KR850000573B1 - Process for preparing lactams - Google Patents

Abstract

The title compds. (I; n = 0 or 1; Y = =0; R1,R2,R3,R4 = H or C1-3 alkyl; R5,R6 = H; R7 = H or C5-7 cycloalkyl), useful as antihypertensives (no data), were prepd. by closing the ring of wmercaptocarboxylic acid or its derivatives. Thus, 2.0 g N- cyclopentyl-N-(3-mercapto-2-methylpropanoyl)glycin was reacted with 2.7 g 2,2'-dipyridyldisulfide and 5.2g triphenylphosphine to give 0.5g 4-cyclopentyl-6,7-dihydro-6-methyl-1,4-thiazaphen-2,5-(3H,4H) dione (27%).

Description

Method of manufacturing lactam

The present invention relates to a method for producing a compound of formula (Ia), which is novel, exhibiting antihypertensive action and angiotensin converting enzyme inhibitory action.

In the general formula, n is an integer of 0 to 2, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and R ₇ are each independently hydrogen, alkyl, alkenyl, alkynyl, Cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, fused arylcycloalkyl, fused arylcycloalkylalkyl, fused hetero Arylcycloalkyl, fused heteroarylcycloalkylalkyl or substituted alkyl (eg, hydroxyalkyl, carboxyalkyl, carboalkoxyalkyl, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, or dialkylaminoalkyl, etc.); When taken together, R ₁ and R ₂ and the carbon to which they are bonded, R ₃ and R ₄ and the carbon to which they are attached, and R ₅ and R ₆ and the carbon to which they are bonded together are cycloalkyl, heterocycloalkyl, heterocycloalkenyl Or cycloalkenyl; When R ₂ is taken together with R ₃ and the carbons to which they are attached, they are cycloalkyl, heterocycloalkyl, aryl or heteroaryl, provided that R ₁ and R ₄ are absent when the ring formed is aryl or heteroaryl; When R ₆ and R ₇ represent together with the carbon to which R ₆ is bonded and the nitrogen to which R ₇ is bonded, they form a heterocyclic ring, which ring is alkyl, substituted alkyl, alkenyl, hydroxy, amino, nitro , Carboxy, carboalkoxy, aryl, heteroaryl, or heterocycloalkyl, and may have substituents such that Y is = O, = S, -NR _1- , = NOR ₁ (wherein R ₁ is as defined above) or = N-NH ₂ .

Alkyl group itself and alkyl moieties in aralkyl, cycloalkyl-alkyl, polycycloalkyl-alkyl, heteroaryl-alkyl, alkoxy, alkylthio, alkanoyl, carvalkoxy and alkylamino are straight or branched chains having 1 to 20 carbon atoms. Can be. Preferably they are lower alkyl groups of 1 to 6 carbon atoms. Examples of such groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl, iso-amyl, hexyl and the like.

Alkenyl and alkynyl groups may also be straight or branched chains having 2 to 20 carbon atoms. Preferably they contain 2 to 6 carbon atoms. Such groups include vinyl, ethynyl, propenyl, allyl, isopropenyl and the like.

Cycloalkyl, polycycloalkyl, aryl, heteroaryl, arylalkyl, fused aryl-cycloalkyl group and the like contain 3 to 16 carbon atoms, and lower alkyl, alkenyl, alkynyl, hydroxy, thio, amino, alkoxy, alkyl And substituents such as thio, alkyl-amino, sulfonyl, sulfonamido and halo. Examples of such radicals are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norbornyl, phenyl, butyl, benzyl, phenethyl, dimethoxyphenyl, hydroxy benzyl, indanyl, naphthyl, tetra Hydronaphthyl, decahydronaphthyl, pyridyl, quinolyl, pyrrolidyl, pyrrolyl, morpholinyl, furyl, furfuryl, tetrahydrofurfuryl, benzimidazolyl, thiomorpholinyl, thienyl, already Dazolyl, tetrahydroindolyl and the like.

The alkylene group may be branched or straight chain having 1 to 20 carbon atoms, preferably 1 to 6 carbon atoms. Examples of such groups are methylene, ethylene, propylene, butylene, 1-methylpropylene, 2-ethylbutylene and the like. Alkenylene and alkynylene groups may also be branched or straight chain of 2 to 16 carbon atoms, preferably 2 to 6 carbon atoms.

