WO2017148357A1 - 一种沙库必曲的中间体及其制备方法 - Google Patents

一种沙库必曲的中间体及其制备方法 Download PDF

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WO2017148357A1
WO2017148357A1 PCT/CN2017/075097 CN2017075097W WO2017148357A1 WO 2017148357 A1 WO2017148357 A1 WO 2017148357A1 CN 2017075097 W CN2017075097 W CN 2017075097W WO 2017148357 A1 WO2017148357 A1 WO 2017148357A1
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formula
compound represented
group
alkyl
compound
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PCT/CN2017/075097
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English (en)
French (fr)
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陈磊
孙国栋
韩小东
李顺
曾洁滨
王仲清
罗忠华
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广东东阳光药业有限公司
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Priority to CN201780013500.0A priority Critical patent/CN109071407A/zh
Priority to EP17759208.6A priority patent/EP3424899B1/en
Publication of WO2017148357A1 publication Critical patent/WO2017148357A1/zh
Priority to US16/112,761 priority patent/US10479753B2/en
Priority to US16/679,154 priority patent/US11370739B2/en

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Definitions

  • the invention relates to the field of medicinal chemical industry, and more particularly to a sandboxed intermediate and a preparation method thereof.
  • LCZ696 anti-heart failure drug Entresto
  • Valsartan can improve vasodilation and stimulate the body to excrete sodium and water, while Shakushi can block the mechanism of action of two peptides that threaten to lower blood pressure.
  • LCZ696 is called angiotensin II receptor and enkephalinase.
  • the dual inhibitors which exhibit a unique mode of action, are superior to the antihypertensive effects of standard drugs and reduce the efficacy of heart failure.
  • WO2008031567A1 discloses a 4-position amino-substituted biphenyl crotonic acid or a derivative thereof obtained by oxidizing to an aldehyde and a Witting reaction using a 2-amino-substituted biphenylpropanol as a starting material, and then in the presence of hydrogen, Preparation of 4-amino substituted phenylbutyric acid or its derivatives by reduction, reaction and chiral resolution in the presence of transition metal elements of Groups 7, 8 and 9 of the Periodic Table of the Elements as catalysts and chiral ligands Methods. This product can be further converted to shakubil.
  • the example reaction is as follows:
  • WO2008083967A2 discloses the use of 2-carbonylproline as a raw material to obtain a sulbacb by a reaction such as carboxyl activation, biphenyl substitution, carbonyl reduction, chiral methylation, ring opening reaction and amidation condensation.
  • the reaction is as follows:
  • CN104557600A is a chiral induction reagent (S)-1-( ⁇ -aminobenzyl)-2-naphthol (S-betti Base) and 2R-methyl-4-oxo-butyric acid by cyclization, addition, The reaction steps of debenzylation, ring opening, esterification and amidation are carried out to obtain a sulbacb.
  • the reaction formula is as follows:
  • the present invention provides an intermediate for preparing shakubil, such as a compound represented by formula (V) and a method for preparing the compound represented by formula (V);
  • R 1 may be phenyl, methoxy, hydroxy, chloro, bromo, iodo, mesylate (-OMs), triflate (-OTf) or p-toluene sulfonate (-OTs) );
  • R 2 can be
  • R 3 may be hydrogen, -(C 1 -C 4 )alkyl or -(C 1 -C 4 )alkyl-aryl.
  • the -(C 1 -C 4 )alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl in some embodiments.
  • the -(C 1 -C 4 )alkyl-aryl group may be a benzyl group or an optionally substituted benzyl group in some embodiments.
  • R 4 may be hydrogen, -(C 1 -C 4 )alkyl, -(C 3 -C 6 )heterocyclyl, -(C 1 -C 4 )alkyl-aryl, trimethylsilyl, three Ethyl silicon or tert-butyldimethylsilyl.
  • the -(C 1 -C 4 )alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl in some embodiments.
  • the -(C 1 -C 4 )alkyl-aryl group may be a benzyl group or an optionally substituted benzyl group in some embodiments.
  • the present invention provides two methods for preparing shakubil by the compound represented by the formula (V).
  • the two methods have the advantages of easy availability of raw materials, simple process, economical and environmental protection, and are suitable for industrial production.
  • substituents of the compounds disclosed herein are disclosed in terms of the type or range of groups.
  • the invention includes each individual sub-combination of each member of the group and range of such groups.
  • -C 1 -C 6 alkyl refers specifically to the methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl groups, as disclosed independently.
  • linking substituents are described.
  • the Markush variable recited for that group is understood to be a linking group.
  • the Markush group definition for the variable is listed as "alkane”
  • alkyl or aryl it is to be understood that the “alkyl” or “aryl” respectively denote a bonded alkylene group or an arylene group.
  • alkyl denotes a saturated straight or branched monovalent hydrocarbyl group containing from 1 to 20 carbon atoms, wherein the alkyl group may be optionally one or more Substituted by the substituents described in the invention.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring containing from 3 to 12 ring atoms, wherein at least one of the ring atoms is selected from the group consisting of nitrogen, sulfur and oxygen.
  • a heterocyclic group can be a carbyl or a nitrogen group, and a -CH 2 - group can be optionally substituted with -C(O)-.
  • the sulfur atom of the ring can be optionally oxidized to an S-oxide.
  • the nitrogen atom of the ring can be optionally oxidized to an N-oxygen compound.
  • heterocyclic groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrroline, 3-pyrrolyl , pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothienyl, 1,3-dioxocyclopentyl, disulfide Pentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl , dioxoalkyl, dithiaalkyl, thiamethane, homopiperazinyl,
  • Examples of the -CH 2 - group in the heterocyclic group substituted by -C(O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidone Base, 3,5-dioxopiperidinyl and pyrimidindione.
  • Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, a sulfolane group and a 1,1-dioxothiomorpholinyl group.
  • the heterocyclyl group can be optionally substituted with one or more substituents described herein.
  • a heterocyclic group is a 6 atom heterocyclic group, and refers to a saturated or partially unsaturated monocyclic ring containing 6 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms.
  • a heterocyclic group consisting of 6 atoms may be a carbon group or a nitrogen group, and a -CH 2 - group may be optionally substituted by -C(O)-.
  • the sulfur atom of the ring can be optionally oxidized to an S-oxide.
  • the nitrogen atom of the ring can be optionally oxidized to an N-oxygen compound.
  • heterocyclic group consisting of 6 atoms include, but are not limited to, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, Morpholinyl, thiomorpholinyl, piperazinyl, dioxoalkyl, dithiaalkyl, thiamethane.
  • Examples of the -CH 2 - group in the heterocyclic group substituted by -C(O)- include, but are not limited to, 2-piperidinone, 3,5-dioxopiperidinyl and pyrimidinone.
  • Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, a 1,1-dioxothiomorpholinyl group.
  • the 6 atomic heterocyclyl group may be optionally substituted with one or more substituents described herein.
  • unsaturated as used in the present invention means that the group contains one or more unsaturations.
  • heteroatom refers to O, S, N, P, and Si, including any form of oxidation states of N, S, and P; forms of primary, secondary, tertiary, and quaternary ammonium salts; or nitrogen atoms in heterocycles. a form in which hydrogen is substituted, for example, N (like N in 3,4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like in N-substituted pyrrolidinyl) NR).
  • aryl denotes a monocyclic, bicyclic and tricyclic carbocyclic ring system containing from 6 to 14 ring atoms, or from 6 to 12 ring atoms, or from 6 to 10 ring atoms, wherein at least one ring system is aromatic Of the family, wherein each ring system comprises a ring of 3-7 atoms and one or more attachment points are attached to the remainder of the molecule.
  • aryl can be used interchangeably with the term "aromatic ring”. Examples of the aryl group may include a phenyl group, a naphthyl group, and an anthracene. The aryl group may be independently and optionally substituted with one or more substituents described herein.
  • the mesylate group (-OMs) of the present invention is Triflate (-OTf) is P-toluenesulfonate group (-OTs) is Ph refers to phenyl.
  • the present invention provides an intermediate for the preparation of sarcupine, such as a compound of formula (V); and a process for the preparation of a compound of formula (V).
  • the present invention provides an intermediate for preparing shakulib, such as a compound represented by formula (V);
  • R 1 may be phenyl, methoxy, hydroxy, chloro, bromo, iodo, mesylate (-OMs), triflate (-OTf) or p-toluene sulfonate (-OTs) In some embodiments, R 1 is phenyl;
  • R 2 can be
  • R 3 may be hydrogen, -(C 1 -C 4 )alkyl or -(C 1 -C 4 )alkyl-aryl; wherein the -(C 1 -C 4 )alkyl group is in some embodiments It may be methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl; the -(C 1 -C 4 )alkyl-aryl group may be a benzyl group in some embodiments. Or optionally substituted benzyl;
  • R 4 may be hydrogen, -(C 1 -C 4 )alkyl, -(C 3 -C 6 )heterocyclyl, -(C 1 -C 4 )alkyl-aryl, trimethylsilyl, three Ethylsilyl or tert-butyldimethylsilyl; wherein the -(C 1 -C 4 )alkyl group may, in some embodiments, be methyl, ethyl, n-propyl, isopropyl, n-Butyl, tert-butyl; the -(C 1 -C 4 )alkyl-aryl group may, in some embodiments, be a benzyl group or an optionally substituted benzyl group.
  • the compound of formula (V) may be a structure having one of the following:
  • the compound of the formula (V) according to the present invention can be obtained by subjecting a compound represented by the formula (IV) to a deprotection reaction.
  • R 1 may be phenyl, methoxy, hydroxy, chloro, bromo, iodo, mesylate (-OMs), triflate (-OTf) or p-toluene sulfonate (-OTs) In some embodiments, R 1 is phenyl;
  • R 2 can be In some embodiments, R2 is
  • R 3 may be hydrogen, -(C 1 -C 4 )alkyl or -(C 1 -C 4 )alkyl-aryl; wherein the -(C 1 -C 4 )alkyl group is in some embodiments It may be methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl; the -(C 1 -C 4 )alkyl-aryl group may be a benzyl group in some embodiments. Or optionally substituted benzyl;
  • R 4 may be hydrogen, -(C 1 -C 4 )alkyl, -(C 3 -C 6 )heterocyclyl, -(C 1 -C 4 )alkyl-aryl, trimethylsilyl, three Ethylsilyl or tert-butyldimethylsilyl; wherein the -(C 1 -C 4 )alkyl group may, in some embodiments, be methyl, ethyl, n-propyl, isopropyl, n-Butyl, tert-butyl; the -(C 1 -C 4 )alkyl-aryl group may, in some embodiments, be a benzyl group or an optionally substituted benzyl group;
  • R 5 may be hydrogen, -(C 1 -C 4 )alkyl or -(C 1 -C 4 )alkyl-aryl; wherein the -(C 1 -C 4 )alkyl group is in some embodiments It may be methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl; the -(C 1 -C 4 )alkyl-aryl group may be a benzyl group in some embodiments. Or an optionally substituted benzyl group.
  • the compound of formula (IV) is subjected to a deprotection reaction in the presence of an acid or a base to obtain a compound of formula (V).
  • the acid in some embodiments is trifluoroacetic acid; in some embodiments the base is lithium hydroxide.
  • the compound of the formula (IV) according to the present invention can be produced by a substitution reaction of a compound represented by the formula (II) and a compound represented by the formula (III).
  • the R 1 , R 2 and R 5 may be a group as described above.
  • the R 6 may be a triflate group (-OTf), a mesylate group (-OMs) or a p-toluenesulfonate group (-OTs).
  • the compound represented by the formula (II) and the compound represented by the formula (III) may be subjected to a substitution reaction to introduce a chiral methyl group, thereby obtaining a compound represented by the formula (IV); in some embodiments, the substitution reaction is It is carried out in the presence of a strong base; in some embodiments, the strong base is sodium hydride.
  • the compound represented by the formula (II) according to the present invention can be obtained by subjecting a compound represented by the formula (I) to a condensation reaction.
  • R 1 may be a group as described above.
  • the compound of formula (I) is subjected to a condensation reaction with N,N'-carbonyldiimidazole and a compound of formula (VIII) in the presence of magnesium chloride and triethylamine to obtain a formula (II).
  • a condensation reaction with N,N'-carbonyldiimidazole and a compound of formula (VIII) in the presence of magnesium chloride and triethylamine to obtain a formula (II).
  • R 5 may be a group as described above.
  • the compound of formula (I) is in the presence of N,N-diisopropylethylamine with Meldrum's acid, 4-dimethylaminopyridine, R 5 OH, and pentylene.
  • the acid chloride is subjected to a condensation reaction to obtain a compound represented by the formula (II), and the R 5 may be a group as described above.
  • the method for preparing the compound of the formula (V) according to the present invention comprises the following steps,
  • R 1 is a phenyl group
  • the R 2 is
  • R 3 may be hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl or benzyl
  • R 4 is hydrogen, methyl, ethyl, propyl , isopropyl, n-butyl, tert-butyl, benzyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, trityl, tetrahydropyranyl;
  • Said R 1 is a phenyl group
  • Said R 5 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl or benzyl;
  • Said R 1 is a phenyl group
  • the R 2 is
  • R 3 may be hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl or benzyl, wherein said R 4 is hydrogen, methyl, ethyl, or Propyl, isopropyl, n-butyl, tert-butyl, benzyl, trimethylsilyl, triethylsilyl or tert-butyldimethylsilyl;
  • the R 5 may be hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl or benzyl.
  • the R 6 may be a triflate group (-OTf), a mesylate group (-OMs) or a p-toluenesulfonate group (-OTs);
  • the method for preparing the compound of the formula (V) or an intermediate thereof according to the present invention can be based on the concept of the present invention by those skilled in the art. As disclosed, the reaction conditions can be appropriately adjusted as needed, such as selecting other suitable reaction solvents, adjusting the temperature of the reaction, and appropriately extending the reaction time to obtain a better reaction effect.
  • the compound represented by the formula (V) described in the present invention can be produced by the above production method of the present invention.
  • the present invention also provides two methods for preparing shakubid by the compound of formula (V).
  • the first method for preparing shakubil by the compound of the formula (V) may be as shown in the following reaction formula:
  • the first method for preparing Shakube can include the following steps:
  • the compound represented by the formula (V) is subjected to an enzymatic reaction to prepare a compound represented by the formula (VI).
  • the R 1 is a phenyl group, a methoxy group, a hydroxyl group, a chlorine, a bromine, an iodine, a mesylate group, a triflate group or a p-toluenesulfonate group;
  • the R 2 is
  • R 3 is hydrogen, -(C 1 -C 4 )alkyl or -(C 1 -C 4 )alkyl-aryl;
  • R 4 is hydrogen, -(C 1 -C 4 )alkyl, -(C 3 -C 6 )heterocyclyl, -(C 1 -C 4 )alkyl-aryl, trimethylsilyl, triethyl Silicon or tert-butyldimethylsilyl.
  • the first method for preparing Shakube can include the following steps:
  • the R 1 may be a phenyl group, a methoxy group, a hydroxyl group, a chlorine, a bromine, an iodine, a mesylate group (-OMs), a triflate group (-OTf) or a p-toluenesulfonate group. (-OTs);
  • the R 2 may be any suitable R 2
  • the R 3 may be hydrogen, -(C 1 -C 4 )alkyl or -(C 1 -C 4 )alkyl-aryl; wherein the -(C 1 -C 4 )alkyl group is In some embodiments, it may be methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, and the -(C 1 -C 4 )alkyl-aryl group may, in some embodiments, Is a benzyl group or an optionally substituted benzyl group;
  • the R 4 may be hydrogen, -(C 1 -C 4 )alkyl, -(C 3 -C 6 )heterocyclyl, -(C 1 -C 4 )alkyl-aryl, trimethylsilane a triethylsilyl or tert-butyldimethylsilyl group; wherein the -(C 1 -C 4 )alkyl group may be methyl, ethyl, n-propyl or iso in some embodiments a propyl, n-butyl, tert-butyl group, the -(C 1 -C 4 )alkyl-aryl group may be a benzyl group or an optionally substituted benzyl group in some embodiments;
  • the first method of preparing a Shakushiqu can include the following steps:
  • R 1 is a phenyl group
  • R 2 is Wherein R 3 is hydrogen, -(C 1 -C 4 )alkyl or -(C 1 -C 4 )alkyl-aryl; wherein the -(C 1 -C 4 )alkyl is in some embodiments It may be methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, and the -(C 1 -C 4 )alkyl-aryl group may be a benzyl group in some embodiments. Or optionally substituted benzyl;
  • the first method of preparing a Shakushiqu can include the following steps:
  • R 1 is benzene
  • R 2 is R 3 is an ethyl group
  • the above method for preparing shakubend wherein the enzyme catalyzed reaction is carried out in the presence of ⁇ -transaminase and pyridoxal phosphate.
  • the above-mentioned method for preparing shakubend wherein the compound represented by the formula (VII) can be subjected to a hydrolysis reaction with a compound represented by the formula (VI), followed by esterification with ethanol. The reaction is prepared.
  • the second method for preparing shakubil by the compound represented by the formula (V) may be as shown in the following reaction formula:
  • the second method of preparing Shakube can include the following steps:
  • the R 1 is a phenyl group, a methoxy group, a hydroxyl group, a chlorine, a bromine, an iodine, a mesylate group, a triflate group or a p-toluenesulfonate group.
  • the R 2 is
  • R 3 is hydrogen, -(C 1 -C 4 )alkyl or -(C 1 -C 4 )alkyl-aryl,
  • the R 7 is phenyl or -(C 1 -C 4 )alkyl or -(C 1 -C 4 )alkyl-aryl.
  • the second method of preparing Shakube can include the following steps:
  • the compound represented by the formula (XI) is produced from the compound represented by the formula (X),
  • the R 1 is a phenyl group, a methoxy group, a hydroxyl group, a chlorine, a bromine, an iodine, a mesylate group, a triflate group or a p-toluenesulfonate group.
  • the R 7 is phenyl or -(C 1 -C 4 )alkyl or -(C 1 -C 4 )alkyl-aryl.
  • the second method of preparing Shakube can include the following steps:
  • the R 1 may be a phenyl group, a methoxy group, a hydroxyl group, a chlorine, a bromine, an iodine, a mesylate group (-OMs), a triflate group (-OTf) or a p-toluenesulfonate group. (-OTs),
  • the R 2 may be any suitable R 2
  • the R 3 may be hydrogen, -(C 1 -C 4 )alkyl or -(C 1 -C 4 )alkyl-aryl, wherein the -(C 1 -C 4 )alkyl group is In some embodiments, it may be methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, and the -(C 1 -C 4 )alkyl-aryl group may, in some embodiments, Is a benzyl group or an optionally substituted benzyl group;
  • the R 7 may be phenyl or -(C 1 -C 4 )alkyl or -(C 1 -C 4 )alkyl-aryl, wherein the -(C 1 -C 4 )alkyl group In some embodiments may be methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, the -(C 1 -C 4 )alkyl-aryl group in some embodiments It may be a benzyl group or an optionally substituted benzyl group;
  • the compound of (IX) is D-phenylglycinol.
  • the compound represented by the formula (X) is prepared by the compound of the formula (XI) in the presence of titanium tetrachloride and triethylsilane.
  • the compound represented by the formula (XI) is prepared by the compound of the formula (XII) in the presence of a palladium on carbon (Pd/C) catalyst.
