CN100484936C - Synthesis of (2S,6R)-6-amino-2(2-thienyl)1,4-parathiazine-5-ketone - Google Patents

Synthesis of (2S,6R)-6-amino-2(2-thienyl)1,4-parathiazine-5-ketone Download PDF

Info

Publication number
CN100484936C
CN100484936C CNB2006100241732A CN200610024173A CN100484936C CN 100484936 C CN100484936 C CN 100484936C CN B2006100241732 A CNB2006100241732 A CN B2006100241732A CN 200610024173 A CN200610024173 A CN 200610024173A CN 100484936 C CN100484936 C CN 100484936C
Authority
CN
China
Prior art keywords
thienyl
ethyl
obtains
halfcystine
nitro
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CNB2006100241732A
Other languages
Chinese (zh)
Other versions
CN101029048A (en
Inventor
马大为
潘强彪
竺伟
李云中
饶卫东
贾慧琴
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Aobo biomedical Co.,Ltd.
Shanghai Institute of Organic Chemistry of CAS
Original Assignee
Shanghai Institute of Organic Chemistry of CAS
Shanghai Aobo Bio Pharmaceutical Technology Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shanghai Institute of Organic Chemistry of CAS, Shanghai Aobo Bio Pharmaceutical Technology Co Ltd filed Critical Shanghai Institute of Organic Chemistry of CAS
Priority to CNB2006100241732A priority Critical patent/CN100484936C/en
Publication of CN101029048A publication Critical patent/CN101029048A/en
Application granted granted Critical
Publication of CN100484936C publication Critical patent/CN100484936C/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Abstract

A process for synthesizing (2S,6R)-6-amino-2-(2-thienyl)-1,4-thioazatropylidene- 5-one, its application, and the new intermediate used in said process are disclosed.

