CN115448864B - Preparation method of 3-fluoro-3- (1-hydroxyethyl) pyrrolidine-1-carboxylic acid tert-butyl ester - Google Patents
Preparation method of 3-fluoro-3- (1-hydroxyethyl) pyrrolidine-1-carboxylic acid tert-butyl ester Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- IOADSJASVUKMCD-UHFFFAOYSA-N tert-butyl 3-fluoro-3-(1-hydroxyethyl)pyrrolidine-1-carboxylate Chemical compound FC1(CN(CC1)C(=O)OC(C)(C)C)C(C)O IOADSJASVUKMCD-UHFFFAOYSA-N 0.000 title claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 86
- 150000001875 compounds Chemical class 0.000 claims abstract description 55
- 239000007818 Grignard reagent Substances 0.000 claims abstract description 25
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims abstract description 24
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 23
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract description 19
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims abstract description 15
- -1 Grignard reagent methyl magnesium chloride Chemical class 0.000 claims abstract description 15
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 15
- USZLCYNVCCDPLQ-UHFFFAOYSA-N hydron;n-methoxymethanamine;chloride Chemical compound Cl.CNOC USZLCYNVCCDPLQ-UHFFFAOYSA-N 0.000 claims abstract description 14
- RULHSLKSRFNQJO-UHFFFAOYSA-N n-(methoxymethyl)-1-phenyl-n-trimethylsilylmethanamine Chemical compound COCN([Si](C)(C)C)CC1=CC=CC=C1 RULHSLKSRFNQJO-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims abstract description 12
- BAPJBEWLBFYGME-UHFFFAOYSA-N acrylic acid methyl ester Natural products COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 claims abstract description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 5
- 239000007858 starting material Substances 0.000 claims abstract description 5
- 238000006736 Huisgen cycloaddition reaction Methods 0.000 claims abstract description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 64
- 238000000034 method Methods 0.000 claims description 48
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 32
- 150000004795 grignard reagents Chemical class 0.000 claims description 18
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical compound [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 claims description 15
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical group OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 14
- 239000003054 catalyst Substances 0.000 claims description 9
- 229910010082 LiAlH Inorganic materials 0.000 claims description 8
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 claims description 8
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 8
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- 150000004678 hydrides Chemical class 0.000 claims description 5
- ZTZJVAOTIOAZGZ-UHFFFAOYSA-N methyl 2-fluoroacrylate Chemical compound COC(=O)C(F)=C ZTZJVAOTIOAZGZ-UHFFFAOYSA-N 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- YCCXQARVHOPWFJ-UHFFFAOYSA-M magnesium;ethane;chloride Chemical compound [Mg+2].[Cl-].[CH2-]C YCCXQARVHOPWFJ-UHFFFAOYSA-M 0.000 claims description 4
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 claims description 4
- 235000005074 zinc chloride Nutrition 0.000 claims description 4
- 239000011592 zinc chloride Substances 0.000 claims description 4
- 239000002994 raw material Substances 0.000 abstract description 10
- 150000001408 amides Chemical class 0.000 abstract description 4
- 238000009903 catalytic hydrogenation reaction Methods 0.000 abstract description 4
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 125000003277 amino group Chemical group 0.000 abstract description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract description 2
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 150
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 141
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 96
- 239000002904 solvent Substances 0.000 description 75
- 239000012074 organic phase Substances 0.000 description 38
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 36
- 238000004809 thin layer chromatography Methods 0.000 description 33
- 239000008346 aqueous phase Substances 0.000 description 30
- 239000000706 filtrate Substances 0.000 description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- 238000004440 column chromatography Methods 0.000 description 24
- 238000000967 suction filtration Methods 0.000 description 24
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 21
- 238000010791 quenching Methods 0.000 description 20
- 238000005292 vacuum distillation Methods 0.000 description 19
- 229910052786 argon Inorganic materials 0.000 description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 17
- 239000003480 eluent Substances 0.000 description 17
- 239000000741 silica gel Substances 0.000 description 17
- 229910002027 silica gel Inorganic materials 0.000 description 17
- 230000000171 quenching effect Effects 0.000 description 15
- 229920006395 saturated elastomer Polymers 0.000 description 15
- 238000001816 cooling Methods 0.000 description 14
- 238000003760 magnetic stirring Methods 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 238000000605 extraction Methods 0.000 description 12
- 238000012544 monitoring process Methods 0.000 description 11
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 10
- 229910052740 iodine Inorganic materials 0.000 description 10
- 239000011630 iodine Substances 0.000 description 10
- 239000000463 material Substances 0.000 description 10
- 238000005481 NMR spectroscopy Methods 0.000 description 9
- 239000000203 mixture Substances 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 125000006239 protecting group Chemical group 0.000 description 6
- 230000003595 spectral effect Effects 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 239000003638 chemical reducing agent Substances 0.000 description 4
- 238000006264 debenzylation reaction Methods 0.000 description 4
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 4
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 238000011534 incubation Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000006722 reduction reaction Methods 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical group F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- GRTOGORTSDXSFK-XJTZBENFSA-N ajmalicine Chemical compound C1=CC=C2C(CCN3C[C@@H]4[C@H](C)OC=C([C@H]4C[C@H]33)C(=O)OC)=C3NC2=C1 GRTOGORTSDXSFK-XJTZBENFSA-N 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 238000007239 Wittig reaction Methods 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 150000002118 epoxides Chemical class 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
- 238000007142 ring opening reaction Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229940122016 Pim kinase inhibitor Drugs 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- XYLXXNFYVQYJRZ-UHFFFAOYSA-M [Cl-].[Mg+]C.C1CCOC1 Chemical compound [Cl-].[Mg+]C.C1CCOC1 XYLXXNFYVQYJRZ-UHFFFAOYSA-M 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000006735 epoxidation reaction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- Y—GENERAL 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
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparation method of 3-fluoro-3- (1-hydroxyethyl) pyrrolidine-1-carboxylic acid tert-butyl ester, which takes easily obtained N- (methoxymethyl) -N- (trimethylsilyl) benzylamine as a starting material, and the easily obtained N- (methoxymethyl) -N- (trimethylsilyl) benzylamine and 2-fluoro methyl acrylate undergo a 1, 3-dipolar cycloaddition reaction under the catalysis of trifluoroacetic acid (TFA) to obtain a compound VI, the compound VI is condensed with N, O-dimethylhydroxylamine hydrochloride under the alkaline condition of Grignard reagent methyl magnesium chloride to obtain a compound Weinreb amide V, and then reacts with Grignard reagent methyl magnesium chloride to obtain a compound methyl ketone IV; the compound IV is reduced by the compound hydride to obtain a compound III, then benzyl protecting group is removed by Pd/C catalytic hydrogenation to obtain a compound II, and finally amino group is reacted with (Boc) under the catalysis of DMAP 2 O protection to obtain the target compound I. The invention has the advantages of low cost and easy availability of raw materials and reagents, mild reaction conditions, simple operation, no harsh reaction conditions, high yield and easy mass production.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a preparation method of 3-fluoro-3- (1-hydroxyethyl) pyrrolidine-1-carboxylic acid tert-butyl ester.
Background
3-fluoro-3- (1-hydroxyethyl) pyrrolidine-1-carboxylic acid tert-butyl ester is an important medical intermediate, is a key molecular building block of PIM kinase inhibitor, has a structural formula shown in the following formula (I),
barberis et al (bioorg. Med. Chem. Lett.,2020, 30:12762-12774.) disclose a process for the preparation of formula (I) comprising the steps of: n-carbobenzoxy pyrrolidine-3-ketone is taken as a starting material, and an intermediate olefin 2 is obtained through Wittig reactionEpoxidation of the double bond by m-CPBA to give epoxide 3; epoxide 3 is selectively opened by HF, F atom is introduced into tertiary carbon of pyrrole ring to generate secondary alcohol 4 (4 a, 4b, 4C, 4d, two pairs of diastereoisomers), pd/C catalytic hydrogenation is used to remove carbobenzoxy protecting group, and then the carbobenzoxy protecting group is reacted with (Boc) 2 O reacts to obtain the target compound (I).