  • the compound represented by the formula (XII) is prepared by the compound of the formula (VII) under acidic conditions in an ethanol solvent.
  • the acidic condition refers to a condition in which hydrochloric acid is present.
  • the second method of preparing Shakube includes the following steps:
  • the reaction route is as follows:
  • the compound represented by the formula (VII) ((2R, 4S)-5-([1,1'-biphenyl]-4-yl)-4- Amino-2-methylpentanoate ethyl ester) can be prepared by amidation condensation reaction with succinic anhydride in the presence of a base to obtain a shakubend; this step has been disclosed in the prior art, such as WO 2008031567 A1 and CN 104557600 A It is disclosed in the art and is known to those skilled in the art.
  • a novel Shakubil intermediate (V) and a preparation method thereof are provided.
  • the intermediate is prepared by using cheap and readily available biphenylacetic acid as a raw material, and is condensed, substituted and deprotected in three steps.
  • the body (V) has higher reaction yield and simple operation in each step; the intermediate has a similar parent structure to Shakubil, and no such structural compound has been reported yet, and no similar structure is used as an intermediate. Report on the preparation method of synthetic shakuqu;
  • reagents used in the present invention are all commercially available or can be prepared by the methods described herein.
  • mL refers to milliliters
  • g refers to grams
  • h refers to hours
  • N refers to moles per liter
  • 1H NMR nuclear magnetic hydrogen spectroscopy
  • MS mass spectrometry
  • HPLC high performance liquid chromatography
  • CDCl 3 refers to deuterated chloroform
  • DMSO-d 6 deuterated generation Dimethyl sulfoxide.
  • reaction solution was heated to 45 ° C for 3 h, cooled to 20 to 30 ° C, and vacuumed under reduced pressure for 1 h.
  • reaction flask B At room temperature, 1 L of reaction flask B was charged with 280 mL of ethyl acetate, 28.06 g of potassium malonate monoethylate (EtO 2 CCH 2 COOK) and 15.70 g of magnesium chloride (MgCl 2 ), and the temperature was controlled at 20 to 30 ° C, and slowly added dropwise to 19.07. g Triethylamine (TEA), stirring was continued for 1 h after the addition was completed. The material in the reaction flask A was added to the reaction flask B at room temperature, and the temperature was raised to 45 ° C, and the reaction was kept for 16 hours.
  • TEA Triethylamine
  • reaction solution was cooled to 20 ° C ⁇ 30 ° C, 180 mL of 4N hydrochloric acid solution was slowly added dropwise, and the organic phase was washed three times with 6.5% sodium hydrogen carbonate solution, 250 mL each time, the organic phase was collected, and the solvent was distilled off under reduced pressure at 45 ° C. Made a yellow-brown oil.
  • 150 mL of n-hexane was added to the obtained oil, and stirred at 20 to 30 ° C for 18 hours, filtered, and the filter cake was washed with n-hexane, and dried under vacuum at 40 to 50 ° C for 5 hours to obtain 4-([1,1'-biphenyl]-4-yl.
  • reaction liquid was heated to 20 to 30 ° C, and stirring was continued for 30 minutes.
  • the reaction solution was cooled to 0 ° C, and a solution of (R)-methyl-2-(p-tosylate)propionate in tetrahydrofuran (THF) (31.37 g (R)-methyl-2-( The tosylate group) propionate was dissolved in 100 mL of tetrahydrofuran (THF).
  • THF tetrahydrofuran
  • the reaction of the starting material was completely determined by HPLC, and 150 mL of 2N hydrochloric acid was slowly added dropwise to the reaction solution to adjust the pH to 2 to 3.
  • the reaction solution was extracted with ethyl acetate three times, each time 100 mL, the organic phase was combined, and the organic phase was washed twice with water. The second amount is 200 mL, the organic phase is combined, and the organic phase is concentrated under reduced pressure to give (3R)-1-ethyl-4-methyl 2-(2-([1,1'-biphenyl]-4-yl)acetyl 3-methyl succinate 48.60 g, directly charged without further purification for the next reaction.
  • reaction solution was cooled to 20-30 ° C, and 100 mL of 1N hydrochloric acid aqueous solution was slowly added dropwise to adjust the pH to 2 to 3.
  • the reaction solution was extracted with ethyl acetate three times, each time 100 mL, the organic phase was combined, organic phase Wash twice with water, 200 mL each time, combine the organic phases, and concentrate the organic phase under reduced pressure to give (R)-5-([1,1'-biphenyl]-4-yl)-2-methyl-4 - 9.80 g of pentanone acid, yield 85.1%.
  • reaction liquid drop Warm to 0 ° C, slowly add dropwise a solution of tert-butyl 4-([1,1'-biphenyl]-4-yl)-3-oxobutanoate in tetrahydrofuran under nitrogen (25.00 g t-butyl 4- ([1,1'-Biphenyl]-4-yl)-3-oxobutanoate was dissolved in 100 mL of tetrahydrofuran).
  • reaction liquid was heated to 20 to 30 ° C, and stirring was continued for 30 minutes.
  • the reaction solution was cooled to 0 ° C, and a solution of (R)-methyl-2-(trifluoromethanesulfonate)propionate in tetrahydrofuran (31.37 g (R)-methyl-2-(trifluoro) was slowly added dropwise.
  • the sulfonate group) propionate was dissolved in 100 mL of tetrahydrofuran.
  • the reaction solution was heated to 20 to 30 ° C, and stirred for 1.5 hours.
  • the reaction of the starting material was completely determined by HPLC, and 150 mL of 2N hydrochloric acid was slowly added dropwise to the reaction solution to adjust the pH to 2 to 3.
  • the reaction solution was extracted with ethyl acetate three times, each time 100 mL, the organic phase was combined, and the organic phase was washed twice with water. The second amount is 200 mL, the organic phase is combined, and the organic phase is concentrated under reduced pressure to give (3R)-1-tert-butyl-4-methyl-2-(2-([1,1'-biphenyl]-4-yl 48.60 g of acetyl)-3-methylsuccinate was directly fed without purification to carry out the next reaction.
  • reaction solution is extracted with ethyl acetate for 3 times, each time 100mL, the organic phase is combined, the organic phase is washed twice with water, 200mL each time, organic phase is combined, organic The phase was concentrated under reduced pressure to give (yield, m.
  • reaction liquid was heated to 20 to 30 ° C, and stirring was continued for 30 minutes.
  • the reaction solution was cooled to 0 ° C, and a solution of (R)-ethyl-2-(trifluoromethanesulfonate)propionate in tetrahydrofuran (33.37 g (R)-ethyl-2-(trifluoromethyl) was slowly added dropwise.
  • the sulfonate group) propionate was dissolved in 100 mL of tetrahydrofuran.
  • the reaction solution was heated to 20 to 30 ° C, and stirred for 1.5 hours.
  • the reaction of the starting material was completely determined by HPLC, and 150 mL of 2N hydrochloric acid was slowly added dropwise to the reaction solution to adjust the pH to 2 to 3, and the reaction solution was treated with acetic acid.
  • the ethyl ester was extracted 3 times, each time 100 mL, the organic phase was combined, the organic phase was washed twice with water, 200 mL each time, the organic phase was combined, and the organic phase was concentrated under reduced pressure to give (3R)-1-tert-butyl-4 49.60 g of ethyl-2-(2-([1,1'-biphenyl]-4-yl)acetyl)-3-methylsuccinate, which was directly subjected to the next reaction without purification.
  • reaction solution is extracted with ethyl acetate for 3 times, each time 100mL, the organic phase is combined, the organic phase is washed twice with water, 200mL each time, organic phase is combined, organic The phase was concentrated under reduced pressure to give (yield, ethyl 4-([1,1'-biphenyl)-4-yl)-2-methyl-4-pentanoic acid ethyl ester.
  • reaction liquid was heated to 20 to 30 ° C, and stirring was continued for 30 minutes.
  • the reaction solution was cooled to 0 ° C, and a solution of (R)-isopropyl-2-(trifluoromethanesulfonate)propionate in tetrahydrofuran (33.37 g (R)-isopropyl-2-(3)
  • the fluoromethanesulfonate-based propionate was dissolved in 100 mL of tetrahydrofuran.
  • the reaction solution was heated to 20 to 30 ° C, and stirred for 1.5 hours.
  • the reaction of the starting material was completely determined by HPLC, and 150 mL of 2N hydrochloric acid was slowly added dropwise to the reaction solution to adjust the pH to 2 to 3.
  • the reaction solution was extracted with ethyl acetate three times, each time 100 mL, the organic phase was combined, and the organic phase was washed twice with water.
  • the second amount is 200 mL, the organic phase is combined, and the organic phase is concentrated under reduced pressure to give (3R)-1-tert-butyl-4-isopropyl-2-(2-([1,1'-biphenyl]-4- 50.60 g of acetyl)-3-methylsuccinate was directly fed without purification to carry out the next reaction.
  • the reaction solution was extracted with ethyl acetate three times, each time 100 mL, the organic phase was combined, and the organic phase was washed twice with water, 200 mL each time, and the organic phase was combined.
  • the organic phase was concentrated under reduced pressure to give (yield: ⁇ /RTI> ⁇ RTIgt; ⁇ /RTI> ⁇ /RTI> ⁇ /RTI> ⁇ /RTI> ⁇ /RTI> ⁇ /RTIgt; .
  • reaction solution was evaporated under reduced pressure to remove the tert-butanol, and 100 mL of dichloromethane was added and washed with water and a saturated aqueous solution of sodium chloride, and the organic phase was collected, and the solvent was evaporated under reduced pressure to give tert-butyl 4-([1 , 1'-biphenyl]-4-yl)-3-oxobutyrate 24.89 g, yield 85%.
  • reaction liquid was heated to 20 to 30 ° C, and stirring was continued for 30 minutes.
  • the reaction solution was cooled to 0 ° C, and a solution of (R)-benzyl-2-(trifluoromethanesulfonate)propionate in tetrahydrofuran (33.37 g (R)-benzyl-2-(trifluoromethyl) was slowly added dropwise.
  • the sulfonate-based propionate is dissolved in 100 mL of tetrahydrofuran.
  • the reaction solution is heated to 20-30 ° C, and stirred. Should be 1.5h.
  • the reaction of the starting material was completely determined by HPLC, and 150 mL of 2N hydrochloric acid was slowly added dropwise to the reaction solution to adjust the pH to 2 to 3.
  • the reaction solution was extracted with ethyl acetate three times, each time 100 mL, the organic phase was combined, and the organic phase was washed twice with water.
  • the second amount is 200 mL, the organic phases are combined, and the organic phase is concentrated under reduced pressure to give (3R)-4-benzyl-1-tert-butyl-2-(2-([1,1'-biphenyl]-4-yl) 50.60 g of acetyl)-3-methylsuccinate was directly fed without purification to carry out the next reaction.
  • the reaction solution is extracted with ethyl acetate for 3 times, each time 100mL, the organic phase is combined, the organic phase is washed twice with water, 200mL each time, organic phase is combined, organic The phase was concentrated under reduced pressure to yield (yield: ⁇ /RTI> ⁇ RTIgt; ⁇ /RTI> ⁇ RTIgt; ⁇ /RTI> ⁇ RTIgt; ⁇ /RTI> ⁇ RTIgt; ⁇ /RTI> benzyl ester of benzyl ester.
  • reaction liquid was heated to 20 to 30 ° C, and stirring was continued for 30 minutes.
  • the reaction solution was cooled to 0 ° C, and a solution of (R)-1-methylamino-1-oxopropyl-2-yl-p-toluenesulfonate in tetrahydrofuran (THF) was slowly added dropwise (31.37 g (R)-1 -Methylamino-1-oxopropyl-2-yl-p-toluenesulfonate was dissolved in 100 mL of tetrahydrofuran (THF).
  • reaction mixture was heated to 20 to 30 ° C, and stirred for 1.5 h.
  • the reaction of the starting material was completely determined by HPLC, and 150 mL of 2N hydrochloric acid was slowly added dropwise to the reaction solution to adjust the pH to 2 to 3.
  • the reaction solution was extracted with ethyl acetate three times, each time 100 mL, the organic phase was combined, and the organic phase was washed twice with water.
  • the second amount is 200 mL, the organic phase is combined, and the organic phase is concentrated under reduced pressure to give (3R)-2-(2-([1,1'-biphenyl]-4-yl)acetyl)-3-methyl-4 - 48.60 g of methylamino-4-oxobutanoate, which was directly subjected to the next reaction without purification.
  • the reaction of the starting material was completely determined by HPLC, and the reaction solution was cooled to 20-30 ° C.
  • the pH was adjusted to 2 to 3 by slowly adding 100 mL of 1N aqueous HCl solution, and the reaction solution was extracted with ethyl acetate three times, each time using 100 mL, the organic phase was combined, and the organic phase was combined. Wash twice with water, 200 mL each time, and concentrate the organic phase under reduced pressure to give an oil (R)-5-([1,1'-biphenyl]-4-yl)-N,2-dimethyl-4- Oxyvaleramide 10.43 g, yield 86.5%.
  • reaction liquid was heated to 20 to 30 ° C, and stirring was continued for 30 minutes.
  • the reaction solution was cooled to 0 ° C, and a solution of (R)-1-tert-butylamino-1-oxopropyl-2-yl-p-toluenesulfonate in tetrahydrofuran (THF) (31.37 g (R)- 1-tert-butylamino-1-oxopropyl-2-yl-p-toluenesulfonate was dissolved in 100 mL of tetrahydrofuran (THF). After the addition was completed, the reaction solution was heated to 20-30 ° C, and stirred for 1.5 h. .
  • the reaction of the starting material was completely determined by HPLC, and 150 mL of 2N hydrochloric acid was slowly added dropwise to the reaction solution to adjust the pH to 2 to 3.
  • the reaction solution was extracted with ethyl acetate three times, each time 100 mL, the organic phase was combined, and the organic phase was washed twice with water. The second amount is 200 mL, and the organic phase is concentrated under reduced pressure to give (3R)-2-(2-([1,1'-biphenyl]-4-yl)acetyl)-3-methyl-4-tert-butylamino 48.60 g of ethyl 4-oxo-butyrate was directly fed without purification to carry out the next reaction.
  • the reaction of the raw materials was completely determined by HPLC.
  • the reaction solution was cooled to 20-30 ° C, and 100 mL of 1N hydrochloric acid aqueous solution was slowly added dropwise to adjust the pH to 2 to 3.
  • the reaction solution was extracted with ethyl acetate three times, each time 100 mL, the organic phase was combined, organic phase Wash twice with water, 200 mL each time, combine the organic phases, and concentrate the organic phase under reduced pressure to give (R)-5-([1,1'-biphenyl]-4-yl)-N-tert-butyl- 2-methyl-4-oxopentamide 10.05 g, yield 81.3%.
  • reaction solution was cooled to 0 ° C, and a toluene solution of (R)-1-triphenylmethoxypropyl-2-yl-p-toluenesulfonate was slowly added dropwise (31.37 g (R)-1-triphenylmethyl).
  • the oxypropyl-2-yl-p-toluenesulfonate was dissolved in 100 mL of toluene.
  • the reaction mixture was heated to 60 to 70 ° C, and stirred for 1.5 hours.
  • the reaction of the starting material was completely determined by HPLC, and 150 mL of 2N HCl was slowly added dropwise to the reaction solution to adjust the pH to 2 to 3.
  • the reaction solution was extracted with ethyl acetate three times, each time 100 mL, the organic phase was combined, and the organic phase was washed twice with water. The amount is 200 mL, the organic phase is combined, and the organic phase is concentrated under reduced pressure to give 4-([1,1'-biphenyl]-4-yl)-3-oxo-2-((R)-1-(triphenyl) 46.60 g of ethyl methoxy)propan-2-yl)-butyrate was directly fed without purification to carry out the next reaction.
  • the reaction of the starting material was completely determined by HPLC, and the reaction solution was cooled to 20-30 ° C.
  • the pH was adjusted to 2 to 3 by slowly adding 100 mL of 1N aqueous HCl solution, and the reaction solution was extracted with ethyl acetate three times, each time using 100 mL, the organic phase was combined, and the organic phase was combined. Wash twice with water, and concentrate 200 mL of organic phase each time to give an oil (R)-1-([1,1'-biphenyl]-4-yl)-4-methyl-5- (triphenyl) Oxy)-2-pentanone 11.24 g, yield 85.6%.
  • Example 9-b Preparation of 4-([1,1'-biphenyl]-4-yl))-3-oxo-2-((R)-1-(triethylsiloxy)propyl -2 base)-ethyl butyrate
  • reaction solution was cooled to 0 ° C, and a solution of (R)-1-triethylsiloxypropyl-2-yl-p-toluenesulfonate in toluene (31.37 g (R)-1-triethylsilyl) was slowly added dropwise.
  • the oxypropyl-2-yl-p-toluenesulfonate was dissolved in 100 mL of toluene.
  • the reaction mixture was heated to 60 to 70 ° C, and stirred for 1.5 hours.
  • the reaction of the starting material was completely determined by HPLC, and 150 mL of 2N hydrochloric acid was slowly added dropwise to the reaction solution to adjust the pH to 2 to 3.
  • the reaction solution was extracted with ethyl acetate three times, each time 100 mL, the organic phase was combined, and the organic phase was washed twice with water.
  • the second amount is 200 mL, and the organic phase is concentrated under reduced pressure to give 4-([1,1'-biphenyl]-4-yl))-3-oxo-2-((R)-1-(triethylsilyl) 44.50 g of ethyl oxy)propyl-2-yl)-butyrate was directly fed without purification to carry out the next reaction.
  • the reaction of the starting material was completely determined by HPLC, and the reaction solution was cooled to 20-30 ° C.
  • the pH was adjusted to 2 to 3 by slowly adding 100 mL of 1N aqueous HCl solution, and the reaction solution was extracted with ethyl acetate three times, each time using 100 mL, the organic phase was combined, and the organic phase was combined. Wash twice with water, 200 mL each time, and concentrate the organic phase under reduced pressure to give an oil (R)-1-([1,1'-biphenyl]-4-yl)-4-methyl-5- (tri-ethyl
  • the base siloxy)-2-pentanone was 10.97 g, and the yield was 86.9%.
  • Example 10-a Preparation of ethyl 4-([4-iodophenyl]-4-yl)-3-oxobutanoate
  • reaction solution was heated to 45 ° C for 3 h, cooled to 20 to 30 ° C, and vacuumed under reduced pressure for 1 h.
  • reaction solution was cooled to 20-30 ° C, 180 mL of 4N hydrochloric acid solution was slowly added dropwise, and the organic phase was washed three times with 6.5% sodium hydrogen carbonate solution, 250 mL each time, the organic phase was collected, and the solvent was distilled off under reduced pressure at 45 ° C. Yellowish brown oil.
  • reaction liquid drop Warm to 0 ° C, slowly add dropwise a solution of ethyl 4-([4-iodophenyl]-4-yl)-3-oxobutanoate in tetrahydrofuran (THF) under nitrogen (25.00 g 4-([4-iodine) Ethyl phenyl]-4-yl)-3-oxobutanoate was dissolved in 100 mL of tetrahydrofuran (THF).
  • reaction liquid was heated to 20 to 30 ° C, and stirring was continued for 30 minutes.
