Title of Invention	PROCESS FOR PREPARING AN AROMATIC COMPOUND SUBSTITUTED BY A TERTLARY NITRILE
Abstract	A process of preparing a tertiary-nitrile-substituted aromatic compound final product of Formula (1 .0.0): comprising treating an aromatic compound of Formula (2.0.0): with a secondary nitrile of Formula (3.0.0): in the presence of a base; in an aprotic solvent having a dielectric constant (e) of less than 20; and at a reaction temperature in the range of from 0°C to 120°C; whereby there is formed said tertiary-nitrile-substituted aromatic compound final product of Formula (1.0.0); wherein the dashed lines; constituent parts W1, W2, W3, W4, and W5; and substituent moieties R1, R2, R3, R4, R5, R6, and R7 wherever they appear in the above-recited compounds of Formulas (1.0.0), (2.0.0) and (3.0.0), all have the following meanings: (I) each of the dashed lines is independently absent or a bond, so that single or double bonds result at the respective positions o~ an aromatic compound of Formula (1.0.0) or (2.0.0), provided that at least one of said dashed lines is a bond; (II) W1, W2, W3, W4, and W5 is each independently a member selected from the group consisting of: i (A) C (carbon) and the dashed :line associated therewith is a bond; (B) N (nitrogen) and the dashed line associated therewith is either absent or a bond; (C) O and the dashed line is absent; (D) S(=O)k where k is an integer selected from 0, 1 and 2 and the dashed line is absent; and (E) absent so that a 5-membered ring results; provided that each W1 through W5 is selected such that no more than one is absent, no more than one is O or S(=0)k optionally together with one N in each case, and no more than four are N where only N is present; (III) R1, R2, R3, R4, and H5 is each independently selected so that: (A) when the corresponding W1-5 is O or S(=0)k said H1-5 is absent;

Title of Invention

PROCESS FOR PREPARING AN AROMATIC COMPOUND SUBSTITUTED BY A TERTLARY NITRILE

Abstract

A process of preparing a tertiary-nitrile-substituted aromatic compound final product of Formula (1 .0.0): comprising treating an aromatic compound of Formula (2.0.0): with a secondary nitrile of Formula (3.0.0): in the presence of a base; in an aprotic solvent having a dielectric constant (e) of less than 20; and at a reaction temperature in the range of from 0°C to 120°C; whereby there is formed said tertiary-nitrile-substituted aromatic compound final product of Formula (1.0.0); wherein the dashed lines; constituent parts W1, W2, W3, W4, and W5; and substituent moieties R1, R2, R3, R4, R5, R6, and R7 wherever they appear in the above-recited compounds of Formulas (1.0.0), (2.0.0) and (3.0.0), all have the following meanings: (I) each of the dashed lines is independently absent or a bond, so that single or double bonds result at the respective positions o~ an aromatic compound of Formula (1.0.0) or (2.0.0), provided that at least one of said dashed lines is a bond; (II) W1, W2, W3, W4, and W5 is each independently a member selected from the group consisting of: i (A) C (carbon) and the dashed :line associated therewith is a bond; (B) N (nitrogen) and the dashed line associated therewith is either absent or a bond; (C) O and the dashed line is absent; (D) S(=O)k where k is an integer selected from 0, 1 and 2 and the dashed line is absent; and (E) absent so that a 5-membered ring results; provided that each W1 through W5 is selected such that no more than one is absent, no more than one is O or S(=0)k optionally together with one N in each case, and no more than four are N where only N is present; (III) R1, R2, R3, R4, and H5 is each independently selected so that: (A) when the corresponding W1-5 is O or S(=0)k said H1-5 is absent;

