MXPA99001928A - Process for preparing amidines - Google Patents

Abstract

The invention concerns a process for preparing amidines and their salts with inorganic or organic acids. According to this process, the corresponding nitrile is reacted with ammonia, a C1-C6 alkylamine or hydrazine in the presence of a mercapto carboxylic acid and optionally in the presence of an inorganic or organic ammonium salt.

Description

PREPARATION OF AMIDINES The present invention relates to a novel process for preparing amidines. Amidines can be prepared by various routes. One of the best-treated methods is the Pinner reaction followed by ammonolysis of the iminocarboxylester (Ber. 18, - (1885) 2845). A disadvantage of this method is the two-step reaction. As a general rule, a large excess of hydrogen chloride is used, which eventually gives rise to large amounts of concomitant salts and can sometimes cause separation problems. Finally, reaction times in this sequence of reactions are relatively long and conversions and yields are only moderate. In a manner similar to the Pinner reaction, mercaptans can be used as auxiliary reagents to prepare amidines (R.C. Schnur, J. Org. Chem. 44, (1979) 3726). A variant of this synthesis is the addition of hydrogen sulfide to the nitriles to give thiocarboxamides, followed by sulfur alkylation and ammonolysis (H. Rappoport, J. Org. Chem. 46, (1981) 2455. M. Ohno, Tetrahedron Lett. (1979) 2517). In all these cases, extremely malodorous and highly toxic compounds have been handled. For the alkylation, methyl iodide or dimethyl sulfate is usually used. Both chemicals have been shown to be potent carcinogens. The ammonia can be added directly under pressure in liquid ammonia to the heteroaomatic or aromatic nitriles, but, this requires prolonged reaction times (16 h) and only gives poor yields of the product (40%) (PC Srivastava, J. Med. Chem 27. (1984) 266). The amidines can also be synthesized from nitriles by reaction with hydroxylamine and the reductive dissociation of the intermediary carboxamide oximes (H. Jendralla, Tetrahedron 51, (1995) 12047). The reductive dissociation, however, considerably limits the nitrile substitution pattern. The double bonds or nitro groups in the same way are easily hydrogenated. The protecting groups, for example the benzyl group, can also be easily dissociated. In 1986, A. Eschenmoser published an amidine synthesis catalyzed by cysteine (Helv. Chim. Acta 69, (1986) 1224). However, the experimental examination of this synthesis showed the yield only of approximately 58O. The simplest synthesis of amidines is the direct addition of ammonia to nitriles. Studies with substituted nitriles showed, however, that there is limited conversion even under pressure and that the yield of amidine is therefore correspondingly low.

An object of the present invention is to develop a simple method by which it is possible to convert even nitriles having complicated substitution patterns, which can not be used by conventional amidine syntheses, in the corresponding amidines. We have found that this objective is achieved by a process to prepare amidines and their salts with inorganic or organic acids, which consists in the reaction of the corresponding nitrile with ammonia, a Ci-C alkylamine or hydrazine in the presence of a mercaptocarboxylic acid which it carries, in addition to the SH and COOH groups, no other reactive group under the reaction conditions, and in the presence or absence of an inorganic or organic ammonium salt. By this process, almost all the amidines of the formula I R-C (NHR ') = NH (I) where R is an aliphatic, aromatic or heterocyclic radical and R 'is a hydrogen atom, an alkyl radical of Ci-C or an amino group, can be prepared. In formula I, R can be a benzene derivative, for example phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, o-chloro-phenyl, m-chlorophenyl, p-chlorophenyl, o-nitrophenyl, m-nitrophenyl , p-nitrophenyl, o-methoxyphenyl, m-methoxyphenyl or p-methoxyphenyl.

