Method for preparing lisinopril intermediate

Abstract

A method for preparing a lisinopril intermediate is provided. The method includes: treating (R)-hydroxy-4-phenylbutyrate with sulfonyl chloride in an organic solvent in the presence of a base to obtain a solution of sulfonate; reacting the obtained solution with a salt of trifluoroacetyl lysine; and obtaining a N.sup.2-[1-(S)-alkoxycarbonyl-3-phenylpropyl]-N.sup.6-trifluoroacetyl-L-lysine by separating after the reaction is completed. The method provided has a shorter synthesis route, is easy to operate, has a low cost, and is suitable for industrial production.

Claims

1. A preparation method of N.sup.2-[1-(S)-alkoxycarbonyl-3-phenylpropyl]-N.sup.6-trifluoroacetyl-L-lysine (II), ##STR00007## wherein the method comprises the following steps: (a) treating (R)-2-hydroxy-4-phenylbutyrate (I) with a sulfonyl chloride (III) in an organic solvent in the presence of a base to obtain a solution of sulfonate of formula (I); ##STR00008## (b) reacting the solution prepared above with a salt of trifluoroacetyl lysine, and obtaining the compound represented by formula (II) by a separation after the reaction is completed, in the above formulas: R.sup.1 is selected from C.sub.1-C.sub.5 alkyls; R.sup.2 is selected from C.sub.1-C.sub.3 alkyls or substituted alkyls, C.sub.6-C.sub.7 aryls or substituted aryls.

2. The preparation method according to claim 1, wherein, R.sup.1 is selected from the group consisting of methyl, ethyl and isopropyl.

3. The preparation method according to claim 1, wherein, the organic solvent described in step (a) is selected from the group consisting of C.sub.2-C.sub.7 ethers, C.sub.2-C.sub.4 halogenated alkanes, C.sub.7-C.sub.10 aromatic compounds and a mixed solvent of any two thereof.

4. The preparation method according to claim 1, wherein, the mass-to-volume ratio of (R)-2-hydroxy-4-phenylbutyrate (I) to the organic solvent in step (a) is 1 g:2-20 mL.

5. The preparation method according to claim 1, wherein, the base is selected from the group consisting of carbonates or bicarbonates of alkali metals, C.sub.5-C.sub.8 pyridine compounds, C.sub.4-C.sub.9 secondary or tertiary amines.

6. The preparation method according to claim 1, wherein, the molar ratio of the base to (R)-2-hydroxy-4-phenylbutyrate (I) is 1-10:1.

7. The preparation method according to claim 1, wherein, the sulfonyl chloride (III) is selected from the group consisting of methylsulfonyl chloride, trifluoromethylsulfonyl chloride, p-nitrobenzenesulfonyl chloride and p-toluenesulfonyl chloride.

8. The preparation method according to claim 1, wherein, the molar ratio of the sulfonyl chloride (III) to (R)-2-hydroxy-4-phenylbutyrate represented by formula (I) is 1-5:1.

9. The preparation method according to claim 1, wherein, the temperature range within which the sulfonyl chloride is added is from 5 C. to 15 C.; the range of the reaction temperature of step (a) is 20-60 C.

10. The preparation method according to claim 1, wherein, the salt of trifluoroacetyl lysine is selected from the group consisting of alkali metal salts of trifluoroacetyl lysine, C.sub.4-C.sub.12 quaternary ammonium salts of trifluoroacetyl lysine.

11. The preparation method according to claim 1, wherein, the molar ratio of the salt of trifluoroacetyl lysine to (R)-2-hydroxy-4-phenylbutyrate (I) is 1-6:1.

12. The preparation method according to claim 1, wherein, the range of the reaction temperature of step (b) is 10-80 C.

13. The preparation method according to claim 1, wherein, the method further comprises crystallizing the crude compound represented by formula (II) obtained by separation in a crystallization solvent, the crystallization solvent is selected from the group consisting of methanol, ethanol, ethyl acetate, isopropyl acetate, methyl tertiary butyl ether, n-hexane, n-heptane, cyclohexane or a mixed solvent of any two thereof; the mass-to-volume ratio of (R)-2-hydroxy-4-phenylbutyrate (I) to the crystallization solvent used is 1 g:2-20 mL; the range of crystallization temperature is from 5 C. to 60 C.

