CN105566194A - Preparation method for Sacubitril intermediate - Google Patents
Preparation method for Sacubitril intermediate Download PDFInfo
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- CN105566194A CN105566194A CN201610068477.2A CN201610068477A CN105566194A CN 105566194 A CN105566194 A CN 105566194A CN 201610068477 A CN201610068477 A CN 201610068477A CN 105566194 A CN105566194 A CN 105566194A
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- PXLLMVOVFCYWKD-UZERJSRWSA-N CC[C@H]1C(C)(C)CCC1CC/N=C/CC(C)C Chemical compound CC[C@H]1C(C)(C)CCC1CC/N=C/CC(C)C PXLLMVOVFCYWKD-UZERJSRWSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/267—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to the ring nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The invention relates to a preparation method for a Sacubitril intermediate. The preparation method comprises the following steps that (3R,5S)-5-(hydroxymethyl)-3-methyl-2-pyrrolidone is esterified with toluene sulfochloride or methanesulfonyl chloride to obtain (3R,5S)-5-(methyl p-toluenesulfonate)-3-methyl-2-pyrrolidinone or (3R,5S)-5-(methyl methanesulfonate)-3-methyl-2-pyrrolidinone; (3R,5S)-5-(methyl p-toluenesulfonate)-3-methyl-2-pyrrolidinone or (3R,5S)-5-(methyl methanesulfonate)-3-methyl-2-pyrrolidinone is coupled with 4-diphenylmagnesium bromide or 4-diphenylmagnesium chloride to obtain (3R,5S)-3-methyl-5-(1,1'-diphenyl-4-yl-methyl)-2-pyrrolidinone. According to the preparation method, the method is novel, the raw materials are easy to obtain, the technology is simple, and the purity and yield of the product are both very high.
Description
Technical field
The invention belongs to the technical field of organic synthetic route design bulk drug Intermediate Preparation, particularly a kind of preparation method of enkephalinase inhibitor Sacubitril intermediate.
Background technology
Entresto (sacubitril+valsartantrisodiumhemipentahydrate) is a kind of Novel blood pressure-reducing medicine developed by Novartis (Novartis) company, for the heart failure patient that ejection fraction reduces, risk that reduction cardiovascular death and heart failure are in hospital.This medicine combines the Valsartan (Diovan of Novartis, popular name: valsartan) and Sacubitril (AHU-377) two kinds of components, wherein valsartan can improve vasorelaxation, stimulate body excretes sodium and water, and the mechanism of action of 2 peptide species that Sacubitri threat capable of blocking reduces blood pressure, thus Entresto is called as the double inhibitor of angiotensin-ii receptor and enkephalinase.
Entresto is a kind of pioneering new drug, is used for the treatment of NYHAII-IV level patients with heart failure, in many ways cardioactive neuroendocrine system, and this medicine is that a greatness in heart failure treatment field in 25 years in the past breaks through.
Entresto is in July, 2015 FDA approval listing.
Sacubitril intermediate, its structural formula is:
The preparation method of a kind of (3R, 5S)-3-methyl of international monopoly WO2008083967 report-5-(1,1 '-biphenyl-4-base-methyl)-2-Pyrrolidone.This route take Pyrrolidonecarboxylic acid as raw material, through activated carboxylic, biphenyl condensation, carbonyl reduction, methylate, deprotection reaction obtains target product.
This route stereoselectivity is poor, needs, by column chromatography purification, to be not suitable for industrial production.
Chinese patent CN201510039610 discloses the method for another preparation (3R, 5S)-3-methyl-5-(1,1 '-biphenyl-4-base-methyl)-2-Pyrrolidone in addition:
There is raw material and be difficult to obtain in this route, and chiral auxiliaries cannot be applied mechanically, and causes cost greatly to increase.The synthetic route developing a simple and convenient based on above reason will have important meaning.The present invention produces thus.