R may also be a heterocyclic system, in particular a pyridine derivative, pyrimidine, thiophene, furan, pyrrole, isoxazole, 1,2-oxadiazole, pyrroline or pyrrolidine, for example pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, isoxazol-3-yl, 1, 2, -oxadiazol-3-yl, pyrimidin-2-yl, pyrimidin-4-yl or thiophen-2-yl. Of the mentioned rings, the pyridine ring is preferred, in particular when it is substituted in the 2-position by a cyano group. Preference is also given to the isoxazole ring with a cyano function in the 3-position and the 1,2,4-oxadiazole ring with a cyano function in the 3-position. Finally, R can also be an oligopeptide structure consisting of up to 12 natural amino acids, the corresponding D-amino acids or compounds that are very similar to natural amino acids. Specifically, these are the following amino acids: glycine, alanine, phenylalanine, proline, valine, 2,3-, 3,4- or 4,5-dihydroproline, cyclohexylalanine. The process is of very special interest for preparing the newly published thrombin inhibitors bearing an amidine radical, which are mentioned for example in patent applications WO 94/29335, WO 94/29336, WO 95/23609, EP 669,317 and WO 95/35309. Most of these have the following structure: where X is the radical of a substituted or unsubstituted amino acid, preferably proline or dihydroproline, and A is the radical: where Y and Z are CH or NH groups. The asymmetric centers in the compounds of the formula I do not interfere with the reaction and remain unaffected by the reaction. The reaction is carried out in an inert solvent, preferably in solvents in which the solubility of ammonia at 0 ° C and 1 bar is greater than 2% by weight. These solvents are in particular alcohols such as methanol and ethanol. The same considerations are applicable for the use of amines and hydrazine. The reaction is generally carried out at a temperature in the range from -10 to 200 ° C and at a pressure in the range of 1 to 20 bar. Preference is given to the boiling point of the reaction mixture and 1 bar. The reaction is very particularly preferably carried out at autogenous pressure. Performing the reaction without using superatmospheric pressure requires occasional resaturation with ammonia or amines. The reaction can be carried out in the presence of an ammonium salt. This usually produces the amidinia salts. corresponding. If an ammonium salt is used, it will be the salt of an acid that is stronger than the mercaptocarboxylic acid used. Specifically, these salts of hydrohalic acids (in particular hydrochloric acids), sulfuric acid, phosphoric acid, nitric acid and carboxylic acids of C] -,. However, preferably the reaction is carried out in the absence of an ammonium salt. In this case, the reaction product is the amidinium salt of the akddak mercaptocarboxylic acid. In addition to the catalytic effect, mercaptocarboxylic acid also exerts a stabilized action on amidine. In the reaction, the mercaptocarboxylic acid is generally used in a cation from 0.05 to 5 mol, preferably approximately 1 mol per mol of nitrile. A specific advantage of mercaptocarboxylic acids is that they have little, if any, odor, while the processes described in the literature often require malodorous and highly toxic substances.

Suitable mercaptocarboxylic acids are those which carry no other reactive group in addition to the SH and COOH groups. These are, in particular, those of the formula HS-R '-COOH where R' is an alkylene radical of d - and where the hydrocarbon chain contains up to 3 rings and can be substituted or interrupted by heteroatoms which are inert under the reaction conditions, such as nitrogen and oxygen, preferably, R 'is an alkylene radical of Ci- ,; or a phenylene group which may be mono- or disubstituted by the following radicals: methyl, methoxy, ethoxy, n-propoxy, i-propoxy, C? - alkylamino, C? -6 dialkylamino, halogen, nitro. Specifically, these are mercaptoacetic acid, α- and β-mercaptopropionic acid, N-acetylated aminothiocarboxylic acids - such as N-acetylated cysteines, mercaptoalkyleneprolines such as N- (3-mercaptopropyl) proline, ercaptoalkanoylprolines such as N- (3-mercaptopropionyl) proline. , or cyclic thiocarboxylic acids such as ercaptobenzoic acid. Captopril and acetyl cysteine have proven to be particularly advantageous for the process. In general, the reaction is terminated in the customary manner when no more nitrile can be detected (eg by GC, HPLC, TLC) in the reaction mixture. The treatment to isolate the product is usually carried out by conventional methods, such as by distillation, filtration, centrifugation or extraction. The process according to the invention can be carried out in the form of batches, for example in a tank reactor with agitation. The simplicity of the process has the advantage that it can be adapted for continuous operation, for example by using a tubular reactor or a cascade of tank reactors with agitation. The stereochemistry of mercaptocarboxylic acids is not important with respect to their effectiveness in the claimed reaction. The raw products obtained can, if desired, be further purified, for example by crystallization, extraction or chromatography. Surprisingly, it has been found that, when carrying out the process according to the invention, undesirable side reactions are not carried out and that the conversion is quantitative if mercaptocarboxylic acids are used.

