JPH01275556A - Proline derivative - Google Patents

Abstract

NEW MATERIAL:A compound of formula I (R is 4-biphenyloyl or 2- naphthylacetyl) and a salt thereof. EXAMPLE:An intermediate for preparing captopril [1-(3-mercapto-2-D- methylpropanoyl)-1-proline], etc., useful as a vasodepressor drug. USE:The compound of formula I is obtained by reacting a compound of formula II or a reactive derivative thereof (e.g., acid chloride or acid bromide) with L-proline in water or a water-containing inactive solvent (e.g., acetone or dioxane containing 1-50% of water, etc.,). The reaction is performed by using the L-proline in an amount of 1-10 equivalents, particularly 1-2 equivalents, based on the compound of formula II.

Description

[Detailed description of the invention]

Industrial Application Field The present invention provides an excellent gamma-angiotecin 1-converting enzyme 1I.
Captopril (1(:l-mercapto-2-D-methylpropanoyl)-1,-B) and alacepril N, which have harmful effects and are useful as antihypertensive agents.
-(3-mercapto-2-D-methylpropanoyl)-
L-bu

The present invention relates to novel intermediates derived from mercapto-substituted amino acids such as [I-L-7enylalanine] and other effective optically active compounds. Prior Art Many methods have been reported to date for the synthesis of captopril. The synthesis methods can be roughly divided into the following method and B method. (Method H) (Method B) In the Δ method, first, the optically inactive mercaptochelopion l'l
12 derivative (1 (1) was optically resolved and the optically active form (■)
Get 0. Compound (■) 0 is then led to captogril (It) via the optically active proline derivative (IV). Here, in the optical resolution method, Rt is lower alkanoyl such as acetyl, unsubstituted or A method of resolving a compound (■I) having γ-sil j, t, benzyl, etc. such as substituted benzoyl such as nido τ1 using an optically active amine as an optical resolving agent (for example, JP-A-151912 Publication No. 5Fi-3
8:186 Publication; 54i-775 (I Publication; 54i-775)
[Publication No. 1-815575, etc.) ii and I' are optically active! A method of separating compound (III), which is a mixture of diastereoisomers substituted with -menthoxyacetyl, and producing compound (Ill)'' (1)
8363) is known. In method B, first, as R', an optically inactive compound (11) having an acyl group such as lower alkanoyl, benzoyl and phenylacetyl, and compound (IV) which is a diastereoisomer mixture of L-proline are used. Next, the mixture is divided into a salt, etc. to obtain an optically active compound (IVY"), from which compound (n) can be obtained (for example, according to Japanese Patent Publication No. 60-4815;
No. 705; No. 60-59226, etc.) are known. Problems to be Solved by the Invention In the Δ method described above, natural alkaloids such as strychnine and brucine are used as optical resolution agents. The use of expensive resolving agents such as cinchonine, cinchonidine, quinine, and quinidine, the use of optically active α-amino alcohols that are problematic in synthesis, or optically active organic amines that are considered difficult to perform with large-scale manual labor; In order to obtain a compound with purity of I'::i (i), it is not necessary to perform many purifications, so the yield is low and a large amount of solvent is required, which is not necessarily satisfactory as an industrial production method. isn't it. On the other hand, in Method B, although the resolution efficiency is excellent, the initially obtained diaspreo isomer mixture (IV) is usually an oily compound that is difficult to handle, and operations such as salt crystallization and chromatography are required for purification. This cannot be said to be an advantageous method for industrial production. An object of the present invention is to provide a novel proline derivative in which the obtained diastereoisomer mixture and its optically active form are easily crystallized by using a more lipophilic group as an acyl group. The present invention provides I-(:i'7'silthio-2-methylpropanoyl)-L-but3 represented by formula (1) (wherein 1 represents 4-biphenyloyl or 2-naphthylacetyl). Phosphorus [hereinafter referred to as a compound (!)] The same applies to other large-numbered compounds] -Ji and its salts, and further relates to optically active forms of the