HU212427B - Process for producing dl-, d- and l-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acids and their derivatives containing urethane-type n-protecting groups - Google Patents

Abstract

The invention relates to new L- and D-1,2,3,4-tetrahydro-isoquinoline-1-carboxylic acids and their derivatives containing urethane-type N-protecting groups of the formula: R-O-CO, wherein R represents a linear or branched C1-6 alkyl group; a benzyl group optionally substituted with one or more halogen atoms, nitro, methyl or methoxy groups; a picolyl group or a 9-fluorenylmethyl group, and their salts, furthermore to a process for preparing these compounds and the corresponding racemates, which comprises condensing glyoxylic acid hydrate and 2-phenethylamine with an N-protecting group of the general formula: R'-O-CO, wherein R' represents a linear or branched C1-3 alkyl group; a benzyl group optionally substituted with one or more halogen atoms or nitro groups; a picolyl group or a 9-fluorenylmethyl group in trifluoroacetic acid or in a halogenated hydrocarbon containing trifluoroacetic acid.

Description

The present invention relates to a process for the preparation of the known DL- and novel L- and D-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acids and R-O-CO

R is a C 1-3 alkyl group, a C 4-6 tertiary alkyl group, a benzyl group or a 9-fluorenylmethyl group, for the preparation of urethane-protected protecting groups.

During the synthesis of biologically active peptides, it has been observed that the incorporation of structural elements that reduce the flexibility of molecules often leads to an analogue with enhanced biological activity and / or metabolic stability [e.g. V. J. Hruby, Life Sci., 31, 189-199 (1982)]. Such a structural element may be an amino acid analogue having a fixed amino acid residue, e.g. 1,2,3,4-tetrahydro-P-carboline-3-carboxylic acid which is substituted for tryptophan [J. Singh and B. A. Morgan, No. 4,839,465; U.S. Patent (1989)] and 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid to replace phenylalanine [W. Kazmierski et al., J. Med. Chem. 31, 2170-2177 (1988). In these compounds, the original amino acid side chain, the 3-indolylmethyl and the phenylalanine benzyl group of tryptophan, is attached to the α-amino group by a methylene bridge. D- or L-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid and D- or L-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid are readily prepared in the literature from tryptophan [K. Lipke, P., et al., J. Med. Chem. 26: 499-503 (1983); J. Singh and B. A. Morgan, U.S. Pat. No. 4,839,465. (U.S. Patent No. 1989) and phenylalanine [A. Pictet and T. Spengler, Wages. 44, 2030-2036 (1911); H. Shinkai et al., J. Med. Chem. 31, 2092-2097 (1988)] with formalin.

1,2,3,4-Tetrahydroisoquinoline-1-carboxylic acid, a fixed side chain analogue of phenylalanine-related phenylglycine, is also useful in the construction of biologically active peptides [R. T. Shuman et al., "A Series of Highly Selective Thrombin Inhibitors," Lecture at the 12th American Peptide Symposium, Boston, USA, June 16-21, 1991, Abstract no. 495].

The only method known for the synthesis of DL-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid is the hydrogenation of isoquinoline-1-carboxylic acid with Adams' catalyst (W. Solomon, J. Chem. Soc. 1947, 129). 65% yield. There is no known procedure in the literature for the resolution of DL-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid.

It is reported in the textbook that 1,2,3,4-tetrahydroisoquinoline and its derivatives can be prepared by the so-called. By Pictet-Spengler synthesis, condensation of 2-phenyl-1-aminoalkanes and aldehydes in hydrochloric acid. For example, 1,2,3,4-tetrahydroisoquinoline was prepared in 36% reaction with (2-phenylethyl) amine and formaldehyde. [THE. Pictet and T. Spengler, Wages. 44, 2030-2036 (1911)]. If the phenyl group contains a suitable substituent, e.g. 3-hydroxy or methoxy group, the condensation results in a better result [J. S. Buck, J. Am. Chem. Soc. 56, 1769-1771 (1934)]. For example, the reaction of 2- (3,4-dihydroxyphenyl) ethylamine with acetaldehyde gives 83% yield of 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline [C.

Schöpf and H. Bayerle, Ann 513, 190-202 (1934)]. However, in the reaction of glyoxylic acid hydrate with 2- (3,4-dimethoxyphenyl) ethylamine only max. 20% formed 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid; no synthesis of 1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid analog, condensation of glyoxylic acid hydrate and (2-phenylethyl) amine has been attempted [F. M. Hershenson: J. Org. Chem. 40, 740-743 (1975)].

SUMMARY OF THE INVENTION It is an object of the present invention to provide a simple, economical process for DL-, D-, and L-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid and an RC-CO group on the N-atom thereof, containing derivatives thereof.