Full Text	FORM 2 THE PATENTS ACT 1970 [39 OF 1970] COMPLETE SPECIFICATION See Section 10. "A prolcems of preparing a tentiany nliltrilte sudstitukd Aromatic compound." PFIZER PRODUCTS, INC., a corporation organized under the laws of the State of Connecticut, United States of America, of Eastern Point Road, Groton, Connecticut 06340, United States of America, The following specification particularly describes the nature of the invention and the manner in which it is to be performed:- ORIGINAL 353/MUMNP/2000 GRANTED 1-6-2005 The present invention relates to a process of preparing a tertiary-nitrile-substituted aromatic compound. REFERENCE TO RELATED COPENDING APPLICATIONS Reference is made to US application Serial No. 09/153762, filed September 15, 1998 (Attorney Docket No. 10004A), which is a continution-in-part of US provisional application Serial No. 60/064211, filed November 4, 1997 (Attorney Docket No, PC10004) and now abandoned; and in corresponding European application Serial No. 98308961.6 based on said continuation-in-part application, filed November 2, 1998 (Attorney Docket No. PC10004A) and published as EP-A-0 915 089 on May 12, 1999. The above-mentioned applications are incorporated herein by reference in their entireties, and priority is claimed of the filing date of the earliest filed of the above-mentioned applications. BACKGROUND OF THE INVENTION The present invention relates to a novel process for preparing an aromatic compound substituted by a tertiary nitrile which is applicable to the preparation of a wide variety of compounds of this type. Such tertiary-nitrile-substituted aromatic compound final products comprise compounds of Formula (1.0.0): (1.0.0) wherein: the constituent parts W1 W2, W3, W, and W5, and the substituent moieties R1, R2, R3, R4, R5, R6 and R7 all have the meanings set out in detail further below. The process of the present invention may be illustrated by the follow reaction scheme: The process of the present invention is one which is both facile and which affords acceptable yields of final product. The process of the present invention is distinguished from those heretofore available by the broad scope of its applicability, and by the criticality which has been discovered relating to the chemical makeup and reaction conditions of the base used to promote the reaction, as well as of the tertiary structure of the nitrile in the final product, both of which are described in detail further below. The character of the base which is used in carrying out the process of the present invention is critical to obtaining the acceptable yields of tertiary-nitrile-substituted aromatic compound final product which serves to distinguish the process of the present invention from the processes of the prior art. The conjugate acid of the base which is used must have a pKa in the range of from about 17 to about 30. An example of a base which meets these critical requirements is the potassium, sodium or lithium salt of bis(trimethylsilyl)amide (KHMDS). It has also been discovered in accordance with the present invention that the type of solvent which is used to carry out the reaction between a secondary nitrile and a substituted aromatic compound represents a choice which is critical to obtaining acceptable yields of final product. The solvent selected should be aprotic and have a dielectric constant (e) of less than about 20. Toluene and tetrahydrofuran (THF) are examples of suitable solvents for use in the process of the present invention. The dielectric constant of THF is 7.6 and the dielectric constant of toluene is 2.4 (Handbook of Chemistry and Physics). It will be appreciated that the nitrile reactant in the method of preparation of the present invention is "secondary", referring to the degree of substitution of the carbon atom to which the nitrile moiety is attached. In the final products prepared by the method of the present invention, it will be further understood that the carbon atom to which the nitrile moiety is attached is "tertiary", since it is not attached to any hydrogen atom. The choice of the temperature at which the reaction mixture containing the secondary nitrile and aromatic compound is to be maintained is of less critical importance than the choice of the above-mentioned base or solvent. However, the proper reaction temperature is essential to obtaining acceptable yields of final product in accordance with the present invention, and should fall within the range of from about 0°C to about 120°C. The tertiary-nitrile-substituted aromatic compound final products prepared in accordance with the process of the present invention are characterized by a wide range of chemical structures and by a significant number of different practical utilities, which include both therapeutic and non-therapeutic applications of the said final products. Preferred tertiary-nitrile-substituted aromatic compound final products prepared in accordance with the process of the present invention are those which are useful as therapeutic agents, especially inhibitors of phosphodiesterase type IV (PDE4). PDE4 inhibitors have applicability in therapeutic methods of treatment in humans and animals of many diseases, illnesses and conditions which are allergic or inflammatory in origin, especially including asthrna, chronic obstructive pulmonary disease, bronchitis, rheumatoid arthritis and osteoarthritis, dermatitis, psoriasis, and allergic rhinitis. Among such PDE4 inhibitors comprising tertiary-nitrile-substituted aromatic compound final products is a preferred class of selective PDE4 inhibitors disclosed in U. S. application Serial No. 08/963904, filed April 1, 1997 (Attorney Docket No. PC9281B), which is a continuation-in-part of U- S. provisional application Serial No. 60/016861, filed May 3, 1996 (Attorney Docket No. 9281), now abandoned; and in international application Serial No. PCT/IB97/00323 based on said provisional application, filed April 1, 1997 (Attorney Docket No. PC9281A), designating the United Sates, and published as WO 97/42174 on November 13, 1997. The above-mentioned preferred class of selective PDE4 inhibitors may be illustrated by the following generic Formula (4.0.0): (4.0.1) (4.0.2) A method for preparing the above-described class of selective PDE4 inhibitors is described in US application Serial No. 09/153762, filed September 15, 1998 (Attorney Docket No. 10004A), which is a continution-in-part of US provisional application Serial No. 60/064211, filed November 4, 1997 (Attorney Docket No. PC10004) and now abandoned; and in corresponding European application Serial No. based on said continuation-in-part application, filed ************ (Attorney Docket No. PC10004A) and published as EP-A-0 * * on *"****. in particular, there is disclosed in the above-mentioned applications the following synthesis procedure for treating an indazole of Formula (2.1.0) with cyclohexane 1,4-dicarbonitrile of Formula (3.1.0) to yield a tertiary-nitrile-substituted aromatic compound final product of Formula (4.0.3): The above-illustrated synthesis procedure is described as being carried out in the presence of a base such as lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide (KHMDS), lithium diisopropylamide, or lithium 2,2,6,6-tetramethylpiperidine. The above-mentioned bases are described as being selective and as permitting desirably high levels of addition of cyclohexane-1,4-dicarbonitrile, Formula (2.0.1), to the R- and R1-substituted indazole, Formula (2.0.0), by displacement of the fluorine atom on the latter, while retaining both carbonitrile functionalities in place. It is further taught that it is preferred to use potassium bis(trimethylsilyl)amide (KHMDS) as the base promotant, in a solvent such as tetrahydrofuran, toluene, or xylene(s), preferably toluene, at a temperature between about 25°C and about 125°C, preferably about 100°C, for a period of from 1 hour to 15 hours, preferably about 5 hours, in order to obtain acceptable yields of a tertiary-nitrile-substituted aromatic compound final product of Formula (1.0.0). Therefore, the present invention relates to a process of preparing a tertiary-nitrile-substituted aromatic compound final product of Formula (1.0.0): comprising treating an aromatic compound of Formula: (2.0.0) with a secondary nitrile of Formula (3.0.0): H in the presence of a base having a pKa numerical value in the range of from 17 to 30, provided that the difference in pKa numerical values between said base and corresponding tertiary nitrile of Formula (3.0.0) is no more than 6; in an aprotic solvent having a dielectric constant (E) of less than 20; and at a reaction temperature in the range of from 0°C to 120°C; whereby there is formed said tertiary-nitrile-substituted aromatic compound final product of Formula (1.0.0); wherein the dashed lines; constituent parts W1, W2, W3, W4, and W5; and substituent moieties R1, R2, R3, R4, R5, R6, and R7 wherever they appear in the above-recited compounds of Formulas (1.0.0), (2.0.0) and (3.0.0), all have the following meanings: (I) each of the dashed lines is independently absent or a bond, so that single or double bonds result at the respective positions of an aromatic compound of Formula (1.0.0) or (2.0.0), provided that at least one of said dashed lines is a bond; (II) W1, W2, W3, W4, and W5 is each independently a member selected from the group consisting of: (A) C (carbon) and the dashed line associated therewith is a bond: (B) N (nitrogen) and the dashed line associated therewith is either absent or a bond; (C) O and the dashed line is absent; (D) S(=0)k where k is an integer selected from 0, 1 and 2 and the dashed line is absent; and (E) absent so that a 5-membered ring results; provided that each W11 through W5 is selected such that no more than one is absent, no more than one is O or S(=0)k optionally together with one N in each case, and no more than four are N where only N is present; (III) R1, R2, R3, R4, and R5 is each independently selected so that: (A) when the corresponding W1-5 is O or S(=0)k said R1-5 is absent (B) when the corresponding W15 is C said R1"5 is a member independently selected from the group consisting of hydrogen; halogen selected from CI, Br, and I; -N(R12)2, -NR12; -OR12; (Ci-C6) alkyl! substituted with 0-3 R9, -N(R12)2, -SR12, or -OR12 (C2-C6) alkenyl substituted with 0-3 R9; (C3-C6) alkynyl substituted with 0-3 R9; a (C3-C14) carbocyclic ring system substituted with 0-3 R9 or 0-3 R10; a heterocyclic ring system independently selected from the group consisting of furanyl, thienyl, pyrrolyl, imidazolyl, pyridyl, pyrazolyl, pyrimidinyl, benzofuranyl, benzothienyl, indolyl, enzimidazolyl, tetrahydroisoquinolinyl, benzotriazolyl, and thiazolyl, said heterocyclic ring system being substituted with 0-2 R10; and any two R1-5 attached to adjacent carbon atoms taken together to form a 3- or 4-carbon chain forming a fused 5- or 6-membered ring, said ring being optionally substituted on any aliphatic carbon atoms thereof with a member selected from the group consisting of halogen selected from C1, Br, and I; (C1-C4) alkyl; (C1-C4) alkoxy; and —NR15R16; where: (1) R9 is a member independently selected from the group consisting of hydrogen; cyano; -CH2NR!5R16; -NR15-R16; -OR15; -S(C2-C6) alkoxy.alkyl; (Ci:C4) alkyl; (C2-C) alkenyl; (C3-C7) cycloalkyl; (C3-C6) cycloalkylmethyl; phenyl, benzyl; phenethyl; phenoxy; benzyloxy; (C3-C6) cycioalkoxy; (C1-C4) alkyl substituted by a member selected from the group consisting of methylenedioxy, ethylenedioxy, phenyl(Ci-C3) alkyl, and a (C5-C14) carbocyclic residue; and a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, substituted with 0 to 3 substituents R15; where: (a) R15 is a member selected from the group consisting of phenyl substituted by 0-3 R11; benzyl substituted by 0-3 R11; (C-C6) alkyl substituted by 0-3 R11; (C2-C4) alkenyl substituted by 0-3 R11; and (C3-C6) alkoxy alkyl substituted by 0-3 R11; where R11 is a member independently selected from the group consisting of cyano; -CH2R18R19; -NR18R19; (C3-C6) alkoxyalkyl; (C1-C4) alkyl; (C2-C4) alkenyl; (C3-C10) cycloalkyl; (C3-C6)cycloalkylmethyl; benzyl; phenethyl; phenoxy; benzyloxy; (C7-C10) arylalkyl; (C3-C6) cycioalkoxy; methylenedioxy; ethylenedioxy; and a (C5-C14) carbocyclic residue; and a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur; where R18and R19are each independently selected from the group consisting of (C2-C6) alkyl; and phenyl substituted with 0-3 R (b) R10 is a member selected from the group consisting of (C1-C4) alkyl substituted by 0-3 groups selected from the group consisting of (C1-C4) alkoxy; (C2-C6) alkoxyalkyl; (C2 -C6) alkenyl; phenyl; and benzyl; (2) R10 when a substituent on a carbon atom, is a member independently selected from the group consisting of phenyl; benzyl; phenethyl; phenoxy; benzyloxy; halogen; cyano; (C1-C4) alkyl; (C3-C7) cycloalkyl; (C3-C6) a (C3-C14) carbocyclic ring system substituted with 0-3 R9 or 0-3 R10; and a heterocyclic ring system independently selected from the group consisting of furanyl, thienyl, pyrrolyl, imidazolyl, tetrahydropyranyl, pyridyl, piperidinyl, pyrazolyl, pyrimidinyl, benzofuranyl, benzothienyl, indolyl, benzimidazolyl, tetrahydroisoquinolinyl, benzotriazolyl, and thiazolyl, said heterocyclic ring system being substituted with 0-2 R10; or R6 and R7 are taken together to form a (C3-C14) carbocyclic ring system substituted with 0-3 R9 or 0-3 R10; phenyl; 1-or 2-naphthyl substituted with 0-3 R9 or 0-3 R10 or a heterocyclic ring system independently selected from the group consisting of furanyl, thienyl, pyrrolyl, imidazolyl, tetrahydropyranyl, pyridyl, piperidinyl, pyrazolyl, pyrimidinyl, benzofuranyl, benzothienyl, indolyl, benzimidazolyl, tetrahydroisoquinolinyl, benzotriazolyl, and thiazolyl, said heterocyclic ring system being substituted with 0-2 R10; where: R9, R10, R12, R15 and R16 each have the same meaning as set out further above under the definitions of R1-5. DESCRIPTION OF THE STATE OF THE ART Loupy et al., Synth. Comm., 1990, 20, 2855-2864, is concerned with the use of solid-liquid phase transfer catalysts without solvents to carry out SNAr reactions on di- or mono-nitro halogeno compounds and unactivated aryl halides. The reaction is carried out with a nucleophile, e.g., Ph2CHCN, in the presence of a base, e.g., a stoichiometric amount of pulverized solid KOH, and a catalyst, e.g., a tetraalkylammonium salt such as Aliquat 336 or TDA-1, which may be represented by the following reaction scheme: Unlike the process of the present invention, the process disclosed by Loupy et al. is carried out with a chloride-, bromide-, or fluoride-substituted arene nucleus, which is permitted by the electron deficiency of the arene nucleus caused by the additional presence of the nitro group. Makosza et al., J. Org. Chem., 1994, 59, 6796-6799, also relates to nucleophilic substitution of halogen in p-halonitrobenzenes, and discloses in particular a reaction which may be represented by the following reaction scheme: The process disclosed by Makosza et al. uses ethylcyanoacetate and may be carried out with either a chloride- or a fluoride-substituted arene nucleus. Neither of these features of the Makosza et al. process, however, can be utilized in the method of the present invention. Rose-Munch et al., J. Organomet. Chem., 1990, 385(1), C1-C3, discloses the synthesis of a-substituted aryl iminonitriles by addition of an a-iminonitrile to (fluoroarene)tricarbonylchromium complexes in the presence of a base, e.g., hexaphophotriamide (HMPT), preceded by lithiation with, e.g., di-/'so-propylaminolithium. Included in particular is a reaction which may be represented by the following reaction scheme: The process disclosed by Rose-Munch ef al. induces an electron poor state in the fluoride-substituted arene nucleus by complexing it with tricarbonylchromium, which permits subsequent lithium anion displacement of the fluoride substituent on the arene nucleus. However, the synthetic approach of the process in Rose-Munch et al. is substantially different from that of the process of the present invention, in which lithiation is unworkable. Plevey and Sampson, J. Chem. Soc, 1987, 2129-2136 is concerned with the synthesis of 4-amino-2,3,5,6-tetrafluoroglutethimide, and as part of that preparation describes the reaction of hexafluorobenzene with ethyl cyanoacetate in the presence of potassium carbonate base, which may be illustrated by the following reaction scheme: The process disclosed in Plevey and Sampson also utilizes an arene nucleus which is in an electron deficient state, as is the case with other above-described methods which characterize the current state of the art. The process of Plevey and Sampson is substantially different from that of the present invention. Sommer ef al., J. Org. Chem., 1990, 55, 4817-4821, describes a process involving displacement of halogen from a 2-halogeno-substituted benzonitrile present as a stabilized carbanion, in order to prepare (2-cyanoaryl)arylacetonitriles. The process is