compounds. Examples of the salt of the compound (+) include alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calciudate and magnesilate, and ammonia salts. Dicyclohexylamine, jetanolamine. Salts with organic salts such as triethylamine, morpholine and piperidine, and salts with amino acids such as lysine and arginine are included. Further, in optical resolution of a mixture, dicyclohexylamine salt is more preferably used. Next, the manufacturing method of the compound → will be explained. Compound (1) can be obtained by reacting a compound represented by formula (V) (wherein R is as defined above) or a reactive derivative thereof with -proline in water or a water-containing inert solvent. Obtainable. - Examples of reactive derivatives of compound (V) include acid chloride, 1% 12 bromide, and #γ iodide. Examples include acid anhydrides. In the reaction, L-proline is preferably used in an amount of 1 to 10 equivalents, particularly 1 to 2 equivalents, relative to compound (V). As the water-containing inert solvent, lower aliphatic alcohols containing 1 to 50% water, such as acetone, dioxane, methanol, ethanol, propatool, impropatol, and butanol, are preferably used. The reaction is carried out by dissolving I4-proline in water and adjusting the pH to a range of 7 to 9 using a reactive derivative of compound (V) and alkaline water under the conditions of the Schotten-Bauman method. Alkaline water is sodium hydroxide! 2. An aqueous solution of an enemy base such as potassium hydroxide. The reaction temperature is preferably 0 to 50°C, and usually 1 to 50°C.
The reaction was completed in 10 hours. For isolation and purification of the reactant, the reaction solution is adjusted to acidity, and the liberated compound (1) is extracted with an organic solvent such as ethyl acetate, chloroform, diethyl ether, benzene, or the like. After drying the organic layer, compound (1) can be crystallized by distilling off the solvent. It can also be easily recrystallized from methanol. In addition, compound (V)
When a racemate is used as the compound (r), the resulting compound (r) is usually a mixture of diastereoisomers. If optically active compound (1) is desired, dicyclohexylamine salt of optically active compound (1) is precipitated by dissolving compound (1), which is a diastereoisomer mixture, in acetonitrile and adding dicyclohexylamine. The dicyclohexylamine salt precipitated in this case is usually the I) form.This salt is neutralized with a p-treated acid and extracted with an organic solvent such as ethyl acetate, chloroform, diethyl needle, benzene, etc. The optically active compound (1
) can be obtained. The starting compound, compound (V), has the formula (Vl)R-X
(Vl) (wherein rt has the same meaning as above and X represents a halogen atom) and 3-mercapto-2-methylpropionic acid are mixed in water or a water-containing inert solvent in the presence of an alkali. It can be obtained by reacting. In the definition of X in formula (Vl), the halogen atom means chlorine,
Includes bromine and iodine atoms. In the reaction, it is preferable to use 1 to 5 equivalents, particularly 1 to 2 equivalents of compound (Vl) relative to 3-mercapto-2-methylpropionic acid. The water-containing inert solvent is detrahydrofuran containing 1 to 50% water. Dioxane and the like are preferably used. The alkali to be used is sodium hydroxide!・, Potassium hydroxide lb, Sodium carbonate A, Potassium carbonate, Sodium hydrogen carbonate!・etc. are used. The use of alkali m is the compound (Vl)
1-I0 equivalent is suitable. The reaction is suitably carried out at 0 to 50°C and is usually completed in 1 to 10 hours. After the reaction, adjust the acidity and extract with an organic solvent such as ethyl acetate, chloroform, diethyl ether, benzene, etc. After drying the organic layer, the solvent is distilled off to obtain compound (V). This compound can also be easily recrystallized from isopropyl ether. 3-Mercapto-2-methylpropionic acid is a known compound, and is described in JP-A-55-38386. In other words, it can be synthesized in high yield by reacting methacrylic acid with thiobenzoic acid, which can be easily done manually, to obtain 3-acetylthio-2-methylpropionic acid, and then treating it with dilute alkaline water. The compound (+) obtained by the present invention is an easily crystallized new compound.
