WO2014101690A1 - 依泽替米贝手性中间体的制备方法 - Google Patents
依泽替米贝手性中间体的制备方法 Download PDFInfo
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- WO2014101690A1 WO2014101690A1 PCT/CN2013/089754 CN2013089754W WO2014101690A1 WO 2014101690 A1 WO2014101690 A1 WO 2014101690A1 CN 2013089754 W CN2013089754 W CN 2013089754W WO 2014101690 A1 WO2014101690 A1 WO 2014101690A1
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- fluorophenyl
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- 238000000034 method Methods 0.000 title claims abstract description 19
- OLNTVTPDXPETLC-XPWALMASSA-N ezetimibe Chemical compound N1([C@@H]([C@H](C1=O)CC[C@H](O)C=1C=CC(F)=CC=1)C=1C=CC(O)=CC=1)C1=CC=C(F)C=C1 OLNTVTPDXPETLC-XPWALMASSA-N 0.000 title abstract description 9
- 229960000815 ezetimibe Drugs 0.000 title abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 51
- 239000003054 catalyst Substances 0.000 claims abstract description 22
- 239000001257 hydrogen Substances 0.000 claims abstract description 22
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 22
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 74
- 238000002360 preparation method Methods 0.000 claims description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-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
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 5
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 claims description 4
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 2
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims 2
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 1
- 229940098779 methanesulfonic acid Drugs 0.000 claims 1
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 claims 1
- 230000003287 optical effect Effects 0.000 abstract description 15
- 125000004435 hydrogen atom Chemical class [H]* 0.000 abstract description 7
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 1
- 239000003513 alkali Substances 0.000 abstract 1
- 230000000694 effects Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 26
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 238000005481 NMR spectroscopy Methods 0.000 description 17
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 16
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
- 239000012074 organic phase Substances 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 239000002904 solvent Substances 0.000 description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 239000007788 liquid Substances 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- PQKOAYKQUKHPDB-UHFFFAOYSA-N FC1=CC=C(C=C1)C(CCCC(=O)O)=C=O Chemical group FC1=CC=C(C=C1)C(CCCC(=O)O)=C=O PQKOAYKQUKHPDB-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000007789 gas Substances 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- JQJBQVRTSMGDJX-UHFFFAOYSA-N 1-[(2-methylpropan-2-yl)oxy]decane Chemical compound CCCCCCCCCCOC(C)(C)C JQJBQVRTSMGDJX-UHFFFAOYSA-N 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
- 238000004296 chiral HPLC Methods 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- 239000008346 aqueous phase Substances 0.000 description 7
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
- 239000012267 brine Substances 0.000 description 6
- MWKFXSUHUHTGQN-UHFFFAOYSA-N decan-1-ol Chemical compound CCCCCCCCCCO MWKFXSUHUHTGQN-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- 229930182558 Sterol Natural products 0.000 description 4
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N Valeric acid Natural products CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 150000003432 sterols Chemical class 0.000 description 4
- 235000003702 sterols Nutrition 0.000 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- 229940005605 valeric acid Drugs 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- FSXKAGUHLIGGRG-UHFFFAOYSA-N 5-(4-fluorophenyl)-5-hydroxypentanoic acid Chemical compound OC(=O)CCCC(O)C1=CC=C(F)C=C1 FSXKAGUHLIGGRG-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- -1 ketone compound Chemical class 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- IXADHCVQNVXURI-UHFFFAOYSA-N 1,1-dichlorodecane Chemical compound CCCCCCCCCC(Cl)Cl IXADHCVQNVXURI-UHFFFAOYSA-N 0.000 description 2
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 2
- PAZJFXNRVLDLFO-UHFFFAOYSA-N 4-sulfanylmorpholine Chemical compound SN1CCOCC1 PAZJFXNRVLDLFO-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- QEWYKACRFQMRMB-UHFFFAOYSA-N fluoroacetic acid Chemical compound OC(=O)CF QEWYKACRFQMRMB-UHFFFAOYSA-N 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 229940070710 valerate Drugs 0.000 description 2
- SKIDNYUZJPMKFC-UHFFFAOYSA-N 1-iododecane Chemical compound CCCCCCCCCCI SKIDNYUZJPMKFC-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- FEQTXQRHYKLVFV-UHFFFAOYSA-N 6-oxohex-5-enoic acid Chemical compound OC(=O)CCCC=C=O FEQTXQRHYKLVFV-UHFFFAOYSA-N 0.000 description 1
- 229940122502 Cholesterol absorption inhibitor Drugs 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 101001110310 Lentilactobacillus kefiri NADP-dependent (R)-specific alcohol dehydrogenase Proteins 0.000 description 1
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 description 1
- ZBQROUOOMAMCQW-UHFFFAOYSA-N OC(CCCC(c(cc1)ccc1F)=O)=O Chemical compound OC(CCCC(c(cc1)ccc1F)=O)=O ZBQROUOOMAMCQW-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- GUQSCTMNEWWGCC-UHFFFAOYSA-L [O-]OOOOOOOO[O-].[Na+].[Na+] Chemical compound [O-]OOOOOOOO[O-].[Na+].[Na+] GUQSCTMNEWWGCC-UHFFFAOYSA-L 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- AQEFLFZSWDEAIP-UHFFFAOYSA-N di-tert-butyl ether Chemical compound CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 description 1
- 150000004985 diamines Chemical class 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 150000002431 hydrogen Chemical group 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- SNMVRZFUUCLYTO-UHFFFAOYSA-N n-propyl chloride Chemical compound CCCCl SNMVRZFUUCLYTO-UHFFFAOYSA-N 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 150000003021 phthalic acid derivatives Chemical class 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- LFQULJPVXNYWAG-UHFFFAOYSA-N sodium;phenylmethanolate Chemical compound [Na]OCC1=CC=CC=C1 LFQULJPVXNYWAG-UHFFFAOYSA-N 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 238000009901 transfer hydrogenation reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/367—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of functional groups containing oxygen only in singly bound form
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
-
- 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
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System compounds of the platinum group
- C07F15/0033—Iridium compounds
-
- 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
Definitions
- the invention relates to the field of medical synthesis, in particular to a preparation method of an ezetimibe chiral intermediate.