Surprisingly, it has been found that condensation of (2-phenylethyl) amine and glyoxylic acid hydrate can be achieved in good yields if (2-phenylethyl) amine is protected with a urethane protecting group, e.g. with a benzyloxycarbonyl group or an acyl derivative thereof with a 9-fluorenylmethyloxycarbonyl group and the reaction in a trifluoroacetic acid or a chlorinated hydrocarbon containing trifluoroacetic acid, e.g. in methylene chloride, optionally in the presence of trifluoroacetic anhydride, at a temperature between 0 and 10 ° C. The resulting N-protected, e.g. The N-benzyloxycarbonyl-DL1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid is deprotected to yield the desired DL-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid.

It has further been found that N-benzyloxycarbonyl-DL-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid is readily resolved in 0.475-0.5 equivalents of D-threo-2-amino-1- ( 4-nitrophenyl) -1,3-propanediol ([.alpha.] D @ 20 = -28.8 DEG, c = 5.1 N HCl) in benzene solution. From the solution crystallizes from the diastereomeric salt, the D-enantiomer and the L-enantiomer can be separated from the mother liquor benzene. The N-benzyloxycarbonyl-DL-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid can be resolved in an analogous manner to the antipode of the above base, L-threo-2-amino-1- (4-nitrophenyl) ) -1,3 propanediol ([α] ^ * = + 30, Γ, c = 5, 1 N HCl), which is a by-product of chloramphenicol production. In this case, the L-crystallization salt and the D-enantiomer can be separated from the crystallising diastereomeric salt. The N-protected compounds give the free L- and D-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acids in a known manner, which can also be converted into other N-protected derivatives, e.g. N- (tert-butoxycarbonyl) -L- and -D-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid, which may be deprotected by acidolysis, e.g. 30-100% trifluoroacetic acid.

SUMMARY OF THE INVENTION The present invention relates to a process for the preparation of DL as well as L and D1, 2,3,4-tetrahydroisoquinoline-1-carboxylic acid and RO-CO at the N atom where R is a C 1-3 alkyl, C 4-6 tertiary. -alkyl, benzyl or 9-fluorenylmethyl derivatives containing a urethane-protecting group, and salts thereof, characterized in that glyoxylic acid hydrate and its N-atom have the formula R'-O-CO

R 'is C 1-3 alkyl, benzyl or 9-fluorenylmethyl 2

The condensed (2-phenylethyl) amine is condensed in trifluoroacetic acid or in a halogenated hydrocarbon containing trifluoroacetic acid, optionally in the presence of (trifluoroacetic) anhydride, to form the N- (R'-O-CO) - DL-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid, where R 'is as defined above, is optionally converted into a salt, the resulting acid or salt is optionally resolved and / or the N-protecting group is cleaved in a manner known per se. The L-, D-, or DL-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid is isolated and optionally acylated at its N atom to form an RO-CO

R is a tertiary alkyl group having from 4 to 6 carbon atoms and the resulting L-, D- or DL-1,2,3,4-tetrahydroisoquinoline-carboxylic acid having the acid-sensitive N-protecting group R-OCO is desired. case.

In a preferred embodiment of the process of the invention, N-benzyloxycarbonyl (2-phenylethyl) amine, glyoxylic acid hydrate and (trifluoroacetic acid) anhydride are reacted in a 1: 1: 1 molar ratio of trifluoro in acetic acid at 0 to 10 ° C for 3 hours. The reaction mixture was diluted with water and extracted with benzene. The product is extracted from the benzene solution with 10% ammonium hydroxide, the solution is acidified with a saturated potassium bisulfate solution and extracted with benzene. The benzene solution was evaporated after washing with water and drying over sodium sulfate and crystallizing the N- (benzyloxycarbonyl) -DL-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid as the cyclohexylammonium salt from diethyl ether. separated. If desired, N-benzyloxycarbonyl-DL-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid is liberated from the resulting salt with 1M potassium bisulfate and the protecting group in 80% aqueous acetic acid, hydrogenation in the presence of palladium catalyst. After filtration of the catalyst, the solution is evaporated and the expected DL-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid is isolated after crystallization from ethanol-water. Alternatively, the N- (benzyloxycarbonyl) -DL-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid liberated from the cyclohexylamine salt is dissolved in benzene and 0.5 equivalent of D-threo-2-amino-1 - (4-Nitrophenyl) -1,3-propanediol was added and allowed to stand for 5-10 hours. The precipitated diastereomeric salt was filtered off and washed with benzene. The benzene mother liquor was combined with the benzene washer, washed with water, dried rapidly over sodium sulfate and then concentrated under reduced pressure to ca. It is evaporated to 2/3 and allowed to stand at 5-10 for 5-10 hours. The precipitated crystalline N- (benzyloxycarbonyl) -L-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid is isolated. The diastereomeric salt was dissolved in ethyl acetate and 1M potassium bisulfate, and the ethyl acetate portion was washed with water and dried over sodium sulfate. The residue is N-benzyloxycarbonyl-D-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid which is isolated after crystallization from benzene. Optionally, the N-benzyloxycarbonyl-D- and / or -L-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid is deprotected by known methods, hydrogenolysis or acidolysis, and the D- and / or D-groups are removed. The L-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid is isolated after crystallization from aqueous ethanol.

