JPH0134987B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to mercaptoacylproline derivatives, and more particularly to novel 1-(mercaptoacyl)-substituted proline derivatives and salts thereof having pharmacological activity. The compounds of the present invention and their salts are useful as antihypertensive agents, particularly as therapeutic agents for angiotensin-related hypertension. The compounds of the present invention include novel ethers represented by the following formulas, thioether mercaptoacylprolines, and basic salts thereof. formula: [In the formula, X-R ₁ group is 3 or 4 of the proline ring
It is located at the top. X is oxygen or sulfur; R is hydrogen; R ₁ is lower alkyl, phenyl or halogen-substituted phenyl; R ₂ is hydrogen or lower alkyl; R ₄ is hydrogen or

[Formula] (where R ₅ is lower alkyl or phenyl); n represents 1]. The present invention relates in its broadest sense to ether and thioether mercaptoacyl prolines [ ];
It includes its salts. Lower alkyl as used in the definitions of R ₁ and R ₂ is a straight-chain or branched hydrocarbon group not exceeding 7 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl. , isopentyl, and the like.
Among these, lower alkyl having not more than 4 carbon atoms is preferred, and methyl and ethyl are most preferred. Halogenated substituted phenyl used in the definition of R ₁ is a group having one or two, preferably one halogen (especially chlorine or fluorine) substituent on the phenyl ring. Lower alkanoyl represented by R ₅ −CO− is
It includes acyl residues of lower fatty acids having 2 to 7 carbon atoms (eg, acetyl, propionyl, butyryl, isobutyryl, etc.). Lower alkanoyl having not more than 4 carbon atoms, especially acetyl, is preferred. Similarly, benzoyl in _R5 -CO- in which _R5 is phenyl is particularly preferred. The * mark in formula [] represents the asymmetric center present in the proline ring. Of course, depending on the type of substituent R ₂ , an asymmetric center may exist in the mercapto side chain. Therefore, the product [] exists as a stereoisomer or a racemic mixture. All of these compounds are included in the present invention. In the production method described below, either the racemate or the optical antipode can be used as a starting material.
When a racemate is used as a starting material in the synthetic process, the stereoisomers obtained as the final product can be separated by conventional chromatography or fractional crystallization methods. Furthermore, the X-R ₁ group becomes a factor that causes cis-trans isomerism. The asymmetric center of the proline ring is preferably in the L-configuration, and if the mercaptoacyl side chain has an asymmetric center, it is preferably in the D-configuration. Preferred compounds [] include R is hydrogen; R ₁ is lower alkyl having 1 to 3 carbon atoms or (A compound [] where R ₆ is hydrogen or fluorine; R ₂ is hydrogen or methyl; R ₃ is hydrogen; n is 1; R ₄ is hydrogen. Also, a compound [] where R ₄ is hydrogen A preferred compound as an intermediate for obtaining is the above compound [ ] in which R ₄ is acetyl or benzoyl. The most preferred compound [ ] is the one in which X is oxygen; R ₁
is methyl or ethyl (especially methyl); n is 1;
R ₂ is hydrogen or methyl (especially methyl); R ₃ is hydrogen; R ₄ is hydrogen, -XR ₁ group is 4 of the proline ring
position, especially a compound [] having a cis configuration. The ether and thioether [] of the present invention can be produced by the following method.
That is, the formula: [In the formula, X, R and R ₁ have the same meanings as above] Ether proline or thioether proline represented by the formula: [In the formula, R ₄ represents hydrogen or R ₅ -CO-.
R ₂ , R ₃ , n and R ₅ have the same meanings as above] By reacting an acid represented by the formula or a reactive derivative thereof, the formula: [wherein, X, R, R ₁ , R ₂ , R ₃ , R ₄ ' and n have _the same meanings as _above ] ]) can be obtained. This reaction is carried out in the presence of a coupling agent such as dicyclohexylcarbodiimide, or
Alternatively, the acid [ ] can be converted into its mixed acid anhydride, symmetric acid anhydride, acid halide or active ester form, or Woodward
The reaction can be advanced by activation with reagent K, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, or the like. (For an explanation of the acylation method, please refer to Metoden del.
Methoden der
Organischen Chemie (published by Houben-Weyl), Volume 1, pp. 1 et seq.). It is preferable to react the acid halide (especially acid chloride) of the compound [] with the compound (). The product [ ] is preferably isolated and purified by crystallization. For example, the dicyclohexylamine salt is formed and then the salt is converted to the free acid by treatment with an aqueous solution of an acid such as potassium hydrogen sulfate. The product [ ] having an acyl group R ₅ -CO- is
The compound of the present invention in which R ₄ is hydrogen by treating this with conventional hydrolysis or ammonolysis []
can be converted to . Note that the proline starting material [] can be produced by various methods. For example, the formula: [In the formula, X has the same meaning as above] Hydroxyproline or mercaptoproline represented by the following is acylated with acetic anhydride, acetyl chloride, propionic anhydride, butyric anhydride, benzyl chloroformate, etc. to protect the nitrogen atom. Next, a halide is added to the compound [] in which the nitrogen atom is protected;
R ₁ -hal (where hal represents a halogen, preferably iodine) is reacted in the presence of silver oxide, sodium hydride, sodium hydroxide, etc.
By introducing _one R group, the formula: [In the formula, Z represents an N-protecting group. X and
R ₁ has the same meaning as above] An intermediate represented by the following is obtained. This intermediate [] is treated with a base such as barium hydroxide, sodium hydroxide or potassium hydroxide to first obtain the free acid (COOH) and then hydrolyzed with a mineral acid such as sulfuric acid to form the starting material. Compound [ ] can be obtained. Another method for producing the proline starting material [] has the formula: [In the formula, Ts is ;Z] represents an N-protecting group (preferably benzyloxycarbonyl or other commonly used acyl protecting group)] A nitrogen-protected tosyloxyproline ester (preferably a methyl ester) of the formula: R ₁ -X-Na [] [wherein X and R ₁ have the same meanings as above] Treated with a sodium salt represented by the formula: An intermediate represented by the formula [wherein X, R ₁ and Z' have the same meanings as above] is obtained. In this reaction, if the tosyloxy group is cis, XR ₁ group becomes trans,
If the tosyloxy group is trans, the XR ₁ group will be cis. This intermediate [ ] can then be treated to remove the alkyl ester group and further reacted with hydrogen bromide to yield the hydrobromide salt of the proline starting material [ ]. The corresponding compound of the present invention [] can be obtained by using this salt as a starting material and reacting it with an acid [] (preferably an acid chloride). A proline starting material in which X is sulfur and _one XR group is bonded to the 3-position of the proline ring can be produced as follows. formula: A 1,2-dehydroproline ester (preferably t-butyl ester) of the formula is treated with an acylating agent such as benzyl chloroformate, acetyl chloride, etc. to give the formula: [In the formula, Z'' represents an N-protecting group] A 4,5-dehydro compound represented by the following formula was obtained, and then reacted with a mercaptan; R ₁ -SH to obtain the formula: A compound represented by the formula [wherein R ₁ and Z'' have the same meanings as defined above] is obtained. In the above compound [XII], the -S-R ₁ substituent has a trans configuration.
Next, by removing the N-protecting group and the alkyl group of compound [XII], the desired starting material, prolines [], can be obtained. The proline starting material [ ] in which R ₁ is phenyl or halogen-substituted phenyl is prepared by converting the benzyl ester of nitrogen-protected proline [ ] to triphenylphosphine and diethyl azodicarboxylate according to the method of Bittner et al. Treatment with alcohol: R ₁ -OH in the presence of alcohol, followed by removal of the N-protecting group and the benzyl ester group, can provide the proline starting material [Bittner et al. Industry）
See page 281 of the May 15, 1975 issue]. Regarding the preparation of starting materials and intermediates, the following documents are of further reference: Ondetti et al.: U.S. Patents 4,046,889, 4,105,776 and 4,154,935; Neuberger;
Journal of the Chemical Society (J.Chem.Soc.) 1945, pp. 429-432; Patchtt et al.: The Journal of the American Chemical Society (J.Amer.Chem.).
Soc.) Vol. 79, pp. 185-192 (1957); Baer et al.: Canadian Journal of
Can.J.Biochem.and Phys., Vol. 37, pp. 583-587 (1959); Sheehan et al.; The Journal of the American Chemical Society (J. Amer.Chem.Soc.) Vol. 85, pp. 3863-3865 (1963); Magerlein: Journal of Medicinal Chemistry (J.
