CN103896700B - The preparation method of ezetimibe chiral intermediate - Google Patents
The preparation method of ezetimibe chiral intermediate Download PDFInfo
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- CN103896700B CN103896700B CN201210567342.2A CN201210567342A CN103896700B CN 103896700 B CN103896700 B CN 103896700B CN 201210567342 A CN201210567342 A CN 201210567342A CN 103896700 B CN103896700 B CN 103896700B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 37
- 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 11
- 229960000815 ezetimibe Drugs 0.000 title abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 50
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 33
- 239000001257 hydrogen Substances 0.000 claims abstract description 31
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000003054 catalyst Substances 0.000 claims abstract description 20
- 239000003513 alkali Substances 0.000 claims abstract description 12
- 230000000694 effects Effects 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 46
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- 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
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 12
- 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 12
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 10
- 239000002994 raw material Substances 0.000 claims description 9
- 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
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 7
- 235000015320 potassium carbonate Nutrition 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- GHVZOJONCUEWAV-UHFFFAOYSA-N [K].CCO Chemical compound [K].CCO GHVZOJONCUEWAV-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
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 150000003053 piperidines Chemical class 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims description 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 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 230000003287 optical effect Effects 0.000 abstract description 16
- 238000000034 method Methods 0.000 abstract description 10
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 29
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 19
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 16
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 16
- 238000001035 drying Methods 0.000 description 16
- 239000012074 organic phase Substances 0.000 description 16
- 238000000967 suction filtration Methods 0.000 description 16
- 229920006395 saturated elastomer Polymers 0.000 description 15
- 235000002639 sodium chloride Nutrition 0.000 description 15
- 239000011780 sodium chloride Substances 0.000 description 15
- 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 14
- 239000007788 liquid 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
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 12
- -1 ketone compound Chemical class 0.000 description 11
- FSXKAGUHLIGGRG-JTQLQIEISA-N (5s)-5-(4-fluorophenyl)-5-hydroxypentanoic acid Chemical compound OC(=O)CCC[C@H](O)C1=CC=C(F)C=C1 FSXKAGUHLIGGRG-JTQLQIEISA-N 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000008346 aqueous phase Substances 0.000 description 9
- 239000007789 gas Substances 0.000 description 9
- 238000004296 chiral HPLC Methods 0.000 description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 8
- 238000010183 spectrum analysis Methods 0.000 description 8
- 238000012544 monitoring process Methods 0.000 description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000000758 substrate Substances 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- 239000007810 chemical reaction solvent Substances 0.000 description 4
- XOJJSCKFUDKCEM-JTQLQIEISA-N (6s)-6-(4-fluorophenyl)oxan-2-one Chemical compound C1=CC(F)=CC=C1[C@H]1OC(=O)CCC1 XOJJSCKFUDKCEM-JTQLQIEISA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
- 239000003638 chemical reducing agent Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- CNSYWQRIAXFIJC-KRWDZBQOSA-N O[C@@H](CCCC(OCC1=CC=CC=C1)=O)C(C=C1)=CC=C1F Chemical compound O[C@@H](CCCC(OCC1=CC=CC=C1)=O)C(C=C1)=CC=C1F CNSYWQRIAXFIJC-KRWDZBQOSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- HNBDRPTVWVGKBR-UHFFFAOYSA-N n-pentanoic acid methyl ester Natural products CCCCC(=O)OC HNBDRPTVWVGKBR-UHFFFAOYSA-N 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- BQZPXBQCPUMINN-ZDUSSCGKSA-N CCCOC(CCC[C@@H](C(C=C1)=CC=C1F)O)=O Chemical compound CCCOC(CCC[C@@H](C(C=C1)=CC=C1F)O)=O BQZPXBQCPUMINN-ZDUSSCGKSA-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
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 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
- 102000004316 Oxidoreductases Human genes 0.000 description 1
- 108090000854 Oxidoreductases Proteins 0.000 description 1
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 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
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002431 hydrogen Chemical group 0.000 description 1
- 150000001261 hydroxy acids Chemical group 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 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
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- SNMVRZFUUCLYTO-UHFFFAOYSA-N n-propyl chloride Chemical compound CCCCl SNMVRZFUUCLYTO-UHFFFAOYSA-N 0.000 description 1
- FJDPDXXVTZSLJK-UHFFFAOYSA-N phenylmethanol;sodium Chemical compound [Na].OCC1=CC=CC=C1 FJDPDXXVTZSLJK-UHFFFAOYSA-N 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 238000009901 transfer hydrogenation reaction Methods 0.000 description 1
- 238000005406 washing 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
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- 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 Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table 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
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- Chemical & Material Sciences (AREA)
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- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to medical synthesis field, be specially the preparation method of ezetimibe chiral intermediate.The method is: one has the preparation method of the compound of formula (b) structure, comprises the steps: that formula (a) structural compounds is at chiral catalyst, namely obtains formula (b) structural compounds under alkali and hydrogen effect;
wherein: R is NR
1r
2, OR
3or OH; R
1and R
2be independently alkyl separately, R
3for C
1~ C
6alkyl or benzyl.Wherein said chiral catalyst is for having the compound of following formula (M) structure:
wherein DTB is:
Description
Technical field
The present invention relates to medical synthesis field, be specifically related to the preparation method of ezetimibe chiral intermediate.