The novel compounds of the present invention can be prepared by phenyl ring corresponding ω-mercapto carboxylic acid or derivatives thereof such as nitrile or imino ether. For example, the compounds of the present invention may be prepared by heating a compound of formula (I) in an inert solvent, preferably a hydrocarbon, in the presence of triphenyl phosphine and 2,2'-dipyridyldisulfide The compound of (la) can be prepared.

In the general formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , Y and n are as defined above. Processes for the preparation of some of the starting compounds of general formula (I) are described in US Pat. No. 057,175.

The compounds according to the invention can also be prepared by heating and closing the compounds of the general formula (II) or (IIa) in polyphosphoric acid to obtain a compound of the general formula (III) or (IIIa):

In the general formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , Y and n are as defined above.

Another suitable synthesis method is a method in which the compound of formula (IV) is heated and closed in the presence of triethylamine, methylene chloride and ethyl chloro-formate or acyl halide.

In the general formula, R ₇ is as defined above.

This ring closure reaction may also use various activators (e.g., N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline or dicyclohexylcarbodiimide) or coupling agents commonly used in the preparation of peptides. It may also be performed.

-톨루엔-설포네이트, 1-(3-디메틸아미노프로필)-3-에틸카보디이미드 하이드로클로라이드, 디페닐포스포닐아지드, 2-이소부톡시-1-이소부톡시-카보닐-1,2-디하이드로퀴놀린, 테트라에틸피로포스파이트, 트리메틸아세틸클로라이드, 1-하이드록시벤조트리아졸 수화물, 폴리인산, 디에틸포스포닐시아니데이트등이 있다.Examples of this include 1-cyclohexyl-3- (2-morpholinoethyl) -carbodiimide meto-

-Toluene-sulfonate, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, diphenylphosphonylazide, 2-isobutoxy-1-isobutoxy-carbonyl-1,2-di Hydroquinoline, tetraethylpyrophosphite, trimethylacetyl chloride, 1-hydroxybenzotriazole hydrate, polyphosphoric acid, diethylphosphonyl cyanidate and the like.

The preparation of dithiolactone and iminothiazepines can be carried out by ring-closing the corresponding mercapto-nitrile and mercapto-iminoether.

Methods of preparing suitable intermediates are described in Examples 1 and 10 below.

Those of ordinary skill in the art know that compounds of the present invention having subatom carbon atoms may exist in racemic or optically active forms. All such forms are included within the scope of the present invention.

The present invention will be explained in more detail in the following examples. These examples are described for the purpose of illustrating the present invention and are not intended to limit the scope of the invention to the following examples.

Example 1

[N- (2-Metcaptopropanoyl) -N- (cyclopentyl)] glycine

After passing anhydrous ammonia in methanol (100 ml) for 15 minutes, the resulting saturated ammonia solution was added to [N- (2-acetylthiopropanoyl) -N- (cyclopentyl)] glycine (5 g, 0.0183 mol) at once. The system is then placed under weak nitrogen pressure. The resulting solution was stirred at room temperature for 2 hours, and then the residue obtained by removing the solvent under vacuum was placed in an AG-50ω-X ₂ (Bio-Rad Laboratories) cation exchange resin column and eluted with methanol. After evaporation of methanol the residue is dissolved in chloroform. This chloroform is washed once with water and then dried over magnesium sulfate. Filtration and evaporation of the solvent gave a colorless oily product (3.8 g, 90%). This product is characterized as a dicyclohexylamine salt having a melting point of 163 to 164 ° C.

Example 2

N- (2-mercaptopropane oil) -thiazolidine-4-carboxylic acid

N- (2-acetylthiopropaneoyl) -thiazolidine-4-carboxylic acid (3.5 g, 13 mmol) is dissolved in 40 ml of ammonia-saturated methanol and then stirred at room temperature for 2 hours. After this solution is concentrated, the residue is partitioned between 5% sodium sulfite solution and ethyl acetate. The organic layer is washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give 2.6 g of solid material. This was polished with acetonitrile to obtain N- (2-mercaptopropaneyl) -thiazolidine-4-carboxylic acid as a colorless solid phase having a melting point of 152 to 154 占 폚.