- Ezetimibe is a new cholesterol absorption inhibitor for the treatment of hypercholesterolemia. Its chemical name is: 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl] _(4S)-(4-hydroxyphenyl) -2-caprolactam.
- US 5,618,707 reports the chiral reduction of the corresponding ketone compound by microbial reductase, which can be resolved without a resolving agent, but the reaction yield is low (68%), and the reductase incubation time is long, about 72 hour.
- WO 2008089984 teaches a process for the asymmetric reduction of a corresponding ketone by a transfer hydrogenation catalyst which uses a phthalic acid derivative as a hydrogen source. The amount of the catalyst is high and environmentally friendly.
- (-) -DIP-C1 has the disadvantages, such as corrosive, easy to absorb moisture and moisture, sensitive to air, expensive, low in atomic economy, and complicated in post-treatment, resulting in a large molar amount of chiral reducing reagent (at least 1. ⁇ 1.8 equivalents), low yield (83%).
- the present invention provides a novel method for preparing the ezetimibe chiral intermediate, the specific scheme as follows:
- a method for preparing a compound of the formula b comprising the steps of: obtaining a structural compound of the formula b under the action of a chiral catalyst, a base and hydrogen;
- R is NR Rs, OR 3 or OH; and R 2 is independently alkyl or R 2 can be cyclically synthesized into piperidine, and R 3 is d-C 6 alkyl or benzyl.
- DTB is:
- the number of bases is 1 ⁇ 5.
- the X is preferably a d ⁇ c 4 alkyl group.
- the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium ethoxide, potassium ethoxide, sodium t-butoxide, potassium t-butoxide, sodium amide, triethylamine, tributylamine or N-mercapto Morpholine;
- the solvent used in the reaction is selected from the group consisting of decyl alcohol, ethanol, propanol, butanol, tetrahydrofuran, toluene, decyl tert-butyl ether, dioxane, DMF, DMSO or a mixed solvent of several of them.
- the hydrogen pressure is 0.2 ⁇ lOMPa
- the molar ratio of the compound of the formula a to the chiral catalyst is 1: (0.001 ⁇ 0.00002); the molar ratio of the compound of the formula a to the base is 1: (0.001-0.7);
- the reaction temperature of the reaction is 0 to 80 °C.
- the compound of formula b is selected from the following compounds: Wherein R 1 R 2 , R 3 have the same definitions as defined above.
- the compound of formula a is specifically the following compound having the a-3 structure:
- the compound of the formula a-3 is prepared by reacting a compound of the formula a-1 with HNRiRs;
- the reaction solvent for the reaction is selected from the group consisting of: tetrahydrofuran, dichlorodecane, toluene, decyl tert-butyl ether, dioxane, DMF, DMSO or a mixed solvent of several of them;
- the molar ratio of the compound of the formula a-1 to the HNR 2 R 3 is 1:1.2 to 1:10; the compound of the formula b-1 can be converted into the compound of the formula b-2 by the following method:
- the compound of formula b-1 gives the compound of formula c under the action of an acid, and the compound of formula c is reacted with R 3 ONa to give the compound of formula b-2 shown.
- Y is I, Br, Cl.
- the base is: sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium ethoxide, potassium ethoxide, sodium t-butoxide, potassium t-butoxide, sodium amide, triethylamine, tributylamine or N-mercapto Morpholine;
- the molar ratio of the compound of the formula b-1 to the R 3 Y is 1:1.2 to 1:10;
- the molar ratio of the compound of the formula b-1 to the base is 1: 1.2 to 1:5;
- the solvent used in the reaction is selected from the group consisting of decyl alcohol, ethanol, propanol, butanol, tetrahydrofuran, toluene, decyl tert-butyl ether, dioxane, acetonitrile, DMAC, DMF, DMSO or several of them. Mixed solvent.
- the acids are: acetic acid, trifluoroacetic acid, hydrochloric acid, Yue acid traces, traces of benzene Yue acid, toluenesulfonic acid pyridine 1 Yue given salt thereof;
- the molar ratio of the compound of the formula b-1 to the acid is: 1 : (0.1 ⁇ 1);
- the molar ratio of the compound of the formula c to the R 3 ONa is: 1 (0.1 to 1);
- the solvent used in the reaction is selected from the group consisting of: decyl alcohol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, and dichlorodecane.
- the compound of the formula b-2 is according to the method provided in the prior art document, for example, the Japanese application file
- Ezetimibe can be prepared by the method provided in JP2008031131, U.S. Patent No. 6,207,822.
- the compound of formula b-3 can be prepared according to the method provided in the prior art document, for example, the method provided in WO2007017705.
- the preparation method of the ezetimibe chiral intermediate of the present invention has the following beneficial effects: 1) the amount of the chiral reducing agent of the invention is low, and the molar ratio to the substrate is less than 1/1000; 2) hydrogen The source is hydrogen, up to 95%.
- the molar amount of the chiral catalyst is 1 / 50,000 of the substrate, and the optical purity of the obtained product can also be 98% or more, and the yield is also It can reach 95% or more; 4)
- the substrate is 5-(4-fluorophenyl)-5-carbonylpentanoic acid
- the catalyst is usually poisoned, thereby
- the molar amount of the chiral catalyst in the present invention is 1/50,000 of the substrate 5-(4-fluorophenyl)-5-carbonylpentanoic acid, and the optical purity of the product is obtained. It can also reach 98% or more, and the yield can reach 95 or more. Therefore, the invention has high application value in the industrial production of ezetimibe.
- Figure 1 is an optical purity report (ee) of (5-(4-fluorophenyl)-5-hydroxyvaleric acid prepared in Example 1;
- FIG. 2 is an optical purity report (ee) of (5-(4-fluorophenyl)-5-hydroxyvalerate) prepared in Example 6;
- FIG. 3 is a preparation of Example 8 (-5-(4-fluorobenzene) Optical purity report (ee) of 5-)-1-hydroxy-1-morpholinium-1-one.