Compared to the methods reported so far, the division in 1) is
Good selectivity in salt crystallization and yield of highly pure compounds <1! ) can be done. In addition, compound (1), including its optically active form, is easy to handle because it is a crystal, and is easy to purify by trL separation.Furthermore, biphenylcarboxylic acid or naphthyl acetic acid, which forms η during the deacylation step, is easy to handle. It has properties that are advantageous for industrial production methods, such as good crystallinity, easy recovery, and easy recycling. Compound (1) is easily hydrolyzed (deacylated) under mild reaction conditions using ammoniacal methanol at room temperature. Captopril can be derived by hydrolyzing the optically active compound (1) (Reference Examples 3 and 4)
. That is, it is dissolved in a 1-10N ammoniacal methanol solvent, stirred at room temperature for 2-10 hours, and then acidified with hydrochloric acid. Organic solvents such as ethyl acetate, chloroform lb. Extract with diethyl needle, benzene, etc., and extract the organic layer with (l
Sill. (After drying the organic layer, captopril is removed by distilling off the solvent. Examples of the present invention and examples are shown below. Example 1 In Reference Example 1, captopril is removed. 17.32 g of L-3-(4-biphenyloylthio)-2-methylpropion N was dissolved in 8.4 ml of thionyl chloride, and 2
After stirring for 11 seconds, the mixture was concentrated under reduced pressure. Add 10ml of toluene and concentrate again to obtain oily paste, L-3-(4-
biphenyloylthio)-2-methylpropimenic acid l
] 7.5 g of ride was obtained. 1. Dissolve 2.81 g of -proline in 2N aqueous sodium hydroxide solution, and at 0-5°C, dissolve the synthesized acid chloride and 2N aqueous sodium hydroxide solution.
The reaction was carried out for 1 hour under the conditions of the Schneider-Baumann method in the range of 9 to 9. After the reaction, the mixture was acidified with hydrochloric acid and extracted three times with ethyl acetate. After washing the organic layer with water and drying it with anhydrous sodium sulfate,
It was concentrated under reduced pressure to obtain 9.57 g of crystals. This was recrystallized from methanol to obtain 9.22 g of white crystals of L-1-[3-(4-biphenyloylthio)-2-methylpropanoyl)-L-proline. Melting point: 131.0°C JR(KBr) cm-': 3400.29
G0. 1735.1645°1600, 1445
．． 1215. 1180.915'H-NMR (
CD (in 13) δ (ppm): 1.20 (d, 3
11), 1.7-2.2 (Im, 411), 2.
97 (m, 1Il). 3.18 (t, 211), 3.60 (a+, III)
, 4.32 (m, III), 7.4-8.0 (m,
911), 12.42 (s, 1ft) elemental analysis value (
%):C□)1.3Actual value as NO<S C:66.
53. II:5.80. N: 3.4G calculated value
C:66.48. II:5.83. N: 3.5
2 Example 2 4.43 g of L-3-(2-naphthylacetylthio)-2-methylpropionic acid obtained in Reference Example 2 was dissolved in 2.3 ffil of thionyl chloride and stirred at 40°C for 2 hours. It was concentrated under reduced pressure. 101 g of toluene was added and concentrated again to obtain 5.01 g of L-3-(2-naphthylacetylthio)-2-methylpropionic acid 1ride as an oily paste. 1.77 g of [,-bu[I
5.80 grfτ of 2-naphthylacetylthio)-2-methylpropanoyl]-L,-florin was added. Melting point: I/12.4°C I R (KB r) am-' :: l-400,29
90,1?35.1680°1G10. 1440.
1250. +180. 1060.790'II-
NMR (CDC1, rtLi δ (ppm): 1.