carried out using two equivalents of a strong base, e.g., potassium terf-butoxide, and is taught to be sensitive to the nature of the base, the solvent, e.g., dimethylformamide (DMF), the leaving group, the substituents on the rings, and the kind of rings involved. The process is taught to be applicable as well to heteroaromatics with ortho-situated halogen and cyano groups. The process of Sommer et al. may be illustrated by the following reaction scheme: The process of Sommer et al. is substantially different from that of the present invention in that displacement of both chloride- and fluoride- substituents on the arene nucleus takes place, and further in that a secondary nitrile substituent is utilized which induces an electron poor state in the substituted arene nucleus in order to facilitate subsequent displacement. SUMMARY OF THE INVENTION The present invention comprises a novel method of preparing an aromatic compound substituted by a tertiary nitrile comprising: treating an aromatic compound of Formula (2.0.0): wherein: the constituent parts W1, W2, W3, W4 and W5, and the substituent moieties R\ R2, R3, R4 and R5 all have the meanings set out in detail further below; with a secondary nitrile of Formula (3.0.0): wherein: the substituent moieties R6 and R7 both have the meanings set out in detail further below, in the presence of a base having a pKa numerical value in the range of from about 17 to about 30, provided that the difference in pKa numerical values between said base and the corresponding secondary nitrile of Formula (3.0.0) is no more than about 6; in an aprotic solvent having a dielectric constant (e) of less than about 20; and at a temperature in the range of from about 0°C to about 120°C; whereby there is formed a tertiary-nitrile-substituted aromatic compound final product of Formula (1.0.0) The above-described starting material comprising a compound of Formula (2.0.0) is reacted with a secondary nitrile of Formula (3.0.0): 5 wherein: the substituent moieties R6 and R7 both have the meanings set out in detail below; in the presence of a base whose conjugate acid pKa is in the range of from about 17 to about 30, provided that the difference in pKa numerical values between said base and said corresponding secondary nitrile of Formula (3.0.0) is no more than about 6, and preferably no more than about 4; and in an aprotic solvent having a dielectric constant (e) of less than about 10 20; and at a temperature in the range of from about 0°C to about 120°C; whereby there is formed a tertiary-nitrile-substituted aromatic compound of Formula (1.0.0): wherein R1 R2, R3, R\ R5, R6 and R7; and W1 W2, W3, W4 and W5 all have the same 15 meanings as set out elsewhere herein. One of the key features of the process of the present invention is that the nitrile moiety is required to be tertiary in the final product of Formula (1.0.0), and therefore as a reactant must be secondary in order of substitution, as shown in Formula (3.0.0): wherein R6 and R7 may not, accordingly, have the meaning of hydrogen. The process of the present invention produces suitable results even where R6 and R7 have a substantial number of different meanings. Accordingly, in the secondary nitrile reactant compounds of Formula (3.0.0): 25 R6 and R7 are each independently selected from the group consisting of -N(R12)2; (C,-C6) alkyl substituted with 0-3 R9; -N(R12)2; -SR12; -OR12; (C2-C6) alkenyl substituted with 0-3 R9; (C3-C6) alkynyl substituted with 0-3 R9; a (C3-C14) carbocyclic ring system substituted -12- with 0-3 R9 or 0-3 R'°; and a heterocyclic ring system independently selected from the group consisting of furanyl, thienyl, pyrrolyl, imidazolyl, tetrahydropyranyl, pyridyl, piperidinyl, pyrazolyl, pyrimidinyl, benzofuranyl, benzothienyl, indolyl, benzimidazolyl, tetrahydroisoquinolinyl, benzotriazolyl, and thiazolyl, said heterocyclic ring system being 5 substituted with 0-2 R10; or R6 and R7 are taken together to form a (C3-C14) carbocyclic ring system substituted with 0-3 R9 or 0-3 R10; phenyl; 1- or 2-naphthyl substituted with 0-3 R9 or 0-3 R10; or a heterocyclic ring system independently selected from the group consisting of furanyl, thienyl, pyrrolyl, imidazolyl, tetrahydropyranyl, pyridyl, piperidinyl, pyrazolyl, pyrimidinyl, benzofuranyl, 10 benzothienyl, indolyl, benzimidazolyl, tetrahydroisoquinolinyl, benzotriazolyl, and thiazolyl, said heterocyclic ring system being substituted with 0-2 R10; where: R9, R10, R12, R'5 and R'6 each have the same meaning as set out further above under the definitions of R1'5. In accordance with the process of the present invention, the reaction which takes 15 place between the aromatic compound of Formula (2.0.0) and the secondary nitrile of Formula (3.0.0) is required to be in the presence of a base having a pKa in the range of from about 17 to about 30, provided that the difference in PKa, numerical values between said base and said corresponding secondary nitrile of Formula (3.0.0) is no more than about 6, and preferably no more than about 4; and in an aprotic solvent having a dielectric constant (e) of less than about 20 20; and at a temperature in the range of from about 0°C to about 120°C. The character of the base which is used in carrying out the process of the present invention is critical to obtaining the acceptable yields of tertiary-nitrile-substituted aromatic compound final product which serves to distinguish the process of the present invention from the processes of the prior art. The relative strength of the base which is used in the process 25 of the present invention should be as close as possible to the relative strength as a base of the secondary nitrile reactant of Formula (3.0.0) which is used in that process. Further, it is desirable to quantify the relative strength of the base which is to be used. Such quantification will permit greater discrimination in selection of the base, as well as permit a more precise comparison of the relative strength of the base to the corresponding relative strength of the 30 secondary nitrile reactant. In order to quantify the relative strength of the base for use in the process of the present invention, use is made herein of the dissociation constant, Ka of the base and the corresponding secondary nitrile of Formula (3.0.0). The dissociation constant is defined as the equilibrium constant for transfer of a proton from an acid HA to water, and is calculated in accordance with the following equation: 5 where the values within the brackets are the molar concentrations at equilibrium for the acid and its dissociated constituents. For convenience, dissociation constants are expressed as a negative logarithm, abbreviated p. Thus, pKa = — log Ka . Stronger acids have larger dissociation constants, but correspondingly smaller pKa values. A value which can be used to quantify the comparative difference between the strength of the base and corresponding 10 secondary nitrile used in the process of the present invention, will prove to be useful in carrying out said process. Accordingly, the relative strength of the base A : __ and corresponding secondary nitrile in question is conveniently expressed in terms of the pKa of its conjugate acid HA. Where a base is characterized as being a strong base, the converse is also inherently true, 15 i.e., that its conjugate acid is a weak acid. Thus, pKa numerical values for the conjugate acids of two or more bases will permit one to readily compare those bases and quickly order them in accordance with which one is the stronger base and which one is the weaker base. The stronger base has the conjugate acid with the higher pKa numerical value. In the present description of the process of the present invention, a given base will be directly or indirectly 20 stated to have a pKa numerical value, it being understood that the pKa numerical value in question is that of the conjugate acid of said base. The base used in the process of the present invention will preferably have a pKa numerical value as close to that of the secondary nitrile of Formula (3.0.0) used in that process, as possible. Consequently, based on the pKa, numerical values of. the secondary 25 nitriles of Formula (3.0.0) which are suitable for use in the process of the present invention, it is considered to be an essential requirement that the base used in the process of the present invention have a pKa value in the range of from about 17 to about 30. It is a further requirement that the difference in pKa numerical values between said base and said corresponding secondary nitrile of Formula (3.0.0) used in the process of the present 30 invention be no more than about 6, and preferably no more than about 4. The secondary nitrile of Formula (3.0.0) used in the process of the present invention has a general chemical structure which may be represented by the following Formula (3.0.1): substantiated by the determination that many such combinations either fail altogether to produce a tertiary-nitrile-substituted aromatic compound final product, or else produce such a final product in unacceptably low yields. For example, it has been found that by using a base/solvent system comprising potassium bis(trimethylsilyl)amide (KHMDS) as the base and 5 either toluene or tetrahydrofuran (THF) as the solvent, that it is possible to produce a tertiary-nitrile-substituted aromatic compound final product in accordance with the present invention in yields of 85% or greater by weight, frequently 90% or greater by weight, and often 95% or greater by weight, based on the weight of the reaction components. The expression "unacceptably low yields" has been used herein to contrast the 10 unexpectedly superior results obtained with the process of the present invention to the unsatisfactory results obtained with the processes of the prior art. It will be understood that the surprising improvement in yields achieved by use of the process of the present invention need not always be reflected solely in very high yield percentages, per se. Thus, it may be the case that for a given final product of Formula (1.0.0) the prior art processes are 15 inoperative, resulting in a 0% yield, or else said prior art processes provide said final product in extremely low yields. Accordingly, it will be appreciated that a 25% yield obtained using the process of the present invention may constitute an unexpected improvement over the results obtained using the processes of the prior art where said processes provide, e.g., a 0% or >1% yield of the same final product. Percentage yields obtained using the process of the present 20 invention are described in detail elsewhere herein. Instances of such failures of prior art processes to yield any final product abound. For example, when the base being used is lithium diisopropylamide (LDA), even though the solvent being used is tetrahydrofuran (THF), which would otherwise be suitable, decomposition of the initial reaction mixture occurs. Similarly, where the base/solvent system 25 utilized is potassium tert-butyloxide (f-BuOK) in tetrahydrofuran (THF), decomposition of the initial reaction mixture occurs. Where the base being used is chosen from cesium, sodium, or potassium carbonate (CsC03, Na2C03, or K2C03, respectively) and the solvent being used is tetrahydrofuran (THF), no reaction takes place at all. The solvent component of the base/solvent system is also critical to obtaining 30 acceptable results. For example, where the base selected is potassium bis(trimethylsilyl)amide (KHMDS), which would otherwise be suitable, and the solvent selected is dimethylsulfoxide (DMSO), no reaction at all takes place. Further, where the base is potassium bis(trimethy!silyl)amide (KHMDS) and the solvent is N-methyl-a-pyrrolidone NMP), the process results in an aromatic compound substituted by tertiary nitrile final product in unacceptably low yields of about 5% or less by weight, based on the weight of the reaction components. The choice of the temperature at which the reaction mixture containing the tertiary nitrile and substituted aromatic compound is to be maintained in accordance with the process 5 of the present invention, is of less critical importance than the choice of the above-mentioned base and solvent system. However, the proper reaction temperature is essential to obtaining acceptable yields of tertiary-nitrile-substituted aromatic compound final product in accordance with the present invention, and should fall within the range of from about 0°C to about 120°C, preferably in the range of from about 20°C to about 110°C, more preferably in the range of from about 30°C to about 105°C, and most preferably in the range of from about 40°C to about 100°C. The choice of temperature at which the reaction in accordance with the process of the present invention is carried out will impact, along with other factors, the amount of time required to carry said reaction to a reasonable stage of completion. It has been found that, as a general matter, where the temperatures employed in carrying out the process are within the 15 above-stated ranges, and particularly within the above-stated preferred, more preferred and most preferred ranges, that the process of the present invention will be reasonably complete within the range of from about 0.1 hour to about 50 hours, more likely within the range of from about 0.5 hour to about 30 hours, and most likely within the range of from about 1 hour to about 18 hours 20 The preparation process of the present invention may be represented by the following reaction scheme: (2.0.0) (3.0.0) (1.0.0) In the above reaction scheme, the starting material of Formula (2.0.0) is reacted with 25 a secondary nitrile of Formula (3.0.0) in the presence of a base such as potassium bis(trimethylsilyl)amide (KHMDS) in a solvent such as toluene, tetrahydrofuran, diethyl ether, diisopropyl ether, methy tert-butyl ether, 1,2-dimethoxy ethane, or a mixture of the aforementioned solvents, preferably toluene or tetrahydrofuran, at a temperature between 0°C and 120°C, preferably between 40°C and 100°C, to provide a final product of Formula (1.0.0). These preferred embodiments of the process of the present invention are further demonstrated in the working examples set forth below. These examples are intended to be illustrative of the present invention and are not for the purpose of, and should not be taken as in any way limiting the scope or content of the process of the present invention. The claims 5 appended to the instant specification should be consulted for a definition of the scope and content of the present invention. EXAMPLE 1 To a solution of an aryl fluoride of Formula (2.0.0) in toluene (10 volumes) was added a nitrile of Formula (3.0.0), the number of equivalents of which are indicated in Table 1below; 10 and a 0.5 M solution of potassium bis(trimethylsilyl)amide in toluene, the number of equivalents of which are indicated in Table 1 below. Each reaction mixture was stirred at a temperature and for an amount of time also indicated in Table 1 below, after which each said reaction mixture was cooled to room temperature, poured into 1N HCI, and thereafter extracted with toluene. The organic extracts were washed with water, dried over magnesium 15 sulfate, filtered and concentrated. The crude product was purified by chromatography on silica gel to afford the desired product of Formula (1.0.0) in the yield indicated in Table 1 below. EXAMPLES 2 through 19 To a solution of an aryl fluoride of Formula (2.0.0) in tetrahydrofuran (10 volumes) 20 was added a nitrile of Formula (3.0.0), the number of equivalents of which are indicated in Table 1 below; and potassium bis(trimethylsilyl)amide, the number of equivalents of which are indicated in Table 1 below. Each reaction mixture was stirred at a temperature and for an amount of time indicated in Table 1 below, after which each said reaction mixture was cooled to room temperature, poured into 1N HCI, and thereafter extracted with methyl terf-butyl ether. 25 The organic extracts were washed with water, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by chromatography on silica gel to afford the desired product of Formula (1.0.0) in the yield indicated in Table 1 below. TABLE 1 -19- 5 (1.1.3) Toluene 60 45 min 1.5 4.0 77 6 (1.1.4) Toluene 70 48 h 1.5 4.0 85 7 (1.1.5) Toluene 70 10 min 1.5 3.9 72 8 (1.1.6) THF 60 50 h 1.5 4.0 66 9 (1.1.7) Toluene 60 18 h 1.5 4.0 95 10 (1.1.8) Toluene R.T. 5h 1.5 2.0 24 11 (1.1.9) THF 75 2h 1.5 4.0 72 12 (1.1.10) THF 75 14 h 1.5 4.0 71 13 (1.1.11) THF 75 14 h 1.5 4.0 69 14 (1.1.12) Toluene 75 48 h 1.5 4.0 47 15 (1.1.13) THF 75 24 h 1.5 4.0 67 16 (1.1.14) THF 75 30 h 1.5 4.0 35 17 (1.1.15) THF 75 27 h 1.5 4.0 30 18 (1.1.16) THF 75 15 min 1.5 4.0 70 19 (1.1.17) THF 80 4h 1.5 4.0 28 EXAMPLE 2 2-Methyl-2-(4-trifluoromethyl-phenyl)-propionitrile (1.1.0) 10 Purified by chromatography on silica gel (ethyl acetate/hexanes 15/85). 1H NMR (400 MHz, CDCI3) 5 1.73 (s, 6), 7.59 (d, 2, J = 9.0), 7.64 (d, 2, J = 9.0). 