- DETAILED DESCRIPTION OF THE INVENTION In view of the contents of this paper, the process parameters are appropriately improved. It is particularly important to note that all similar substitutions and modifications are It is obvious to those skilled in the art that the present invention is intended to be included in the present invention.
- the method of the present invention has been described by the preferred embodiments thereof, and it is obvious to those skilled in the art without departing from the scope of the invention.
- the (5 mg, 0.005 mmol) chiral catalyst M (X is 3-mercapto) and (30.3 g, 270 mmol) potassium t-butoxide were weighed into the reaction tube, and the reaction tube was placed in an autoclave.
- Example 4 Preparation of (-5-(4-fluorophenyl)-5-hydroxyvaleric acid Weigh (1.0 mg, 0.001 mmol) of the chiral catalyst M (X is 3-ethoxy) and (50.5 mg, 0.5 mmol) of triethylamine into the reaction tube, and place the reaction tube into the autoclave. 5 mL of ethanol and (0.2 g, 1 mmol) of 5-(4-fluorophenyl)-5-carbonylpentanoic acid were added to the reaction tube, and the gas in the autoclave was replaced with hydrogen to maintain the hydrogen pressure at 0.2 to 10 MPa. The reaction was carried out at 50 °C. After reacting for 20 'J, the reaction solution was concentrated.
- Example 6 Preparation of (-5-(4-fluorophenyl)-5-hydroxyvalerate decyl ester Weigh (1.0 mg, 0.001 mmol) of chiral catalyst M (X is 3-mercapto) and (44.8 mg, 0.4 mmol) sodium ethoxide into the reaction tube, and place the reaction tube into the autoclave. 5 mL of ethanol and (2.24 g, 10 mmol) of 5-(4-fluorophenyl)-5-carbonyl valerate were added to the inner tube, and the gas in the autoclave was replaced with hydrogen to maintain the hydrogen pressure at 0.2-10 MPa. The reaction was heated to 30 ° C to carry out the reaction.
- Example 7 Preparation of l-(4-fluorophenyl)-5-morpholinium-1,dione To a 500 mL three-necked flask was added (10.5 g, 50 mmol) of 5-(4-fluorophenyl)-5-carbonylpentanoic acid, 150 mL of tetrahydrofuran was added, the system was cooled to -5 °C, and 16 mL of triethylamine was added. Pivaloyl chloride (llmL, 90 mmol) was added dropwise. After the addition was completed, the reaction was kept at this temperature for 1 hour.
- 5-(4-Fluorophenyl)-5-carbonylpentanoic acid (10.5 g, 50 mmol) was added to a 500 mL three-necked flask, 150 mL of tetrahydrofuran was added, the system was cooled to -5 °C, and 16 mL of triethylamine was added. Pivaloyl chloride (llmL, 90 mmol) was added dropwise. After the addition was completed, the reaction was kept at this temperature for 1 hour.