Example 1: Synthesis of (S) - (3, 4, -dihydroprolyl (6-amidino-3-picolinyl) amide using N-acetyl- (S) -cysteine as a catalyst 2.63 g (10 mmol) of hydrochloride (S) ) - (3,4-dihydroproline (6-cyano-3-picolinyl) amide together with 1.79 g (11 mmol) of N-acetyl- (S) -cysteine were initially charged in 10 ml of methanol. , the reaction mixture was saturated with ammonia After 2 hours, no more initial material could be detected by thin layer chromatography The reaction mixture was concentrated using a rotary evaporator 4.7 g of an almost colorless solid containing 70.5% of the desired product was obtained: MP: 66 ° C, iJC, NMR [sic] (CDCl ,, ppm): 162.1 (amidine).

Example 2: Synthesis of N- ((t-butoxycarbonyl) methylene) - (R) -cyclohexylalanyl- (S) -prolin (6-amidino-3-picolinyl) amide using N-acetyl- (S) -cysteine as a catalyst. 50 g (105 mmol) of N- ((t-butoxycarbonyl) methylene) - (R) -cyclohexylalanyl- (S) -prolyl (6-amidino-3-picolinyl) amide together with 17.7 g (109 mmol) of N- acetyl- (S) -cysteine were initially charged in 50 ml of methanol. At 65 ° C, the reaction mixture was saturated with ammonia. After 4 hours, no more initial material could be detected by thin layer chromatography. The reaction mixture was concentrated using a rotary evaporator. 70.3 g of an almost colorless solid containing 75.3% of N - ((t-butoxycarbonyl) methylene) - (R) -cyclohexylalanyl- (S) -prolin (6-amidino-3-picolinyl) amide were obtained, 3C-NMR (CDCl ,, ppm): 162.3 (amidine).

Example 3: Synthesis of N-Boc-N- ((t-butoxycarbonyl) methylene) - (R) -cyclohexylalanyl- (S) -3,4-dihydroproline (6-amidino-3-picolinyl) amide using N-acetyl- (S) -Cysteine as a catalyst. 124.3 g (105 mmol) of N-Boc-N- ((t-butoxycarbonyl) methylene) - (R) -cyclohexylalayl- (S) -3,4-dihydroproline (6-cyano-3-picolinyl) amide together with 35.5 g (218 mmol) of N-acetyl- (S) -cysteine were initially charged in 400 ml of methanol. At 65 ° C, the reaction mixture was saturated with ammonia. After 6.5 hours, no more initial material could be detected by thin layer chromatography. The reaction mixture was concentrated using a rotary evaporator. 165.2 g of an almost colorless solid containing 81.6% of N-Boc-N- ((t-butoxycarbonyl) methylene) - (R) -cyclohexylalanyl- (S) -3,4-dihydroproline (6-amidino-3-picolinyl) ) amide were obtained, mp: 91-118 ° C (decomposition). MS (El): 612.4 g / mol).

Example 4: Synthesis of N- ((t-butoxycarbonyl) methylene) - (R) -cyclohexylalanyl- (S) - (3,4-dihydroproline (6-amidino-3-picolinyl) amide using N-acetyl- (S) -Cysteine as catalyst: 2.5 g (5 mmol) of N- ((t-butoxycarbonyl) methylene) - (R) -cyclohexylalayl- (S) -3,4-dihydroproline (6-cyano-3-picolinyl) amide together with 0.89 g (5.5 mmol) of N-acetyl- (S) -cysteine were initially charged in 6 ml of methanol.At 65 ° C, the reaction mixture was saturated with ammonia.After 5 hours, no more initial material could be added. detected by thin layer chromatography The reaction mixture was concentrated using a rotary evaporator 3.3 g of an almost colorless solid containing 73.6% N- ((t-butoxycarbonyl) methylene) - (R) -cyclohexylalanyl- (S) ) -3,4-dihydroproline (6-amidino-3-picolinyl) amide were obtained.