In another preferred embodiment of the process of the invention, N- (9-fluorenylmethoxycarbonyl) -2-phenylethylamine, glyoxylic acid hydrate and (trifluoroacetic acid) anhydride are reacted in a 1: 1: 1 molar ratio. in trifluoroacetic acid at 0 to 10 ° C for 3 hours. The reaction mixture was diluted with water and extracted with benzene. The benzene solutions were combined, washed with water to neutral and then dried over sodium sulfate. The resulting N- (9-fluorenylmethoxycarbonyl) -DL-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid is isolated after crystallization from diethyl ether.

In a further preferred embodiment of the process according to the invention, the racemic and / or phenolic compounds obtained in the phenyls are obtained. D- and L-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid are reacted with di- (tert-butyl) dicarbonate in a mixture of tert-butanol-water in the presence of triethylamine and the resulting racemic or D- and L- (tert-butoxycarbonyl) -1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid is isolated as a cyclohexylammonium salt after crystallization from diethyl ether.

The (2-phenylethyl) amine protecting group represented by the formula R'-O-CO-, wherein R 'is as defined above, used as starting material in the process of the invention is a novel compound, the preparation of which is illustrated in the Examples in.

The process of the present invention provides a novel, simple and economical process for the preparation of the known DL and the novel D- and L1, 2,3,4-tetrahydroisoquinoline-1-carboxylic acids and their N-atoms in the formula RO-CO new derivatives of the above-protected urethane type, e.g. for the synthesis of N-benzyloxycarbonyl, Ν-9-fluorenylmethoxycarbonyl and N-tert-butoxycarbonyl. Derivatives containing a N-protecting group are suitable for incorporation of DL, D-, and L-1,2,3,4-tetrahydroisoquinoline-carboxylic acid into a peptide chain using various combinations of protecting groups.

Generally, three types of protecting group combinations are used in the synthesis of peptides:

a) The side chains are provided with groups derived from tert-butanol, i.e. tert-butyl ester, tert-butyl ether and the like. Ω-Ν-tert-butoxycarbonyl group; and α-amino groups can be removed by hydrogenolysis, e.g. benzyloxycarbonyl. In this case, N-benzyloxycarbonyl-DL, -D- or -L-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid may be used.

(b) The side-chains have the same protection as in (a); the α-amino groups are protected by a base, e.g. Protected by 9-fluorenylmethoxycarbonyl. In this case, N- (9-fluorenylmethoxycarbonyl) -DL-, -D- or -L-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid may be used.

c) The side chains are provided with groups derived from benzyl alcohol, i.e., benzyl ester, benzyl ether, and the like.

HU 212 427 Β

Ω-Ν-benzyloxy-carbonyl group; and the α-amino group with a highly acid-sensitive protecting group, e.g. protected by tert-butoxycarbonyl. In this case, N- (tert-butoxycarbonyl) -DL-, -D or -L-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid may be used.

The invention is illustrated by the following non-limiting examples.

The R values given in the examples were determined by layer chromatography on silica gel (DC-Alufolien Kieselgel 60 F254, Merck, Darmstadt) in the following solvents:

1. chloroform-methanol (98: 2)

2. (ethyl acetate-pyridine-acetic acid-water (30: 20: 6: 11)

3. (ethyl acetate) pyridine-acetic acid-water (480: 20: 6: 11)

Example 1

Preparation of cyclohexylammonium salt of N-benzyloxycarbonyl-DL-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid

18.4 g (0.2 mol) of glyoxylic acid hydrate are dissolved in 100 ml of trifluoroacetic acid with stirring. The solution was cooled to 0-5 ° C and added

51.6 g (0.2 mol) of N-benzyloxycarbonyl-2-phenylethylamine and, after dissolution, 27.8 ml (0.2 mol) of trifluoroacetic anhydride. The reaction mixture was stirred for 0.5 hours at 0 to 5 ° C and for 3 hours at room temperature. The reaction mixture was diluted with water (150 mL) and extracted with benzene (3 x 50 mL). The benzene solutions were combined, washed with water (3 x 20 mL) and extracted with 12% ammonium hydroxide (2 x 50 mL). The ammonium hydroxide solutions were combined, acidified to pH 3 with saturated potassium hydrogen sulfate solution and extracted with 3 x 30 benzene. The benzene solutions were combined, washed with water to neutral (3-4 x 20 mL), dried over anhydrous sodium sulfate, and pressurized to 20-25 mbar. Evaporate from a 40 'C bath. The residue was dissolved in diethyl ether (400 mL), cyclohexylamine (23 mL, 0.201 mol) was added and allowed to stand overnight at room temperature. The precipitated crystals are filtered off, washed with diethyl ether and dried in a vacuum desiccator. 66 g (80.5%) of the title product are obtained.