14. The preparation method according to claim 1, wherein, the organic solvent described in step (a) is tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, toluene, xylene or a mixed solvent of any two thereof.

15. The preparation method according to claim 1, wherein, the mass-to-volume ratio of (R)-2-hydroxy-4-phenylbutyrate (I) to the organic solvent in step (a) is 1 g: 5-10 mL.

16. The preparation method according to claim 1, wherein, the base is selected from sodium carbonate, potassium carbonate, sodium bicarbonate, pyridine, 2,6-lutidine, triethylamine, diisopropylamine.

17. The preparation method according to claim 1, wherein, the molar ratio of the sulfonyl chloride (III) to (R)-2-hydroxy-4-phenylbutyrate represented by formula (I) is 1.1-3:1.

18. The preparation method according to claim 1, wherein, the temperature range within which the sulfonyl chloride is added is from 5 C. to 10 C.; the range of the reaction temperature of step (a) is 20-40 C.

19. The preparation method according to claim 1, wherein, the salt of trifluoroacetyl lysine is selected from a lithium salt of trifluoroacetyl lysine, a sodium salt of trifluoroacetyl lysine, a tetramethylammonium salt of trifluoroacetyl lysine.

20. The preparation method according to claim 1, wherein, the range of the reaction temperature of step (b) is 20-60 C.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 is the HPLC spectrogram of the product, N.sup.2-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-N.sup.6-trifluoroacetyl-L-lysine, prepared in example 1 of the present application.

EMBODIMENTS

(2) The present invention will be further illustrated by the examples, however, these examples do not constitute any limitation to the present invention.

(3) HPLC instrument model: Shimadzu LC-20A

(4) HPLC conditions:

(5) Chromatographic Column: Agilent Zorbax SB-18 1503.0 mm, 3.5 m;

(6) Mobile phase: 2.5 KH.sub.2PO.sub.4 solution:acetonitrile=60:40;

(7) Flow rate: 1.0 mL/min, column temperature: 25 C., detection wavelength: 210 nm.

EXAMPLE 1

(8) 20.8 g of (R)-ethyl 2-hydroxy-4-phenylbutyrate, 110 mL of dichloromethane and 42.4 g of sodium carbonate were added to a 250 mL three-necked flask, and 26.6 g of p-toluenesulfonyl chloride was slowly added at 0 C. The mixture was heated to 25 C. and reacted under stirring for 8 hours; the reaction solution was filtered, and 62.3 g of a tetramethylammonium salt of trifluoroacetyl lysine was added to the filtrate, and the obtained system reacted under stirring at 15 C. for 10 hours. The reaction solution was filtered, and the filtrate was distilled under reduced pressure to remove dichloromethane. 240 mL of n-hexane was added to the residue and the obtained system was stirred for 5 hours at 0-5 C., 37.2 g of product was obtained, it was determined by HPLC spectrogram that the product was N.sup.2-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-N.sup.6-trifluoroacetyl-L-lysine, the yield was 86.0%, the HPLC purity was 98.6%, and the HPLC related data are shown in Table 1 below.

(9) TABLE-US-00001 TABLE 1 Peak Ret. Theoretical # Time Area Height Area % Plates Resolution 1 2.595 11291 930 0.071 738.127 0.000 2 2.912 41363 3661 0.260 1742.500 0.959 3 4.707 3283 240 0.021 1215.483 4.383 4 4.931 3117 222 0.020 700.093 0.348 5 6.109 15671095 924068 98.634 3031.845 1.982 6 7.317 8360 652 0.053 278.804 1.099 7 7.654 103728 4708 0.653 3036.779 0.292 8 11.017 32718 1141 0.206 3657.974 5.238 9 12.113 9111 301 0.057 3951.075 1.462 10 13.660 4140 124 0.026 4256.754 1.924 Total 15888206 936048 100.000