The preparation method avoids the synthesis of pyrrolidine framework, and adopts well-known reactions such as Wittig reaction, epoxidation reaction, hydrogen fluoride ring opening and the like. But are limited to: firstly, the Wittig reaction adopts butyl lithium as alkali, has high requirement on anhydrous operation, has high production safety risk, and has the literature yield of only 60 percent; secondly, the total yield of the hydrogen fluoride ring-opening literature is 60 percent, which is lower; third, hydrogen fluoride gas is dangerous and has great corrosion to equipment. In summary, this preparation method is not suitable for the scale-up reaction.
Disclosure of Invention
The invention aims to overcome the defects of the prior art, and provides a synthetic route of 3-fluoro-3- (1-hydroxyethyl) pyrrolidine-1-carboxylic acid tert-butyl ester (I), so that the process is more reasonable, safer and more environment-friendly, and a product with low cost and high quality is obtained, and is suitable for amplification reaction.
The aim of the invention is realized by adopting the following technical scheme.
In one aspect, the invention provides a process for the preparation of 3-fluoro-3- (1-hydroxyethyl) pyrrolidine-1-carboxylic acid tert-butyl ester (I), which comprises the following steps:
the invention takes easily available N- (methoxymethyl) -N- (trimethylsilyl) benzylamine as a starting material, and takes 1, 3-dipolar cycloaddition reaction with 2-fluoro methyl acrylate under the catalysis of trifluoroacetic acid (TFA) to obtain a compound VI, which is condensed with N, O-dimethylhydroxylamine hydrochloride under the alkaline condition of Grignard reagent methyl magnesium chloride to obtain a compound Weinreb amide V, and then reacts with the Grignard reagent methyl magnesium chloride to obtain a compound methyl ketone IV; the compound IV is reduced by the compound hydride to obtain a compound III, then benzyl protecting group is removed by Pd/C catalytic hydrogenation to obtain a compound II, and finally amino group is reacted with (Boc) under the catalysis of DMAP 2 O protection to obtain the target compound I.
The preparation method of the 3-fluoro-3- (1-hydroxyethyl) pyrrolidine-1-carboxylic acid tert-butyl ester (I) comprises the following steps:
(1) Taking N- (methoxymethyl) -N- (trimethylsilyl) benzylamine as a starting material, and carrying out 1, 3-dipolar cycloaddition reaction with 2-fluoro methyl acrylate in the presence of a catalyst to obtain a compound VI
(2) Dissolving the compound VI prepared in the step (1) in an organic solvent A, and condensing with N, O-dimethylhydroxylamine hydrochloride in the presence of a Grignard reagent A to obtain a compound V
(3) Reacting the compound V prepared in the step (2) with a Grignard reagent B to generate methyl ketone IV
(4) Reducing carbonyl by compound IV prepared in the step (3) through compound hydride to obtain a compound III
(5) Carrying out Pd/C catalytic hydrogenation on the compound III prepared in the step (4) to obtain a compound II
(6) The compound II prepared in the step (5) is catalyzed by DMAP to prepare (Boc) 2 O protection to obtain the target compound I
Preferably, in the step (1), the molar ratio of the N- (methoxymethyl) -N- (trimethylsilyl) benzylamine, the 2-fluoro methyl acrylate and the catalyst is 1.0:1.0-1.5:0.1-1.0.
Preferably, in step (1), the catalyst is selected from trifluoroacetic acid, zinc chloride, titanium tetrachloride, etc., preferably trifluoroacetic acid (TFA).
Preferably, in step (1), the reaction temperature is 20 to 25 ℃.
Preferably, in the step (2), the molar ratio between the compound VI, the N, O-dimethylhydroxylamine hydrochloride and the Grignard reagent A is 1.0:1.5-2.4:3.0-5.7.
Preferably, in step (2), the organic solvent a is selected from tetrahydrofuran, 1, 4-dioxane, preferably tetrahydrofuran.
Preferably, in step (2), the grignard reagent a is selected from methyl magnesium chloride, ethyl magnesium chloride, isopropyl magnesium chloride, preferably methyl magnesium chloride.
Preferably, in step (2), the reaction temperature is from 0 to 5 ℃.
Preferably, in step (3), the molar ratio between the compound v and the grignard reagent B is between 1.0:1.0 and 5.0, preferably 1:2.
preferably, in step (3), the reaction temperature is from 0 to 5 ℃.
Preferably, in step (3), the grignard reagent B is methyl magnesium chloride.
Preferably, in step (4), the molar ratio between the compound IV and the complex hydride is 1.0:0.4-1.0.
Preferably, in step (4), the complex hydride is selected from NaBH 4 、KBH 4 And LiAlH 4 Preferably LiAlH 4 。
Preferably, in step (4), the reaction temperature is from 0 to 5 ℃.
Preferably, in step (5), the mass fraction of Pd/C is 10% Pd/C.
Preferably, in step (5), the mass ratio of said compound iii to said 10% pd/C is from 1.0:0.2 to 0.5, preferably 1.0:0.5.
preferably, in step (5), the reaction time is 2 to 6 hours.
Preferably, in step (6), said compound II, said (Boc) 2 The mol ratio between O and the DMAP is 1.0:1.0-1.5:0.06-0.1.
Preferably, in step (6), the reaction temperature is 20 to 25℃and the reaction time is 1 to 6 hours.
In a specific embodiment, the process for preparing 3-fluoro-3- (1-hydroxyethyl) pyrrolidine-1-carboxylic acid tert-butyl ester (I) comprises the steps of:
(1)
sequentially adding N- (methoxymethyl) -N- (trimethylsilyl) benzylamine and 2-fluoro methyl acrylate into an organic solvent (such as dichloromethane), dropwise adding trifluoroacetic acid (TFA) into the reaction liquid under a cooling condition, cooling and reacting for 1 hour after dropwise adding, and then heating to room temperature for reacting for 2 hours until the N- (methoxymethyl) -N- (trimethylsilyl) benzylamine point disappears when TLC monitors the reaction system; adding alkali (saturated sodium bicarbonate solution) to quench the reaction, adjusting the pH to 7, extracting, drying, distilling under reduced pressure to remove the solvent, and purifying by column chromatography to obtain yellow oily matter VI.
The molar ratio of the N- (methoxymethyl) -N- (trimethylsilyl) benzylamine, the 2-fluoro methyl acrylate and the trifluoroacetic acid (TFA) is 1.0:1.0-1.5:0.1-1.0, and the reaction temperature is 20-25 ℃.
(2)
Dissolving a compound VI in tetrahydrofuran solution, cooling to 0-5 ℃ in an ice bath, adding N, O-dimethylhydroxylamine hydrochloride, and protecting by argon; slowly adding tetrahydrofuran solution (3M) of methyl magnesium chloride until the VI point of the compound disappears when TLC monitors the reaction system; adding saturated NH 4 Quenching the Cl solution, adding dichloromethane for extraction, drying, distilling under reduced pressure to remove the solvent, and purifying by column chromatography to obtain yellow oily matter V.
The molar ratio of the compound VI, the N, O-dimethylhydroxylamine hydrochloride and the Grignard reagent methyl magnesium chloride is 1.0:1.5-2.4:3.0-5.7, and the reaction temperature is 0-5 ℃.
(3)
Dissolving the compound V in tetrahydrofuran solution, cooling to 0-5 ℃ in ice bath, and slowly adding tetrahydrofuran solution (3M) of methyl magnesium chloride until the V point disappears when TLC monitors the reaction system; adding saturated NH 4 Quenching the Cl solution, adding dichloromethane for extraction, drying, distilling under reduced pressure to remove the solvent, and purifying by column chromatography to obtain yellow oily matter IV.