20 (d, 311), 1.7-2.3 (m, 411
), 2.82 (n+, 211). 3.03 (t, 211), 3.36 (m, III),
4.29 (s, 211). 4.44 (m, 1ll), 7.4-8.0 (m, 71
1), 9.78 (s, lH) elemental analysis value (%): C
2, II, , NO, S are actual measured values (::(i5.2
5. ll:6.00. N::ll, 58 calculated value C: 65.43. 11?6.01. N:3.
63 Example 3 4.0 g of L-1-[3-(4-biphenyloylthio)-2-methylpropanoyl]-L-proline obtained in Example 1 was dissolved in 1 GO ml of acetonitrile, and the solution was dissolved at room temperature. Dicyclohexylamine! , 81g were added. After stirring at room temperature for 2 hours, precipitated white crystals were collected. Washed with 70ml of acetonitrile and dried.3.96
g white crystals were obtained. Recrystallization from acetonitrile yields l-(3-(4-biphenyloylthio)-2-1)-methylpropanoyl)-
Fine white needle-like crystals of L-proline dicyclohexylamine salt were obtained. The crystals were mixed with 40 ml of ethyl acetate and 40 ml of normal hydrochloric acid.
1, stirred for 10 minutes at room temperature, and then separated into layers. The organic layer was separated, washed with water, and dried over anhydrous sodium sulfate. Removal of the solvent 61 gives 1-(3-(4-biphenyloylthio)-2-D-methylpropanoyl)-L-proline 1
．． 68 g of white crystals were obtained. Note that recrystallization from methanol is also possible. Melting point: 131.6°C [α), = -110,9° (cm1.0. methanol) IR (Kr3r) and') I-NMR (CDCIl
The spectrum of compound (i) at all °C in Example 1 was consistent with that of compound (i). Example 4 5.0 g of L, -1-[3-(2-naphthylacetylthio)-2-methylpropanoyl)-L-proline obtained in Example 2 was dissolved in 1001 acetonitrile, and dicyclohexylamine 2 .36 g was added. Actual M below
In the same manner as in Example 3, 2.0 g of I-(3-(2-naphthylacetylthio)-2-D-methylpropanoyl]-[,-proline was obtained (yield: 4!40%). Melting point: 142.4°C [α)e=-102.5° (C=1.0.methanol) IR (KBr) and 'H-NMR (in CDCIl.) spectra all match the compound obtained in Example 2 did. Reference example ■ D, L-3-mercapto-2-methylpropion Nl
l O, Og in 2N aqueous sodium hydroxide solution 83.3
ml and cooled to 5°C. To this solution was added a solution of 18.05 g of 4-biphenylchloride [1] dissolved in tetrahydrofuran 1001 at 20°C at 5 to 10°C.
After the mixture was added dropwise over 1 minute, the mixture was further stirred at 5 to 10° C. for 2 hours. After the reaction, the pH was adjusted to 2 with 6N hydrochloric acid, and then extracted twice with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield 27.5 g.
crystals were obtained. Recrystallized from isopropyl needle. 9.7 g of white crystals of L-3-(4-biphenyloylthio)-2-methylpropion FIR1 were obtained. Melting point: 125.4°C IR(KBr) as-': 34G
0. 2950. 1 (i95. 1fi30°1600, 140G, 1225.1180.920'
H-NMR (CDCj, medium) δ (pptri): 1.
38 (d, 311), 2.85 (s, l1l), 3
．． 33 (t, 211). 7.3-8.2 (n+, 911), 11.28 (s,
1ll) Elemental analysis value (%): Actual value as C, IH,, O, S: C: 67.95. H: 5.40 calculated value
C: 67.9B, H: 5.37 Reference Example 2 D, I, -: 8.12 g of 3-mercapto-2-methylpropion #2 was dissolved in 2N sodium hydroxide! , aqueous solution 55
1 and cooled to 5°C. To this, 24 g of 2-naphthylacetyl chloride I O was added to 4 g of tetrahydrofuran.
