CN114920771A - Novel synthesis process of intermediate of novel oral medicine for overactive bladder - Google Patents
Novel synthesis process of intermediate of novel oral medicine for overactive bladder Download PDFInfo
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- CN114920771A CN114920771A CN202210522855.5A CN202210522855A CN114920771A CN 114920771 A CN114920771 A CN 114920771A CN 202210522855 A CN202210522855 A CN 202210522855A CN 114920771 A CN114920771 A CN 114920771A
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- 238000000034 method Methods 0.000 title claims abstract description 18
- 206010020853 Hypertonic bladder Diseases 0.000 title claims abstract description 14
- 208000009722 Overactive Urinary Bladder Diseases 0.000 title claims abstract description 14
- 208000020629 overactive bladder Diseases 0.000 title claims abstract description 14
- 239000003814 drug Substances 0.000 title claims abstract description 12
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 12
- 230000008569 process Effects 0.000 title claims abstract description 11
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 10
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract description 12
- 239000007858 starting material Substances 0.000 claims abstract description 7
- YCWRFIYBUQBHJI-UHFFFAOYSA-N 2-(4-aminophenyl)acetonitrile Chemical group NC1=CC=C(CC#N)C=C1 YCWRFIYBUQBHJI-UHFFFAOYSA-N 0.000 claims abstract description 5
- NYCVCXMSZNOGDH-UHFFFAOYSA-N pyrrolidine-1-carboxylic acid Chemical compound OC(=O)N1CCCC1 NYCVCXMSZNOGDH-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229940079593 drug Drugs 0.000 claims abstract description 4
- 239000002243 precursor Substances 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 65
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 60
- 239000000543 intermediate Substances 0.000 claims description 53
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 38
- 239000012074 organic phase Substances 0.000 claims description 36
- 239000000243 solution Substances 0.000 claims description 28
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 26
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 21
- 229910052757 nitrogen Inorganic materials 0.000 claims description 19
- -1 methyl (R) -2- ((tert-butoxycarbonyl) amino) -6- (4-chlorophenyl) -5-oxohexanoate Chemical compound 0.000 claims description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 15
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 14
- 230000035484 reaction time Effects 0.000 claims description 13
- 238000003756 stirring Methods 0.000 claims description 13
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 239000003153 chemical reaction reagent Substances 0.000 claims description 11
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 claims description 10
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 9
- GVNSCNGKEXNKBU-UHFFFAOYSA-M magnesium;1-chloro-4-methanidylbenzene;chloride Chemical compound [Mg+2].[Cl-].[CH2-]C1=CC=C(Cl)C=C1 GVNSCNGKEXNKBU-UHFFFAOYSA-M 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 claims description 9
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 8
- 239000012454 non-polar solvent Substances 0.000 claims description 8
- ANRQGKOBLBYXFM-UHFFFAOYSA-M phenylmagnesium bromide Chemical compound Br[Mg]C1=CC=CC=C1 ANRQGKOBLBYXFM-UHFFFAOYSA-M 0.000 claims description 8
- 239000002798 polar solvent Substances 0.000 claims description 8
- 238000010791 quenching Methods 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 7
- FNTAOUUEQHKLIU-SSDOTTSWSA-N 1-o-tert-butyl 2-o-methyl (2r)-5-oxopyrrolidine-1,2-dicarboxylate Chemical compound COC(=O)[C@H]1CCC(=O)N1C(=O)OC(C)(C)C FNTAOUUEQHKLIU-SSDOTTSWSA-N 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 239000008346 aqueous phase Substances 0.000 claims description 6
- 230000000171 quenching effect Effects 0.000 claims description 6
- 239000000741 silica gel Substances 0.000 claims description 6
- 229910002027 silica gel Inorganic materials 0.000 claims description 6
- 238000010898 silica gel chromatography Methods 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 5
- 238000003818 flash chromatography Methods 0.000 claims description 5
- 239000002994 raw material Substances 0.000 claims description 5
- 239000012445 acidic reagent Substances 0.000 claims description 4
- SXZIXHOMFPUIRK-UHFFFAOYSA-N diphenylmethanimine Chemical compound C=1C=CC=CC=1C(=N)C1=CC=CC=C1 SXZIXHOMFPUIRK-UHFFFAOYSA-N 0.000 claims description 4
- 239000008213 purified water Substances 0.000 claims description 4
- 239000011541 reaction mixture Substances 0.000 claims description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 4
- 238000001704 evaporation Methods 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 239000010410 layer Substances 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 239000012044 organic layer Substances 0.000 claims description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims description 3
