CN106699604A - Sacubitril and preparation method of midbody of sacubitril - Google Patents

Sacubitril and preparation method of midbody of sacubitril Download PDF

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Publication number
CN106699604A
CN106699604A CN201710015234.7A CN201710015234A CN106699604A CN 106699604 A CN106699604 A CN 106699604A CN 201710015234 A CN201710015234 A CN 201710015234A CN 106699604 A CN106699604 A CN 106699604A
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bent
compound
reaction
storehouse
chiral
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CN201710015234.7A
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CN106699604B (en
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李庚�
黄青春
杨龙
伍万兵
陈纹锐
白顺强
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四川同晟生物医药有限公司
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D263/00Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings 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
    • C07D263/18Oxygen atoms
    • C07D263/20Oxygen atoms attached in position 2
    • C07D263/26Oxygen atoms attached in position 2 with hetero atoms or acyl radicals directly attached to the ring nitrogen atom
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07BGENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07Optical isomers
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02PCLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00Technologies relating to chemical industry
    • Y02P20/50Improvements relating to the production of bulk chemicals
    • Y02P20/55Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention discloses sacubitril and a preparation method of midbody of the sacubitril, and relates to the field of pharmaceutical synthesis. According to preparation method of the sacubitril midbody, a compound I of a first chiral center is taken as a starting material, and is subjected to acylation reaction prothetic group adding, asymmetric methylation reaction and hydrolysis prothetic group removal, so that the sacubitril midbody is obtained. Asymmetric methylation in the alpha-position of the carbanyl group is effectively and selectively is realized through the adding of chiral prothetic group and the cooperative control of the chiral prothetic group and the first chiral center, so as to construct a second chiral center. The preparation method of the sacubitril midbody has the advantages that the raw materials are easy to get, the method is simple to operate, separation and purification are convenient, the yield and diastereoselectivity are high, and the dose is convenient to magnify to realize industrial production. The obtained sacubitril midbody is high in chiral purity, a tedious step for separating a diastereoisomer is canceled, and the production efficiency is improved.

Description

Preparation method of the one planting sand storehouse than bent and its intermediate
Technical field
The present invention relates to pharmaceutical synthesis field, the preparation method in particular to a planting sand storehouse than bent and its intermediate.
Background technology
LCZ696 is a kind of economic benefits and social benefits angiotensin receptor enkephalinase inhibitor of Novartis's research, is obtained in July 7 in 2015 FDA ratifies, and is developed for the treatment of heart failure (HErEF) patient of LVEF reduction.LCZ696 is than bent by Sha Ku The compound of (Sacubitril, AHU-377) and Valsartan (Diovan) composition, it has the binding mode of uniqueness, is considered as The strain of failure heart can be reduced.Wherein husky storehouse can block the mechanism of action of polypeptide in be responsible for reducing blood pressure two, figured silk fabrics than song It is husky smooth, vasodilation can be improved, stimulate body to drain sodium and water.
Sha Ku is a kind of pro-drug than song, and its chemical name is:4- (((2S, 4R) -1- ([1,1'- biphenyl] -4- bases) - 5- ethyoxyl -4- methyl -5- oxo-pentane -2- bases) amino) -4- ketobutyric acids, its structural formula is as shown in formula one.
Sha Ku has two chiral centres than bent, including the first chiral centre and the second of the carbonyl α chirality of amino α Center.In common synthetic route, Sha Ku is needed by the husky storehouse as shown in formula two than bent intermediate than bent synthesis, and Need to complete husky storehouse when the husky storehouse is built than bent intermediate than two structures of chiral centre in bent molecule.
In the prior art, be initiation material generally with the substrate with the first chiral centre, first synthesizing five-membered ring it is interior Acid amides, then methyl is introduced using methylating reagent in five-membered ring, methyl is induced jointly using ring structure and the first chiral centre Change reagent attack direction, so as to realize it is asymmetric methylate, build the second chiral centre, finally by open loop, amido protecting Sha Ku is obtained than bent intermediate.But the cis-selectivity of the method is poor, the husky storehouse for obtaining is more different with its diastereomeric than bent intermediate Separate difficult between structure body, cause the relatively low of yield and purity.
The content of the invention
Preparation method it is an object of the invention to provide a planting sand storehouse than bent intermediate, it can by simple step Target sand storehouse is obtained than bent intermediate, raw material is easy to get, simple to operate, with yield and cis-selectivity higher.