Description

(2S, 6R)-6-amino-2-(2-thienyl)-1, the synthetic method of 4-sulphur azatropylidene-5-ketone
Technical field
The present invention relates to treat hypertensive medicine temocapril key intermediate (2S, 6R)-6-amino-2-(2-thienyl)-1, the synthetic method of 4-sulphur azatropylidene-5-ketone.
Background technology
Temocapril, English name are Temocapril, chemical name be (2S, 6R)-6-[[(1S)-1-(ethoxy carbonyl)-3-phenylpropyl aldehyde] amino]-4H-5-oxo-2-(2-thienyl)-1,4-thiazine-4 (5H)-acetate, structure as shown in the figure.
Figure C200610024173D00051
Temocapril is this year newfound a kind of bile, renal excretion type angiotensin-converting enzyme (ACE) inhibitor, and side effect is less.Be widely used in treatment hypertension clinically, for example treat the substantive hypertension of kidney, renovascular hypertension.
The mechanism of action of temocapril is to suppress angiotensin-converting enzyme (ACE) on the one hand by its metabolic in vivo diacid compounds (Temocaprilat) that is produced, strengthen the effect of depressurizing system in the body on the other hand, thereby restrain the booster reaction and the aortal contractile response that cause by Angiotensin, strengthen hypotensive effect bradykinin.
At present, several main synthetic routes of temocapril are as follows:
1.US 4699905 and EP 161801
Figure C200610024173D00052
Figure C200610024173D00061
Can find out significantly from top synthetic route: splitting step is arranged on the penultimate stride of synthetic route, loses 50% isomer so at least; The expensive raw material price that this synthetic route adopted simultaneously, reactions steps is long, and total recovery is low, and industrial production cost is very high.
2.J.Med.Chem.30,1984 (1987) and CA 1332943
Figure C200610024173D00062
Contrast above-mentioned two synthetic routes, though the described synthetic route of this method is shorter than article one synthetic route, rationally distributed, because the L-halfcystine directly adopts (Boc) in this method 2O protects amino under the routine operation condition, may exist multiple reaction to make and the product complexity be difficult to adopt the ordinary method purifying; Product behind the amido protecting and 2-(2-nitroethylene base) thiophene carries out the product of Michael addition reaction and the product of follow-up reduction reaction in addition, adopts ordinary method still to be difficult to purifying.Be difficult to suitability for industrialized production.
Indulge the above, the synthetic route that above document is reported all has yield low, unworkable defective.Therefore, this area needs still that development and operation is simple, product is easy to purifying, and the synthetic method of the preparation temocapril that chemical yield is high particularly prepares temocapril key intermediate (2S, 6R)-and 6-amino-2-(2-thienyl)-1, the method for 4-sulphur azatropylidene-5-ketone.
Summary of the invention
Purpose of the present invention just provides a kind of simple to operate; product is easy to the preparation temocapril intermediate (2S of purifying; 6R)-6-amino-2-(2-thienyl)-1; the method of 4-sulphur azatropylidene-5-ketone 1; this method key intermediate is the S-[(RS of amido protecting)-2-nitro-1-(2-thienyl) ethyl]-L-cysteine ester 2; intermediate 2 is the mixture of compound 2a and 2b, and structural formula is as follows:
Figure C200610024173D00071
Wherein, R 1Be C 1-C 4Straight chain or the alkyl or the benzyl of side chain; R 2Be tertbutyloxycarbonyl (Boc), carbobenzoxy-(Cbz) (Cbz) or fluorenylmethyloxycarbonyl (Fmoc); Preferred R 1Be methyl, ethyl or benzyl; R 2Be Boc.
Described method intermediate 2 obtains non-corresponding isomer 3 through nitroreduction, hydrolysis of ester group and ring-closure reaction, and classified again crystallization obtains single stereoisomers 4, and hydrolysis afterwards obtains compound 1, and synthetic route is:
Wherein, R 1Be C 1-C 4Straight chain or the alkyl or the benzyl of side chain; R 2Be Boc, Cbz or Fmoc; Preferred R 1Be methyl, ethyl or benzyl; R 2Be Boc.
The method that described reduction reaction adopted can be under metal catalyst catalysis hydrogenating reduction.Temperature when the solvent of the kind of the metal catalyst that adopts, catalyst consumption, reaction, hydrogenation time institute's applied pressure and hydrogenation is a principle not destroy other functional groups and chiral centre.For example employed catalyzer is 7%Pd/C in one embodiment of the invention; This catalyst consumption is 40% weight of reactant; Reaction solvent is a glacial acetic acid; Reaction pressure is 50psi (absolute pressure); Temperature of reaction is 50-60 ℃.
Described hydrolysis reaction adopts this area ordinary method, is principle with the amino protecting group that does not destroy in the reactant.
The cyclizing agent that described ring-closure reaction adopted can be selected from diphenylphosphine acylazide thing (DPPA), EDCI/HOBt, BOPCl, HATU etc.The solvent that reaction is adopted is non-proton property polar solvent, can be selected from tetrahydrofuran (THF), N, dinethylformamide, dimethyl sulfoxide (DMSO), HMPA or its any mixed solvent.Temperature of reaction from icy salt solution temperature (2--3 ℃) to room temperature.
The solvent that fractional crystallization adopted of described diastereomer 3 can be selected from mixing solutions, ethyl acetate or the ethyl acetate of mixing solutions, methylene dichloride and sherwood oil of mixing solutions, Virahol, methylene dichloride and isopropyl ether of methyl alcohol, ethanol, aqueous ethanolic solution, toluene and sherwood oil and the mixing solutions of sherwood oil.
Toluene and sherwood oil volume ratio are 1:0.5～1:5 in the mixing solutions of described toluene and sherwood oil.
Methylene dichloride and isopropyl ether volume ratio are 1:0.5～1:10 in the mixing solutions of described methylene dichloride and isopropyl ether; Be preferably 1:0.5～1:5; 1:0.8～1:3 more preferably.For example methylene dichloride and isopropyl ether volume ratio 1:1 in a preferred embodiment of the present invention.
Methylene dichloride and sherwood oil volume ratio are 1:0.5～1:10 in the mixing solutions of described methylene dichloride and sherwood oil; Be preferably 1:0.5～1:5; 1:0.8～1:3 more preferably.