13C NMR (100 MHz, CDCI3) 5 28.90, 37.25, 123.12 (q, J = 272.7), 123.75, 125.64, 125.93, 130.15 (q, J = 33.2), 145.38. IR2988, 2239, 1622, 1415, 1330, 1170, 1128, 1069,842 cm"1. Analysis calculated for C„H10F3N: C, 61.97; H, 4.73; N, 6.57. Found: C, 61.91; H, 4.96; N, 6.61. EXAMPLE 3 4-(Cyano-dimethyl-methyl)-benzonitrile (1.1.1) 10 (1.1.1) Purified by filtration on a pad of silica gel eluting with ethyl acetate; Mp = 88-89°C. 1H NMR (300 MHz, CDCI3) 5 1.78 (s, 6), 7.64 (d, 2, J = 8.1), 7.74 (d, 2, J = 8.3). 13C NMR (100 MHz, CDCI3) 5 28.87, 37.49, 112.06, 118.19, 123.32, 126.08, 132.85, 146.48. IR (CHCI3) 2989, 2233, 1611, 1505, 1463, 1408, 1371, 1100,838 cm"1. Analysis calculated for C11H10N2: C, 77.62; H, 5.92; N, 16.46. Found: C, 77.26; H, 5.90; N, 16.52. EXAMPLE 4 2-(3-Methoxy-phenyl)-2-methyl-propionitrile (1.1.2) 15 20 (1.1.2) Purified by chromatography on silica gel (ethyl acetate/hexanes 10/90). 1H NMR (300 MHz, CDCI3) 5 1.75 (s, 6), 3.86 (s, 3), 6.88 (dd, 1, J = 2.5, 8.3), 7.04-7.06 (m, 1), 7.07-7.11 (m, 1), 7.34 (t, 1, J = 8.3). 13C NMR (100 MHz, CDCI3) 5 29.02, 37.09, 55.24, 111.40, 112.60, 117.23, 124.41, 129.91, 142.93, 159.83. IR 2983, 2940, 2236, 1602, 1586, 1489, 1463, 1434, 1294, 1268, 1048, 782 cm"1. Analysis calculated for C„H13NO: C, 75.40; H, 7.48; N, 7.99. Found: C, 75.61; H, 7.67; N, 7.86. EXAMPLE 5 _2-(2-Chloro-phenyl)-2-methyl-propionitrile (1.1.3) Purified by chromatography on silica gel (ethyl acetate/hexanes 10/90). 'H NMR (300 MHz, CDCI3) 5 1.91 (s, 6), 7.29-7.34 (m, 2), 7.46-7.53 (m, 2). 13C NMR (100 MHz, CDCI3) 27.19, 36.24, 123.50, 127.00, 127.33, 129.41, 131.92, 133.31, 136.95. IR 2984, 2236, 1473, 1432, 1234, 1043, 759 cm"1. Analysis calculated for C10H10CIN: C, 66.86; H, 5.61; N, 7.80. Found: C, 67.22; H, 5.64; N, 7.63. EXAMPLE 6 2-(3,5-Dimethoxy-phenyl)-2-methyl-propionitrile (1.1.4) Purified by chromatography on silica gel (ethyl acetate/hexanes 15/85). 1H NMR (300 MHz, CDCI3) 5 1.74 (s, 6), 3.85 (s, 6), 6.43 (t, 1, J = 2.2), 6.64 (d, 2, J = 2.2). 13C NMR (100 MHz, CDCI3) 5 29.06, 37.34, 55.44, 99.12, 103.63, 124.44, 143.81, 161.10. IR 2982, 2939, 2236, 1598, 1459, 1427, 1207, 1159, 1067, 1052,696 cm"1. Analysis calculated for C,2H15N02: C, 70.22; H, 7.37; N, 6.82. Found: C, 70.17; H, 7.65; N, 6.96. EXAMPLE 7 2-Methyl-2-(4-methyl-pyridin-2-yl)-propionitrile (1.1.5) Purified by chromatography on silica gel (ethyl acetate/hexanes 20/80). 1H NMR (300 MHz, CDCI3) 6 1.77 (s, 6), 2.41 (s, 3), 7.08 (dd, 1, J = 0.8, 5.0), 7.43 (d, 1, J = 0.8), 8.47 (d, 1, J = 5.0). 13C NMR (75 MHz, CDCI3) 5 22.39, 29.06, 40.54, 121.98, 124.89, 125.66, 149.79, 150.48, 160.55. IR 2982, 2238, 1605, 1478, 1130, 995, 830 cm-1. Analysis calculated for C10H12N2: C, 74.97; H, 7.55; N, 17.48. Found: C, 74.96; H, 7.85; N, 17.45. EXAMPLE 8 2-(4-Methoxy-phenyl)-2-methyl-propionitrile (1.1.6) Purified by chromatography on silica gel (ethyl acetate/hexanes 20/80). 1H NMR (300 MHz, CDCI3) 6 1.74 (s, 6), 3.85 (s, 3), 6.94 (d, 2, J = 8.9), 7.42 (d, 2, J = 8.9). 13C NMR (100 MHz, CDCI3) 6 29.25, 36.44, 55.34, 114.19, 124.82, 126.25, 133.50, 159.02. IR 2982, 2235, 1513, 1256,1186, 1033,831 cm1. Analysis calculated for C11H13NO: C, 75.40; H, 7.48; N, 7.99. Found: C, 75.48; H, 7.55; N, 8.10. EXAMPLE 9 2-(2-Methoxy-phenyl)-2-methyl-propionitrile (1.1.7) Purified by chromatography on silica gel (ethyl acetate/hexanes 20/80). 1H NMR (300 MHz, CDCI3) 1.80 (s, 6), 3.96 (s, 3), 6.97-7.02 (m, 2), 7.29-7.39 (m, 2). 13C NMR (100 MHz, CDCI3) 6 27.00, 34.43, 55.51, 112.02, 120.76, 124.80, 125.92, 128.62, 129.39,157.30. IR 2980, 2235, 1493, 1462, 1437, 1253, 1027, 756 cm1. Analysis calculated for C11H13NO: C, 75.40; H, 7.48; N, 7.99. Found: C, 75.29; H, 7.30; N, 8.25. EXAMPLE 10 1-(2-Chloro-phenyl)-cyclopropanecarbonitrile (1.1.8) Purified by chromatography on silica gel (ethyl acetate/hexanes 20/80). 1H NMR (300 MHz, CDCI3) 5 1.28-1.38 (m, 2), 1.71-1.75 (m, 2), 7.21-7.43 (m, 4). 13C NMR (100 MHz, CDCI3) 5 13.17, 16.27, 121.78, 127.16, 130.07, 131.16, 133.60, 136.54. IR 3063, 3020, 2235, 1477, 1435, 1051, 1033, 759 cm1. Analysis calculated for C10H8CIN: C, 67.62; H, 4.54; N, 7.89. Found: C, 67.35; H, 4.58; N, 7.88. EXAMPLE 11 2-(4-Chloro-phenyl)-2-methyl-propionitrile (1.1.9) Purified by chromatography on silica gel (ethyl acetate/hexanes 10/20). 1H NMR (300 MHz, CDC13 d 1.75 (s, 6), 7.39 (d, 2, J = 9.0), 7.45 (d, 2, J = 8.9). 13C NMR (100 MHz, CDCI3) d 30.34, 38.06, 125.34, 127.80, 130.33, 135.03, 141.22. IR 2984, 2237, 1495, 1106, 1013,828 cm-1. Analysis calculated for C10H10CIN: C, 66.86; H, 5.61; N, 7.80. Found: C, 66.51; H, 5.83; N, 7.74. EXAMPLE 12 2-Methyl-2-r77-tolyl-propionitrile (1.1.10) Purified by chromatography on silica gel (ethyl acetate/hexanes 10/90). 1H NMR (300 MHz, CDCI3) 8 1.75 (s, 3), 2.42 (s, 3), 7.14-7.18 (m. 1), 7.27-7.18 (m, 3). 13C NMR (75 MHz, CDCI3) 5 22.81, 30.42, 38.35, 123.26, 125.95, 127.13, 129.80, 130.09, 139.94,142.61. IR 2983, 2237, 1607, 1490, 1461, 1368, 1198, 1090,787 cm-1. Analysis calculated for C11H13N: C, 82.97; H, 8.23; N, 8.80. Found: C, 82.97; H, 8.23; N.8.80. EXAMPLE 13 2-Methyl-2-phenyl-propionitrile (1.1.11) Purified by chromatography on silica gel (ethyl acetate/hexanes 10/90). 1H NMR (300 MHz, CDCI3) 5 1.76 (s, 3), 7.35-7.53 (m, 5). 13C NMR (100 MHz, CDCI3) 6 29.15, 37.16, 124.55, 125.05, 127.79, 128.94, 141.42. IR 2983, 2237, 1495, 1448, 764 cm-1. Analysis calculated for C10H 11N: C, 82.72; H, 7.64; N, 9.65. Found: C, C, 82.76; H, 7.90; N.9.88. EXAMPLE 14 1 -(2-Methoxy-phenyl)-cyclopropanecarbonitrile (1.1.12) Purified by chromatography on silica gel (ethyl acetate/hexanes 10/90 to provide an oil which crystallized upon standing); Mp = 49-59°C. 1H NMR (300 MHz, CDCI3) 5 1.26-1.30 (m, 2), 1.61 -1.66 (m, 2), 3.97 (s, 3), 6.92-6.97 (m, 2), 7.24 (dd, 1, J = 7.9, 1.7), 7.29-7.37 (m, 1). 13C NMR (100 MHz, CDCI3) 5 10.18, 15.24, 55.61, 110.89, 120.38, 123.08, 124.07, 129.82, 129.92, 158.97. IR 2234, 1496, 1465, 1248, 1026, 756 cm'1. Analysis calculated for C11H11 NO: C, 76.28; H, 6.40; N, 8.09. Found: C, 76.28; H, 6.40; N, 8.09. EXAMPLE 15 (2S)-2-(2-Methoxy-phenyl)-bicyclo[2.2.1]hept-5-ene-2-carbonitrile (1.1.13) Purified by filtration on a pad of silica gel (ethyl acetate/hexanes 35/65 to provide an oil which was crystallized from ethanol); Mp = 135-137°C. 1H NMR (400 MHz, CDCI3) 5 1.52 (d, 1, J = 9.0), 1.61-1.64 (m, 1), 2.02 (dd, 1, J = 12.6, 3.4), 2.21 (dd, 1, J = 11.8, 2.8), 2.99 (bs, 1), 3.62 (bs, 1), 3.91 (s, 3), 6.40 (dd, 1,J = 5.8, 3.0), 6.67 (dd, 1, J = 5.8, 3.0), 6.91-6.96 (m, 2), 7.24-7.30 (m, 2). 13C NMR (100 MHz, CDCI3) 8 41.42, 43.13, 43.68, 46.90, 48.41, 55.60, 111.66, 120.41, 124.51, 125.36, 129.02, 129.38, 134.44, 140.87, 158.08. IR (KBr)2990, 2977, 2226, 1597, 1489, 1439, 1248, 1023, 764, 723 cm"1. Analysis calculated for C15H15NO: C, 79.97; H, 6.71; N, 6.22. Found: C, 79.97; H, 6.71; N, 6.22. EXAMPLE 16 2-(4'-Bromo-biphenyl-4-yl)-2-methyl-propionitrile (1.1.14) Purified by chromatography on silica gel (ethyl acetate/hexanes 10/90); Mp = 111-112°C. 1H NMR (400 MHz, CDCI3) 5 1.76 (s, 6), 7.44 (dd, 2, J = 6.6, 1.9), 7.52-7.57 (m, 6). 13C NMR(100MHz, CDCI3) 5 29.13, 39.98, 121.90, 124.38, 125.68, 127.40, 128.64, 131.98, 139.13, 139.57, 140.86. IR (KBr) 2986, 2235, 1483, 1461, 1105,815 cm-1. Analysis calculated for C16H14BrN: C, 64.02; H, 4.70; N, 4.67. Found: C, 64.27; H, 4.70; N.4.58. EXAMPLE 17 1-(4'-Bromo-biphenyl-4-yl)-cyclohexane-1,4-dicarbonitrile (1.1.15) Purified by chromatography on silica gel (IPE/Ch^C^/Hexanes 25/25/50) to provide the product as a 1:1 mixture of diastereoisomers; Mp = 211°C. 1 H NMR (400 MHz, CDCI3) 5 1.84-2.62 (m, 8), 3.15 (bs, 1), 7.41-7.62 (m, 8). 13C NMR (100 MHz, CDCI3) 5 25.82, 25.92, 26.41, 27.24, 33.12, 35.74, 42.79, 43.52, 120.88, 121.11, 121.20, 121.47, 122.05, 122.11, 126.00, 126.10, 127.63, 128.62, 128.65, 132.02, 138.82, 138.91, 139.00, 140.17, 140.25. IR (KBr) 2945, 2235, 1484, 1455, 1388, 1081, 1003,812 cm-1. Analysis calculated for C20H17 BrN2: C, 65.76; H, 4.69; N, 7.67. Found: C, 65.76; H, 4.65; N, 7.67. EXAMPLE 18 (2S)-2-(2-Methoxy-phenyl)-bicyclo[2.2.1 ]heptane-2-carbonitrite (1.1.16) Purified by chromatography on silica gel (ethyl acetate/hexanes 5/95); Mp = 87-88°C. 1HNMR(400MHz,CDCI3)6 1.30-1.48 (m, 2), 1.52 (d, 1, J = 10.0), 1.60-1.80 (m, 2), .98 (dt, 1, J = 13.5, 3.5), 2.12-2.18 (m, 1), 2.23 (dd, 1, J = 13.5, 2.4), 2.33 (s, 1), 2.97 (d, 1, J 3.6), 3.91 (s, 3), 6.89-6.94 (m, 2), 7.24-7.28 (m, 2). 13C NMR (100 MHz, CDCM 8 25.99, -28- 28.64, 37.02, 37.09, 37.41, 42.97, 46.67, 55.58, 111.99, 120.14, 124.16, 125.26, 128.86, 129.68, 157.48. IR(KBr) 2971, 2225, 1597, 1491, 1251, 1026, 764 cm-1. Analysis calculated for C15H175NO: C, 79.26; H, 7.54; N, 6.16. Found: C, 79.08; H, 7.58; N, 6.19. EXAMPLE 19 2-(3,4-Dimethoxy-phenyl)-2-methyl-propionitrile (1.1.17) (1.1.17) 10 Purified by high pressure liquid chromatography (hexanes/2-propanol 95/5) using a Chiracel OJ column (5cm X 25cm). 1H NMR (300 MHz, CDCI3) 5 1.75 (s, 6), 3.92 (s, 3), 3.95 (s, 3), 8.89 (d, 1, J = 8.1), 7.01 (s, 1), 7.03 (d, 1, J = 7.9). 13C NMR (100 MHz, CDCI3) 5 29.24, 36.73, 55.95, 55.98, 108.71, 111.16, 117.06, 124.73, 133.94, 148.52, 149.06. WE CLAIM: 1. A process of preparing a tertiary-nitrile-substituted aromatic compound final product of Formula (1 .0.0): comprising treating an aromatic compound of Formula (2.0.0): with a secondary nitrile of Formula (3.0.0): in the presence of a base; in an aprotic solvent having a dielectric constant (e) of less than 20; and at a reaction temperature in the range of from 0°C to 120°C; whereby there is formed said tertiary-nitrile-substituted aromatic compound final product of Formula (1.0.0); wherein the dashed lines; constituent parts W1, W2, W3, W4, and W5; and substituent moieties R1, R2, R3, R4, R5, R6, and R7 wherever they appear in the above-recited compounds of Formulas (1.0.0), (2.0.0) and (3.0.0), all have the following meanings: (I) each of the dashed lines is independently absent or a bond, so that single or double bonds result at the respective positions o~ an aromatic compound of Formula (1.0.0) or (2.0.0), provided that at least one of said dashed lines is a bond; (II) W1, W2, W3, W4, and W5 is each independently a member selected from the group consisting of: i (A) C (carbon) and the dashed :line associated therewith is a bond; (B) N (nitrogen) and the dashed line associated therewith is either absent or a bond; (C) O and the dashed line is absent; (D) S(=O)k where k is an integer selected from 0, 1 and 2 and the dashed line is absent; and (E) absent so that a 5-membered ring results; provided that each W1 through W5 is selected such that no more than one is absent, no more than one is O or S(=0)k optionally together with one N in each case, and no more than four are N where only N is present; (III) R1, R2, R3, R4, and H5 is each independently selected so that: (A) when the corresponding W1-5 is O or S(=0)k said H1-5 is absent; (B) when the corresponding W1-5 C said R1-5 a member independently selected from the group consisting of hydrogen; halogen selected from CI, Br, and I; -N(R12)2; -SR12; -OR12; (C1-C6)alkyl substituted with 0-3 R9, -N(R12)2, -SR12, or -OR12; (C2-C6)alkenyl substituted with 0-3 R9; (C3-C6)alkynyl substituted with 0-3 R9; a (C3-C14)carbocyclic ring system substituted with 0-3 R9 or 0-3 R10; a heterocyclic ring system independently selected from the group consisting of furanyl, thienyl, pyrrolyl, imidazolyl, pyridyl, pyrazolyl, pyrimidinyl, benzofuranyl, benzothienyl, indolyl, benzimidazolyl, tetrahydroisoquinolinyl, benzotriazolyl, and thiazolyl, said heterocyclic ring system being substituted with 0-2 R10; and any two R1-5 attached to adjacent carbon atoms taken together to form a 3- or 4-carbon chain forming a fused 5- or 6-membered ring, or a carbon-nitrogen chain forming an indazolyl fused ring said rings being optionally substituted on any aliphatic carbon atoms thereof with a member selected from the group consisting of halogen selected from C1, Br, and I; (C1-C4) alkyl; (C1-C4)alkoxy; and -NR15R16; where: (1) R9 is a member independently selected from the group consisting of hydrogen; cyano; -CH2NR15R16; -NR15R16; -RJ5; -OR15; -S(C2-C6)alkoxyalkyl; (C1-C4)alkyl; (C2) alkenyl; (C3-C7) . cycloalkyl; (C3-C6) cycloalkylmethyl; phenyl, benzyl; phenethyl; phenoxy; benzyloxy; (C3-C6) cycloalkoxy; (C1-C4) alkyl substituted by a member selected from the group consisting of methylenedioxy, ethylenedioxy, phehyl(C1-C3) alkyl, and a (C5-C14) carbocyclic residue; and a 5-to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, substituted with 0 to 3 substituents R15; where: i (a) R15 s a member selected from the group consisting of phenyl substituted by 0-3 R11; benzyl substituted by 0-3 R11; (C1 - C6)alkyl substituted by 0-3 R11; (C2-C4) alkenyl substituted by 0-3 R11; and (C3-C6) alkoxyalkyl substituted by 0-3 R11; where R11 is a member independently selected from the group consisting of cyano; -CH2NR18R19; -NR18R19; (C3-C6) alkoxyalkyl; (C1-C4) alkyl; (C2-C4) alkenyl; (C3-C10) cycloalkyl; (C3-C6) cycloalkylmethyl; benzyl; phenethyl; phenoxy; benzyloxy; (C7-C10) arylalkyl; (C3- C6) ' cycloalkoxy; methylenedioxy; ethylenedioxy; and a (C5-C14) carbocyclic residue; and a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur; where R16 and R19 are each independently selected from the group consisting of (C1-C6) alkyl; and phenyl substituted with 0-3 R11; R16 is a member selected from the group consisting of (C1-C4) alkyl substituted by 0-3 groups selected from the group consisting of (C1-C4) alkoxy; (C2-C6) alkoxyalkyl; (C2-C6) alkenyl; phenyl; and benzyl; R10 when a substituent on a carbon atom, is a member independently selected from the group consisting of phenyl; benzyl; phenethyl; phenoxy; benzyloxy; halogen; cyano; (C1-C4) alkyl; (C3-C7) cycloalkyl; (C3-C6) cycloalkylmethyl; (C1-C6)alkoxy; (C1-C4) alkoxy(C1-C3) alkyl; (C3-C6) cycloalkoxy; (C1-C6) alkylthio; (Ci-C4)alkylthio(Ci-C3) alkyl; -OR15; -NR15R16; (C1-C4) alkyl substituted by -NR15R16 (C2-C6)alkoxyalkylene optionally substituted by Si[(C1-C3)alkyl]3; methylenedioxy; ethyl-enedioxy; -S(0)mR15; -S02NR15R16; -OCH2CO2R15; C(R16)=N(OR16); and a 5-or 6-membered heterocyclic ring system containing from 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur, or R10 when a substituent on a nitrogen atom, is a member independently selected from the group consisting of phenyl; benzyl; phenethyl; (C1-C4)alkyl; (C1-C4)alkoxy; (C3-C6)cycloalkyl; (C3-Cejcycloalkylmethyl; (C2-C6)alkoxyalkyl; -CH2N R15R16; -NR15R16; ^d -C(R16)=N(OR16); where R15 and R16 have the same meaning as i recited further above; t (3) R12 is a member selected from the group consisting of (C1-C6) alkyl substituted by 0-3 R9; and (C3-C6) alkoxyalkyl substituted by 0-3 R9; where R10 has the same meaning as recited further above; and when the corresponding W1-5 is N said R1-5 is a member independently selected from the group con¬sisting of phenyl; benzyl; phenethyl; phenoxy; (C1-C4) alkyl; (C1-C4)alkoxy; (C3-C6)cycloalkyl; (C3-C6) cycloalkylmethyl; -CH2NR15R16; NR15SR16; (c2-C6)alkoxyalkyl; and-C(R16)=N(OR16); tetxahydroispquinolinyl, benzotriazolyl, and thiazolyl, said heterocyclic ring system being substituted with 0-2 R10; where: R9, R10, R12, R15 and R16 each have the same meaning as set out further above under the definitions of R1-5; wherein said base is a compound of Formula (5.0.1): wherein R20, R21, R22,f R23, R24, and R25 are each independently selected from the group consisting of (C1-C5) alkyl and phenyl; and X+ is a suitable cation. 2. The process as claimed in claim 1, wherein said suitable cation is a member selected from the group consisting of potassium, sodium, and lithium. 3. The process as claimed in claim 1, wherein for said base of Formula (5.0.1), one R group on each Si atom is fert-butyl while tne reinainirig R groups all have the meaning of methyl. 4. The process as claimed in claim 1, wherein for said base of Formula (5.0.1), two R groups on each Si atom are tert-butyl while each remaining R group on each Si atom has the meaning of phenyl. 5. The process as claimed in claim 1, wherein said base is the potassium, sodium or lithium salt of bis(trimethylsilyl) amide (HMDS). 6. The process as claimed in claim 5, wherein said base is the potassium salt of HMDS of Formula (5.0.0): 7. The process as claimed in claim 1, wherein said solvent is a member selected from the group consisting of toluene; tetrahydrofuran; hexane; benzene; o-, m-, and p-xylene; diethyl ether; diisopropyl ether; methyl tert-butyl ether; 1,2-dimethoxyethane; and mixtures comprising one or more of said above-recited solvents. 8. The process as claimed in claim 1, wherein the base/solvent system employed therein comprises the potassium salt of bis(trimethylsilyl)amide (KHMDS) as the base and toluene or tetrahydrofuran (THF) as the solvent. 9. A process of preparing a tertiary-nitrile-substituted aromatic compound substantially as herein described with reference to the foregoing examples. Dated this 17th day of April, 2000. [RITUSHKA NEGI] OF REMFRY & SAGAR ATTORNEY FOR THE APPLICANTS