EXAMPLE 2

(10) 20.8 g of (R)-ethyl 2-hydroxy-4-phenylbutyrate, 150 mL of tetrahydrofuran and 20.2 g of triethylamine were added to a 250 mL three-necked flask, and 12.6 g of methylsulfonyl chloride was slowly added at 0 C. The mixture was heated to 25 C. and reacted under stirring for 8 hours; the reaction solution was filtered, and 37.2 g of a lithium salt of trifluoroacetyl lysine was added to the filtrate, and the obtained system reacted under stirring at 25 C. for 10 hours. The reaction solution was filtered, and the filtrate was distilled under reduced pressure to remove tetrahydrofuran. 85 mL of ethanol was added to the residue and the obtained system was stirred for 5 hours at 0 C., 35.9 g N.sup.2-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-N.sup.6-trifluoroacetyl-L-lysine was obtained, the product showed a HPLC spectrogram that is the same as FIG. 1, the yield was 83.0%, the HPLC purity was 98.9%.

EXAMPLE 3

(11) 20.8 g of (R)-ethyl 2-hydroxy-4-phenylbutyrate, 150 mL of tetrahydrofuran and 19.8 g of pyridine were added to a 250 mL three-necked flask, and 13.5 g of methylsulfonyl chloride was slowly added at 0 C. The mixture was heated to 35 C. and reacted under stirring for 6 hours; the reaction solution was filtered, and 39.6 g of a sodium salt of trifluoroacetyl lysine was added to the filtrate, and the obtained system reacted under stirring at 25 C. for 10 hours. The reaction solution was filtered, and the filtrate was distilled under reduced pressure to remove tetrahydrofuran. 40 mL of n-hexane and 200 mL cyclohexane was added to the residue, the obtained system was stirred for 8 hours at 0 C., 36.6 g N.sup.2-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-N.sup.6-trifluoroacetyl-L-lysine was obtained, the product showed a HPLC spectrogram that is the same as FIG. 1, the yield was 84.7%, the HPLC purity was 98.8%.

EXAMPLE 4

(12) 9.7 g of (R)-methyl 2-hydroxy-4-phenylbutyrate, 95 mL of toluene and 20.2 g of triethylamine were added to a 250 mL three-necked flask, and 28.6 g of p-toluenesulfonyl chloride was added at 0 C. The mixture was heated to 35 C. and reacted under stirring for 10 hours; the reaction solution was filtered, and 49.6 g of a lithium salt of trifluoroacetyl lysine was added to the filtrate, and the obtained system reacted under stirring at 40 C. for 12 hours. The reaction solution was filtered, and the filtrate was distilled under reduced pressure to remove toluene. 115 mL of ethyl acetate was added to the residue, the obtained system was stirred for 12 hours at 25 C., 16.4 g N.sup.2-[1-(S)-methoxycarbonyl-3-phenylpropyl]-N.sup.6-trifluoroacetyl-L-lysine was obtained, the yield was 78.6%, the HPLC purity was 99.1%.

EXAMPLE 5

(13) 19.4 g of (R)-methyl 2-hydroxy-4-phenylbutyrate, 160 mL of 2-methyltetrahydrofuran and 33.6 g of sodium bicarbonate were added to a 250 mL three-necked flask, and 18.5 g of trifluoromethylsulfonyl chloride was added at 5 C. The mixture was heated to 25 C. and reacted under stirring for 10 hours; the reaction solution was filtered, and 37.2 g of a lithium salt of trifluoroacetyl lysine was added to the filtrate, and the obtained system reacted under stirring at 30 C. for 12 hours. The reaction solution was filtered, and the filtrate was distilled under reduced pressure to remove 2-methyltetrahydrofuran. 195 mL of n-heptane was added to the residue, the obtained system was stirred for 10 hours at 25 C., 33.8 g N.sup.2-[1-(S)-methoxycarbonyl-3-phenylpropyl]-N.sup.6-trifluoroacetyl-L-lysine was obtained, the yield was 80.9%, the HPLC purity was 98.1%.