Summary of the invention
For the above-mentioned technical problem of prior art, the invention provides the preparation method of the intermediate of the Sacubitril of one of a kind of anti-heart failure Entresto component, it is with (3R, 5S)-5-(methylol)-3-N-methyl-2-2-pyrrolidone N-is raw material, prepare the method for Sacubitril intermediate through reactions such as over-churning, coupling or esterification, halo, couplings, the method for this preparation method is novel, raw material is easy to get, concise in technology.
For achieving the above object, the present invention is achieved by the following technical solutions:
A preparation method for Sacubitril intermediate, comprises the following steps:
A, with (3R, 5S)-5-(methylol)-3-N-methyl-2-2-pyrrolidone N-is raw material, (3R is obtained with Tosyl chloride or methylsulfonyl chloride esterification, 5S)-5-(methyl tosylate)-3-N-methyl-2-2-pyrrolidone N-or (3R, 5S)-5-(methyl mesylate)-3-N-methyl-2-2-pyrrolidone N-;
B, described (3R, 5S)-5-(methyl tosylate)-3-N-methyl-2-2-pyrrolidone N-or (3R, 5S)-5-(methyl mesylate)-3-N-methyl-2-2-pyrrolidone N-and 4-phenylbenzene magnesium bromide or the coupling of 4-phenylbenzene magnesium chloride obtain product (3R, 5S)-3-methyl-5-(1,1 '-biphenyl-4-base-methyl)-2-Pyrrolidone;
Or,
B、
B1, described (3R, 5S)-5-(methyl tosylate)-3-N-methyl-2-2-pyrrolidone N-or (3R, 5S)-5-(methyl mesylate)-3-N-methyl-2-2-pyrrolidone N-and halo reacting metal salt obtain (3R, 5S)-5-(halogenated methyl)-3-N-methyl-2-2-pyrrolidone N-;
(the 3R of B2, gained, 5S)-5-(halogenated methyl)-3-N-methyl-2-2-pyrrolidone N-and 4-phenylbenzene magnesium bromide or the coupling of 4-phenylbenzene magnesium chloride obtain product (3R, 5S)-3-methyl-5-(1,1 '-biphenyl-4-base-methyl)-2-Pyrrolidone;
Or,
B2
(3R, 5S)-5-(the halogenated methyl)-3-N-methyl-2-2-pyrrolidone N-of B2-1, gained and zinc or zinc copper couple are obtained by reacting the zincon of (3R, 5S)-5-(halogenated methyl)-3-N-methyl-2-2-pyrrolidone N-;
The zincon of B2-2, gained and 4-halogenated biphenyl carry out Negishicoupling and are obtained by reacting product (3R, 5S)-3-methyl-5-(1,1 '-biphenyl-4-base-methyl)-2-Pyrrolidone;
Or,
B2, be prepared into 4-halogenated biphenyl zincon by 4-halogenated biphenyl, described 4-halogenated biphenyl zincon and (3R, 5S)-5-(halogenated methyl)-3-N-methyl-2-2-pyrrolidone N-carries out Negishicoupling and is obtained by reacting product (3R, 5S)-3-methyl-5-(1,1 '-biphenyl-4-base-methyl)-2-Pyrrolidone.
The reaction equation of described preparation method is as follows:
In described steps A: the mol ratio of described (3R, 5S)-5-(methylol)-3-N-methyl-2-2-pyrrolidone N-and Tosyl chloride or methylsulfonyl chloride is 1:1-2; The solvent of reaction is toluene, water, methylene dichloride, trichloromethane, 1,2-ethylene dichloride, DMF, pyridine, triethylamine, acetonitrile or methyl-sulphoxide; Temperature of reaction is 0-80 DEG C; The catalyzer of reaction is DMAP, dicyclohexylcarbodiimide, 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride, I-hydroxybenzotriazole or O-benzotriazole-N, N, N', N'-tetramethyl-urea Tetrafluoroboric acid ester; The acid-binding agent of reaction is sodium carbonate, sodium bicarbonate, salt of wormwood, saleratus, sodium hydroxide, potassium hydroxide, triethylamine, pyridine or diisopropylethylamine.
