Title of Invention

A PROCESS FOR PREPARATION OF AMINO SUBSTITUTED BENZOTHIAZOLE DERIVATIVE

Abstract

ABSTRACT 1502/CHENp/2005 A process for preparation of imino substituted benzothiazole derivative The present invention relates to a process for preparation of amino substituted benzothiazcle derivatives of formula (I), wherein R<1>, R<2> and R<3> are independently from each other hydrogen, lower alkyl, lower alkoxy or halogen; R<4> is hydrogen, lower alkyl, lower alkyloxy, halogen, or is a five or six membered non aromatic heterocyclyl group, unsubstituted or substituted by lower alkyl or an oxo-group, or is -NR<5>R<6> wherein R<5> and R<6> are independently from each other hydrogen, lower alkyl, -C(0)-]ower alkyl, -(CH2)nO-lower alkyl or benzyl, opionally substituted by lower alkyl, or is an five or six membered heteroaryl group; R<1> and R<2> or R<2> and R<3> may form together with the corresponding carbon atoms a ring containing -0-CH2-0- or -CH=CH-CH=CH-; R is hydrogen or -C(0)R'; R' is a five or six membered non aromatic heterocyclyl group, five or six membered heteroaryl group or is aryl, which rings may be substituted by the groups, selected from lower alkyl, halogen-lower alkyi, lower alkoxy, cyano, nitro, -C(0)H, -C(0)OH or by pyrrolidin-1-yl-methyl; n is 1 to 4; and to their pharmaceutically acceptable salts, wherein the cyclization is carried out by the treatment of a compound of formula with sulphoxide/HBr/solvent to give the desired products of formula (I) for R is hydrogen (formula lA) and for R is -C(0)R' (formula IB).

Full Text

-J :::> I -J o o O CN L c c Cyclization process for substituted benzothjazole derivatives The present invention relates to an improved cyclization process for the preparation of benzotliiazoles of formula wherein R' , R' and R' are independenfty from each other hydrogen, lower alkyl, lower alkoxy or halogen; V} is hydrogen, lower alkyl, lower alkyloxy, halogen, or is a five or six membered non aromatic heterocyclyl group, unsubstituted or substituted by lower aikyl or an oxo-group, or is -NR^R'i wherein R^ and R^ are independently from each other hydrogen, lower alkyl, --C(0)-lower alkyl, -(CH:)r.O-!ower alkyl or benzyl, opionaliy substituted by lower alM' or is a five or six membered heteroaryl grotip; R' and R^ or R" and R'"' may form together with the corresponding carbon atoms a ring containing -O-CH.-O- or -CH=CH~CH=CH-; R is hydrogen or-C(0)R'; R' is a five or six membered non aromatic heterocyclyl group, five or six membered heteroaryl group oris aryl, which rings maybe substituted by the groups, selected from lower alkyl, halogen-lower alkyl, lower aikoxy, cyano, nitro, -C(0)H, -C[O)0H orbypyrrohdin-l-ykmethyl; n is 1 to 4; ^ and to their pbarmaceutically acceptable salts. The compounds of formula I are known connpoiinds, described in WO 01/97786. The object of the present invention is a cyclization process forSJpr^Iration"of ~^ benzothiazole derivatives of formula I for R = hydrogen (formula lA) and for R = -C(0)R' (formula IB), in good yields and with minimal sideproducts. The compounds of formula lA may be used as intermediates for the preparation of compounds of formula IB, which compounds are pharmaceutically active as adenosine receptor hgands. They are important in the regulation of many aspects of cellular metabolism and in the modulation of different central nervous system activities. The compounds of formula IB maybe used in the control or prevention of illnesses based on the modulation of the adenosine system, such as Alzheimer's disease, Parldnson's disease, neuroprotection, schizophrenia, anxiety, pain, respiration deficits, depression, asthma, allergic responses, hypoxia, ischaemia, seizure and substance abuse. Furthermore, compounds of the present invention maybe useful as sedatives, muscle relaxants, antipsychotics, antiepileptics, anticonvulsants and cardioprotective agents. The most preferred