Example 3

4-cyclopentyl-6,7-dihydro-6-methyl-1,4-thiazepine-2,5- (3H, 4H) -dione

Air is removed by passing nitrogen through a solution of N-cyclopental-N- (3-mercapto-2-methylpropane oil) glycine (2.0 g, 8.1 mmol) in 125 ml of toluene. To this solution was added 2,2'-dipyridyldisulfide (2.7 g, 12.2 mmol) and triphenylphosphine (3.2 g, 12.2 mmol), and the resulting solution was stirred for 5 hours under nitrogen.

The solution is diluted with 250 ml of toluene and then added to reflux toluene (2 L) under nitrogen at a rate of 20-25 ml / hour. The resulting mixture is stirred at reflux for 48 hours and then cooled to room temperature. The solution is washed successively with 0.1 N hydrochloric acid, saturated sodium bicarbonate, water and brine, then dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The solid material thus produced was dissolved in 25% ethyl acetate / hexane, filtered to separate the crystallized triphenyl phosphine oxide, and then purified by eluting with 25% ethyl acetate / hexane by medium pressure liquid chromatography to give a pale yellow solid. 0.8 g is obtained. This solid was recrystallized from 10% ethyl acetate / hexane to give 4-cyclopentyl-6,7-dihydro-6-methyl-1,4-thiazaphen-2,5 as a white crystalline solid having a melting point of 77 to 79 ° C. 0.5 g (27%) of-(3H, 4H) -dione is obtained.

Example 4

4- (exo-2-bicyclo [2.2.1] heptyl) -6,7, -dihydro-6-methyl-1,4-thiazepine-2,5- (3H, 4H) -dione

Nitrogen (N- (exo-2-bicyclo [2.2.1] heptyl) -N- (3-mercapto-2-methylpropane oil) glycine (3.5 g, 13 mmol) in 150 ml of toluene was passed through Remove it. To this solution was added 2,2'-dipyridylsulfide (4.28 g, 19.5 mmol) and triphenylphosphine (5.1 g, 19.5 mmol), and the resulting solution was stirred for 5 hours under nitrogen.

The solution is diluted with toluene to 255 ml and added to reflux toluene (2.5 L) at a rate of 15 ml / hour. The resulting mixture is stirred at reflux for 48 hours and then cooled to room temperature. The solution is washed successively with 0.1 N hydrochloric acid, saturated sodium bicarbonate, water and brine, then dried over anhydrous magnesium sulfate and then concentrated by filtration under vacuum. The resulting solid is dissolved in 35% ethyl acetate / hexanes, then filtered and purified by medium pressure liquid chromatography eluting with 35% ethyl acetate / hexanes. This affords 1.2 g (36%) of a viscous oily phase which is then scratched to crystallize. After dissolving half (0.6 g) of the foreign material in ethyl acetate, most of them were evaporated to dryness and hexane was added. 0.35 g of 6,7-dihydro-6-methyl-1,4-thiazaphen-2,5- (3H, 4H) -dione is obtained.

Example 5

6-methyl-1H, 3H-thiazolo [4,3-c] [1,4] thiazine-5,8-dione

Polyphosphoric acid (36 g) is added to N- (2-mercapto propanoyl) thiazolidine-4-carboxylic acid (1.5 g, 6.78 mmol), and then the mixture is stirred at 50 ° C. for 4 hours. The reaction mixture is dissolved in water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and concentrated to give [4,3-c] [1,4] thiazine-5,8 with 6-methyl-1H, 3H-thiazole as light yellow oil. -Di yields 0.7 g.

Example 6

(4R-trans) -hexahydro-4-methyl-1H, 5H-pyrrolo [2,1-c] [1,4] thiazin-1,5-dione

The solution of (D-3-mercapto-2-methylpropaneoyl) -L-proline (S, S) (817 mg, 3.76 mmol) in 30 ml of methylene chloride was cooled to 0 ° C. and then triethylamine (380 mg, 3.76 mmol) ) To this solution is added dropwise a solution of ethylchloroformate (408 mg, 3.76 mmol) in 9 ml of methylene chloride. The reaction mixture thus prepared is stirred for 3.5 hours while gradually warming to room temperature. The mixture is washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give a white solid phase. It was ground with 95% hexanes / ether and filtered to give crystalline (4R-trans) -hexahydro-4-methyl-1H, 5H-pyrrolo [2,1-c] [1,4 having a melting point of 98-101 ° C. 451 mg (60%) of thiazin-1,5-dione are obtained.