Med.Chem) Vol. 10, pp. 1161-1163 (1967). The methods described in these documents can be applied as general synthesis methods and stereoisomer conversion methods for compounds used in the present invention. More detailed experimental conditions are described in Examples below. The compound of the present invention [] forms basic salts with various inorganic bases or organic bases. Salt-forming ions derived from such bases can be metal ions, such as aluminum ions, alkali metal ions such as sodium or potassium, alkaline earth metal ions such as calcium or magnesium, or amine salt ions. .
A large number of amine salt ions are known to be used for this purpose, including dibenzylamine, aralkylamines such as N,N-dibenzylethylenediamine, methylamine, t
- Lower alkyl amines such as butylamine, procaine, lower alkyl piperidines such as N-ethylpiperidine, cycloalkylamines such as cyclohexylamine or dicyclohexylamine, 1-adamantanamine, benzathine or arginine, lysine, etc. Examples include salts derived from amino acids. Physiologically acceptable salts such as sodium or potassium salts can be used as medicines as described below and are preferred. These and other salts may not necessarily be physiologically acceptable and may be useful for the isolation and purification of compounds useful for the purposes described below, as described for dicyclohexylamine salts and cyclohexylamine salts in the Examples. Very useful. Salts can be prepared by reacting the acid form of the compound with an equivalent of a base which releases the aforementioned base ions in a medium in which the salt is precipitated, or by reacting in an aqueous medium followed by lyophilization. The free acid can be obtained from the salt by neutralization using conventional neutralization methods such as sodium bicarbonate or hydrochloric acid. The compounds of the present invention inhibit the conversion of decapeptide angiotensin to angiotensin and are therefore useful in lowering or alleviating hypertension. The compound of the present invention inhibits angiotensin converting enzyme,
It mediates the renin → angiotensinogen → angiotensin → angiotensin conversion system by reducing or blocking the production of the blood pressure increasing substance angiotensin. Thus, blood pressure in hypertensive mammals can be reduced by administering an effective amount of a composition containing the compound of the present invention or a mixture of two or more of its physiologically acceptable salts. It can be lowered or reduced. Approximately 0.1 of the compound of the present invention lowers blood pressure.
~100mg/Kg/day, preferably about 1-50mg/Kg/
Once a day, take a drug prepared based on the daily dose.
Preferably, it is appropriate to administer the drug in 2 to 4 divided doses a day. This dosage is based on Angel (SL)
Engel, TR Schaeffer, MHWaugh, and B. Rubin [Proceedings of the Society for Experimental Biology]. and Medicine (Proc.Soc.Exp.Biol.Med.) Vol. 143, p. 483 (1973)]. Although the substance of the present invention is preferably administered orally, it can also be administered parenterally, such as subcutaneously, intramuscularly, intravenously, or intraperitoneally. For lowering blood pressure, the compounds of the present invention can be formulated into compositions for oral administration, such as tablets, capsules, or elixirs, or sterile solutions or suspensions for parenteral administration.
For this purpose, about 10 to 500 mg of the compound of the present invention or one of its physiologically acceptable salts or a mixture thereof
in a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavoring agent, etc., in a unit dosage form compatible with pharmacologically acceptable practice. . The amount of active ingredient in these compositions or medicaments must be such that the required dosage is contained therein. Examples of adjuvants that can be incorporated into tablets, capsules, etc. include gum tragacanth, gum arabic, binders such as corn starch or gelatin, excipients such as dicalcium phosphate or microcrystalline cellulose, corn starch, potato starch,
Disintegrants such as alginic acid, lubricants such as magnesium stearate, sweeteners such as sucrose, lactose or saccharin, peppermint,
Flavoring agents such as wintergreen oil or cherry oil may be mentioned. When the dosage unit is a capsule, it can contain, in addition to materials such as those enumerated above, a liquid carrier such as a fatty oil. Various other materials may be present as coatings or to modify the physical form of the dosage unit.
For example, tablets may be coated with Siekla, sugar or both. A syrup or elixir can contain the active substance, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a coloring agent and cherry or orange flavor. Sterile injectable compositions can be prepared in accordance with normal pharmacological practice by dissolving or suspending the active substance in a carrier such as water for injection, natural vegetable oils (e.g., sesame oil, coconut oil, peanut oil, cottonseed oil). . Next, Examples will be shown to explain the method for producing the compound of the present invention in more detail. Compounds of the present invention not shown in the Examples can be produced by replacing the reaction reagents with appropriate substituted analogs. Example 1 1-(3-acetylthio-1-oxopropyl)
-Production of -trans-4-methoxy-L-proline: - a N-acetyl-trans-4-hydroxy-L
- Production of proline: - trans-4-hydroxy-L-proline 26.2g
A 400 ml suspension of (0.2 mol) in acetic acid is treated with 26 ml of acetic anhydride with stirring. After stirring for 2 hours at room temperature, the solids gradually dissolve. Transfer the solution to 2 flasks and remove the solvent on a rotary evaporator with a bath temperature of 45°C. 57.5g of syrupy residue is dissolved in ether.
Dilute with 100 ml to obtain a crystalline solid. After cooling overnight,
The solids are filtered off, washed with cold ethanol, and dried in a desiccator. 35.7 g of the resulting material was ground, suspended in 100 ml of ether, cooled, filtered and purified with N
33.8 g (yield 98%) of -acetyl-trans-4-hydroxy-L-proline was obtained. 0.5g of this substance
Recrystallize from 5 ml of acetonitrile to obtain a colorless solid.
0.45g was obtained. Melting point 130-132℃. [α] ²⁵ _D −92° (in methanol, concentration 1%). b N-acetyl-trans-4-methoxy-L-
Production of proline methyl ester: -N-acetyl-trans-4-hydroxy-L-
30.0g (0.17mol) of proline and 130g of silver oxide
Grind the mixture in a mortar and add the resulting intimate mixture to one flask with 300 ml of acetone. The slurry is stirred and treated with 130 ml of methyl iodide in portions. During this time, keep the temperature below 40°C by cooling in a cold water bath. After stirring for 7 hours, the mixture is left overnight. After filtering the solid and thoroughly washing with acetone, the filtrate is concentrated on a rotary evaporator to obtain 38.3 g of syrupy residue. Add this to acetone
Redissolve in 350 ml and treat again with 130 g of silver oxide and 130 ml of methyl iodide to obtain 41 g of residue. Distill this to obtain 32.2 g of concentrated liquid. Boiling point 130-140℃/
0.3mmHg. Soak in 30 ml of cyclohexane and cool to form an almost colorless solid N-acetyl-trans-4.
-Methoxy-L-proline methyl ester 31.4
I got g. Melting point 71-75℃. Recrystallization from 31 ml of ethyl acetate gave 25.1 g (66%) of a colorless solid product.
Melting point 76-77℃. [α] ²⁵ _D = -83° (in ethanol, concentration 1%). c Production of trans-4-methoxy-L-proline: - Barium hydroxide octahydrate 27.0 g (0.085 mol)
11.0 g (0.5 mol) of N-acetyl-trans-4-methoxy-L-proline methyl ester is added to a 525 ml solution (approximately 3.3 N) of water with stirring. The solution was stirred at 18-20°C for 3 hours, cooled and treated with dilute sulfuric acid (8.8g concentrated sulfuric acid in 20ml water).
This acidic suspension is left overnight. The mixture is filtered through a thick layer of Celite to obtain a milky filtrate.
Concentrate the filtrate at 50°C on a rotary evaporator using a high-speed vacuum pump to obtain a milky residue of 121 g.
get. Add this substance to dilute sulfuric acid (concentrated sulfuric acid in 75 ml of water).
19.0 g) and the mixture is stirred and refluxed for 3 hours. After cooling to 30° C., 48 g of barium hydroxide octahydrate is added little by little to the mixture, and then the pH is adjusted to 6.0-4.0 with dilute sulfuric acid. The mixture is allowed to stand overnight and then filtered through a thick layer of Celite. The milky filtrate is concentrated as before to give 50 g of a colorless dry residue. This is combined with 200 ml of hot chloroform and passed through a Celite bed to remove barium sulfate. The slightly cloudy filtrate is concentrated on a rotary evaporator and the resulting gelatin-like material, 17.7 g, is suspended in 100 ml of ether and filtered to give 7.5 g (94%) of an almost colorless solid. Melting point 185-190℃ (decomposition). This material was suspended in 30 ml of warm acetonitrile,
Cool and filter to obtain 4.0 g (50%) of trans-4-methoxy-L-proline as a colorless solid. Melting point 209-211°C (decomposition). [α] ²⁵ _D = -75° (in ethanol, concentration 1%). d Production of 1-(3-acetylthio-1-oxopropyl)-trans-4-methoxy-L-proline: - 3.5 g of trans-4-methoxy-L-proline
(0.024 mol) in 50 ml of water is stirred, cooled to 5°C, and 3 g of sodium carbonate are added. Add this mixture to 4.0 g of 3-acetylthiopropionyl chloride.