indications in accordance with the present invention are those, which base on the A2A receptor antagonistic activity and which include disorders of the central nervous system, for example the treatment or prevention of certain depressive disorders, neuroprotection and Parldnson's disease. The compounds are further usefiil in the treatment of diabetes mellitus, obesit}' and ADHD (attention deficit h\'peractivity" disorder). As used herein, the term "lower alkyl" denotes a saturated straight- or branched-; chain alkyl group containing from I to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-but)'l, i-butyl, 2-butyl, t-butyl and the like. Preferred lower allq'l groups are groups with 1' 4 carbon atoms. The term "halogen" denotes chlorine, iodine, fluorine and bromine. 3 The term "lower alkoxv-" denotes a group wherein the alkyi residues are as defined above, and which is attached via an oxj'gen atom. The term "five or six merabered heteroaryl" denotes the following group: pyrrol-1-yl, tetrazolyl, imidazol-1 or 2-yl, pyrazoU-yl, pyridin-l, 2, 3 or 4-yl, pyraziny], pyrimidinyl, pyridazinyl, isothiazolyl, isoxazolyl, thienyl or furyl; The term "five or six membered non aromatic heterocyclyl" denotes the following groups: pyrrolidinyl, hydro-pyranyl, Imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiomorpholin-l,l-dioxo or thiomorpholin-1-oxo. The term "aryl" denotes phenyl, benzyl or naphthyl. The term "pharmaceutically acceptable acid addition salts" embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, p-toluenesulfonic acid and the hke. In general, the preparation of compounds of formula 1, wherein R is hydrogen, is well Icnown. For example, in WO 01/97786 the following process is described: Scheme 1 wherein the numbers 1-4 have the following meaning: 1 HR^ Pd(OAc);, BDCP, K3PO4, DME ( ethylene glycol dimethyl ether), SO °C/24h/90 %; 2 H2, PQ^C, EtOH/CH^CL, RT/12h/95 %; 3 PhCONCS, acetone, RT/30min/95 % and NaOMe, MeOH, RT/2h/90 %; 4 SOC!2,55'C/10niin/75%; It has been shown that the reaction variants, conducted according to literature precedent, such as Bra/CHCl;, or AcOH, hlUeOK or SOCb/CHClj are often not suitable for the preparation of amino-benzothiazoles, especially in large amounts. Due to the relative high electron density within the amino-substituted phenyl ring in some specific cases required for the present purposes, competing reactions on this ring before or after cyclization always occurred to a certain extents. Other approaches such as the use of aq NH4Br and H3SO4 (EP 529600) or treating the aniline directly with NaSCN/Br2/ AcOH (Synthesis, 970, 31, 2000) failed to offer any impiovement, A more suitable way of activating the thione sulphur atom was found in the acid catalyzed transfer oxidation of thioureas with DMSO (/. Heterocyclic ChEm., 63, 37, 2000). But in the absence of suitable trapping agents a dimerization reaction took place to give nndesired iminothiadiazoles. All methods, described m the Hterature, do not give the desired end products of formula lA and IB in good yields without anpredictabie side products. In order to overcome this problem, it has been found that the treatment of compoiinds of formulas in a good yield of up to 90 % and with minimal or no side reactions. As a sulphoxide, for example, DMSO is suitable, since it is commercially available, cheap and non-toxic. HBr may be used in any form, including gaseous, or for example in form of an in situ prepared bromide salt and a strong acid. Suitable is HBr-AcOH, since this represents a convenient form of 'liquid' concentrated HBr. As a solvent may be used, for example, CH2CI2, CH?CN, THF, AcOH or EtOAc, Preferred solvents are AcOH or EtOAc. In more detail, the reactions maybe described as follows: A thiourea of formula IT or III is suspended with vigorous stirrin.g in ethyl acetate (EtOAc) at 80 '^C. Hydrogen bromide (HBr = 33 %) in acetic acid is added