Ordinary method does not have essential distinction in the working method of described fractional crystallization and this area.With the mixed solvent is that example is dissolved in diastereomer 3 earlier in the bigger methylene chloride of polarity, stir and slowly add the less solvent isopropyl ether of polarity down, the crystal after-filtration is separated out in cooling, solid after filtrate decompression concentrates adopts same working method to handle once more, and the solid after gained filtrate concentrates is steric isomer 4.
It is principle that the method that protective reaction on single stereoisomers 4 deaminizes is adopted adopts with other functional groups and chiral centre in the not broken reactant.
The preparation of intermediate 2 can be a raw material with L-halfcystine 5 also, obtains with 2-(2-nitroethylene base) thiophene Michael addition through carboxyl esterification and the resulting product 6 of amido protecting, and synthetic route is as follows:
Wherein, R 1Be C 1-C 4Straight chain or the alkyl or the benzyl of side chain; R 2Be Boc, Cbz or Fmoc.
The esterification of carboxyl and amido protecting can adopt this area ordinary method in the L-halfcystine 5.
Described compound 6 can be selected from benzene class (for example toluene, dimethylbenzene, benzene), THF, chloroparaffin (for example methylene dichloride, trichloromethane), alcohols (for example methyl alcohol, ethanol, Virahol), DMSO or DMF with the solvent that the Michae1 addition reaction of 2-(2-nitroethylene base) thiophene is adopted.Temperature of reaction from icy salt solution temperature (5～0 ℃) to room temperature.Can add an amount of mineral alkali or organic bases in the reaction and help the carrying out that react; For example the solvent that is adopted in a preferred embodiment of the present invention is a toluene; The temperature that is adopted be 0 ℃ to room temperature, the alkaline matter that is adopted is the N-methylmorpholine.
The preparation of intermediate 2 also can be carried out the resulting product 8 of Michael addition with 2-(2-nitroethylene base) thiophene with the derivative 7 of L-halfcystine 5 and obtain behind amido protecting, and synthetic route is:
R wherein 1Be C 1-C 4Straight chain or the alkyl or the benzyl of side chain; R 2Be Boc, Cbz or Fmoc; R 3Be hydrochloric acid or sulfuric acid; Preferred R 1Be methyl, ethyl or benzyl; R 2Be Boc; R 3Hydrochloric acid.
The resulting product 8 of Michael addition is the mixture of compound 8a and 8b, and its structural formula is as follows:
Figure C200610024173D00091
R wherein 1And R 2As implied above respectively.
Described compound 7 and 2-(2-nitroethylene base) thiophene carry out reaction conditions and aforesaid method that the Michael addition reaction adopted does not have substantial difference.
The amido protecting of described compound 8 can adopt method conventional in this area.For example adopt (Boc) 2When O reagent was protected amino, the reaction solvent that is adopted can be water, lower alcohols (for example methyl alcohol, ethanol), alkyl chloride hydro carbons (for example methylene dichloride, trichloromethane), THF etc.The complexity of carrying out according to reaction can add alkaline matter in right amount to promote the carrying out of reaction, and described alkaline matter can be selected from Et 3N, pyridine, NaHCO 3, Na 2CO 3, CaCO 3, NaOH, KOH or its any mixture.The temperature that adopted of reaction from frozen water temperature (5-0 ℃) to room temperature.For example the reaction solvent that is adopted in a preferred embodiment of the present invention is a methyl alcohol, and the alkaline matter that is adopted is Et 3N, the temperature of reaction that is adopted is 20 ℃.
Provided by the present invention second kind simple to operate, be easy to purifying ground prepare the temocapril intermediate (2S, 6R)-6-amino-2-(2-thienyl)-1, the method for 4-sulphur azepine-5-ketone 1, this method key intermediate is a compound 9, structural formula is as follows:
Figure C200610024173D00092
In this method L-halfcystine 5 directly and 2-(2-nitroethylene base) thiophene carry out the Michael addition, resultant product 9 obtains compound 1 through amido protecting, reduction, cyclization and fractional crystallization, hydrolysis, its synthetic route as
Figure C200610024173D00093
R wherein 2Be Boc, Cbz or Fmoc; Preferred R 2Be Boc.
Reaction conditions that described addition reaction is adopted and above-claimed cpd 7 do not have essential distinction with the condition that 2-(2-nitroethylene base) thiophene addition reaction is adopted.For example reacting the solvent that is adopted in a preferred embodiment of the present invention is methyl alcohol; The temperature that is adopted is a room temperature.
Described amido protecting reaction can be adopted method conventional in this area.Described reduction reaction can adopt in this area conventional method, is principle with other the functional group that does not destroy in the reactant.For example employed catalyzer is 7% Pd/C in one embodiment of the invention; This catalyst consumption is 0.2 equivalent of reactant; Solvent is an ethanol; Reaction pressure is 50psi (absolute pressure); Temperature of reaction is 45-50 ℃.
The ring-closure reaction of described compound 10 and follow-up fractional crystallization and hydrolysis reaction and method mentioned above do not have substantial difference.
Room temperature of the present invention is 10-30 ℃.
The compound 1 that the present invention prepares can be used for the preparation hypertensive medicine temocapril of treatment and pharmacy acceptable salt, for example temocapril hydrochloride.Adopt (R)-2-hydroxyl-4-ethyl phenylbutyrate and compound 1 reacted product 11 after trifyl activates, with the bromo-acetic acid tert-butyl reaction, remove the tertiary butyl under the acidic conditions again, promptly get the hydrochloride of temocapril.Concrete building-up reactions can be according to J.Med.Chem.30, and 1984 (1987) and CA 1332943, synthetic route is as follows:
Figure C200610024173D00101
Method raw material sources provided by the present invention are extensive, low price, synthesis step is simple to operate, the reaction conditions gentleness, product is easy to purifying, prepares resulting compound 1 optical purity height, the synthetic route total recovery height that is provided, not only be suitable for the laboratory and prepare on a small scale, also be suitable for large-scale industrial production.