In described step B: described (3R, 5S) mol ratio of-5-(methyl tosylate)-3-N-methyl-2-2-pyrrolidone N-or (3R, 5S)-5-(methyl mesylate)-3-N-methyl-2-2-pyrrolidone N-and 4-phenylbenzene magnesium bromide or 4-phenylbenzene magnesium chloride is 1:1-6; The solvent of described linked reaction is ether, methyl tertiary butyl ether, tetrahydrofuran (THF) or 2-methyltetrahydrofuran; The temperature of described linked reaction is-40-40 DEG C; The catalyzer of described linked reaction is FERRIC CHLORIDE ANHYDROUS, Lithium chloride (anhydrous), anhydrous chlorides of rase is cuprous, anhydrous cupric chloride, nitrilation are cuprous, one or more mixtures of cuprous bromide, cuprous iodide, cuprous bromide dimethylsulfide complex.
In described step B1: described (3R, 5S) molar ratio of-5-(methyl tosylate)-3-N-methyl-2-2-pyrrolidone N-or (3R, 5S)-5-(methyl mesylate)-3-N-methyl-2-2-pyrrolidone N-and halo reacting metal salt is 1:1-2; The solvent of reaction is acetone, butanone, DMF, acetonitrile or N,N-dimethylacetamide; The temperature of reaction is 20-100 DEG C; Described halo metal-salt is lithium chloride, lithiumbromide, lithium iodide, Potassium Bromide, potassiumiodide or sodium iodide.
In described step B2: described (3R, 5S)-5-(halogenated methyl)-3-N-methyl-2-2-pyrrolidone N-and the linked reaction molar ratio of 4-phenylbenzene magnesium bromide or 4-phenylbenzene magnesium chloride are 1:1-6; The solvent of linked reaction is ether, methyl tertiary butyl ether, tetrahydrofuran (THF) or 2-methyltetrahydrofuran; The temperature of linked reaction is-40-40 DEG C; The catalyzer of linked reaction is FERRIC CHLORIDE ANHYDROUS, Lithium chloride (anhydrous), anhydrous chlorides of rase is cuprous, anhydrous cupric chloride, nitrilation are cuprous, one or more mixtures of cuprous bromide, cuprous iodide or cuprous bromide dimethylsulfid complex.
In described step B2-1: the reaction molar ratio that described (3R, 5S)-5-(halogenated methyl)-3-N-methyl-2-2-pyrrolidone N-(4) and zinc or zinc copper couple prepare zincon is 1:1-2; The solvent of reaction is tetrahydrofuran (THF), ether, 2-methyltetrahydrofuran, DMF, N,N-dimethylacetamide; The temperature of reaction is-30-20 DEG C; Described zinc or zinc copper couple are zinc powder, activated zinc powder, high purity zinc paper tinsel or zinc copper couple.
In described step B2-2: the zincon of described (3R, 5S)-5-(halogenated methyl)-3-N-methyl-2-2-pyrrolidone N-and 4-halogenated biphenyl carry out Negishicoupling to react molar ratio be 1:1-6; The solvent of linked reaction is ether, methyl tertiary butyl ether, tetrahydrofuran (THF), DMF or 2-methyltetrahydrofuran; The temperature of linked reaction is-10-80 DEG C; One or more mixtures that the catalyzer of linked reaction is cuprous chloride, cuprous iodide, four (triphenyl phosphorus) close palladium, four triphenyl phosphorus Palladous chlorides or NiCl2.
Described 4-halogenated biphenyl zincon and (3R, 5S)-5-(halogenated methyl)-3-N-methyl-2-2-pyrrolidone N-carry out Negishicoupling, and to react molar ratio be 1:1-6; The solvent of linked reaction is ether, methyl tertiary butyl ether, tetrahydrofuran (THF), DMF or 2-methyltetrahydrofuran; The temperature of linked reaction is 10-90 DEG C; One or more mixtures that the catalyzer of linked reaction is cuprous chloride, cuprous iodide, four (triphenyl phosphorus) close palladium, four triphenyl phosphorus Palladous chlorides or NiCl2.