- Example 16 Preparation of (-5-(4-fluorophenyl)-5-hydroxyvalerate benzyl ester To a 250 mL two-necked flask was added 03 ⁇ 4-5-(4-fluorophenyl)-valerolactone (27.7 g, 142.6 mmol) and sodium benzylate (2.65 g, 20.4 mmol), and the system was replaced with a nitrogen atmosphere. 100 mL of sterol was added, and the reaction was carried out for 10 hours at room temperature after the addition. TLC monitored the reaction completely. The sterol was removed by rotary distillation, and 100 mL of dichloromethane was added to separate the mixture.
Abstract
本发明涉及医药合成领域,具体为依泽替米贝手性中间体的制备方法。该方法为:一种具有式(b)结构的化合物的制备方法,包括如下步骤:式(a)结构化合物在手性催化剂,碱和氢气作用下即得到式(b)结构化合物;其中:R为NR1R2,OR3或OH;R1和R2各自独立的为烷基,R3为C1~C6烷基或苄基。其中所述的手性催化剂为具有下列式(M)结构的化合物:其中DTB为如式DTB所示。利用该方法制备得到的式(b)化合物收率可以达到95%以上,光学纯度最高可以达到100%。
Description
依' W米贝手性中间体的制备方法
本申请要求于 2012 年 12 月 25 日提交中国专利局、 申请号为 20120567342.2、 发明名称为"依泽替米贝手性中间体的制备方法"的中国专利 申请的优先权, 其全部内容通过引用结合在本申请中。 技术领域
本发明涉及医药合成领域, 具体涉及依泽替米贝手性中间体的制备方法。
背景技术
依泽替米贝(Ezetimibe )是一种新型胆固醇吸收抑制剂, 用于高胆固醇血 症的治疗。 其化学名称为: 1- ( 4-氟苯基) - ( 3R ) -[3-(4-氟苯基 )-(3S)-羟基丙 基] _(4S)-(4-羟基苯基) -2-并内酰胺。
该化合物合成关键步骤在于如何得到结构式中所标注的 S构型 ,
US20090047716报道了用酮还原酶对相应的酮化合物进行手性还原,但该 方法普遍收率低, 大约在 60%左右。
US5618707报道了用微生物还原酶对相应的酮化合物进行手性还原,利用 该方法可以不经拆分剂进行拆分, 但反应收率低(68% ), 且还原酶培养时间 长, 大约需要 72小时。
WO 2008089984 道了一种用转移氢化催化剂对相应的酮进行不对称还 原的制备方法, 该方法以曱酸衍生物为氢源, 催化剂的用量高, 不利环保。
(-) -DIP-C1缺点为, 比如腐蚀性, 容易吸湿变潮, 对空气敏感, 价格昂贵, 原子经济性低, 后处理繁瑣, 导致手性还原试剂的摩尔用量大(至少需要 1. ~ 1.8当量) , 收率低(83% ) 。 发明内容
为了解决上述现有技术中,反应过程中手性还原剂用量大,产品收率低等 问题, 本发明提供了一种新的用于制备依泽替米贝手性中间体的方法, 具体方 案如下:
其中: R为 NR Rs, OR3或 OH; 和 R2各自独立的为烷基或 与 R2可环合 成哌啶, R3为 d~C6烷基或苄基。
为 11、 C广 C8烷基, d~C8烷氧基, 苯基、 取代苯基或苄基, 所述的苯 基上的取代基为 d~C8的烃基、 烷氧基, 取代基数量为 1~ 5。
所述 X优选为 d~ c4烷基。
所述碱选自氢氧化钠、 氢氧化钾、 碳酸钠、 碳酸钾、 乙醇钠、 乙醇钾、 叔 丁醇钠、 叔丁醇钾、 氨基钠、 三乙胺、 三丁胺或 N-曱基吗啉;
所述反应所用溶剂选自曱醇、 乙醇、 丙醇、 丁醇、 四氢呋喃、 曱苯、 曱基 叔丁基醚、 二氧六环、 DMF、 DMSO中的一种或其中几种的混合溶剂。
所述氢气压力为 0.2 ~ lOMPa;
所述式 a化合物与手性催化剂的摩尔用量比为 1: (0.001 ~ 0.00002); 所述式 a化合物与碱的摩尔用量比为 1: (0.001-0.7 );
所述反应的反应温度为 0 ~ 80°C。
所述反应的反应溶剂选自: 四氢呋喃、 二氯曱烷、 曱苯、 曱基叔丁基醚、 二氧六环、 DMF、 DMSO中的一种或其中几种的混合溶剂;
所述式 a-1化合物与所述 HNR2R3的摩尔用量比为: 1:1.2~1:10; 所述式 b-1化合物可按下述方法转化为式 b-2化合物:
式 b-1化合物在碱作用下与 R3Y进行反应, 或
其中: Y为 I, Br, Cl。
所述碱为: 氢氧化钠、 氢氧化钾、 碳酸钠、 碳酸钾、 乙醇钠、 乙醇钾、 叔 丁醇钠、 叔丁醇钾、 氨基钠、 三乙胺、 三丁胺或 N-曱基吗啉;
所述式 b-1化合物与所述 R3Y的摩尔用量比为: 1:1.2~1:10;
所述式 b-1化合物与所述碱的摩尔用量比为: 1: 1.2~1:5;
该步反应所用溶剂选自曱醇、 乙醇、 丙醇、 丁醇、 四氢呋喃、 曱苯、 曱基 叔丁基醚、 二氧六环、 乙腈、 DMAC、 DMF、 DMSO 中的一种或其中几种的 混合溶剂。
所述酸为: 乙酸、 三氟乙酸、 盐酸、 酸、 曱蹟酸、 对曱苯蹟酸、 对曱苯 磺酸吡 1定盐;
所述式 b-1化合物与所述酸的摩尔用量比为: 1 :(0.1~1);
所述式 c化合物与所述 R3ONa的摩尔用量比为: 1(0.1~1);
该反应所用溶剂选自: 曱醇、 乙醇、 丙醇、 异丙醇、 丁醇、 四氢呋喃、 二 氯曱烷。
所述的式 b-2 化合物按照现有技术文件提供的方法, 例如日本申请文件
JP2008031131 , 美国专利 US6207822 中提供的方法, 可以制备得到依泽替米 贝。
所述的式 b-3化合物按照现有技术文件提供的方法, 例如 WO2007017705 中提供的方法, 可以制备得到依泽替米贝。 本发明给出的依泽替米贝手性中间体的制备方法, 具有的有益效果为: 1 ) 本发明的手性还原剂用量低, 与底物的摩尔比小于 1/1000; 2 ) 氢源为氢气, 到 95%以上。 3 ) 当式 M结构化合物中所述 X为 d~ C4烷基时, 手性催化剂 的摩尔用量为底物的 1/50000, 得到的产物的光学纯度也可达到 98%以上, 收 率也可以达到 95%以上; 4 )本发明中, 当底物为 5-(4-氟苯基 )-5-羰基戊酸时, 由于底物中含有羧 ½团,通常情况下可毒化催化剂,从而要加大催化剂的用