The present invention will be further described below in conjunction with embodiment.
Specific embodiment
The preparation of the L-cysteine ester of amido protecting
The preparation of embodiment 1 N-Boc-L-acthiol-J
Under the room temperature, with L-halfcystine (12.1g, 0.1mol) join 30% methanol hydrochloride solution (24.3g, 0.2mol) and 225mL carbinol mixture liquid in, after stirring heating refluxed 4 hours, add in the 50mL hot methanol in the residuum behind the concentrating under reduced pressure, slowly drip the 200mL isopropyl ether after the dissolving, separate out solid, filtration, drying obtain white solid 12.5g, and yield is 73%.
(14.8g 0.086mol) joins 175mL CH to the L-acthiol-J hydrochloride for preparing according to the method described above 2Cl 2In, under room temperature, agitation and dropping Et successively 3N (11.9mL, 0.087mol) and 50mL (Boc) 2O (18.9g, dichloromethane solution 0.087mol), and at room temperature react up to HPLC tracking reaction and finish.(3 * 100mL) wash, separate the organic phase anhydrous Na that obtains to resulting mixture water 2SO 4Drying, filtration, concentrating under reduced pressure obtain colourless liquid N-Boc-L-acthiol-J 19.2g, and yield is 95%.
Embodiment 2 N-Cbz-L-acthiol-Js
(15.86g 93mmol) is dissolved in the 800mL frozen water L-acthiol-J hydrochloride for preparing according to method described in the embodiment 1, under the cold water cooling and stirring, adds NaHCO successively 3(15.63g, 186mmol) and CbzCl (20mL 139.5mmol), dropwises the back and stirred 1 hour in 0 ℃, and returning to stirring at room, to detect raw material reaction up to TLC complete.(3 * 250mL) extractions, the organic phase that separation obtains washes with water, saturated common salt is washed, anhydrous Na with ethyl acetate in reactant 2SO 4Drying, filtration, concentrating under reduced pressure obtain colourless liquid N-Cbz-L-acthiol-J 24g, and yield is 96%.
The preparation of embodiment 3 N-Boc-L-halfcystine benzyl esters
At room temperature, L-halfcystine (12.1g, 0.1mol) join the vitriol oil (10g, 0.1mol) and the mixed solution of 250mL benzylalcohol in, be heated to the reflux state reaction, it is complete to detect raw material reaction up to TLC, the resultant white solid of cooling back concentrating under reduced pressure is dissolved in the 50mL benzylalcohol, slowly drip the 200mL isopropyl ether after the dissolving and separate out solid, cooled and filtered, drying obtain white solid L-halfcystine benzyl ester vitriol 21.6g, and yield is 70%.
(14.8g 47.7mol) joins in the methylene dichloride of 180mL the L-halfcystine benzyl ester vitriol for preparing according to the method described above, stirs to add Et down successively 3N (13.2mL, 95.4mol) and 50mL (Boc) 2(it is complete to detect raw material reaction in 20-25 ℃ of stirring up to HPLC for 10.3g, dichloromethane solution 47.7mol), the organic phase anhydrous Na that resulting reactant washing, separation obtain for O 2SO 4Obtain oily matter N-Boc-L-halfcystine benzyl ester 14.1g behind drying, filtration, the concentrating under reduced pressure, yield is 95%.
The S-[(RS of amido protecting)-2-nitro-1-(2-thienyl) ethyl]-preparation of L-cysteine ester
Embodiment 4 N-Boc-S-[(RS)-2-nitro-1-(2-thienyl) ethyl]-preparation of L-acthiol-J
N-Boc-L-acthiol-J (19.8g, 0.084mol) and 2-(2-nitroethylene base) thiophene (13.14g, 0.084mol) join in the 300mL toluene, after mixing, dropping N-methylmorpholine under the cryosel water-bath cooling (16.97g, 0.168mol), after dripping, return to room temperature continuation stirring and finish up to TLC tracking reaction, (3 * 150mL) wash, separate the organic phase anhydrous Na that obtains to react resulting mixture water 2SO 4Obtain N-Boc-S-[(RS behind drying, filtration, the concentrating under reduced pressure)-2-nitro-1-(2-thienyl) ethyl]-L-acthiol-J 32.8g, yield is 99%.
Embodiment 5 N-Cbz-S-[(RS)-2-nitro-1-(2-thienyl) ethyl]-preparation of L-acthiol-J
N-Cbz-L-acthiol-J (22.6g, 0.084mol) and 2-(2-nitroethylene base) thiophene (13.14g, 0.084mol) join in the 300mL toluene, cryosel water-bath cooling down, dropping N-methylmorpholine (16.97g, 0.168mol), after dripping, return to room temperature and continue to stir 15 hours, (3 * 120mL) wash, separate the organic phase anhydrous Na that obtains to resulting reactant water 2SO 4Obtain red liquid N-Cbz-S-[(RS behind drying, the concentrating under reduced pressure)-2-nitro-1-(2-thienyl) ethyl]-L-acthiol-J 34.2g, yield is 96%.
Embodiment 6 N-Boc-S-[(RS)-2-nitro-1-(2-thienyl) ethyl]-preparation of L-halfcystine benzyl ester
With N-Boc-L-halfcystine benzyl ester (19.7g, 63.3mmol) and 2-(2-nitroethylene base) thiophene (9.87g, 63.3mmol) join in the 250mL toluene, after mixing, the icy salt solution cooling adds N-methylmorpholine (12.79kg down, 126.6mmol), returning to room temperature reaction after stirring, to detect raw material reaction up to TLC complete, and (3 * 150mL) wash, separate the organic phase anhydrous Na that obtains to resulting reactant water 2SO 4Obtain reddish black liquid N-Boc-S-[(RS behind drying, filtration, the concentrating under reduced pressure)-2-nitro-1-(2-thienyl) ethyl]-L-halfcystine benzyl ester 29.5g, yield is 100%.
Embodiment 7 N-Boc-S-[(RS)-2-nitro-1-(2-thienyl) ethyl]-preparation of L-acthiol-J
At N 2Protection down; acthiol-J hydrochloride (the 10g that will prepare by embodiment 1; 58.5mmol) and 2-(2-nitroethylene base) thiophene (8.24g; 53.2mmol) be dissolved in the 120mL anhydrous methanol; stir 15h in room temperature (10-20 ℃); after TLC shows that 2-(2-nitroethylene base) thiophene reacts completely, add the 150mL ethyl acetate in the residuum behind the concentrating under reduced pressure, use saturated NaHCO successively 3Solution (3 * 70mL), water (3 * 100mL) wash, anhydrous MgSO 4Drying, filtration, concentrating under reduced pressure obtain brown oil S-[(RS)-2-nitro-1-(2-thienyl) ethyl]-L-acthiol-J 12.21g, yield is 79.2%.