EXAMPLE 6

(14) 19.4 g of (R)-methyl 2-hydroxy-4-phenylbutyrate, 160 mL of 2-methyltetrahydrofuran and 26.8 g of 2,6-dimethyl pyridine were added to a 250 mL three-necked flask, and 17.2 g of methyl sulfonyl chloride was added at 0 C. The mixture was heated to 30 C. and reacted under stirring for 7 hours; the reaction solution was filtered, and 37.2 g of a lithium salt of trifluoroacetyl lysine was added to the filtrate, and the obtained system reacted under stirring at 30 C. for 12 hours. The reaction solution was filtered, and the filtrate was distilled under reduced pressure to remove 2-methyltetrahydrofuran. 80 mL of methanol was added to the residue, the obtained system was stirred for 8 hours at 0 C., 35.2 g N.sup.2-[1-(S)-methoxycarbonyl-3-phenylpropyl]-N.sup.6-trifluoroacetyl-L-lysine was obtained, the yield was 84.2%, the HPLC purity was 98.6%.

EXAMPLE 7

(15) 22.2 g of (R)-isopropyl 2-hydroxy-4-phenylbutyrate, 180 mL of dichloromethane and 28.4 g of diisopropylamine were added to a 250 mL three-necked flask, and 28.8 g of p-nitrobenzenesulfonyl chloride was added at 0 C. The mixture was heated to 30 C. and reacted under stirring for 10 hours; the reaction solution was filtered, and 34.6 g of a tetramethylammonium salt of trifluoroacetyl lysine was added to the filtrate, and the obtained system reacted under stirring at 30 C. for 10 hours. The reaction solution was filtered, and the filtrate was distilled under reduced pressure to remove dichloromethane. 100 mL of methyl tertiary butyl ether was added to the residue, the obtained system was stirred for 8 hours at 5 C. to crystallize, filtered, 36.4 g N.sup.2-[1-(S)-isopropoxycarbonyl-3-phenylpropyl]-N.sup.6-trifluoroacetyl-L-lysine was obtained by drying the filter cake, the yield was 81.4%, the HPLC purity was 98.7%.

EXAMPLE 8

(16) 22.2 g of (R)-isopropyl 2-hydroxy-4-phenylbutyrate, 120 mL of tetrahydrofuran and 41.7 g of potassium carbonate were added to a 250 mL three-necked flask, and 28.6 g of p-toluenesulfonyl chloride was added at 10 C. The mixture was heated to 35 C. and reacted under stirring for 8 hours; the reaction solution was filtered, and 37.2 g of a lithium salt of trifluoroacetyl lysine was added to the filtrate, and the obtained system reacted under stirring at 30 C. for 10 hours. The reaction solution was filtered, and the filtrate was distilled under reduced pressure to remove tetrahydrofuran. 200 mL of n-heptane was added to the residue, the obtained system was stirred for 8 hours at 5 C. to crystallize, filtered, 34.3 g N.sup.2-[1-(S)-isopropoxycarbonyl-3-phenylpropyl]-N.sup.6-trifluoroacetyl-L-lysine was obtained by drying the filter cake, the yield was 76.8%, the HPLC purity was 97.4%.

EXAMPLE 9

(17) 20.8 g of (R)-ethyl 2-hydroxy-4-phenylbutyrate, 90 mL of xylene, 60 mL of tetrahydrofuran and 20.0 g of triethylamine were added to a 250 mL three-necked flask, and 13.0 g of methylsulfonyl chloride was added at 0 C. The mixture was heated to 35 C. and reacted under stirring for 8 hours; the reaction solution was filtered, and 37.5 g of a lithium salt of trifluoroacetyl lysine was added to the filtrate, and the obtained system reacted under stirring at 30 C. for 10 hours. The reaction solution was filtered, and the filtrate was distilled under reduced pressure to remove the solvent. 30 mL of isopropyl acetate and 120 mL of n-heptane was added to the residue, the obtained system was stirred for 10 hours at 5 C., 35.5 g N.sup.2-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-N.sup.6-trifluoroacetyl-L-lysine was obtained, the product showed a HPLC spectrogram that is the same as FIG. 1, the yield was 82.3%, the HPLC purity was 97.5%.