Title of Invention

PROCESS FOR THE MANUFACTURE OF PHENYLACETIC ACID DERIVATIVES

Abstract

The present invention relates to a process for the manufacture of compounds of general formula (I), wherein R<sup>2a</sup>, R<sup>2b</sup> are, independently from each other, hydrogen; halogen; lower alkoxy; cyano; -COOH; lower alkoxycarbonyl; or lower alkyl, optionally substituted by halogen; and R<sup>3a</sup>, R<sup>3b</sup> are, independently from each other, hydrogen; lower alkyl; lower cycloalkyl or, if taken together, -(CH <sub>2</sub>) <sub>n</sub> with n=2,3 or 5. The compounds of formula (I) are valuable intermediates for the manufacture of therapeutically active compounds such as 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide and 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(2-morpholin-4-yl-4-o-tolyloxy-pyrimidin-5-yl)-isobutyramide.

Full Text

Process for the manufacture of phenylacetic add derivatives The present invention relates to a process for the manufacture of compounds of general formula wherein R2a, R2b are, independently from each other, hydrogen; halogen; lower alkoxy; cyano; -COOH, lower alkoxycarbonyl; or lower alkyl, optionally substituted by halogen; and R3A, R3B are, independently from each other, hydrogen; lower alkyl; lower cycloalkyl or, if taken together, -(CH2)n- "with n=2,3 or 5. The compounds of formula I are valuable intermediate products for the manufacture of therapeutically active compounds of general formula R is hydrogen; lower alkyl; lower alkoxy, halogen; or trifluoromethyl; (R1)m are, independently from each other, hydrogen or halogen; or RandR1 may be together-CH=CH-CH=CHs R2a, R2b, R3a, R3b have the meanings mentioned above; R4 is hydrogen; halogen; lower alkyl; lower alkoxy; -N(R5)2; -N(R5)S(0)2"lower aikyl; -N(R5)C(0)R5 or a cyclic tertiary amine of the group R5 is, independently from each other, hydrogen; C3-6-cycloalkyl; benzyl; or lower alkyl; R6 is hydrogen; hydroxy, lower alkyl; -N(R^)CO-lower alkyl; hydroxy-lower alkyl; cyano; -CHO; or a 5-or 6 membered heterocyclic group, optionally bonded via an alkylene group; Y is a single bond; -(CH2)„-; -Os -Ss -SO2S -0(0)-; or -N(R^)-; X is =N-; -CH=; or -C(C1)=; W iS"CH=;or=N-; m is 0,1,2,3 or 4. Examples of compounds of formula II can be found among the 4-phenyl-pyridine derivatives such as 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholm-4-yl-4--o-tolyl-pyridin-3-yl)-isobutyramide and among the 4-phenyl pyrimidin derivatives such as 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(2-morpholin-4-yl-4-o-tolyloxy-pyrimidin"5-yl)-isobutyramide. It has been surprisingly found that the compounds of formula II are antagonists of the neurokinin-l (NK-1, substance P) receptor. Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being so-named because of their prompt contractile action on extravaiScular.smooth muscle tissue. The receptor for substance P is a member of the superfamily of G protein-coupled receptors. Compounds of formula II are described e.g. in EP-A-1035115 and WO 00/50398. The following definitions of the general terms used in the present description apply irrespective of whether the terms in question appear alone or in combination. As used herein, the term "lower alkyr denotes a straight- or branched-chain alkyl group containing from 1-7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl and the like. Preferred lower alkyl groups are groups with 1 to 4 carbon atoms, A preferred 'lower alkyl substituted by halogen" is trifluoromethyl. The term "lower alkoxy" denotes a group wherein the alkyl residues are as defined above, and which is attached via an oxygen atom. The term "halogen" denotes chlorine, iodine, fluorine and bromine. The term "cycloalkyF denotes a saturated carbocyclic group, containing 3-7 carbon atoms. The term "cyclic tertiary amine" denotes, for example, pyrrol-l-yl, ixnidazol-1-yI, piperidin-1-yi, piperazin-l-yl, morphoIin-4-yi,thiomorpholin-4-yl, 1-oxo-thiomorpholin-4-yi or l,l-dioxo-thiomorpholin-4-yl. The term "5 or 6 membered heterocyclic group" denotes, for example