  • the reaction solution was cooled to 0 ° C, and a solution of (R)-methyl-2-(p-toluenesulfonate)propionate in tetrahydrofuran (THF) was slowly added dropwise (31.37 g of (R)-methyl-2-(p-toluene)
  • the sulfonic acid) propionate was dissolved in 100 mL of tetrahydrofuran (THF).
  • the reaction mixture was heated to 20 to 30 ° C, and stirred for 1.5 h.
  • the reaction of the starting material was completely determined by HPLC, and 150 mL of 2N hydrochloric acid was slowly added dropwise to the reaction solution to adjust the pH to 2 to 3.
  • the reaction solution was extracted with ethyl acetate three times, each time 100 mL, the organic phase was combined, and the organic phase was washed twice with water.
  • the second amount was 200 mL, and concentrated under reduced pressure to give (3R)-1-ethyl-4-methyl 2-(2-([4-phenylphenyl])acetyl)-3-methyl succinate.
  • the mixture was directly fed without purification for the next reaction.
  • reaction solution was cooled to 20-30 ° C, and 100 mL of 1N hydrochloric acid aqueous solution was slowly added dropwise to adjust the pH to 2 to 3.
  • the reaction solution was extracted with ethyl acetate three times, each time 100 mL, the organic phase was combined, organic phase It was washed twice with water, 200 mL each time, and concentrated under reduced pressure to give an oil (R)-5-([4-iodophenyl])-2-methyl-4-pentanoic acid 8.46 g, yield: 82.0%.
  • the reaction solution was extracted with ethyl acetate three times, the organic phase was combined, the organic phase was washed with water, the organic phase was collected, and the organic phase was decompressed. Concentration gave 48.60 g of an oil, which was used in the next step without purification.
  • the synthesis method provided by the present invention can efficiently prepare a compound represented by the formula (V), and further synthesizes shakubil by the compound represented by the formula (V).
  • the method of the invention has the advantages of easy availability of raw materials, simple process, economy and environmental protection.

Abstract

本发明涉及一种沙库必曲中间体及其制备方法，本发明所述的沙库必曲中间体，其可以通过一种化合物经过脱保护反应制备获得；另外，可采用所述中间体作为物料进一步地合成沙库必曲化合物。本发明所述的方法具有原料易得、工艺简洁、经济环保等优点，非常适合工业化生产。

Description

一种沙库必曲的中间体及其制备方法 技术领域
本发明涉及医药化工领域，更具体地涉及一种沙库必曲中间体及其制备方法。
背景技术
沙库必曲(Sacubitril)，化学名为4-(((2S,4R)-1-([1,1'-联苯]-4-基)-5-乙氧基-4-甲基-5-氧代戊烷-2-基)氨基)-4-氧代丁酸，其结构式如下：
Figure PCTCN2017075097-appb-000001
2015年7月日，美国FDA批准上市抗心衰药物Entresto(也称为LCZ696)，其是血管紧张素II抑制剂缬沙坦(Valsartan)和脑啡肽酶抑制剂沙库必曲(Sacubitril)的复方组合。缬沙坦可改善血管舒张，刺激身体排泄钠和水，而沙库必曲可阻断威胁降低血压的2种多肽的作用机制，因而LCZ696被称为血管紧张素II受体与脑啡肽酶的双重抑制剂，其临床表现出独特作用模式，优于标准药物的降压作用和减少心脏衰竭的功效。
现有技术中公开了一些沙库必曲的制备方法，如：
WO2008031567A1公开了以2位氨基被取代的联苯丙醇为起始物料，经氧化成醛和Witting反应制得4位氨基被取代的联苯丁烯酸或其衍生物，然后在氢气存在下，以化学元素周期表中7、8和9族过渡金属元素作为催化剂和手性配位体存在下，经过还原和反应和手性拆分制备4位氨基被取代的联苯丁酸或其衍生物的方法。该产物可进一步转化为沙库必曲。示例反应式如下：
Figure PCTCN2017075097-appb-000002
WO2008083967A2公开了以2-羰基脯氨酸为原料，经过羧基活化、联苯取代、羰基还原、手性甲基化、开环反应和酰胺化缩合等反应制得沙库必曲。反应如下：
Figure PCTCN2017075097-appb-000003
WO 2008031567A1和WO 2008083967A2公开的合成路线，虽然在起始原料的使用、手性的形成的方法和单元反应的顺序上存在一定的差别，但均存在手性原料难以获得、反应步骤繁多、手性催化还原催化剂昂贵、立体选择性差以及反复使用羧基或氨基保护和脱保护等缺点，难以顺利地实现其产业化。
CN104557600A以手性诱导试剂(S)-1-(α-氨基苄基)-2-萘酚(S-betti Base)与2R-甲基-4-氧代-丁酸经环合、加成、脱苄基、开环、酯化及酰胺化等反应步骤制得沙库比曲。反应式如下：
Figure PCTCN2017075097-appb-000004
所述制备沙库必曲的工艺方法，S-betti Base及手性起始物料昂贵不易获得，加成反应需要先制备格式试剂，反应条件严格，不易控制，且合成路线比较繁琐。
发明内容
发明概述
第一方面，本发明提供了制备沙库必曲的一种中间体，如式(Ⅴ)所示的化合物及所述式(Ⅴ)所示化合物的制备方法；
Figure PCTCN2017075097-appb-000005
其中，
R1可以是苯基、甲氧基、羟基、氯、溴、碘、甲磺酸酯基(-OMs)、三氟甲磺酸酯基(-OTf)或对甲苯磺酸酯基(-OTs)；
R2可以是
Figure PCTCN2017075097-appb-000006
R3可以是氢、-(C1-C4)烷基或-(C1-C4)烷基-芳基。其中，所述的-(C1-C4)烷基在一些实施例中可以是甲基、乙基、正丙基、异丙基、正丁基、叔丁基。其中，所述的-(C1-C4)烷基-芳基在一些实施例中可以是苄基或被任意取代的苄基。
R4可以是氢、-(C1-C4)烷基、-(C3-C6)杂环基、-(C1-C4)烷基-芳基、三甲基硅基、三乙基硅基或叔丁基二甲基硅基。其中，所述的-(C1-C4)烷基在一些实施例中可以是甲基、乙基、正丙基、异丙基、正丁基、叔丁基。其中，所述的-(C1-C4)烷基-芳基在一些实施例中可以是苄基或被任意取代的苄基。
第二方面，本发明提供通过式(Ⅴ)所示的化合物制备沙库必曲的两种方法，两种方法具有原料易得、工艺简洁、经济环保等优点，适合工业化生产。
术语定义
本发明意图涵盖所有的替代、修改和等同技术方案，它们均包括在如权利要求定义的本发明范围内。本领域技术人员应认识到，许多与本文所述类似或等同的方法和材料能够用于实践本发明。本发明绝不限于本文所述的方法和材料。在所结合的文献、专利和类似材料的一篇或多篇与本申请不同或相矛盾的情况下(包括但不限于所定义的术语、术语应用、所描述的技术等等)，以本申请为准。
应进一步认识到，本发明的某些特征，为清楚可见，在多个独立的实施方案中进行了描述，但也可以在单个实施例中以组合形式提供。反之，本发明的各种特征，为简洁起见，在单个实施方案中进行了描述，但也可以单独或以任意合适的子组合提供。
除非另外说明，本发明所使用的所有科技术语具有与本发明所属领域技术人员的通常理解相同的含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。
除非另外说明，应当应用本文所使用的下列定义。出于本发明的目的，化学元素与元素周期表CAS版，和1994年第75版《化学和物理手册》一致。术语“包含”或“包括”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。
在本说明书的各部分，本发明公开化合物的取代基按照基团种类或范围公开。特别指出，本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如，术语“-C1-C6烷基”特别指独立公开的甲基、乙基、C3烷基、C4烷基、C5烷基和C6烷基。
在本发明的各部分，描述了连接取代基。当该结构清楚地需要连接基团时，针对该基团所列举的马库什变量应理解为连接基团。例如，如果该结构需要连接基团并且针对该变量的马库什基团定义列举了“烷 基”或“芳基”，则应该理解，该“烷基”或“芳基”分别代表连接的亚烷基基团或亚芳基基团。
本发明使用的术语“烷基”，表示含有1至20个碳原子，饱和的直链或支链一价烃基基团，其中，所述烷基基团可以任选地被一个或多个本发明描述的取代基所取代。
术语“杂环基”，都是指包含3-12个环原子的饱和或部分不饱和的单环、双环或三环，其中至少一个环原子选自氮、硫和氧原子。除非另外说明，杂环基可以是碳基或氮基，且-CH2-基团可以任选地被-C(O)-替代。环的硫原子可以任选地被氧化成S-氧化物。环的氮原子可以任选地被氧化成N-氧化合物。杂环基的实例包括，但不限于：环氧乙烷基、氮杂环丁基，氧杂环丁基，硫杂环丁基，吡咯烷基，2-吡咯啉基，3-吡咯啉基，吡唑啉基，吡唑烷基，咪唑啉基，咪唑烷基，四氢呋喃基，二氢呋喃基，四氢噻吩基，二氢噻吩基，1,3-二氧环戊基，二硫环戊基，四氢吡喃基，二氢吡喃基，2H-吡喃基，4H-吡喃基，四氢噻喃基，哌啶基，吗啉基，硫代吗啉基，哌嗪基，二噁烷基，二噻烷基，噻噁烷基，高哌嗪基，高哌啶基，氧杂环庚烷基，硫杂环庚烷基，氧氮杂
Figure PCTCN2017075097-appb-000007
基，二氮杂
Figure PCTCN2017075097-appb-000008
基，硫氮杂
Figure PCTCN2017075097-appb-000009
基，吲哚啉基，1,2,3,4-四氢异喹啉基、1,3-苯并二噁茂基、2-氧杂-5-氮杂双环[2.2.1]庚-5-基。杂环基中-CH2-基团被-C(O)-取代的实例包括，但不限于，2-氧代吡咯烷基、氧代-1,3-噻唑烷基、2-哌啶酮基、3,5-二氧代哌啶基和嘧啶二酮基。杂环基中硫原子被氧化的实例包括，但不限于，环丁砜基、1,1-二氧代硫代吗啉基。所述的杂环基基团可以任选地被一个或多个本发明所描述的取代基所取代。
在一些实施方案中，杂环基为6个原子组成的杂环基，是指包含6个环原子的饱和或部分不饱和的单环，其中至少一个环原子选自氮、硫和氧原子。除非另外说明，6个原子组成的杂环基可以是碳基或氮基，且-CH2-基团可以任选地被-C(O)-替代。环的硫原子可以任选地被氧化成S-氧化物。环的氮原子可以任选地被氧化成N-氧化合物。6个原子组成的杂环基的实例包括，但不限于：四氢吡喃基，二氢吡喃基，2H-吡喃基，4H-吡喃基，四氢噻喃基，哌啶基，吗啉基，硫代吗啉基，哌嗪基，二噁烷基，二噻烷基，噻噁烷基。杂环基中-CH2-基团被-C(O)-取代的实例包括，但不限于，2-哌啶酮基、3,5-二氧代哌啶基和嘧啶二酮基。杂环基中硫原子被氧化的实例包括，但不限于，1,1-二氧代硫代吗啉基。所述的6个原子组成的杂环基基团可以任选地被一个或多个本发明所描述的取代基所取代。
在本发明中所使用的术语“不饱和的”表示基团中含有一个或多个不饱和度。
术语“杂原子”是指O、S、N、P和Si，包括N、S和P任何氧化态的形式；伯、仲、叔胺和季铵盐的形式；或者杂环中氮原子上的氢被取代的形式，例如，N(像3,4-二氢-2H-吡咯基中的N)，NH(像吡咯烷基中的NH)或NR(像N-取代的吡咯烷基中的NR)。
术语“芳基”表示含有6-14个环原子，或6-12个环原子，或6-10个环原子的单环、双环和三环的碳环体系，其中，至少一个环体系是芳香族的，其中每一个环体系包含3-7个原子组成的环，且有一个或多个附着点与分子的其余部分相连。术语“芳基”可以和术语“芳香环”交换使用。芳基基团的实例可以包括苯基、萘基和蒽。所述芳基基团可以独立任选地被一个或多个本发明所描述的取代基所取代。
本发明所述的甲磺酸酯基(-OMs)是
Figure PCTCN2017075097-appb-000010
三氟甲磺酸酯基(-OTf)是
Figure PCTCN2017075097-appb-000011
对甲苯磺酸 酯基(-OTs)是
Figure PCTCN2017075097-appb-000012
Ph指苯基。
发明详述
第一方面，本发明提供了制备沙库必曲的一种中间体，如式(Ⅴ)所示的化合物；还提供了所述式(Ⅴ)所示化合物的制备方法。
本发明提供了制备沙库必曲的一种中间体，如式(Ⅴ)所示的化合物；
Figure PCTCN2017075097-appb-000013
其中，
R1可以是苯基、甲氧基、羟基、氯、溴、碘、甲磺酸酯基(-OMs)、三氟甲磺酸酯基(-OTf)或对甲苯磺酸酯基(-OTs)；在一些实施例中，R1是苯基；
R2可以是
Figure PCTCN2017075097-appb-000014
R3可以是氢、-(C1-C4)烷基或-(C1-C4)烷基-芳基；其中，所述的-(C1-C4)烷基在一些实施例中可以是甲基、乙基、正丙基、异丙基、正丁基、叔丁基；所述的-(C1-C4)烷基-芳基在一些实施例中可以是苄基或被任意取代的苄基；
R4可以是氢、-(C1-C4)烷基、-(C3-C6)杂环基、-(C1-C4)烷基-芳基、三甲基硅基、三乙基硅基或叔丁基二甲基硅基；其中，所述的-(C1-C4)烷基在一些实施例中可以是甲基、乙基、正丙基、异丙基、正丁基、叔丁基；所述的-(C1-C4)烷基-芳基在一些实施例中可以是苄基或被任意取代的苄基。
在一些实施例中，本发明所述的如式(Ⅴ)所示的化合物，其中所述的R2是-COOH、-COOCH3、-COOCH2CH3、-COOCH(CH3)2、-COOC(CH3)3、-COOCH2Ph、-CH2OH、-CH2O CH3、-CH2O CH2CH3、-CH2O CH(CH3)2、-CH2O C(CH3)3、-CH2O CH2Ph、-CH2O C(Ph)3、-CH2O Si(CH3)3、-CH2O Si(CH2CH3)3、-CH2O Si(CH3)2C(CH3)3、-CONH2、-CONHCH3、-CONHCH2CH3、-CONHCH(CH3)2、-CONHC(CH3)3、-CONHCH2Ph或
Figure PCTCN2017075097-appb-000015
在一些实施例中，式(Ⅴ)所示的化合物可以是具有以下之一的结构：
Figure PCTCN2017075097-appb-000016
Figure PCTCN2017075097-appb-000017
Figure PCTCN2017075097-appb-000018
Figure PCTCN2017075097-appb-000019
本发明所述的式(Ⅴ)所示的化合物，可以通过式(Ⅳ)所示的化合物经过脱保护反应制备获得，
Figure PCTCN2017075097-appb-000020
其中，
R1可以是苯基、甲氧基、羟基、氯、溴、碘、甲磺酸酯基(-OMs)、三氟甲磺酸酯基(-OTf)或对甲苯磺酸酯基(-OTs)；在一些实施例中，R1是苯基；
R2可以是
Figure PCTCN2017075097-appb-000021
在一些实施例中，R2是
Figure PCTCN2017075097-appb-000022
R3可以是氢、-(C1-C4)烷基或-(C1-C4)烷基-芳基；其中，所述的-(C1-C4)烷基在一些实施例中可以是甲基、乙基、正丙基、异丙基、正丁基、叔丁基；所述的-(C1-C4)烷基-芳基在一些实施例中可以是苄基或被任意取代的苄基；
R4可以是氢、-(C1-C4)烷基、-(C3-C6)杂环基、-(C1-C4)烷基-芳基、三甲基硅基、三乙基硅基或叔丁基二甲基硅基；其中，所述的-(C1-C4)烷基在一些实施例中可以是甲基、乙基、正丙基、异丙基、正丁基、叔丁基；所述的-(C1-C4)烷基-芳基在一些实施例中可以是苄基或被任意取代的苄基；
R5可以是氢、-(C1-C4)烷基或-(C1-C4)烷基-芳基；其中，所述的-(C1-C4)烷基在一些实施例中可以是甲基、乙基、正丙基、异丙基、正丁基、叔丁基；所述的-(C1-C4)烷基-芳基在一些实施例中可以是苄基或被任意取代的苄基。
在一些实施例中，式(Ⅳ)所示的化合物在酸或碱存在的条件下，经过脱保护反应获得式(Ⅴ)所示的化合 物；在一些实施例中的所述的酸是三氟乙酸；在一些实施例中所述的碱是氢氧化锂。
本发明所述的式(Ⅳ)所示的化合物，可以通过式(Ⅱ)所示的化合物和式(Ⅲ)所示的化合物进行取代反应制备，
Figure PCTCN2017075097-appb-000023
其中，
所述的R1、R2和R5可以是如前所述的基团，
所述的R6可以是三氟甲磺酸酯基(-OTf)、甲磺酸酯基(-OMs)或对甲苯磺酸酯基(-OTs)。
式(Ⅱ)所示的化合物和式(Ⅲ)所示的化合物进行取代反应可引入手性甲基，从而得到式(Ⅳ)所示的化合物；在一些实施例中，所述的取代反应是在强碱存在的条件下进行的；在一些实施例中，所述的强碱为氢化钠。