Example 7

Hexahydro-7-methyl-1H, 3H-thiazolo [4,3-c] [1,4] thiazine-1,5-dione

The solution of N- (3-mercapto-2-methylpropaneoyl) thiazolidine-4-carboxylic acid (7.1 g, 30.2 mmol) in 250 ml methylene chloride was cooled to 0 ° C., followed by triethylamine (5.78 g, 30.2 mmol). ) To this was added dropwise ethyl chloroformate (2.55 g, 30.2 mmol) in 50 ml methylene chloride over 75 minutes. The solution is stirred for 3.5 hours, bringing the temperature of the bath back to room temperature. The solution is washed with water, dehydrated over anhydrous sodium sulfate, filtered and concentrated to give 6.5 g of crude. This material was purified by HPLC to give 0.9 g of solid hexahydro-7-methyl-1H, 3H-thiazolo having a melting point of 70 to 100 ° C. [4,3-c] [1,4] thiazepine-1,5 -Dione is obtained.

[α] _D =-82.3 °

Example 8

Hexahydro-4-methyl-6,7,12,13-tetrahydroisoquinoline- [3,2-c] [1,4] thiazepine-1,5-dione

[N- (3-mercapto-2-methylpropaneoyl-L- (1,2,3,4-tetrahydroisoquinoline)]-1-3-carboxylic acid (2.5 g, 0.00896 mol) in chloroform (100 ml) The resulting solution was cooled in an ice bath and then triethylamine (0.91 g, 0.009 mol) was added, and ethylchloroformate (0.97 g, 0.009 mol) in chloroform (40 ml) was added dropwise over 10 minutes. The resulting solution is stirred for 2 hours 30 minutes at room temperature The chloroform is washed successively with water and saturated sodium chloride and then dehydrated over magnesium sulfate, filtered and the solvent is evaporated to give the crude product as a yellow oil. It is chromatographed on silica gel (CHCl ₃ ) and crystallized with ether-hexane to give 1.1 g (43%) of the desired 1,5-dione as colorless crystals.

Melting Point: 142 ℃

Example 9

6-methyl [1,4] thiazine-2,5-dione

A solution made by adding N- (2-mercaptopropaneyl) glycine (5 g, 0.031 mol) to methylene chloride (250 ml) is cooled in an ice bath and then triethylamine (3.1 g, 0.031 mol) is added. To this solution was added dropwise ethylchloroformate (3.4 g, 0.031 mol) in methylene chloride (25 ml) over 15 minutes. The resulting solution is stirred at room temperature for 2 hours 30 minutes. This methylene chloride is washed successively with water and saturated aqueous sodium chloride and dehydrated over magnesium sulfate. Filtration and evaporation of the solvent gave the crude product as a yellow oil which was then chromatographed on silica gel (CHCl ₃ ) and crystallized with ether-hexane to give 1.5 g (30%) of 6-methyl [1,4] thiazine- 2,5-dione is obtained in the form of colorless crystals. Melting Point 81-83 ° C

Example 10

N-cyclopentyl-6-methyl [1,4] thiazine-2,5-dione

A solution of [N- (2-mercaptopropane oil) -N- (cyclopentyl)] glycine (3.0 g, 0.0139 mol) in 150 ml of methylene chloride was cooled in an ice bath and then triethylamine (1.4 g, 0.0139). Mole). Ethyl chloroformate (1.5 g, 0.0139 mol) in methylene chloride (20 ml) is added dropwise over 10 minutes. The resulting solution is stirred at room temperature for 2 hours 30 minutes. This methylene chloride is washed successively with water and saturated sodium chloride and then dehydrated on magnesium sulfate. Filtration and evaporation of the solvent gave the crude product as a pale yellow oil which was then chromatographed on silica gel (CHCl ₃ ) and crystallized with ether-hexane to give 0.9 g (25.7%) of N-cyclopentyl-6-methyl [1,4 Thiazine-2,5-dione is obtained in the form of colorless crystals. Melting Point: 66 ~ 68 ℃