量才能得到期望的收率和光学纯度,而在本发明中手性催化剂的摩尔用量为底 物 5-(4-氟苯基 )-5-羰基戊酸的 1/50000, 得到产物的光学纯度也可以达到 98% 以上, 收率也可以达到 95以上。 因此本发明在依泽替米贝的工业生产中具有 很高的应用价值。 附图说明
图 1为实施例 1制备 ( -5-(4-氟苯基 )-5-羟基戊酸的光学纯度报告 ( ee );
图 2为实施例 6制备 ( -5-(4-氟苯基 )-5-羟基戊酸曱酯的光学纯度报告 ( ee ); 图 3 为实施例 8 制备 ( -5-(4-氟苯基 )-5-羟基 -1-吗啉戊 -1-酮的光学纯度报告 ( ee )。 具体实施方式 鉴本文内容, 适当改进工艺参数实现。 特别需要指出的是, 所有类似的替换和 改动对本领域技术人员来说是显而易见的, 它们都被视为包括在本发明。本发 明的方法已经通过较佳实施例进行了描述,相关人员明显能在不脱离本发明内 容、精神和范围内对本文所述的方法和应用进行改动或适当变更与组合, 来实 现和应用本发明技术。 为了更好的理解本发明的内容, 下面结合具体实施例来做进一步的说明, 但具体的实施方式并不是对本发明的内容所做的限制。所述的手性催化剂均由 浙江九洲药业股份有限公司提供。
实施例 1: ( -5-(4-氟苯基 )-5-羟基戊酸的制备
称取 ( 5.0 mg , 0.005 mmol )手性催化剂 M ( X为 3-曱基 )和 ( 30.3 g , 270 mmol )叔丁醇钾至反应内管中, 把反应内管放入高压反应釜中, 向反应内管 中加入 500 mL乙醇和( 52.6 g , 250mmol ) 5-(4-氟苯基 )-5-羰基戊酸, 用氢气 置换釜体内的气体, 使氢气压力保持 0.2 ~ lOMPa, 加热至 50°C进行反应。 反 应 10小时后,将反应液浓缩。 向体系中加入 300 mL水和浓盐酸,调 pH=3~4。 加入 300 mL乙酸乙酯, 分液, 有机相用饱和食盐水洗涤, 无水硫酸钠干燥。 抽滤, 浓缩得浅黄色固体 ( -5-(4-氟苯基 )-5-羟基戊酸 53.0 g, 收率 100%, 经 核磁氢谱分析, 原料 5-(4-氟苯基 )-5-羰基戊酸转化完全。 产物经手性 HPLC分 析, 其光学纯度为 99.5%。
HPLC分析条件:
仪器: Agilent 1200
色谱柱: Chiracel OD-H, 4.6 mm x 250 mm x 5 μηι
柱温: 35 0C
流动相: 正己烷:乙醇:三氟乙酸:二乙胺 = 96:4:0.2:0.1
流速: 1.0 mL/min
波长: 210匪
¾ NMR (400 MHz, MeOD) δ 7.35 (dd, J = 5.6, 8.4 Hz, 2H), 7.02 (t, J = 8.8 Hz, 2H), 4.62 (t, / = 6.4 Hz, 1H), 2.17 (t, / = 7.0 Hz, 2H), 1.52-1.81 (m, 4H)。 实施例 2: ( -5-(4-氟苯基 )-5-羟基戊酸的制备
称取( 1.0 mg , 0.001 mmol )手性催化剂 M( X为 H )和( 606 mg , 5.4 mmol ) 叔丁醇钾至反应内管中, 把反应内管放入高压反应釜中, 向反应内管中加入 5 mL乙醇和(1.05 g , 5 mmol ) 5-(4-氟苯基 )-5-羰基戊酸, 用氢气置换釜体内 的气体, 使氢气压力保持 0.2 ~ 10MPa, 加热至 50°C进行反应。 反应 20小时 后,将反应液浓缩。向体系中加入 10 mL水和浓盐酸,调 pH=3~4。加入 10 mL 乙酸乙酯, 分液, 有机相用饱和食盐水再洗一次, 无水硫酸钠干燥。 抽滤, 浓 缩溶剂得浅黄色固体 ( -5-(4-氟苯基 )-5-羟基戊酸 1.06 g, 收率 96.1%, 经核磁 氢谱分析, 原料 5-(4-氟苯基 )-5-羰基戊酸转化完全。 产物经手性 HPLC分析, 其光学纯度为 97.5%。 实施例 3: ( -5-(4-氟苯基 )-5-羟基戊酸的制备
称取( 1.0 mg , 0.001 mmol )手性催化剂 M ( X为 4-曱基)和( 40 mg , 1.0 mmol ) 氢氧化钾至反应内管中, 把反应内管放入高压反应釜中, 向反应内管 中加入 5 ml DMF和(10.5 g , 50 mmol ) 5-(4-氟苯基 )-5-羰基戊酸, 用氢气置 换蒼体内的气体, 使氢气压力保持 0.2 ~ lOMPa, 加热至 50°C进行反应。 反应 20 'J、时后, 将反应液浓缩。 向体系中加入 10 mL水和浓盐酸, 调 pH=3~4。 加 入 10 mL乙酸乙酯, 分液, 有机相用饱和食盐水再洗一次, 无水硫酸钠干燥。 抽滤, 浓缩溶剂得浅黄色固体 ( -5-(4-氟苯基 )-5-羟基戊酸 10.3 g,收率 97.2%, 经核磁氢谱分析, 原料 5-(4-氟苯基 )-5-羰基戊酸转化完全。 产物经手性 HPLC 分析, 其光学纯度为 98.5%。 实施例 4: ( -5-(4-氟苯基 )-5-羟基戊酸的制备
称取( 1.0 mg , 0.001 mmol )手性催化剂 M ( X为 3-乙氧基 )和( 50.5 mg , 0.5 mmol )三乙胺至反应内管中, 把反应内管放入高压反应釜中, 向反应内管 中加入 5 mL乙醇和(0.2 g , 1 mmol ) 5-(4-氟苯基 )-5-羰基戊酸, 用氢气置换 釜体内的气体, 使氢气压力保持 0.2 ~ lOMPa, 加热至 50 °C进行反应。 反应 20 'J、时后, 将反应液浓缩。 向体系中加入 10 mL水和浓盐酸, 调 pH=3~4。 加入 10 mL乙酸乙酯, 分液, 有机相用饱和食盐水再洗一次, 无水硫酸钠干燥。 抽 滤, 浓缩溶剂得浅黄色固体 ( -5-(4-氟苯基 )-5-羟基戊酸 0.2 g, 收率 100%, 经 核磁氢谱分析, 原料 5-(4-氟苯基 )-5-羰基戊酸转化完全。 产物经手性 HPLC分 析, 其光学纯度为 98.8%。 实施例 5: ( -5-(4-氟苯基 )-5-羟基戊酸的制备