pyridinyl, pyrimidinyl, oxadiazolyl, triazolyl, tetrazolyl, thiazolyl, thienyl, fiiryl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, piperazinyl or piperidyl. The term "aryl" denotes 5 or 6 membered carbocyclic aromatic compounds or condensed carbocyclic aromatic compounds such as phenyl and naphthyl The compounds of formula II can be manufactured according to e.g. WO 00/50398, i.e. by converting a compound of formula into the corresponding acid halide (chloride or bromide), and by reacting the obtained halide with a compound of formula to a compound of formula II, wherein the definition of the substituents is given above. Compounds of general formula I can be manufactured, on their turn, by successively alkylating (twice) a compound of formula with an R3a-halide (in the presence of a strong base such as BuLi) to a compound of general formula and I, respectively. This method for manufacturing the compounds of general formula I is high-yielding but requires the use of the expensive starting materials of formula IV. Furthermore, the dialkylated product of general formula I may contain rather high quantities of the mono alkylated intermediate V and/or of overalkylated compounds, e.g. at the benzene ring. These by-products are quite difficult to remove by crystallization and their concentration in the final product mixture strongly varies in accordance with the reaction conditions. Consequently the above process is unsuitable for scale-up. Alternatively, the acid of formula IV can be converted into the corresponding ester of formula wherein R2a, R2b, R3a, R3b have the significance given above and R7 is lower alkyl. The ester of formula VI is then dialkyiated and subsequently saponified (or hydrolyzed) to the compound of formula I. The second variant of the state-of-the-art method allows to overcome the above purification problem, but it involves an additional esterification/ saponification (hydrolysis) step, thus still increasing the costs and complexity of the whole manufacturing process. The problem at the root of the present invention is therefore to provide a process for preparing the compounds of formula I which can overcome the disadvantages mentioned above. This problem is solved, according to the invention, by a process for preparing the compounds of formula I comprising the steps ofi a) reacting a Grignard derivative of a compound of formula wherein X is C1, Br or I, with a compound of formula to a compound of formula b) carbonylating the compound of formula IX in the presence of a strong acid, wherein the compound of formula I is obtained. The process according to the present invention allows to obtain yields which are higher than those provided by the above described conventional process, no major side-products are observed and no complex purification operations are necessary. Furthermore, the reactants used (formulae VII and VIII) are much cheaper than those applied in the above conventional processes (compounds of formula IV) and are easily available on the market, so that the overall manufacturing costs of compounds of formula I, and therefore also of compounds of formula II, are strongly decreased. The process according to the present invention is therefore suitable for the scale-up production of the compounds of formula 11. According to a preferred embodiment of the present invention R3a, R3a^ are, independently from each other, hydrogen; halogen; lower alkyl, optionally substituted by halogen; lower alkoxy, or cyano; and R3a, R3B are, independently from each other, hydrogen; lower aUcyl; lower cycloalkyl or, if taken together, -(CH2)n- with n=2,3 or 5. According to another preferred embodiment of the present invention, R3a, R2a are, independently from each other, lower alkoxy; lower alkoxycarbonyl; or lower alkyl optionally substituted by halogen and R3a, R3b are, independently from each other, lower alkyl or, if taken together, -(CH2)5-, According to a still more preferred embodiment of the invention, the process is applied for the manufacture of 2-(3,5-bis-trifluoromethyphenyl)-2-methyl-propionic