本发明所述的式(Ⅱ)所示的化合物，可以通过以式(Ⅰ)所示的化合物，进行缩合反应制备获得，
Figure PCTCN2017075097-appb-000024
其中所述的R1可以是如前所述的基团。
在一些实施例中，式(Ⅰ)所示的化合物在氯化镁和三乙胺存在条件下与N,N'-羰基二咪唑和式(Ⅷ)所示的化合物进行缩合反应获得式(Ⅱ)所示的化合物，
Figure PCTCN2017075097-appb-000025
其中所述R5可以是如前所述基团。
在一些实施例中，式(Ⅰ)所示的化合物在N,N-二异丙基乙胺存在条件下与米氏酸(Meldrum’s acid)、4-二甲氨基吡啶、R5OH和特戊酰氯进行缩合反应获得式(Ⅱ)所示的化合物，所述的R5可以是如前所述基团。
在一些实施例中，本发明所述的式(Ⅴ)所示的化合物的制备方法包括以下步骤，
Figure PCTCN2017075097-appb-000026
其中所述的R1是苯基，
所述R2是
Figure PCTCN2017075097-appb-000027
其中所述的R3可以是氢、甲基、乙基、丙基、异丙基、正丁基、叔丁基或苄基，其中所述R4是氢、甲基、乙基、丙基、异丙基、正丁基、叔丁基、苄基，三甲基硅基，三乙基硅基，叔丁基二甲基硅基，三 苯甲基，四氢吡喃基；
a)式(Ⅰ)所示的化合物，在碱性条件下，进行缩合反应制备获得式(Ⅱ)所示的化合物，
Figure PCTCN2017075097-appb-000028
其中，
所述的R1是苯基；
所述的R5是氢、甲基、乙基、正丙基、异丙基、正丁基或苄基；
b)式(Ⅱ)所示的化合物和式(Ⅲ)所示的化合物在强碱存在的条件下进行取代反应，制备获得式(Ⅳ)所示的化合物，
Figure PCTCN2017075097-appb-000029
其中，
所述的R1是苯基，
所述R2是
Figure PCTCN2017075097-appb-000030
其中所述的R3可以是氢、甲基、乙基、正丙基、异丙基、正丁基、叔丁基或苄基，其中所述R4是氢、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、苄基，三甲基硅基，三乙基硅基或叔丁基二甲基硅基；
所述R5可以是氢、甲基、乙基、丙基、异丙基、正丁基或苄基，
所述R6可以是三氟甲磺酸酯基(-OTf)、甲磺酸酯基(-OMs)或对甲苯磺酸酯基(-OTs)；
c)式(Ⅳ)所示的化合物在酸或者碱存在的条件下反应，经过脱保护反应，制备获得式(Ⅴ)所示的化合物。
本发明所述的制备式(Ⅴ)化合物的反应路线如下所示：
Figure PCTCN2017075097-appb-000031
本发明所述的制备式(Ⅴ)化合物或其中间体的方法，本领域技术人员，在本发明的构思下，可以根据 公开的内容，视情况需要可以适当地调整反应条件，如选择其他适当的反应溶剂，调整反应的温度，适当延长反应时间已获得更好的反应效果等。通过本发明上述制备方法可以制备获得本发明所描述的式(Ⅴ)所示的化合物。
第二方面，本发明还提供通过式(Ⅴ)所示的化合物制备沙库必曲的两种方法。
第一种通过式(Ⅴ)所示的化合物制备沙库必曲的方法可以是如以下反应通式所示：
Figure PCTCN2017075097-appb-000032
第一种制备沙库必曲的方法，可包括以下步骤：
将式(Ⅴ)所示的化合物作经过酶催化反应，制备获得式(Ⅵ)所示的化合物，
Figure PCTCN2017075097-appb-000033
其中，
所述的R1是苯基、甲氧基、羟基、氯、溴、碘、甲磺酸酯基、三氟甲磺酸酯基或对甲苯磺酸酯基；
所述的R2是
Figure PCTCN2017075097-appb-000034
R3是氢、-(C1-C4)烷基或-(C1-C4)烷基-芳基；
R4是氢、-(C1-C4)烷基、-(C3-C6)杂环基、-(C1-C4)烷基-芳基、三甲基硅基、三乙基硅基或叔丁基二甲基硅基。
第一种制备沙库必曲的方法，可以包括以下步骤：
a)式(Ⅴ)所示的化合物经过酶催化反应，制备获得式(Ⅵ)所示的化合物，
Figure PCTCN2017075097-appb-000035
其中，
所述的R1可以是苯基、甲氧基、羟基、氯、溴、碘、甲磺酸酯基(-OMs)、三氟甲磺酸酯基(-OTf)或对甲苯磺酸酯基(-OTs)；
所述的R2可以是
Figure PCTCN2017075097-appb-000036
所述的R3可以是氢、-(C1-C4)烷基或-(C1-C4)烷基-芳基；其中，所述的-(C1-C4)烷基在一些实施例中可以是甲基、乙基、正丙基、异丙基、正丁基、叔丁基，所述的-(C1-C4)烷基-芳基在一些实施例中可以是苄基或被任意取代的苄基；
所述的R4可以是氢、-(C1-C4)烷基、-(C3-C6)杂环基、-(C1-C4)烷基-芳基、三甲基硅基、三乙基硅基或叔丁基二甲基硅基；其中，所述的-(C1-C4)烷基在一些实施例中可以是甲基、乙基、正丙基、异丙基、正丁基、叔丁基，所述的-(C1-C4)烷基-芳基在一些实施例中可以是苄基或被任意取代的苄基；
b)可选择性的，通过式(Ⅵ)所示的化合物制备式(Ⅶ)所示的化合物，
Figure PCTCN2017075097-appb-000037
c)通过式(Ⅶ)所示的化合物反应制备获得沙库必曲。
在一些实施例中，第一种制备沙库必曲的方法，可以包括以下步骤：
a)式(Ⅴ)所示的化合物经过酶催化反应，制备获得式(Ⅵ)所示的化合物，
Figure PCTCN2017075097-appb-000038
其中，R1是苯基，
R2是
Figure PCTCN2017075097-appb-000039
其中R3是氢、-(C1-C4)烷基或-(C1-C4)烷基-芳基；其中，所述的-(C1-C4)烷基在一些实施例中可以是甲基、乙基、正丙基、异丙基、正丁基、叔丁基，所述的-(C1-C4)烷基-芳基在一些实施例中可以是苄基或被任意取代的苄基；
b)可选择性的，通过式(Ⅵ)所示的化合物制备式(Ⅶ)所示的化合物，
Figure PCTCN2017075097-appb-000040
c)通过式(Ⅶ)所示的化合物反应制备获得沙库必曲。
在一些实施例中，第一种制备沙库必曲的方法，可以包括以下步骤：
a)式(Ⅴ)所示的化合物经过酶催化反应，制备获得式(Ⅶ)所示的化合物，
Figure PCTCN2017075097-appb-000041
其中R1是苯，
其中R2是
Figure PCTCN2017075097-appb-000042
R3是乙基；
b)式(Ⅶ)所示的化合物与丁二酸酐经过酰胺化缩合反应制备获得沙库必曲。
在一些实施例中，上述制备沙库必曲的方法，其中所述的酶催化反应是在ω-转氨酶和磷酸吡哆醛存在的条件下进行的。
在一些实施例中，上述制备沙库必曲的方法，其中所述式(Ⅶ)所示的化合物，可以通过先将式(Ⅵ)所示的化合物进行水解反应，然后再与乙醇进行酯化反应制备而得。
第二种通过式(Ⅴ)所示的化合物制备沙库必曲的方法可以是如以下反应通式所示：
Figure PCTCN2017075097-appb-000043
第二种制备沙库必曲的方法，可以包括以下步骤：
以式(Ⅴ)所示的化合物与式(Ⅸ)所示的化合物反应制备获得式(Ⅹ)所示的化合物，
Figure PCTCN2017075097-appb-000044
其中，
所述的R1是苯基、甲氧基、羟基、氯、溴、碘、甲磺酸酯基、三氟甲磺酸酯基或对甲苯磺酸酯基，
所述的R2是
Figure PCTCN2017075097-appb-000045
所述的R3是氢、-(C1-C4)烷基或-(C1-C4)烷基-芳基，
所述的R7是苯基或-(C1-C4)烷基或-(C1-C4)烷基-芳基。
第二种制备沙库必曲的方法，可以包括以下步骤：
通过式(Ⅹ)所示的化合物制备式(ⅩⅠ)所示的化合物，
Figure PCTCN2017075097-appb-000046
其中，
所述的R1是苯基、甲氧基、羟基、氯、溴、碘、甲磺酸酯基、三氟甲磺酸酯基或对甲苯磺酸酯基，
所述的R7是苯基或-(C1-C4)烷基或-(C1-C4)烷基-芳基。
第二种制备沙库必曲的方法，可以包括以下步骤：
a)式(Ⅴ)所示的化合物与式(Ⅸ)所示的化合物反应制备获得式(Ⅹ)所示的化合物，
Figure PCTCN2017075097-appb-000047
其中，
所述的R1可以是苯基、甲氧基、羟基、氯、溴、碘、甲磺酸酯基(-OMs)、三氟甲磺酸酯基(-OTf)或对甲苯磺酸酯基(-OTs)，
所述的R2可以是
Figure PCTCN2017075097-appb-000048
所述的R3可以是氢、-(C1-C4)烷基或-(C1-C4)烷基-芳基，其中，所述的-(C1-C4)烷基在一些实施例中可以是甲基、乙基、正丙基、异丙基、正丁基、叔丁基，所述的-(C1-C4)烷基-芳基在一些实施例中可以是苄基或被任意取代的苄基；
所述的R7可以是苯基或-(C1-C4)烷基或-(C1-C4)烷基-芳基，其中，所述的-(C1-C4)烷基在一些实施例中可以是甲基、乙基、正丙基、异丙基、正丁基、叔丁基，所述的-(C1-C4)烷基-芳基在一些实施例中可以是苄基或被任意取代的苄基；
b)通过式(Ⅹ)所示的化合物制备式(ⅩⅠ)所示的化合物，
Figure PCTCN2017075097-appb-000049
所述R1和R7如步骤a)中所描述；
c)通过式(ⅩⅠ)所示的化合物制备式(ⅩⅡ)所示的化合物，
Figure PCTCN2017075097-appb-000050
d)通过式(ⅩⅡ)所示的化合物制备式(Ⅶ)所示的化合物，
Figure PCTCN2017075097-appb-000051
e)通过式(Ⅶ)所示的化合物反应制备获得沙库必曲。
在一些实施例中，所述的(Ⅸ)所示化合物是D-苯甘氨醇。
在一些实施例中，所述的式(Ⅹ)所示的化合物制备(ⅩⅠ)所示的化合物是在四氯化钛和三乙基硅烷存在下进行的。
在一些实施例中，所述的式(ⅩⅠ)所示的化合物制备(ⅩⅡ)所示的化合物是在钯炭(Pd/C)催化剂存在的条件下进行的。
在一些实施例中，所述的式(ⅩⅡ)所示的化合物制备(Ⅶ)所示的化合物是在酸性条件下，乙醇溶剂中进行的。在一些实施例中，所述酸性条件是指有盐酸存在的条件。
在一些实施例中，第二种制备沙库必曲的方法包括以下步骤：
a)(R)-5-([1,1'-联苯]-4-基)-2-甲基-4-戊酮酸(如前文表格中所述的化合物(1))与D-苯甘氨醇反应制备获得式(ⅩⅢ)所示的化合物，
Figure PCTCN2017075097-appb-000052
b)通过式(ⅩⅢ)所示的化合物在四氯化钛和三乙基硅烷存在的条件下制备式(ⅩⅣ)所示的化合物，
Figure PCTCN2017075097-appb-000053
c)通过式(ⅩⅣ)所示的化合物以钯炭(Pd/C)作为催化剂制备式(ⅩⅡ)所示的化合物；
Figure PCTCN2017075097-appb-000054
d)通过式(ⅩⅡ)所示的化合物开环反应制备式(Ⅶ)所示的化合物，
Figure PCTCN2017075097-appb-000055
e)通过式(Ⅶ)所示的化合物反应制备获得沙库必曲；
其反应路线如下所示：
Figure PCTCN2017075097-appb-000056
本发明所述的制备沙库必曲的方法中，其中式(Ⅶ)所示的化合物((2R,4S)-5-([1,1'-联苯]-4-基)-4-氨基-2-甲基戊酸乙酯)可在碱存在下与丁二酸酐经过酰胺化缩合反应制备获得沙库必曲；该步骤在现有技术中已经公开，如WO 2008031567 A1和CN 104557600 A中均有公开，为本领域技术人员所知。
本发明所提供的技术方案和现有技术相比，具有以下优势：
1、提供了一种全新的沙库必曲中间体(V)及其制备方法，该中间体的制备以廉价易得的联苯乙酸为原料，经缩合、取代、脱保护三步即得中间体(V)，每一步反应收率较高，操作简单；该中间体与沙库必曲具有类似的母体结构，目前尚未见有该类结构化合物报道，也未见有以类似结构为中间体合成沙库必曲的制备方法报道；
2、提供了一种以中间体(V)为原料，以酶催化反应为关键步骤的制备沙库必曲的方法；该路线中，手性氨基在酶催化作用下在一步之内高收率高立体选择性的引入，反应条件温和，最短路线在两步之内即可得到沙库必曲；而现有技术引入该手性氨基一般需要手性原料、手性诱导试剂、手性催化剂或者手性拆分，存在成本高、环境不友好、收率低、立体选择性差、路线长及需要反复上保护脱保护等问题；
3、提供了一种以中间体(V)为原料，以手性的取代甘氨醇为手性助剂，经过环合、脱保护、开环、酰胺化等步骤合成沙库必曲的方法，该方法和现有技术相比，手性助剂由(S)-1-(α-氨基苄基)-2-萘酚替换为取代甘氨醇，更加廉价易得，原料中间体(V)制备方法简单，每一步反应条件温和简单，适合工业化生产。
具体实施方式
为了使本领域的技术人员更好地理解本发明的技术方案，本发明示例地提供一部分制备实施例，下面 进一步披露一些非限制实施例对本发明作进一步的详细说明。
本发明所使用的试剂均可以从市场上购得或者可以通过本发明所描述的方法制备而得。
mL指毫升，g指克，h指小时，N指摩尔/升，1H NMR指核磁氢谱，MS指质谱，HPLC指高效液相色谱，CDCl3指氘代氯仿，DMSO-d6指氘代二甲基亚砜。
中间体(V)及其制备方法
实施例1制备(R)-5-([1,1'-联苯]-4-基)-2-甲基-4-戊酮酸
实施例1-a：制备4-([1,1'-联苯]-4-基)-3-氧代丁酸乙酯
Figure PCTCN2017075097-appb-000057
室温下向500mL三口反应瓶A中加入200mL乙酸乙酯和28.64gN,N'-羰基二咪唑，25.00g 4-联苯乙酸分批加入到反应瓶A中，控制气体产生速度。加料完毕后反应液升温至45℃反应3h，降温至20～30℃，减压抽真空1h，备用。室温下1L反应瓶B中加入280mL乙酸乙酯、28.06g丙二酸单乙酯钾盐(EtO2CCH2COOK)和15.70g氯化镁(MgCl2)，控温20～30℃，缓慢滴加入19.07g三乙胺(TEA)，滴加完毕后继续搅拌1h。室温下将反应瓶A中物料加入至反应瓶B中，升温至45℃，保温反应16h。反应液降温至20℃～30℃，缓慢滴加180mL 4N盐酸溶液，分液，有机相用6.5％碳酸氢钠溶液洗涤三次，每次用量250mL，收集有机相，45℃下减压蒸除溶剂得黄棕色油状物。向所得油状物中加入150mL正己烷，20～30℃搅拌18h，过滤，滤饼用正己烷洗涤，40～50℃真空干燥5h得4-([1,1'-联苯]-4-基)-3-氧代丁酸乙酯26.3g，收率79.1％。1H NMR(600MHz,CDCl3)δ7.60(dt,J＝15.9,6.1Hz,4H),7.47(t,J＝7.7Hz,2H),7.37(dt,J＝9.7,7.9Hz,1H),7.33–7.28(m,2H),4.25–4.18(m,2H),3.90(s,2H),3.52(s,2H),1.30(t,J＝7.1Hz,3H).ESI-MS(m/z):283.3([M+H]+).
实施例1-b：制备(3R)-1-乙基-4-甲基2-(2-([1,1'-联苯]-4-基)乙酰基)-3-甲基琥珀酸酯
Figure PCTCN2017075097-appb-000058
向500mL反应瓶中加入5.31g氢化钠(NaH)和100mL干燥四氢呋喃(THF)，氮气置换3次。反应液降温至0℃，氮气保护下缓慢滴加4-([1,1'-联苯]-4-基)-3-氧代丁酸乙酯的四氢呋喃(THF)溶液(25.00g 4-([1,1'-联苯]-4-基)-3-氧代丁酸乙酯溶解于100mL四氢呋喃(THF)中)。滴加完毕后，反应液升温至20～30℃，继续搅拌30分钟。反应液降温至0℃，缓慢滴加(R)-甲基-2-(对甲苯磺酸酯基)丙酸酯的四氢呋喃(THF)溶液(31.37g(R)-甲基-2-(对甲苯磺酸酯基)丙酸酯溶解于100mL四氢呋喃(THF)中)，滴加完毕后反应液升温至20～30℃，搅拌反应1.5h。HPLC检测原料反应完全，向反应液中缓慢滴加150mL 2N盐酸调节pH至2～3，反应液用乙酸乙酯萃取3次，每次用量100mL，合并有机相，有机相用水洗涤两次，每次用量200mL，合并有机相，有机相减压浓缩得到油状物(3R)-1-乙基-4-甲基2-(2-([1,1'-联苯]-4-基)乙酰基)-3-甲基琥珀酸酯 48.60g，不经纯化直接投料进行下一步反应。
实施例1-c：制备(R)-5-([1,1'-联苯]-4-基)-2-甲基-4-戊酮酸
Figure PCTCN2017075097-appb-000059
向500mL反应瓶中加入13.04g(3R)-1-乙基-4-甲基2-(2-([1,1'-联苯]-4-基)乙酰基)-3-甲基琥珀酸酯和130mL四氢呋喃(THF)，反应液降温至0℃，缓慢滴加氢氧化锂一水合物(LiOH.H2O)的水溶液(3.71g氢氧化锂一水合物溶解于130mL水中)。滴加完毕后，反应液升温至60～70℃，继续搅拌反应16h。HPLC检测原料反应完全，反应液降温至20～30℃，缓慢滴加100mL 1N盐酸水溶液调节pH至2～3，反应液用乙酸乙酯萃取3次，每次用量100mL，合并有机相，有机相用水洗涤两次，每次用量200mL，合并有机相，有机相减压浓缩得到油状物(R)-5-([1,1'-联苯]-4-基)-2-甲基-4-戊酮酸8.50g，收率85.1％。1H NMR(600MHz,DMSO-d6)δ12.16(s,1H),7.66(d,J＝7.3Hz,2H),7.61(d,J＝8.1Hz,2H),7.46(t,J＝7.7Hz,2H),7.36(t,J＝7.4Hz,1H),7.28(d,J＝8.1Hz,2H),3.82(s,2H),2.88(dd,J＝17.7,8.1Hz,1H),2.76–2.69(m,1H),2.61(dd,J＝17.7,5.4Hz,1H),1.05(dd,J＝16.4,7.1Hz,3H).ESI-MS(m/z):283.3([M+H]+).
实施例2制备(R)-5-([1,1'-联苯]-4-基)-2-甲基-4-戊酮酸甲酯
实施例2-a：制备叔丁基4-([1,1'-联苯]-4-基)-3-氧代丁酸酯
Figure PCTCN2017075097-appb-000060
室温下向500mL反应瓶中依次加入10.61g 4-联苯乙酸、8.65g米氏酸(Meldrum's acid)、0.61g 4-二甲氨基吡啶(DMAP)和80mL二甲基乙酰胺(DMAC)，搅拌至溶清。向反应液中缓慢滴加13.57gN，N-二异丙基乙胺(DIPEA)，滴加完毕后缓慢滴加6.63g特戊酰氯，滴加完毕后升温至50℃反应20h。向反应液中加入18.50g叔丁醇(t-BuOH)，升温至100℃反应7h。HPLC检测原料反应完全，反应液降温至20～30℃，加入200mL水，反应液用乙酸乙酯萃取3次，每次用量100mL，合并有机相，有机相用饱和氯化钠水溶液洗涤两次，每次用量200mL，合并有机相，有机相减压浓缩得到叔丁基4-([1,1'-联苯]-4-基)-3-氧代丁酸酯13.34g，收率86％。1H NMR(600MHz,CDCl3)δ7.57(t,J＝6.8Hz,4H),7.43(t,J＝7.4Hz,2H),7.38–7.32(m,1H),7.31–7.25(m,2H),3.87(s,2H),3.41(s,2H),1.47(s,9H).ESI-MS(m/z):311.4([M+H]+).