dropwise within 0.2 h, followed by the addition of dimethylsulfoxide in one portion. The suspension is refluxed for 4 h. Then the reaction mixture is cooled to RT and after 0.2 h is filtered. The product is washed portionwise with ethyl acetate. The aminobenzothiazole lA or the corresponding benzamide of formula IB is then purified by Hberating it from the crude HBr-salt. This is dissolved in ethanol, diluted with water and heated to 55 °C. The obtained solution is basified with aqueous ammonia to pH 9-iO, forming a suspension which is stirred and allowed to cool to RT overnight (16 h). The products are filtered and washed portionwise with aqueous ethanol and then dried for 24 h at 45 "C. Yield -90 %. Furthermore, it has b een shown that the treatment of a thiourea of formulas II or III with DMSO/HBr/AcOH delivered the desired product of formula lA or IB (yield: -60 - SO %), but always accompanied by unpredictable amounts of iminothiazoles (-5 — 25 %). The formation of the side product was attributed to the partial solubility of the protonated thioureas of formula II or III in hot AcOH, Aqueous HBr was also effective, but induced some thiourea-urea transformation. Two equivalents of HBr was necessary for complete conversion in the cases where a basic unit was attached to the aryl-ring. The reaction proceeded best at >70 °C, but was rapid and fairly exothermic at this temperature. The starting material quickly dissolved upon DMSO addition and the product almost completely precipitated immediately thereafter. It has been found that after cooling and filtration, the benzothiazoles of formulas lA or IE may be isolated in good purity. By conducting the reaction entirely in EtOAc, the problem of competitive dimerization was finally overcome since the HBr-salts of both reactant and product were barely soluble in this solvent thus averting all further side reactions. The compounds of formula lA may then used for the preparation of end-products of formula IB as described in the following scheme: Scheme 5 This reaction is described in more detail in WO 01/97786. The starting compounds of formulas II and III maybe prepared as described in the above scheme: Compounds of formula III may be prepared as follows: A compound of formula IV is dissolved in sulphuric acid, maintaining a temperature between 0-10 °C. The obtained solution Is cooled to ca. -5 "C. In a separate flask, nitric acid is added to sulphuric acid and precooled to ca. 10 °C. This mixture is then added the above solution witliin 1 h ensuring that the temperature remained 1 Ammonium thiocyanate is dissolved in acetone at RT and benzoyl chloride is added to create PhCONCS in situ. The reaction mixture is heated to reflux and then treated with a warm solution of a compound of formula \T in acetone over 0.25 h. After 2.5h, the solvent is removed by distillation at ambient pressure with the continuous addition of water. After cooling the suspension to RT, the product of formula III is filtered, washed with water and dried. The benzoylthiourea of forrnula III is suspended in methanol at RT and sodium methoxide is added over 0-75 h. The suspension is stirred for 2.75 h. The reaction mixture is cooled to ~0 "C and stirred for 1 h before being filtered. The obtained product of formula II is washed with methanol and dried. The further conversion of compounds of formula III to IB and II to lA is described above. The following examples are described to illustrate the present invention without limiting it: Example 1 N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-methyI-isomcotinamide z) 4-(4-Methoxy-3-nitro-p.henvl)-morpliohne 60.0 gArylmorphoIine (0.31 mol) were dissolved in 273 ml 95 % sulphuric acid (4,S4moI, 15.6 eq.