Rf (3) = 0.70-0.74 (and cyclohexylamine: 0.0). Mp: 155-160'C.

Analysis for C ₂₄ H ₃₀ N ₂ O ₄ (410.60):

Calculated: C, 70.20; H, 7.60; N, 6.82.

Found: C, 70.0; H, 7.4; N, 6.6.

The starting material of this example, N-benzyloxycarbonyl-2-phenylethylamine, is prepared, for example, as follows.

Dissolve 2-phenylethylamine (50.6 mL, 0.4 mol) in chloroform (1000 mL) and sodium bicarbonate (33.7 g, 0.4 mol) in water (240 mL). The solutions were combined, cooled to about 5 ° C, and at this temperature, 75 ml (0.44 mol) of benzyloxycarbonyl chloride and 37.05 g (0.44 mol) in water (300 ml) were added dropwise with vigorous stirring. sodium bicarbonate so that the pH of the reaction mixture is above 7. Stirring is continued for half an hour at about 5 ° C and for one hour at room temperature, and the phases are separated. The aqueous phase is extracted with 30 ml of chloroform, which is added to the chloroform phase. The chloroform solution was first extracted with 40 ml of 1 M hydrochloric acid, then washed with water to neutral, dried over anhydrous sodium sulfate and pressurized to 20-25 millibar. Evaporate from a 40 'C bath. The residue is crystallized with 200 ml of n-hexane, the crystals are filtered off, washed with n-hexane and air dried. 86 g (84%) of the title compound are obtained.

RX3) = 0.88-0.92. Mp: 60 'C.

Analysis for C ₁₆ H ₁₇ NO ₂ (255.30):

Found: C, 75.27; H, 6.71; N, 5.49.

Found: C, 75.4; H, 6.7; N, 5.3.

Example 2

Preparation of N-benzyloxycarbonyl-DL-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid cyclohexylammonium salt

Glyoxylic acid hydrate (0.46 g, 5 mmol) was dissolved in methylene chloride (50 mL, 50% trifluoroacetic acid) with stirring. The solution was cooled to 0-5 ° C, N-benzyloxycarbonyl-2-phenylethylamine (1.26 g, 5 mmol) was added and, after dissolution, 0.69 mL (5 mmol) was added. trifluoroacetic acid) anhydride. The reaction mixture was stirred for 0.5 hours at 0 to 5 ° C and for 3 hours at room temperature. The reaction mixture was then diluted with water (20 mL) and extracted with methylene chloride (3 x 10 mL). The methylene chloride solutions were combined, washed with water (3 x 5 mL) and extracted with 12 mL of 12% ammonium hydroxide (2 x 5 mL). The ammonium hydroxide solutions were combined, acidified to pH 3 with saturated potassium bisulfate and extracted with 3 x 5 mL of methylene chloride. The methylene chloride solutions were combined, washed neutral with water, dried over anhydrous sodium sulfate, and pressurized to 20-25 millibar. Evaporate from a bath at 40 ° C. The residue was dissolved in diethyl ether (20 mL), cyclohexylamine (0.6 mL, 5.4 mmol) was added and the mixture was allowed to stand overnight at room temperature. The precipitated crystals are filtered off, washed with diethyl ether and dried in a vacuum desiccator.

1.63 g (80%) of the title product of the same quality as in Example 1 are obtained.

Example 3

Preparation of cyclohexylammonium salt of N-methoxycarbonyl-DL-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid

N-Methoxycarbonyl-2-phenylethylamine (3.58 g, 20 mmol) and glyoxylic acid hydrate (1.84 g, 20 mmol) were condensed as described in Example 1 using proportional reagents and solvents. except that the cyclohexylammonium salt is separated from diisopropyl ether. 5 g (75%) of the title product are obtained.

Rf (3) = 0.44-0.48 (and cyclohexylamine: 0.0). Mp 141-144'C.

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Analysis for C ₁₈ H ₂₆ N ₂ O ₄ (334.40):

Found: C, 64.65; H, 7.84; N, 8.38. Found: C, 64.5; H, 8.0; N, 8.15.

For example, the N-methoxycarbonyl-2-phenylethylamine starting material of this example can be prepared as follows.