Another object of the present invention is to provide a planting sand storehouse than bent preparation method, it includes above-mentioned planting sand storehouse than bent The preparation method of intermediate, can obtain Sha Ku than bent intermediate high efficiency cis-selectivity high, and by the high chiral purity Husky storehouse set out to prepare than bent intermediate and complete husky storehouse than bent preparation, eliminate the tedious steps for separating diastereoisomer, Easy to operate, raw material is easy to get, and is adapted to large-scale industrial production.
What embodiments of the invention were realized in:
Than the preparation method of bent intermediate, it includes in one planting sand storehouse:
Be there is into acylation reaction in compound I and chiral auxiliary reagent and obtain compound II;
Be there is into asymmetric methylation reaction in compound II and methylating reagent and alkali and obtain compound III;
Compound III hydrolysis is obtained into Sha Ku than bent intermediate;
The structural formula of compound I isThe structural formula of compound II is The structural formula of compound III isSha Ku is than the structural formula of bent intermediate Wherein, R*It is chiral auxiliary, PG is blocking group.
Than bent preparation method, it includes preparation method of the above-mentioned planting sand storehouse than bent intermediate in one planting sand storehouse.
The beneficial effect of the embodiment of the present invention is:Preparation side of the planting sand storehouse provided by the present invention than bent and its intermediate Method, using the compound I with the first chiral centre as initiation material, by adding chiral auxiliary, and chiral auxiliary with Under the Collaborative Control of the first chiral centre, realize α of carbonyl it is asymmetric methylate, build the second chiral centre.The preparation Method raw material is easy to get, simple to operate, with yield and cis-selectivity higher, is easy to amplify dosage and realizes industrial metaplasia Produce.The husky storehouse for obtaining is higher than bent intermediate chiral purity, during husky storehouse is further prepared than song, eliminates separation non-right The tedious steps of isomers are reflected, Sha Ku is improved than bent production efficiency.
Specific embodiment
To make the purpose, technical scheme and advantage of the embodiment of the present invention clearer, below will be in the embodiment of the present invention Technical scheme be clearly and completely described.Unreceipted actual conditions person, builds according to normal condition or manufacturer in embodiment The condition of view is carried out.Agents useful for same or the unreceipted production firm person of instrument, are the conventional product that can be obtained by commercially available purchase Product.
The planting sand storehouse to the embodiment of the present invention is specifically described than the preparation method of bent and its intermediate below.
A kind of preparation method of the husky storehouse than bent intermediate with structure shown in compound IV, its reaction equation such as institute of formula three Show,
Specifically, comprise the following steps:Be there is into acylation reaction in compound I and chiral auxiliary reagent and obtain compound II。
Further, chiral auxiliary reagent is chiral oxazoline ketone prosthetic reagent, the chiral oxazoline ketone prosthetic reagent tool Structural formula beWherein, R is any one in phenyl, benzyl and isopropyl.
The chiral oxazoline ketone prosthetic reagent has a chiral carbon for R configurations, in the follow-up asymmetric process for methylating In, the chiral carbon of the R configurations can produce guide effect to the attack direction of methyl, asymmetric methylation reaction is obtained higher Cis-selectivity.
The chiral oxazoline ketone prosthetic reagent has amino, acylation reaction, the acyl can occur with the carboxyl in compound I Change reaction is carried out at 80~120 DEG C, preferably 100 DEG C, and adds triethylamine and pivaloyl chloride as activator.Further Ground, compound I, chiral oxazoline ketone prothetic group and triethylamine are dissolved in organic solvent, then are slowly added dropwise pivaloyl chloride, and speed is added dropwise Degree is unsuitable too fast, and to prevent, temperature is too high to cause slug and side reaction increase.Wherein, organic solvent is non-protonic solvent, Preferably toluene.Under the catalysis of triethylamine, pivaloyl chloride can carry out activation generation mixed acid anhydride to the carboxyl of compound I, Mixed acid anhydride is reacted with the amino of chiral oxazoline ketone prothetic group, obtains compound II.