The following compounds are prepared by the method described in the above Examples:

4-cyclopentyl-6,7-dihydro-6-methyl-1,4-oxazepine-2,5- (3H, 4H) -dione; Hexahydro-4-cyclopentyl-6-methyl-1,4-diazepine-2,5-dione; 4-cyclopentyl-6-methyl-benzo [1,2-f] [1,4] -thiazepine-2,5- (3H, 4H) -dione; 4-cyclohexyl-6,7-dihydro-6-methyl-1, 4-diazepin-2-methylimino-5- (3H, 4H) -one; Tetrahydro-4-ethyl-piperidino [2,1-c] [1,4] -thiazepin-1-thiooxa-5-one; 4- (4-pyridyl) -6,7-dihydro-6-methyl-1,4-thiazepine-2,5- (3H, 4H) -dione; 4-cyclopentyl-6-ethylidene-1,4-thiazepine-2,5- (3H, 4H, 7H) -dione; 4- (4-methylphenyl) -6-methyl-benzo [2,3-f] [1,4] thiazepine-2,5- (3H, 4H) -dione; 1,1,3,3,6-pentamethyl-1H, 3H-thiazolo [4,3-c] [1,4] thiazepine-5,8-dione; Hexahydro-4,10-dimethyl-1H, 5H-pyrrolo [2,1-c] [1,4] thiazepine-1,5-dione; Hexahydro-4-methyl-6,7-dihydroisoquinolino [3,4-c] [1,4] thiazepine-1,5-dione; Hexahydro-4-methyl-10,11-dimethyl-6,7,8,13-tetrahydro isoquinolino [1,2-c] [1,4] thiazepine-1,5-dione; N-cyclopentyl-3,3,6,6-tetramethyl [1,4] thiazepine-2,5-dione; Hexahydro-4-methyl-6,8,12,13-tetrahydro-1,7-naphthylidino [6,7-c] [1,4] thiazine-1,5-dione; 3-methyl-5,6,11,12-tetrahydro isoquinoline [3,2-c] [1,4] thiazine-1,4-dione; 3-methyl-1H, 4H-pyrrolo [2,1-c] [1,4] thiazepine-1,4-dione; 4-cyclopentyl-6,7-dihydro-6-methyl-2-imino-1,4-thiazepin-5- (3H, 4H) -one; 4-methyl-7-phenyl-6,7,13,14-tetrahydro-carbonyl [3,2-c] [1,4] thiazepine-1,5-dione; 4-cyclopentyl-tetrahydro-benzo [1,4] thiazepine-2,5-dione; Hexahydro-4-methyl-azabicyclo [2.2.2] octyl [2,1-c] [1,4] thiazepine-1,5-dione; 3-methyl-5,11-dihydrobenzothiazolo [3,2-c] [1,4] thiazine-1,4-dione; 2-methyl-2,3,6,7,7a, 8-hexahydro-1,3-thiazolo [3,4-d] [1,4-thiazine] -3,8-dione.

Compounds according to the present invention were tested by the methods described in science 196, 441-4 (1977), and found to exhibit potent activity (I ₅₀ activity between 0.0075 and 0.05) that inhibits angiotensin converting enzyme (ACEI activity). μ mole). Thus, the compounds according to the invention are very useful for the treatment of hypertension. The compound according to the present invention was administered to a rat with high blood pressure at a dose of 100 mg / kg (intraperitoneal administration), and the blood pressure dropped by about 25 to 35% for about 10 to 13 hours. The compound may be administered orally or parenterally in the treatment of hypertension, and the exact dosage and route of administration will be determined by physicians skilled in the art.

Claims (1)

A method for preparing a compound of formula (Ia), characterized by ring closure of the corresponding ω-mercaptocarboxylic acid or derivative thereof.

In the general formula, n is 0 or 1, Y is = O, R ₁ , R ₂ , R ₃ and R ₄ are hydrogen or alkyl having 1 to 3 carbon atoms, R ₅ and R ₆ are hydrogen, R ₇ Silver, when separated, is hydrogen or cycloalkyl having 5 to 7 carbon atoms, and when R ₆ and R ₇ represent together with R ₆ bonded carbon and R ₇ bonded nitrogen, these are thiazolopyrrolo or tetra To form hydroisoquinoline substituents.