称取( 1.0 mg , 0.001 mmol )手性催化剂 M ( X为 4- ( 3-曱氧基苯基 ) )和 ( 50.5 mg , 0.5 mmol )叔丁醇钠至反应内管中,把反应内管放入高压反应釜中, 向反应内管中加入 5 mL乙醇和( 0.2 g ,1 mmol ) 5-(4-氟苯基 )-5-羰基戊酸, 用 氢气置换蒼体内的气体,使氢气压力保持 0.2 ~ lOMPa,加热至 50°C进行反应。 反应 24小时后,将反应液浓缩。向体系中加入 10 mL水和浓盐酸,调 pH=3~4。 加入 10 mL 乙酸乙酯, 分液, 有机相用饱和食盐水再洗一次, 无水硫酸钠干 燥。抽滤,浓缩溶剂得浅黄色固体 ( -5-(4-氟苯基 )-5-羟基戊酸 0.2 g,收率 100%, 经核磁氢谱分析, 原料 5-(4-氟苯基 )-5-羰基戊酸转化完全。 产物经手性 HPLC 分析, 其光学纯度为 97.1%。 实施例 6: ( -5-(4-氟苯基 )-5-羟基戊酸曱酯的制备
称取 ( 1.0 mg , 0.001 mmol )手性催化剂 M ( X为 3-曱基 )和 ( 44.8 mg , 0.4 mmol ) 乙醇钠至反应内管中, 把反应内管放入高压反应釜中, 向反应内管中 加入 5 mL乙醇和(2.24 g , 10 mmol ) 5-(4-氟苯基 )-5-羰基戊酸曱酯, 用氢气 置换釜体内的气体, 使氢气压力保持 0.2 ~ 10MPa, 将反应加热至 30°C进行反 应。 反应 2小时后, 将应液浓缩, 向体系中加入 10 mL曱醇, 加热至回流 3 小时。 将反应液冷却后浓缩, 加入 15 mL水和 15 mL乙酸乙酯, 分液。 水相 再用乙酸乙酯萃取两次( 10 mLx2 ), 合并有机相, 用饱和食盐水再洗一次, 无水硫酸钠干燥。抽滤,旋干溶剂得浅黄色液体 ( -5-(4-氟苯基 )-5-羟基戊酸曱 酯 2.2 g, 收率 97% , 经核磁氢谱分析, 原料 5-(4-氟苯基 )-5-羰基戊酸曱酯转化 完全。 产物经手性 HPLC分析, 其光学纯度为 99.3%。
HPLC分析条件:
仪器: Agilent 1200
色谱柱: Chiracel AD-H, 4.6 mm x 250 mm x 5 μηι
柱温: 35 0C
流动相: 正己烷:乙醇:三氟乙酸 =75:25 :0.1
流速: 1.0 mL/min
波长: 210匪
¾ NMR (400 MHz, CDC13) δ 7.33-7.29 (m, 2H), 7.03 (t, J = 8.8 Hz, 2H), 4.67 (t, J = 6.0 Hz, 1H), 3.66 (s, 3H), 2.34 (t, J = 7.2 Hz, 2H), 2.09 (s, 1H), 1.60-1.83 (m, 4H)。 实施例 7: l-(4-氟苯基 )-5-吗啉戊 -1, 二酮的制备
向 500mL三口瓶中加入( 10.5 g, 50 mmol ) 5-(4-氟苯基 )-5-羰基戊酸, 加 入 150 mL四氢呋喃, 体系冷却到 -5 °C , 加入 16mL 三乙胺。 滴加特戊酰氯 ( llmL, 90 mmol )。 加完后保持在该温度下反应 1小时。 加入 4-二曱氨基吡 啶(0.6mg, 5mmol )和吗啉( 5.25g, 60 mmol ), 室温反应 3小时, 反应完毕, 加入 100 mL水和 100 mL乙酸乙酯, 分液, 水相再用乙酸乙酯萃取两次( 50 mLx2 ), 合并有机相, 用饱和食盐水再洗一次, 无水硫酸钠干燥。 抽滤, 浓缩 溶剂得浅黄色液体 1-(4-氟苯基 )-5-吗啉戊 -1,5-二酮 12.9 g, 收率 92%。
^ NMR (400 MHz, CDC13) δ 8.04-7.99 (m, 2Η), 7.16-7.10 (m, 2H), 3.69-3.61 (m, 6H), 3.52-3.49 (m, 2H), 3.08 (t, J = 6.8 Hz, 2H), 2.44 (t, J = 7.2 Hz, 2H), 2.10-2.05 (m, 2H)。 实施例 8: ( -5-(4-氟苯基 )-5-羟基 -1-吗啉戊 -1-酮的制备
称取( 1.0 mg , 0.001 mmol )手性催化剂 M ( X为 3-曱基 )和( 22.4 mg , 0.2 mmol )叔丁醇钾至反应内管中, 把反应内管放入高压反应釜中, 向反应内管 中加入 5 mL乙醇和( 1.4 g , 5 mmol ) 1-(4-氟苯基 )-5-吗啉戊 -1,5-二酮, 用氢 气置换蒼体内的气体, 使氢气压力保持 0.2 ~ lOMPa, 将反应加热至 50°C进行 反应。 反应 10小时后将反应液浓缩。 向体系中加入 15 mL水和 15 mL乙酸乙 酯, 分液。 有机相用饱和食盐水再洗一次, 无水硫酸钠干燥。 抽滤, 浓缩得浅 黄色液体 ( -5-(4-氟苯基 )-5-羟基 -1-吗啉戊 -1-酮 1.4 g, 收率 100%, 经核磁氢 谱分析, 原料 1-(4-氟苯基 )-5-吗啉戊 -1,5-二酮转化完全。 产物经手性 HPLC分 析, 其光学纯度为 97.8%。
HPLC分析条件:
仪器: Agilent 1200
色谱柱: Chiracel AD-H, 4.6 mm x 250 mm x 5 μηι
柱温: 35 0C
流动相: 正己烷:乙醇:三氟乙酸 =75:25 :0.1
流速: 1.0 mL/min
波长: 210匪
¾ NMR (400 MHz, CDC13) δ 7.33-7.30 (m, 2H), 7.03-6.99 (m, 2H), 4.67 (t, J = 5.6 Hz, 1H), 3.64-3.58 (m, 6H), 3.44-3.41 (m, 2H), 2.40-2.28 (m, 2H), 1.83-1.66 (m, 4H)。 实施例 9: l-(4-氟苯基 )-5-N,N-二曱基戊 -1,5-二酮的制备