(0.024 mol) in 5 ml of ether and maintained at a pH of about 8.0 by adding 3 g of sodium carbonate intermittently over a period of 10 minutes. Place the mixture on the ice bath for another 1
Stir for an hour, add 25 ml of water, then add 5 ml of concentrated hydrochloric acid to 25 ml of water.
Add solution (carbon dioxide gas will be released). Saturate this strongly acidic solution with sodium chloride and ethyl acetate.
Extract 4 times with 50 ml. The organic layers were combined, dried over magnesium sulfate, filtered, and the solvent was evaporated to give 6.0 g (90 g) of 1-(3-acetylthio-1-oxopropyl)-trans-4-methoxy-L-proline in the form of a colorless syrup. %). Add this acid to ethyl acetate25
ml and treated with 4.7 g of dicyclohexylamine to obtain a solution (this solution quickly forms a lumpy solid. A further 15 ml of ethyl acetate is added, the mixture is heated on a steam bath, cooled and filtered. 8.7 g of the dicyclohexylamine salt of the above proline compound is obtained.
Melting point 170-172℃. Crystallization from 60 ml of acetonitrile gave 8.3 g (75%) of a colorless solid product. melting point
171-173℃. [α] ²⁵ _D = -35° (in ethanol, concentration 1%). 8.0 g of the above dicyclohexylamine salt was suspended in 60 ml of ethyl acetate cooled on an ice bath, and 60 ml of 10% potassium hydrogen sulfate was added little by little. The clear layer is separated and the aqueous layer is extracted twice with 60 ml of ethyl acetate. The organic layers were combined, dried over magnesium sulfate, filtered, and the solvent was evaporated to give a colorless syrup of 1-(3-acetylthio-1-oxopropyl)-.
trans-4-methoxy-L-proline 4.6g (80
%) was obtained. Example 2 1-(3-mercapto-1-oxopropyl)-
Production of trans-4-methoxy-L-proline:
- 1-(3-acetylthio- obtained in Example 1)
1-oxopropyl)-trans-4-methoxy-L
- To 4.6 g (0.017 mol) of proline is added a cold solution of 9 ml of concentrated ammonia in 22 ml of water. The base was dissolved in about 30 minutes and the solution was incubated at room temperature for 2 hours under an argon atmosphere.
Leave it for a while. Cool the solution, extract twice with 25 ml of ethyl acetate, and discard the ethyl acetate extract. The solution was extracted again with 25 ml of ethyl acetate and diluted with hydrochloric acid (1:1)17
Acidify with ml. The mixture is shaken, the layers are separated and the aqueous layer is extracted three times with 25 ml of ethyl acetate. The organic layers were combined, dried over magnesium sulfate, filtered, and the solvent was removed using a rotary evaporator to obtain 2.3 g of 1-(3-mercapto-1-oxopropyl)-trans-4-methoxy-L-proline in the form of a colorless syrup.
(5.9%). [α] ²⁵ _D = -60° (in ethanol, concentration 1%).
Rf0.49 (visualized on silica gel, methanol, nitroprusside reagent). Elemental analysis, calculated values as _C9H15NO4S・1/ _4H2O : C, 45.46%; H, 6.57 _% ; _N , 5.87%;
S, 13.48%, actual value: C, 45.42%; H, 6.78
%; N, 5.96%; S, 13.27%. The aqueous layer was saturated with sodium chloride and ethyl acetate
An additional 1.1 g of product was obtained by extracting twice with ml. Total yield 3.4g (87%). The syrupy product was treated with aqueous sodium bicarbonate solution and lyophilized to obtain its sodium salt. Example 3 (trans)-1-[D-3-(acetylthio)-2
-Methyl-1-oxopropyl]-4-methoxy-L-proline production: -4.3 g of trans-4-methoxy-L-proline
(0.029 mol) in 50 ml of water is stirred, cooled to 5°C, and 3 g of sodium carbonate are added. This solution is D
It is treated with 5.2 g (0.029 mol) of -3-(acetylthio)-2-methylpropionyl chloride and 5 ml of ether and maintained at a pH of about 8.0 by adding 3 g of sodium carbonate intermittently over a period of 10 minutes. The mixture is stirred on an ice bath for 1.5 hours and 25 ml of water are added followed by a solution of 6 ml of concentrated hydrochloric acid in 25 ml of water (carbon dioxide gas is evolved). Add 50% of this strong acidic solution to ethyl acetate.
Extract 4 times with ml. The organic layers were combined, dried over magnesium sulfate, filtered, and the solvent was evaporated to give (trans)-L-[D-3
-(acetylthio)-2-methyl-1-oxopropyl]-4-methoxy-L-proline 6.1 g (73
%) was obtained. This acid is dissolved in 50 ml of ethyl acetate and treated with a solution of 4.0 g of dicyclohexylamine in 20 ml of ethyl acetate. Product begins to precipitate out of solution in about 1 minute. After cooling the solution overnight, the nearly colorless solid is collected by filtration and dried to yield 6.7 g of the dicyclohexylamine salt of the above acid. Melting point 175-177℃. [α] ²⁵ _D = -55° (in ethanol, concentration 1%). This was crystallized from 60 ml of acetonitrile to yield 5.6 g (41%) of almost colorless solid dicyclohexylamine salt.
I got it. Melting point 179-181℃. [α] ²⁵ _D = -62° (in ethanol, concentration 1%). 5.5 g of the above dicyclohexylamine salt is suspended in 50 ml of ethyl acetate, cooled on an ice bath, and treated with 50 ml of 10% potassium hydrogen sulfate. The layers are separated and the aqueous layer is extracted twice with 50 ml of ethyl acetate. The organic layers were combined, dried over magnesium sulfate, filtered and the almost colorless syrupy acid product (trans)-1-
[D-3-(acetylthio)-2-methyl-1-oxopropyl]-4methoxy-L-proline 3.4g
(41%). Example 4 (trans)-4-menoxy-1-(D-3-mercapto-2-methyl-1-oxopropyl)-
Production of L-proline: -(trans)-1-[D-3-(acetylthio)-2
-Methyl-1-oxopropyl]-4-methoxy-L-proline (3.4 g), concentrated ammonia (8 ml) and water.
Add 20ml cold solution and dissolve the base for about 10 minutes,
The solution is left for 2 hours at room temperature under an argon atmosphere. The solution is cooled, extracted twice with 20 ml of ethyl acetate, separated into layers with an additional 20 ml of ethyl acetate, and acidified with 15 ml of hydrochloric acid (1:1). The mixture is saturated with sodium chloride, the layers are separated and the aqueous layer is extracted three times with 20 ml of ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and the solvent was evaporated to give an almost colorless (trans)-1-methoxy-1
2.9 g (100%) of -(D-3-mercapto-2-methyl-1-oxopropyl)-L-proline was obtained. [α] ²⁵ _D = -80° (in ethanol, concentration 1%).
Rf = 0.53 (on silica gel, eluted with methanol, visualized with nitroprusside reagent). Elemental analysis, calculated as _C10H17NO4S・1/ _4H2O : C, 47.69%; H, 6.83 _% ; _N , 5.56%; S,
12.73%, actual value: C, 47.90%; H, 6.84%; N,
5.85%; S, 12.76%. Example 5 (trans)-1-[D-3-(acetylthio)-2
Preparation of -methyl-1-oxopropyl]-4-ethoxy-L-proline: - trans-4-ethoxy-L-proline [Journal of Medicinal. Chemistry (J.