- 238000004440 column chromatography Methods 0.000 claims description 2
- 238000006073 displacement reaction Methods 0.000 claims description 2
- 239000000178 monomer Substances 0.000 claims description 2
- 239000002547 new drug Substances 0.000 claims description 2
- 239000012321 sodium triacetoxyborohydride Substances 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 239000011345 viscous material Substances 0.000 claims description 2
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 claims 5
- 238000004587 chromatography analysis Methods 0.000 claims 2
- 125000006239 protecting group Chemical group 0.000 claims 2
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 claims 1
- 239000012071 phase Substances 0.000 claims 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 229950007643 vibegron Drugs 0.000 abstract description 3
- DJXRIQMCROIRCZ-XOEOCAAJSA-N vibegron Chemical compound C1([C@H]([C@@H]2N[C@H](CC=3C=CC(NC(=O)[C@H]4N5C(=O)C=CN=C5CC4)=CC=3)CC2)O)=CC=CC=C1 DJXRIQMCROIRCZ-XOEOCAAJSA-N 0.000 abstract description 3
- 239000012467 final product Substances 0.000 abstract 1
- 239000000047 product Substances 0.000 abstract 1
- 238000010189 synthetic method Methods 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000009776 industrial production Methods 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 208000000921 Urge Urinary Incontinence Diseases 0.000 description 2
- 238000006345 epimerization reaction Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000027939 micturition Effects 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- UKIUSKWWNRYHOO-UHFFFAOYSA-N pent-1-yn-1-ol Chemical compound CCCC#CO UKIUSKWWNRYHOO-UHFFFAOYSA-N 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 2
- 206010046494 urge incontinence Diseases 0.000 description 2
- ZQXCQTAELHSNAT-UHFFFAOYSA-N 1-chloro-3-nitro-5-(trifluoromethyl)benzene Chemical compound [O-][N+](=O)C1=CC(Cl)=CC(C(F)(F)F)=C1 ZQXCQTAELHSNAT-UHFFFAOYSA-N 0.000 description 1
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 101001110310 Lentilactobacillus kefiri NADP-dependent (R)-specific alcohol dehydrogenase Proteins 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 238000003477 Sonogashira cross-coupling reaction Methods 0.000 description 1
- 238000007059 Strecker synthesis reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000001414 amino alcohols Chemical group 0.000 description 1
- 125000005219 aminonitrile group Chemical group 0.000 description 1
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 102000016959 beta-3 Adrenergic Receptors Human genes 0.000 description 1
- 108010014502 beta-3 Adrenergic Receptors Proteins 0.000 description 1
- KZIBQYUFIVUOHY-UHFFFAOYSA-N bis(2-methylpropyl)alumane toluene Chemical compound Cc1ccccc1.[H][Al](CC(C)C)CC(C)C KZIBQYUFIVUOHY-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- ANSXAPJVJOKRDJ-UHFFFAOYSA-N furo[3,4-f][2]benzofuran-1,3,5,7-tetrone Chemical compound C1=C2C(=O)OC(=O)C2=CC2=C1C(=O)OC2=O ANSXAPJVJOKRDJ-UHFFFAOYSA-N 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 206010029446 nocturia Diseases 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000002618 waking effect Effects 0.000 description 1
- 238000003809 water extraction Methods 0.000 description 1
- 229940126158 β3 adrenergic receptor agonist Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- 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)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of chemical synthesis of medicines, and particularly relates to a novel synthesis process of an intermediate of a novel oral medicine for overactive bladder. The invention takes 1- (tert-butyl) 2-methyl (R) -5-oxypyrrolidine-1, 2-dicarboxylic acid ester as a starting material to synthesize an intermediate: (2S,5R) -2- (4-aminobenzyl) -5- (R) - (tert-butyldimethylsilyloxy) (phenyl) methyl) pyrrolidine-1-carboxylic acid ester (intermediate V). The intermediate V protected by the patent application can obtain a final product after fractional TBS guarantee removal treatment and BOC guarantee removal: wibelegun (Vibegron), structural formula as follows:
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemical synthesis, in particular to a novel synthesis process of an intermediate of a new oral medicine for overactive bladder.
Background
Overactive bladder (OAB) is a clinical condition that occurs when the bladder muscle contracts involuntarily. Symptoms may include urgency (sudden urge to urinate which is difficult to control), urge incontinence (involuntary urination immediately after urge), frequency (typically 8 or more urination within 24 hours), and nocturia (waking up overnight to urinate more than 2 times). The disturbing symptoms of OAB can cause significant damage to the daily activities of the patient.