With the above-mentioned S-[(RS for preparing)-2-nitro-1-(2-thienyl) ethyl]-(6.25g 21.6mmol) is dissolved in the 100mL dehydrated alcohol L-acthiol-J, and (3.0mL 21.6mmol), drips 30mL (Boc) under the room temperature to add triethylamine 2The ethanol solution of O (4.71g, 21.6mmol), and after stirring 15h under the room temperature, it is complete that TLC detects raw material reaction, adds the 120mL ethyl acetate in the residuum behind the reactant concentrating under reduced pressure, dissolving back water (3 * 200mL) wash, anhydrous MgSO 4Dry, concentrating under reduced pressure gets dark red liquid N-Boc-S-[(RS)-2-nitro-1-(2-thienyl) ethyl]-L-acthiol-J 8.2g, productive rate 97.4%.
Embodiment 8 N-Cbz-S-[(RS)-2-nitro-1-(2-thienyl) ethyl]-preparation of L-halfcystine benzyl ester
At N 2Protection down; the L-halfcystine benzyl ester vitriol (18g that will prepare by embodiment 3; 58mmol) and 2-(2-nitroethylene base) thiophene (8.24g; 53.2mmol) be dissolved in the anhydrous benzylalcohol of 120mL; after room temperature (10-20 ℃) stirred 15h, TLC detected 2-(2-nitroethylene base) thiophene and reacts completely, and subtracted in the residuum after concentrating; add the 200mL saturated sodium bicarbonate aqueous solution under the cooling and stirring, stir after 10 minutes with ethyl acetate (3 * 150mL) extractions, the saturated NaHCO of organic phase 3The aqueous solution (3 * 120mL) wash, anhydrous MgSO 4Drying, filtration, concentrating under reduced pressure get brown oil S-[(RS)-2-nitro-1-(2-thienyl) ethyl]-L-halfcystine benzyl ester 14.6g, yield is 75%.
The S-[(RS for preparing according to the method described above)-2-nitro-1-(2-thienyl) ethyl]-(25.1g 68.3mmol) is dissolved in the 300mL tetrahydrofuran (THF) L-halfcystine benzyl ester, adds 150mL NaHCO 3(11.5g, 137mmol), under the frozen water cooling and stirring, (11.75mL, tetrahydrofuran solution 82mmol) dropwise the back and stir in 0 ℃ and returned to stirring at room in 1 hour to detect raw material reaction up to TLC complete Dropwise 5 0mL CbzCl the aqueous solution.Concentrating under reduced pressure remove add in the residuum behind the tetrahydrofuran (THF) ethyl acetate (3 * 250mL) extractions, separate the organic phase that obtains successively water (3 * 200mL), saturated aqueous common salt (3 * 50mL) wash, anhydrous Na 2SO 4Drying, filtration, concentrating under reduced pressure obtain viscous liquid N-Cbz-S-[(RS)-2-nitro-1-(2-thienyl) ethyl]-L-halfcystine benzyl ester 31.76g, yield is 93%.
Amido protecting (2RS, 6R)-6-amino-2-(2-thienyl)-1, the preparation of 4-sulphur azatropylidene-5-ketone
Embodiment 9 (2RS, 6R)-6-t-butoxycarbonyl amino-2-(2-thienyl)-1, the preparation of 4-sulphur azatropylidene-5-ketone
With N-Boc-S-[(RS)-2-nitro-1-(2-thienyl) ethyl]-L-acthiol-J (29.5g, 0.076mol) be dissolved in the 500mL acetate, the Pd/C that adds 12g7%, under hydrogen 50psi (absolute pressure), stir 5 hours after-filtration in 50-60 ℃, (3 * 50mL) wash filter cake Pd/C with acetate, merge acetic acid solution, the saturated NaHCO of residue oily matter behind the concentrating under reduced pressure 3Being neutralized to pH is 7.0-8.0, and (3 * 200mL) extractions, organic phase is used anhydrous Na after merging to add ethyl acetate 2SO 4Obtain dark-brown oily matter N-Boc-S-[(RS behind drying, the concentrating under reduced pressure)-2-amino-1-(2-thienyl) ethyl]-L-acthiol-J 23.1g, yield is 85%.
With above-mentioned oily matter (10g, 0.028mol) be dissolved among the 180mL THF, (80mL 0.04mol), returns to room temperature and continues to stir 1 hour after dripping to drip the 0.5N NaOH aqueous solution under ice-water bath, the methyl alcohol that concentrating under reduced pressure THF and reaction generate, add in the residuum ethyl acetate (3 * 100mL) extractions, aqueous phase drip the 1N HCl aqueous solution (40mL, 0.04mol), (3 * 50mL) extractions obtain white solid behind the water concentrating under reduced pressure with ethyl acetate to drip the back.Resulting white solid 100mLCH 2Cl 2Fully obtain white solid 5.3g behind twice of stirring and dissolving, filtration, merging, the concentrating under reduced pressure, yield is 56%.
The white solid for preparing according to the method described above (5.19g 15mmol) dissolves in the 50mL DMF solvent, and cryosel is bathed under the cooling and stirring, add successively DPPA (5.0g, 18mol), NaHCO 3Solution (6.3g, 75mmol), bathing under the cooling reaction at cryosel after being added dropwise to complete, to detect raw material reaction up to TLC complete, adds 80mL toluene and 160mL water in reactant, separate the organic phase water that obtains (3 * 100mL) wash, anhydrous Na 2SO 4Add the 30mL isopropyl ether in the residuum behind drying, filtration, the concentrating under reduced pressure, and the white solid powder that collection is separated out (2RS, 6R)-6-t-butoxycarbonyl amino-2-(2-thienyl)-1,4-sulphur azatropylidene-5-ketone 3.95g, yield is 80%.
Embodiment 10 (2RS, 6R)-6-t-butoxycarbonyl amino-2-(2-thienyl)-1, the preparation of 4-sulphur azatropylidene-5-ketone
To prepare the N-Boc-S-[(RS of gained according to embodiment 6 described methods)-2-nitro-1-(2-thienyl) ethyl]-L-halfcystine benzyl ester (46.6g, 0.1mol) be dissolved in the 700mL acetate, the Pd/C that adds 23g7%, under hydrogen 50psi (absolute pressure), reacted 5 hours in 55-60 ℃, the filtrate filtered concentrating under reduced pressure, the residuum re-crystallizing in ethyl acetate obtains white solid 17.3g, and yield is 50%.
Above-mentioned gained white solid adopts the method described in the embodiment 9 to carry out cyclization.
Embodiment 11 (2RS, 6R)-6-benzyloxycarbonyl amino-2-(2-thienyl)-1, the preparation of 4-sulphur azatropylidene-5-ketone
Will be according to the N-Cbz-S-[(RS of the method among the embodiment 5 preparation)-2-nitro-1-(2-thienyl) ethyl]-L-acthiol-J (42.4g, 0.1mol) be dissolved in the 800mL glacial acetic acid, the Pd/C that adds 40g7%, under hydrogen 50psi (absolute pressure), reacted 5 hours in 65-70 ℃, it is complete that TLC detects raw material reaction, filter, (3 * 50mL) wash, merge acetic acid solution to filter cake, the saturated NaHCO of residue oily matter behind the concentrating under reduced pressure with acetate 3Being neutralized to pH is 7.0-8.0, and (3 * 100mL) extractions, organic phase is used anhydrous Na after merging to mixed solution with ethyl acetate 2SO 4Drying obtains dark-brown oily matter N-Cbz-S-[(RS behind the concentrating under reduced pressure)-2-amino-1-(2-thienyl) ethyl]-L-acthiol-J 38.0g, yield is 96%.