Full Text

FORM 2
THE PATENTS ACT 1970
[39 OF 1970]
COMPLETE SPECIFICATION

See Section 10.
"A prolcems of preparing a tentiany nliltrilte sudstitukd
Aromatic compound."
PFIZER PRODUCTS, INC., a corporation organized under the laws of the State of Connecticut, United States of America, of Eastern Point Road, Groton, Connecticut 06340, United States of America,
The following specification particularly describes the nature of the invention and the manner in which it is to be performed:-

ORIGINAL
353/MUMNP/2000

GRANTED
1-6-2005

The present invention relates to a process of preparing a tertiary-nitrile-substituted aromatic compound.
REFERENCE TO RELATED COPENDING APPLICATIONS
Reference is made to US application Serial No. 09/153762, filed September 15, 1998 (Attorney Docket No. 10004A), which is a continution-in-part of US provisional application Serial No. 60/064211, filed November 4, 1997 (Attorney Docket No, PC10004) and now abandoned; and in corresponding European application Serial No. 98308961.6 based on said continuation-in-part application, filed November 2, 1998 (Attorney Docket No. PC10004A) and published as EP-A-0 915 089 on May 12, 1999. The above-mentioned applications are incorporated herein by reference in their entireties, and priority is claimed of the filing date of the earliest filed of the above-mentioned applications.
BACKGROUND OF THE INVENTION The present invention relates to a novel process for preparing an aromatic compound substituted by a tertiary nitrile which is applicable to the preparation of a wide variety of compounds of this type. Such tertiary-nitrile-substituted aromatic compound final products comprise compounds of Formula (1.0.0):

(1.0.0) wherein: the constituent parts W1 W2, W3, W, and W5, and the substituent moieties R1, R2, R3, R4, R5, R6 and R7 all have the meanings set out in detail further below. The process of the present invention may be illustrated by the follow reaction scheme:

The process of the present invention is one which is both facile and which affords acceptable yields of final product. The process of the present invention is distinguished from those heretofore available by the broad scope of its applicability, and by the criticality which has been discovered relating to the chemical makeup and reaction conditions of the base used to promote the reaction, as well as of the tertiary structure of the nitrile in the final product, both of which are described in detail further below.
The character of the base which is used in carrying out the process of the present invention is critical to obtaining the acceptable yields of tertiary-nitrile-substituted aromatic compound final product which serves to distinguish the process of the present invention from the processes of the prior art. The conjugate acid of the base which is used must have a pKa in the range of from about 17 to about 30. An example of a base which meets these critical requirements is the potassium, sodium or lithium salt of bis(trimethylsilyl)amide (KHMDS).
It has also been discovered in accordance with the present invention that the type of solvent which is used to carry out the reaction between a secondary nitrile and a substituted aromatic compound represents a choice which is critical to obtaining acceptable yields of final product. The solvent selected should be aprotic and have a dielectric constant (e) of less than about 20. Toluene and tetrahydrofuran (THF) are examples of suitable solvents for use in the process of the present invention. The dielectric constant of THF is 7.6 and the dielectric constant of toluene is 2.4 (Handbook of Chemistry and Physics).
It will be appreciated that the nitrile reactant in the method of preparation of the present invention is "secondary", referring to the degree of substitution of the carbon atom to which the nitrile moiety is attached. In the final products prepared by the method of the present invention, it will be further understood that the carbon atom to which the nitrile moiety is attached is "tertiary", since it is not attached to any hydrogen atom.
The choice of the temperature at which the reaction mixture containing the secondary nitrile and aromatic compound is to be maintained is of less critical importance than the choice of the above-mentioned base or solvent. However, the proper reaction temperature is essential to obtaining acceptable yields of final product in accordance with the present invention, and should fall within the range of from about 0°C to about 120°C.
The tertiary-nitrile-substituted aromatic compound final products prepared in accordance with the process of the present invention are characterized by a wide range of chemical structures and by a significant number of different practical utilities, which include both therapeutic and non-therapeutic applications of the said final products.

Preferred tertiary-nitrile-substituted aromatic compound final products prepared in accordance with the process of the present invention are those which are useful as therapeutic agents, especially inhibitors of phosphodiesterase type IV (PDE4). PDE4 inhibitors have applicability in therapeutic methods of treatment in humans and animals of many diseases, illnesses and conditions which are allergic or inflammatory in origin, especially including asthrna, chronic obstructive pulmonary disease, bronchitis, rheumatoid arthritis and osteoarthritis, dermatitis, psoriasis, and allergic rhinitis.
Among such PDE4 inhibitors comprising tertiary-nitrile-substituted aromatic compound final products is a preferred class of selective PDE4 inhibitors disclosed in U. S. application Serial No. 08/963904, filed April 1, 1997 (Attorney Docket No. PC9281B), which is a continuation-in-part of U- S. provisional application Serial No. 60/016861, filed May 3, 1996 (Attorney Docket No. 9281), now abandoned; and in international application Serial No. PCT/IB97/00323 based on said provisional application, filed April 1, 1997 (Attorney Docket No. PC9281A), designating the United Sates, and published as WO 97/42174 on November 13, 1997.

The above-mentioned preferred class of selective PDE4 inhibitors may be illustrated by the following generic Formula (4.0.0):

(4.0.1) (4.0.2)
A method for preparing the above-described class of selective PDE4 inhibitors is described in US application Serial No. 09/153762, filed September 15, 1998 (Attorney Docket No. 10004A), which is a continution-in-part of US provisional application Serial No. 60/064211, filed November 4, 1997 (Attorney Docket No. PC10004) and now abandoned; and in corresponding European application Serial No. based on said continuation-in-part application, filed ************** (Attorney Docket No. PC10004A) and published as EP-A-0 *** *** on *****"******. in particular, there is disclosed in the above-mentioned applications the following synthesis procedure for treating an indazole of Formula (2.1.0) with cyclohexane 1,4-dicarbonitrile of Formula (3.1.0) to yield a tertiary-nitrile-substituted aromatic compound final product of Formula (4.0.3):

The above-illustrated synthesis procedure is described as being carried out in the presence of a base such as lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide (KHMDS), lithium diisopropylamide, or lithium 2,2,6,6-tetramethylpiperidine. The above-mentioned bases are described as being selective and as permitting desirably high levels of addition of cyclohexane-1,4-dicarbonitrile, Formula (2.0.1), to the R- and R1-substituted indazole, Formula (2.0.0), by displacement of the fluorine atom on the latter, while retaining both carbonitrile functionalities in place. It is further taught that it is preferred to use potassium bis(trimethylsilyl)amide (KHMDS) as the base promotant, in a solvent such as tetrahydrofuran, toluene, or xylene(s), preferably toluene, at a temperature between about 25°C and about 125°C, preferably about 100°C, for a period of from 1 hour to 15 hours, preferably about 5 hours, in order to obtain acceptable yields of a tertiary-nitrile-substituted aromatic compound final product of Formula (1.0.0).

Therefore, the present invention relates to a process of preparing a tertiary-nitrile-substituted aromatic compound final product of Formula (1.0.0):

comprising treating an aromatic compound of Formula: (2.0.0)

with a secondary nitrile of Formula (3.0.0):
H

in the presence of a base having a pKa numerical value in the range of from 17 to 30, provided that the difference in pKa numerical values between said base and corresponding tertiary nitrile of Formula (3.0.0) is no more than 6; in an aprotic solvent having a dielectric constant (E) of less than 20; and at a reaction temperature in the range of from 0°C to 120°C; whereby there is formed said tertiary-nitrile-substituted aromatic compound final product of Formula (1.0.0);
wherein the dashed lines; constituent parts W1, W2, W3, W4, and W5; and substituent moieties R1, R2, R3, R4, R5, R6, and R7 wherever they appear in the above-recited compounds of Formulas (1.0.0), (2.0.0) and (3.0.0), all have the following meanings:
(I) each of the dashed lines is independently absent or a bond, so that single or double bonds result at the respective positions of an aromatic compound of Formula (1.0.0) or (2.0.0), provided that at least one of said dashed lines is a bond;
(II) W1, W2, W3, W4, and W5 is each independently a member selected from the group consisting of:

(A) C (carbon) and the dashed line associated therewith is a bond:
(B) N (nitrogen) and the dashed line associated therewith is either absent or a bond;
(C) O and the dashed line is absent;
(D) S(=0)k where k is an integer selected from 0, 1 and 2 and the dashed line is absent; and

(E) absent so that a 5-membered ring results; provided that each W11 through W5 is selected such that no more than one is absent, no more than one is O or S(=0)k optionally together with one N in each case, and no more than four are N where only N is present; (III) R1, R2, R3, R4, and R5 is each independently selected so that:
(A) when the corresponding W1-5 is O or S(=0)k said R1-5 is absent
(B) when the corresponding W15 is C said R1"5 is a member independently selected from the group consisting of hydrogen; halogen selected from CI, Br, and I; -N(R12)2, -NR12; -OR12; (Ci-C6) alkyl! substituted with 0-3 R9, -N(R12)2, -SR12, or -OR12 (C2-C6) alkenyl substituted with 0-3 R9; (C3-C6) alkynyl substituted with 0-3 R9; a (C3-C14) carbocyclic ring system substituted with 0-3 R9 or 0-3 R10; a heterocyclic ring system independently selected from the group consisting of furanyl, thienyl, pyrrolyl, imidazolyl, pyridyl, pyrazolyl, pyrimidinyl, benzofuranyl, benzothienyl, indolyl, enzimidazolyl, tetrahydroisoquinolinyl, benzotriazolyl, and thiazolyl, said heterocyclic ring system being substituted with 0-2 R10; and any two R1-5 attached to adjacent carbon atoms taken together to form a 3- or 4-carbon chain forming a fused 5- or 6-membered ring, said ring being optionally substituted on any aliphatic carbon atoms thereof with a member selected from the group consisting of halogen selected from C1, Br, and I; (C1-C4) alkyl; (C1-C4) alkoxy; and —NR15R16; where:
(1) R9 is a member independently selected from the group consisting of
hydrogen; cyano; -CH2NR!5R16; -NR15-R16; -OR15; -S(C2-C6) alkoxy.alkyl;
(Ci:C4) alkyl; (C2-C) alkenyl; (C3-C7) cycloalkyl; (C3-C6) cycloalkylmethyl;
phenyl, benzyl; phenethyl; phenoxy; benzyloxy; (C3-C6) cycioalkoxy; (C1-C4)
alkyl substituted by a member selected from the group consisting of
methylenedioxy, ethylenedioxy, phenyl(Ci-C3) alkyl, and a (C5-C14)
carbocyclic residue; and a 5- to 10-membered heterocyclic ring system
containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen,
and sulfur, substituted with 0 to 3 substituents R15; where:
(a) R15 is a member selected from the group consisting of phenyl
substituted by 0-3 R11; benzyl substituted by 0-3 R11; (C-C6) alkyl
substituted by 0-3 R11; (C2-C4) alkenyl substituted by 0-3 R11; and (C3-C6)
alkoxy alkyl substituted by 0-3 R11;
where R11 is a member independently selected from the group consisting of cyano; -CH2R18R19; -NR18R19; (C3-C6) alkoxyalkyl; (C1-C4) alkyl; (C2-C4) alkenyl; (C3-C10) cycloalkyl; (C3-C6)cycloalkylmethyl; benzyl; phenethyl; phenoxy; benzyloxy; (C7-C10) arylalkyl; (C3-C6) cycioalkoxy; methylenedioxy; ethylenedioxy; and a (C5-C14) carbocyclic residue; and a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur;
where R18and R19are each independently selected from the group consisting of (C2-C6) alkyl; and phenyl substituted with 0-3 R
(b) R10 is a member selected from the group consisting of (C1-C4) alkyl
substituted by 0-3 groups selected from the group consisting of (C1-C4)
alkoxy; (C2-C6) alkoxyalkyl; (C2 -C6) alkenyl; phenyl; and benzyl;
(2) R10 when a substituent on a carbon atom, is a member independently
selected from the group consisting of phenyl; benzyl; phenethyl; phenoxy;
benzyloxy; halogen; cyano; (C1-C4) alkyl; (C3-C7) cycloalkyl; (C3-C6)

a (C3-C14) carbocyclic ring system substituted with 0-3 R9 or 0-3 R10; and a heterocyclic ring system independently selected from the group consisting of furanyl, thienyl, pyrrolyl, imidazolyl, tetrahydropyranyl, pyridyl, piperidinyl, pyrazolyl, pyrimidinyl, benzofuranyl, benzothienyl, indolyl, benzimidazolyl, tetrahydroisoquinolinyl, benzotriazolyl, and thiazolyl, said heterocyclic ring system being substituted with 0-2 R10; or
R6 and R7 are taken together to form a (C3-C14) carbocyclic ring system
substituted with 0-3 R9 or 0-3 R10; phenyl; 1-or 2-naphthyl substituted with
0-3 R9 or 0-3 R10 or a heterocyclic ring system independently selected from
the group consisting of furanyl, thienyl, pyrrolyl, imidazolyl,
tetrahydropyranyl, pyridyl, piperidinyl, pyrazolyl, pyrimidinyl, benzofuranyl,
benzothienyl, indolyl, benzimidazolyl, tetrahydroisoquinolinyl,
benzotriazolyl, and thiazolyl, said heterocyclic ring system being substituted with 0-2 R10; where:
R9, R10, R12, R15 and R16 each have the same meaning as set out further above under the definitions of R1-5.