向 500mL三口瓶中加入 5-(4-氟苯基 )-5-羰基戊酸( 10.5 g, 50 mmol ), 加入 150 mL 四氢呋喃,体系冷却到 -5 °C ,加入 16mL三乙胺。滴加特戊酰氯( llmL, 90 mmol )。加完后保持在该温度下反应 1小时。加入 4-二曱氨基吡啶( 0.6mg, 5mmol ), 通入二曱胺气体, 室温反应 2小时, 反应完毕, 加入 100 mL水和 100 mL乙酸乙酯, 分液, 水相再用乙酸乙酯萃取两次(50 mLx2 ), 合并有机 相, 用饱和食盐水再洗一次, 无水硫酸钠干燥。 抽滤, 浓缩溶剂得浅黄色液体 1—(4-氟苯基 )-5-N,N-二曱基戊 -1,5-二酮 11.1 g, 收率 93.2%。
^ NMR (400 MHz, CDC13) δ 8.04-7.99 (m, 2Η), 7.16-7.10 (m, 2H), 3.69-3.61
(m, 6H), 3.52-3.49 (m, 2H), 3.08 (t, J = 6.8 Hz, 2H), 2.44 (t, J = 7.2 Hz, 2H), 2.10-2.05 (m, 2H)。
实施例 10: 0 )-5-(4-氟苯基 )-5-羟基 -Ν,Ν-二曱基戊酰胺的制备
称取( 1.0 mg , 0.001 mmol )手性催化剂 M ( X为 3-曱基 )和( 22.4 mg , 0.2 mmol )叔丁醇钾至反应内管中, 把反应内管放入高压反应釜中, 向反应内管 中加入 5 mL乙醇和 ( 1.2 g , 5 mmol ) 1-(4-氟苯基 )-5-N,N-二曱基戊 -1,5-二酮, 用氢气置换釜体内的气体, 使氢气压力保持 0.2 ~ lOMPa, 将反应加热至 50°C 进行反应。 反应 8小时后将反应液浓缩。 向体系中加入 15 mL水和 15 mL乙 酸乙酯, 分液。 有机相用饱和食盐水再洗一次, 无水硫酸钠干燥。 抽滤, 浓缩 得浅黄色液体 ( -5-(4-氟苯基 )-5-羟基 -Ν,Ν-二曱基戊酰胺 1.2 g, 收率 100%, 经核磁氢谱分析, 原料 1-(4-氟苯基 )-5-吗啉戊 -1,5-二酮转化完全。 产物经手性 HPLC分析, 其光学纯度为 98.2%。 实施例 11: ( -5-(4-氟苯基)-戊内酯的制备
向 250mL二口瓶中加入 ( -5-(4-氟苯基 )-5-羟基戊酸( 14.0 g, 66 mmol ), 加入 120 mL二氯曱烷,体系冷却到 0 °C。 滴加三氟乙酸( 3.4 mL, 45 mmol )。 加完后室温下反应 2小时。 TLC监测反应完全, 加入 100 mL饱和碳酸氢钠, 分液, 水相再用二氯曱烷萃取两次(50 mLx2 ), 合并有机相, 用饱和食盐水 再洗一次, 无水硫酸钠干燥。 抽滤, 旋干溶剂得白色固体 ( -5-(4-氟苯基) -戊 内酯 12.2 g, 收率 95%。
¾ NMR (400 MHz, CDC13) δ 7.35-7.31 (m, 2H), 7.10-7.04 (m, 2H), 5.33 (dd,
J = 3.2, 10.8 Hz, 1H), 2.76-2.68 (m, 1H), 2.62-2.53 (m, 1H), 2.19-2.13 (m, 1H), 2.03-1.96 (m, 2H), 1.87-1.82 (m, 1H)。
实施例 12: ( -5-(4-氟苯基 )-5-羟基戊酸曱酯的制备
向 250mL二口瓶中加入 ( -5-(4-氟苯基)-戊内酯(27.7 g, 142.6 mmol )和 曱醇钠 (1.54 g, 28.5 mmol ), 将体系置换成氮气氛围。 加入 100 mL 曱醇, 加完后室温下反应 6小时。 TLC监测反应完全。 旋蒸除去曱醇, 加入 lOO mL 二氯曱烷, 分液, 水相再用二氯曱烷萃取两次(50 mLx2 ), 合并有机相, 用 饱和食盐水再洗一次,无水硫酸钠干燥。抽滤,旋干溶剂得浅黄色液体 ( -5-(4- 氟苯基 )-5-羟基戊酸曱酯 29.0 g, 收率 90%。
¾ NMR (400 MHz, CDC13) δ 7.33-7.29 (m, 2H), 7.03 (t, J = 8.8 Hz, 2H), 4.67 (t, J = 6.0 Hz, 1H), 3.66 (s, 3H), 2.34 (t, J = 7.2 Hz, 2H), 2.09 (s, 1H), 1.60-1.83 (m, 4H)。 实施例 13: ( -5-(4-氟苯基 )-5-羟基戊酸曱酯的制备
向 250mL圓底瓶中加入 0¾-5-(4-氟苯基 )-5-羟基戊酸( 10.6 g, 50 mmol )、 碳酸钾( 9.0 g, 65 mmol )和 DMF 50 mL, 搅拌得一悬浊液。 加入碘曱烷 ( 4.4 mL, 70mmol ), 加完后室温下反应 2小时。 TLC监测反应完全。 加入 300 mL 水和 100 mL 曱基叔丁基醚, 分液, 水相再用曱基叔丁基醚萃取两次 (100 mLx2 ), 合并有机相, 用饱和食盐水再洗一次, 无水硫酸钠干燥。 抽滤, 旋干 溶剂得浅黄色液体 ( -5-(4-氟苯基 )-5-羟基戊酸曱酯 10.4 g, 收率 92%。
¾ NMR (400 MHz, CDC13) δ 7.33-7.29 (m, 2H), 7.03 (t, J = 8.8 Hz, 2H),
4.67 (t, J = 6.0 Hz, 1H), 3.66 (s, 3H), 2.34 (t, J = 7.2 Hz, 2H), 2.09 (s, 1H), 1.60-1.83 (m, 4H)。
实施例 14: ( -5-(4-氟苯基 )-5-羟基戊酸苄酯的制备
向 lOOmL圓底瓶中加入 ( 10.6 g, 50 mmol ) ( -5-(4-氟苯基 )-5-羟基戊酸、 碳酸钾(9.0 g, 65 mmol )和二曱基曱酰胺 25 mL, 搅拌得一悬浊液。 加入苄 溴(12g, 70mmol ), 加完后室温下反应 3小时。 TLC监测反应完全。 加入 300 mL水和 100 mL曱基叔丁基醚, 分液, 水相再用曱基叔丁基醚萃取两次( 100 mLx2 ), 合并有机相, 用饱和食盐水再洗一次, 无水硫酸钠干燥。 抽滤, 旋干 溶剂得浅黄色液体 ( -5-(4-氟苯基 )-5-羟基戊酸苄酯 20 g, 收率 95.2%。 实施例 15: ( -5-(4-氟苯基 )-5-羟基戊酸丙酯的制备