}, while maintaining a temperature between 0-10 °C. Stirring at 10 °C was continued for 0.5 h to produce a brown solution which was cooled to ca. -5 °C. In a separate flask, 20.9 ml 65 % nitric acid (0,34 mol, 0.98 eq.) were added to 30 ml 95 % sulphuric acid (0.53 mol, 1.7 eq) precookd to ca. 10 "C. This nitrating mixture was then added to the above solution within 1 h ensuring that the temperature remained The crude product was sufficiently pure to be used directly in the next step. ,0 40.2 g Nitroanisole (0.169 mmol) were suspended in 402 ml methanol and 65 ml dichloromethane were added to generate a solution. 2.0 g 5 % Pd-C were added and the reduction was commenced at RT under hydrogen. The reaction was complete after 1.5 h. The reaction mixture was then worlced up in a conventional manner. The crude product was sufficiently pure to be used directly in the next step. 32.Sg{93 13.1 g Ammonium th-iocyanate (AmSCN) (142 mmol, 1.1 eq.) were dissolved in 135 ml acetone atRT. 22.7 g Benzoyl chloride (160 mmol, 1.02 eq.) were added in one portion. The reaction mixture was heated to reflux (-60 °C) for 0.5 h and then treated with a warm (-40 "C) solution of 32.5 g the aniline (156 mmol) in 260 mi acetone over 0.25 h. The heating was continued for 2.5 h. The work-up was carried out in conventional manner. The crude product was sufficiently pure to be used directly in the next step. 54.8 g (94 %}. 212 g Benzoyl thiourea (571 mmol) were suspended in 1270 ml methanol atRTand 155 ml 30 % methanolic sodium methoxide (861 mmol, 1.5 eq.) were added over 0.75 h. The suspension was stirred for 2.75 h, cooled to ~0 "C and stirred for 1 h before being filtered. The crude product was sufficiently pure to be used directly in the next step. I4S.7g(97%). 50 g (187 mmol) thiovirea were suspended with vigorous stirring in 560 ml ethyl acetate. Thelight grey suspension was brought to reflux and 1.8 g hydrogen bromide (33 % in acetic acid, 65.5 ml, 374 mmol, 2.0 eq.) were added dropwise within 0.2 h, followed by, Q.2 h later, 17.5 g dimethyisulfoxide (224 mmol, 15.9 nU, 1.2 eq.) in one portion. The Suspension was refluxed for 4 h during which the colour changed from dark to light yellow. The reaction mixture was cooled to RT and after 0.2 h was filtered. The product was washed portionwise with 190 ml ethyl acetate. The aminobenzothiazole was purified by liberating it from the undried crude HBr-salt. This was dissolved in 450 ml ethanol, diluted with 600 ml water and heated to 55 "C. The red solution was basified with 50 ml 25 % aqueous ammonia to pH 9-10, forming a suspension which was stirred and allowed to cool to RT overnight (16 h). The product v/as filtered and washed portionwise with 140 ml 50 % aqueous ethanol and then dried for 24 h at 45 "C/l mb. 45.1 g (90%) 'H-NMR: (400 MKz, CDCI5): 5 = 3.05 (m> 4H), 3.86 (m, 4H), 3.95 (s, 3H), 5.14 (bs, 2H), 2Q.0 g Pyridine acid (115 mmol) were suspended at RT in 100 ml dichioromethane. 0.5 m! Dimethylformamide (6.5 mmol) was added and after 0.2 h, 14.9 g oxaiyi chloride (10.2 ml, 115 mmol) were added over 2 min. The dropping ft.mnel was rinsed with 4 ml dichioromethane. The brown suspension was stirred at RT for 3 h. Then 200 ml tetrahydrofuran were added causing the acid chloride to partially precipitate. After 0.2h, 24.3 g aminobenzothiazole (lA) (92 mmol) were added in one portion at RT. Directly afterwards, 56.0 mlN-etbyldiisopropylamine (42 g, 321 mmol) were added over 0.1 h. and the reaction mixture was stirred at RT overnight (~17 h). The contents were heated to reflux (~60 "C) and 300 ml water were added whilst maintaining ca. constant volume thr^ougbout a distillation process until the internal temperature reached 90 "C. Once all the water was added, heating was increased to 110 °C and a total of 280 ml of distillate was collected. A further 320 ml water was added in one portion and the temperature was increased to 120 °C whereby the internal and distillate temperature rose to ~70 °C. Around 20 ml more solvent was removed and after 0.1 h, the internal and distillate temperatures reached 90 ° and 75 °C respectively. The