The preparation method of Sacubitril intermediate of the present invention, with (3R, 5S) the method for-5-(methylol)-3-N-methyl-2-2-pyrrolidone N-to be raw material through reactions such as over-churning, coupling or esterification, halo, couplings the prepare intermediate of Sacubitril, the method for this preparation method is novel, raw material is easy to get, concise in technology and the purity of product and yield are all very high.
Embodiment
Below in conjunction with specific embodiment, the present invention is further illustrated, but protection scope of the present invention is not limited to this.
The reaction equation of the preparation method of Sacubitril intermediate of the present invention is as follows:
The preparation of raw material (3R, 5S)-5-(the methylol)-3-N-methyl-2-2-pyrrolidone N-in the present invention can with reference to Tetrahedron, Vol.52, No.10, pp.3719-3740, and 1996.The chloride of succinic acid list benzyl ester can with reference to JournalofOrganicChemistry, 1990, Vol.55,18,5217-5221.
Embodiment 1
By (3R, 5S)-5-(methylol)-3-N-methyl-2-2-pyrrolidone N-2.3g joins in 250ml there-necked flask, add tetrahydrofuran (THF) 100ml again, 10% sodium hydroxide solution 16ml is added under stirring, ice-water bath cools, when interior temperature drop to 5 DEG C, slowly drip the solution of 7.76g Tosyl chloride and tetrahydrofuran (THF) 50ml, in dropping process keeps, temperature is below 10 DEG C, drip and finish, remove cryostat, stirred overnight at room temperature, reaction solution is poured in frozen water 200ml, HCl with 37% adjusts PH=6-7, steam except tetrahydrofuran (THF), add normal hexane 250ml and stir precipitation solid, suction filtration, dry to obtain 4.5g.Yield: 88.9%
1HNMR(DMSO-d6ppm)0.97(d,J＝7.2,3H),1.66-1.74(m,1H),1.89-1.94(m,1H),2.25-2.29(m,1H),2.43(s,3H),3.6-3.7(m,1H),3.87-3.90(m,1H),3.94-3.99(m,1H),7.48-7.50(d,J＝8,2H),7.76(brs,1H),7.79-7.81(d,J＝8,2H)。
Embodiment 2
By (3R, 5S)-5-(methylol)-3-N-methyl-2-2-pyrrolidone N-2.3g joins in 250ml there-necked flask, add methylene dichloride 100ml again, triethylamine 5.6ml, DMAP0.02g, ice-water bath cools, when interior temperature drop to 5 DEG C, slowly drip the solution of 7.76g Tosyl chloride and methylene dichloride 50ml, in dropping process keeps, temperature is below 10 DEG C, drip and finish, remove cryostat, stirred overnight at room temperature, reaction solution is poured in frozen water 200ml, HCl with 37% adjusts PH=6-7, layering, water layer methylene dichloride 100ml extracts once, combined dichloromethane layer, anhydrous magnesium sulfate drying, steam except methylene dichloride, by re-crystallizing in ethyl acetate, suction filtration, dry to obtain 3.1g.Yield: 91.1%
Embodiment 3
(3R, 5S)-5-(methyl tosylate)-3-N-methyl-2-2-pyrrolidone N-2.72g is joined in 100ml there-necked flask, then adds acetone 50ml and sodium iodide 2.25g, temperature rising reflux 24 hours, cooling, steams except acetone, adds 40ml water, three times are extracted with ethyl acetate 150ml, combined ethyl acetate layer, anhydrous magnesium sulfate drying, steams except ethyl acetate, by re-crystallizing in ethyl acetate, dry to obtain 2.1g.Yield: 92.1%1HNMR (DMSO-d6ppm) 1.03 (d, 3H), 1.74-1.82 (m, 1H), 1.96-2.02 (m, 1H), 2.42-2.49 (m, 1H), 3.27-3.28 (m, 2H), 3.58-3.59 (m, 1H), 7.79 (brs, 1H).