Example 5: Synthesis of N- ((t-butoxycarbonyl) methylene) -. { R) -cyclohexylalanyl- (S) -prolin (6-amidino-3-picolinyl) amide using mercaptoacetic acid as catalyst 5 g (10.5 mmol) of N- ((t-butoxycarbonyl) methylene) - (R) -cyclohexylalanyl- ( S) -proline (6-cyano-3-picolinyl) amide together with 1.1 g (12 mmol) of mercaptoacetic acid were initially charged in 10 ml of methanol. At 25 ° C, the reaction mixture was saturated with ammonia. After 4 hours, no more initial material could be detected by thin layer chromatography. The reaction mixture was concentrated using a rotary evaporator. 6.3 g of a green solid containing 70% of N - ((t-butoxycarbonyl) methylene) - (R) -cyclohexylalanyl- (S) -prolin (6-amidino-3-picolinyl) amide were obtained.

• Example 6: Synthesis of N-Boc-N- ((t-butoxycarbonyl) methylene) - (R) -cyclohexylalanyl- (S) -3,4-dihydroproline (6-amidino-3-picolinyl) amide using N- ((R) -3-mercaptoisobutaniol) - (S) -proline (captopril) as a catalyst. 3 g (5 mmol) of N-Boc-N- ((t-butoxycarbonyl) methylene) - (R) -cyclohexylalanyl- (S) -3,4-dihydroproline (6-cyano-3-picolinyl) amide together with 1.21 g (5.5 mmol) of N - ((R) -3-mercaptoisobutaniol) - (S) -proline were initially charged in 8 ml of methanol. At 65 ° C, the reaction mixture was saturated with ammonia. After 4 hours, no more initial material could be detected by thin layer chromatography. The reaction mixture was concentrated using a rotary evaporator. 4.1 g of an almost colorless solid containing 54.9% of N-Boc-N- ((t-butoxycarbonyl) methylene) - (R) -cyclohexylalanyl- (S) - (3,4-dihydroproline (6-amidino-3-) picolinyl) amide were obtained, MS (El): 612.4 g / mol). 13 C-NMR (CDCl ,, ppm): 162.1 (amidine).

Example 7: Synthesis of Boc- (R) -cyclohexylalanyl- (S) -prolin (6-amidino-3-picolinyl) amide using N-acetyl- (S) -cysteine as catalyst 5 g (10.5 mmol) of Boc- ( R) -cyclohexylalanyl- (S) -prolin (6-cyano-3-picolinyl) amide together with 1.7 g (10.5 mmol) of N-acetyl- (S) -cysteine were initially charged in 20 ml of methanol. At 65 ° C, the reaction mixture was saturated with ammonia. After 5 hours, no further starting material could be detected by thin layer chromatography. After stirring overnight, the reaction mixture was concentrated using a rotary evaporator. 7 g of an almost colorless solid containing 78.3% of Boc- (R) -cyclohexylalanyl- (S) - (prolin (6-amidino-3-picolinyl) amide were obtained, 13C-NMR (CDC13, ppm): 162.3 ( amidine).

The following compounds were synthesized by the method of Example 1: Example 8: N- (1,3-dihydroxypropan-2-yl) - (R) -cyclohexylglycyl- (S) -prolin (6-amidino-3-picolinyl) amide . 13 C-NMR (DMSO, ppm): d-162.3 (amidine), FAB-MS: (M + H) * -461.

Example 9: N-Boc-N- ((t-butoxycarbonyl) ethylene) - (R> -cyclohexylalanyl- (S) -prol (6-amidino-3-picolinyl) amide 13C-NMR (DMSO, ppm): d = 161.9 (amidine), FAB-MS: (M + H) '-629.

Example 10: N-Boc-N- ((t-butoxycarbonyl) methylene) - (R) cyclohexylalanyl-l-aminociclopropan-1- (6-amidino-3-picolinyl) carboxamide 13C-NMR (DMSO, ppm): d = 162.2 (amidine), FAB-MS: (M + H) '-601.5.

Example 11: N- (6-Amidinopyridin-3-ylmethyl) -2- (2-oxo-3-phenyl-methanesulfonylaminopyrrolidin-1-yl) acetamide FAB-MS: (M + H) * - 445.