The molar ratio between the compound V and the Grignard reagent methyl magnesium chloride is 1.0:1.0-5.0, and the reaction temperature is 0-5 ℃.
(4)
Dissolving a compound IV in tetrahydrofuran solution, cooling to 0-5 ℃ in ice bath, and slowly adding the tetrahydrofuran solution (2.5M) of the compound hydride until IV point disappears when TLC monitors the reaction system; adding water for quenching, adding dichloromethane for extraction, drying, and distilling under reduced pressure to remove the solvent to obtain yellow oily matter IV, and directly adding the yellow oily matter IV into the next reaction without purification.
The molar ratio between the compound IV and the compound hydride is 1.0:0.4-1.0.
The compound hydride reducing agent is selected from NaBH 4 、KBH 4 And LiAlH 4 Preferably LiAlH 4 。
(5)
Dissolving a compound III in a methanol solution, adding 10% Pd/C, replacing air with argon for 3 times, replacing argon with hydrogen for 3 times, reacting at room temperature, and monitoring III point disappearance by TLC; suction filtration to obtain pale yellow filtrate, vacuum distillation to remove solvent, obtaining yellow oily matter II, and directly putting into the next reaction without purification.
The mass ratio of the compound III to the 10% Pd/C is 1.0:0.2-0.5, and the reaction time is 2-6 hours.
(6)
Compound II was dissolved in dichloromethane, DMAP was added, and (Boc) was added 2 O, reacting at room temperature, wherein the point of the compound II disappears when the TLC monitors the reaction system; adding water for quenching, adding dichloromethane for extraction, drying, distilling under reduced pressure to remove the solvent, and purifying by column chromatography to obtain yellow oily substance I.
The compound II, the (B)oc) 2 The mol ratio between O and DMAP is 1.0:1.0-1.5:0.06-0.1, the reaction temperature is 20-25 ℃, and the reaction time is 1-6 hours.
Compared with the prior art, the invention has at least the following technical effects:
(1) The invention has reasonable process design and simple reaction steps; constructing pyrrole rings by adopting a 1, 3-dipole cycloaddition reaction;
(2) Under the condition that a Grignard reagent methyl magnesium chloride is used as a base, the compound Weinreb amide V is directly synthesized by ester, the reaction is carried out without strict low temperature and strict anhydrous, the yield is 75% and the operation is simple;
(3) The compound Weinreb amide V reacts with the methyl magnesium chloride of the same Grignard reagent to generate the compound methyl ketone IV, so that excessive addition side reaction which is easy to occur when the ester reacts with the Grignard reagent to synthesize ketone is avoided, the reaction is carried out without strict low temperature, ice bath is carried out, the yield is high, and the operation is simple;
(4) The compound hydride is selected as the reducing agent, thereby avoiding the generation of impurities.
(5) The invention has higher reaction yield and lower raw material cost in each step; the operation is simple, no harsh reaction conditions exist, and the amplification reaction is easy.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to examples, but it will be understood by those skilled in the art that the following examples are only for illustrating the present invention and should not be construed as limiting the scope of the present invention. Any equivalent substitution in the art according to the present disclosure is intended to be within the scope of the present invention.
The examples were conducted under conventional conditions, except that the specific conditions were not specified. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
The structure of the compound is confirmed by thin layer chromatography, column chromatography, mass spectrum and nuclear magnetic resonance tests.
Example 1: preparation method of 3-fluoro-3- (1-hydroxyethyl) pyrrolidine-1-carboxylic acid tert-butyl ester (I)
(1) Preparation of Compound VI
25.00g (94.77 mmol) of N- (methoxymethyl) -N- (trimethylsilyl) benzylamine (90% strength) was added to a 500mL four port round bottom flask, 125.0mL of dichloromethane was added, magnetic stirring, ice bath, 9.87g of methyl 2-fluoroacrylate (94.83 mmol) was added; 1.52g (13.33 mmol) of trifluoroacetic acid is added dropwise to a constant pressure dropping funnel at 0-5 ℃ for about 15 minutes; reacting for 1 hour at 0-5 ℃, then heating to 20-25 ℃ in water bath, and reacting for 2 hours. TLC monitored the progress of the reaction: developing solvent ethyl acetate, n-hexane=1:5, and the iodine chromogenic material was reacted completely. 60.0mL of saturated NaHCO was added 3 Quenching the solution for 10 minutes, and separating a water phase and an organic phase; the aqueous phase was extracted 2 times with 50.0ml of dichloromethane and the organic phases were combined; 25.5g of anhydrous sodium sulfate is dried for 1h and stirred magnetically. Suction filtration to obtain yellow filtrate, and vacuum distillation at 40 ℃ to remove the solvent to obtain yellow oily matter. Purifying by column chromatography, wherein 183.2g of silica gel (200-300 meshes) is eluted by gradient of eluent ethyl acetate and normal hexane, and the ratio is 1:20,1:15,1:10 and 1:5 in sequence; the eluates were combined and the solvent was distilled off under reduced pressure at 50℃to give 22.10g of yellow oil VI in 98.3% yield.
Spectral data:
1 H NMR(400MHz,CDCl 3 ,ppm):δ＝2.13-2.27(m,1H,CH 2 ),2.34-2.47(m,1H,CH 2 ),2.59-2.65(m,1H,CH 2 ),2.87-3.03(m,3H,CH 2 ),3.64(s,2H,CH 2 ),3.75(s,3H,CH 3 ),7.20-7.29(m,5H,ArH)； 13 C NMR(100MHz,CDCl 3 ,ppm):δ＝37.1(d, 2 J CF ＝23.6Hz),52.8,53.0,59.7,63.4(d, 2 J CF ＝24.7Hz),99.8(d, 1 J CF ＝193.7Hz),127.2,128.4(2C),128.7(2C),138.3,171.5(d, 2 J CF ＝28.3Hz)；
HRMS(EI):m/z[M] + calcd.for C 13 H 16 NO 2 F:237.1165；found:237.1168.
(2) Preparation of Compound V
19.30g (0.08 mol) of compound VI is added into a 1L three-neck round bottom flask, 200.0mL of tetrahydrofuran solution is added, magnetic stirring and ice bath cooling are carried out, 16.58g (0.17 mol) of N, O-dimethylhydroxylamine hydrochloride is added, and argon protection is carried out; thermometer indicated 140.0mL (0.42 mol) of tetrahydrofuran solution (3M) of methyl magnesium chloride was slowly added at 0-5℃and reacted at 0-5℃for 0.5 hours. TLC monitored the progress of the reaction: developing solvent ethyl acetate, n-hexane=1:5, and the iodine chromogenic material was reacted completely. 120.0mL of saturated NH was added 4 The Cl solution is quenched for 10 minutes, 200.0mL of dichloromethane is added and stirred for 5 minutes, and the aqueous phase and the organic phase are separated; the aqueous phase was extracted 3 times with 150.0mL of dichloromethane and the organic phases were combined; 80.0g of anhydrous sodium sulfate is dried for 1 hour and magnetically stirred. Suction filtration to obtain yellow filtrate, and vacuum distillation at 40 ℃ to remove the solvent to obtain yellow oily matter. Purifying by column chromatography: 214.5g of silica gel (200-300 meshes), eluting with ethyl acetate as an eluent and n-hexane in a gradient manner, wherein the ratio of the ethyl acetate to the n-hexane is 1:25,1:20,1:15 and 1:5 in sequence; the eluates were combined and the solvent was distilled off under reduced pressure at 50℃to give 14.80g of yellow oil V in 69.5% yield.