Wibeloglobin is a novel, potent, highly selective β 3-adrenergic receptor agonist, and activation of β 3 adrenergic receptors increases bladder capacity by relaxing the detrusor smooth muscle during bladder filling, with a long half-life (25-38 hours).
The drug was originally discovered by merck corporation, developed jointly by Kyorinpharmaceutical co, ltd, and Kissei pharmaceutial co; 9 months 2018, PMDA approved Wibeculon (Vibegron) for treating overactive bladder, 12 months 2020, U.S. Food and Drug Administration (FDA) approved by Urovant Sciences
(vibegron) for the treatment of overactive bladder (OAB) patients with urge incontinence (UUI), urgency, frequency.
Flick et al synthesized the precursor of Viberagliflorin with pentynol (number 383 in the following formula): namely, the amino alcohol structure-containing compound (number 386 in the following formula), the specific route is as follows: pentynol is synthesized into racemic aminonitrile (No. 384 in the following formula) by Strecker reaction, BOC protection, and after grignard addition, acidic treatment to produce racemic ketone (No. 385 in the following formula), since epimerization of BOC-protected amine stereocenter in racemic ketone is observed under basic condition, ketoreductase (KRED-p301) was designed to selectively promote nadpn and (R) -385 to efficiently convert (R) -385 into aminoalcohol within pH range capable of promoting epimerization and reduction of ketone. Taking the compound as a raw material, acidifying the compound into a compound containing a double-substituent structure (the number is 387 in the following formula) through sonogashira coupling reaction; diisopropylethylamine hydrogen trifluoride is used for promoting intramolecular cyclization reaction to generate a corresponding compound with a pyrrolidine alcohol structure (numbered 388 in the following formula), the compound is converted into corresponding silicon ether (numbered 389 in the following formula) before hydrogenation, a compound with an aniline structure (numbered 390 in the following formula) is formed through hydrogenation reaction, and the compound reacts with carboxylic ester substances (numbered 391 in the following formula) under the traditional amide bond forming condition to finally synthesize the wibeled. (see: FlickA C, Leverett C A, Ding H X, et al. synthetic intermediates to New Drugs Approved Dual 2018[ J ]. Journal of medical chemistry 2020,63(19):10652-
In conclusion, the process of the invention has the following advantages:
1. taking 1- (tert-butyl) 2-methyl (R) -5-oxypyrrolidine-1, 2-dicarboxylate as a starting material to synthesize a precursor of the wibeled: the intermediate V and reactants are cheap and easy to obtain, the synthesis path can be shortened, and the production cost is reduced;
2. the whole synthesis line has five steps, high-toxicity and complex starting materials are avoided, low-toxicity reagents are used as reaction environments, the method is safe and environment-friendly, the reaction conditions are mild, the overall yield of intermediates is remarkably improved, the subsequent reaction is simple, the process is pure and mature and reliable, the method has great advantages, and the method is suitable for industrial production.
Disclosure of Invention
In view of the above prior art, the object of the present invention is to obtain a starting material starting from 1- (tert-butyl) 2-methyl (R) -5-oxopyrrolidine-1, 2-dicarboxylate via methyl (R) -2- ((tert-butoxycarbonyl) amino) -6- (4-chlorophenyl) -5-oxohexanoate (intermediate I), 1- (tert-butyl) 2-methyl (2R,5S) -5- (4-chlorobenzyl) pyrrolidine-1, 2-dicarboxylate (intermediate II), (2S,5R) -2- (4-chlorobenzyl) -5- (R) -hydroxy (phenyl) methyl-pyrrolidine-1-carboxylate (intermediate III), tert-butyl (2R,5S) -2- ((R) - (tert-butyldimethylsilyl) oxy) (phenyl) methyl) -5- (4-chlorobenzyl) pyrrolidine-1-carboxylic acid ester (intermediate iv) to give the final intermediate: (2S,5R) -2- (4-aminobenzyl) -5- (R) - (tert-butyldimethylsilyloxy) (phenyl) methyl) pyrrolidine-1-carboxylic acid ester (intermediate V).
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention provides a new synthesis process method of a medicine for treating overactive bladder, which comprises the following steps:
(1) taking 1- (tert-butyl) 2-methyl (R) -5-oxypyrrolidine-1, 2-dicarboxylic acid ester as a starting material, replacing and protecting nitrogen at low temperature, slowly dropwise adding a tetrahydrofuran solution containing 4-chlorobenzyl magnesium chloride, after the dropwise adding is finished and the temperature is recovered to about 0 ℃, after the reaction is completed, quenching the mixture by using an acid reagent, extracting and separating an organic phase, drying the organic phase by using anhydrous sodium sulfate, and concentrating under reduced pressure to obtain an oily substance. The oil was purified by silica gel column chromatography eluting with polar and non-polar solvents to give methyl (R) -2- ((tert-butoxycarbonyl) amino) -6- (4-chlorophenyl) -5-oxohexanoate (intermediate I).