reaction contents were allowed to cool to RT (ca, 1.2 h) then stirring was continued for 1.5 h to complete the precipitation of the product. This was filtered and washed in 30 ml portions with a total of 150 ml water. Further purification was carried out in conventional manner. Yield; 30.4 g (S6 % from amine). Example 2 A'-(7-Acetylamino-4-mefhoxy-henzothiazol-2-yl)-benzamide \2> (4-Methylphenyl)thiourea {2 mmol) was added to AcQH (4 ml) and the suspension was heated to 80 "C. To the solution formed was added 33 % HBr in AcOH (4 mmol) followed by DMSO (2.1 mmol). After stirring at SO °C fori h, the reaction mixture was cooled to 50 °C, dOuted with EtOAc (10 ml) and fihered. The product (as HBr-salt) was taken up in H2O (5 ml) and treated with IM aq. NaHCO., (2 ml). Stirring was continued for 0.2 h, the precipitated aminobenzothiazole was then filtered, washed with H1O (10 ml) and dried (]6h at 45 °C/20 mb); yield 67 %. ^H-NMR (400 MHz, DMSO-4): 5 = 2.31 (s, 3H, CH3), 7.00 (d, IH, ArH-5), 7.21 (d, IH, ArH-4),7.31 (bs,2H,NH2),7.44(E, lH,ArH-7). MS: 165(M-rH"). l-Eenzoyl-3-o-tolyl-thioLirea was treated in the same manner as in Example 7; yield 52 %. 'H^NMR (400 MHz, DMSO-4): 5 = 2.64 (s, 3H, CH3), 7.26 (m, 2H), 7.57 (m, 2H), 7.67 (m, IH), 7.83 (dd, IH), 8,15 (dd, IH), 12.9 (bs, IH). MS:269(M+H^). l-BenzoyI-3-(2-methox)'-5-morpho!in-4-yl-phenyl)-thiourea was treated in CH2CI2 (5 ml) in the same manner as in Example 7. An extractive work-up with CHjCL/aq. NaHCOs provided the crude product which was triturated in TBME (4 ml) at 50 °C, cooled to RT and filtered; yield 68%. 'H-NMR: (400 MHz, CDCh): 5 = 3,08 (m, 4H), 3.80 (s, 3H), 3.S6 (m, 4H), 6.73 (d, 2H), 6.83 (d, 2H), 7.44 (m, 2H), 7.56 (m, IH), 7.88 (d, 2H). ■ MS: 370 (M + H^), 392 (M + Na""). Example 15 N-(5,7-DLmethoxy'benzothiazol-2-yl)-benzamide 18- WE CLAIM: 1. A process for preparation of amino substituted benzothiazole derivatives of formula 1 wherein R , R2 and R^ are independently from each other hydrogen, lower alkyl, lower alkoxy or halogen; R'is hydrogen, lower alkyl, lower alkyloxy, halogen, or is a five or six membered non aromatic heterocyclyl group, unsubstituted or substituted by lower alkyl or an oxo-group, or is —NR^R^ wherein R^ and R^ are independently from each other hydrogen, lower alkyl, - C(0)-lower alkyl, -(CHi X 0-lower alkyl or benzyl, optionally substituted by lower alkyl, or is a five or six membered heteroaryl group; R' and R^ or R^ and R^ may form together with the corresponding carbon atoms a ring containing -O-CH2-O- or-CH=CH-CH=CH-; R is hydrogen or-C(0)R'; R' is a five or six membered non aromatic heterocyclyl group, five or six membered heteroaryl group or is aryl, which rings may be substituted by the groups, selected from lower alkyl, halogen-lower alkyl, lower alkoxy, cyano, nitro, -C(0)H, -C{ O) OH or by pyrrolidin- 1 -yl-methyl; n is 1 to 4; 20 and their pharmaceutJcally acceptable salts, wherein the cyclization is carried out by the treatment of a compound of formula 2. The process as claimed in claim 1, wherein the sulphoxide is dimethyl sulphoxide. 3. The process as claimed in claim 1, wherein HBr is an in situ prepared bromide salt and a strong acid. 4. The process as claimed in claim 3, wherein the in situ prepared bromide sah and the strong acid is HBr-AcOH. 21 5. The process as claimed in claim 1, wherein the solvent is CH2CI2, CH3CN, THF, AcOH or EtOAc. 6. The process as claimed in claim 5, wherein the solvent is AcOH or EtOAc. 7. The process as claimed in claim 1, wherein a compound of formula II or III is suspended in a solvent and then treated with HBr and a sulphoxide. 8. The process as claimed in claim 7, wherein to a suspension of a compound of formula II or III in ethyl acetate or acetic acid is added hydrogen bromide in acetic acid and then dimethylsulfoxide is added. Dated this 4"' day of July 2005

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