acid. The Grignard reaction (step a) takes place in an ether, such as diethyl ether, tetrahydrofuran, dipropyl ether, dibutyl ether and the like, or in a mixture of ethers and aromatic solvents such as toluene and xylene. The reaction is carried out at atmospheric pressure and at a temperature varying between 15°C and the boiling point of the reaction mixture itself (reflux). The purity of the alcohol intermediate of formula IX is not critical; it can be as low as 70%, for preparing the acid of formula I in a purity of at least 97%. The carbonylation reaction (step b) is preferably performed at a temperature varying between -20 C and 60C, more preferably between 10 °C and 30 °C, and in the presence of a chlorinated solvent such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and dichlorobehzene. The addition of a strong acid is necessary for the carbonylation reaction to proceed. Preferred acids are the fluorinated sulfonic acids of formula CnF2n+iSO3H (n= 0-20, preferably 0-6), C2F5O-C2F4SO3H and mbctures thereof, The acids FSO3H, CF3SOsH-and mixtures thereof are particularly preferred. The strong acid is preferably added in amounts varying between 1 and 10 molar equiv,, preferably between 2 and 5 molar equiv.. According to a preferred embodiment of the present invention water is added to the reactants mixture of step b) in an amount up to 5 molar equiv. (relative to the alcohol of formula IX), preferably in an amount varying between 0.1 and 1 molar equiv. and, still more preferably, in an amount varying between 0.2 and 0.7 molar equiv.. The addition of water is not mandatory but it generally enables a reproducible increase of the selectivity towards the compound of formula I. The addition of a reagent such as formic acid, which under the reaction conditions decomposes to give water and CO, has the same effect. The carbonylation may take place at pressures of CO varying between 1 and 500 bar, preferably between 10 and 100 bar and, even more preferably, between 20 and 60 bar. The concentration, defined as gram of alcohol of formula IX per gram of solvent used, may vary between 1 and 30%, preferably between 1 and 15%, without implying major consequences on yield and selectivity towards the compounds of formula I. In order to avoid possible decomposition of the alcohol IX during the charging of the reactor, i.e. before the carbonylation starts, it may be appropriate, on a large scale, to add it to the mixture of solvent, acid and water (if necessary), already under CO pressure. The carbonylation reaction is then almost instantaneous. Accordingly, the carbonylation step may take place either in a semi-batch or in a continuous flow reactor. Another aspect of the present invention concerns a process for the manufacture of compounds of formula II comprising the subsequent steps of converting a compound of formula I into the corresponding acid halide (chloride or bromide) and reacting said halide with a compound of formula III to a compound of formula II, wherein the compound of formula I is obtained by the steps of: a) reacting a Grignard derivative of a compound of formula VII with a compound of formula VIII, to a compound of formula DC; and b) carbonylating the compound of formula IX wherein the compound of formula I is obtained. Preferably, the process acicording to the present invention is applied for manufiacturing therapeutically active compounds 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yI)-isobutyramideor2-(3,5"bis-trifluoromethyl-phenyl)-N-methyl-N"(2-morpholin-4-yl-4-o-tolyloxy-pyrimidin-5-yl)-isobutyramide. By way of examples, preferred embodiments of the present invention will now be described. Synthesis of 2-(3,5-biS'trifluoromethyl-phenyl)-propan'2'Ol 16.10 g (0.659 mol) of magnesium turnings were treated under argon in 450 ml of diethyl ether with 150 g (0.507 mol) of 3,5-bis-trifluoromethylbromobenzene at i^C for 1.5 h. Then a solution of 56.0 ml (0,763 mol) of acetone in 100 ml of diethylether was added at 16-22^*0 under stirring. 