实施例2-b：制备(3R)-1-叔丁基-4-甲基-2-(2-([1,1'-联苯]-4-基)乙酰基)-3-甲基琥珀酸酯
Figure PCTCN2017075097-appb-000061
向500mL反应瓶中加入5.31g氢化钠(NaH)和100mL干燥四氢呋喃(THF)，氮气置换3次。反应液降 温至0℃，氮气保护下缓慢滴加叔丁基4-([1,1'-联苯]-4-基)-3-氧代丁酸酯的四氢呋喃溶液(25.00g叔丁基4-([1,1'-联苯]-4-基)-3-氧代丁酸酯溶解于100mL四氢呋喃中)。滴加完毕后，反应液升温至20～30℃，继续搅拌30分钟。反应液降温至0℃，缓慢滴加(R)-甲基-2-(三氟甲磺酸酯基)丙酸酯的四氢呋喃溶液(31.37g(R)-甲基-2-(三氟甲磺酸酯基)丙酸酯溶解于100mL四氢呋喃中)，滴加完毕后反应液升温至20～30℃，搅拌反应1.5h。HPLC检测原料反应完全，向反应液中缓慢滴加150mL 2N盐酸调节pH至2～3，反应液用乙酸乙酯萃取3次，每次用量100mL，合并有机相，有机相用水洗涤两次，每次用量200mL，合并有机相，有机相减压浓缩得到油状物(3R)-1-叔丁基-4-甲基-2-(2-([1,1'-联苯]-4-基)乙酰基)-3-甲基琥珀酸酯48.60g，不经纯化直接投料进行下一步反应。
实施例2-c：制备(R)-5-([1,1'-联苯]-4-基)-2-甲基-4-戊酮酸甲酯
Figure PCTCN2017075097-appb-000062
向100mL反应瓶中加入6.00g(3R)-1-叔丁基-4-甲基-2-(2-([1,1'-联苯]-4-基)乙酰基)-3-甲基琥珀酸酯、30mL二氯甲烷(DCM)和11.01g三氟乙酸(CF3COOH)，搅拌下升温至42℃反应22h，HPLC检测原料反应完全，加入150mL 6.5％碳酸氢钠溶液向反应液中缓慢滴加150mL 2N盐酸调节pH至2～3，反应液用乙酸乙酯萃取3次，每次用量100mL，合并有机相，有机相用水洗涤两次，每次用量200mL，合并有机相，有机相减压浓缩得到油状物(R)-5-([1,1'-联苯]-4-基)-2-甲基-4-戊酮酸甲酯4.10g，收率91.5％。1H NMR(400MHz,CDCl3)δ7.60(t,J＝7.7Hz,4H),7.46(t,J＝7.6Hz,2H),7.37(t,J＝7.3Hz,1H),7.30(d,J＝8.1Hz,2H),3.78(s,2H),3.69(s,3H),3.04–2.94(m,2H),2.60–2.51(m,1H),1.18(d,J＝6.8Hz,3H).ESI-MS(m/z):297.3([M+H]+).
实施例3制备(R)-5-([1,1'-联苯]-4-基)-2-甲基-4-戊酮酸乙酯
实施例3-a：制备叔丁基4-([1,1'-联苯]-4-基)-3-氧代丁酸酯
同实施例2-a。
实施例3-b：制备(3R)-1-叔丁基-4-乙基-2-(2-([1,1'-联苯]-4-基)乙酰基)-3-甲基琥珀酸酯
Figure PCTCN2017075097-appb-000063
向500mL反应瓶中加入5.31g氢化钠(NaH)和100mL干燥四氢呋喃(THF)，氮气置换3次。反应液降温至0℃，氮气保护下缓慢滴加叔丁基4-([1,1'-联苯]-4-基)-3-氧代丁酸酯的四氢呋喃溶液(25.00g叔丁基4-([1,1'-联苯]-4-基)-3-氧代丁酸酯溶解于100mL四氢呋喃中)。滴加完毕后，反应液升温至20～30℃，继续搅拌30分钟。反应液降温至0℃，缓慢滴加(R)-乙基-2-(三氟甲磺酸酯基)丙酸酯的四氢呋喃溶液(33.37g(R)-乙基-2-(三氟甲磺酸酯基)丙酸酯溶解于100mL四氢呋喃中)，滴加完毕后反应液升温至20～30℃，搅拌反应1.5h。HPLC检测原料反应完全，向反应液中缓慢滴加150mL 2N盐酸调节pH至2～3，反应液用乙酸 乙酯萃取3次，每次用量100mL，合并有机相，有机相用水洗涤两次，每次用量200mL，合并有机相，有机相减压浓缩得到油状物(3R)-1-叔丁基-4-乙基-2-(2-([1,1'-联苯]-4-基)乙酰基)-3-甲基琥珀酸酯49.60g，不经纯化直接投料进行下一步反应。
实施例3-c：制备(R)-5-([1,1'-联苯]-4-基)-2-甲基-4-戊酮酸乙酯
Figure PCTCN2017075097-appb-000064
向100mL反应瓶中加入6.00g(3R)-1-叔丁基-4-乙基-2-(2-([1,1'-联苯]-4-基)乙酰基)-3-甲基琥珀酸酯、30mL二氯甲烷(DCM)和11.01g三氟乙酸(CF3COOH)，搅拌下升温至42℃反应22h，HPLC检测原料反应完全，加入150mL 6.5％碳酸氢钠溶液向反应液中缓慢滴加150mL 2N盐酸调节pH至2～3，反应液用乙酸乙酯萃取3次，每次用量100mL，合并有机相，有机相用水洗涤两次，每次用量200mL，合并有机相，有机相减压浓缩得到油状物(R)-5-([1,1'-联苯]-4-基)-2-甲基-4-戊酮酸乙酯4.17g，收率92％。1H NMR(400MHz,CDCl3)δ7.60(t,J＝7.7Hz,4H),7.47(t,J＝7.7Hz,2H),7.37(t,J＝7.3Hz,1H),7.30(d,J＝8.1Hz,2H),4.06(q,J＝7.1Hz,2H),3.78(s,2H),3.04–2.94(m,2H),2.60–2.51(m,1H),1.20-1.15(m,6H)..ESI-MS(m/z):311.4([M+H]+).
实施例4制备(R)-苄基-5-([1,1'-联苯]-4-基)-2-甲基-4-戊酮酸异丙酯
实施例4-a：制备叔丁基4-([1,1'-联苯]-4-基)-3-氧代丁酸酯
同实施例2-a。
实施例4-b：制备(3R)-1-叔丁基-4-异丙基-2-(2-([1,1'-联苯]-4-基)乙酰基)-3-甲基琥珀酸酯
Figure PCTCN2017075097-appb-000065
向500mL反应瓶中加入5.31g氢化钠(NaH)和100mL干燥四氢呋喃(THF)，氮气置换3次。反应液降温至0℃，氮气保护下缓慢滴加叔丁基4-([1,1'-联苯]-4-基)-3-氧代丁酸酯的四氢呋喃溶液(25.00g叔丁基4-([1,1'-联苯]-4-基)-3-氧代丁酸酯溶解于100mL四氢呋喃中)。滴加完毕后，反应液升温至20～30℃，继续搅拌30分钟。反应液降温至0℃，缓慢滴加(R)-异丙基-2-(三氟甲磺酸酯基)丙酸酯的四氢呋喃溶液(33.37g(R)-异丙基-2-(三氟甲磺酸酯基)丙酸酯溶解于100mL四氢呋喃中)，滴加完毕后反应液升温至20～30℃，搅拌反应1.5h。HPLC检测原料反应完全，向反应液中缓慢滴加150mL 2N盐酸调节pH至2～3，反应液用乙酸乙酯萃取3次，每次用量100mL，合并有机相，有机相用水洗涤两次，每次用量200mL，合并有机相，有机相减压浓缩得到油状物(3R)-1-叔丁基-4-异丙基-2-(2-([1,1'-联苯]-4-基)乙酰基)-3-甲基琥珀酸酯50.60g，不经纯化直接投料进行下一步反应。
实施例4-c：制备(R)-苄基-5-([1,1'-联苯]-4-基)-2-甲基-4-戊酮酸异丙酯
Figure PCTCN2017075097-appb-000066
向100mL反应瓶中加入6.00g(3R)-1-叔丁基-4-异丙基-2-(2-([1,1'-联苯]-4-基)乙酰基)-3-甲基琥珀酸酯、30mL二氯甲烷(DCM)和11.01g三氟乙酸(CF3COOH)，搅拌下升温至42℃反应22h，HPLC检测原料反应完全，加入150mL 6.5％碳酸氢钠溶液向反应液中缓慢滴加150mL 2N盐酸调节pH至2～3，反应液用乙酸乙酯萃取3次，每次用量100mL，合并有机相，有机相用水洗涤两次，每次用量200mL，合并有机相，有机相减压浓缩得到油状物(R)-5-([1,1'-联苯]-4-基)-2-甲基-4-戊酮酸异丙酯3.80g，收率83.0％。1H NMR(600MHz,CDCl3)δ7.60(dt,J＝15.9,6.1Hz,4H),7.47(t,J＝7.7Hz,2H),7.37(dt,J＝9.7,7.9Hz,1H),7.33–7.28(m,2H),4.93(m,1H),3.78(s,2H),3.04–2.94(m,2H),2.60–2.51(m,1H),1.30(d,J＝7.1Hz,6H),1.18(d,J＝6.8Hz,3H).ESI-MS(m/z):325.4([M+H]+).
实施例5制备(R)-苄基-5-([1,1'-联苯]-4-基)-2-甲基-4-戊酮酸苄基酯
实施例5-a：制备叔丁基4-([1,1'-联苯]-4-基)-3-氧代丁酸酯
Figure PCTCN2017075097-appb-000067
室温下向1L反应瓶中依次加入20.00g 4-联苯乙酸、14.96g米氏酸(Meldrum's acid)、0.61g 4-二甲氨基吡啶(DMAP)、21.40gN，N'-二环己基碳二亚胺(DCC)和200mL二氯甲烷，降温至0℃反应12h。过滤，滤除析出固体，滤液浓缩至干得到浅黄色油状物。向上述油状物中加入95mL叔丁醇，氮气保护下升温至82℃反应。TLC检测原料反应完全，反应液减压蒸馏除去叔丁醇，加入100mL二氯甲烷，分别用水和饱和氯化钠水溶液洗涤，收集有机相，减压蒸除溶剂得到叔丁基4-([1,1'-联苯]-4-基)-3-氧代丁酸酯24.89g，收率85％。1H NMR(600MHz,CDCl3)δ7.57(t,J＝6.8Hz,4H),7.43(t,J＝7.4Hz,2H),7.38–7.32(m,1H),7.31–7.25(m,2H),3.87(s,2H),3.41(s,2H),1.47(s,9H).ESI-MS(m/z):311.4([M+H]+).
实施例5-b：制备(3R)-4-苄基-1-叔丁基-2-(2-([1,1'-联苯]-4-基)乙酰基)-3-甲基琥珀酸酯
Figure PCTCN2017075097-appb-000068
向500mL反应瓶中加入5.31g氢化钠(NaH)和100mL干燥四氢呋喃(THF)，氮气置换3次。反应液降温至0℃，氮气保护下缓慢滴加叔丁基4-([1,1'-联苯]-4-基)-3-氧代丁酸酯的四氢呋喃溶液(25.00g叔丁基4-([1,1'-联苯]-4-基)-3-氧代丁酸酯溶解于100mL四氢呋喃中)。滴加完毕后，反应液升温至20～30℃，继续搅拌30分钟。反应液降温至0℃，缓慢滴加(R)-苄基-2-(三氟甲磺酸酯基)丙酸酯的四氢呋喃溶液(33.37g(R)-苄基-2-(三氟甲磺酸酯基)丙酸酯溶解于100mL四氢呋喃中)，滴加完毕后反应液升温至20～30℃，搅拌反 应1.5h。HPLC检测原料反应完全，向反应液中缓慢滴加150mL 2N盐酸调节pH至2～3，反应液用乙酸乙酯萃取3次，每次用量100mL，合并有机相，有机相用水洗涤两次，每次用量200mL，合并有机相，有机相减压浓缩得到油状物(3R)-4-苄基-1-叔丁基-2-(2-([1,1'-联苯]-4-基)乙酰基)-3-甲基琥珀酸酯50.60g，不经纯化直接投料进行下一步反应。
实施例5-c：制备(R)-苄基-5-([1,1'-联苯]-4-基)-2-甲基-4-戊酮酸苄基酯
Figure PCTCN2017075097-appb-000069
向100mL反应瓶中加入6.00g(3R)-4-苄基-1-叔丁基-2-(2-([1,1'-联苯]-4-基)乙酰基)-3-甲基琥珀酸酯、30mL二氯甲烷(DCM)和11.01g三氟乙酸(CF3COOH)，搅拌下升温至42℃反应22h，HPLC检测原料反应完全，加入150mL 6.5％碳酸氢钠溶液向反应液中缓慢滴加150mL 2N盐酸调节pH至2～3，反应液用乙酸乙酯萃取3次，每次用量100mL，合并有机相，有机相用水洗涤两次，每次用量200mL，合并有机相，有机相减压浓缩得到油状物(R)-5-([1,1'-联苯]-4-基)-2-甲基-4-戊酮酸苄基酯4.10g，收率86.7％。1H NMR(400MHz,CDCl3)δ7.60(t,J＝7.7Hz,4H),7.46(t,J＝7.6Hz,2H),7.40-7.33(m,5H),7.37(t,J＝7.3Hz,1H),7.30(d,J＝8.1Hz,2H),5.22(s,2H),3.78(s,2H),3.04–2.94(m,2H),2.60–2.51(m,1H),1.18(d,J＝6.8Hz,3H).ESI-MS(m/z):373.5([M+H]+).
实施例6制备(R)-5-([1,1'-联苯]-4-基)-N,2-二甲基-4-氧代戊酰胺
实施例6-a：制备4-([1,1'-联苯]-4-基)-3-氧代丁酸乙酯
同实施例1-a。
实施例6-b：制备(3R)--2-(2-([1,1'-联苯]-4-基)乙酰基)-3-甲基-4-甲氨基-4-氧代丁酸乙酯
Figure PCTCN2017075097-appb-000070
向500mL反应瓶中加入5.31g氢化钠(NaH)和100mL干燥四氢呋喃(THF)，氮气置换3次。反应液降温至0℃，氮气保护下缓慢滴加4-([1,1'-联苯]-4-基)-3-氧代丁酸乙酯的四氢呋喃(THF)溶液(25.00g 4-([1,1'-联苯]-4-基)-3-氧代丁酸乙酯溶解于100mL四氢呋喃(THF)中)。滴加完毕后，反应液升温至20～30℃，继续搅拌30分钟。反应液降温至0℃，缓慢滴加(R)-1-甲基氨基-1-氧代丙基-2-基-对甲苯磺酸酯的四氢呋喃(THF)溶液(31.37g(R)-1-甲基氨基-1-氧代丙基-2-基-对甲苯磺酸酯溶解于100mL四氢呋喃(THF)中)，滴加完毕后反应液升温至20～30℃，搅拌反应1.5h。HPLC检测原料反应完全，向反应液中缓慢滴加150mL 2N盐酸调节pH至2～3，反应液用乙酸乙酯萃取3次，每次用量100mL，合并有机相，有机相用水洗涤两次，每次用量200mL，合并有机相，有机相减压浓缩得到油状物(3R)-2-(2-([1,1'-联苯]-4-基)乙酰基)-3-甲基-4-甲氨基-4-氧代丁酸乙酯48.60g，不经纯化直接投料进行下一步反应。
实施例6-c：制备(R)-5-([1,1'-联苯]-4-基)-N,2-二甲基-4-氧代戊酰胺
Figure PCTCN2017075097-appb-000071
向500mL反应瓶中加入15.00g(3R)-2-(2-([1,1'-联苯]-4-基)乙酰基)-3-甲基-4-甲氨基-4-氧代丁酸乙酯和130mL四氢呋喃(THF)，反应液降温至0℃，缓慢滴加氢氧化锂一水合物(LiOH.H2O)的水溶液(4.00g氢氧化锂一水合物溶解于130mL水中)。滴加完毕后，反应液升温至60～70℃，继续搅拌反应16h。HPLC检测原料反应完全，反应液降温至20～30℃，缓慢滴加100mL 1N HCl水溶液调节pH至2～3，反应液用乙酸乙酯萃取3次，每次用量100mL，合并有机相，有机相用水洗涤两次，每次用量200mL，有机相减压浓缩得到油状物(R)-5-([1,1'-联苯]-4-基)-N,2-二甲基-4-氧代戊酰胺10.43g，收率86.5％。1H NMR(600MHz,DMSO-d6)δ12.16(s,1H),7.66(d,J＝7.3Hz,2H),7.61(d,J＝8.1Hz,2H),7.46(t,J＝7.7Hz,2H),7.36(t,J＝7.4Hz,1H),7.28(d,J＝8.1Hz,2H),3.82(s,2H),3.05(s,3H),2.88(dd,J＝17.7,8.1Hz,1H),2.76–2.69(m,1H),2.61(dd,J＝17.7,5.4Hz,1H),1.05(dd,J＝16.4,7.1Hz,3H).ESI-MS(m/z):296.3([M+H]+)。
实施例7制备(R)-5-([1,1'-联苯]-4-基)-N-叔丁基-2-甲基-4-氧代戊酰胺
实施例7-a：制备4-([1,1'-联苯]-4-基)-3-氧代丁酸乙酯
同实施例1-a。
实施例7-b：制备(3R)--2-(2-([1,1'-联苯]-4-基)乙酰基)-3-甲基-4-叔丁氨基-4-氧代-丁酸乙酯
Figure PCTCN2017075097-appb-000072
向500mL反应瓶中加入5.31g氢化钠(NaH)和100mL干燥四氢呋喃(THF)，氮气置换3次。反应液降温至0℃，氮气保护下缓慢滴加4-([1,1'-联苯]-4-基)-3-氧代丁酸乙酯的四氢呋喃(THF)溶液(25.00g 4-([1,1'-联苯]-4-基)-3-氧代-丁酸乙酯溶解于100mL四氢呋喃(THF)中)。滴加完毕后，反应液升温至20～30℃，继续搅拌30分钟。反应液降温至0℃，缓慢滴加(R)-1-叔丁基氨基-1-氧代丙基-2-基-对甲苯磺酸酯的四氢呋喃(THF)溶液(31.37g(R)-1-叔丁基氨基-1-氧代丙基-2-基-对甲苯磺酸酯溶解于100mL四氢呋喃(THF)中)，滴加完毕后反应液升温至20～30℃，搅拌反应1.5h。HPLC检测原料反应完全，向反应液中缓慢滴加150mL 2N盐酸调节pH至2～3，反应液用乙酸乙酯萃取3次，每次用量100mL，合并有机相，有机相用水洗涤两次，每次用量200mL，有机相减压浓缩得到油状物(3R)-2-(2-([1,1'-联苯]-4-基)乙酰基)-3-甲基-4-叔丁氨基-4-氧代-丁酸乙酯48.60g，不经纯化直接投料进行下一步反应。
实施例7-c：制备(R)-5-([1,1'-联苯]-4-基)-N-叔丁基-2-甲基-4-氧代戊酰胺
Figure PCTCN2017075097-appb-000073