(2) And fully stirring the intermediate I and sodium triacetoxyborohydride at a low temperature. Ethyl acetate containing trifluoroacetic acid was added dropwise to the above reaction solution, and the reaction was stirred at room temperature. After the reaction was complete, saturated sodium bicarbonate solution and ethyl acetate were added. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with polar and non-polar solvents to give 1- (tert-butyl) 2-methyl (2R,5S) -5- (4-chlorobenzyl) pyrrolidine-1, 2-dicarboxylate (intermediate II) as a colorless viscous substance.
(3) And (4) cooling the intermediate II to-78 ℃ under the protection of sufficient nitrogen replacement. Slowly dropwise adding diisobutyl aluminum hydride toluene solution, and stirring and reacting under the condition of nitrogen protection. After the reaction is completed, the phenylmagnesium bromide solution is added dropwise. Reacting at room temperature, quenching the mixture with an acidic reagent after the reaction is finished, separating an organic layer, drying an organic phase by anhydrous sodium sulfate, and concentrating under reduced pressure. The residue was purified by silica gel chromatography eluting with polar and non-polar solvents to give (2S,5R) -2- (4-chlorobenzyl) -5- (R) -hydroxy (phenyl) methyl-pyrrolidine-1-carboxylic acid tert-butyl ester as an oil (intermediate iii).
(4) And (3) adding imidazole into the intermediate III under the condition of low-temperature nitrogen protection, adding TBSCl, after the reaction is finished, purifying, quenching and reacting with water, separating an organic phase, drying by using anhydrous sodium sulfate, and concentrating under reduced pressure. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with polar and non-polar solvents to give tert-butyl (2R,5S) -2- ((R) - (tert-butyldimethylsilyl) oxy) (phenyl) methyl) -5- (4-chlorobenzyl) pyrrolidine-1-carboxylate (intermediate iv) as an oil.
(5) Intermediate IVBenzophenone imine, Pd 2 (DBA) 3 Mixing 1, 3-bis (2, 6-diisopropylphenyl) imidazole-2-ene, sodium tert-butoxide and ethylene glycol dimethyl ether, and reacting under the protection of nitrogen. After the reaction was completed, ethyl acetate was added to dilute the reaction solution. The reaction solution was washed with water. The organic phase was separated. The organic phase and hydrochloric acid are mixed and stirred for reaction. After standing, the aqueous phase was separated and neutralized with sodium bicarbonate. The organic phase was extracted, concentrated and purified by flash chromatography to give (2S,5R) -2- (4-aminobenzyl) -5- (R) - (tert-butyldimethylsilyloxy) (phenyl) methyl) pyrrolidine-1-carboxylic acid ester as an oil (intermediate V).
In the step (1), the preferable molar ratio of 1- (tert-butyl) 2-methyl (R) -5-oxypyrrolidine-1, 2-dicarboxylic acid ester to 4-chlorobenzyl magnesium chloride is 1: 1.1.
In step (1), tetrahydrofuran is preferably used to dissolve 1- (tert-butyl) 2-methyl (R) -5-oxopyrrolidine-1, 2-dicarboxylic acid ester, preferably at a low temperature of-25 ℃.
In step (1), preferably, 4-chlorobenzyl magnesium chloride reagent is added as a tetrahydrofuran solution to 1- (tert-butyl) 2-methyl (R) -5-oxopyrrolidine-1, 2-dicarboxylate in tetrahydrofuran, and after cooling to 0 ℃ is added.
In the step (1), the dripping time of the 4-chlorobenzyl magnesium chloride reagent is preferably 30min, the temperature of the reaction mixture is preferably 0 ℃ after the dripping is finished, and the reaction time is 1.5 h;
in the step (1), after the reaction is completed, preferably, a saturated ammonium chloride aqueous solution is selected for quenching; preferably methyl tert-butyl ether.
In step (2), preferred intermediate i: NaBH (OAc) 3 : the molar ratio of trifluoroacetic acid is 1:1.1: 1.3.
In the step (2), the low-temperature during feeding is preferably 0 ℃, the preferable reaction temperature is 26 ℃, and the reaction time is 15 h.