DESCRIPTION OF THE STATE OF THE ART
Loupy et al., Synth. Comm., 1990, 20, 2855-2864, is concerned with the use of solid-liquid phase transfer catalysts without solvents to carry out SNAr reactions on di- or mono-nitro halogeno compounds and unactivated aryl halides. The reaction is carried out with a nucleophile, e.g., Ph2CHCN, in the presence of a base, e.g., a stoichiometric amount of pulverized solid KOH, and a catalyst, e.g., a tetraalkylammonium salt such as Aliquat 336 or TDA-1, which may be represented by the following reaction scheme:

Unlike the process of the present invention, the process disclosed by Loupy et al. is carried out with a chloride-, bromide-, or fluoride-substituted arene nucleus, which is permitted by the electron deficiency of the arene nucleus caused by the additional presence of the nitro group.
Makosza et al., J. Org. Chem., 1994, 59, 6796-6799, also relates to nucleophilic substitution of halogen in p-halonitrobenzenes, and discloses in particular a reaction which may be represented by the following reaction scheme:

The process disclosed by Makosza et al. uses ethylcyanoacetate and may be carried out with either a chloride- or a fluoride-substituted arene nucleus. Neither of these features of the Makosza et al. process, however, can be utilized in the method of the present invention.
Rose-Munch et al., J. Organomet. Chem., 1990, 385(1), C1-C3, discloses the synthesis of a-substituted aryl iminonitriles by addition of an a-iminonitrile to (fluoroarene)tricarbonylchromium complexes in the presence of a base, e.g., hexaphophotriamide (HMPT), preceded by lithiation with, e.g., di-/'so-propylaminolithium. Included in particular is a reaction which may be represented by the following reaction scheme:

The process disclosed by Rose-Munch ef al. induces an electron poor state in the fluoride-substituted arene nucleus by complexing it with tricarbonylchromium, which permits subsequent lithium anion displacement of the fluoride substituent on the arene nucleus. However, the synthetic approach of the process in Rose-Munch et al. is substantially different from that of the process of the present invention, in which lithiation is unworkable.
Plevey and Sampson, J. Chem. Soc, 1987, 2129-2136 is concerned with the synthesis of 4-amino-2,3,5,6-tetrafluoroglutethimide, and as part of that preparation describes the reaction of hexafluorobenzene with ethyl cyanoacetate in the presence of potassium carbonate base, which may be illustrated by the following reaction scheme:

The process disclosed in Plevey and Sampson also utilizes an arene nucleus which is in an electron deficient state, as is the case with other above-described methods which characterize the current state of the art. The process of Plevey and Sampson is substantially different from that of the present invention.
Sommer ef al., J. Org. Chem., 1990, 55, 4817-4821, describes a process involving displacement of halogen from a 2-halogeno-substituted benzonitrile present as a stabilized carbanion, in order to prepare (2-cyanoaryl)arylacetonitriles. The process is carried out using two equivalents of a strong base, e.g., potassium terf-butoxide, and is taught to be sensitive to the nature of the base, the solvent, e.g., dimethylformamide (DMF), the leaving group, the substituents on the rings, and the kind of rings involved. The process is taught to be applicable as well to heteroaromatics with ortho-situated halogen and cyano groups. The process of Sommer et al. may be illustrated by the following reaction scheme:

The process of Sommer et al. is substantially different from that of the present invention in that displacement of both chloride- and fluoride- substituents on the arene nucleus takes place, and further in that a secondary nitrile substituent is utilized which induces an electron poor state in the substituted arene nucleus in order to facilitate subsequent displacement.
SUMMARY OF THE INVENTION
The present invention comprises a novel method of preparing an aromatic compound substituted by a tertiary nitrile comprising: treating an aromatic compound of Formula (2.0.0):

wherein: the constituent parts W1, W2, W3, W4 and W5, and the substituent moieties R\ R2, R3, R4 and R5 all have the meanings set out in detail further below; with a secondary nitrile of Formula (3.0.0):

wherein: the substituent moieties R6 and R7 both have the meanings set out in detail further below, in the presence of a base having a pKa numerical value in the range of from about 17 to about 30, provided that the difference in pKa numerical values between said base and the corresponding secondary nitrile of Formula (3.0.0) is no more than about 6; in an aprotic solvent having a dielectric constant (e) of less than about 20; and at a temperature in the range of from about 0°C to about 120°C; whereby there is formed a tertiary-nitrile-substituted aromatic compound final product of Formula (1.0.0)

The above-described starting material comprising a compound of Formula (2.0.0) is reacted with a secondary nitrile of Formula (3.0.0):

5 wherein: the substituent moieties R6 and R7 both have the meanings set out in detail below; in the presence of a base whose conjugate acid pKa is in the range of from about 17 to about 30, provided that the difference in pKa numerical values between said base and said corresponding secondary nitrile of Formula (3.0.0) is no more than about 6, and preferably no more than about 4; and in an aprotic solvent having a dielectric constant (e) of less than about 10 20; and at a temperature in the range of from about 0°C to about 120°C; whereby there is formed a tertiary-nitrile-substituted aromatic compound of Formula (1.0.0):

wherein R1 R2, R3, R\ R5, R6 and R7; and W1 W2, W3, W4 and W5 all have the same 15 meanings as set out elsewhere herein.
One of the key features of the process of the present invention is that the nitrile moiety is required to be tertiary in the final product of Formula (1.0.0), and therefore as a reactant must be secondary in order of substitution, as shown in Formula (3.0.0):

wherein R6 and R7 may not, accordingly, have the meaning of hydrogen. The process of the present invention produces suitable results even where R6 and R7 have a substantial number of different meanings. Accordingly, in the secondary nitrile reactant compounds of Formula (3.0.0):
25 R6 and R7 are each independently selected from the group consisting of -N(R12)2;
(C,-C6) alkyl substituted with 0-3 R9; -N(R12)2; -SR12; -OR12; (C2-C6) alkenyl substituted with 0-3 R9; (C3-C6) alkynyl substituted with 0-3 R9; a (C3-C14) carbocyclic ring system substituted

-12-
with 0-3 R9 or 0-3 R'°; and a heterocyclic ring system independently selected from the group consisting of furanyl, thienyl, pyrrolyl, imidazolyl, tetrahydropyranyl, pyridyl, piperidinyl, pyrazolyl, pyrimidinyl, benzofuranyl, benzothienyl, indolyl, benzimidazolyl, tetrahydroisoquinolinyl, benzotriazolyl, and thiazolyl, said heterocyclic ring system being 5 substituted with 0-2 R10; or
R6 and R7 are taken together to form a (C3-C14) carbocyclic ring system substituted with 0-3 R9 or 0-3 R10; phenyl; 1- or 2-naphthyl substituted with 0-3 R9 or 0-3 R10; or a heterocyclic ring system independently selected from the group consisting of furanyl, thienyl, pyrrolyl, imidazolyl, tetrahydropyranyl, pyridyl, piperidinyl, pyrazolyl, pyrimidinyl, benzofuranyl, 10 benzothienyl, indolyl, benzimidazolyl, tetrahydroisoquinolinyl, benzotriazolyl, and thiazolyl, said heterocyclic ring system being substituted with 0-2 R10; where:
R9, R10, R12, R'5 and R'6 each have the same meaning as set out further above under the definitions of R1'5.
In accordance with the process of the present invention, the reaction which takes 15 place between the aromatic compound of Formula (2.0.0) and the secondary nitrile of Formula (3.0.0) is required to be in the presence of a base having a pKa in the range of from about 17 to about 30, provided that the difference in PKa, numerical values between said base and said corresponding secondary nitrile of Formula (3.0.0) is no more than about 6, and preferably no more than about 4; and in an aprotic solvent having a dielectric constant (e) of less than about 20 20; and at a temperature in the range of from about 0°C to about 120°C.
The character of the base which is used in carrying out the process of the present invention is critical to obtaining the acceptable yields of tertiary-nitrile-substituted aromatic compound final product which serves to distinguish the process of the present invention from the processes of the prior art. The relative strength of the base which is used in the process
25 of the present invention should be as close as possible to the relative strength as a base of the secondary nitrile reactant of Formula (3.0.0) which is used in that process. Further, it is desirable to quantify the relative strength of the base which is to be used. Such quantification will permit greater discrimination in selection of the base, as well as permit a more precise comparison of the relative strength of the base to the corresponding relative strength of the
30 secondary nitrile reactant.
In order to quantify the relative strength of the base for use in the process of the present invention, use is made herein of the dissociation constant, Ka of the base and the corresponding secondary nitrile of Formula (3.0.0). The dissociation constant is defined as

the equilibrium constant for transfer of a proton from an acid HA to water, and is calculated in accordance with the following equation:

5 where the values within the brackets are the molar concentrations at equilibrium for the acid and its dissociated constituents. For convenience, dissociation constants are expressed as a negative logarithm, abbreviated p. Thus, pKa = — log Ka . Stronger acids have larger dissociation constants, but correspondingly smaller pKa values. A value which can be used to quantify the comparative difference between the strength of the base and corresponding 10 secondary nitrile used in the process of the present invention, will prove to be useful in carrying out said process.
Accordingly, the relative strength of the base A : __ and corresponding secondary nitrile in question is conveniently expressed in terms of the pKa of its conjugate acid HA. Where a base is characterized as being a strong base, the converse is also inherently true,
15 i.e., that its conjugate acid is a weak acid. Thus, pKa numerical values for the conjugate acids of two or more bases will permit one to readily compare those bases and quickly order them in accordance with which one is the stronger base and which one is the weaker base. The stronger base has the conjugate acid with the higher pKa numerical value. In the present description of the process of the present invention, a given base will be directly or indirectly
20 stated to have a pKa numerical value, it being understood that the pKa numerical value in question is that of the conjugate acid of said base.
The base used in the process of the present invention will preferably have a pKa numerical value as close to that of the secondary nitrile of Formula (3.0.0) used in that process, as possible. Consequently, based on the pKa, numerical values of. the secondary
25 nitriles of Formula (3.0.0) which are suitable for use in the process of the present invention, it is considered to be an essential requirement that the base used in the process of the present invention have a pKa value in the range of from about 17 to about 30. It is a further requirement that the difference in pKa numerical values between said base and said corresponding secondary nitrile of Formula (3.0.0) used in the process of the present
30 invention be no more than about 6, and preferably no more than about 4. The secondary nitrile of Formula (3.0.0) used in the process of the present invention has a general chemical structure which may be represented by the following Formula (3.0.1):

substantiated by the determination that many such combinations either fail altogether to produce a tertiary-nitrile-substituted aromatic compound final product, or else produce such a final product in unacceptably low yields. For example, it has been found that by using a base/solvent system comprising potassium bis(trimethylsilyl)amide (KHMDS) as the base and 5 either toluene or tetrahydrofuran (THF) as the solvent, that it is possible to produce a tertiary-nitrile-substituted aromatic compound final product in accordance with the present invention in yields of 85% or greater by weight, frequently 90% or greater by weight, and often 95% or greater by weight, based on the weight of the reaction components.
The expression "unacceptably low yields" has been used herein to contrast the
10 unexpectedly superior results obtained with the process of the present invention to the
unsatisfactory results obtained with the processes of the prior art. It will be understood that
the surprising improvement in yields achieved by use of the process of the present invention
need not always be reflected solely in very high yield percentages, per se. Thus, it may be
the case that for a given final product of Formula (1.0.0) the prior art processes are
15 inoperative, resulting in a 0% yield, or else said prior art processes provide said final product
in extremely low yields. Accordingly, it will be appreciated that a 25% yield obtained using the
process of the present invention may constitute an unexpected improvement over the results
obtained using the processes of the prior art where said processes provide, e.g., a 0% or >1%
yield of the same final product. Percentage yields obtained using the process of the present
20 invention are described in detail elsewhere herein.
Instances of such failures of prior art processes to yield any final product abound. For example, when the base being used is lithium diisopropylamide (LDA), even though the solvent being used is tetrahydrofuran (THF), which would otherwise be suitable, decomposition of the initial reaction mixture occurs. Similarly, where the base/solvent system 25 utilized is potassium tert-butyloxide (f-BuOK) in tetrahydrofuran (THF), decomposition of the initial reaction mixture occurs. Where the base being used is chosen from cesium, sodium, or potassium carbonate (CsC03, Na2C03, or K2C03, respectively) and the solvent being used is tetrahydrofuran (THF), no reaction takes place at all.
The solvent component of the base/solvent system is also critical to obtaining
30 acceptable results. For example, where the base selected is potassium
bis(trimethylsilyl)amide (KHMDS), which would otherwise be suitable, and the solvent selected is dimethylsulfoxide (DMSO), no reaction at all takes place. Further, where the base is potassium bis(trimethy!silyl)amide (KHMDS) and the solvent is N-methyl-a-pyrrolidone NMP), the process results in an aromatic compound substituted by tertiary nitrile final product

in unacceptably low yields of about 5% or less by weight, based on the weight of the reaction components.
The choice of the temperature at which the reaction mixture containing the tertiary nitrile and substituted aromatic compound is to be maintained in accordance with the process 5 of the present invention, is of less critical importance than the choice of the above-mentioned base and solvent system. However, the proper reaction temperature is essential to obtaining acceptable yields of tertiary-nitrile-substituted aromatic compound final product in accordance with the present invention, and should fall within the range of from about 0°C to about 120°C, preferably in the range of from about 20°C to about 110°C, more preferably in the range of
from about 30°C to about 105°C, and most preferably in the range of from about 40°C to about 100°C. The choice of temperature at which the reaction in accordance with the process of the present invention is carried out will impact, along with other factors, the amount of time required to carry said reaction to a reasonable stage of completion. It has been found that, as a general matter, where the temperatures employed in carrying out the process are within the
15 above-stated ranges, and particularly within the above-stated preferred, more preferred and most preferred ranges, that the process of the present invention will be reasonably complete within the range of from about 0.1 hour to about 50 hours, more likely within the range of from about 0.5 hour to about 30 hours, and most likely within the range of from about 1 hour to about 18 hours
20 The preparation process of the present invention may be represented by the following
reaction scheme:

(2.0.0) (3.0.0) (1.0.0)
In the above reaction scheme, the starting material of Formula (2.0.0) is reacted with 25 a secondary nitrile of Formula (3.0.0) in the presence of a base such as potassium bis(trimethylsilyl)amide (KHMDS) in a solvent such as toluene, tetrahydrofuran, diethyl ether, diisopropyl ether, methy tert-butyl ether, 1,2-dimethoxy ethane, or a mixture of the aforementioned solvents, preferably toluene or tetrahydrofuran, at a temperature between 0°C and 120°C, preferably between 40°C and 100°C, to provide a final product of Formula (1.0.0).