向500mL反应瓶中加入15.00g(3R)-2-(2-([1,1'-联苯]-4-基)乙酰基)-3-甲基-4-叔丁氨基-4-氧代-丁酸乙酯和130mL四氢呋喃(THF)，反应液降温至0℃，缓慢滴加氢氧化锂一水合物(LiOH.H2O)的水溶液(4.00g氢氧化锂一水合物溶解于130mL水中)。滴加完毕后，反应液升温至60～70℃，继续搅拌反应16h。HPLC检测原料反应完全，反应液降温至20～30℃，缓慢滴加100mL 1N盐酸水溶液调节pH至2～3，反应液用乙酸乙酯萃取3次，每次用量100mL，合并有机相，有机相用水洗涤两次，每次用量200mL，合并有机相，有机相减压浓缩得到油状物(R)-5-([1,1'-联苯]-4-基)-N-叔丁基-2-甲基-4-氧代戊酰胺10.05g，收率81.3％。1H NMR(600MHz,DMSO-d6)δ12.16(s,1H),7.66(d,J＝7.3Hz,2H),7.61(d,J＝8.1Hz,2H),7.46(t,J＝7.7Hz,2H),7.36(t,J＝7.4Hz,1H),7.28(d,J＝8.1Hz,2H),3.82(s,2H),2.88(dd,J＝17.7,8.1Hz,1H),2.76–2.69(m,1H),2.61(dd,J＝17.7,5.4Hz,1H),1.39(s,9H),1.05(dd,J＝16.4,7.1Hz,3H).ESI-MS(m/z):338.4([M+H]+)。
实施例8制备(R)-1-([1,1'-联苯]-4-基)-4-甲基-5-(三苯甲氧基)-2-戊酮
实施例8-a：制备4-([1,1'-联苯]-4-基)-3-氧代丁酸乙酯
同实施例1-a。
实施例8-b：制备4-([1,1'-联苯]-4-基)-3-氧代-2-((R)-1-(三苯甲氧基)丙烷-2-基)-丁酸乙酯
Figure PCTCN2017075097-appb-000074
向500mL反应瓶中加入5.31g氢化钠(NaH)和100mL干燥甲苯中，氮气置换3次。反应液降温至0℃，氮气保护下缓慢滴加4-([1,1'-联苯]-4-基)-3-氧代丁酸乙酯的甲苯溶液(25.00g 4-([1,1'-联苯]-4-基)-3-氧代丁酸乙酯溶解于100mL甲苯中)。滴加完毕后，反应液升温至20～30℃，继续搅拌30分钟。反应液降温至0℃，缓慢滴加(R)-1-三苯基甲氧基丙基-2-基-对甲苯磺酸酯的甲苯溶液(31.37g(R)-1-三苯基甲氧基丙基-2-基-对甲苯磺酸酯溶解于100mL甲苯中)，滴加完毕后反应液升温至60～70℃，搅拌反应1.5h。HPLC检测原料反应完全，向反应液中缓慢滴加150mL 2NHCl调节pH至2～3，反应液用乙酸乙酯萃取3次，每次用量100mL，合并有机相，有机相用水洗涤两次，每次用量200mL，合并有机相，有机相减压浓缩得到油状物4-([1,1'-联苯]-4-基)-3-氧代-2-((R)-1-(三苯甲氧基)丙烷-2-基)-丁酸乙酯46.60g，不经纯化直接投料进行下一步反应。
实施例8-c：制备(R)-1-([1,1'-联苯]-4-基)-4-甲基-5-(三苯甲氧基)-2-戊酮
Figure PCTCN2017075097-appb-000075
向500mL反应瓶中加入15.00g 4-([1,1'-联苯]-4-基)-3-氧代-2-((R)-1-(三苯甲氧基)丙烷-2-基)-丁酸乙酯和130mL四氢呋喃(THF)，反应液降温至0℃，缓慢滴加氢氧化锂一水合物(LiOH.H2O)的水溶液(4.00g氢氧化锂一水合物溶解于130mL水中)。滴加完毕后，反应液升温至60～70℃，继续搅拌反应16h。HPLC检测原料反应完全，反应液降温至20～30℃，缓慢滴加100mL 1N HCl水溶液调节pH至2～3，反应液用乙酸乙酯萃取3次，每次用量100mL，合并有机相，有机相用水洗涤两次，每次用量200mL有机相减压浓缩得到油状物(R)-1-([1,1'-联苯]-4-基)-4-甲基-5-(三苯甲氧基)-2-戊酮11.24g，收率85.6％。1H NMR(400MHz,CDCl3)δ7.60(t,J＝7.7Hz,4H),7.46(t,J＝7.6Hz,2H),7.40-7.33(m,5H),7.38(m,15H),7.37(t,J＝7.3Hz,1H),7.30(d,J＝8.1Hz,2H),3.71(s,2H),3.21(d,J＝6.8Hz,2H),3.04–2.94(m,2H),2.60–2.51(m,1H),1.18(d,J＝6.8Hz,3H).ESI-MS(m/z):511.6([M+H]+)。
实施例9制备(R)-1-([1,1'-联苯]-4-基)-4-甲基-5-(三乙基硅氧基)-2-戊酮
实施例9-a：制备4-([1,1'-联苯]-4-基)-3-氧代丁酸乙酯
同实施例1-a。
实施例9-b：制备4-([1,1'-联苯]-4-基))-3-氧代-2-((R)-1-(三乙基硅氧基)丙基-2基)-丁酸乙酯
Figure PCTCN2017075097-appb-000076
向500mL反应瓶中加入5.31g氢化钠(NaH)和100mL干燥甲苯中，氮气置换3次。反应液降温至0℃，氮气保护下缓慢滴加4-([1,1'-联苯]-4-基)-3-氧代丁酸乙酯的甲苯溶液(25.00g 4-([1,1'-联苯]-4-基)-3-氧代丁酸乙酯溶解于100mL甲苯中)。滴加完毕后，反应液升温至20～30℃，继续搅拌30分钟。反应液降温至0℃，缓慢滴加(R)-1-三乙基硅氧基丙基-2-基-对甲苯磺酸酯的甲苯溶液(31.37g(R)-1-三乙基硅氧基丙基-2-基-对甲苯磺酸酯溶解于100mL甲苯中)，滴加完毕后反应液升温至60～70℃，搅拌反应1.5h。HPLC检测原料反应完全，向反应液中缓慢滴加150mL 2N盐酸调节pH至2～3，反应液用乙酸乙酯萃取3次，每次用量100mL，合并有机相，有机相用水洗涤两次，每次用量200mL，有机相减压浓缩得到油状物4-([1,1'-联苯]-4-基))-3-氧代-2-((R)-1-(三乙基硅氧基)丙基-2基)-丁酸乙酯44.50g，不经纯化直接投料进行下一步反应。
实施例9-c：制备(R)-1-([1,1'-联苯]-4-基)-4-甲基-5-(三乙基硅氧基)-2-戊酮
Figure PCTCN2017075097-appb-000077
向500mL反应瓶中加入15.00g4-([1,1'-联苯]-4-基))-3-氧代-2-((R)-1-(三乙基硅氧基)丙基-2基)-丁酸乙酯和130mL四氢呋喃(THF)，反应液降温至0℃，缓慢滴加氢氧化锂一水合物(LiOH.H2O)的水溶液(4.00g氢氧化锂一水合物溶解于130mL水中)。滴加完毕后，反应液升温至60～70℃，继续搅拌反应16h。HPLC检测原料反应完全，反应液降温至20～30℃，缓慢滴加100mL 1N HCl水溶液调节pH至2～3，反应液用乙酸乙酯萃取3次，每次用量100mL，合并有机相，有机相用水洗涤两次，每次用量200mL，有机相减压浓缩得到油状物(R)-1-([1,1'-联苯]-4-基)-4-甲基-5-(三乙基硅氧基)-2-戊酮10.97g，收率86.9％。1H NMR(400MHz,CDCl3)δ7.60(t,J＝7.7Hz,4H),7.46(t,J＝7.6Hz,2H),7.40-7.33(m,5H),7.37(t,J＝7.3Hz,1H),7.30(d,J＝8.1Hz,2H),3.71(s,2H),3.63(m,2H),3.04–2.94(m,2H),2.60–2.51(m,1H),1.36(m,6H),1.18(m,12H).ESI-MS(m/z):383.6([M+H]+)。
实施例10制备(R)-5-([4-碘苯基])-2-甲基-4-戊酮酸
实施例10-a：制备4-([4-碘苯基]-4-基)-3-氧代丁酸乙酯
Figure PCTCN2017075097-appb-000078
室温下向500mL三口反应瓶A中加入200mL乙酸乙酯和28.64gN,N'-羰基二咪唑，25.00g 4-碘苯乙酸分批加入到反应瓶A中，控制气体产生速度。加料完毕后反应液升温至45℃反应3h，降温至20～30℃，减压抽真空1h，备用。室温下1L反应瓶B中加入280mL乙酸乙酯、28.06g EtO2CCH2COOK和15.70g氯化镁(MgCl2)，控温20～30℃，缓慢滴加入19.07g三乙胺(TEA)，滴加完毕后继续搅拌1h。室温下将反应瓶A中物料加入至反应瓶B中，升温至45℃，保温反应16h。反应液降温至20～30℃，缓慢滴加180mL 4N盐酸溶液，分液，有机相用6.5％碳酸氢钠溶液洗涤三次，每次用量250mL，收集有机相，45℃下减压蒸除溶剂得黄棕色油状物。向所得油状物中加入150mL正己烷，20～30℃搅拌18h，过滤，滤饼用正己烷洗涤，40～50℃真空干燥5h得4-([4-碘苯基]-4-基)-3-氧代丁酸乙酯27.4g，收率86.5％。1H NMR(600MHz,CDCl3)δ,7.47(t,J＝7.7Hz,2H),7.33–7.28(m,2H),4.25–4.18(m,2H),3.90(s,2H),3.52(s,2H),1.30(t,J＝7.1Hz,3H).ESI-MS(m/z):333.1([M+H]+)。
实施例10-b：制备(3R)-1-乙基-4-甲基2-(2-([4–碘苯基])乙酰基)-3-甲基琥珀酸酯
Figure PCTCN2017075097-appb-000079
向500mL反应瓶中加入5.31g氢化钠(NaH)和100mL干燥四氢呋喃(THF)，氮气置换3次。反应液降 温至0℃，氮气保护下缓慢滴加4-([4-碘苯基]-4-基)-3-氧代丁酸乙酯的四氢呋喃(THF)溶液(25.00g4-([4-碘苯基]-4-基)-3-氧代丁酸乙酯溶解于100mL四氢呋喃(THF)中)。滴加完毕后，反应液升温至20～30℃，继续搅拌30分钟。反应液降温至0℃，缓慢滴加(R)-甲基-2-(对甲苯磺酸基)丙酸酯的四氢呋喃(THF)溶液(31.37g(R)-甲基-2-(对甲苯磺酸基)丙酸酯溶解于100mL四氢呋喃(THF)中)，滴加完毕后反应液升温至20～30℃，搅拌反应1.5h。HPLC检测原料反应完全，向反应液中缓慢滴加150mL 2N盐酸调节pH至2～3，反应液用乙酸乙酯萃取3次，每次用量100mL，合并有机相，有机相用水洗涤两次，每次用量200mL，减压浓缩得到油状物(3R)-1-乙基-4-甲基2-(2-([4–碘苯基])乙酰基)-3-甲基琥珀酸酯48.60g，不经纯化直接投料进行下一步反应。
实施例10-c：制备(R)-5-([4-碘苯基])-2-甲基-4-戊酮酸
Figure PCTCN2017075097-appb-000080
向500mL反应瓶中加入13.00g(3R)-1-乙基-4-甲基2-(2-([4–碘苯基])乙酰基)-3-甲基琥珀酸酯和130mL四氢呋喃(THF)，反应液降温至0℃，缓慢滴加氢氧化锂一水合物(LiOH.H2O)的水溶液(3.71g氢氧化锂一水合物溶解于130mL水中)。滴加完毕后，反应液升温至60～70℃，继续搅拌反应16h。HPLC检测原料反应完全，反应液降温至20～30℃，缓慢滴加100mL 1N盐酸水溶液调节pH至2～3，反应液用乙酸乙酯萃取3次，每次用量100mL，合并有机相，有机相用水洗涤两次，每次用量200mL，减压浓缩得到油状物(R)-5-([4-碘苯基])-2-甲基-4-戊酮酸8.46g，收率82.0％。1H NMR(600MHz,DMSO-d6)δ12.16(s,1H),7.66(d,J＝7.3Hz,2H),7.28(d,J＝8.1Hz,2H),3.82(s,2H),2.88(dd,J＝17.7,8.1Hz,1H),2.76–2.69(m,1H),2.61(dd,J＝17.7,5.4Hz,1H),1.05(dd,J＝16.4,7.1Hz,3H).ESI-MS(m/z):333.1([M+H]+)。
实施例11制备(R)-5-([1,1'-联苯]-4-基)-2-甲基-4-戊酮酸
实施例11-a：制备4-([1,1'-联苯]-4-基)-3-氧代丁酸甲酯
Figure PCTCN2017075097-appb-000081
室温下向1L反应瓶中依次加入20.00g 4-联苯乙酸、14.96g米氏酸(Meldrum's acid)、0.61g 4-二甲氨基吡啶(DMAP)、21.40gN，N'-二环己基碳二亚胺(DCC)和200mL二氯甲烷，降温至0℃反应12h，过滤，滤除析出固体，滤液浓缩至干得到浅黄色油状物。向上述油状物中加入150mL甲醇，氮气保护下升温至50℃反应，TLC检测原料反应完全，反应液降温至0℃搅拌2h，过滤，滤饼50℃真空干燥得白色固体23.00g，收率91％。1H NMR(600MHz,CDCl3)δ7.59-7.55(m,4H),7.44(t,J＝7.7Hz,2H),7.37–7.31(m,1H),7.30–7.25(m,2H),3.87(s,2H),3.72(d,J＝6.0Hz,3H),3.50(d,J＝10.0Hz,2H),.ESI-MS(m/z):269.3([M+H]+).
实施例11-b：制备(3R)-二甲基-2-(2-([1,1'-联苯]-4-基)乙酰基)-3-甲基琥珀酸酯
Figure PCTCN2017075097-appb-000082
向500mL反应瓶中加入5.31gNaH和100mL干燥THF，氮气置换3次，反应液降温至0℃，氮气保护下缓慢滴加4-([1,1'-联苯]-4-基)-3-氧代丁酸甲酯的THF溶液(25.00g 4-([1,1'-联苯]-4-基)-3-氧代丁酸甲酯溶解于100mL THF中)。滴加完毕后，反应液升温至20～30℃，继续搅拌30分钟，然后反应液降温至0℃，缓慢滴加(R)-甲基-2-(三氟甲磺酸酯基)丙酸酯的THF溶液(31.37g(R)-甲基-2-(三氟甲磺酸酯基)丙酸酯溶解于100mL THF中)，滴加完毕后反应液升温至20～30℃，搅拌反应1.5h。TLC检测原料反应完全，向反应液中缓慢滴加150mL 2N盐酸调节pH至2～3，反应液用乙酸乙酯萃取3次，合并有机相，有机相用水洗涤，收集有机相，有机相减压浓缩得到油状物48.60g，不需纯化直接用于下一步反应。
实施例11-c：制备(R)-5-([1,1'-联苯]-4-基)-2-甲基-4-戊酮酸
Figure PCTCN2017075097-appb-000083
向500mL反应瓶中加入15.00g(3R)-二甲基-2-(2-([1,1'-联苯]-4-基)乙酰基)-3-甲基琥珀酸酯、130mL四氢呋喃和3.71g氢氧化锂。反应液升温至60～70℃，继续搅拌反应16h，TLC检测原料反应完全，反应液降温至20～30℃，缓慢滴加100mL 1N盐酸水溶液调节pH至2～3，反应液用乙酸乙酯萃取3次，合并有机相，有机相用水洗涤，收集有机相，有机相减压浓缩得到油状物，用乙酸乙酯和正己烷(体积比1:1)重结晶得白色固体7.76g，收率65％。1H NMR(600MHz,DMSO-d6)δ12.16(s,1H),7.66(d,J＝7.3Hz,2H),7.61(d,J＝8.1Hz,2H),7.46(t,J＝7.7Hz,2H),7.36(t,J＝7.4Hz,1H),7.28(d,J＝8.1Hz,2H),3.82(s,2H),2.88(dd,J＝17.7,8.1Hz,1H),2.76–2.69(m,1H),2.61(dd,J＝17.7,5.4Hz,1H),1.05(dd,J＝16.4,7.1Hz,3H).ESI-MS(m/z):283.3([M+H]+).
第一种制备沙库必曲的方法
实施例12制备沙库必曲
实施例12-a：制备(2R,4S)-5-([1,1'-联苯]-4-基)-4-氨基-2-甲基戊酸
Figure PCTCN2017075097-appb-000084
将异丙胺100g溶于100mL水中，用盐酸水溶液调节pH7.5～8.0，加入250mL二甲基亚砜(DMSO)，然后用0.1M的盐酸三(羟甲基)氨基甲烷-盐酸(Tris-盐酸)缓冲溶液稀释至1000mL，并加热至40℃，加入10gω-转氨酶冷冻干粉和磷酸吡哆醛(PLP)8.0g，然后滴加依照实施例1的方法所得的100g(R)-5-([1,1'-联苯]-4-基)-2-甲基-4-戊酮酸的250mL二甲基亚砜(DMSO)溶液，反应过程中用20％的异丙胺水溶液控制pH＝7.5～8.0， 温度保持40～45℃反应24h以上，TLC监控反应完毕。过滤除去固体，母液用乙酸乙酯萃取3次，合并后有机相减压浓缩蒸干，得到淡黄色固体90.2g，收率约90.2％,ee值99％。1H NMR(600MHz,DMSO-d6)δ8.22(s,2H),7.66(dd,J＝14.2,7.7Hz,4H),7.47(t,J＝7.7Hz,2H),7.36(t,J＝8.0Hz,3H),3.43(d,J＝5.4Hz,1H),3.05(dd,J＝13.9,5.7Hz,1H),2.86(dd,J＝13.9,7.7Hz,1H),2.66(m,J＝13.9,7.0Hz,1H),1.86(m,J＝14.2,8.7,5.5Hz,1H),1.59(m,J＝13.9,7.7,5.9Hz,1H),1.07(d,J＝7.0Hz,3H).ESI-MS(m/z):284.3([M+H]+).
实施例12-b：制备(2R,4S)-5-([1,1'-联苯]-4-基)-4-氨基-2-甲基戊酸乙酯
Figure PCTCN2017075097-appb-000085
向500mL反应瓶中依次加入70.00g(2R,4S)-5-([1,1'-联苯]-4-基)-4-氨基-2-甲基戊酸和350mL无水乙醇，升温至40℃搅拌溶解得到澄清溶液。向反应液中缓慢滴加32.57g氯化亚砜，滴加完毕后升温至70℃反应。HPLC检测原料反应完全，反应体系缓慢降至室温，减压蒸除溶剂得到类白色固体，向所得固体中加入630mL乙酸乙酯，升温至60℃搅拌2h，降至25℃继续搅拌2h，过滤，滤饼50℃真空干燥得白色固体70.77g，收率92％。1H NMR(600MHz,CDCl3)δ8.62(s,2H),7.54(dd,J＝14.1,7.7Hz,4H),7.41(t,J＝7.6Hz,2H),7.36-7.29(m,3H),4.07(q,J＝7.1Hz,2H),3.67(s,1H),3.40-3.34(m,1H),2.97(dd,J＝24.3,10.9Hz,2H),2.07-2.00(m,1H),1.90-1.83(m,1H),1.20-1.15(m,6H).ESI-MS(m/z):312.4([M+H]+).