In step (2), preferably, a saturated sodium bicarbonate solution is extracted and the layers are separated.
In step (3), the preferred intermediate II: DIBAL-H: the molar ratio of phenylmagnesium bromide was 1:1.35: 1.2.
In step (3), the intermediate II is preferably redissolved with anhydrous tetrahydrofuran, and the temperature for dissolving the intermediate II is preferably-78 ℃.
In step (3), the reaction temperature of the intermediate II and DIBAL-H is preferably-78 ℃ and the reaction time is 2H. After the phenylmagnesium bromide is added, the reaction temperature is preferably 20 ℃, and the reaction time is 18 h.
In the step (3), the preferable dropping time of the phenylmagnesium bromide is 20min
In the step (3), the reaction temperature of the mixture is preferably 90 ℃ and the reaction time is 12 h.
In step (3), the mixture is preferably quenched with a saturated ammonium chloride solution after the reaction is completed.
In step (4), preferred intermediate iii: TBSCl: the molar ratio of imidazole is 1:1.5: 1.05.
In step (4), intermediate III is preferably dissolved in dichloromethane.
In the step (4), the intermediate III is preferably added with imidazole first and then TBSCl, and in the adding process, the temperature is preferably 0 ℃, and the reaction time is 2 h.
In step (4), purified water extraction and separation are preferred.
In step (5), the preferred intermediate IV: benzophenone imine: pd 2 (DBA) 3 :1, 3-bis (2, 6-diisopropylphenyl) imidazol-2-ene: the molar ratio of sodium tert-butoxide is 1:1.8:0.01:0.03: 1.1.
In step (5), the above materials are charged in solid form, preferably dissolved with ethylene glycol dimethyl ether.
In the step (5), the reaction temperature is preferably 60 ℃ and the reaction time is preferably 10 hours.
In the step (5), after completion of the reaction, the reaction solution is preferably diluted with ethyl acetate, washed with purified water, and the organic phase is separated.
In step (5), preferably hydrochloric acid is mixed with the organic phase, preferably with stirring for a reaction time of 2h, and the aqueous phase is separated, preferably sodium bicarbonate is used to neutralize the aqueous phase containing hydrochloric acid.
In step (5), the aqueous phase is preferably extracted with ethyl acetate, and the concentrated organic phase is separated.
In step (5), intermediate V is preferably purified by flash chromatography.
The invention has the beneficial effects that:
by adopting the novel synthesis process method of the new medicine for treating overactive bladder, 1- (tert-butyl) 2-methyl (R) -5-oxypyrrolidine-1, 2-dicarboxylic acid ester is taken as a starting raw material, the raw materials are cheap and easy to obtain, and the production cost can be reduced; the whole synthesis line adopts a low-toxicity reagent as a reaction environment, does not produce industrial pollution, is safe and environment-friendly, has mild reaction conditions, obviously improves the overall yield, has great advantages and is suitable for industrial production.
Detailed Description
It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.
As introduced in the background section, the synthetic route of the invention avoids using expensive, flammable and explosive reagents, and is suitable for industrial production.
In order to make the technical solutions of the present application more clearly understood by those skilled in the art, the technical solutions of the present application will be described in detail below with reference to specific embodiments.
The test materials used in the examples of the present invention, which were not specifically described, were all those conventionally used in the art and commercially available.