These preferred embodiments of the process of the present invention are further demonstrated in the working examples set forth below. These examples are intended to be illustrative of the present invention and are not for the purpose of, and should not be taken as in any way limiting the scope or content of the process of the present invention. The claims 5 appended to the instant specification should be consulted for a definition of the scope and content of the present invention.
EXAMPLE 1
To a solution of an aryl fluoride of Formula (2.0.0) in toluene (10 volumes) was added a nitrile of Formula (3.0.0), the number of equivalents of which are indicated in Table 1below;
10 and a 0.5 M solution of potassium bis(trimethylsilyl)amide in toluene, the number of equivalents of which are indicated in Table 1 below. Each reaction mixture was stirred at a temperature and for an amount of time also indicated in Table 1 below, after which each said reaction mixture was cooled to room temperature, poured into 1N HCI, and thereafter extracted with toluene. The organic extracts were washed with water, dried over magnesium
15 sulfate, filtered and concentrated. The crude product was purified by chromatography on silica gel to afford the desired product of Formula (1.0.0) in the yield indicated in Table 1 below.
EXAMPLES 2 through 19
To a solution of an aryl fluoride of Formula (2.0.0) in tetrahydrofuran (10 volumes) 20 was added a nitrile of Formula (3.0.0), the number of equivalents of which are indicated in Table 1 below; and potassium bis(trimethylsilyl)amide, the number of equivalents of which are indicated in Table 1 below. Each reaction mixture was stirred at a temperature and for an amount of time indicated in Table 1 below, after which each said reaction mixture was cooled to room temperature, poured into 1N HCI, and thereafter extracted with methyl terf-butyl ether. 25 The organic extracts were washed with water, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by chromatography on silica gel to afford the desired product of Formula (1.0.0) in the yield indicated in Table 1 below.

TABLE 1

-19-

5 (1.1.3) Toluene 60 45 min 1.5 4.0 77
6 (1.1.4) Toluene 70 48 h 1.5 4.0 85
7 (1.1.5) Toluene 70 10 min 1.5 3.9 72
8 (1.1.6) THF 60 50 h 1.5 4.0 66
9 (1.1.7) Toluene 60 18 h 1.5 4.0 95
10 (1.1.8) Toluene R.T. 5h 1.5 2.0 24
11 (1.1.9) THF 75 2h 1.5 4.0 72
12 (1.1.10) THF 75 14 h 1.5 4.0 71
13 (1.1.11) THF 75 14 h 1.5 4.0 69
14 (1.1.12) Toluene 75 48 h 1.5 4.0 47
15 (1.1.13) THF 75 24 h 1.5 4.0 67
16 (1.1.14) THF 75 30 h 1.5 4.0 35
17 (1.1.15) THF 75 27 h 1.5 4.0 30
18 (1.1.16) THF 75 15 min 1.5 4.0 70
19 (1.1.17) THF 80 4h 1.5 4.0 28
EXAMPLE 2 2-Methyl-2-(4-trifluoromethyl-phenyl)-propionitrile (1.1.0)

10

Purified by chromatography on silica gel (ethyl acetate/hexanes 15/85).
1H NMR (400 MHz, CDCI3) 5 1.73 (s, 6), 7.59 (d, 2, J = 9.0), 7.64 (d, 2, J = 9.0). 13C NMR (100 MHz, CDCI3) 5 28.90, 37.25, 123.12 (q, J = 272.7), 123.75, 125.64, 125.93, 130.15 (q, J = 33.2), 145.38.
IR2988, 2239, 1622, 1415, 1330, 1170, 1128, 1069,842 cm"1.
Analysis calculated for C„H10F3N: C, 61.97; H, 4.73; N, 6.57. Found: C, 61.91; H, 4.96; N, 6.61.

EXAMPLE 3
4-(Cyano-dimethyl-methyl)-benzonitrile (1.1.1)

10

(1.1.1) Purified by filtration on a pad of silica gel eluting with ethyl acetate; Mp = 88-89°C.
1H NMR (300 MHz, CDCI3) 5 1.78 (s, 6), 7.64 (d, 2, J = 8.1), 7.74 (d, 2, J = 8.3). 13C NMR (100 MHz, CDCI3) 5 28.87, 37.49, 112.06, 118.19, 123.32, 126.08, 132.85, 146.48.
IR (CHCI3) 2989, 2233, 1611, 1505, 1463, 1408, 1371, 1100,838 cm"1.
Analysis calculated for C11H10N2: C, 77.62; H, 5.92; N, 16.46. Found: C, 77.26; H, 5.90; N, 16.52.
EXAMPLE 4

2-(3-Methoxy-phenyl)-2-methyl-propionitrile (1.1.2)

15
20

(1.1.2) Purified by chromatography on silica gel (ethyl acetate/hexanes 10/90).
1H NMR (300 MHz, CDCI3) 5 1.75 (s, 6), 3.86 (s, 3), 6.88 (dd, 1, J = 2.5, 8.3), 7.04-7.06 (m, 1), 7.07-7.11 (m, 1), 7.34 (t, 1, J = 8.3). 13C NMR (100 MHz, CDCI3) 5 29.02, 37.09, 55.24, 111.40, 112.60, 117.23, 124.41, 129.91, 142.93, 159.83.
IR 2983, 2940, 2236, 1602, 1586, 1489, 1463, 1434, 1294, 1268, 1048, 782 cm"1.
Analysis calculated for C„H13NO: C, 75.40; H, 7.48; N, 7.99. Found: C, 75.61; H, 7.67; N, 7.86.

EXAMPLE 5 _2-(2-Chloro-phenyl)-2-methyl-propionitrile (1.1.3)

Purified by chromatography on silica gel (ethyl acetate/hexanes 10/90).
'H NMR (300 MHz, CDCI3) 5 1.91 (s, 6), 7.29-7.34 (m, 2), 7.46-7.53 (m, 2). 13C NMR (100 MHz, CDCI3) 27.19, 36.24, 123.50, 127.00, 127.33, 129.41, 131.92, 133.31, 136.95.
IR 2984, 2236, 1473, 1432, 1234, 1043, 759 cm"1.
Analysis calculated for C10H10CIN: C, 66.86; H, 5.61; N, 7.80. Found: C, 67.22; H, 5.64; N, 7.63.

EXAMPLE 6 2-(3,5-Dimethoxy-phenyl)-2-methyl-propionitrile (1.1.4)

Purified by chromatography on silica gel (ethyl acetate/hexanes 15/85).
1H NMR (300 MHz, CDCI3) 5 1.74 (s, 6), 3.85 (s, 6), 6.43 (t, 1, J = 2.2), 6.64 (d, 2, J = 2.2). 13C NMR (100 MHz, CDCI3) 5 29.06, 37.34, 55.44, 99.12, 103.63, 124.44, 143.81, 161.10.
IR 2982, 2939, 2236, 1598, 1459, 1427, 1207, 1159, 1067, 1052,696 cm"1.
Analysis calculated for C,2H15N02: C, 70.22; H, 7.37; N, 6.82. Found: C, 70.17; H, 7.65; N, 6.96.

EXAMPLE 7 2-Methyl-2-(4-methyl-pyridin-2-yl)-propionitrile (1.1.5)

Purified by chromatography on silica gel (ethyl acetate/hexanes 20/80).
1H NMR (300 MHz, CDCI3) 6 1.77 (s, 6), 2.41 (s, 3), 7.08 (dd, 1, J = 0.8, 5.0), 7.43 (d, 1, J = 0.8), 8.47 (d, 1, J = 5.0). 13C NMR (75 MHz, CDCI3) 5 22.39, 29.06, 40.54, 121.98, 124.89, 125.66, 149.79, 150.48, 160.55.
IR 2982, 2238, 1605, 1478, 1130, 995, 830 cm-1.
Analysis calculated for C10H12N2: C, 74.97; H, 7.55; N, 17.48. Found: C, 74.96; H, 7.85; N, 17.45.
EXAMPLE 8
2-(4-Methoxy-phenyl)-2-methyl-propionitrile (1.1.6)

Purified by chromatography on silica gel (ethyl acetate/hexanes 20/80).
1H NMR (300 MHz, CDCI3) 6 1.74 (s, 6), 3.85 (s, 3), 6.94 (d, 2, J = 8.9), 7.42 (d, 2, J = 8.9). 13C NMR (100 MHz, CDCI3) 6 29.25, 36.44, 55.34, 114.19, 124.82, 126.25, 133.50, 159.02.
IR 2982, 2235, 1513, 1256,1186, 1033,831 cm1.
Analysis calculated for C11H13NO: C, 75.40; H, 7.48; N, 7.99. Found: C, 75.48; H, 7.55; N, 8.10.

EXAMPLE 9 2-(2-Methoxy-phenyl)-2-methyl-propionitrile (1.1.7)

Purified by chromatography on silica gel (ethyl acetate/hexanes 20/80).
1H NMR (300 MHz, CDCI3) 1.80 (s, 6), 3.96 (s, 3), 6.97-7.02 (m, 2), 7.29-7.39 (m, 2). 13C NMR (100 MHz, CDCI3) 6 27.00, 34.43, 55.51, 112.02, 120.76, 124.80, 125.92, 128.62, 129.39,157.30.
IR 2980, 2235, 1493, 1462, 1437, 1253, 1027, 756 cm1.
Analysis calculated for C11H13NO: C, 75.40; H, 7.48; N, 7.99. Found: C, 75.29; H, 7.30; N, 8.25.
EXAMPLE 10
1-(2-Chloro-phenyl)-cyclopropanecarbonitrile (1.1.8)

Purified by chromatography on silica gel (ethyl acetate/hexanes 20/80).
1H NMR (300 MHz, CDCI3) 5 1.28-1.38 (m, 2), 1.71-1.75 (m, 2), 7.21-7.43 (m, 4). 13C NMR (100 MHz, CDCI3) 5 13.17, 16.27, 121.78, 127.16, 130.07, 131.16, 133.60, 136.54.
IR 3063, 3020, 2235, 1477, 1435, 1051, 1033, 759 cm1.
Analysis calculated for C10H8CIN: C, 67.62; H, 4.54; N, 7.89. Found: C, 67.35; H, 4.58; N, 7.88.

EXAMPLE 11 2-(4-Chloro-phenyl)-2-methyl-propionitrile (1.1.9)

Purified by chromatography on silica gel (ethyl acetate/hexanes 10/20). 1H NMR (300 MHz, CDC13 d 1.75 (s, 6), 7.39 (d, 2, J = 9.0), 7.45 (d, 2, J = 8.9). 13C NMR (100 MHz, CDCI3) d 30.34, 38.06, 125.34, 127.80, 130.33, 135.03, 141.22.
IR 2984, 2237, 1495, 1106, 1013,828 cm-1.
Analysis calculated for C10H10CIN: C, 66.86; H, 5.61; N, 7.80. Found: C, 66.51; H, 5.83; N, 7.74.
EXAMPLE 12
2-Methyl-2-r77-tolyl-propionitrile (1.1.10)

Purified by chromatography on silica gel (ethyl acetate/hexanes 10/90).
1H NMR (300 MHz, CDCI3) 8 1.75 (s, 3), 2.42 (s, 3), 7.14-7.18 (m. 1), 7.27-7.18 (m,
3). 13C NMR (75 MHz, CDCI3) 5 22.81, 30.42, 38.35, 123.26, 125.95, 127.13, 129.80, 130.09, 139.94,142.61.
IR 2983, 2237, 1607, 1490, 1461, 1368, 1198, 1090,787 cm-1.
Analysis calculated for C11H13N: C, 82.97; H, 8.23; N, 8.80. Found: C, 82.97; H, 8.23; N.8.80.

EXAMPLE 13 2-Methyl-2-phenyl-propionitrile (1.1.11)

Purified by chromatography on silica gel (ethyl acetate/hexanes 10/90).
1H NMR (300 MHz, CDCI3) 5 1.76 (s, 3), 7.35-7.53 (m, 5). 13C NMR (100 MHz, CDCI3) 6 29.15, 37.16, 124.55, 125.05, 127.79, 128.94, 141.42.
IR 2983, 2237, 1495, 1448, 764 cm-1.
Analysis calculated for C10H 11N: C, 82.72; H, 7.64; N, 9.65. Found: C, C, 82.76; H, 7.90; N.9.88.
EXAMPLE 14
1 -(2-Methoxy-phenyl)-cyclopropanecarbonitrile (1.1.12)

Purified by chromatography on silica gel (ethyl acetate/hexanes 10/90 to provide an oil which crystallized upon standing); Mp = 49-59°C.
1H NMR (300 MHz, CDCI3) 5 1.26-1.30 (m, 2), 1.61 -1.66 (m, 2), 3.97 (s, 3), 6.92-6.97
(m, 2), 7.24 (dd, 1, J = 7.9, 1.7), 7.29-7.37 (m, 1). 13C NMR (100 MHz, CDCI3) 5 10.18, 15.24, 55.61, 110.89, 120.38, 123.08, 124.07, 129.82, 129.92, 158.97.
IR 2234, 1496, 1465, 1248, 1026, 756 cm'1.
Analysis calculated for C11H11 NO: C, 76.28; H, 6.40; N, 8.09. Found: C, 76.28; H, 6.40; N, 8.09.

EXAMPLE 15 (2S)-2-(2-Methoxy-phenyl)-bicyclo[2.2.1]hept-5-ene-2-carbonitrile (1.1.13)

Purified by filtration on a pad of silica gel (ethyl acetate/hexanes 35/65 to provide an oil which was crystallized from ethanol); Mp = 135-137°C.
1H NMR (400 MHz, CDCI3) 5 1.52 (d, 1, J = 9.0), 1.61-1.64 (m, 1), 2.02 (dd, 1, J =
12.6, 3.4), 2.21 (dd, 1, J = 11.8, 2.8), 2.99 (bs, 1), 3.62 (bs, 1), 3.91 (s, 3), 6.40 (dd, 1,J = 5.8,
3.0), 6.67 (dd, 1, J = 5.8, 3.0), 6.91-6.96 (m, 2), 7.24-7.30 (m, 2). 13C NMR (100 MHz, CDCI3)
8 41.42, 43.13, 43.68, 46.90, 48.41, 55.60, 111.66, 120.41, 124.51, 125.36, 129.02, 129.38, 134.44, 140.87, 158.08.
IR (KBr)2990, 2977, 2226, 1597, 1489, 1439, 1248, 1023, 764, 723 cm"1.
Analysis calculated for C15H15NO: C, 79.97; H, 6.71; N, 6.22. Found: C, 79.97; H, 6.71; N, 6.22.
EXAMPLE 16 2-(4'-Bromo-biphenyl-4-yl)-2-methyl-propionitrile (1.1.14)

Purified by chromatography on silica gel (ethyl acetate/hexanes 10/90); Mp = 111-112°C.
1H NMR (400 MHz, CDCI3) 5 1.76 (s, 6), 7.44 (dd, 2, J = 6.6, 1.9), 7.52-7.57 (m, 6).
13C NMR(100MHz, CDCI3) 5 29.13, 39.98, 121.90, 124.38, 125.68, 127.40, 128.64, 131.98, 139.13, 139.57, 140.86.
IR (KBr) 2986, 2235, 1483, 1461, 1105,815 cm-1.