Example 12: N [(t-butoxycarbonyl) ethylene] -N-Boc- (R) -cyclohexylalanyl- (S) -N-methylalanin (6-amidino-3-picolinyl) amide FAB-MS: (M + H) ' - 603 Example 13: N [(t-Butoxycarbonyl) ethylene] -N-benzylglycyl- (S) -3,4-dihydroproline (6-amidino-3-picolinyl) amide FAB-MS: (M + H) + -507.

Example 14: N-Boc-N- [(butoxycarbonyl) methylene] - (R) cyclohexylalanyl- (S) - (3,4-dihydroproline (6- (N-methyl) amidino-3-picolylnyl) amide FAB-MS: (M + H) * »626.6.

Example 15: N-Boc-N- [(t-butoxycarbonyl) methylene] - (R) cyclohexylalanyl- (S) - (3,4-dihydroproline (6- (N-amino) amidino-3-picolinyl) amide [sic] ] FAB-MS: (M + H) '= 627.6.

Example 16: N-Boc-N- [(t-butoxycarbonyl) methylene] - (R) cyclohexylalanyl (4,4-dimethyl) prolin (6-amidino-3-picolinyl) amide FAB-MS: (M + H) t - 642.7.

Example 17: N-Boc-N- [(t-butoxycarbonyl) methylene] - (R) -cyclohexylalanyl- (S) - (3,4-dihydroproline (3-amidinoisoxazol-5-yl) methylamide [sic] FAB-MS : (M + H) + - 602.7.

Example 18: 3-a? T? Idino-5-N-Boc-aminomethyl-l, 2,4-oxadiazole FAB-MS: (M + H) + -242.

Example 19: 3- (2-trifluoromethylbenzyl) benzoyl- (5) -3,4-dihydroproline (6-amidino-3-picolinyl) amide acetate white crystals, m.p. 188-191 ° C, FAB-MS: (M + H) + -508.

Example 20: 9-Hydroxyfluorenyl-9-carboxy (S) -3,4-dihydroproline (6-amidino-3-picolinyl) amide acetate white crystals, m.p. 181-185 ° C (decomposition), FAB-MS: (M + H) + - 454.

Example 21: N-methylsulfonyl- (R) -cyclohexylalanyl- (S) -dihydroproline (6-amidino-3-picolinyl) amide acetate white crystals, m.p. 175-176 ° C, FAB-MS: (M + H) + - 477.

Comparative example with ammonia without catalyst In a 300 ml autoclave, 10 g (21 mmol) of Boc- (R) -cyclohexylalanyl- (S) prolin- (6-cyano-3-picolinyl) amide and 2.25 g (42 mmol) of aluminum chloride in 100 ml of methanol together with 60 ml of liquid ammonia were initially charged and adjusted to an internal pressure of 40 bar by applying pressurized nitrogen. After a reaction time of 100 h at 30 ° C, the reaction mixture was concentrated using a rotary evaporator. By HPLC, the yield of Boc- (R) -cyclohexylalanyl- (S) prolin- (6-amidino-3-picolinyl) mide was only 48.5%.

Comparative example using cysteine as a catalyst. 10 g (21 mmol) of Boc- (R) -cyclohexylalanyl- (S) -prolol (6-cyano-3-picolinyl) amide together with 2.25 g of ammonium chloride and 2.54 g (21 mmol) of (S) - cysteine were initially loaded in 100 ml of methanol. At 20-30 ° C, the reaction mixture was saturated with ammonia. After 1.5 hours, no more initial material could be detected by thin layer chromatography. After stirring overnight, the reaction mixture was concentrated using a rotary evaporator. 15 g of an almost colorless solid containing 40% Boc- (R) -cyclohexylalanyl- (S) -prolin (6-amidino-3-picolinyl) amide by HPLC were obtained.

Claims (2)

1. A process for preparing amidines and their salts with inorganic or organic acids, which consists of the reaction of the corresponding nitrile with ammonia, an alkylamine of Cj, -C or hydrazine in the presence of a mercaptocarboxylic acid which bears, in addition to the SH and COOH groups , no other group reactive under the reaction conditions, and in the presence or absence of an inorganic or organic ammonium salt.

2. The process as mentioned in claim 1, wherein the process is carried out in the absence of an ammonium salt.