Preferably, in above-mentioned acylation reaction, the mol ratio of compound I, chiral auxiliary reagent and pivaloyl chloride is 1:1~ 1.5:1~1.2.It is highly preferred that the mol ratio of compound I, chiral auxiliary reagent and pivaloyl chloride is 1:1.1:1.1.The ratio It is preferred value that inventor obtains by creative work and with reference to experience, carries out being acylated in the range of the preferred value anti- Should, reaction rate is fast, yield is high, side reaction is few.
Further, blocking group is in tertbutyloxycarbonyl (Boc), benzyloxycarbonyl group (Cbz) and tablet held before the breast by officials methoxycarbonyl group (Fmoc) Any one, preferably tertbutyloxycarbonyl.This kind of blocking group is conventional amido protecting group, with ripe protection and Deprotection method, removing extremely facilitates.This kind of blocking group shows good tolerance, Neng Goubao in whole building-up process Stay in the husky storehouse that obtains than in bent intermediate with it is follow-up prepare husky storehouse than song during continue to play a role, it is to avoid to ammonia The base troublesome operation that protection/deprotection is brought repeatedly.
Above-mentioned planting sand storehouse also includes than the preparation method of bent intermediate:Compound II and methylating reagent and alkali are occurred Asymmetric methylation reaction obtains compound III.
Further, methylating reagent is any one in iodomethane, dimethyl suflfate and dimethyl carbonate, preferably iodine Methane.Alkali pulls out hydrogen reagent, such as alkyl lithium reagents, amino lithium reagent, potassamide reagent for the routine of the class of organometallic reagent one Deng preferably lithium diisopropylamine (LDA) or lithium hexamethyldisilazide (LiHMDS), most preferably diisopropylaminoethyl Lithium.These reagents are the common agents in chemical reaction, can directly from directly buying on the market, and collocation use can obtain height The methylate of yield.
Further, asymmetric methylation reaction is carried out at -80~-50 DEG C, preferably -78 DEG C.The temperature range is The preferred value that inventor obtains by creative work and with reference to experience, when reaction temperature is too high, is susceptible to secondary anti- Should, cause yield to reduce.
Further, above-mentioned asymmetric methylation reaction is carried out under nitrogen protection, to prevent oxygen and aqueous vapor pair in air Reaction produces influence, causes yield to reduce.Preferably, under nitrogen protection, it is added dropwise in the tetrahydrofuran solution of compound II Alkali, process is added dropwise should not be too fast, and side reaction occurs to prevent temperature from raising, and 2~4h is reacted after being added dropwise to complete, and adds and methylates Reagent.Preferably, after methylating reagent is added, continue to react 2~4h at low temperature, then move to room temperature reaction, to accelerate Reaction process, obtains conversion ratio higher.
Further, in above-mentioned asymmetric methylation reaction, the mol ratio of compound II, alkali and methylating reagent is 1: 1~3:1~2, preferably 1:1.5:2.The ratio be inventor by creative work and with reference to experience obtain it is preferred Value, carries out asymmetric methylation reaction in the range of the preferred value, and reaction rate is fast, side reaction is few, can obtain receipts higher Rate.
Above-mentioned planting sand storehouse also includes than the preparation method of bent intermediate:Compound III hydrolysis is obtained into Sha Ku than in song Mesosome.
Further, compound III is hydrolyzed in 15~30 DEG C and obtains sand in the presence of hydrogen peroxide and lithium hydroxide Storehouse is than bent intermediate.Preferably, at 0 DEG C, in the tetrahydrofuran solution to compound III, addition hydrogen peroxide, stirring 0.5~ 1h.Then, lithium hydroxide is added, lithium hydroxide prevents reaction from excessively acutely causing slug using a small amount of multiple addition manner. Preferably, hydrogen peroxide uses the hydrogen peroxide solution of 30wt%.
Than bent preparation method, it includes preparation method of the above-mentioned husky storehouse than bent intermediate in one planting sand storehouse.
Feature of the invention and performance are described in further detail with reference to embodiments.
Embodiment 1
The present embodiment provides a kind of preparation method of compound II, and it uses Boc as blocking group, with compound I and Chiral auxiliaryReaction, obtains compoundIt is specifically prepared Step is as follows:
320mL toluene is added in there-necked flask, is opened and is stirred, addition compound I (16g, 1eq), triethylamine (13.1g, 3eq) with compound IV-a (8.37g, 1.1eq), PH=7~8.To be slowly added in reaction system pivaloyl chloride (5.67g, 1.1eq), 100 DEG C of back flow reaction 16h are warming up to.After reaction terminates, ethyl acetate dilution is added, and washed successively and satisfied With sodium acid carbonate washing, organic phase anhydrous sodium sulfate drying is collected, filtering, filtrate removes solvent through vacuum distillation, obtain thick Product.Crude product obtains compound II-a (21.0g, yield 91%) by column chromatography purifying.