实施例12-c：制备沙库必曲
按照CN 104557600 A说明书第[0038]段至[0039]段的实施例8所记载的方法，得沙库必曲，收率91.8％。
1H NMR(400MHz,DMSO)δ7.96(d,J＝8.2Hz,1H),7.62(d,J＝7.4Hz,2H),7.55(d,J＝8.1Hz,2H),7.43(t,J＝7.6Hz,2H),7.33(t,J＝7.3Hz,1H),7.24(d,J＝8.1Hz,2H),4.02–3.86(m,3H),2.74(dd,J＝13.4,6.3Hz,1H),2.64(dd,J＝13.4,6.8Hz,1H),2.50–2.44(m,1H),2.26(dd,J＝22.4,7.3Hz,4H),1.81–1.68(m,1H),1.47–1.36(m,1H),1.10(t,J＝7.1Hz,3H),1.04(d,J＝7.0Hz,3H).ESI-MS(m/z):412.2([M+H]+)。
实施例13制备沙库必曲
实施例13-a：制备(2R,4S)-5-([1,1'-联苯]-4-基)-4-氨基-2-甲基戊酸甲酯
Figure PCTCN2017075097-appb-000086
将异丙胺10g溶于10mL水中，用盐酸水溶液调节pH7.5～8.0，加入25mL二甲基亚砜(DMSO)，然后用0.1M的盐酸三(羟甲基)氨基甲烷-盐酸(Tris-盐酸)缓冲溶液稀释至100mL，并加热至40℃，加入1.0gω-转氨酶冷冻干粉和磷酸吡哆醛(PLP)0.8g，然后滴加依照实施例2的方法所得的10g(R)-5-([1,1'-联苯]-4-基)-2-甲基-4-戊酮酸甲酯的25mL二甲基亚砜(DMSO)溶液，反应过程中用20％的异丙胺水溶液控制pH＝7.5～8.0，温度保持40～45℃反应24h以上，TLC监控反应完毕。过滤除去固体，母液用乙酸乙酯萃取3次，合并后有机相减压浓缩蒸干，得到淡黄色固体8.95g，收率约89.6％,ee值98.5％。1H NMR(600MHz, DMSO-d6)δ8.22(s,2H),7.65(dd,J＝14.2,7.7Hz,4H),7.46(t,J＝7.7Hz,2H),7.36(t,J＝8.0Hz,3H),3.68(s,3H),3.43(d,J＝5.4Hz,1H),3.05(dd,J＝13.9,5.7Hz,1H),2.86(dd,J＝13.9,7.7Hz,1H),2.66(m,J＝13.9,7.0Hz,1H),1.86(m,J＝14.2,8.7,5.5Hz,1H),1.59(m,J＝13.9,7.7,5.9Hz,1H),1.07(d,J＝7.0Hz,3H).ESI-MS(m/z):311.3([M+H]+).
实施例13-b：制备(2R,4S)-5-([1,1'-联苯]-4-基)-4-氨基-2-甲基戊酸
Figure PCTCN2017075097-appb-000087
向250mL反应瓶中依次加入10g(2R,4S)-5-([1,1'-联苯]-4-基)-4-氨基-2-甲基戊酸甲酯、50mL四氢呋喃、50mL甲醇和2.41g氢氧化锂，20～40℃搅拌反应12h，TLC监控反应完毕，减压蒸馏除去溶剂，向残留物中加入100mL水和100mL乙酸乙酯，搅拌10分钟，分出有机相，减压浓缩蒸干，得到淡黄色固体8.19g，收率86％。1H NMR(600MHz,DMSO-d6)δ8.22(s,2H),7.66(dd,J＝14.2,7.7Hz,4H),7.47(t,J＝7.7Hz,2H),7.36(t,J＝8.0Hz,3H),3.43(d,J＝5.4Hz,1H),3.05(dd,J＝13.9,5.7Hz,1H),2.86(dd,J＝13.9,7.7Hz,1H),2.66(m,J＝13.9,7.0Hz,1H),1.86(m,J＝14.2,8.7,5.5Hz,1H),1.59(m,J＝13.9,7.7,5.9Hz,1H),1.07(d,J＝7.0Hz,3H).ESI-MS(m/z):284.3([M+H]+).
实施例13-c：制备(2R,4S)-5-([1,1'-联苯]-4-基)-4-氨基-2-甲基戊酸乙酯
同实施例12-b。
实施例13-d：制备沙库必曲
同实施例12-c。
实施例14制备沙库必曲
实施例14-a：制备(2R,4S)-5-([1,1'-联苯]-4-基)-4-氨基-2-甲基戊酸乙酯
Figure PCTCN2017075097-appb-000088
将异丙胺10g溶于10mL水中，用盐酸水溶液调节pH7.5～8.0，加入25mL二甲基亚砜(DMSO)，然后用0.1M的盐酸三(羟甲基)氨基甲烷-盐酸(Tris-盐酸)缓冲溶液稀释至100mL，并加热至40℃，加入1.0gω-转氨酶冷冻干粉和磷酸吡哆醛(PLP)0.8g，然后滴加依照实施例3的方法所得的10g(R)-5-([1,1'-联苯]-4-基)-2-甲基-4-戊酮酸乙酯的25mL二甲基亚砜(DMSO)溶液，反应过程中用20％的异丙胺水溶液控制pH＝7.5～8.0，温度保持40～45℃反应24h以上，TLC监控反应完毕。过滤除去固体，母液用乙酸乙酯萃取3次，合并后有机相减压浓缩蒸干，得到淡黄色固体8.80g，收率约88.1％,ee值99.0％。1H NMR(600MHz,CDCl3)δ8.62(s,2H),7.54(dd,J＝14.1,7.7Hz,4H),7.41(t,J＝7.6Hz,2H),7.36-7.29(m,3H),4.07(q,J＝7.1Hz,2H),3.67(s,1H),3.40-3.34(m,1H),2.97(dd,J＝24.3,10.9Hz,2H),2.07-2.00(m,1H),1.90-1.83(m,1H),1.20-1.15(m,6H).ESI-MS(m/z):312.4([M+H]+).
实施例14-b：制备沙库必曲
同实施例12-c。
实施例15制备沙库必曲
实施例15-a：制备(2R,4S)-5-([1,1'-联苯]-4-基)-4-氨基-2-甲基戊酸异丙酯
Figure PCTCN2017075097-appb-000089
将异丙胺10g溶于10mL水中，用盐酸水溶液调节pH7.5～8.0，加入25mL二甲基亚砜(DMSO)，然后用0.1M的盐酸三(羟甲基)氨基甲烷-盐酸(Tris-盐酸)缓冲溶液稀释至100mL，并加热至40℃，加入1.0gω-转氨酶冷冻干粉和磷酸吡哆醛(PLP)0.8g，然后滴加依照实施例4的方法所得的10g(R)-5-([1,1'-联苯]-4-基)-2-甲基-4-戊酮酸异丙酯的25mL二甲基亚砜(DMSO)溶液，反应过程中用20％的异丙胺水溶液控制pH＝7.5～8.0，温度保持40～45℃反应24h以上，TLC监控反应完毕。过滤除去固体，母液用乙酸乙酯萃取3次，合并后有机相减压浓缩蒸干，得到淡黄色固体8.20g，收率约82.1％,ee值96.5％。1H NMR(600MHz,CDCl3)δ8.62(s,2H),7.54(dd,J＝14.1,7.7Hz,4H),7.41(t,J＝7.6Hz,2H),7.36-7.29(m,3H),4.93(m,1H),3.67(s,1H),3.40-3.34(m,1H),2.97(dd,J＝24.3,10.9Hz,2H),2.07-2.00(m,1H),1.90-1.83(m,1H),1.31(d,J＝7.1Hz,6H),1.17(d,J＝6.8Hz,3H).ESI-MS(m/z):326.4([M+H]+).
实施例15-b：制备(2R,4S)-5-([1,1'-联苯]-4-基)-4-氨基-2-甲基戊酸
Figure PCTCN2017075097-appb-000090
向250mL反应瓶中依次加入10g(2R,4S)-5-([1,1'-联苯]-4-基)-4-氨基-2-甲基戊酸异丙酯、50mL四氢呋喃、50mL甲醇和2.65g氢氧化钠，20～40℃搅拌反应12h，TLC监控反应完毕，减压蒸馏除去溶剂，向残留物中加入100mL水和100mL乙酸乙酯，搅拌10分钟，分出有机相，减压浓缩蒸干，得到淡黄色固体7.40g，收率85％。1H NMR(600MHz,DMSO-d6)δ8.22(s,2H),7.66(dd,J＝14.2,7.7Hz,4H),7.47(t,J＝7.7Hz,2H),7.36(t,J＝8.0Hz,3H),3.43(d,J＝5.4Hz,1H),3.05(dd,J＝13.9,5.7Hz,1H),2.86(dd,J＝13.9,7.7Hz,1H),2.66(m,J＝13.9,7.0Hz,1H),1.86(m,J＝14.2,8.7,5.5Hz,1H),1.59(m,J＝13.9,7.7,5.9Hz,1H),1.07(d,J＝7.0Hz,3H).ESI-MS(m/z):284.3([M+H]+).
实施例15-c：制备(2R,4S)-5-([1,1'-联苯]-4-基)-4-氨基-2-甲基戊酸乙酯
同实施例12-b。
实施例15-d：制备沙库必曲
同实施例12-c。
实施例16制备沙库必曲
实施例16-a：制备(2R,4S)-5-([1,1'-联苯]-4-基)-4-氨基-2-甲基戊酸苄基酯
Figure PCTCN2017075097-appb-000091
将异丙胺10g溶于10mL水中，用盐酸水溶液调节pH7.5～8.0，加入25mL二甲基亚砜(DMSO)，然后用0.1M的盐酸三(羟甲基)氨基甲烷-盐酸(Tris-盐酸)缓冲溶液稀释至100mL，并加热至40℃，加入1.0gω-转氨酶冷冻干粉和磷酸吡哆醛(PLP)0.8g，然后滴加依照实施例5的方法所得的10g(R)-5-([1,1'-联苯]-4-基)-2-甲基-4-戊酮酸苄基酯的25mL二甲基亚砜(DMSO)溶液，反应过程中用20％的异丙胺水溶液控制pH＝7.5～8.0，温度保持40～45℃反应24h以上，TLC监控反应完毕。过滤除去固体，母液用乙酸乙酯萃取3次，合并后有机相减压浓缩蒸干，得到淡黄色固体7.90g，收率约79.1％,ee值88.0％。1H NMR(600MHz,CDCl3)δ8.62(s,2H),7.54(dd,J＝14.1,7.7Hz,4H),7.41(t,J＝7.6Hz,2H),7.40-7.33(m,5H),7.36-7.29(m,3H),5.22(s,2H),3.67(s,1H),3.40-3.34(m,1H),2.97(dd,J＝24.3,10.9Hz,2H),2.07-2.00(m,1H),1.90-1.83(m,1H),1.15(d,J＝6.8Hz,3H).ESI-MS(m/z):374.4([M+H]+).
实施例16-b：制备(2R,4S)-5-([1,1'-联苯]-4-基)-4-氨基-2-甲基戊酸
Figure PCTCN2017075097-appb-000092
向250mL反应瓶中依次加入10g(2R,4S)-5-([1,1'-联苯]-4-基)-4-氨基-2-甲基戊酸苄基酯、50mL四氢呋喃、50mL甲醇和2.65g氢氧化钠，20～40℃搅拌反应12h，TLC监控反应完毕，减压蒸馏除去溶剂，向残留物中加入100mL水和100mL乙酸乙酯，搅拌10分钟，分出有机相，减压浓缩蒸干，得到淡黄色固体6.22g，收率82％。1H NMR(600MHz,DMSO-d6)δ8.22(s,2H),7.66(dd,J＝14.2,7.7Hz,4H),7.47(t,J＝7.7Hz,2H),7.36(t,J＝8.0Hz,3H),3.43(d,J＝5.4Hz,1H),3.05(dd,J＝13.9,5.7Hz,1H),2.86(dd,J＝13.9,7.7Hz,1H),2.66(m,J＝13.9,7.0Hz,1H),1.86(m,J＝14.2,8.7,5.5Hz,1H),1.59(m,J＝13.9,7.7,5.9Hz,1H),1.07(d,J＝7.0Hz,3H).ESI-MS(m/z):284.3([M+H]+).
实施例16-c：制备(2R,4S)-5-([1,1'-联苯]-4-基)-4-氨基-2-甲基戊酸乙酯
同实施例12-b。
实施例16-d：制备沙库必曲
同实施例12-c。
第二种制备沙库必曲的方法
实施例17制备沙库必曲
实施例17-a：制备(3R,6R,7aR)-7a-([1,1'-联苯]-4-基-甲基)-6-甲基-3-苯基四氢吡咯并-[2,1-b]恶唑-5(6H)-酮
Figure PCTCN2017075097-appb-000093
室温下向250mL反应瓶中依次加入依照实施例11的方法所得的5.90g(R)-5-([1,1'-联苯]-4-基)-2-甲基-4-戊酮酸、3.42gD-苯甘氨醇和60mL甲苯，搅拌升温至125℃反应13h，TLC检测原料反应完全，反应液降温至20～30℃，减压浓缩得到油状物7.37g，收率92％。1H NMR(600MHz,CDCl3)δ7.61(dd,J＝8.2,7.1Hz,2H),7.53(d,J＝8.1Hz,2H),7.49–7.40(m,6H),7.39–7.32(m,2H),7.30–7.27(m,2H),5.30(t,J＝7.5Hz,1H),4.73(t,J＝8.4Hz,1H),4.45(dd,J＝8.8,7.1Hz,1H),3.09(d,J＝13.9Hz,1H),2.96(d,J＝13.9Hz,1H),2.69(dd,J＝12.8,8.3Hz,1H),2.61–2.51(m,1H),1.74(t,J＝12.1Hz,1H),1.16(d,J＝7.1Hz,3H).ESI-MS(m/z):384.4([M+H]+).
实施例17-b：制备(3R,5S)-5-([1,1'-联苯]-4-基-甲基)-1-((R)-2-羟基-1-苯乙基)-3-甲基-2-吡咯烷酮
Figure PCTCN2017075097-appb-000094
室温下向250mL三口瓶中依次加入8.02g(3R,6R,7aR)-7a-([1,1'-联苯]-4-基-甲基)-6-甲基-3-苯基四氢吡咯并-[2,1-b]恶唑-5(6H)-酮和80mL甲苯，氮气保护下加入7.29g三乙基硅烷，反应液降温至-35℃，缓慢滴加42mL四氯化钛甲苯溶液，滴加完毕后搅拌反应12h，TLC检测原料反应完全，向反应液中加入350mL25％氯化铵水溶液，分离出有机相，有机相减压浓缩得到油状物6.05g，收率75％。1H NMR(600MHz,CDCl3)δ7.56(d,J＝7.4Hz,2H),7.48(d,J＝8.1Hz,2H),7.47–7.40(m,4H),7.40–7.34(m,4H),7.01(d,J＝8.0Hz,2H),4.89(dd,J＝8.0,4.3Hz,1H),4.19(dd,J＝11.6,4.3Hz,1H),3.78–3.72(m,2H),3.51(t,J＝6.7Hz,1H),3.13(dd,J＝13.0,3.9Hz,1H),2.61–2.51(m,1H),2.24(dd,J＝12.8,11.0Hz,1H),2.19(ddd,J＝13.0,8.9,6.9Hz,1H),1.32(d,J＝7.1Hz,3H).ESI-MS(m/z):386.3([M+H]+).
实施例17-c：制备(3R,5S)-3-甲基-5-([1,1'-联苯]-4-基-甲基)-2-吡咯烷酮
Figure PCTCN2017075097-appb-000095
向250mL氢化反应瓶中加入7.00g(3R,5S)-5-([1,1'-联苯]-4-基-甲基)-1-((R)-2-羟基-1-苯乙基)-3-甲基-2-吡咯烷酮、3.50g 10％Pd/C和70mL甲醇，体系氮气置换3次，室温和常压下通入氢气至4.0Mpa，搅拌下升温至80℃反应24h，TLC检测原料反应完全，过滤回收催化剂，滤液减压浓缩，剩余物用乙酸乙酯和正己烷(体积比1:1)重结晶得白色固体4.29g，收率89％。1H NMR(400MHz,CDCl3)δ7.63–7.53(m,4H),7.46(t,J＝7.6Hz,2H),7.37(t,J＝7.3Hz,1H),7.30–7.24(m,3H),5.75(s,1H),3.92–3.82(m,1H),2.88(dd,J＝13.4,5.5Hz,1H),2.77(dd,J＝13.4,8.4Hz,1H),2.58–2.46(m,1H),2.18(dt,J＝12.5,7.2Hz,1H),1.96(dt,J＝12.9,7.8Hz,1H),1.22(d,J＝7.2Hz,3H).ESI-MS(m/z):266.1([M+H]+)
实施例17-d：制备(2R,4S)-5-([1,1'-联苯]-4-基)-4-氨基-2-甲基戊酸乙酯盐酸盐
Figure PCTCN2017075097-appb-000096
向100mL反应瓶中加入0.65g(3R,5S)-3-甲基-5-([1,1'-联苯]-4-基-甲基)-2-吡咯烷酮、20mL甲醇和2mL浓盐酸，搅拌下升温至70-85℃反应24h，TLC检测原料反应完全，反应液减压浓缩，剩余物用乙酸乙酯重结晶得白色固体0.70g，收率82％。1H NMR(600MHz,CDCl3)δ8.62(s,3H),7.54(dd,J＝14.1,7.7Hz,4H),7.41(t,J＝7.6Hz,2H),7.36-7.29(m,3H),4.07(q,J＝7.1Hz,2H),3.67(s,1H),3.40-3.34(m,1H),2.97(dd,J＝24.3,10.9Hz,2H),2.07-2.00(m,1H),1.90-1.83(m,1H),1.20-1.15(m,6H).ESI-MS(m/z):312.1([M+H]+
实施例17-e：制备沙库必曲
同实施例12-c。
实施例18制备沙库必曲
实施例18-a：制备(3R,6R,7aR)-7a-([1,1'-联苯]-4-基-甲基)-6-甲基-3-苯基四氢吡咯并-[2,1-b]恶唑-5(6H)-酮
Figure PCTCN2017075097-appb-000097
室温下向250mL反应瓶中依次加入依照实施例2的方法所得的6.50g(R)-5-([1,1'-联苯]-4-基)-2-甲基-4-戊酮酸甲酯、3.70g D-苯甘氨醇和70mL甲苯，搅拌升温至125℃反应13h，TLC检测原料反应完全，反应液降温至20～30℃，减压浓缩得到油状物7.23g，收率86％。1H NMR(600MHz,CDCl3)δ7.61(dd,J＝8.2,7.1Hz,2H),7.53(d,J＝8.1Hz,2H),7.49–7.40(m,6H),7.39–7.32(m,2H),7.30–7.27(m,2H),5.30(t,J＝7.5Hz,1H),4.73(t,J＝8.4Hz,1H),4.45(dd,J＝8.8,7.1Hz,1H),3.09(d,J＝13.9Hz,1H),2.96(d,J＝13.9Hz,1H),2.69(dd,J＝12.8,8.3Hz,1H),2.61–2.51(m,1H),1.74(t,J＝12.1Hz,1H),1.16(d,J＝7.1Hz,3H).ESI-MS(m/z):384.4([M+H]+).