Example 1:
1- (tert-butyl) 2-methyl (R) -5-oxopyrrolidine-1, 2-dicarboxylate (0.3mol) was dissolved in 220mL of tetrahydrofuran under nitrogen displacement. Controlling the temperature to-25 ℃, gradually and slowly adding 540mL of tetrahydrofuran solution (0.5M) containing 4-chlorobenzyl magnesium chloride reagent dropwise, and after the dropwise addition is finished, keeping the temperature at about 0 ℃ for reaction for 1.5 h. Tracing the reaction by TLC, quenching the mixture with saturated ammonium chloride solution after the reaction is completed, extracting and separating an organic phase by methyl tert-butyl ether, drying the organic phase by anhydrous sodium sulfate, and concentrating under reduced pressure to obtain an oily substance. Purifying the oily substance with 200 mesh silica gel chromatographic column, eluting with ethyl acetate petroleum ether (1:1, V: V) to obtain intermediate I;
about 14.3g of intermediate I were dissolved in 140mL of ethyl acetate, cooled to 0 ℃ and 16.4g of NaBH (OAc) were added 3 . 120mL of ethyl acetate containing 19.0 g of trifluoroacetic acid was added dropwise to the reaction mixture, the temperature was slowly raised to 26 ℃ and the reaction was stirred for 15 hours. Saturated sodium bicarbonate solution and ethyl acetate were added and the layers were separated. The organic phase was separated, washed three times with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purifying the residue with 200 mesh silica gel column chromatography, eluting with ethyl acetate petroleum ether (1:10, V: V) to obtain intermediate II;
500mg of intermediate II is dissolved in 15mL of anhydrous tetrahydrofuran, and the temperature is reduced to-78 ℃ under the protection of sufficient nitrogen replacement. Slowly dropwise adding 1.1ml of toluene solution (1.5M) of LDIBAL-H, and after dropwise adding, keeping the temperature and stirring for reaction for 2 hours under the condition of nitrogen protection. The reaction was followed by TLC. After the reaction was complete, 4.5mL of phenylmagnesium bromide solution (1M) was added dropwise over 20 min. Naturally heating to room temperature and reacting for 18 h. After the reaction, the mixture was quenched by dropping a saturated ammonium chloride solution, the organic layer was separated, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purifying the residue with 300 mesh silica gel column, eluting with ethyl acetate petroleum ether (1:4, V: V) to obtain intermediate III;
dissolving 300mg of intermediate III in 5mL of dichloromethane, stirring at room temperature, replacing and protecting with nitrogen, adding 100mg of imidazole, and cooling to low temperature. 168mg of TBSCl was added and the reaction was followed by TLC. Adding purified water to quench and react, separating an organic phase, drying by anhydrous sodium sulfate, and concentrating under reduced pressure. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purifying the residue with 300 mesh silica gel chromatography column, eluting with ethyl acetate petroleum ether (1:2, V: V) to obtain intermediate IV;
520mg of intermediate IV, 220mg of benzophenone imine and 10mg of Pd 2 (DBA) 3 8mg of 1, 3-bis (2, 6-diisopropylphenyl) imidazole-2-ene, 144mg of sodium tert-butoxide and 10mL of ethylene glycol dimethyl ether are mixed and reacted at 60 ℃ for 10 hours under the protection of nitrogen. The reaction was completed by TLC and diluted with 10mL of ethyl acetate. The reaction solution was washed with water. The organic phase was separated. The organic phase is mixed with 10mL of hydrochloric acid (6M) and reacted for 2h with stirring. After standing, the aqueous phase was separated and neutralized with sodium bicarbonate. Extracting the organic phase with ethyl acetate, concentrating, and purifying by flash chromatography to obtain extractFinal product: and (5) an intermediate V.
Example 2:
500mg of intermediate V was dissolved in 20mL of acetic acid: water: tetrahydrofuran (13:7:3) mixed solvent, reaction at 30 ℃ for 15h, extraction of the organic phase with ethyl acetate and concentration, addition of 20mL of trifluoroacetic acid: and (2) mixing a dichloromethane (1:1, V: V) mixed solvent, stirring and reacting for 10h at 25 ℃, evaporating the solvent after the evaporation reaction is finished, adding 10mL of sodium hydroxide (4M) into the alkalized reaction solution, extracting an organic phase by using ethyl acetate, concentrating, and purifying by using a flash chromatography to finally obtain the Weibeigong monomer raw material medicine.
The hydrogen spectrum results are as follows:
1 H NMR(DMSO):δ10.55(s，NH)，8.01(d，J＝6.9，1H)，7.55(m，2H)， 7.30(m，2H)，7.29-7.28(m，2H)，7.20(m，1H)，7.15(m，2H)，6.24(d，J＝6.7， 1H)，5.12(dd，J＝10.1，3.2，1H)，5.05(brs，OH)，4.16(d，J＝7.1，1H)，3.16 (p，J＝7.2，1H)，3.18-3.05(m，3H)，2.61(m，1H)，2.53-2.45(m，2H)，2.41 (BRS，NH)，2.10(ddt，J＝15.1，9.3，3.0，1H)，1.53(m，1H)，1.32(m，1H)， 1.29-1.21(m，2H)
the carbon spectrum results are as follows:
13 C NMR(DMSO):δ167.88，165.23，156.09，153.33，142.98，136.41，135.17，128.13， 126.22，126.18，126.02，118.33，111.84，76.01，63.23，61.00，59.23，41.03，31.06，29.38， 26.62，22.76
the above description is only an example of the present application, and the protection scope of the present application is not limited by these specific examples, but is defined by the claims of the present application. Various modifications and changes may occur to those skilled in the art to which the present application pertains. Any modification, equivalent replacement, improvement, etc. made within the technical idea and principle of the present application should be included in the protection scope of the present application.