Embodiment 2
The present embodiment provides a kind of preparation method of compound II, and it uses Boc as blocking group, with compound I and Chiral auxiliaryReaction, obtains compoundIt is specifically made Standby step is as follows:
320mL toluene is added in there-necked flask, is opened and is stirred, addition compound I (16g, 1eq), triethylamine (13.1g, 3eq) with compound IV-b (7.27g, 1.1eq), PH=7~8.To be slowly added in reaction system pivaloyl chloride (5.67g, 1.1eq), 90 DEG C of back flow reaction 16h are warming up to.After reaction terminates, ethyl acetate dilution is added, and washed successively and saturation Sodium acid carbonate is washed, and collects organic phase anhydrous sodium sulfate drying, and filtering, filtrate removes solvent, slightly produced through vacuum distillation Product.Crude product obtains compound II-b (17.7g, yield 86%) by column chromatography purifying.
Embodiment 3
The present embodiment provides a kind of preparation method of compound II, and it uses Boc as blocking group, with compound I and Chiral auxiliaryReaction, obtains compoundIt is specifically prepared Step is as follows:
320mL toluene is added in there-necked flask, is opened and is stirred, addition compound I (16g, 1eq), triethylamine (13.1g, 3eq) with compound IV-c (7.07g, 1eq), PH=7~8.To be slowly added in reaction system pivaloyl chloride (5.67g, 1.1eq), 100 DEG C of back flow reaction 16h are warming up to.After reaction terminates, ethyl acetate dilution is added, and washed successively and satisfied With sodium acid carbonate washing, organic phase anhydrous sodium sulfate drying is collected, filtering, filtrate removes solvent through vacuum distillation, obtain thick Product.Crude product obtains compound II-c (19.61g, yield 86%) by column chromatography purifying.
Embodiment 4
The present embodiment provides a kind of preparation method of compound II, and it uses Boc as blocking group, with compound I and Chiral auxiliaryReaction, obtains compoundIt is specifically prepared Step is as follows:
320mL toluene is added in there-necked flask, is opened and is stirred, addition compound I (16g, 1eq), triethylamine (13.1g, 3eq) with compound IV-a (11.41g, 1.5eq), PH=7~8.To be slowly added in reaction system pivaloyl chloride (5.67g, 1.1eq), 120 DEG C of back flow reaction 16h are warming up to.After reaction terminates, ethyl acetate dilution is added, and washed successively and satisfied With sodium acid carbonate washing, organic phase anhydrous sodium sulfate drying is collected, filtering, filtrate removes solvent through vacuum distillation, obtain thick Product.Crude product obtains compound II-a (20.53g, yield 88%) by column chromatography purifying.
Embodiment 5
The present embodiment provides a kind of preparation method of compound III, and it obtains chemical combination with compound II-a as reaction substrate ThingIts specific preparation process is as follows:
200mL tetrahydrofurans and compound II-a (18g, 1eq) are added in there-necked flask, stirring is opened, nitrogen displacement is simultaneously It is cooled to -78 DEG C.To the LDA (18.74mL, 1.1eq) that 2M is slowly added dropwise in reaction system, iodine is added after anti-2h at -78 DEG C Methane (5.3g, 1.1eq), moves to after continuation reaction 2h and react at room temperature overnight.After reaction terminates, saturated ammonium chloride solution is added It is quenched, adds ethyl acetate extraction, saturated sodium bicarbonate is washed, and organic phase is through anhydrous sodium sulfate drying and filters, and filtrate is through subtracting Pressure is distilled off solvent, obtains crude product.Crude product obtains target compound III-a (17.55g, yield by column chromatography purifying 95%).Without diastereoisomer detection, chiral purity is 100%.