With above-mentioned oily matter (11g, 0.028mol) be dissolved among the 180mL THF, the dropping 0.5N NaOH aqueous solution under the ice-water bath cooling (80mL, 0.04mol), returning to room temperature after dripping continues to stir after 1 hour, concentrating under reduced pressure is removed the methyl alcohol of THF and generation, and (3 * 100mL) extract residuum, the water 1N HCl aqueous solution (40mL with ethyl acetate, 0.04mol) neutralize, (3 * 50mL) extractions, the resulting white solid of water concentrating under reduced pressure is used 100mL CH with ethyl acetate in the cooling back 2Cl 2Fully stirring and dissolving twice is filtered, and merges CH 2Cl 2, obtaining white solid 5.85g behind the concentrating under reduced pressure, yield is 55%.
With above-mentioned white solid (5.7g 15mmol) dissolves in the 50mL DMF solvent, and cryosel is bathed under the cooling and stirring, add DPPA (5.0g, 18mol).Back adding NaHCO stirs 3(6.3g 75mmol), bathes after (5-0 ℃) cooling stirs 24h down at cryosel, adding 80mL toluene and 160mL water in reaction solution, the organic phase water of telling (3 * 100mL) wash, anhydrous Na 2SO 4Drying, filtration, concentrating under reduced pressure, purification by silica gel column chromatography, the eluent that is adopted is an ethyl acetate: sherwood oil (v:v=1:4), white solid (2RS, 6R)-6-benzyloxycarbonyl amino-2-(2-thienyl)-1,4-sulphur azatropylidene-5-ketone 3.95g, yield is 80%.
(2S, 6R)-6-t-butoxycarbonyl amino-2-(2-thienyl)-1, the preparation of 4-sulphur azatropylidene-5-ketone
Embodiment 12
With embodiment 9, the 10 non-corresponding isomer (2RS that obtain, 6R)-6-t-butoxycarbonyl amino-2-(2-thienyl)-1,4-sulphur azatropylidene-5-ketone (100g, 0.29mol) be dissolved in the 1L methylene dichloride, add the 1L isopropyl ether after the reflux, the postcooling that stirs is removed resulting solid to 10 hours after-filtration of stirring at room.Solid after filtrate concentrated carries out same treatment with methylene dichloride and isopropyl ether again, resulting filtrate decompression is concentrated obtain white solid (2S, 6R)-6-t-butoxycarbonyl amino-2-(2-thienyl)-1,4-sulphur azatropylidene-5-ketone 40g, yield is 40%.
Embodiment 13
With embodiment 9, the 10 non-corresponding isomer (2RS that obtain, 6R)-6-t-butoxycarbonyl amino-2-(2-thienyl)-1,4-sulphur azatropylidene-5-ketone (100g, 0.29mol) be dissolved in the 1L methylene dichloride, add the 1L isopropyl ether after the reflux, stir postcooling to 10 hours after-filtration of stirring at room, add the 300mL ethyl acetate, heating for dissolving in the solid after filtrate concentrates, be cooled to room temperature and separate out crystal, filter, filtrate decompression concentrate obtain white solid (2S, 6R)-6-t-butoxycarbonyl amino-2-(2-thienyl)-1,4-sulphur azatropylidene-5-ketone 41g, yield is 41%.
Embodiment 14
With embodiment 9, the 10 non-corresponding isomer (2RS that obtain, 6R)-6-t-butoxycarbonyl amino-2-(2-thienyl)-1,4-sulphur azatropylidene-5-ketone (100g, 0.29mol) also can adopt mixed solvent methylene dichloride and sherwood oil to carry out fractional crystallization by embodiment 12 described methods, yield is 36%.
S-[(RS)-2-nitro-1-(2-thienyl) ethyl]-preparation of L-halfcystine
Embodiment 15
At N 2Protection down; successively with 2-(2-nitroethylene base) thiophene (23.25g; 0.15mol), halfcystine (18.15g; 0.15mol) join in the anhydrous methanol of 700mL powerful 5 days or 3 days after-filtration of 30-40 ℃ of mechanical stirring, the filter cake 200mL methanol wash of stirring under the room temperature; filter cake added the 500mL ethyl acetate backflow 2 hours; the cooling room temperature after, filter, dry gray solid S-[(RS)-2-nitro-1-(2-thienyl) ethyl]-L-halfcystine 32.7g, productive rate 79%.
N-Boc-S-[(RS)-2-amino-1-(2-thienyl) ethyl]-preparation of L-halfcystine
Embodiment 16
Successively with S-[(RS)-2-nitro-1-(2-thienyl) ethyl]-the L-halfcystine (11.04g, 0.04mol), NaHCO 3(3.36g 0.04mol) joins in 70mL tetrahydrofuran (THF) and the 140mL water, and the back that stirs adds 50mL Boc 2O (8.72g, tetrahydrofuran solution 0.04mol), behind reaction 8-10h under the room temperature, reactant with the salt acid for adjusting pH value of 1N to 2-3, use afterwards ethyl acetate (3 * 100mL) extractions, separate the organic phase water that obtains (3 * 100mL) wash, anhydrous MgSO 4Get spumescence brown solid N-Boc-S-[(RS after drying, filtration, concentrating under reduced pressure, the drying)-2-nitro-1-(2-thienyl) ethyl]-L-halfcystine 14.29g, yield is 95%.
With the above-mentioned N-Boc-S-[(RS for preparing)-2-nitro-1-(2-thienyl) ethyl]-L-halfcystine (8.65g, 23mmol) join in the 100mL dehydrated alcohol, in the Pd/C of 6.92g7% and 45-50 ℃, 50psi (under the absolute pressure) hydrogenation down, reaction 12h after-filtration, filter cake is used 30mL ethanol respectively, 100mL hot water (70-80 ℃) washing, filtrate concentrating adds the 100mL ethyl acetate after removing most ethanol, after telling organic phase, wash organic phase repeatedly with water, detecting organic phase up to TLC does not have product to show, merge all water layers, concentrating under reduced pressure, drying obtains product 3.9g, and yield is 49%.
(2S, 6R)-6-amino-2-(2-thienyl)-1, the preparation of 4-sulphur azatropylidene-5-ketone
Embodiment 17
Will (2S, 6R)-6-t-butoxycarbonyl amino-2-(2-thienyl)-1,4-sulphur azatropylidene-5-ketone (10g, 0.030mol) join in the 10mL methylene dichloride, the back that stirs adds 1 of 30mL4N, the HCl solution of 4-dioxane, stirring reaction 5h under room temperature, suction filtration gets white solid.Resulting solid joins the mixed solvent (v:v=20:1) of 160mL methylene dichloride and methyl alcohol, and the back that stirs adds 35mL salt of wormwood, and (10.5g, aqueous solution 0.076mol) is in stirring at room 5h.Tell organic layer, water layer mixed solvent (v:v=9:1) (3 * 100mL) extractions, merging organic layer, the anhydrous MgSO of methylene dichloride and methyl alcohol 4Dry, filter, be evaporated to about 10mL, add ethyl acetate 20mL in the residuum, stir and separate out solid, filtration obtain (2S, 6R)-6-amino-2-(2-thienyl)-1,4-sulphur azatropylidene-5-ketone 5.9g, yield is 85%.
The technician of the technical field of the invention is on the basis of technical scheme provided by the present invention, and any improvement by simple logic analysis, reasoning or limited test are done is included in the technical scheme of the present invention.