Dissolve (2-phenylethyl) amine (5.31 g, 42 mmol) in chloroform (100 mL) and sodium bicarbonate (3.37 g, 40 mmol) in water (24 mL). The solutions were combined, cooled to about 5 ° C, and added dropwise at this temperature with vigorous stirring.

Methoxycarbonyl chloride (3.4 mL, 44 mmol) and sodium bicarbonate (3.7 g, 44 mmol) in water (30 mL) were added so that the pH of the reaction mixture was above 7. Stirring is continued for half an hour at about 5 ° C and for one hour at room temperature, and the phases are separated. The chloroform phase is first extracted with 40 ml of 1M hydrochloric acid, then washed with water to neutral, dried over anhydrous sodium sulfate and dried at 2025 mbar for max. Evaporate from a bath at 40 ° C. The residue was dissolved in benzene (20 ml) and evaporated. The resulting oily product was 3.6 g Rf (1) = 0.70-0.75; Rf (3) = 0.79-0.84-20 mmol N- (methoxycarbonyl) -2-phenylethylamine and is used directly in the above condensation reaction.

Example 4

Preparation of N- (9-fluorenylmethoxycarbonyl) -DL-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid

Glyoxylic acid hydrate (1.29 g, 14 mmol) was dissolved in trifluoroacetic acid (7 mL) with stirring. The solution was cooled to 0-5 ° C, and N-9-fluorenylmethoxycarbonyl-2-phenylethylamine (4.81 g, 14 mmol) was added and, after dissolution, 1.89 mL (14 mmol) was added. ) (trifluoroacetic acid) anhydride. The reaction mixture was stirred for 0.5 hours at 0 to 5 ° C and for 2 hours at room temperature. The reaction mixture was then diluted with water (15 mL) and extracted with benzene (2 x 10 mL). The benzene solutions were combined, washed with water to neutral, dried over anhydrous sodium sulfate, and pressurized to 20-25 millibar for max. Evaporate from a 40 'C bath. The residue was dissolved in diethyl ether (40 ml) and allowed to stand in the refrigerator for 1-2 days. The activated crystals are filtered off. Wash with 2 x 5 mL diethyl ether and dry in a vacuum desiccator.

3.93 g (70.4%) of the title product are obtained.

RK3) = 0.72-0.75. 156-158 ° C.

Analysis for C ₂₅ H ₂₁ NO ₄ (399.43):

Calculated: C, 75.17; H, 5.30; N, 3.51; Found: C, 75.2; H, 5.4; N, 3.5.

The starting material of this example, N- (9-fluorenylmethoxycarbonyl) -2-phenylethylamine, is prepared, for example, as follows.

(2-Phenylethyl) amine (2.65 mL, 21 mmol) was dissolved in chloroform (50 mL) and 10% sodium carbonate solution (22 mL) was added. The resulting biphasic system was cooled to 0 to 5 ° C and 5.17 g (20 mmol) of 9-fluorenylmethoxycarbonyl chloride was added with vigorous stirring. The reaction mixture was further stirred for 1 hour at room temperature. The phases are separated, the chloroform phase is washed with water to neutral, dried over anhydrous sodium sulfate, and at a pressure of 20-25 millibar max. Evaporate from a 40 'C bath. The residue was crystallized with n-hexane (20 mL), the crystals were filtered off, washed with n-hexane and air dried. 5.83 g (85%) of the title product are obtained.

RX3) = 0.89-0.93. M.p .: 130-131 'C.

Analysis for C ₂₃ H ₂₁ NO ₂ (343.41):

date; C, 80.44; H, 6.16; N, 4.08;

Found: C, 80.3; H, 6.2; N, 4.1.

Example 5

Diastereomeric salt of N- (benzyloxycarbonyl) -DJ, 2,3,4-tetrahydroisoquinoline-1-carboxylic acid D-threo-2-amino-1- (4-nitrophenyl) -1,3-propanediol and Preparation of N- (benzyloxycarbonyl) -L, 2,3,4-tetrahydroisoquinoline-1-carboxylic acid g (80 mmol) of N- (benzyloxycarbonyl) -DL-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid The cyclohexylammonium salt (Examples 1 or 2) was dissolved in 85 mL of 1 M potassium bisulfate and 200 mL of benzene. The benzene solution was washed neutral with water, dried over anhydrous sodium sulfate, and at a pressure of about 20-25 millibar for approx. 40 'C bath approx. Concentrate to 150 ml. To the resulting benzene solution was added D-threo-2-amino-1- (4-nitrophenyl) 1,3-propanediol base (8 g, 37.7 mmol) with stirring. Stirring is continued until the base dissolves or new crystals (diastereomeric salt) appear. The crystal slurry was left in the refrigerator overnight, then filtered and washed with benzene (4 x 30 mL). The benzene washer was combined with the benzene mother liquor ("benzene solution, processing below") and the crystals were dried in a vacuum desiccator with paraffin shavings.