(Trans)-1
-[D-3-(acetylthio)-2-methyl-1-
Oxopropyl]-4-ethoxy-L-proline was obtained. The product was purified as its dicyclohexylamine salt. Melting point 170-172°C (crystallized from isopropyl alcohol). [α] ²⁵ _D = -64° (in ethanol, concentration 1%). The above 7.75 g was converted to the corresponding free acid by treatment with potassium hydrogen sulfate solution as in Example 4, and the (trans)-1-
[D-3-(acetylthio)-2-methyl-1-oxopropyl]-4-ethoxy-L-proline
4.85g was obtained. Example 6 (trans)-4-ethoxy-1-(D-3-mercapto-2-methyl-1-oxopropyl)-
Preparation of L-proline: - Under an argon atmosphere, a cold solution of 9 ml of concentrated ammonia in 22 ml of water is added to 4.85 g of the product of Example 5. The mixture was treated as in Example 4 to form an almost colorless syrupy substance (trans)-4-ethoxy-1-
4.2 g (100%) of (D-3-mercapto-2-methyl-1-oxopropyl)-L-proline was obtained.
[α] ²⁵ _D = -80° (in ethanol, concentration 1%). Rf＝
0.64 (on silica gel, eluted with methanol, visualized with nitroprusside reagent). Elemental analysis, calculated value as C ₁₁ H ₁₉ NO ₄ S: C,
50.55%; H, 7.33%; N, 5.36%; S, 12.27%,
Actual value: C, 50.34%; H, 7.34%; N, 5.39%;
S, 12.11%. Example 7 (cis)-1-[D-3-(acetylthio)-2-
Production of methyl-1-oxopropyl]-4-methoxy-L-proline: - a Production of N-carbobenzyloxy-cis-4-hydroxy-L-proline: - N-carbobenzyloxy-4-keto-L - Dissolve 10 g (0.038 mol) of proline in 300 ml of methanol and add
Reduced with 5.8 g (0.15 mol) of sodium borohydride and 20 ml of water according to the method described in Japan Chemical Society (JACS) Vol. 79, p. 189 (1957),
8.7 g of foam is obtained. Add this substance to 30ml of ethanol
Treat with 3.5 g of cyclohexylamine and some amount of ethanol, and dilute to 500 ml with ether. Add seed crystals, stir, and quickly separate the crystalline material to obtain 10.8 g of cyclohexylamine salt. Melting point 163-165℃. This cyclohexylamine salt was treated with 30 ml of 2N hydrochloric acid, and then treated with 50 ml of ethyl acetate.
After extraction, 8 g of N-carbobenzyloxy-cis-4-hydroxy-L-proline was obtained as a glass-like substance. b Production of N-carbobenzyloxy-cis-4-methoxy-L-proline methyl ester:
- N-carbobenzyloxy-cis-4-hydroxy-L-proline according to the procedure of Example 1b
13.9 g (0.052 mol) was mixed with 40 g of silver oxide and 40 ml of methyl iodide (twice) and acetone (100 ml for the first time,
The second time was 120 ml), and N was treated as a yellow oil.
-carbobenzyloxy-cis-4-methoxy-
L-proline methyl ester 17.5g (100%)
I got it. c Production of N-carbobenzyloxy-cis-4-methoxy-L-proline: - N-carbobenzyloxy obtained in step b above.
Dissolve 17.5 g (about 0.052 mol) of cis-4-methoxy-L-proline methyl ester in 135 ml of methanol, and add 32 ml of 2N sodium hydroxide at -1 to 4°C.
(0.064 mol) dropwise and kept at 0° C. for 1 hour and then at room temperature overnight. After removing about half the volume of the solvent on a rotary evaporator, the solution was diluted with 300 ml of water, washed with ether (discard the washings), and adjusted to pH 2 with 12.5 ml of hydrochloric acid (1:1) while cooling.
Extract 4 times with 150 ml of ethyl acetate. Combine the extracts,
After drying over magnesium sulfate and filtration, the solvent is evaporated to give 15 g of an orange-yellow syrupy product. This is dissolved in 60 ml of ethanol, treated with a mixture of 6 g of cyclohexylamine and 10 ml of ethanol, and diluted to 900 ml with ether. Add seed crystals and stir;
The crystallized product was separated, cooled overnight, and then N-
Carbobenzyloxy-cis-4-methoxy-L
-10.2 g of proline cyclohexylamine salt was obtained. Melting point 148-150℃ (sintering point 144℃). [α] ²⁶ _D = -
35° (in ethanol, concentration 1%). acetonitrile
Almost colorless solid product recrystallized from 40ml
8.8g was obtained. Melting point 150-152℃ (sintering point 145℃).
[α] ²⁶ _D = -34° (in ethanol, concentration 1%). Treating the above cyclohexylamine salt with hydrochloric acid,
6.9 g (48%) of N-carbobenzyloxy-cis-4-methoxy-L-proline was obtained as a pale yellow viscous syrupy product. [α] ²⁶ _D = -32° (in ethanol, concentration 1%). d Production of cis-4-methoxy-L-proline:
- On the hydrogenation equipment, N-carbobenzyloxy-
A mixture of 6.8 g of cis-4-methoxy-L-proline, 210 ml of methanol-water (2:1) and 2.3 g of 5% palladium-carbon is hydrogenated at 3 atmospheres of hydrogen for 4 hours. The catalyst is filtered off from the mixture and the filtrate is evaporated to give 3.15 g of a gray solid product. melting point
218-220℃ (decomposition). A portion of this product was crystallized from methanol-ether to give a colorless cis-4-
Methoxy-L-proline was obtained. Melting point 224-226℃
(Disassembly). [α] ²⁵ _D = -42° (in methanol, concentration 1
%). Elemental analysis, calculated value as C ₆ H ₁₁ NO ₃ : C,
49.64%; H, 7.64%; N, 9.65%, actual value: C,
49.63%; H, 7.71%; N, 9.54%. e (cis)-1-[D-3-(acetylthio)-2
- Preparation of methyl-1-oxopropyl]-4-methoxy-L-proline: - cis in 60 ml of water in the presence of sodium bicarbonate.
-4-methoxy-L-proline 3g (0.021 mol)
and D-3-acetylthio-2-methylpropionyl chloride 4.2 g (0.023 mol) and ether 5
ml are reacted according to the procedure of Example 3. During the above acylation, 25% (w/v) sodium carbonate approx.
After adjusting the pH to 8.5 using ml, maintain the pH between 7.5 and 8.4. 6.4 g of the obtained viscous crude product was dissolved in ethyl acetate.
Dissolve in 50 ml and treat with 3.9 g of dicyclohexylamine and 20 ml of ethyl acetate. The product crystallized from the solution is filtered and dried to obtain 6.6 g of dicyclohexylamine salt. Melting point 172-174℃ (sintering point 170
℃). [α] ²⁶ _D = -60° (in ethanol, concentration 1%)
.
Recrystallize 6.5 g of this product from 35 ml of acetonitrile to obtain 6 g of colorless solid dicyclohexylamine salt.
I got it. Melting point 173-175℃ (sintering point 170℃). [α] ²⁶ _D
= -60° (in ethanol, concentration 1%). Elemental analysis, calculated values as C ₁₂ H ₁₉ NO ₅ S and C ₁₂ H ₂₃ N: C, 61.24%; H, 9.00%; N, 5.95%;
S, 6.81%, actual value: C; 61.16%; H, 8.81%;
N, 5.95%; S, 6.67%. Following the procedure of Example 3, 5.9 g of the above dicyclohexylamine salt is suspended in 60 ml of ethyl acetate, cooled on an ice bath and treated with 60 ml of 10% potassium hydrogen sulfate. The layers are separated and the aqueous layer is extracted four times with 50 ml of ethyl acetate. The organic layers were combined, dried over magnesium sulfate, filtered, and the solvent was evaporated to convert the dicyclohexylamine salt to the corresponding acid to give the colorless (cis)-1-[D-3-(acetylthio). 3.5 g (60%) of -2-methyl-1-oxopropyl]-4-methoxy-L-proline was obtained. Melting point 90-92°C after treatment with ether. [α] ²⁶ _D = -139° (in ethanol, concentration 1%). Rf = 0.63 (on silica gel, eluted with methanol). Elemental analysis, calculated value as C ₁₂ H ₁₉ NO ₅ S: C,
49.81%; H, 6.62%; N, 4.84%, actual value: C,
49.85%; H, 6.66%; N, 4.97%. Example 8 (cis)-4-methoxy-1-(D-3-mercapto-2-methyl-1-oxopropyl)-L
- Preparation of proline: - Example 7 in 15 ml of water containing 6.5 ml of concentrated ammonia.