Embodiment 4
Under nitrogen protection by 4-phenylbenzene magnesium bromide (1.0MTHF, 50ml) enter in 250ml there-necked flask, add the cuprous 1.8g of nitrilation again, be cooled to-30 DEG C, drip by (3R, 5S) the solution of-5-(methyl tosylate)-3-N-methyl-2-2-pyrrolidone N-2.72g and tetrahydrofuran (THF) 30ml, drip and finish, remove cryostat, stirred overnight at room temperature, add saturated ammonia chloride solution 100ml, layering, aqueous layer with ethyl acetate 200ml extracts secondary, merge organic layer, anhydrous magnesium sulfate drying, steaming desolventizes, silicagel column is purified to obtain white solid product (3R, 5S)-3-methyl-5-(1, 1 '-biphenyl-4-base-methyl)-2-Pyrrolidone 2.11g.Yield: 82.3%1HNMR
(CDCl):1.19(d,3H),1.91-1.96(m,1H),2.13-2.17(m,1H),2.45-2.49(m,1H),2.73-2.79(m,1H),2.83-2.87(m,1H),3.84-3.86(m,1H),6.04(brs,1H),7.26(d,2H),7.34(m,1H),7.42-7.46(m,2H),7.53-7.55(m,2H),7.56-7.58(m,2H)。
Embodiment 5
Under nitrogen protection by (3R; 5S)-5-(iodomethyl)-3-N-methyl-2-2-pyrrolidone N-2.39g and dry tetrahydrofuran 50ml joins in the there-necked flask of 250ml; add the cuprous 0.2g of sulfonation again; be cooled to-5 DEG C; drip 4-phenylbenzene magnesium bromide (1.0MTHF; 50ml), drip and finish, remove cryostat; 20 DEG C of stirring reactions 48 hours; add saturated ammonia chloride solution 100ml, layering, aqueous layer with ethyl acetate 200ml extracts secondary; merge organic layer; anhydrous magnesium sulfate drying, steaming desolventizes, and silicagel column is purified to obtain product 1.82g.
Embodiment 6
By 1.0g with 1, 2-ethylene dibromide, zinc powder after trimethylchlorosilane activation is placed in 250ml there-necked flask, under nitrogen protection, add dry N, N-N,N-DIMETHYLACETAMIDE 40ml, be cooled to 0 DEG C, drip by (3R, 5S)-5-(iodomethyl)-3-N-methyl-2-2-pyrrolidone N-1.91g and dry N, the solution of N-N,N-DIMETHYLACETAMIDE 40ml, in dropping process keeps, temperature is lower than 5 DEG C, drip and finish, be incubated 1 hour, add cuprous iodide 0.15g and four (triphenyl phosphorus) and close palladium 0.5g, stir 10 minutes, drip by 4-bromo biphenyl 2.1g and N, the solution of N-N,N-DIMETHYLACETAMIDE 20ml, drip and finish, 5 DEG C of stirring reactions 24 hours, add water 200ml, be extracted with ethyl acetate five times, product ethyl acetate, recrystallisation from isopropanol obtains white solid 1.86g.Yield: 87.8%
Embodiment 7
By 4-phenylbenzene magnesium bromide (1.0MTHF; 20ml) join under nitrogen protection in 100ml there-necked flask; be cooled to 0 DEG C; drip the tetrahydrofuran solution (1.0M of zinc chloride; 22ml); drip to finish and stir half an hour; add cuprous iodide 0.1g and four (triphenyl phosphorus) and close palladium 0.4g; stir 10 minutes; drip by the solution of (3R, 5S)-5-(brooethyl)-3-N-methyl-2-2-pyrrolidone N-1.32g and tetrahydrofuran (THF) 20ml, drip and finish; remove cryostat, stirred overnight at room temperature.Add saturated aqueous ammonium chloride solution 100ml, layering, aqueous layer with ethyl acetate extraction secondary, product silicagel column is purified to obtain white solid 0.32g.