向 lOOmL圓底瓶中加入 ( 10.6 g, 50 mmol ) ( -5-(4-氟苯基 )-5-羟基戊酸、 ( 9.0 g, 65 mmol )碳酸钾和 25 mL DMF, 搅拌得一悬浊液。 加入( 7.9 g, lOOmmol ) 氯丙烷, 加完后加热至 60°C下反应 10小时。 TLC监测反应完全。 加入 300 mL水和 100 mL曱基叔丁基醚, 分液, 水相再用曱基叔丁基醚萃取 两次(100 mLx2 ), 合并有机相, 用饱和食盐水再洗一次, 无水硫酸钠干燥。 抽滤, 旋干溶剂得浅黄色液体 0¾-5-(4-氟苯基 )-5-羟基戊酸丙酯 10.9g, 收率 86%。
¾ NMR (400 MHz, CDC13) δ 7.35-7.29 (m, 2H), 7.04 (t, J = 8.8 Hz, 2H), 4.67 (t, / = 5.6 Hz, 1H), 4.02 (t, / = 6.8 Hz, 2H), 2.38-2.30 (m, 2H), 2.19 (s, 1H), 1.82-1.59 (m, 6H), 0.93 (t, / = 7.2 Hz, 3H)。 实施例 16: ( -5-(4-氟苯基 )-5-羟基戊酸苄酯的制备
向 250mL二口瓶中加入 0¾-5-(4-氟苯基)-戊内酯(27.7 g, 142.6 mmol )和 苄醇钠 (2.65 g, 20.4 mmol ), 将体系置换成氮气氛围。 加入 100 mL 曱醇, 加完后室温下反应 10小时。 TLC监测反应完全。 旋蒸除去曱醇, 加入 lOO mL 二氯曱烷, 分液, 水相再用二氯曱烷萃取两次(50 mLx2 ), 合并有机相, 用 饱和食盐水再洗一次,无水硫酸钠干燥。抽滤,旋干溶剂得浅黄色液体 ( -5-(4- 氟苯基 )-5-羟基戊酸苄酯 39.6 g, 收率 92.0%。 需要说明的是在本发明中提及的所有文献在本申请中引用作为参考,就如 同每一篇文献被单独引用作为参考那样。此外应理解, 以上所述的是本发明的 具体实施例及所运用的技术原理,在阅读了本发明的上述内容之后, 本领域技 术人员可以对本发明作各种改动或修改而不背离本发明的精神与范围,这些等 价形式同样落在本发明的范围内。
Claims
其中: R为 NRiRs, OR3或 OH;
Ri和 R2各自独立的为烷基或 与 R2可环合成哌啶;
R3为 d~C6烷基或苄基;
Μ
为 11、 C广 C8烷基, d~C8烷氧基, 苯基、 取代苯基或苄基, 所述的苯 基上的取代基为 d~C8的烃基、 烷氧基, 取代基数量为 1~5个。
2、 根据权利要求 1所述的制备方法, 其中所述 X为 d~C4烷基。
3、 根据权利要求 1所述的制备方法, 其中所述碱选自氢氧化钠、 氢氧化 钾、 碳酸钠、 碳酸钾、 乙醇钠、 乙醇钾、 叔丁醇钠、 叔丁醇钾、 氨基钠、 三乙 胺、 三丁胺或 N-曱基吗啉。
4、 根据权利要求 1所述的制备方法, 所述式(a)化合物与所述手性催化 剂的摩尔用量比为 1: ( 0.001 ~ 0.00002 )。
5、 根据权利要求 1所述的制备方法, 所述式(a)化合物与所述碱的摩尔 用量比为 1: (0.001 ~ 0.7)。
6、 根据权利要求 1所述的制备方法, 该反应是在温度为 0~80°C范围内 进行的。
其中 Rl R2, R3的定义与权利要求 1的定义相同。
8、 根据权利要求 1所述的制备方法, 式(b)化合物中 R为 OH, 进一步 的包括将所述的式(b)化合物转化为式(b-2)化合物的步骤:
其中 Y为 I, Br或 CI; R3的定义与权利要求 1相同。
9、 根据权利要求 8所述的制备方法, 其中所述的碱为氢氧化钠、 氢氧化 钾、 碳酸钠、 碳酸钾、 乙醇钠、 乙醇钾、 叔丁醇钠、 叔丁醇钾、 氨基钠、 三乙
胺、 三丁胺或 N-曱基吗啉; 所述的酸为乙酸、 三氟乙酸、 盐酸、 硫酸、 曱磺 酸、 对曱苯橫酸或对曱苯橫酸吡啶盐。
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CN101423511A (zh) * | 2007-11-05 | 2009-05-06 | 中山奕安泰医药科技有限公司 | 依泽替米贝中间体及依泽替米贝的合成方法 |
WO2009067960A2 (en) * | 2007-11-30 | 2009-06-04 | Zentiva, A.S. | A method of manufacturing (3r,4s)-l-(4-fluorophenyl)-3-[(3s)-3-(4-fluorophenyl)-3- hydroxypropyl)]-4-(4-hydroxyphenyl)-2-azetidinone and its intermediates |
CN101565366A (zh) * | 2008-04-25 | 2009-10-28 | 南开大学 | 铱络合物在不饱和羧酸不对称催化氢化中的应用 |
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CN101346349A (zh) * | 2005-12-20 | 2009-01-14 | 吉瑞工厂 | 依泽替米贝的制备方法及该方法中所用的中间体 |
CN101423511A (zh) * | 2007-11-05 | 2009-05-06 | 中山奕安泰医药科技有限公司 | 依泽替米贝中间体及依泽替米贝的合成方法 |
WO2009067960A2 (en) * | 2007-11-30 | 2009-06-04 | Zentiva, A.S. | A method of manufacturing (3r,4s)-l-(4-fluorophenyl)-3-[(3s)-3-(4-fluorophenyl)-3- hydroxypropyl)]-4-(4-hydroxyphenyl)-2-azetidinone and its intermediates |
CN101565366A (zh) * | 2008-04-25 | 2009-10-28 | 南开大学 | 铱络合物在不饱和羧酸不对称催化氢化中的应用 |
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CN107827802A (zh) * | 2017-10-17 | 2018-03-23 | 南京红杉生物科技有限公司 | 一种d‑脯氨酸的合成方法 |
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