2.9 g (0.01 mol) of (cis)-1-[D-3-(acetylthio)-2-methyl-1-oxopropyl]-4-methoxy-L-proline obtained in Example 4 was added with water in the same manner as in Example 4. Upon decomposition, 2.3 g (93%) of (cis)-4-methoxy-1-(D-3-mercapto-2-methyl-1-oxopropyl)-L-proline with significant viscosity was obtained. After leaving it
It becomes waxy. ). [α] ²⁶ _D = -88° (in ethanol, concentration 1%). Example 8a (cis)-1-methoxy-1-(D-3-mercapto-2-methyl-1-oxopropyl)-L
- Production of proline adamantanamine salt: - Under argon atmosphere, cis-4-methoxy-1-
(D-3-mercapto-2-methyl-1-oxopropyl)-L-proline 0.55 g (0.0022 mol)
A 15 ml solution of 1-adamantanamine in 10 ml of ethyl acetate is treated with a warm solution of 0.34 g (0.0022 mol) of 1-adamantanamine in 10 ml of ethyl acetate to precipitate the salt. After being kept in the cold for 3 hours, the colorless solid was collected by filtration under an argon atmosphere (keeping the solvent viscous), washed with some cold ethyl acetate, and dried under reduced pressure for 20 hours to give (cis)-4. -Methoxy-1-(D-3-mercapto-2-methyl-1-oxopropyl)-L-proline adamantanamine salt 0.7 g (79%) was obtained. Melting point 215~
217℃. Sintering point 210℃ (decomposes at 220℃). [α] ²⁶ _D = -
60° (in methanol, concentration 1%). Example 9 Preparation of (cis)-4-methoxy-1-(3-mercapto-2-methyl-1-oxopropyl)-L-proline: - a (cis)-4-methoxy-1-[3-( benzoylthio)-2-methyl-1-oxopropyl]-
Preparation of L-proline: - 3-benzoylthio-2-methylpropanoic acid chloride (prepared by treatment of 3-benzoylthio-2-methylpropanoic acid with thionyl chloride) according to the general procedure described in Example 3. ) and cis-4
-Methoxy-L-proline is reacted with (cis)
-4-methoxy-1-[3-(benzoylthio)-
2-Methyl-1-oxopropyl]-L-proline was obtained. b (cis)-4-methoxy-1-(3-mercapto-2-methyl-1-oxopropyl)-L-
Preparation of proline: - (cis)-4-methoxy-1-[3-(benzoylthio)-2-methyl-1-oxopropyl]-2-proline with aqueous ammonia solution according to the general procedure of Example 4. Hydrolysis yielded (cis)-4-methoxy-1-(3-mercapto-2-methyl-1-oxopropyl)-L-proline. Example 10 (trans)-1-[D-3-(acetylthio)-2
-Methyl-1-oxopropyl]-4-propoxy-L-proline production: - a N-acetyl-trans-4-propoxy-L
- Preparation of proline propyl ester: - N-acetyl-trans according to the procedure of Example 1b
30 g of -4-hydroxy-L-proline (product of Example 1a) are treated with 110 g of silver oxide and 110 ml of propyl iodide and 300 ml of acetone to give a pale yellow-orange N-acetyl-trans-4-propoxy-L −
19.6 g (41%) of proline propyl ester are obtained. Boiling point (0.2mmHg) 155-165℃. b N-acetyl-trans-4-propoxy-L
- Production of proline: - 6 g (0.15 mol) of sodium hydroxide in 150 ml of water
The solution is N-acetyl-trans-4-propoxy-
L-proline propyl ester 19.4g (0.075
mol) to obtain a pale yellow solution. After standing overnight at room temperature, the solution is extracted with 60 ml of ethyl acetate (discarding the washings), acidified with hydrochloric acid (1:1), saturated with sodium chloride and extracted three times with 50 ml of chloroform. The organic layers were combined, dried over magnesium sulfate, filtered, and the solvent was evaporated to give 12.6 g of a brown oil.
get. This is dissolved in 80 ml of ethyl acetate and treated with a solution of 10.7 g of dicyclohexylamine in 20 ml of ethyl acetate (the salt crystallizes at room temperature). After standing overnight in the refrigerator, the crystallized dicyclohexylamine salt is filtered off and washed with cold ethyl acetate to obtain 17.3 g of almost colorless solid dicyclohexylamine salt. Melting point 148-153℃. Add this to 125ml of ethyl acetate.
Colorless dicyclohexylamine salt recrystallized from
14.5g was obtained. Melting point 157-159℃. [α] ²⁵ _D = -30° (in ethanol, concentration 1%). Elemental analysis, calculated values _{as C10H17NO4・C12H23N : C ,} 66.63%; H, 10.17%; _N , 7.07%,
Actual value C, 66.47%; H, 10.22%; N, 7.06%. Grind 14.4 g of the above dicyclohexylamine salt, suspend it in 100 ml of ethyl acetate, and add this slurry.
Treat with small portions of 100 ml of 10% potassium hydrogen sulfate. The organic layer is separated and the aqueous layer is extracted twice with 100 ml of ethyl acetate. By combining the organic layers, drying over magnesium sulfate, filtering, and evaporating the solvent.
The above dicyclohexylamine salt was converted to the corresponding free acid and N-acetyl-
trans-4-propoxy-L-proline 6.7g (41
%) was obtained. c (trans)-1-[D-3-(acetylthio)-
Preparation of 2-methyl-1-oxopropyl]-4-propoxy-L-proline: - N-acetyl-trans-4-propoxy-L-
6.4 g (0.03 mol) of proline in 10 g of concentrated sulfuric acid and 100 g of water.
ml solution and the solution is stirred and refluxed for 3 hours. Cool the solution to 15°C, add 12 g of sodium carbonate little by little to bring the pH to 8.0, and add D-3-acetylthio-2-methylpropionyl while maintaining the pH at approximately 8.0 by adding 7 g of sodium carbonate over 10 minutes. Treat with a solution of 5.4 g (0.03 mol) of chloride in 5 ml of ether. The mixture is stirred on the ice bath for 30 minutes and then at room temperature for 1 hour. The product was isolated and purified as the dicyclohexylamine salt according to the procedure described in Example 3, yielding 6.3 g of the dicyclohexylamine salt. Melting point 165-167°C (crystallized from acetonitrile). [α] ²⁵ _D = -56° (in ethanol, concentration 1%). Elemental analysis, calculated values as C ₁₄ H ₂₃ NO ₅ S and C ₁₂ H ₂₃ N: C, 62.62%; H, 9.30%; N, 5.61%; S,
6.43%, actual value: C, 62.35%; H, 6.48%; N,
5.88%; S, 6.45%. 6.1 g of the above dicyclohexylamine salt was suspended in 60 ml of ethyl acetate, cooled on an ice bath, and treated with 60 ml of 10% potassium hydrogen sulfate. The layers are separated and the aqueous layer is extracted twice with 60 ml of ethyl acetate. The dicyclohexylamine salt was converted to the corresponding free acid by combining the organic layers, drying over magnesium sulfate, filtering, and evaporating the solvent, giving (trans)-1-[D-3 as an almost colorless syrupy substance. -(acetylthio)-2-methyl-1-oxopropyl]
-4-propoxy-L-proline 4.0g (42%)
I got it. Example 11 1-(D-3-mercapto-2-methyl-1-
oxopropyl)-trans-4-propoxy-L
- Preparation of proline: - (trans)-1-[D-3-(acetylthio)-2-methyl-1-oxopropyl]-4-propoxy- according to the procedure of Example 4 under an argon atmosphere.
4.0g of L-proline, 8ml of concentrated ammonia and 20ml of water
1-(D-3-mercapto-2-methyl-1-
oxopropyl)-trans-4-propoxy-L-
3.42 g (97%) of proline was obtained. [α] ²⁵ _D = -72° (in ethanol, concentration 1%). Elemental analysis, calculated values _{as C12H2NO4S}・1/ _4H2O : C, 51.49%; H, 7.74%; _N , 5.05%; S,
11.46%, actual value: C, 51.66%; H, 7.76%; N,
5.94%; S, 10.51%. Example 12 (cis)-1-[D-3-(benzoylthio)-2
-Methyl-1-oxopropyl]-4-methylthio-L-proline production:-(cis)-4-methylthio-L-proline [the...