Embodiment 8
By (3R, 5S)-5-(methyl tosylate)-3-N-methyl-2-2-pyrrolidone N-5.44g joins in reaction flask, add tert-Butyl dicarbonate 6.54g successively, triethylamine 4.3ml, DMAP2.46g and methylene dichloride 50ml, the uncovered stirring of room temperature 8 hours, PH=6-7 is adjusted with 5%HCl, layering, water layer dichloromethane extraction secondary, combined dichloromethane layer, PH=7-8 is washed till with 5% sodium hydrogen carbonate solution, anhydrous magnesium sulfate drying, product (3R, 5S)-1-Boc-5-(methyl tosylate)-3-N-methyl-2-2-pyrrolidone N-to be purified to obtain 6.3g with short silicagel column.
Embodiment 9
Succinic acid list benzyl ester 4.16g is joined in 100ml there-necked flask, adds sulfur oxychloride 14ml, methylene dichloride 50ml, a DMF, stirring at room temperature 6 hours, steam and desolventize and unnecessary sulfur oxychloride, for subsequent use.
By (3R; 5S)-5-(methyl tosylate)-3-N-methyl-2-2-pyrrolidone N-4.9g joins in reaction flask; add dry tetrahydrofuran 50ml; be cooled to-15 DEG C; washed sodium hydrogen 0.45g and potassiumiodide 0.2g is carefully added under nitrogen protection; stir 2 hours, drip by the acyl chlorides of above-mentioned preparation and 20ml tetrahydrofuran solution at this temperature, drip and finish; remove cryostat; stirring at room temperature 8 hours, careful dropping 20ml water, stirs half an hour; layering; aqueous layer with ethyl acetate extraction secondary, anhydrous magnesium sulfate drying, product silicagel column is purified to obtain 6.4g.
The structural formula of the Sacubitril intermediate that the present invention obtains is:
Wherein G be the protecting groups such as H, Boc or
p is protecting group, and Boc protecting group is exactly tertiary butyl oxycarbonyl: (CH
3)
3o-CO-, Boc are through being commonly used to protect amido, and the most frequently used upper guard method is with Boc acid anhydrides Boc
2o and Boc-Cl, goes to protect general TFA/DCM or HCl-MeOH.This intermediate is reacted by easy esterification by ring opening and esterification by ring opening, deprotection obtain Sacubitril.
Above-described embodiment only illustrates inventive concept of the present invention for explaining, but not the restriction to rights protection of the present invention, all changes utilizing this design the present invention to be carried out to unsubstantiality, all should fall into protection scope of the present invention.
Claims (9)
1. a preparation method for Sacubitril intermediate, is characterized in that comprising the following steps:
A, with (3R, 5S)-5-(methylol)-3-N-methyl-2-2-pyrrolidone N-is raw material, (3R is obtained with Tosyl chloride or methylsulfonyl chloride esterification, 5S)-5-(methyl tosylate)-3-N-methyl-2-2-pyrrolidone N-or (3R, 5S)-5-(methyl mesylate)-3-N-methyl-2-2-pyrrolidone N-;
B, described (3R, 5S)-5-(methyl tosylate)-3-N-methyl-2-2-pyrrolidone N-or (3R, 5S)-5-(methyl mesylate)-3-N-methyl-2-2-pyrrolidone N-and 4-phenylbenzene magnesium bromide or the coupling of 4-phenylbenzene magnesium chloride obtain product (3R, 5S)-3-methyl-5-(1,1 '-biphenyl-4-base-methyl)-2-Pyrrolidone;
Or,
B、
B1, described (3R, 5S)-5-(methyl tosylate)-3-N-methyl-2-2-pyrrolidone N-or (3R, 5S)-5-(methyl mesylate)-3-N-methyl-2-2-pyrrolidone N-and halo reacting metal salt obtain (3R, 5S)-5-(halogenated methyl)-3-N-methyl-2-2-pyrrolidone N-;
(the 3R of B2, gained, 5S)-5-(halogenated methyl)-3-N-methyl-2-2-pyrrolidone N-and 4-phenylbenzene magnesium bromide or the coupling of 4-phenylbenzene magnesium chloride obtain product (3R, 5S)-3-methyl-5-(1,1 '-biphenyl-4-base-methyl)-2-Pyrrolidone;
Or,
B2
(3R, 5S)-5-(the halogenated methyl)-3-N-methyl-2-2-pyrrolidone N-of B2-1, gained and zinc or zinc copper couple are obtained by reacting the zincon of (3R, 5S)-5-(halogenated methyl)-3-N-methyl-2-2-pyrrolidone N-;
The zincon of B2-2, gained and 4-halogenated biphenyl carry out Negishicoupling and are obtained by reacting product (3R, 5S)-3-methyl-5-(1,1 '-biphenyl-4-base-methyl)-2-Pyrrolidone;
Or,
B2, be prepared into 4-halogenated biphenyl zincon by 4-halogenated biphenyl, described 4-halogenated biphenyl zincon and (3R, 5S)-5-(halogenated methyl)-3-N-methyl-2-2-pyrrolidone N-carries out Negishicoupling and is obtained by reacting product (3R, 5S)-3-methyl-5-(1,1 '-biphenyl-4-base-methyl)-2-Pyrrolidone.