The crystalline product, the title diastereomeric salt, weighed 18.75 g (35.81 mmol, 95%).

Mp: 166-172 ° C. [.alpha.] D @ 20 = -24.9 '(c = 1, in methanol).

Analysis for C ₂₇ H ₂₉ N ₃ O ₈ (523.53):

Calculated: C, 61.94; H, 5.58; N, 8.03; Found: C, 61.9; H, 5.6; N, 8.05.

(See Example 6 for processing of the diastereomeric salt.)

The above benzene solution (about 270 mL) was washed with 2 x 20 mL of 1 M potassium bisulfate, then washed with water to neutral, dried over anhydrous sodium sulfate,

At a pressure of 20-25 millibars, approx. 40 'C bath approx. Concentrate to 150 ml and allow to stand in the refrigerator overnight. The precipitated crystals are filtered off. Wash with 3 x 20 mL benzene and dry in a vacuum desiccator with paraffin chips. 9.05 g (29.1 mmol, 76.9%) of the title L-carboxylic acid are obtained.

Mp: 146-147.5 ° C. [α] D 20 = + 39.1 (c = 1 in methanol).

Analysis for C ₁₈ H ₇ NO ₄ (311.32):

Found: C, 69.44; H, 5.50; N, 4.50;

Found: C, 69.8; H, 5.5; N, 4.6.

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Example 6

Preparation of N-benzyloxycarbonyl-D-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid

15.2 g (29 mmol) of N- (benzyloxycarbonyl) -D1.2.3.4-tetrahydroisoquinoline-1-carboxylic acid D-threo-2-amino-1- (4-nitrophenyl) -1, The diastereomeric salt of 3-propanediol (Example 5) was dissolved in 31 mL of 1 M potassium bisulfate and 100 mL of ethyl acetate. The ethyl acetate solution was washed neutral with water, dried over anhydrous sodium sulfate, and at a pressure of about 20-25 millibar. Evaporate from a 40 'C bath. The residue was distilled off with 2 x 30 ml of benzene. To the more crystalline oil residue was added benzene (50 mL) and allowed to stand at room temperature for 3-4 hours, then filtered, washed with benzene and dried in a vacuum desiccator with paraffin chips. Yield: 8.6 g (95%).

M.p. 147-148,5 'C. [α] D 20 = -40.1 '(c = 1, in methanol).

Analysis for C ₁₈ H ₁₇ NO 4 (311.32):

Found: C, 69.44; H, 5.50; N, 4.50;

Found: C, 69.7; H, 5.6; N, 4.5.

Example 7

N- (Benzyloxycarbonyl) -L -], 2,3,4-tetrahydroisoquinoline-1-carboxylic acid L-threo-2-amino] - (4-nitrophenyl) -1,3-propanediol diastereomer salt and N- (benzyloxycarbonyl) -D1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid

17.5 g (42.5 mmol) of N-benzyloxycarbonyl-DL1.2.3.4-tetrahydroisoquinoline-1-carboxylic acid cyclohexylammonium salt (Example 1 or 2) as described in Example 5 with a proportional amount of reagents and solvents, except that L-threo-2-amino-1- (4-nitrophenyl) -1,3-propanediol is used as the base to form the diastereomeric salt. 8.4 g (16 mmol, 80%) of the title diastereomeric salt are obtained.

M.p .: 188-172 'C. [.Alpha.] D @ 20 = + 24.5 DEG (c = 1 in methanol).

Analysis for C ₂₇ H ₂₉ N ₃ O ₈ (523.53):

Calculated: C, 61.94; H, 5.58; N, 8.03; Found: C, 61.9; H, 5.6; N, 8.05.

(See Example 8 for processing of the diastereomeric salt.) After working up the benzene solution, 4.7 g (15 mmol,

75%) of N-benzyloxycarbonyl-D-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid are obtained.

Mp: 146-147 ° C. [.alpha.] D @ 20 = -40 DEG (c = 1 in methanol). Analysis for C ₁₈ H ₁₇ NO ₄ (311.32):

Found: C, 69.44; H, 5.50; N, 4.50; Found: C, 69.8; H, 5.5; % N, 4.6.

Example 8

Preparation of N-benzyloxycarbonyl-L-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid

5.25 g (10 mmol) of N- (benzyloxycarbonyl) -L 1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid L-freo-2-amino-1- (4-nitrophenyl) -1, The diastereomeric salt of 3-propanediol (Example 7) was converted as described in Example 6 using proportional amounts of reagents and solvents. 3 g (95%) of the title product are obtained.

146-147 ° C. [.Alpha.] D @ 20 = + 40.1 '(c = 1, in methanol).