Journal of the American Chemical
Society (J.Amer.Chem.Soc.) Vol. 79, p. 185 (1957)] and D-3-(benzoylthio)-
Equivalents of 2-methyl-propionyl chloride are reacted with each other according to the procedure of Example 3 to form (cis)-1
-[D-3-(benzoylthio)-2-methyl-1
-oxopropyl]-4-methylthio-L-proline was obtained. Example 13 (cis)-4-(4-fluorophenoxy)-1-
Production of (D-3-mercapto-2-methyl-1-oxopropyl)-L-proline: - a (cis)-4-(4-fluorophenoxy)-L
- Production of proline: - N-carbobenzoxy-trans-4-hydroxy-L-proline benzyl ester [Baer et al.: Canadian Journal of
Biochemistry and Physiology (Can.J.Biochem.&Phys.) Vol. 37, p. 583 (1959)
8.4 g (0.024 mol), 4.0 g (0.036 mol) of 4-fluorophenol, and 9.27 g (0.036 mol) of triphenylphosphine were dissolved in 75 ml of dry tetrahydrofuran, and 25 ml of tetrahydrofuran and azodicarbonate were dissolved in this solution. diethyl acid
6.2 g (0.036 mol) are added dropwise to the mixture over the course of 1 hour. The solution is stirred at room temperature overnight. The mixture is evaporated to dryness and 100 ml of ether are added to the residue. Triphenylphosphine and diethyl azodicarboxylate are filtered off. By column chromatography (silica gel) 8.1 g of a mixture containing approximately 70% of N-carbobenzoxy-cis-4-(4-fluorophenoxy)-L-proline benzyl ester are separated. Mixture 7.5 containing the above benzyl ester
1 g of solution with 0.8 g of 10% palladium/carbon
Hydrogenate at atmospheric pressure (room temperature). A white precipitate forms during the reaction. After the absorption of hydrogen has ended, the mixture is filtered and the filter residue is soaked three times with 125 ml each of hot methanol. Evaporate the methanol solution to dryness
Cis-4-(4-fluorophenoxy)-L-proline was obtained. Melting point 235-236℃. Elemental analysis, calculated values as C1 ₁ H ₁₂ FNO ₃ 1/3 H ₂ O: C, 57.14%; H, 5.48%; N, 6.06%;
F, 8.22%, actual value: C, 56.94%; H, 5.19%;
N, 5.94%; F, 7.97%. b Preparation of 1-[D-3-(acetylthio)-2-methyl-1-oxopropyl]-cis-4-(4-fluorophenoxy)-L-proline: - At room temperature, 125 ml of dry pyridine and the above 1.0 g (0.01 mol) of triethylamine and D-3-(acetylthio)-2 were added to the suspension of 2.25 g (0.01 mol) of cis-4-(4-fluorophenoxy)-L-proline obtained in step a. -Methylpropionyl chloride 2
g (0.011 mol). After stirring overnight at room temperature, the mixture is evaporated to dryness. Dissolve the residue in water,
Add ether and acidify with 10% hydrochloric acid. Extract the aqueous layer repeatedly with ether, combine the ether layers,
Wash with water, dry over sodium sulfate, and evaporate to dryness to obtain 3.9 g of residue. Pour this residue into 250ml of silica gel.
The above is chromatographed with ether to obtain fractions containing the desired product. The column is washed with methanol and the methanol wash is rechromatographed on a short silica gel column to obtain more product. Repeat this process once more to obtain pure 1-[D-3-(acetylthio)-2-methyl-1
A total of 1.2 g of -oxopropyl]-cis-4-(4-fluorophenoxy)-L-proline was obtained. c (cis)-4-(4-fluorophenoxy)-1
- Production of (D-3-mercapto-2-methyl-1-oxopropyl)-L-proline: - 1-[D-3-(acetylthio)-2-methyl-1-oxopropyl obtained in b above ]-cis-
4-(4-fluorophenoxy)-L-proline
1.2 g was dissolved in 25 ml of methanol and treated with 5 ml of concentrated aqueous ammonia for 40 minutes under an argon atmosphere. Remove volatiles and add ethyl acetate to the residue.
Acidify the aqueous layer with 10% hydrochloric acid. Separate the layers and wash the acid layer with ethyl acetate. The organic layers are combined, washed with water (twice), saturated sodium chloride solution (twice) and dried over sodium sulfate. remove the solvent,
1.1 g of cis-4-(4-fluorophenoxy)-1-(D-3-mercapto-2-methyl-1-oxopropyl)-L-proline was obtained as a foamy solid residue. Elemental analysis, calculated values as C ₁₅ H ₁₈ FNSO ₄・1/3H ₂ O: C, 54.05%; H, 5.70%; 4.20%; F,
5.70%; S, 9.60%, actual value: C, 54.04%; H,
5.71%; N, 4.05%; F, 5.40%; S, 9.61%. Rf0.30 by thin layer chromatography of the product
(Detected with ultraviolet light, SH reagent (yellow spot) and vanillin (yellow spot)). [α] ²⁵ _D = -80° (in chloroform, concentration 1%). Example 14 (cis)-4-(4-fluorophenylthio)-1
Preparation of proline of -(D-3-mercapto-2-methyl-1-oxopropyl)-L-: - Using 4-fluorophenyl mercaptan instead of 4-fluorophenol in the treatment of Example 13a and similarly (cis)-4-(4-fluorophenylthio)-1-(D-3-mercapto-
Proline of 2-methyl-1-oxopropyl)-L was obtained. Example 15 1-(D-3-mercapto-2-methyl-1-
oxopropyl)-cis-4-phenylthio-L
- Production of proline: - a Production of N-carbobenzyloxy-cis-4-phenylthio-L-proline methyl ester: - Dissolve 0.85 g (0.037 mol) of sodium metal in 40 ml of absolute ethanol. In this, thiophenol
3.7 ml (0.036 mol) followed by N-carbobenzyloxy-trabs-4-tosyloxy-L-proline methyl ester [The Journal of
The American Chemical Society (J.
Amer.Chem.Soc.) Vol. 79, p. 191 (1957)]
Add 7.5 g (0.017 mol) with stirring. The remaining compounds gradually dissolve into solution, but shortly thereafter the solid product separates. Stir for 4 hours,
After standing overnight at room temperature, most of the ethanol is removed on a rotary evaporator. The mainly solid residue is stirred with 120 ml of dichloromethane and 60 ml of water. Separate each layer (add some methanol to prevent emulsion),
Extract the aqueous layer with additional dichloromethane (2 x 60 ml). Combine the organic layers and add saturated sodium chloride solution
N-carbobenzyloxy-cis
6.5 g (100%) of -4-phenylthio-L-proline methyl ester was obtained as a pale yellow viscous oil. b Production of N-carbobenzyloxy-cis-4-phenylthio-L-proline: - Dissolve 6.5 g (0.017 mol) of the methyl ester product in a above in 55 ml of methanol, and dissolve 2N at -1 to 4°C.
13 ml (0.026 mol) of sodium hydroxide is treated in portions, stirred at 0° C. for 1 hour and kept at room temperature for about 16 hours. Approximately half of the solvent was removed on a rotary evaporator, the cooled solution was diluted with 100 ml of water, washed with 60 ml of ether (discarding the washings), and diluted with 70 ml of ethyl acetate.
Extract with 4.8 ml of hydrochloric acid (1:1), stir, cool and
Acidify with ml. After separating the layers, the aqueous layer is extracted with additional cm ² of ethyl acetate (3 x 40 ml) and the organic layers are combined, dried over magnesium sulfate and evaporated to give 5.9 g of a pale yellow viscous oil. This was dissolved in 30 ml of ethanol, treated with a mixture of 3 ml of ethanol and 1.9 g of cyclohexylamine, and treated with ether.
Dilute to 330ml. Seed crystals are added to precipitate crystalline cyclohexylamine salt. Cool this for about 16 hours to obtain 5.3 g of cyclohexylamine salt.
Melting point 148-151℃ (sintering point 135℃). This material was combined with 1.5 g of the same product obtained from the previous operation, stirred with 200 ml of boiling acetonitrile, and cooled to yield 6.3 g of the colorless cyclohexylamine salt. Melting point 152-155℃ (sintering point 137℃). [α] ²⁶ _D = -
24° (in ethanol, concentration 1%). Add this cyclohexylamine salt to 25 ml of ethyl acetate.
Suspend in water, stir, and treat with 25 ml of N-hydrochloric acid. When two clear layers form, they are separated and the aqueous layer is extracted with additional ethyl acetate (3 x 25 ml). The combined organic layers were combined, dried over magnesium sulfate, and the solvent was evaporated to give 5.0 g of N-carbobenzyloxy-cis-4-phenylthio-L-proline.