110 ml of 25% Ammonium chloride solution was added at ca. 20*'C after 1.5 h to the reaction mixture and the suspension stirred for 1 h. The organic phase was dried over sodium sulfete, rotary evaporated and finally dried at 35**C and 10 mbar, affording 136.96 g of 2"(3,5-bis-trifluoromethyl-phenyl)-propan-2-ol, which had a 99.2% purity according to GC analysis. Light yellow crystals, m.p. 59-60°C. EXAMPLE 2 Synthesis of2'(3,5'biS'trifluoromethylphenyl)'2-methyUpropionic acid with addition of water A 185 ml stainless steel autoclave was charged under argon with 25 ml of dichloromethane, 22.30 ml (0.25 mol) of trifluoromethanesulfonic acid and 0.45 ml (25 mmol) of water. The autoclave was sealed and pressurized with 30 bar of carbon monoxide. Then under stirring a solution of 14.13 g (50 mmol) of 2-(3,5-bis-trifluoromethyl-pheriyl)-propan-2-ol in 35 ml of dichloromethane was added with a pump within 50 min at 20°C and the reaction mixture was stirred for additional 2 h. Thereafter the autoclave was vented and the biphasic reaction mixture was treated in an ice bath with a solution of 13.2 g of sodium hydroxide in 130 ml of water. The organic phase was removed and the aqueous phase was washed with dichloromethane. After filtration, 35 ml of 36.5% hydrochloric acid solution were added to the aqueous phase under stirring at 8-12°C, The resulting suspension was extracted twice with dichloromethane and, after drying with sodium sulfate, the organic phase was evaporated and thfe solid residue dried at room temperature and 10 mbar vacuum. 14.98 g of 2-(3,5-bis-trifluoromethylphenyl)-2-methyl-propionic acid were isolated as light brown crystals with m.p. 105.5-107°C and 99.0% purity according to HPLC analysis. EXAMPLES Synthesis of2-(3,5-biS'trifluoro}nethylphenyl)-2'methy-propionic acid without addition of water, A 21 stainless steel autoclave was charged under argon with 250 ml of dichloromethane and 218.5 ml (2.45 mol) of trifluoromethanesulfonic acid. The autoclave was sealed and pressurized with 30 bar of carbon monoxide. Then under stirring a solution of 136,7 g (0,49 mol) of 2-(3,5-bis-trifluoromethyl-phenyl)-propan-2-oI in 350 ml of dichloromethane was added with a pump within 50 min at 20°C and the reaction mixture was stirred for additional 2 h. An isolation procedure analogous to that described in Example 2 affording after acidification of the aqueous phase with hydrochloric acid a precipitate which was isolated by filtration and dried at 55°C and 10 mbar to constant weight. 138.31 g of 2-(3,5"bis-trifluoromethylphenyI)-2-methyl-propionic acid were isolated as light yellow crystals with m.p. 106-'106.5°C and 98% purity according to HPLC analysis. bSulfonic acid is in all examples CF3S03H, with exception of 4.5, where it is FSO3H. c)P = 50 bar of CO. d)Molar ratio sulfonic acid / SM is 2.5. e)Molar ratio sulfonic acid / SM is 3.0, The reaction was heated for additional 3 h. % Yield was determined by GC. N.d. means not determined. EXAMPLE 6 a) Synthesis of2-(3,5'bis-tHfiuoromethyl'phenyl)-2-methYl'propionyl chloride, 15.0 g (50 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionic acid were dissolved in 127.5 ml dichloromethane in the presence of 0.75 ml DMF. 8.76 ml (2 eq.) Oxalyl chloride were added and after 4.5 hours, the solution was rotary evaporated to dryness. 9 ml Toluene were added and the resulting solution was again rotary evaporated, then dried under high vacuum yielding 16.25 g (quant) of 2-'(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyi chloride as a yellow oil of 86% purity according to HPLC analysis, NMR (250 MHz, CDCU): 7,86 (br s, IH); 7.77 (br s, 2H, 3 Harom); 1.77 (s, 6H, 2 CH5). b) Synthesis of 2'(3,5-bi5-trifluoromethyUphmyl)-N~[4[(2'chloro-pyridin-3-ylJ'N'inethyl-isobutyramide. 