Spectral data:
1 H NMR(400MHz,CDCl 3 ,ppm):δ＝2.08-2.23(m,1H,CH 2 ),2.42-2.47(m,1H,CH 2 ),2.53-2.66(m,1H,CH 2 ),2.81-3.08(m,3H,CH 2 ),3.14(s,3H,CH 3 ),3.60(s,2H,CH 2 ),3.63(s,3H,CH 3 ),7.18-7.28(m,5H,ArH)； 13 C NMR(100MHz,CDCl 3 ,ppm):δ＝33.3,35.7(d, 2 J CF ＝23.6Hz),52.6,59.9,61.6,62.6(d, 2 J CF ＝24.6Hz),102.1(d, 1 J CF ＝191.9Hz),127.1,128.3(2C),128.7(2C),138.5,169.8；
HRMS(EI):m/z[M] + calcd.for C 14 H 19 N 2 O 2 F:266.1431；found:266.1433.
(3) Preparation of Compound IV
11.50g (43.18 mmol) of compound V is added into a 500mL four-necked round bottom flask, 120.0mL of tetrahydrofuran solution is added, argon protection is carried out, and ice bath cooling is carried out; 30.0mL (90.00 mmol) of tetrahydrofuran solution (3M) of methyl magnesium chloride is slowly added dropwise at the temperature of 0-5 ℃ by a thermometer; the reaction was incubated for 15 min, and TLC monitored the progress of the reaction: developing solvent ethyl acetate, n-hexane=1:3. 60.0mL of saturated NH was added 4 Quenching the Cl solution for 10 minutes, adding 120.0mL of dichloromethane, stirring and extracting for 5 minutes, and separating an aqueous phase and an organic phase; the aqueous phase was extracted 3 times with 80.0mL dichloromethane and the organic phases were combined; 36.1g of anhydrous sodium sulfate is dried for 1 hour and stirred magnetically. Suction filtration to obtain yellow filtrate, and vacuum distillation at 40 ℃ to remove the solvent to obtain yellow oily matter. Purifying by column chromatography: 186.3g of silica gel (200-300 meshes), eluting with ethyl acetate as an eluent and n-hexane in a gradient manner, wherein the ratio of the ethyl acetate to the n-hexane is 1:25,1:20,1:15 and 1:5 in sequence; the eluates were combined and the solvent was distilled off under reduced pressure at 50℃to give 7.91g of yellow oil IV in 82.8% yield.
Spectral data:
1 H NMR(400MHz,CDCl 3 ,ppm):δ＝2.02-2.16(m,1H,CH 2 ),2.24(d,3H,J＝4.7Hz,CH 3 ),2.27-2.35(m,1H,CH 2 ),2.53-2.59(m,1H,CH 2 ),2.72-2.94(m,3H,CH 2 ),3.62(q,2H,J＝12.9Hz,CH 2 ),7.18-7.29(m,5H,ArH)； 13 C NMR(100MHz,CDCl 3 ,ppm):δ＝26.1,36.4(d, 2 J CF ＝23.4Hz),53.3,59.7,62.7(d, 2 J CF ＝24.8Hz),105.9(d, 1 J CF ＝191.2Hz),127.2,128.4(2C),128.7(2C),138.4,208.2(d, 2 J CF ＝32.5Hz)；
HRMS(EI):m/z[M] + calcd.for C 13 H 16 NOF:221.1216；found:221.1214.
(4) Preparation of Compound III
6.42g (29.01 mmol) of Compound IV was added to a 500mL four-necked round bottom flask, 60.0mL of tetrahydrofuran was added, and magnetically stirred, ice-bath; slowly dripping LiAlH into the mixture at the temperature of 0-5 ℃ according to the indication of a thermometer 4 5.0mL (12.50 mmol) of tetrahydrofuran solution (2.5M); incubation for 15 min, TLC monitored the progress of the reaction: developing solvent ethyl acetate, n-hexane=1:2. Adding 180.0mL of water slowly for quenching, and magnetically stirring for 10 minutes; 180.0mL of dichloromethane is added for extraction for 2 times, 90.0mL of dichloromethane is added for extraction for 2 times, and the organic phases are combined; 54.0g of anhydrous sodium sulfate is dried for 1 hour and stirred magnetically. Suction filtration gave a yellow filtrate, which was distilled off under reduced pressure at 40℃to give 6.50g of yellow oily substance III. The product was pure and almost no impurity points were seen as monitored by TLC, so that it was directly taken to the next step without purification.
Spectral data:
MS(ESI):m/z[M+H] + calcd.for C 13 H 19 FNO:224.15；found:224.13.
(5) Preparation of Compound II
To a 250mL single neck round bottom flask containing 6.50g of Compound III was added 30.0mL of methanol and the solution was magnetically stirred; 3.25g (0.5 m) of 10% Pd/C was added; argon replaces air 3 times, and hydrogen replaces argon 3 times; water bath at 20-25 deg.c for 2 hr, TLC monitoring the reaction progress: developing solvent ethyl acetate, n-hexane=1:1. Suction filtration gave a pale yellow filtrate, and the solvent was distilled off under reduced pressure at 50℃to give 3.85g of a yellow oily substance II. Directly put into the next reaction without purification.
Spectral data:
MS(ESI):m/z[M+H] + calcd.for C 6 H 13 FNO:134.17；found:134.16.
(6) Preparation of Compound I
3.85g (28.91 mmol) of compound II is added into a 100mL three-neck round bottom flask, 40.0mL of dichloromethane is added, magnetic stirring is carried out, and water bath is carried out at 20-25 ℃; 0.21g (1.72 mmol) of DMAP was added; 6.95g (31.84 mmol) of (Boc) are slowly added dropwise 2 O, about 5 minutes; reacting for 2h at 20-25 ℃, and monitoring the reaction progress by TLC: developing solvent ethyl acetate n-hexane=1:1 monitoring formation of i; developing solvent dichloromethane methanol=4:1 the residue of substrate ii was monitored. Quench for 10 minutes with 20.0mL of water; separating the liquid to obtain an aqueous phase and an organic phase; the aqueous phase was extracted 1 more times with 20.0mL of dichloromethane and the organic phases were combined; 8.06g of anhydrous sodium sulfate is dried for 1 hour and stirred magnetically. Suction filtration to obtain yellow filtrate, and vacuum distillation at 40 ℃ to remove the solvent to obtain yellow oily matter. Purifying by column chromatography: 195.6g of silica gel (200-300 meshes), and eluting with ethyl acetate as an eluent and n-hexane in a gradient manner, wherein the ratio of the ethyl acetate to the n-hexane is 1:20,1:15,1:10,1:8,1:5 and 1:3 in sequence; the eluates were combined and the solvent was distilled off under reduced pressure at 50℃to give 5.16g of yellow oily substance I. Three steps of reaction: carbonyl reduction reaction, debenzylation protecting group and amino protection, and the total yield is 76.2%.