2. the preparation method of Sacubitril intermediate as claimed in claim 1, is characterized in that the reaction equation of described preparation method is as follows:
3. the preparation method of Sacubitril intermediate as claimed in claim 1 or 2, it is characterized in that in described steps A: the mol ratio of described (3R, 5S)-5-(methylol)-3-N-methyl-2-2-pyrrolidone N-and Tosyl chloride or methylsulfonyl chloride is 1:1-2; The solvent of reaction is toluene, water, methylene dichloride, trichloromethane, 1,2-ethylene dichloride, DMF, pyridine, triethylamine, acetonitrile or methyl-sulphoxide; Temperature of reaction is 0-80 DEG C; The catalyzer of reaction is DMAP, dicyclohexylcarbodiimide, 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride, I-hydroxybenzotriazole or O-benzotriazole-N, N, N', N'-tetramethyl-urea Tetrafluoroboric acid ester; The acid-binding agent of reaction is sodium carbonate, sodium bicarbonate, salt of wormwood, saleratus, sodium hydroxide, potassium hydroxide, triethylamine, pyridine or diisopropylethylamine.
4. the preparation method of Sacubitril intermediate as claimed in claim 1 or 2, it is characterized in that in described step B: described (3R, 5S) mol ratio of-5-(methyl tosylate)-3-N-methyl-2-2-pyrrolidone N-or (3R, 5S)-5-(methyl mesylate)-3-N-methyl-2-2-pyrrolidone N-and 4-phenylbenzene magnesium bromide or 4-phenylbenzene magnesium chloride is 1:1-6; The solvent of described linked reaction is ether, methyl tertiary butyl ether, tetrahydrofuran (THF) or 2-methyltetrahydrofuran; The temperature of described linked reaction is-40-40 DEG C; The catalyzer of described linked reaction is FERRIC CHLORIDE ANHYDROUS, Lithium chloride (anhydrous), anhydrous chlorides of rase is cuprous, anhydrous cupric chloride, nitrilation are cuprous, one or more mixtures of cuprous bromide, cuprous iodide, cuprous bromide dimethylsulfide complex.
5. the preparation method of Sacubitril intermediate as claimed in claim 1 or 2, it is characterized in that in described step B1: described (3R, 5S) molar ratio of-5-(methyl tosylate)-3-N-methyl-2-2-pyrrolidone N-or (3R, 5S)-5-(methyl mesylate)-3-N-methyl-2-2-pyrrolidone N-and halo reacting metal salt is 1:1-2; The solvent of reaction is acetone, butanone, DMF, acetonitrile or N,N-dimethylacetamide; The temperature of reaction is 20-100 DEG C; Described halo metal-salt is lithium chloride, lithiumbromide, lithium iodide, Potassium Bromide, potassiumiodide or sodium iodide.