Claims (14)

1. (2S, 6R)-6-amino-2-(2-thienyl)-1, the synthetic method of 4-sulphur azatropylidene-5-ketone (1), its key intermediate is the S-[(RS of amido protecting)-2-nitro-1-(2-thienyl) ethyl]-L-cysteine ester (2), structural formula is as follows:
Figure C200610024173C00021
R wherein 1Be C 1-C 4Straight chain or the alkyl or the benzyl of side chain; R 2Be tertbutyloxycarbonyl, carbobenzoxy-(Cbz) or fluorenylmethyloxycarbonyl.
2. the method for claim 1, this method comprises that intermediate (2) obtains diastereomer (3) through nitroreduction, hydrolysis of ester group and ring-closure reaction, classified again crystallization obtains single stereoisomers (4), and hydrolysis afterwards obtains compound (1), and synthetic route is as follows:
Figure C200610024173C00022
3. method as claimed in claim 1 or 2, the synthetic of its intermediate (2) obtains with 2-(2-nitroethylene base) thiophene Michael (Michael) addition with the carboxyl esterification of L-halfcystine (5) and the product (6) of amido protecting, and synthetic route is as follows:
Figure C200610024173C00023
4. method as claimed in claim 3, wherein R 1Be methyl, ethyl or benzyl; R 2Be tertbutyloxycarbonyl.
5. method as claimed in claim 1 or 2; the synthetic of its intermediate (2) obtains product (8) with product (7) behind L-halfcystine (5) carboxyl esterification and the amino salify and 2-(2-nitroethylene base) thiophene Michael addition; obtain through amido protecting afterwards, synthetic route is as follows:
Figure C200610024173C00031
R wherein 3Be hydrochloric acid or sulfuric acid.
6. method as claimed in claim 5, wherein R 1Be methyl, ethyl or benzyl; R 2Be tertbutyloxycarbonyl.
7. (2S, 6R)-6-amino-2-(2-thienyl)-1, the synthetic method of 4-sulphur azatropylidene-5-ketone (1), its key intermediate is S-[(RS)-2-nitro-1-(2-thienyl) ethyl]-L-halfcystine (9), structural formula is as follows:
Figure C200610024173C00032
8. method as claimed in claim 7; its L-halfcystine (5) obtains intermediate (9) with 2-(2-nitroethylene base) thiophene Michael addition; product (10) behind amido protecting and the nitroreduction obtains compound (1) through cyclization, fractional crystallization and hydrolysis afterwards, and synthetic route is as follows:
Figure C200610024173C00033
R wherein 2Be tertbutyloxycarbonyl, carbobenzoxy-(Cbz) or fluorenylmethyloxycarbonyl.
9. method as claimed in claim 8, wherein R 2Be tertbutyloxycarbonyl.
10. the S-[(RS of the amido protecting shown in the following formula (2))-2-nitro-1-(2-thienyl) ethyl]-the L-cysteine ester;
Figure C200610024173C00041
R wherein 1Be C 1-C 4Straight chain or the alkyl or the benzyl of side chain; R 2Be tertbutyloxycarbonyl, carbobenzoxy-(Cbz) or fluorenylmethyloxycarbonyl.
11. the compound shown in the formula (4)
Figure C200610024173C00042
12. the S-[(RS shown in the following formula (8))-2-nitro-1-(2-thienyl) ethyl]-the L-cysteine ester:
Figure C200610024173C00043
R wherein 1Be methyl, ethyl or benzyl.
13. the compound shown in the formula (9)
Figure C200610024173C00044
14. the compound in the claim 1 (1) is used for the hypertensive medicine temocapril of preparation treatment.
CNB2006100241732A 2006-02-27 2006-02-27 Synthesis of (2S,6R)-6-amino-2(2-thienyl)1,4-parathiazine-5-ketone Active CN100484936C (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CNB2006100241732A CN100484936C (en) 2006-02-27 2006-02-27 Synthesis of (2S,6R)-6-amino-2(2-thienyl)1,4-parathiazine-5-ketone