A solution dissolved in 0ml was added dropwise at 5 to 10°C over 20 minutes. Hereinafter, in the same manner as in Reference Example I), L-3-(2-naphthylacetylthio)-2-methylpropion al l 6
．． 8 g was obtained. Melting point: G8.0°C IR (KB r) cm-': 340G, 29
90.1735.16g0゜1610, 1440.12
50.1180.10 (io, 790'If-NMR
(CDCIl, medium) δ(ppa+): 1, 20(d
, :]ll), 2.70(n+, !I+>, 3
．． (1G(t, 211). 4, 26(s, 211), 7.3~8.O(m,
711), 10.86 (s, III) Elemental analysis value (%): C, sH,, actually measured value as S: C: (i
6.59. Il: 5.6G calculated value C: 66. (
i4. Il: 5.59 Reference Example 3 2.07 g of l-[3-(2-naphthylacetylthio)-2-D-methylbu-11panoyl]-L-proline obtained in Example 4 was added to 5.5 gamma The mixture was dissolved in methanol solution 171111 and stirred at room temperature for 3 hours, and then poured into ice water 501. The precipitated white crystals are classified by p,
Washed. The lv solution and washing solution were combined and washed twice with chloroform 2011, acidified with hydrochloric acid, and extracted twice with chloroform l-1-5O. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 0.88 g of captopril as an oily substance. This substance is
r) Forno, crystallized from n-hexane and 0.75
g of white crystals (2 pieces. Melting point: 102℃ [α) −= −135@(cm2.0.methanol)
I R (K B r) cm-': 2
5G0. 1740. 1585. 1470'
H-NMR (CI) (in 13) δ (ppm): 1.
22 (d, 3H), 1.57 (t, l1l), 2.
17 (m, 4 fl). 2.47 (m, III), 2.87<m, 211),
3.65 (t, 2H). 4, Go <m, l II), I l, :l
(s, I If) Reference Example 4 I-C3-(4-biphenytau1ylti:t)-2-D-methylbutanoyl]-I,-proline2. obtained in Example 3. OOg was dissolved in 15 ml of 5.5N ammoniacal methanol. Hereinafter, 0.77 g of Captogril was prepared in the same manner as in Reference Example 3 (i). Melting point: 102°C 1) All physical properties of the obtained crystals were consistent with those obtained in Reference Example 3 (1). The present invention provides useful synthetic intermediates. Procedural amendment (spontaneous) June 20, 1988 1, Indication of the case 1988 Patent Application No. 103381 2, Name of the invention Proline derivative 3, Person making the amendment Relationship to the case Patent issuer Postal code 100 Address: 6-1 Otemachi-chome, Chiyoda-ku, Tokyo Name:
(102) Kyowa Hakko Kogyo Co., Ltd. (2) "Publication No. 56-815575" on page 4, line 6 of the same book as "Publication No. 56-815575"
5.7 Publication”. (3) Same: Page 12, line 3, “captopril” is
-Corrected to ``Prill''. (4) On page 16 of the same book, line 2, "spectrum" is corrected to "spectrum." (5) In the 5th line from the bottom of the 16th line of the same sentence, ``suhektor'' is corrected to ``spectrum.'' (6) "Captopril" in page 19, line 11 of the same offense is corrected to "captopril."

Claims (5)

[Claims] (1) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R represents 4-biphenyloyl or 2-naphthylacetyl) 1-(3-acylthio-2
-Methylpropanoyl)-L-proline and its salts. (2) The compound according to claim (1), wherein 1-(3-acylthio-2-methylpropanoyl)-L-proline is optically active. (3) Claim (2) wherein the optically active substance is 1-(3-acylthio-2-D-methylpropanoyl)-L-proline.
Compounds described. (4) The compound according to claim (3), wherein the acyl group is selected from 4-biphenyloyl or 2-naphthylacetyl. (5) Claim (1) wherein the salt is a dicyclohexylamine salt.
).