Embodiment 6
The present embodiment provides a kind of preparation method of compound III, and it obtains chemical combination with compound II-a as reaction substrate ThingIts specific preparation process is as follows:
200mL tetrahydrofurans and compound II-a (18g, 1eq) are added in there-necked flask, stirring is opened, nitrogen displacement is simultaneously It is cooled to -65 DEG C.To the LDA (18.74mL, 1.1eq) that 2M is slowly added dropwise in reaction system, iodine is added after anti-2h at -65 DEG C Methane (7.22g, 1.5eq), moves to after continuation reaction 2h and react at room temperature overnight.After reaction terminates, add saturated ammonium chloride molten Liquid is quenched, and adds ethyl acetate extraction, and saturated sodium bicarbonate is washed, and organic phase is through anhydrous sodium sulfate drying and filters, filtrate warp Vacuum distillation removes solvent, obtains crude product.Crude product obtains target compound III-a (16.62g, yield by column chromatography purifying 90%).Without diastereoisomer detection, chiral purity is 100%.
Embodiment 7
The present embodiment provides a kind of preparation method of compound III, and it obtains chemical combination with compound II-b as reaction substrate ThingIts specific preparation process is as follows:
200mL tetrahydrofurans and compound II-b (18g, 1eq) are added in there-necked flask, stirring is opened, nitrogen displacement is simultaneously It is cooled to -70 DEG C.To the LDA (20.61mL, 1.1eq) that 2M is slowly added dropwise in reaction system, sulphur is added after anti-2h at -75 DEG C Dimethyl phthalate (7.09g, 1.5eq), moves to after continuation reaction 2h and react at room temperature overnight.After reaction terminates, saturation chlorination is added Ammonium salt solution is quenched, and adds ethyl acetate extraction, and saturated sodium bicarbonate is washed, and organic phase is through anhydrous sodium sulfate drying and filters, filter Liquid removes solvent through vacuum distillation, obtains crude product.Crude product by column chromatography purifying obtain target compound III-b (16.11g, Yield 87%).Without diastereoisomer detection, chiral purity is 100%.
Embodiment 8
The present embodiment provides a kind of preparation method of compound III, and it obtains chemical combination with compound II-c as reaction substrate ThingIts specific preparation process is as follows:
200mL tetrahydrofurans and compound II-c (18g, 1eq) are added in there-necked flask, stirring is opened, nitrogen displacement is simultaneously It is cooled to -75 DEG C.To the LDA (19.25mL, 1.1eq) that 2M is slowly added dropwise in reaction system, sulphur is added after anti-2h at -75 DEG C Dimethyl phthalate (6.14g, 1.3eq), moves to after continuation reaction 2h and react at room temperature overnight.After reaction terminates, saturation chlorination is added Ammonium salt solution is quenched, and adds ethyl acetate extraction, and saturated sodium bicarbonate is washed, and organic phase is through anhydrous sodium sulfate drying and filters, filter Liquid removes solvent through vacuum distillation, obtains crude product.Crude product by column chromatography purifying obtain target compound III-c (15.74g, Yield 85%).Without diastereoisomer detection, chiral purity is 100%.
Embodiment 9
The present embodiment provides preparation method of the planting sand storehouse than bent intermediate, and it is obtained with compound III-a as reaction substrate To husky storehouse than bent intermediateIts specific preparation process is as follows:
III-a (10g, 1eq) and 100mL tetrahydrofurans are added in there-necked flask, 0 DEG C is cooled to, added under agitation The hydrogen peroxide (8.3g, 4eq) of 30wt%, addition continues stirring reaction 0.5h after finishing at 0 DEG C.Hydrogen-oxygen is added in multiple times on a small quantity Change lithium (1.53g, 2eq), addition moves to 25~30 DEG C of stirring reaction 3h after finishing.After reaction terminates, saturation bisulfite is added Sodium solution removes unnecessary peroxide, and point liquid removes water phase, and removes organic solvent through vacuum distillation, adds 2M hydrochloric acid regulation PH To 3~4, it is extracted with ethyl acetate, organic phase anhydrous sodium sulfate drying, filters, filtrate removes solvent through vacuum distillation, obtains Crude product.Crude product is recrystallized in isopropyl acetate and normal heptane mixed solvent:Be heated to 100 DEG C of backflows, it is molten it is clear after, drop Temperature to 70 DEG C, there is crystal to separate out, be further cooled to room temperature, be filtrated to get Sha Ku than bent intermediate (19.95g, white solid, Yield=95%, ee=99.8%).