(65%) was obtained as an almost colorless, very viscous syrup. c Preparation of (cis)-4-phenylthio-L-proline hydrobromide: - 4.9 g (0.014 mol) of N-carbobenzyloxy-cis-4-phenylthio-L-proline was dissolved in acetic acid (30-32% ) Treat with 25 ml of hydrogen bromide, loosely cap the container, and stir with a magnetic stirrer. After 1 hour, the orange-yellow solution was diluted to 250 ml with ether and
The product precipitates as a heavy oil which gradually crystallizes upon seeding, stirring and cooling. After stirring in an ice bath for 1 hour, the material was filtered under a nitrogen atmosphere, washed with ether, suspended in fresh ether, cooled for approximately 16 hours, and filtered again to give a colorless solid (cis)-4. 3.2 g (77%) of -phenylthio-L-proline hydrobromide was obtained. Melting point 106~109
°C (sintering point 99 °C). [α] ²⁶ _D = −3° (in methanol,
concentration 1%). d Production of 1-[D-3-(acetylthio)-2-methyl-1-oxopropyl]-cis-4-phenylthio-L-proline: - (cis)-4-phenylthio- obtained in step c above
L-proline hydrobromide 3.0g (0.0094mol)
and D-3-acetylthio-2-methylpropionyl chloride in 25 ml of water.
React as described in 1d (using approximately 15 ml of 20% sodium carbonate solution to maintain the PH between 8.0 and 8.4) to obtain 3.8 g of a pale yellow viscous oil. Dicyclohexylamine salt of the product (using 1.89 g of dicyclohexylamine and 30 g of ethyl acetate)
2.9 g (product isolated twice) are obtained. Melting point 184-188℃ (sintering point 180℃). The mixture was then triturated with 15 ml of acetonitrile to obtain 2.4 g of colorless solid dicyclohexylamine salt. Melting point 184-186
℃ (sintering point 180℃). [α] ²⁶ _D = -75° (in ethanol, concentration 1%). This dicyclohexylamine salt was treated with 30 ml of 10% potassium hydrogen sulfate in the same manner as in Example 1, extracted into ethyl acetate, and a glass-like 1-[D-3-(acetylthio)-2-methyl-1-oxopropyl ]−
cis-4-phenylthio-L-proline 2.0g (59
%) was obtained. e 1-(D-3-mercapto-2-methyl-1
-oxopropyl)-cis-4-phenylthio-
Production of L-proline: - 1-[D-3-(acetylthio)-2-methyl-1-oxopropyl]-cis- obtained in step d above
4-phenylthio-L-proline 2.0g (0.0042
mol) is treated with 8.5 ml of water and 3.5 ml of concentrated ammonia according to the procedure of Example 2 (the solid ammonium salt of the product separates from the reaction mixture) to form a viscous syrupy 1-(D- 3-Mercapto-2
1.35 g (100%) of -methyl-1-oxopropyl)-cis-4-phenylthio-L-proline was obtained.
[α] ²⁶ _D = -43° (in ethanol, concentration 1%). Example 16 1-(D-3-mercapto-2-methyl-1-
Preparation of 1-oxopropyl)-cis-4-(4-chlorophenylthio)-L-proline:-Production of 1- (D-3-Mercapto-
2-methyl-1-oxopropyl)-cis-4-
(4-chlorophenylthio)-L-proline was obtained. Example 17 Production of (trans)-1-(3-mercapto-1-oxopropyl)-3-methylthio-D,L-proline: - a Production of 1,2-dehydroproline t-butyl ester: - Proline・Add newly produced t-butyl hypochlorite [Organic Synthesis Collective Volume V ( Crg.Syn., Coll.Vol.V)
184 (1973)] 21.7 g (23.9 ml, 0.20 mol) are added dropwise over 10 minutes. The temperature is maintained between -5 and 0°C during the dropwise addition. After the addition is complete, the solution is stirred at this temperature for a further 5 minutes. This solution was stirred vigorously and potassium 7.8
A solution of g (0.20 mol) of t-butanol (freshly distilled and dried over calcium hydride) is added quickly (over 3-5 minutes). After the addition, the temperature of the reaction mixture is approximately 18°C. Remove the reaction vessel from the cooling bath and stir for 30 minutes. The reaction mixture is filtered through Celite (diatomaceous earth) and the filtrate is concentrated under reduced pressure. The residue is dissolved in ether and washed several times with water. The ether solution is dried and concentrated under reduced pressure to obtain 31.6 g of a yellow liquid. A trace amount of hydroquinone was added and the crude product was distilled to yield 22.4 g (66%) of 1,2-dehydropurine t-butyl ester. Boiling point 60-62℃/0.1mm. b 1-benzyloxycarbonyl-4,5-dihydro-1H-pyrrole-2-carboxylic acid t
-Manufacture of butyl ester:-1,2-dehydroproline obtained in above a.
A solution of 16.9 g (0.1 mol) of t-butyl ester in 70 ml of dichloromethane is cooled to -10 DEG C. under an argon atmosphere. Freshly distilled benzyl chloroformate
A solution of 14.2 ml (0.1 mol, boiling point 62-64° C./0.4 mm) in 70 ml dichloromethane is added dropwise over 30 minutes. 30 more
After cooling and stirring for a minute, a solution of 15.22 g (0.1 mol) of 1,5-diazobicyclo[5.4.0]undec-5-ene in 70 ml of dichloromethane is added over a period of 20 minutes. Remove the cooling bath and stir the mixture for 1 hour at room temperature. After washing twice with cold dilute hydrochloric acid and once with saturated sodium carbonate solution, the solution was dried under reduced pressure and 1-benzyloxycarbonyl-4,5-dihydro-
18.2 g (60%) of 1H-pyrrole-2-carboxylic acid t-butyl ester was obtained as a pale yellow oil. c (trans)-1-benzyloxycarbonyl-
Production of 3-methylthio-D,L-proline/t-butyl ester: - 18.2 g of 1-benzyloxycarbonyl-4,5-dihydro-1H-pyrrole-2-carboxylic acid t-butyl ester obtained in step b above. (0.06 mol)
A solution of 180 ml of dry methanol is treated with 3.24 g (0.06 mol) of sodium methoxide and cooled in an ice bath. Slowly add methanethiol to the solution for 30 minutes.
Let it bubble for a minute. The mixture is stirred at room temperature under an argon atmosphere overnight. Add dilute aqueous acetic acid until the solution becomes slightly acidic. The solution is bubbled with argon for 1 hour and then brought to near dryness under reduced pressure. Ethyl acetate is added, the solution is washed twice with saturated sodium carbonate solution, dried and the solvent is removed under reduced pressure to give 17 g of a yellow oil. This oil was chromatographed using 300 g of silica gel and petroleum ether:ether (4:1),
(trans)-1-benzyloxycarbonyl-3-
11.1 g of methylthio-D,L-proline was obtained as a colorless oil. d Production of (trans)-3-methylthio-D,L-proline: - 8.4 g (0.024 mol) of (trans)-1-benzyloxycarbonyl-3-methylthio-D,L-proline obtained in step c above. 4N hydrobromide in acetic acid
Process with 45ml. After stirring for 1 hour at room temperature, the solution is dried under reduced pressure. Add a little water and wash this twice with ether. Ion exchange resin aqueous solution
Apply to a column containing 300 ml and pass water through until the eluate is no longer strongly acidic. The product is eluted with PH6.5 (aqueous pyridine acetate) buffer. The fractions positive for ninhydrin are combined and lyophilized to yield 3.4 g (88%) of a white fluffy product. A small amount of this material was crystallized from methanol to yield (trans)-3-methylthio-D,L-proline. Melting point 196~200℃
(Disassembly). Sintering point 192℃. Elemental analysis, calculated value as C ₆ H ₁₁ O ₂ NS: C,
44.70%; H, 6.88%; N, 8.69%; S, 19.89%,
Actual value: C, 44.53%; H, 7.10%; N, 8.61%;
S, 19.95%. e (trans)-1-[3-(acetylthio)-1-
oxopropyl]-3-methylthio-D,L-
Production of proline: - (trans)-3-methylthio- obtained in step d above
Dissolve 3.05 g (0.019 mol) of D,L-proline in 19 ml of 1N sodium carbonate and dilute with 10 ml of water. Cool the solution in an ice bath and add 20 ml of ether of 3-acetylthiopropionyl chloride with rapid stirring.
Add solution. Add 1N sodium carbonate to pH 8
Keep it. After 30 minutes, already 45 ml of sodium carbonate solution
is added, so the pH is kept constant.