Analysis calculated for C16H14BrN: C, 64.02; H, 4.70; N, 4.67. Found: C, 64.27; H, 4.70; N.4.58.
EXAMPLE 17 1-(4'-Bromo-biphenyl-4-yl)-cyclohexane-1,4-dicarbonitrile (1.1.15)

Purified by chromatography on silica gel (IPE/Ch^C^/Hexanes 25/25/50) to provide the product as a 1:1 mixture of diastereoisomers; Mp = 211°C.
1 H NMR (400 MHz, CDCI3) 5 1.84-2.62 (m, 8), 3.15 (bs, 1), 7.41-7.62 (m, 8). 13C
NMR (100 MHz, CDCI3) 5 25.82, 25.92, 26.41, 27.24, 33.12, 35.74, 42.79, 43.52, 120.88,
121.11, 121.20, 121.47, 122.05, 122.11, 126.00, 126.10, 127.63, 128.62, 128.65, 132.02, 138.82, 138.91, 139.00, 140.17, 140.25.
IR (KBr) 2945, 2235, 1484, 1455, 1388, 1081, 1003,812 cm-1.
Analysis calculated for C20H17 BrN2: C, 65.76; H, 4.69; N, 7.67. Found: C, 65.76; H, 4.65; N, 7.67.
EXAMPLE 18
(2S)-2-(2-Methoxy-phenyl)-bicyclo[2.2.1 ]heptane-2-carbonitrite (1.1.16)

Purified by chromatography on silica gel (ethyl acetate/hexanes 5/95); Mp = 87-88°C.
1HNMR(400MHz,CDCI3)6 1.30-1.48 (m, 2), 1.52 (d, 1, J = 10.0), 1.60-1.80 (m, 2), .98 (dt, 1, J = 13.5, 3.5), 2.12-2.18 (m, 1), 2.23 (dd, 1, J = 13.5, 2.4), 2.33 (s, 1), 2.97 (d, 1, J 3.6), 3.91 (s, 3), 6.89-6.94 (m, 2), 7.24-7.28 (m, 2). 13C NMR (100 MHz, CDCM 8 25.99,

-28-
28.64, 37.02, 37.09, 37.41, 42.97, 46.67, 55.58, 111.99, 120.14, 124.16, 125.26, 128.86, 129.68, 157.48.
IR(KBr) 2971, 2225, 1597, 1491, 1251, 1026, 764 cm-1.
Analysis calculated for C15H175NO: C, 79.26; H, 7.54; N, 6.16. Found: C, 79.08; H,
7.58; N, 6.19.
EXAMPLE 19 2-(3,4-Dimethoxy-phenyl)-2-methyl-propionitrile (1.1.17)

(1.1.17)
10 Purified by high pressure liquid chromatography (hexanes/2-propanol 95/5) using a
Chiracel OJ column (5cm X 25cm).
1H NMR (300 MHz, CDCI3) 5 1.75 (s, 6), 3.92 (s, 3), 3.95 (s, 3), 8.89 (d, 1, J = 8.1),
7.01 (s, 1), 7.03 (d, 1, J = 7.9). 13C NMR (100 MHz, CDCI3) 5 29.24, 36.73, 55.95, 55.98, 108.71, 111.16, 117.06, 124.73, 133.94, 148.52, 149.06.

WE CLAIM:
1. A process of preparing a tertiary-nitrile-substituted aromatic compound final product of Formula (1 .0.0):

comprising treating an aromatic compound of Formula (2.0.0):

with a secondary nitrile of Formula (3.0.0):

in the presence of a base; in an aprotic solvent having a dielectric constant (e) of less than 20; and at a reaction temperature in the range of from 0°C to 120°C; whereby there is formed said tertiary-nitrile-substituted aromatic compound final product of Formula (1.0.0);
wherein the dashed lines; constituent parts W1, W2, W3, W4, and W5; and substituent moieties R1, R2, R3, R4, R5, R6, and R7

wherever they appear in the above-recited compounds of Formulas (1.0.0), (2.0.0) and (3.0.0), all have the following meanings:
(I) each of the dashed lines is independently absent or a bond, so that single or double bonds result at the respective positions o~ an aromatic compound of Formula (1.0.0) or (2.0.0), provided that at least one of said dashed lines is a bond;
(II) W1, W2, W3, W4, and W5 is each independently a member selected from the group consisting of:
i
(A) C (carbon) and the dashed :line associated therewith is a bond;
(B) N (nitrogen) and the dashed line associated therewith is either absent or a bond;
(C) O and the dashed line is absent;
(D) S(=O)k where k is an integer selected from 0, 1 and 2 and the dashed line is absent; and
(E) absent so that a 5-membered ring results; provided
that each W1 through W5 is selected such that no more
than one is absent, no more than one is O or S(=0)k
optionally together with one N in each case, and no
more than four are N where only N is present;
(III) R1, R2, R3, R4, and H5 is each independently selected so that:
(A) when the corresponding W1-5 is O or S(=0)k said H1-5 is
absent;
(B) when the corresponding W1-5 C said R1-5 a member

independently selected from the group consisting of hydrogen; halogen selected from CI, Br, and I; -N(R12)2; -SR12; -OR12; (C1-C6)alkyl substituted with 0-3 R9, -N(R12)2, -SR12, or -OR12; (C2-C6)alkenyl substituted with 0-3 R9; (C3-C6)alkynyl substituted with 0-3 R9; a (C3-C14)carbocyclic ring system substituted with 0-3 R9 or 0-3 R10; a heterocyclic ring system independently selected from the group consisting of furanyl, thienyl, pyrrolyl, imidazolyl, pyridyl, pyrazolyl, pyrimidinyl, benzofuranyl, benzothienyl, indolyl, benzimidazolyl, tetrahydroisoquinolinyl, benzotriazolyl, and thiazolyl, said heterocyclic ring system being substituted with 0-2 R10; and any two R1-5 attached to adjacent carbon atoms taken together to form a 3- or 4-carbon chain forming a fused 5- or 6-membered ring, or a carbon-nitrogen chain forming an indazolyl fused ring said rings being optionally substituted on any aliphatic carbon atoms thereof with a member selected from the group consisting of halogen selected from C1, Br, and I; (C1-C4) alkyl; (C1-C4)alkoxy; and -NR15R16; where: (1) R9 is a member independently selected from the group consisting of hydrogen; cyano; -CH2NR15R16; -NR15R16; -RJ5; -OR15; -S(C2-C6)alkoxyalkyl; (C1-C4)alkyl; (C2) alkenyl; (C3-C7) . cycloalkyl; (C3-C6) cycloalkylmethyl; phenyl,

benzyl; phenethyl; phenoxy; benzyloxy; (C3-C6) cycloalkoxy; (C1-C4) alkyl substituted by a member selected from the group consisting of methylenedioxy, ethylenedioxy, phehyl(C1-C3) alkyl, and a (C5-C14) carbocyclic residue; and a 5-to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur,
substituted with 0 to 3 substituents R15; where:
i (a) R15 s a member selected from the group
consisting of phenyl substituted by 0-3
R11; benzyl substituted by 0-3 R11; (C1 -
C6)alkyl substituted by 0-3 R11; (C2-C4)
alkenyl substituted by 0-3 R11;
and (C3-C6) alkoxyalkyl substituted by 0-3
R11;
where R11 is a member independently
selected from the group consisting of
cyano;
-CH2NR18R19; -NR18R19; (C3-C6)
alkoxyalkyl; (C1-C4) alkyl; (C2-C4) alkenyl;
(C3-C10) cycloalkyl; (C3-C6)
cycloalkylmethyl; benzyl; phenethyl;
phenoxy; benzyloxy; (C7-C10) arylalkyl; (C3-
C6) ' cycloalkoxy; methylenedioxy;

ethylenedioxy; and a (C5-C14) carbocyclic residue; and a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur; where R16 and R19 are each independently selected from the group consisting of (C1-C6) alkyl; and phenyl substituted with 0-3 R11;
R16 is a member selected from the group
consisting of (C1-C4) alkyl substituted by
0-3 groups selected from the group
consisting of (C1-C4) alkoxy; (C2-C6)
alkoxyalkyl; (C2-C6) alkenyl; phenyl; and
benzyl;
R10 when a substituent on a carbon atom, is a
member independently selected from the group
consisting of phenyl; benzyl; phenethyl;
phenoxy; benzyloxy; halogen; cyano; (C1-C4)
alkyl; (C3-C7) cycloalkyl; (C3-C6)
cycloalkylmethyl; (C1-C6)alkoxy; (C1-C4)
alkoxy(C1-C3) alkyl; (C3-C6) cycloalkoxy; (C1-C6) alkylthio; (Ci-C4)alkylthio(Ci-C3) alkyl; -OR15; -NR15R16; (C1-C4) alkyl substituted by -NR15R16 (C2-C6)alkoxyalkylene optionally substituted by

Si[(C1-C3)alkyl]3; methylenedioxy; ethyl-enedioxy; -S(0)mR15; -S02NR15R16; -OCH2CO2R15; C(R16)=N(OR16); and a 5-or 6-membered heterocyclic ring system containing from 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur, or
R10 when a substituent on a nitrogen atom, is a member independently selected from the group consisting of phenyl; benzyl; phenethyl; (C1-C4)alkyl; (C1-C4)alkoxy; (C3-C6)cycloalkyl; (C3-Cejcycloalkylmethyl; (C2-C6)alkoxyalkyl; -CH2N R15R16; -NR15R16; ^d -C(R16)=N(OR16);
where R15 and R16 have the same meaning as
i recited further above;
t (3) R12 is a member selected from the group
consisting of (C1-C6) alkyl substituted by 0-3 R9;
and (C3-C6) alkoxyalkyl substituted by 0-3 R9;
where R10 has the same meaning as recited
further above; and when the corresponding W1-5 is N said R1-5 is a member independently selected from the group con¬sisting of phenyl; benzyl; phenethyl; phenoxy; (C1-C4) alkyl; (C1-C4)alkoxy; (C3-C6)cycloalkyl; (C3-C6) cycloalkylmethyl; -CH2NR15R16; NR15SR16; (c2-C6)alkoxyalkyl; and-C(R16)=N(OR16);

tetxahydroispquinolinyl, benzotriazolyl, and thiazolyl, said heterocyclic ring system being substituted with 0-2 R10; where:
R9, R10, R12, R15 and R16 each have the same
meaning as set out further above under the
definitions of R1-5;
wherein said base is a compound of Formula
(5.0.1):

wherein R20, R21, R22,f R23, R24, and R25 are each
independently selected from the group consisting
of (C1-C5) alkyl and phenyl; and X+ is a suitable
cation.
2. The process as claimed in claim 1, wherein said suitable cation is a member selected from the group consisting of potassium, sodium, and lithium.
3. The process as claimed in claim 1, wherein for said base of Formula (5.0.1), one R group on each Si atom is fert-butyl while tne reinainirig R groups all have the meaning of methyl.

4. The process as claimed in claim 1, wherein for said base of Formula (5.0.1), two R groups on each Si atom are tert-butyl while each remaining R group on each Si atom has the meaning of phenyl.
5. The process as claimed in claim 1, wherein said base is the potassium, sodium or lithium salt of bis(trimethylsilyl) amide (HMDS).
6. The process as claimed in claim 5, wherein said base is the potassium salt of HMDS of Formula (5.0.0):

7. The process as claimed in claim 1, wherein said solvent is a member selected from the group consisting of toluene; tetrahydrofuran; hexane; benzene; o-, m-, and p-xylene; diethyl ether; diisopropyl ether; methyl tert-butyl ether; 1,2-dimethoxyethane; and mixtures comprising one or more of said above-recited solvents.
8. The process as claimed in claim 1, wherein the base/solvent system employed therein comprises the potassium salt of

bis(trimethylsilyl)amide (KHMDS) as the base and toluene or tetrahydrofuran (THF) as the solvent.
9. A process of preparing a tertiary-nitrile-substituted aromatic compound substantially as herein described with reference to the foregoing examples.
Dated this 17th day of April, 2000.
[RITUSHKA NEGI]
OF REMFRY & SAGAR
ATTORNEY FOR THE APPLICANTS

Documents:

353-mum-2000-cancelled pages(01-06-2005).pdf

353-mum-2000-claims(granted)-(01-06-2005).doc

353-mum-2000-claims(granted)-(01-06-2005).pdf

353-mum-2000-correspondence(01-06-2005).pdf

353-mum-2000-correspondence(ipo)-(19-07-2007).pdf

353-mum-2000-form 1(17-04-2000).pdf

353-mum-2000-form 19(16-04-2004).pdf

353-mum-2000-form 2(granted)-(01-06-2005).doc

353-mum-2000-form 2(granted)-(01-06-2005).pdf

353-mum-2000-form 3(08-05-2001).pdf

353-mum-2000-form 3(17-04-2000).pdf

353-mum-2000-form 3(31-05-2005).pdf

353-mum-2000-petition under rule 137(01-06-2005).pdf

353-mum-2000-petition under rule 138(01-06-2005).pdf

353-mum-2000-power of authrity (01-06-2005).pdf

« Previous Patent

Next Patent »

Patent Number

208221

Indian Patent Application Number

353/MUM/2000

PG Journal Number

43/2008

Publication Date

24-Oct-2008

Grant Date

19-Jul-2007

Date of Filing

17-Apr-2000

Name of Patentee

PFIZER PRODUCTS INC.

Applicant Address

EASTERN POINT ROAD, GROTON, CONNECTICUT 06340, UNITED STATES OF AMERICA.

Inventors:

#	Inventor's Name	Inventor's Address
1	STEPHANE CARON	PFIZER CENTRAL RESEARCH, EASTERN POINT ROAD, GROTON, CONNECTICUT-06340, UNITED STATES OF AMERICA.

PCT International Classification Number

C07C 253/30

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	60/130,175	1999-04-20	U.S.A.