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CNB2006100241732A CN100484936C (en) 2006-02-27 2006-02-27 Synthesis of (2S,6R)-6-amino-2(2-thienyl)1,4-parathiazine-5-ketone

Publications (2)

Publication Number Publication Date
CN101029048A CN101029048A (en) 2007-09-05
CN100484936C true CN100484936C (en) 2009-05-06

Family

ID=38714618

Family Applications (1)

Application Number Title Priority Date Filing Date
CNB2006100241732A Active CN100484936C (en) 2006-02-27 2006-02-27 Synthesis of (2S,6R)-6-amino-2(2-thienyl)1,4-parathiazine-5-ketone

Country Status (1)

Country Link
CN (1) CN100484936C (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101475518B (en) * 2009-02-12 2013-01-09 吉林修正药业新药开发有限公司 Preparation of expectorant mecysteine hydrochloride raw material L-2-amino-3-mercaptopropionic acid methyl ester hydrochloride

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0161801A2 (en) * 1984-04-10 1985-11-21 Sankyo Company Limited Perhydrothiazepine derivatives, their preparation and their therapeutic use

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0161801A2 (en) * 1984-04-10 1985-11-21 Sankyo Company Limited Perhydrothiazepine derivatives, their preparation and their therapeutic use

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Angiotensin-Converting Enzyme Inhibitors:Perhydro-1,4-thiazepin-5-one Derivatives. Hiroaki Yanagisawa et al.J. Med. Chem.,Vol.30 . 1987
Angiotensin-Converting Enzyme Inhibitors:Perhydro-1,4-thiazepin-5-one Derivatives. Hiroaki Yanagisawa et al.J. Med. Chem.,Vol.30. 1987 *

Also Published As

Publication number Publication date
CN101029048A (en) 2007-09-05

Similar Documents

Publication Publication Date Title
NO336349B1 (en) The intermediate and process for the synthesis of perindopril and pharmaceutically acceptable salts thereof
CN101712645B (en) Preparation method for (2R, 4R)-4-substituted-2-piperidine carboxylic acid compound and intermediate thereof
CN107778223B (en) Preparation method of betrixaban maleate
CN107474107B (en) Process for the preparation of GLYX-13 and compounds useful for the preparation of GLYX-13
CN101265271B (en) Method for synthesizing penem-like pharmaceutical intermediate 4AA
CN109867673B (en) Method for synthesizing palbociclib
CN112142638A (en) Chiral binaphthyl-aza polycyclic ligand and preparation method thereof
CN100484936C (en) Synthesis of (2S,6R)-6-amino-2(2-thienyl)1,4-parathiazine-5-ketone
CN102070635B (en) Preparation method for ganciclovir valine ester derivative
CN103342656B (en) Synthesis method of Telaprevir intermediate
CN101155803A (en) Method for obtaining a pharmaceutically active compound (irbesartan) and its synthesis intermediate
CN105358529A (en) Novel method for synthesizing key intermediate of apixaban
CN102675415B (en) Method for preparing bortezomib
CN102070526B (en) Method for synthesizing 3-aza-bicyclo[4.1.0]heptane-6-formic acid with protective group
US7183308B1 (en) Metod for the synthesis of perindopril and the pharmaceutically acceptable salts thereof
CN109354580A (en) A kind of preparation method of Doneppezil Hydrochloride
CN109053528A (en) A kind of synthesis technology of Levetiracetam
CN100363380C (en) Liquid phase synthetic method for endomorphine -1 and endomorphine -2
CN107151246B (en) The preparation method of one kind (R)-praziquantel amine salt and levo-praziquantel
CN101565380B (en) Preparation method of L(+)-p-fluorophenyl glycine
CN102786543A (en) Preparation methods for imidazole[1,2-a]pyridine-6-boric acid pinacol ester and derivatives thereof
CN108358887B (en) Synthesis of optically pure sulfur-containing quaternary heterocyclic drug intermediate
CN104610215A (en) Preparation method of nebivolol intermediates and preparation method of nebivolol
CN111471085A (en) Method for continuously preparing argatroban
DE60311730T2 (en) Process for the synthesis of perindopril and its pharmaceutically acceptable salts

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
CP03 Change of name, title or address
CP03 Change of name, title or address

Address after: Room 304, building 1, 538 Cailun Road, China (Shanghai) pilot Free Trade Zone, Pudong New Area, Shanghai, 201203

Patentee after: Shanghai Aobo biomedical Co.,Ltd.

Patentee after: SHANGHAI INSTITUTE OF ORGANIC CHEMISTRY, CHINESE ACADEMY OF SCIENCES

Address before: 201203, room 1011, 601 Harley Road, Zhangjiang hi tech park, Shanghai

Patentee before: Shanghai Aobo Biomedical Technology Co.,Ltd.

Patentee before: SHANGHAI INSTITUTE OF ORGANIC CHEMISTRY, CHINESE ACADEMY OF SCIENCES