Separate the layers and wash the aqueous layer once with ether.
The aqueous layer is acidified with 10% potassium hydrogen sulfate solution, the product is extracted into ethyl acetate, dried and the solvent is removed under reduced pressure to yield 5.2 g of an oil. This material is chromatographed on 150 g of silica gel using ethyl acetate as eluent. Some impurity (trans)-1-[3-(acetylthio)-1-oxopropyl]-3-methylthio-D,L-proline
Obtain 3.85g. A small amount of the product was dissolved in ether, converted to the dicyclohexylamine salt, and recrystallized from ethyl acetate to give (trans)-1-[3-(acetylthio)-1-
Oxopropyl]-3-methylthio-D,L-proline dicyclohexylamine salt was obtained. melting point
153-157℃. Elemental analysis, calculated values as C ₁₁ H ₁₇ O ₄ NS・(C ₆ H ₁₁ ) ₂ NH: C, 58.44%; H, 8.53%; N, 5.83
%; S, 13.57%, actual value: C, 58.77%; H,
8.57%; N, 5.68%; S, 13.74%. Production of f (trans)-1-(3-mercapto-1-oxopropyl)-3-methylthio-D,L-proline: - (trans)-1-[3-(acetylthio)-1-oxopropyl]- 2.05 g (0.007 mol) of 3-methylthio-D,L-proline was added under an argon atmosphere.
Cool in an ice bath and treat with a cold argon-saturated mixture of 7 ml water and 7 ml concentrated ammonia. After stirring for 30 minutes at 0°C, the solution is acidified with hydrochloric acid. The product is extracted with ethyl acetate, dried and the solvent removed under reduced pressure, yielding 1.85 g of material. If left alone, it will partially crystallize. Trituration with ether gives 1.0 g (57%) of white crystalline product. ethyl acetate 5
Recrystallized from (trans)-1-(3-mercapto-1-oxopropyl)-3-methylthio D,
0.85 g of L-proline was obtained. Melting point 89-93℃. Elemental analysis, calculated value as C ₉ H ₁₅ O ₃ NS ₂ : C,
43.35%; H, 6.06%; N, 5.62%; S, 25.72%,
Actual value: C, 43.35%; H, 6.27%; N, 5.54%;
S, 25.91%.

Claims (1)

[Claims] 1 Formula: Compounds represented by and their salts. [In the formula, X-R ₁ group is 3 or 4 of the proline ring
position. X is oxygen or sulfur; R is hydrogen;
R ₁ is lower alkyl, phenyl, or halogen-substituted phenyl; R ₂ is hydrogen or lower alkyl;
R ₃ is hydrogen; R ₄ is hydrogen or [Formula] (wherein R ₅ is lower alkyl or phenyl; n represents 1). 2 The compound according to claim 1, wherein X is oxygen. 3 4. A compound according to claim 1, wherein X is sulfur. 4. A compound according to claim 1, wherein R ₄ is hydrogen. 5. A compound according to claim 1, wherein the proline ring is in the L-configuration. Compound described in Section 6. Formula: The compound according to claim 1, which is represented by: and its basic salts. [In the formula, X-R ₁ group is 3 or 4 of the proline ring
position. X is oxygen or sulfur; R is hydrogen;
R ₁ is lower alkyl having 1 to 3 carbon atoms or (where R ₆ is hydrogen or fluorine); R ₂ is hydrogen or methyl; R ₃ is hydrogen; R ₄ is hydrogen, acetyl or benzoyl; n is 1]. 7. The compound according to claim 6, wherein X is oxygen. 8. The compound according to claim 7, wherein R ₄ is hydrogen; R ₂ is hydrogen or methyl. 9. The compound according to claim 8, wherein _R1 is lower alkyl having 1 to 3 carbon atoms. 10 Proline ring has L-configuration; when R ₂ is a group other than hydrogen, the asymmetric carbon atom to which R ₂ is bonded has D-configuration; -O-R ₁ group is at the 4-position of the proline ring. 10. A compound according to claim 9, wherein the compound is in the cis configuration. 11 Claim 10 in which R ₁ is methyl
Compounds described in Section. 12 The compound name is (cis)-4-methoxy-1-
12. The compound according to claim 11, which is (D-3-mercapto-2-methyl-1-nexopropyl)-L-proline. 13 The compound name is (cis)-4-methoxy-1-
12. The compound according to claim 11, which is (3-mercapto-1-oxopropyl)-L-proline. 14 The proline ring has an L-configuration; when R ₂ is a group other than hydrogen, the asymmetric carbon atom to which R ₂ is bonded has a D-configuration; -O-R ₁ group is at the 4-position of the proline ring. 10. A compound according to claim 9 which is in the trans configuration. 15 Claim 14 in which R ₁ is methyl
Compounds described in Section. 16 The compound name is (trans)-4-methoxy-1-
16. The compound according to claim 15, which is (D-3-mercapto-2-methyl-1-oxopropyl)-L-proline. 17 The compound name is (trans)-4-methoxy-1-
16. The compound according to claim 15, which is (3-mercapto-1-oxopropyl)-L-proline. 18 Claim 14 in which R ₁ is ethyl
Compounds described in Section. 19 The compound name is (trans)-4-ethoxy-1-
19. The compound according to claim 18, which is (D-3-mercapto-2-methyl-1-oxopropyl)-L-proline. 15. The compound according to claim 14, wherein 20 R ₁ is n-propyl. 21 The compound name is (trans)-4-propoxy-1
21. The compound according to claim 20, which is -(D-3-mercapto-2-methyl-1-oxopropyl)-L-proline. 22 R ₁ is The compound according to claim 8, wherein R ₆ is hydrogen or fluorine. 23 The proline ring has an L-configuration; when R ₂ is a group other than hydrogen, the asymmetric carbon atom to which R ₂ is bonded has a D-configuration; -O-R ₁ group is at the 4-position of the proline ring. 23. A compound according to claim 22, wherein: 24 Claim 23, wherein the compound name is (cis)-4-(4-fluorophenoxy)-1-(D-3-mercapto-2-methyl-1-oxopropyl)-L-proline Compounds described. 7. A compound according to claim 6, wherein 25 X is sulfur. 26. The compound according to claim 25, wherein R ₄ is hydrogen; R ₂ is hydrogen or methyl. 27. The compound according to claim 26, wherein R ₁ is lower alkyl having 1 to 3 carbon atoms. 28 Claim 27 in which R ₁ is methyl
Compounds described in Section. 29 The compound name is (trans)-1-(3-mercapto-1-oxopropyl)-3-methylthio-D,
29. The compound according to claim 28, which is L-proline. 30 R ₁ is The compound according to claim 26, wherein R ₆ is hydrogen or fluorine. 31 The compound name is 1-(D-3-mercapto-2
-Methyl-1-oxopropyl)-cis-4-phenylthio-L-proline. 32. The compound according to claim 7, wherein R ₄ is acetyl; R ₂ is hydrogen or methyl. 33. The compound according to claim 32, wherein _R1 is lower alkyl having 1 to 3 carbon atoms. 34 The proline ring has the L-configuration; when R ₂ is a group other than hydrogen, the asymmetric carbon atom to which R ₂ is bonded has the D-configuration; -O-R ₁ group is at the 4-position of the proline ring. 34. A compound according to claim 33, wherein the compound is in the cis configuration. 35 Claim 34 in which R ₁ is methyl
Compounds described in Section. 36 The compound name is (cis)-4-methoxy-1-
36. The compound according to claim 35, which is [D-(acetylthio)-2-methyl-1-oxopropyl]-L-proline. 37 Proline ring has L-configuration; when R ₂ is a group other than hydrogen, the asymmetric carbon atom to which R ₂ is bonded has D-configuration; -O-R ₁ group is at the 4-position of the proline ring. 34. A compound according to claim 33, wherein the compound is in the trans configuration. 38 Claim 37 in which R ₁ is methyl
Compounds described in Section. 39 Claim 37 in which R ₁ is ethyl
Compounds described in Section. 38. A compound according to claim 37, wherein _R1 is n-propyl. 41 R ₁ 33. The compound according to claim 32, wherein R ₆ is hydrogen or fluorine. 42. The compound according to claim 25, wherein R ₄ is acetyl; R ₂ is hydrogen or methyl. 43. The compound according to claim 42, wherein R ₁ is lower alkyl having 1 to 3 carbon atoms. 44 R ₁ is 43. The compound according to claim 42, wherein R ₆ is hydrogen or fluorine.