Spectral data:
1 H NMR(400MHz,CDCl 3 ,ppm):δ＝1.27(d,3H,J 3 ＝6.2Hz,CH 3 ),1.45(s,9H,Boc),1.97-2.06(m,2H,CH 2 ),2.19(s,1H,OH),3.37-3.69(m,4H,CH 2 ),3.86-3.90(m,1H,CH)； 13 C NMR(100MHz,CDCl 3 ,ppm):δ＝18.0,28.5(3C),32.2(d, 2 J CF ＝23.4Hz),44.3,52.8(d, 2 J CF ＝24.5Hz),69.3(d, 2 J CF ＝24.9Hz),79.7,105.5(d, 1 J CF ＝178.8Hz),154.5；
HRMS(EI):m/z[M] + calcd.for C 11 H 20 NO 3 F:233.1427；found:233.1431.
example 2: preparation of Compound VI
In order to examine the influence of each parameter in step (1) on the reaction result, compound VI was prepared by the following three methods, the reaction route is as follows:
the method comprises the following steps: in comparison with step (1) of example 1, the difference is the ratio of the raw materials of step (1)
25.00g (94.77 mmol) of N- (methoxymethyl) -N- (trimethylsilyl) benzylamine (90% strength) were added to a 500mL four port round bottom flask, 125.0mL of dichloromethane were added, magnetic stirring, ice bath, and 14.79g of methyl 2-fluoroacrylate (0.14 mol) were added; 10.81g (94.81 mmol) of trifluoroacetic acid is added dropwise to a constant pressure dropping funnel at 0-5 ℃ for about 30 minutes; reacting for 1 hour at 0-5 ℃, then heating to 20-25 ℃ in water bath, and reacting for 2 hours. TLC monitored the progress of the reaction: developing solvent ethyl acetate, n-hexane=1:5, and the iodine chromogenic material was reacted completely. 60.0mL of saturated NaHCO was added 3 Quenching the solution for 10 minutes, and separating a water phase and an organic phase; the aqueous phase was extracted 2 times with 50.0ml of dichloromethane and the organic phases were combined; 25.5g of anhydrous sodium sulfate is dried for 1h and stirred magnetically. Suction filtration to obtain yellow filtrate, and vacuum distillation at 40 ℃ to remove the solvent to obtain yellow oily matter. Purifying by column chromatography, wherein 183.0g of silica gel (200-300 meshes) is eluted by gradient of eluent ethyl acetate and normal hexane, and the ratio is 1:20,1:15,1:10 and 1:5 in sequence; the eluates were combined and the solvent was distilled off under reduced pressure at 50℃to give 20.23g of yellow oil VI in 90.0% yield.
The second method is as follows: in comparison with step (1) of example 1, the difference is that the catalyst of step (1) is titanium tetrachloride
25.00g (94.77 mmol) of N- (methoxymethyl) -N- (trimethylsilyl) benzylamine (90% strength) was added to a 500mL four port round bottom flask, 125.0mL of dichloromethane was added, magnetic stirring, ice bath, 9.87g of methyl 2-fluoroacrylate (94.83 mmol) was added; 2.53g (13.33 mmol) of titanium tetrachloride is added dropwise to a constant pressure dropping funnel at the temperature of 0-5 ℃ for about 15 minutes; reacting for 1 hour at 0-5 ℃, then heating to 20-25 ℃ in water bath, and reacting for 2 hours. TLC monitored the progress of the reaction: developing solvent ethyl acetate, n-hexane=1:5, and the iodine chromogenic material was reacted completely. 60.0mL of saturated NaHCO was added 3 Quenching the solution for 10 minutes, and separating a water phase and an organic phase; the aqueous phase was extracted 2 times with 50.0ml of dichloromethane,combining the organic phases; 25.5g of anhydrous sodium sulfate is dried for 1h and stirred magnetically. Suction filtration to obtain yellow filtrate, and vacuum distillation at 40 ℃ to remove the solvent to obtain yellow oily matter. Purifying by column chromatography, wherein 183.0g of silica gel (200-300 meshes) is eluted by gradient of eluent ethyl acetate and normal hexane, and the ratio is 1:20,1:15,1:10 and 1:5 in sequence; the eluates were combined and the solvent was distilled off under reduced pressure at 50℃to give 18.26g of yellow oil VI in a yield of 81.2%.
And a third method: in comparison with step (1) of example 1, the difference is that the catalyst of step (1) is zinc chloride
25.00g (94.77 mmol) of N- (methoxymethyl) -N- (trimethylsilyl) benzylamine (90% strength) was added to a 500mL four port round bottom flask, 125.0mL of dichloromethane was added, magnetic stirring, ice bath, 9.87g of methyl 2-fluoroacrylate (94.83 mmol) was added; 1.82g (13.35 mmol) of zinc chloride is added into a constant pressure dropping funnel with the temperature of 0-5 ℃ in a dropwise manner; reacting for 1 hour at 0-5 ℃, then heating to 20-25 ℃ in water bath, and reacting for 2 hours. TLC monitored the progress of the reaction: developing solvent ethyl acetate, n-hexane=1:5, and the iodine chromogenic material was reacted completely. 60.0mL of saturated NaHCO was added 3 Quenching the solution for 10 minutes, and separating a water phase and an organic phase; the aqueous phase was extracted 2 times with 50.0ml of dichloromethane and the organic phases were combined; 25.5g of anhydrous sodium sulfate is dried for 1h and stirred magnetically. Suction filtration to obtain yellow filtrate, and vacuum distillation at 40 ℃ to remove the solvent to obtain yellow oily matter. Purifying by column chromatography, wherein 183.0g of silica gel (200-300 meshes) is eluted by gradient of eluent ethyl acetate and normal hexane, and the ratio is 1:20,1:15,1:10 and 1:5 in sequence; the eluates were combined and the solvent was distilled off under reduced pressure at 50℃to give 15.48g of yellow oil VI in 68.8% yield.
Example 3: preparation of Compound V
In order to examine the influence of each parameter in the step (2) on the reaction result, the following five methods were adopted to prepare the compound V, and the reaction route is as follows:
the method comprises the following steps: in comparison with step (2) of example 1, the difference is the ratio of the raw materials of step (2)
19.30g (0.08 mol) of compound VI is added into a 1L three-neck round bottom flask, 200.0mL of tetrahydrofuran solution is added, magnetic stirring and ice bath cooling are carried out, 10.73g (0.11 mol) of N, O-dimethylhydroxylamine hydrochloride is added, and argon protection is carried out; 70.0mL (0.21 mol) of tetrahydrofuran solution (3M) of methyl magnesium chloride is slowly added into the mixture at the temperature of 0 to 5 ℃ by a thermometer, and the mixture is reacted for 0.5 hours at the temperature of 0 to 5 ℃. TLC monitored the progress of the reaction: developing solvent ethyl acetate, n-hexane=1:5, and the iodine chromogenic material was reacted completely. 120.0mL of saturated NH was added 4 The Cl solution is quenched for 10 minutes, 200.0mL of dichloromethane is added and stirred for 5 minutes, and the aqueous phase and the organic phase are separated; the aqueous phase was extracted 3 times with 150.0mL of dichloromethane and the organic phases were combined; 80.0g of anhydrous sodium sulfate is dried for 1 hour and magnetically stirred. Suction filtration to obtain yellow filtrate, and vacuum distillation at 40 ℃ to remove the solvent to obtain yellow oily matter. Purifying by column chromatography: 214.0g of silica gel (200-300 meshes), eluting with ethyl acetate as an eluent and n-hexane in a gradient manner, wherein the ratio of the ethyl acetate to the n-hexane is 1:25,1:20,1:15 and 1:5 in sequence; the eluates were combined and the solvent was distilled off under reduced pressure at 50℃to give 10.60g of yellow oil V in 49.8% yield.
The second method is as follows: in comparison with step (2) of example 1, the difference is that the solvent of step (2) is dioxane
19.30g (0.08 mol) of compound VI is added into a 1L three-neck round bottom flask, 200.0mL of 1, 4-dioxane solution is added, magnetic stirring and ice bath cooling are carried out, 16.58g (0.17 mol) of N, O-dimethylhydroxylamine hydrochloride is added, and argon protection is carried out; thermometer indicated 140.0mL (0.42 mol) of tetrahydrofuran solution (3M) of methyl magnesium chloride was slowly added at 0-5℃and reacted at 0-5℃for 0.5 hours. TLC monitored the progress of the reaction: developing solvent ethyl acetate, n-hexane=1:5, and the iodine chromogenic material was reacted completely. 120.0mL of saturated NH was added 4 The Cl solution is quenched for 10 minutes, 200.0mL of dichloromethane is added and stirred for 5 minutes, and the aqueous phase and the organic phase are separated; the aqueous phase was extracted 3 times with 150.0mL of dichloromethane and the organic phases were combined; 80.0g of anhydrous sodium sulfate is dried for 1 hour and magnetically stirred. Suction filtration to obtain yellow filtrate, and vacuum distillation at 40 ℃ to remove the solvent to obtain yellow oily matter. Purifying by column chromatography: 214.0g of silica gel (200-300 meshes), eluting with ethyl acetate as an eluent and n-hexane in a gradient manner, wherein the ratio of the ethyl acetate to the n-hexane is 1:25,1:20,1:15 and 1:5 in sequence; combining the eluates, reducing at 50deg.CThe solvent was distilled off under pressure to give 11.30g of a yellow oil V in 53.0% yield.