8.56 g (28.1 mmol) [4-(2-Chloro-phenyl)-6-morpholin-4-yl-pyridin-3-yi]-methyl-amine were dissolved in 50 ml dichloromethane in the presence of 5.5 ml (1,4 eq.) triethylamine and cooled to 0°C. A solution of 10.8 g (1.05 eq.) 2-(3,5-bistrifluoromethyl-phenyl)-2-methyl-propionyl chloride (step a) in 10 ml dichloromethane was added slowly and after 2 hours, 80 ml water was added. After 15 minutes stirring, the phases were separated, the aqueous phase was extracted with 2 portions of 80 ml dichloromethane and the combined organic extracts were washed with 80 ml water, 80 ml 2% aqueous NaOH, 80 ml water and 80 ml 5% aqueous NaHCOa, dried over Na2S04 and concentrated under reduced pressure. Crystallization from 40 ml 2-propanoi and 20 txd ethanol at-20°C yielded 14.2 g (86%) of 2-(3,5-bis-trifluoromediyl-phenyi)-N-[4-(2-chloro-phenyl)-6-morpholin-4-yl-pyridin-3-yl]-N-methyl-isobutyramide as a white powder of m.p. = 134.4-135.5 EXAMPLE 7.1-7.4 Examples 7,1-7.4 (Table 3) were run in analogy to Example 2 (water added) using different starting materials. The carbonylation substrates were prepared by reaction of the aryl Grignard reagent with the corresponding ketone in diethyl ether as solvent. The alcohol of experiment 7.4 was prepared according to P. Knochel et al, Angew. Chem. Int. Ed. 1998,37,1701,' 'The product of the carbonylation of 4"(l-hydroxy-l"methyl-ethyi)-ben2oic acid ethyl ester is 4-(l-carboxy-l-methyl-ethyl)-benzoic acid ethyl ester. However, the corresponding benzoic acid is obtained: a) at least in part already during the carbonylation reaction by acid-catalyzed reaction with excess water and b) during the work-up of the reaction mixture by saponification, when this is extracted with aqueous sodium hydroxide. WE CLAIM: 1. A process for the manufacture of 2-(3,5-bis- trifluoromethyl) -2-methyl-propionic acid of general formula wherein R ^5 R are, independently from each other, hydrogen; halogen; C1-7 alkoxy; cyano; -COOH; C1-7 alkoxycarbonyl; or C1-7 alkyl, substituted or unsubstituted by halogen; and R3a, R3b are, independently from each other, hydrogen; C1-7 alkyl; C3-7 cycloalkyl or, if taken together, -(CH2)n- with n=2,3 or 5; characterized in that it comprises the steps of b) carbonylating the compound of formula IX in the presence of a strong acid selected from CnFin+iSOsH, (n=0-20, preferably 0-6), C2F5O-C2F4SO3H and mixtures thereof wherein the compound of formula I is obtained. The process as claimed in claim 1, wherein are, independently from each other, hydrogen; halogen; C1-7 alkoxy; cyano; or C 1.7 alkyl, substituted or unsubstituted by halogen; R 3a, R 3b are, independently from each other, hydrogen; C1-7 alkyl; C3.7 Cycloalkyl or, if taken together with the carbon atom to which they are attached, -(CH2)n- with n=2,3 or 5. The process as claimed in claim 1, wherein R ,R are, independently from each other, C1-7 alkoxy; C 1-7 alkoxycarbonyl; or C 1.7 alkyl, substituted or unsubstituted by halogen; R3a, R3b are, independently from each other, C1-7 alkyl or, if taken together with the carbon atom to which they are attached, -CH2)5-. The process as claimed in any one of the preceding claims, wherein step a) is carried out at atmospheric pressure and at a temperature varying between 15°C and the boiling point of the reaction mixture. The process as claimed in any one of the preceding claims, wherein step b) is carried out at a temperature varying between -20°C and 60°C and at a CO pressure varying between 1 and 500 bar. The process as claimed in claim 5, wherein step b) is carried out at a temperature varying between 10°C and 30°C. 7. The process as claimed in claim 5 or 6, wherein step b) is carried out at a CO pressure varying between 10 and 100 bar. 8. The process as claimed in claim 6, wherein step b) is carried out at a CO pressure varying between 20 and 60 bar. 9. The process as claimed in claim 1, wherein the strong acid is chosen among FSO3H, CF3SO3H and mixtures thereof. 10. The process as claimed in any one of the preceding claim, wherein water is added to the reactantsmixture of step b) in an amount up to 5 molar equiv. (relative to the compound of formula IX). 11. The process as claimed in claim 10, wherein the water is added in an amount between 0.1 and 1 molar equiv. 12. The process as claimed in claim 9, wherein the water is added in an amount between 0.2 and 0.7 molar equiv.

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