Claims (13)
1. A new synthesis process of an intermediate of a new oral medicine for overactive bladder is characterized by comprising the following steps: starting from 1- (tert-butyl) 2-methyl (R) -5-oxopyrrolidine-1, 2-dicarboxylate the synthetic route was via methyl (R) -2- ((tert-butoxycarbonyl) amino) -6- (4-chlorophenyl) -5-oxohexanoate (intermediate I), 1- (tert-butyl) 2-methyl (2R,5S) -5- (4-chlorobenzyl) pyrrolidine-1, 2-dicarboxylate (intermediate II), (2S,5R) -2- (4-chlorobenzyl) -5- (R) -hydroxy (phenyl) methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (intermediate III), tert-butyl (2R,5S) -2- ((R) - (tert-butyldimethylsilyl) oxy) (phenyl) methyl) -5- (4-chlorobenzyl) pyrrolidine-1-carboxylic acid ester (intermediate iv) to give (2S,5R) -2- (4-aminobenzyl) -5- (R) - (tert-butyldimethylsilyloxy) (phenyl) methyl) pyrrolidine-1-carboxylic acid ester (intermediate v) by the following specific synthetic route:
2. the compound of claim 1, wherein the starting material is 1- (tert-butyl) 2-methyl (R) -5-oxopyrrolidine-1, 2-dicarboxylic acid ester, and the starting material is dissolved in tetrahydrofuran under nitrogen displacement protection. Controlling the temperature to be below 0 ℃, gradually and slowly dripping tetrahydrofuran solution containing 4-chlorobenzyl magnesium chloride reagent, and keeping the temperature at about 0 ℃ for reaction after dripping. Tracing the reaction by TLC, quenching the mixture with acid reagent after the reaction is completed, extracting and separating the organic phase by using organic reagent, drying the organic phase by using anhydrous sodium sulfate, and concentrating under reduced pressure to obtain oily matter. The oil was purified by silica gel chromatography eluting with polar and non-polar solvents to give methyl (R) -2- ((tert-butoxycarbonyl) amino) -6- (4-chlorophenyl) -5-oxohexanoate (intermediate I) of the formula:
3. according to claim 1, intermediate I is prepared by dissolving in ethyl acetate, cooling to about 0 deg.C, adding sodium triacetoxyborohydride (NaBH (OAc)) 3 ). Trifluoroacetic acid-containing ethyl acetate dropwiseThe reaction mixture was slowly warmed to room temperature and stirred. Saturated sodium bicarbonate solution and ethyl acetate were added and the layers were separated. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with polar and non-polar solvents to give 1- (tert-butyl) 2-methyl (2R,5S) -5- (4-chlorobenzyl) pyrrolidine-1, 2-dicarboxylic acid ester (intermediate II) as a colorless viscous material of the formula:
4. according to the method, the intermediate II is dissolved in anhydrous tetrahydrofuran, and the temperature is reduced to-78 ℃ under the protection of sufficient nitrogen replacement. Slowly dropwise adding a toluene solution containing diisobutyl aluminum hydride (DIBAL-H), and after dropwise adding, keeping the temperature and stirring for reaction under the condition of nitrogen protection. The reaction was followed by TLC. After the reaction is completed, the solution of phenylmagnesium bromide is added dropwise. Naturally heating to room temperature for reaction. After the reaction, the mixture was quenched with an acidic reagent, the organic layer was separated, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column eluting with polar and non-polar solvents to give (2S,5R) -2- (4-chlorobenzyl) -5- (R) -hydroxy (phenyl) methyl-pyrrolidine-1-carboxylic acid tert-butyl ester as an oil (intermediate iii) of the formula:
5. according to the method, the intermediate III is dissolved in dichloromethane, stirred at room temperature, protected by nitrogen replacement, added with imidazole and cooled to low temperature. T-butyldimethylsilyl chloride (TBSCl) was added and the reaction was followed by TLC. Adding purified water to quench and react, separating an organic phase, drying the organic phase by anhydrous sodium sulfate, and concentrating the organic phase under reduced pressure. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column eluting with a polar solvent and a non-polar solvent to give tert-butyl (2R,5S) -2- ((R) - (tert-butyldimethylsilyl) oxy) (phenyl) methyl) -5- (4-chlorobenzyl) pyrrolidine-1-carboxylate (intermediate iv) as an oil of the formula:
6. according to claim 1, intermediates IV, benzophenone imine and tris (dibenzylideneacetone) dipalladium (Pd) 2 (DBA) 3 ) And 1, 3-bis (2, 6-diisopropylphenyl) imidazole-2-ene, sodium tert-butoxide and ethylene glycol dimethyl ether are mixed and reacted under the protection of nitrogen. The reaction was completed by TLC and diluted with ethyl acetate. The reaction solution was washed with water. The organic phase was separated. The organic phase and hydrochloric acid are mixed and stirred for reaction. After standing, the aqueous phase was separated and neutralized with sodium bicarbonate. The organic phase is extracted, concentrated and purified by flash chromatography to give (2S,5R) -2- (4-aminobenzyl) -5- (R) - (tert-butyldimethylsilyloxy) (phenyl) methyl) pyrrolidine-1-carboxylic acid ester as an oil (intermediate v) of the formula:
7. the patent finally identified and obtained, according to the claim 1, is a precursor of the new drug of wibelegun for the treatment of overactive bladder: an intermediate V; but it can be prepared by reacting acetic acid: water: reaction environment of tetrahydrofuran (13:7:3), at the temperature of 30 ℃, reaction is carried out for 10-20h to remove tert-butyldimethylsilyloxy (protecting group), and reaction is carried out by trifluoroacetic acid: reacting for 5-10h under the condition of stirring at room temperature in a reaction environment of dichloromethane (1:1), evaporating a solvent, alkalifying with sodium hydroxide, and removing tert-butyloxycarbonyl (a protective group) to finally obtain the raw material drug of the Weibeige dragon monomer.
8. According to claim 2, starting from 1- (tert-butyl) 2-methyl (R) -5-oxopyrrolidine-1, 2-dicarboxylate and 4-chlorobenzyl magnesium chloride reagent in a ratio of 1 (on a molar basis) with respect to 1- (tert-butyl) 2-methyl (R) -5-oxopyrrolidine-1, 2-dicarboxylate, the 4-chlorobenzyl magnesium chloride reagent is used in an amount of 1.0 to 5.0; the dripping time of the 4-chlorobenzyl magnesium chloride reagent is within 30min, the temperature of the reaction mixture is raised to about 0 ℃, and the temperature range is as follows: the reaction time is 0.5-6h at 0 +/-3 ℃.
9. The process according to claim 3, wherein the amount of intermediate I used is 1 (by mole) and NaBH (OAc) 3 The dosage is 1.0-2.5, and the dosage of trifluoroacetic acid is 0.6-1.8; the reaction is carried out in a low-temperature mode, and the temperature range is as follows: heating to room temperature at 0 +/-3 ℃, and stirring for reaction, wherein the room temperature range is as follows: the reaction time is 3-25h at 10-30 ℃.
10. According to claim 4, when the amount of DIBAL-H is 1 (by mole) based on the intermediate II, the amount of DIBAL-H is 0.8-1.8, the amount of phenylmagnesium bromide is 1.0-2.3; after the intermediate II is dissolved, preferably cooling to-78 ℃, replacing and protecting by using enough nitrogen, and carrying out the reaction at the temperature and in the nitrogen protection environment, wherein the reaction temperature range is as follows: the reaction time is 1-5h at-65 ℃ to-80 ℃;
11. according to claim 4, the phenylmagnesium bromide solution is added after the intermediate II and DIBAL-H have reacted sufficiently, the addition is completed within 30 minutes, the temperature is raised to room temperature, and the mixture is stirred overnight, the room temperature range is as follows: the reaction time is 12-24h at 10-30 ℃.
12. According to claim 5, when the amount of TBSCl is 1 (by mole) and the amount of imidazole is 0.3-1.1 based on the intermediate III, the amount of TBSCl is 0.5-2.6; under the conditions of nitrogen replacement protection and stirring, imidazole is firstly added into the intermediate III, and the temperature is reduced to a low temperature within the following range: and finally adding TBSCl at the temperature of 0 +/-3 ℃, maintaining the low temperature, and stirring for reaction for 1-3 h.
13. According to claim 6, wherein the amount of benzophenone imine is 1.0 to 2.2 and Pd is 1 (mole) based on intermediate IV 2 (DBA) 3 The dosage is 0.005-0.03, the dosage of 1, 3-bis (2, 6-diisopropylphenyl) imidazole-2-alkene is 0.01-0.05, and the dosage of sodium tert-butoxide is 1.0-3.5; the reaction is carried out under the protection of nitrogen, and the reaction temperature ranges are as follows: the reaction time is 8 to 24 hours at the temperature of between 50 and 85 ℃; the reaction solution was diluted and washed with water. The organic phase was separated. Mixing the organic phase and hydrochloric acid, stirring for reaction for 1-3h, standing, and separating the water phase.
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