6. the preparation method of Sacubitril intermediate as claimed in claim 1 or 2, it is characterized in that in described step B2: described (3R, 5S)-5-(halogenated methyl)-3-N-methyl-2-2-pyrrolidone N-and the linked reaction molar ratio of 4-phenylbenzene magnesium bromide or 4-phenylbenzene magnesium chloride are 1:1-6; The solvent of linked reaction is ether, methyl tertiary butyl ether, tetrahydrofuran (THF) or 2-methyltetrahydrofuran; The temperature of linked reaction is-40-40 DEG C; The catalyzer of linked reaction is FERRIC CHLORIDE ANHYDROUS, Lithium chloride (anhydrous), anhydrous chlorides of rase is cuprous, anhydrous cupric chloride, nitrilation are cuprous, one or more mixtures of cuprous bromide, cuprous iodide or cuprous bromide dimethylsulfid complex.
7. the preparation method of Sacubitril intermediate as claimed in claim 1 or 2, it is characterized in that in described step B2-1: the reaction molar ratio that described (3R, 5S)-5-(halogenated methyl)-3-N-methyl-2-2-pyrrolidone N-(4) and zinc or zinc copper couple prepare zincon is 1:1-2; The solvent of reaction is tetrahydrofuran (THF), ether, 2-methyltetrahydrofuran, DMF, N,N-dimethylacetamide; The temperature of reaction is-30-20 DEG C; Described zinc or zinc copper couple are zinc powder, activated zinc powder, high purity zinc paper tinsel or zinc copper couple.
8. the preparation method of Sacubitril intermediate as claimed in claim 1 or 2, it is characterized in that in described step B2-2: the zincon of described (3R, 5S)-5-(halogenated methyl)-3-N-methyl-2-2-pyrrolidone N-and 4-halogenated biphenyl carry out Negishicoupling to react molar ratio be 1:1-6; The solvent of linked reaction is ether, methyl tertiary butyl ether, tetrahydrofuran (THF), DMF or 2-methyltetrahydrofuran; The temperature of linked reaction is-10-80 DEG C; The catalyzer of linked reaction is cuprous chloride, cuprous iodide, four (triphenyl phosphorus) close palladium, four triphenyl phosphorus Palladous chloride or NiCl
2one or more mixtures.
9. the preparation method of Sacubitril intermediate as claimed in claim 1 or 2, it is characterized in that: described 4-halogenated biphenyl zincon and (3R, 5S)-5-(halogenated methyl)-3-N-methyl-2-2-pyrrolidone N-carry out Negishicoupling to react molar ratio be 1:1-6; The solvent of linked reaction is ether, methyl tertiary butyl ether, tetrahydrofuran (THF), DMF or 2-methyltetrahydrofuran; The temperature of linked reaction is 10-90 DEG C; The catalyzer of linked reaction is cuprous chloride, cuprous iodide, four (triphenyl phosphorus) close palladium, four triphenyl phosphorus Palladous chloride or NiCl
2one or more mixtures.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106496055A (en) * | 2016-10-09 | 2017-03-15 | 杭州科巢生物科技有限公司 | A kind of key component sand storehouse of anti-heart failure new drug is than bent novel synthesis |
| WO2018007919A1 (en) | 2016-07-05 | 2018-01-11 | Novartis Ag | New process for early sacubitril intermediates |
| WO2018033866A1 (en) | 2016-08-17 | 2018-02-22 | Novartis Ag | New processes and intermediates for nep inhibitor synthesis |
| WO2018116203A1 (en) | 2016-12-23 | 2018-06-28 | Novartis Ag | New process for early sacubitril intermediates |
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| WO2018007919A1 (en) | 2016-07-05 | 2018-01-11 | Novartis Ag | New process for early sacubitril intermediates |
| WO2018033866A1 (en) | 2016-08-17 | 2018-02-22 | Novartis Ag | New processes and intermediates for nep inhibitor synthesis |
| CN106496055A (en) * | 2016-10-09 | 2017-03-15 | 杭州科巢生物科技有限公司 | A kind of key component sand storehouse of anti-heart failure new drug is than bent novel synthesis |
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