Analysis for C ₈ H ₁₇ NO ₄ (311.32):

Found: C, 69.44; H, 5.50; N, 4.50; Found: C, 69.75; H, 5.6; N, 4.5.

Example 9

Preparation of DL-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid Cyclohexylammonium salt of N- (benzyloxycarbonyl) -DL1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (1 g, 24.34 mmol). Example 2 or Example 2) was dissolved in 30 mL of 1 M potassium bisulfate and 50 mL of benzene. The benzene solution was washed neutral with water, dried over anhydrous sodium sulfate, and at a pressure of 20-25 millibar to max. Evaporate from a 40 'C bath. The residue was dissolved in 250 ml of 80% acetic acid and hydrogenated with 0.3 g of 10% palladium on carbon at room temperature. Hydrogenolysis is followed by layer chromatography. At the end of the reaction, the catalyst is filtered off, washed with acetic acid, and the solution is pressurized to 20 to 25 millibars at max. Evaporate from a 40 'C bath. The residue was dissolved in ethanol-water (1: 2, 50 mL) and allowed to stand overnight in a refrigerator. The precipitated crystals are filtered off, washed with the above ethanol-water mixture and dried in a vacuum desiccator. 3.25 g (75%) of the title compound are obtained.

RK2) = 0.34-0.39. M.p. 243-248 'C.

Analysis for C ₁₀ H _n NO ₂ (177.20):

Calculated: C, 67.78; H, 6.26; N, 7.90;

Found: C, 67.7; H, 6.2; N, 7.7.

Example 10

Preparation of DL-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid

The cyclohexylammonium salt of N-methoxycarbonyl-DL-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (Example 3) (1.67 g, 5 mmol) was dissolved in 1 M potassium hydrogen sulfate (6 mL) and benzene (10 mL). . The benzene solution was washed with water to neutral, dried over anhydrous sodium sulfate and concentrated at 20-25 millibar from a 40 ° C bath. To the residue was added 5 ml of glacial acetic acid containing 32% hydrobromic acid, allowed to stand at room temperature for 3 hours, and then at a pressure of about 20-25 millibar for approx. It is evaporated from a bath at 40 'C and dried overnight in a vacuum desiccator with potassium hydroxide. The dried residue was dissolved in 1: 2 ethanol-water (10 mL), adjusted to pH 5-6 with ammonium hydroxide, and allowed to stand in the refrigerator overnight. The precipitated crystals are filtered off, washed with 3 x 1 mL of ethanol-water and dried in a vacuum desiccator. 0.45 g (50%) of the title product are obtained.

R # (2) = 0.34-0.39. M.p. 243-248 'C.

HU 212 427 Β

Example 11

Preparation of L-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid

3.11 g (10 mmol) of N- (benzyloxycarbonyl) -1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (Examples 5 or 8) are dissolved in 100 ml of 80% acetic acid and 0. Hydrogenate with 3 g of 10% palladium on carbon at room temperature. Hydrogenolysis is followed by layer chromatography. At the end of the reaction, the catalyst is filtered off, washed with acetic acid, and the solution is pressurized to 20-25 millibar at max. Evaporate from a 40 'C bath. The residue was dissolved in 1: 2 ethanol-water (50 mL) and allowed to stand overnight in a refrigerator. The precipitated crystals are filtered off, washed with the above ethanol-water mixture and dried in a vacuum desiccator. 1.35 g (76%) of the title product are obtained.

Rf (2) = 0.34-0.39. Mp: 272 'C.

Md ³ = -22.7 '(c = 2.1 in 1N sodium hydroxide).

Analysis for C ₁₀ HnNO ₂ (177.20):

Calculated: C, 67.78; H, 6.26; N, 7.90; Found: C, 67.6; H, 6.2; N, 7.6.

Example 12

Preparation of D-1,2,3,4-Tetrahydroisoquinoline-1-carboxylic acid g (3.2 mmol) of N- (benzyloxycarbonyl) -D1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (Example 6 or 7) the

II. The reaction is carried out in the same manner as described in Example 1, using a proportional amount of catalyst and solvents. Yield: 0.35 g (75%).

RX2) = 0.34-0.39. Mp: 273 'C.

[.alpha.] D @ 20 = +22 '(c = 2.1 in 1N sodium hydroxide).

Analysis for C 10 H 11 NO 2 (177.20):

Calculated: C, 67.78; H, 6.26; N, 7.90; Found: C, 67.8; H, 6.2; N, 7.8.