And a third method: in comparison with step (2) of example 1, the difference is that the Grignard reagent of step (2) is ethyl magnesium chloride
19.30g (0.08 mol) of compound VI is added into a 1L three-neck round bottom flask, 200.0mL of tetrahydrofuran solution is added, magnetic stirring and ice bath cooling are carried out, 16.58g (0.17 mol) of N, O-dimethylhydroxylamine hydrochloride is added, and argon protection is carried out; 200.0mL (0.40 mol) of a tetrahydrofuran solution (2M) of ethyl magnesium chloride was slowly added thereto at 0 to 5℃and the reaction was carried out at 0 to 5℃for 0.5 hours. TLC monitored the progress of the reaction: developing solvent ethyl acetate, n-hexane=1:5, and the iodine chromogenic material was reacted completely. 120.0mL of saturated NH was added 4 The Cl solution is quenched for 10 minutes, 200.0mL of dichloromethane is added and stirred for 5 minutes, and the aqueous phase and the organic phase are separated; the aqueous phase was extracted 3 times with 150.0mL of dichloromethane and the organic phases were combined; 80.0g of anhydrous sodium sulfate is dried for 1 hour and magnetically stirred. Suction filtration to obtain yellow filtrate, and vacuum distillation at 40 ℃ to remove the solvent to obtain yellow oily matter. Purifying by column chromatography: 214.5g of silica gel (200-300 meshes), eluting with ethyl acetate as an eluent and n-hexane in a gradient manner, wherein the ratio of the ethyl acetate to the n-hexane is 1:25,1:20,1:15 and 1:5 in sequence; the eluates were combined and the solvent was distilled off under reduced pressure at 50℃to give 12.88g of yellow oil V in 60.5% yield.
The method four: in comparison with step (2) of example 1, the difference is that the Grignard reagent of step (2) is isopropyl magnesium chloride
19.30g (0.08 mol) of compound VI is added into a 1L three-neck round bottom flask, 200.0mL of tetrahydrofuran solution is added, magnetic stirring and ice bath cooling are carried out, 16.58g (0.17 mol) of N, O-dimethylhydroxylamine hydrochloride is added, and argon protection is carried out; 200.0mL (0.40 mol) of tetrahydrofuran solution (2M) of isopropyl magnesium chloride is slowly added into the mixture at the temperature of 0-5 ℃ by a thermometer, and the mixture is reacted for 0.5 hours at the temperature of 0-5 ℃. TLC monitored the progress of the reaction: developing solvent ethyl acetate, n-hexane=1:5, and the iodine chromogenic material was reacted completely. 120.0mL of saturated NH was added 4 The Cl solution is quenched for 10 minutes, 200.0mL of dichloromethane is added and stirred for 5 minutes, and the aqueous phase and the organic phase are separated; the aqueous phase was extracted 3 times with 150.0mL of dichloromethane and the organic phases were combined; 80.0g of anhydrous sodium sulfate is dried for 1 hour and magnetically stirred. Filtering to obtain yellowThe solvent was removed from the color filtrate by distillation under reduced pressure at 40℃to give a yellow oil. Purifying by column chromatography: 214.5g of silica gel (200-300 meshes), eluting with ethyl acetate as an eluent and n-hexane in a gradient manner, wherein the ratio of the ethyl acetate to the n-hexane is 1:25,1:20,1:15 and 1:5 in sequence; the eluates were combined and the solvent was distilled off under reduced pressure at 50℃to give 13.32g of yellow oil V in 62.5% yield.
And a fifth method: in comparison with step (2) of example 1, the difference is the ratio of the raw materials of step (2)
19.30g (0.08 mol) of compound VI is added into a 1L three-neck round bottom flask, 200.0mL of tetrahydrofuran solution is added, magnetic stirring and ice bath cooling are carried out, 8.2g (0.08 mol) of N, O-dimethylhydroxylamine hydrochloride is added, and argon protection is carried out; thermometer indicated 0-5 degrees C, slowly adding methyl magnesium chloride tetrahydrofuran solution (3M) 28.0mL (0.08 mol), 0-5 degrees C reaction for 0.5 hours. TLC monitored the progress of the reaction: developing solvent ethyl acetate, n-hexane=1:5, and the iodine chromogenic material was reacted completely. 120.0mL of saturated NH was added 4 The Cl solution is quenched for 10 minutes, 200.0mL of dichloromethane is added and stirred for 5 minutes, and the aqueous phase and the organic phase are separated; the aqueous phase was extracted 3 times with 150.0mL of dichloromethane and the organic phases were combined; 80.0g of anhydrous sodium sulfate is dried for 1 hour and magnetically stirred. Suction filtration to obtain yellow filtrate, and vacuum distillation at 40 ℃ to remove the solvent to obtain yellow oily matter. Purifying by column chromatography: 214.0g of silica gel (200-300 meshes), eluting with ethyl acetate as an eluent and n-hexane in a gradient manner, wherein the ratio of the ethyl acetate to the n-hexane is 1:25,1:20,1:15 and 1:5 in sequence; the eluates were combined and the solvent was distilled off under reduced pressure at 50℃to give 6.20g of yellow oil V in 29.1% yield.
Example 4: preparation of Compound V
In order to examine the influence of each parameter in the step (3) on the reaction result, the compound IV is prepared by adopting the following two methods, and the reaction route is as follows:
the method comprises the following steps: in comparison with step (3) of example 1, the difference is the ratio of the raw materials of step (3)
11.50g (43.18 mmol) of Compound V are added to 500mL of a four-port circle120.0mL of tetrahydrofuran solution is added into the bottom flask, argon is used for protection, and ice bath is used for cooling; 14.5mL (43.50 mmol) of tetrahydrofuran solution (3M) of methyl magnesium chloride is slowly added dropwise at the temperature of 0-5 ℃ by a thermometer; the reaction was incubated for 15 min, and TLC monitored the progress of the reaction: developing solvent ethyl acetate, n-hexane=1:3. 60.0mL of saturated NH was added 4 Quenching the Cl solution for 10 minutes, adding 120.0mL of dichloromethane, stirring and extracting for 5 minutes, and separating an aqueous phase and an organic phase; the aqueous phase was extracted 3 times with 80.0mL dichloromethane and the organic phases were combined; 36.1g of anhydrous sodium sulfate is dried for 1 hour and stirred magnetically. Suction filtration to obtain yellow filtrate, and vacuum distillation at 40 ℃ to remove the solvent to obtain yellow oily matter. Purifying by column chromatography: 186.0g of silica gel (200-300 meshes), eluting with ethyl acetate as an eluent and n-hexane in a gradient manner, wherein the ratio of the ethyl acetate to the n-hexane is 1:25,1:20,1:15 and 1:5 in sequence; the eluates were combined and the solvent was distilled off under reduced pressure at 50℃to give 6.56g of yellow oil IV in a yield of 68.7%.