实施例18-b：制备(3R,5S)-5-([1,1'-联苯]-4-基-甲基)-1-((R)-2-羟基-1-苯乙基)-3-甲基-2-吡咯烷酮
同实施例17-b。
实施例18-c：制备(3R,5S)-3-甲基-5-([1,1'-联苯]-4-基-甲基)-2-吡咯烷酮
同实施例17-c。
实施例18-d：制备(2R,4S)-5-([1,1'-联苯]-4-基)-4-氨基-2-甲基戊酸乙酯盐酸盐
同实施例17-d。
实施例18-e：制备沙库必曲
同实施例12-c。
综上实施例所述，本发明提供的合成方法能够有效制备式(Ⅴ)所示的化合物，并通过所述的式(Ⅴ)所示的化合物进一步合成沙库必曲。本发明所述的方法具有原料易得、工艺简洁、经济环保等优点。
本发明的方法已经通过较佳实施例进行了描述，相关人员明显能在本发明内容、精神和范围内对本文 所述的方法和应用进行改动或适当变更与组合，来实现和应用本发明技术。本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明内。

Claims (35)

  1. 如式(Ⅴ)所示化合物，
    Figure PCTCN2017075097-appb-100001
    其中R1是苯基、甲氧基、羟基、氯、溴、碘、甲磺酸酯基、三氟甲磺酸酯基或对甲苯磺酸酯基；
    其中R2是
    Figure PCTCN2017075097-appb-100002
    R3是氢、-(C1-C4)烷基或-(C1-C4)烷基-芳基；
    R4是氢、-(C1-C4)烷基、-(C3-C6)杂环基、-(C1-C4)烷基-芳基、三甲基硅基、三乙基硅基或叔丁基二甲基硅基。
  2. 根据权利要求1所述的化合物，其中所述的R1是苯基。
  3. 根据权利要求1所述的化合物，其中所述的R3是氢、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、苄基或被任意取代的苄基。
  4. 根据权利要求1所述的化合物，其中所述的R4是氢、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、三甲基硅基、三乙基硅基、叔丁基二甲基硅基、三苯甲基、四氢呋喃、苄基或被任意取代的苄基。
  5. 根据权利要求1所述的化合物，其中所述的R2是-COOH、-COOCH3、-COOCH2CH3、-COOCH(CH3)2、-COOC(CH3)3、-COOCH2Ph、-CH2OH、-CH2OCH3、-CH2OCH2CH3、-CH2OCH(CH3)2、-CH2OC(CH3)3、-CH2OCH2Ph、-CH2OC(Ph)3、-CH2OSi(CH3)3、-CH2OSi(CH2CH3)3、-CH2OSi(CH3)2C(CH3)3、-CONH2、-CONHCH3、-CONHCH2CH3、-CONHCH(CH3)2、-CONHC(CH3)3、-CONHCH2Ph或
    Figure PCTCN2017075097-appb-100003
  6. 根据权利要求1所述的化合物，其具有以下之一的结构：
    Figure PCTCN2017075097-appb-100004
    Figure PCTCN2017075097-appb-100005
    Figure PCTCN2017075097-appb-100006
  7. 一种制备如式(Ⅴ)所示化合物的方法，
    Figure PCTCN2017075097-appb-100007
    其中R1是苯基、甲氧基、羟基、氯、溴、碘、甲磺酸酯基、三氟甲磺酸酯基或对甲苯磺酸酯基；
    其中R2是
    Figure PCTCN2017075097-appb-100008
    R3是氢、-(C1-C4)烷基或-(C1-C4)烷基-芳基；
    R4是氢、-(C1-C4)烷基、-(C3-C6)杂环基、-(C1-C4)烷基-芳基、三甲基硅基、三乙基硅基或叔丁基二甲基硅基；
    其通过式(Ⅳ)所示的化合物经过脱保护反应制备获得，
    Figure PCTCN2017075097-appb-100009
    所述的R1和R2是如上所述的基团；
    所述的R5是氢、-(C1-C4)烷基或-(C1-C4)烷基-芳基。
  8. 根据权利要求7所述的方法，
    其中所述的R1是苯基；
    其中所述的R2是
    Figure PCTCN2017075097-appb-100010
    R3是氢、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、苄基或被任意取代的苄基；
    其中所述的R5是甲基、乙基、正丙基、异丙基、正丁基、叔丁基、苄基或被任意取代的苄基。
  9. 根据权利要求7所述的方法，式(Ⅳ)所示的化合物在酸或碱存在的条件下，经过脱保护反应获得式(Ⅴ)所示的化合物。
  10. 一种制备式(Ⅴ)所示的化合物的方法，
    Figure PCTCN2017075097-appb-100011
    其中R1是苯基、甲氧基、羟基、氯、溴、碘、甲磺酸基、三氟甲磺酸基或对甲苯磺酸基；
    其中R2是
    Figure PCTCN2017075097-appb-100012
    R3是氢、-(C1-C4)烷基或-(C1-C4)烷基-芳基；
    R4是氢、-(C1-C4)烷基、-(C3-C6)杂环基、-(C1-C4)烷基-芳基、三甲基硅基、三乙基硅基或叔丁基二甲基硅基；
    包括以下步骤：
    a)式(Ⅱ)所示的化合物和式(Ⅲ)所示的化合物进行取代反应，制备获得式(Ⅳ)所示的化合物；
    Figure PCTCN2017075097-appb-100013
    所述的R1、R2是如上所述的基团，
    所述的R5是氢、-(C1-C4)烷基或-(C1-C4)烷基-芳基，
    所述的R6是三氟甲磺酸基、甲磺酸基或对甲苯磺酸基；
    b)式(Ⅳ)所示的化合物经过脱保护反应，制备获得式(Ⅴ)所示的化合物。
  11. 根据权利要求10所述的方法，所述步骤(a)中的取代反应在强碱存在条件下进行。
  12. 一种制备式(Ⅴ)所示的化合物的方法，
    Figure PCTCN2017075097-appb-100014
    其中R1是苯基、甲氧基、羟基、氯、溴、碘、甲磺酸酯基、三氟甲磺酸酯基或对甲苯磺酸酯基；
    其中R2是
    Figure PCTCN2017075097-appb-100015
    R3是氢、-(C1-C4)烷基或-(C1-C4)烷基-芳基；
    R4是氢、-(C1-C4)烷基、-(C3-C6)杂环基、-(C1-C4)烷基-芳基、三甲基硅基、三乙基硅基或叔丁基二甲基硅基；
    包括以下步骤：
    a)式(Ⅰ)所示的化合物，经过缩合反应制备获得式(Ⅱ)所示的化合物；
    Figure PCTCN2017075097-appb-100016
    所述的R1是如上所述的基团，
    所述的R5是氢、-(C1-C4)烷基或-(C1-C4)烷基-芳基；
    b)式(Ⅱ)所示的化合物和式(Ⅲ)所示的化合物进行取代反应，制备获得式(Ⅳ)所示的化合物；
    Figure PCTCN2017075097-appb-100017
    所述的R1、R2和R5是如上所述的基团，
    所述的R6是三氟甲磺酸酯基、甲磺酸酯基或对甲苯磺酸酯基；
    c)式(Ⅳ)所示的化合物经过脱保护反应，制备获得式(Ⅴ)所示的化合物。
  13. 一种制备式(Ⅴ)所示的化合物的方法，包括以下步骤：
    Figure PCTCN2017075097-appb-100018
    其中所述的R1是苯基，
    其中R2是
    Figure PCTCN2017075097-appb-100019
    R3是氢、甲基、乙基、正丙基、异丙基、正丁基、叔丁基或苄基；
    R4是氢、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、苄基，三甲基硅基，三乙基硅基，叔丁基二甲基硅基，三苯甲基，四氢吡喃基；
    a)式(Ⅰ)所示的化合物，在碱性条件下，进行缩合反应制备获得式(Ⅱ)所示的化合物；
    Figure PCTCN2017075097-appb-100020
    所述的R1是如上所述的基团，
    所述的R5是氢、甲基、乙基、正丙基、异丙基、正丁基或苄基；
    b)式(Ⅱ)所示的化合物和式(Ⅲ)所示的化合物在强碱存在条件下进行取代反应，制备获得式(Ⅳ)所示的化合物，
    Figure PCTCN2017075097-appb-100021
    所述的R1、R2和R5是如上所述的基团，
    所述R6是三氟甲磺酸酯基、甲磺酸酯基或对甲苯磺酸酯基；
    c)式(Ⅳ)所示的化合物在酸或者碱存在的条件下反应，经过脱保护反应，制备获得式(Ⅴ)所示的化合物。
  14. 根据权利要求12或13所述的方法，所述的式(Ⅱ)所示的化合物，通过式(Ⅰ)所示的化合物在氯化镁和三乙胺存在条件下与N,N'-羰基二咪唑和式(Ⅷ)所示的化合物进行缩合反应获得，
    Figure PCTCN2017075097-appb-100022
    所述的R5是氢、-(C1-C4)烷基或-(C1-C4)烷基-芳基。
  15. 根据权利要求12或13所述的方法，所述的式(Ⅱ)所示的化合物，通过式(Ⅰ)所示的化合物在N,N-二异丙基乙胺存在条件下与米氏酸、4-二甲氨基吡啶、R5OH和特戊酰氯进行缩合反应获得，所述的R5是氢、-(C1-C4)烷基或-(C1-C4)烷基-芳基。
  16. 一种制备沙库必曲的方法，
    Figure PCTCN2017075097-appb-100023
    其包括以下步骤：通过式(V)所示的化合物制备沙库必曲，
    Figure PCTCN2017075097-appb-100024
    其中，
    所述的R1是苯基、甲氧基、羟基、氯、溴、碘、甲磺酸基、三氟甲磺酸基或对甲苯磺酸基；
    所述的R2是
    Figure PCTCN2017075097-appb-100025
    R3是氢、-(C1-C4)烷基或-(C1-C4)烷基-芳基；
    R4是氢、-(C1-C4)烷基、-(C3-C6)杂环基、-(C1-C4)烷基-芳基、三甲基硅基、三乙基硅基或叔丁基二甲基硅基。
  17. 一种制备沙库必曲的方法，
    Figure PCTCN2017075097-appb-100026
    其包括以下步骤：通过式(V)所示的化合物制备沙库必曲，
    Figure PCTCN2017075097-appb-100027
    其中R1是苯基，
    其中R2是
    Figure PCTCN2017075097-appb-100028
    R3是甲基、乙基、正丙基、异丙基、正丁基、叔丁基、苄基或被任意取代的苄基。
  18. 一种制备式(Ⅵ)所示的化合物的方法，
    Figure PCTCN2017075097-appb-100029
    包括以下步骤：
    将式(Ⅴ)所示的化合物作经过酶催化反应，制备获得式(Ⅵ)所示的化合物，
    Figure PCTCN2017075097-appb-100030
    其中，
    所述的R1是苯基、甲氧基、羟基、氯、溴、碘、甲磺酸酯基、三氟甲磺酸酯基或对甲苯磺酸酯基；
    所述的R2是
    Figure PCTCN2017075097-appb-100031
    R3是氢、-(C1-C4)烷基或-(C1-C4)烷基-芳基；
    R4是氢、-(C1-C4)烷基、-(C3-C6)杂环基、-(C1-C4)烷基-芳基、三甲基硅基、三乙基硅基或叔丁基二甲基硅基。
  19. 一种制备沙库必曲的方法，
    Figure PCTCN2017075097-appb-100032
    其包括以下步骤：
    a)式(Ⅴ)所示的化合物经过酶催化反应，制备获得式(Ⅵ)所示的化合物，
    Figure PCTCN2017075097-appb-100033
    其中，
    所述的R1是苯基、甲氧基、羟基、氯、溴、碘、甲磺酸酯基、三氟甲磺酸酯基或对甲苯磺酸酯基；
    所述的R2是
    Figure PCTCN2017075097-appb-100034
    R3是氢、-(C1-C4)烷基或-(C1-C4)烷基-芳基；
    R4是氢、-(C1-C4)烷基、-(C3-C6)杂环基、-(C1-C4)烷基-芳基、三甲基硅基、三乙基硅基或叔丁基二甲基硅基；
    b)可选择性的，通过式(Ⅵ)所示的化合物制备式(Ⅶ)所示的化合物
    Figure PCTCN2017075097-appb-100035
    c)通过式(Ⅶ)所示的化合物反应制备沙库必曲。
  20. 一种制备沙库必曲的方法，
    Figure PCTCN2017075097-appb-100036
    其包括以下步骤：
    a)式(Ⅴ)所示的化合物经过酶催化反应，制备获得式(Ⅵ)所示的化合物，
    Figure PCTCN2017075097-appb-100037
    其中R1是苯基，
    其中R2是
    Figure PCTCN2017075097-appb-100038
    R3是甲基、乙基、丙基、异丙基、正丁基、叔丁基、苄基或被任意取代的苄基；
    b)通过式(Ⅵ)所示的化合物制备式(Ⅶ)所示的化合物，
    Figure PCTCN2017075097-appb-100039
    c)通过式(Ⅶ)所示的化合物与丁二酸酐经过酰胺化缩合反应制备沙库必曲。
  21. 一种制备沙库必曲的方法，
    Figure PCTCN2017075097-appb-100040
    其包括以下步骤：
    a)式(Ⅴ)所示的化合物经过酶催化反应，制备获得式(Ⅶ)所示的化合物，
    Figure PCTCN2017075097-appb-100041
    其中R1是苯基，
    其中R2是
    Figure PCTCN2017075097-appb-100042
    R3是乙基；
    b)式(Ⅶ)所示的化合物与丁二酸酐经过酰胺化缩合反应制备获得沙库必曲。
  22. 根据权利要求19或20所述的制备沙库必曲的方法，其中，式(Ⅶ)所示的化合物是通过将式(Ⅵ)所示的化合物进行水解反应，然后再与乙醇进行酯化反应制备而得。
  23. 根据权利要求18-21中任一所述的制备沙库必曲的方法，其中所述的酶催化反应是在ω-转氨酶和磷酸吡哆醛存在的条件下进行的。
  24. 一种制备沙库必曲的方法，其至少包括以下步骤：
    式(Ⅴ)所示的化合物与式(Ⅸ)所示的化合物反应制备获得式(Ⅹ)所示的化合物，
    Figure PCTCN2017075097-appb-100043
    其中，
    所述的R1是苯基、甲氧基、羟基、氯、溴、碘、甲磺酸酯基、三氟甲磺酸酯基或对甲苯磺酸酯基，
    所述的R2是
    Figure PCTCN2017075097-appb-100044
    所述的R3是氢、-(C1-C4)烷基或-(C1-C4)烷基-芳基，
    所述的R7是苯基或-(C1-C4)烷基或-(C1-C4)烷基-芳基。
  25. 一种制备沙库必曲的方法，其包括以下步骤：
    a)式(Ⅴ)所示的化合物与式(Ⅸ)所示的化合物反应制备获得式(Ⅹ)所示的化合物，
    Figure PCTCN2017075097-appb-100045
    其中，
    所述的R1是苯基、甲氧基、羟基、氯、溴、碘、甲磺酸酯基、三氟甲磺酸酯基或对甲苯磺酸酯基，
    所述的R2是
    Figure PCTCN2017075097-appb-100046
    所述的R3是氢、-(C1-C4)烷基或-(C1-C4)烷基-芳基，
    所述的R7是苯基或-(C1-C4)烷基或-(C1-C4)烷基-芳基；
    b)通过式(Ⅹ)所示的化合物制备式(ⅩⅠ)所示的化合物，
    Figure PCTCN2017075097-appb-100047
    所述R1和R7如步骤a)中所描述；
    c)通过式(ⅩⅠ)所示的化合物制备式(ⅩⅡ)所示的化合物；
    Figure PCTCN2017075097-appb-100048
    d)通过式(ⅩⅡ)所示的化合物制备式(Ⅶ)所示的化合物；
    Figure PCTCN2017075097-appb-100049
    e)通过式(Ⅶ)所示的化合物制备获得沙库必曲。
  26. 根据权利要求25所述的方法，其中a)步骤中式(Ⅸ)所示化合物是D-苯甘氨醇。
  27. 根据权利要求25所述的方法，其中b)步骤中式(Ⅹ)所示化合物制备(ⅩⅠ)所示化合物是在四氯化钛和三乙基硅烷存在下进行的。
  28. 根据权利要求25所述的方法，其中c)步骤中式(ⅩⅠ)所示化合物制备(ⅩⅡ)所示化合物是在钯炭存在下进行。
  29. 根据权利要求25所述的方法，其中d)步骤中式(ⅩⅡ)所示化合物制备(Ⅶ)所示化合物是在酸性条件下，乙醇溶剂中进行。
  30. 一种制备沙库必曲的方法，其包括以下步骤：
    a)(R)-5-([1,1'-联苯]-4-基)-2-甲基-4-戊酮酸与D-苯甘氨醇反应制备获得式(ⅩⅢ)所示的化合物，
    Figure PCTCN2017075097-appb-100050
    b)通过式(ⅩⅢ)所示的化合物在四氯化钛和三乙基硅烷存在的条件下制备式(ⅩⅣ)所示的化合物，
    Figure PCTCN2017075097-appb-100051
    c)通过式(ⅩⅣ)所示的化合物在钯炭存在下制备式(ⅩⅡ)所示的化合物，
    Figure PCTCN2017075097-appb-100052
    d)通过式(ⅩⅡ)所示的化合物开环反应制备式(Ⅶ)所示的化合物，
    Figure PCTCN2017075097-appb-100053
    e)通过式(Ⅶ)所示的化合物制备获得沙库必曲。
  31. 如式(Ⅹ)所示化合物，
    Figure PCTCN2017075097-appb-100054
    所述的R1是苯基、甲氧基、羟基、氯、溴、碘、甲磺酸酯基、三氟甲磺酸酯基或对甲苯磺酸酯基；
    所述的R7是苯基或-(C1-C4)烷基或-(C1-C4)烷基-芳基。
  32. 根据权利要求31所述的化合物，所述的R7是甲基、乙基、丙基、异丙基、正丁基、叔丁基、苄基或被任意取代的苄基。
  33. 如式(Ⅺ)所示化合物，
    Figure PCTCN2017075097-appb-100055
    所述的R1是苯基、甲氧基、羟基、氯、溴、碘、甲磺酸酯基、三氟甲磺酸酯基或对甲苯磺酸酯基；
    所述的R7是苯基或-(C1-C4)烷基或-(C1-C4)烷基-芳基。
  34. 根据权利要求33所述的化合物，所述的R7是甲基、乙基、丙基、异丙基、正丁基、叔丁基、苄基或被任意取代的苄基。
  35. 一种制备沙库必曲的方法，其至少包括以下步骤：
    通过式(Ⅹ)所示的化合物制备式(ⅩⅠ)所示的化合物，
    Figure PCTCN2017075097-appb-100056
    其中，
    所述的R1是苯基、甲氧基、羟基、氯、溴、碘、甲磺酸酯基、三氟甲磺酸酯基或对甲苯磺酸酯基，
    所述的R7是苯基或-(C1-C4)烷基或-(C1-C4)烷基-芳基。
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