Example 13

Preparation of cyclohexylammonium salt of N-tert-butoxycarbonyl-L-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid

L-1,2,3,4-Tetrahydroisoquinoline-1-carboxylic acid (0.35 g, 2 mmol) (Example 11) and triethylamine (0.56 mL, 4 mmol) were dissolved in water (1.5 mL), treated with butanol, followed by di-tert-butyl dicarbonate (0.48 mL, 2.2 mmol) and stirred for 15 hours. The reaction mixture was diluted with water (5 mL), extracted with n-hexane (3 x 3 mL), acidified to pH 3 with 1M potassium bicarbonate and extracted with ethyl acetate (3 x 5 mL). The combined ethyl acetate phases were washed to neutral with water, dried over anhydrous sodium sulfate, and at a pressure of 20 to 25 millibars. Evaporate from a 40 'C bath. The residue was dissolved in diethyl ether (5 mL), cyclohexylamine (0.23 mL, 2 mmol) was added and allowed to stand overnight at room temperature. The precipitated crystals are filtered off, washed with diethyl ether and dried in a vacuum desiccator.

Yield: 0.65 g (85%).

R (3) = 0.74-0.78 (and cyclohexylamine: 0.0).

M.p. 170-172,5 'C. [ce] g, ° = +11.1 '(c = 1, in methanol).

Analysis for C ₂₁ H ₃₂ N ₂ O ₄ (376.48):

Found: C, 66.99; H, 8.57; N, 7.44.

Found: C, 65.9; H, 8.6; N, 7.1.

Example 14

Preparation of cyclohexylammonium salt of N-tert-butoxycarbonyl-D-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid

0.35 g (2 mmol) of D-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (Example 12) were acylated using the same amounts of reagents and solvents as described in Example 13 and the product was prepared as described in Example 13. we form salt. 0.64 g (85%) of the title compound is obtained.

Rf (3) = 0.74-0.78 (and cyclohexylamine: 0.0). op .:

170.5-173 ° C.

Md = -12.3 '(c = 1, in methanol).

Analysis for C ₂₁ H ₃₂ N ₂ O ₄ (376.48):

Found: C, 66.99; H, 8.57; N, 7.44. Found: C, 66.9; H, 8.7; N, 7.1.

Claims (13)

PATENT CLAIMS A process for the preparation of DL-, L- and D-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid and R-O-CO on its N atom R is a C 1 -C 3 alkyl group, a C 4 -C 6 tertiary alkyl group, a benzyl group or a 9-fluorenylmethyl group containing urethane-protecting group, and salts thereof, characterized in that the glyoxylic acid hydrate and R ' O-CO - wherein R 'is a (1-3C) alkyl or 9-fluorenylmethyl-protected (2-phenylethyl) amine in trifluoroacetic acid or a halogenated hydrocarbon containing trifluoroacetic acid, optionally in the presence of N (R) Optionally converting '-O-CO) -DL-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid, where R' is as defined above, to a salt, optionally resolving the resulting acid or salt and / or N-protecting group. cleaved in a known manner, the resulting L-, D-, or DL-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid is isolated and, if desired, acylated to its N atom by a formula RO-CO R is a C 4 -C 6 tertiary alkyl group and the resulting L-, D- or DL-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid having the acid-sensitive N-protecting group RO-CO optionally converted to a salt. A process according to claim 1, characterized by The condensation is carried out in a halogenated hydrocarbon containing 30-90% by volume of trifluoroacetic acid in the presence of up to 1 equivalent (trifluoroacetic acid) anhydride. The process according to claim 1 or 2, wherein the N-protected DL-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid is D-threo-2-amino-1- (4-nitrophenyl). -1,3-propanediol. The process according to claim 1 or 2, wherein the N-protected DL-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid is L-threo-2-amino-1- (4-nitrophenyl). Resolved with -1,3-propanediol. Process for the preparation of N-benzyloxycarbonyl-DL-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid according to claim 1 or 2, characterized in that the appropriate starting materials are used. 6. Process for the preparation of N-benzyloxycarbonyl-L-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid according to any one of claims 1 to 3, characterized in that the appropriate starting materials are used. 7. Process for the preparation of N-benzyloxycarbonyl-D-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid according to any one of claims 1 to 3, characterized in that the appropriate starting materials are used. The process for the preparation of N- (9-fluorenylmethoxycarbonyl) -DL-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid according to claim 1 or 2, characterized in that the appropriate starting materials are used. 9. Process for the preparation of N-tert-butoxycarbonyl-L-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid according to any one of claims 1 to 3, characterized in that the appropriate starting materials are used. 10. A process for the preparation of N- (tert-butoxycarbonyl) -D-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid according to any one of claims 1 to 3, characterized in that the appropriate starting materials are used. A process for the preparation of N- (methoxycarbonyl) -DL-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid according to claims 1 and 2, characterized in that the appropriate starting materials are used. 12. Process for the preparation of L-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid according to claims 1 to 3, characterized in that the appropriate starting materials are used. 13. A process for the preparation of D-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid according to claim 1, wherein the appropriate starting materials are used.