The second method is as follows: in comparison with step (3) of example 1, the difference is the ratio of the raw materials of step (3)
11.50g (43.18 mmol) of compound V is added into a 500mL four-necked round bottom flask, 120.0mL of tetrahydrofuran solution is added, argon protection is carried out, and ice bath cooling is carried out; 72.0mL (216.00 mmol) of tetrahydrofuran solution (3M) of methyl magnesium chloride is slowly added dropwise at the temperature of 0-5 ℃ by a thermometer; the reaction was incubated for 15 min, and TLC monitored the progress of the reaction: developing solvent ethyl acetate, n-hexane=1:3. 60.0mL of saturated NH was added 4 Quenching the Cl solution for 10 minutes, adding 120.0mL of dichloromethane, stirring and extracting for 5 minutes, and separating an aqueous phase and an organic phase; the aqueous phase was extracted 3 times with 80.0mL dichloromethane and the organic phases were combined; 36.1g of anhydrous sodium sulfate is dried for 1 hour and stirred magnetically. Suction filtration to obtain yellow filtrate, and vacuum distillation at 40 ℃ to remove the solvent to obtain yellow oily matter. Purifying by column chromatography: 186.0g of silica gel (200-300 meshes), eluting with ethyl acetate as an eluent and n-hexane in a gradient manner, wherein the ratio of the ethyl acetate to the n-hexane is 1:25,1:20,1:15 and 1:5 in sequence; the eluates were combined and the solvent was distilled off under reduced pressure at 50℃to give 5.17g of yellow oil IV in 54.1% yield.
Example 5: preparation of Compound III
In order to examine the influence of each parameter in the step (4) on the reaction result, the following three methods are adopted to prepare the compound IV, and the reaction route is as follows:
the method comprises the following steps: in comparison with step (4) of example 1, the difference is the ratio of the raw materials of step (4)
6.42g (29.01 mmol) of Compound IV was added to a 500mL four-necked round bottom flask, 60.0mL of tetrahydrofuran was added, and magnetically stirred, ice-bath; slowly dripping LiAlH into the mixture at the temperature of 0-5 ℃ according to the indication of a thermometer 4 11.5mL (28.75 mmol) of tetrahydrofuran solution (2.5M); incubation for 15 min, TLC monitored the progress of the reaction: developing solvent ethyl acetate, n-hexane=1:2. Adding 180.0mL of water slowly for quenching, and magnetically stirring for 10 minutes; 180.0mL of dichloromethane is added for extraction for 2 times, 90.0mL of dichloromethane is added for extraction for 2 times, and the organic phases are combined; 54.0g of anhydrous sodium sulfate is dried for 1 hour and stirred magnetically. Suction filtration gave a yellow filtrate, which was distilled off under reduced pressure at 40℃to give 6.48g of yellow oily substance III. The product was pure and almost no impurity points were seen as monitored by TLC, so that it was directly taken to the next step without purification.
The second method is as follows: in comparison with step (4) of example 1, the difference is that the reducing agent of step (4) is NaBH 4
6.42g (29.01 mmol) of Compound IV was added to a 500mL four-necked round bottom flask, 60.0mL of tetrahydrofuran was added, and magnetically stirred, ice-bath; slowly dripping NaBH into the mixture at the temperature of 0-5 ℃ according to the indication of a thermometer 4 1.10g (30.71 mmol); incubation for 15 min, TLC monitored the progress of the reaction: developing solvent ethyl acetate, n-hexane=1:2. Adding 180.0mL of water slowly for quenching, and magnetically stirring for 10 minutes; 180.0mL of dichloromethane is added for extraction for 2 times, 90.0mL of dichloromethane is added for extraction for 2 times, and the organic phases are combined; 54.0g of anhydrous sodium sulfate is dried for 1 hour and stirred magnetically. Suction filtration to obtain yellow filtrate, and vacuum distillation at 40 ℃ to remove the solvent to obtain yellow oily matter. Purifying by column chromatography: 2.25g of yellow oil III are obtained in 34.7% yield.
And a third method: in comparison with step (4) of example 1, the difference is that the reducing agent of step (4) is KBH 4
Will be 6.42g (29.01 mmol) of Compound IV was added to a 500mL four-necked round bottom flask, 60.0mL tetrahydrofuran was added, and magnetically stirred, ice-bath; slowly dripping KBH into the temperature range of 0-5 ℃ according to the indication of a thermometer 4 1.57g (29.11 mmol); incubation for 15 min, TLC monitored the progress of the reaction: developing solvent ethyl acetate, n-hexane=1:2. Adding 180.0mL of water slowly for quenching, and magnetically stirring for 10 minutes; 180.0mL of dichloromethane is added for extraction for 2 times, 90.0mL of dichloromethane is added for extraction for 2 times, and the organic phases are combined; 54.0g of anhydrous sodium sulfate is dried for 1 hour and stirred magnetically. Suction filtration to obtain yellow filtrate, and vacuum distillation at 40 ℃ to remove the solvent to obtain yellow oily matter. Purifying by column chromatography: 5.62g of yellow oil III was obtained in 86.8% yield.
Example 6: preparation of Compound II
In order to examine the influence of each parameter in step (5) on the reaction result, compound II was prepared by the following method, and the reaction route is as follows:
the method comprises the following steps: in comparison with step (5) of example 1, the difference is the ratio of 10% Pd/C in step (5)
To a 250mL single neck round bottom flask containing 6.50g of Compound III was added 30.0mL of methanol and the solution was magnetically stirred; 10% Pd/C1.30 g (0.2 m) was added; argon replaces air 3 times, and hydrogen replaces argon 3 times; water bath at 20-25 deg.c for 6 hr, TLC monitoring the reaction progress: developing solvent ethyl acetate, n-hexane=1:1. Suction filtration gave a pale yellow filtrate, and the solvent was distilled off under reduced pressure at 50℃to give 3.83g of a yellow oily substance II. Directly put into the next reaction without purification.
The second method is as follows: in comparison with step (5) of example 1, the difference is the mass fraction of Pd/C in step (5)
To a 250mL single neck round bottom flask containing 6.50g of Compound III was added 30.0mL of methanol and the solution was magnetically stirred; 3.25g (0.5 m) of 5% Pd/C was added; argon replaces air 3 times, and hydrogen replaces argon 3 times; water bath at 20-25 deg.c for 12 hr, TLC monitoring the reaction progress: developing solvent ethyl acetate, n-hexane=1:1. Suction filtration gave a pale yellow filtrate, and the solvent was distilled off under reduced pressure at 50℃to give 3.72g of a yellow oily substance II. Directly put into the next reaction without purification.
Example 7: preparation of Compound I
In order to examine the influence of each parameter in step (6) on the reaction result, compound I was prepared by the following method, and the reaction route is as follows:
the method comprises the following steps: in comparison with step (6) of example 1, the difference is the ratio of the raw materials of step (6)
3.85g (28.91 mmol) of compound II is added into a 100mL three-neck round bottom flask, 40.0mL of dichloromethane is added, magnetic stirring is carried out, and water bath is carried out at 20-25 ℃; 0.21g (1.72 mmol) of DMAP was added; 6.31g (28.91 mmol) of (Boc) are slowly added dropwise 2 O, about 5 minutes; reacting for 3h at 20-25 ℃, and monitoring the reaction progress by TLC: developing solvent ethyl acetate n-hexane=1:1 monitoring formation of i; developing solvent dichloromethane methanol=4:1 the residue of substrate ii was monitored. Quench for 10 minutes with 20.0mL of water; separating the liquid to obtain an aqueous phase and an organic phase; the aqueous phase was extracted 1 more times with 20.0mL of dichloromethane and the organic phases were combined; 8.06g of anhydrous sodium sulfate is dried for 1 hour and stirred magnetically. Suction filtration to obtain yellow filtrate, and vacuum distillation at 40 ℃ to remove the solvent to obtain yellow oily matter. Purifying by column chromatography: 195.0g of silica gel (200-300 meshes), eluting with ethyl acetate as an eluent and n-hexane in a gradient manner, wherein the ratio of the ethyl acetate to the n-hexane is 1:20,1:15,1:10,1:8,1:5 and 1:3 in sequence; the eluates were combined and the solvent was distilled off under reduced pressure at 50℃to give 4.18g of yellow oil I. Three steps of reaction: carbonyl reduction reaction, debenzylation protecting group and amino protection, and the total yield is 62.0%.