The husky storehouse is as follows than the characterization result of bent intermediate:
1H NMR (400MHz, DMSO) δ 7.61 (d, J=7.7Hz, 1H), 7.54 (d, J=8.0Hz, 1H), 7.42 (t, J =7.6Hz, 1H), 7.31 (t, J=7.3Hz, 1H), 7.23 (t, J=7.4Hz, 1H), 6.71 (d, J=8.7Hz, 1H), 6.28 (d, J=9.3Hz, 1H), 2.66 (d, J=6.8Hz, 1H), 1.03 (d, J=7.1Hz, 1H).MS (ESI, m/e)=789.5 [2M +Na]+
In sum, than the preparation method of bent and its intermediate, it is used with the in planting sand storehouse provided by the present invention The compound I of one chiral centre as initiation material, by adding chiral auxiliary, and in chiral auxiliary and the first chiral centre Under Collaborative Control, realize α of carbonyl it is asymmetric methylate, build the second chiral centre.System of the husky storehouse than bent intermediate Preparation Method raw material is easy to get, it is simple to operate, be easy to isolate and purify, with yield and cis-selectivity higher, be easy to amplification agent Amount realizes industrialized production.The husky storehouse for obtaining is higher than bent intermediate chiral purity, during husky storehouse is further prepared than song, Eliminate the tedious steps for separating diastereoisomer, improve production efficiency.
The preferred embodiments of the present invention are the foregoing is only, is not intended to limit the invention, for the skill of this area For art personnel, the present invention can have various modifications and variations.It is all within the spirit and principles in the present invention, made any repair Change, equivalent, improvement etc., should be included within the scope of the present invention.

Claims (10)

1. preparation method of the planting sand storehouse than bent intermediate, it is characterised in that it includes:
Be there is into acylation reaction in compound I and chiral auxiliary reagent and obtain compound II;
Be there is into asymmetric methylation reaction in the compound II and methylating reagent and alkali and obtain compound III;
Compound III hydrolysis is obtained into the husky storehouse than bent intermediate;
The structural formula of the compound I isThe structural formula of the compound II is The structural formula of the compound III isThe husky storehouse is than the structural formula of bent intermediateWherein, R*It is chiral auxiliary, PG is blocking group.
2. preparation method of the planting sand storehouse according to claim 1 than bent intermediate, it is characterised in that the chiral auxiliary Reagent is chiral oxazoline ketone prosthetic reagent, and the structural formula of the chiral oxazoline ketone prosthetic reagent isWherein, R is Any one in phenyl, benzyl and isopropyl.
3. preparation method of the planting sand storehouse according to claim 1 than bent intermediate, it is characterised in that the blocking group It is any one in tertbutyloxycarbonyl, benzyloxycarbonyl group and tablet held before the breast by officials methoxycarbonyl group.
4. preparation method of the planting sand storehouse according to claim 1 than bent intermediate, it is characterised in that the examination that methylates Agent is any one in iodomethane, dimethyl suflfate and dimethyl carbonate.
5. preparation method of the planting sand storehouse according to claim 1 than bent intermediate, it is characterised in that the alkali is two different In propylcarbamic lithium or lithium hexamethyldisilazide.
6. preparation method of the planting sand storehouse according to claim 2 than bent intermediate, it is characterised in that the acylation reaction Carried out at 80~120 DEG C, and add triethylamine and pivaloyl chloride as activator.
7. preparation method of the planting sand storehouse according to claim 6 than bent intermediate, it is characterised in that the compound I, The mol ratio of the chiral auxiliary reagent and the pivaloyl chloride is 1:1~1.5:1~1.2.
8. preparation method of the planting sand storehouse according to claim 4 than bent intermediate, it is characterised in that the asymmetric first Glycosylation reaction is carried out at -80~-50 DEG C.
9. preparation method of the planting sand storehouse according to claim 8 than bent intermediate, it is characterised in that the compound The mol ratio of II, the alkali and the methylating reagent is 1:1~3:1~2.
10. a planting sand storehouse is than bent preparation method, it is characterised in that including the planting sand as described in any one of claim 1~9 Preparation method of the storehouse than bent intermediate.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109400504A (en) * 2018-12-11 2019-03-01 重庆三圣实业股份有限公司 The isolation and purification method of LCZ696 intermediate diastereoisomer
CN109400493A (en) * 2017-08-15 2019-03-01 成都博腾药业有限公司 Sha Ku is than bent and its intermediate preparation method

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