The second method is as follows: in comparison with step (6) of example 1, the difference is the ratio of the raw materials of step (6)
3.85g (28.91 mmol) of compound II is added into a 100mL three-neck round bottom flask, 40.0mL of dichloromethane is added, magnetic stirring is carried out, and water bath is carried out at 20-25 ℃; 0.35g (2.86 mmol) of DMAP was added; 9.46g (43.34 mmol) of (Boc) are slowly added dropwise 2 O, about 5 minutes; reaction 1 at 20-25 DEG Ch, TLC monitored the progress of the reaction: developing solvent ethyl acetate n-hexane=1:1 monitoring formation of i; developing solvent dichloromethane methanol=4:1 the residue of substrate ii was monitored. Quench for 10 minutes with 20.0mL of water; separating the liquid to obtain an aqueous phase and an organic phase; the aqueous phase was extracted 1 more times with 20.0mL of dichloromethane and the organic phases were combined; 8.06g of anhydrous sodium sulfate is dried for 1 hour and stirred magnetically. Suction filtration to obtain yellow filtrate, and vacuum distillation at 40 ℃ to remove the solvent to obtain yellow oily matter. Purifying by column chromatography: 195.0g of silica gel (200-300 meshes), eluting with ethyl acetate as an eluent and n-hexane in a gradient manner, wherein the ratio of the ethyl acetate to the n-hexane is 1:20,1:15,1:10,1:8,1:5 and 1:3 in sequence; the eluates were combined and the solvent was distilled off under reduced pressure at 50℃to give 4.77g of yellow oil I. Three steps of reaction: carbonyl reduction reaction, debenzylation protecting group and amino protection, and the total yield is 70.7%.
And a third method: in comparison with step (6) of example 1, the difference is the solvent of step (6)
3.85g (28.91 mmol) of compound II is added into a 100mL three-neck round bottom flask, 40.0mL acetonitrile is added, magnetic stirring is carried out, and water bath is carried out at 20-25 ℃; 0.21g (2.86 mmol) of DMAP was added; 6.95g (31.84 mmol) of (Boc) are slowly added dropwise 2 O, about 5 minutes; reacting for 2h at 20-25 ℃, and monitoring the reaction progress by TLC: developing solvent ethyl acetate n-hexane=1:1 monitoring formation of i; developing solvent dichloromethane methanol=4:1 the residue of substrate ii was monitored. Quench for 10 minutes with 20.0mL of water; separating the liquid to obtain an aqueous phase and an organic phase; the aqueous phase was extracted 1 more times with 20.0mL of dichloromethane and the organic phases were combined; 8.06g of anhydrous sodium sulfate is dried for 1 hour and stirred magnetically. Suction filtration to obtain yellow filtrate, and vacuum distillation at 40 ℃ to remove the solvent to obtain yellow oily matter. Purifying by column chromatography: 195.0g of silica gel (200-300 meshes), eluting with ethyl acetate as an eluent and n-hexane in a gradient manner, wherein the ratio of the ethyl acetate to the n-hexane is 1:20,1:15,1:10,1:8,1:5 and 1:3 in sequence; the eluates were combined and the solvent was distilled off under reduced pressure at 50℃to give 4.93g of yellow oily substance I. Three steps of reaction: carbonyl reduction reaction, debenzylation protecting group and amino protection, and the total yield is 73.1%.
Claims (20)
1. A process for the preparation of 3-fluoro-3- (1-hydroxyethyl) pyrrolidine-1-carboxylic acid tert-butyl ester (i), which comprises the steps of:
(1) Taking N- (methoxymethyl) -N- (trimethylsilyl) benzylamine as a starting material, and carrying out 1, 3-dipolar cycloaddition reaction with 2-fluoro methyl acrylate in the presence of a catalyst to obtain a compound VI
(2) Dissolving the compound VI prepared in the step (1) in an organic solvent A, and condensing with N, O-dimethylhydroxylamine hydrochloride in the presence of a Grignard reagent A to obtain a compound V
(3) Reacting the compound V prepared in the step (2) with a Grignard reagent B to generate methyl ketone IV
(4) Reducing carbonyl by compound IV prepared in the step (3) through compound hydride to obtain compound III
(5) The compound III prepared in the step (4) is hydrogenated by Pd/C catalysis to obtain a compound II
(6) The compound II prepared in the step (5) is catalyzed by DMAP (Boc) 2 O protection to obtain the target compound I
In the step (2), the molar ratio of the compound VI, N, O-dimethylhydroxylamine hydrochloride to the Grignard reagent A is 1.0:1.5-2.4:3.0-5.7;
in step (4), the complex hydride is selected from KBH 4 And LiAlH 4 ；
In step (1), the catalyst is selected from trifluoroacetic acid, zinc chloride, titanium tetrachloride;
in step (2), the grignard reagent a is selected from methyl magnesium chloride, ethyl magnesium chloride, isopropyl magnesium chloride;
in step (3), the grignard reagent B is methyl magnesium chloride.
2. The process according to claim 1, wherein in step (1), the molar ratio of the N- (methoxymethyl) -N- (trimethylsilyl) benzylamine, the methyl 2-fluoroacrylate to the catalyst is 1.0:1.0 to 1.5:0.1 to 1.0.
3. The process of claim 1 wherein in step (1) the catalyst is trifluoroacetic acid.
4. The process according to claim 1, wherein in step (1), the reaction temperature is 20 to 25 ℃.
5. The process according to any one of claims 1 to 4, wherein in step (2), the organic solvent A is selected from tetrahydrofuran, 1, 4-dioxane.
6. The process according to claim 5, wherein in step (2), the organic solvent A is tetrahydrofuran.
7. The method of claim 1, wherein in step (2), the grignard reagent a is methyl magnesium chloride.
8. The process according to any one of claims 1 to 4, wherein in step (2), the reaction temperature is 0 to 5 ℃.
9. The process according to any one of claims 1 to 4, wherein in step (3), the molar ratio of the compound v to the grignard reagent B is 1.0:1.0 to 5.0.
10. The process according to claim 9, wherein in step (3), the molar ratio of compound v to grignard reagent B is 1:2.
11. the process according to any one of claims 1 to 4, wherein in step (3), the reaction temperature is 0 to 5 ℃.
12. The process according to any one of claims 1 to 4, wherein in step (4), the molar ratio of the compound IV to the complex hydride is 1.0:0.4 to 1.0.
13. The process according to any one of claims 1 to 4, wherein in step (4), the complex hydride is LiAlH 4 。
14. The process according to any one of claims 1 to 4, wherein in step (4), the reaction temperature is 0 to 5 ℃.
15. The process according to any one of claims 1 to 4, wherein in step (5), the Pd/C is 10% Pd/C.
16. The process according to any one of claims 1 to 4, wherein in step (5), the mass ratio of the compound III to 10% Pd/C is from 1.0:0.2 to 0.5.
17. The process according to claim 16, wherein in step (5), the mass ratio of compound iii to 10% pd/C is 1.0:0.5.
18. the process according to any one of claims 1 to 4, wherein in step (5), the reaction time is 2 to 6 hours.
19. The process according to claim 1 to 4, wherein in step (6), the compound II, (Boc) 2 The mol ratio of O to DMAP is 1.0:1.0-1.5:0.06-0.1.
20. The process according to any one of claims 1 to 4, wherein in step (6), the reaction temperature is 20 to 25℃and the reaction time is 1 to 6 hours.
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