Background technology
Ezetimibe (Ezetimibe) is a kind of novel cholesterol absorption inhibitor, for the treatment of hypercholesterolemia.Its chemical name is: 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydroxy phenyl)-2-lactan.
This compou nd synthesis committed step is how to obtain to mark in structural formula
sconfiguration,
US20090047716 reports and carries out chiral reduction with ketoreductase to corresponding ketone compound, but the general yield of the method is low, greatly about about 60%.
US5618707 reports and carries out chiral reduction with micro-reduction enzyme to corresponding ketone compound, utilizes the method can split without resolving agent, but reaction yield low (68%), and reductase enzyme incubation time is long, approximately needs 72 hours.
WO2008089984 reports a kind of transfer hydrogenation catalyzer carries out asymmetric reduction preparation method to corresponding ketone, and the method take carboxylic acid derivatives as hydrogen source, and the consumption of catalyzer is high, unfavorable environmental protection.
International patent application WO2005066120 and WO2004099132 is all that chiral reducing agent carries out chiral reduction to corresponding ketone compound with (-)-DIP-Cl, and wherein chiral reducing agent (-)-DIP-Cl has having structure:
(-)-DIP-Cl shortcoming is, such as corrodibility, and easy moisture absorption becomes tide, and to air-sensitive, expensive, Atom economy is low, and aftertreatment is loaded down with trivial details, causes the mole dosage of chiral reducing agent large (at least needing 1. ~ 1.8 equivalents), yield low (83%).
Summary of the invention
In order to solve in above-mentioned prior art, in reaction process, chiral reduction agent consumption is large, the problems such as product yield is low, and the invention provides a kind of method for the preparation of ezetimibe chiral intermediate newly, concrete scheme is as follows:
A preparation method for the compound of formula b structure, comprises the steps: that formula a structural compounds is at chiral catalyst, namely obtains formula b structure compound under alkali and hydrogen effect;
Wherein: R is NR
1r
2, OR
3or OH; R
1and R
2be independently alkyl or R separately
1with R
2cyclization can become piperidines, R
3for C
1~ C
6alkyl or benzyl.
Described chiral catalyst is the compound with following formula M structure:
Wherein DTB is:
X is H, C
1~ C
8alkyl, C
1~ C
8alkoxyl group, phenyl, substituted-phenyl or benzyl, the substituting group on described phenyl is C
1~ C
8alkyl, alkoxyl group, substituting group quantity is 1 ~ 5.
Described X is preferably C
1~ C
4alkyl.
Described alkali is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium ethylate, potassium ethylate, sodium tert-butoxide, potassium tert.-butoxide, sodium amide, triethylamine, Tributylamine or N-methylmorpholine;
Described reaction solvent for use is selected from a kind of or wherein several mixed solvent in methyl alcohol, ethanol, propyl alcohol, butanols, tetrahydrofuran (THF), toluene, methyl tertiary butyl ether, dioxane, DMF, DMSO.
Described hydrogen pressure is 0.2 ~ 10MPa;
Described formula a compound is 1:(0.001 ~ 0.00002 with the mole dosage ratio of chiral catalyst);
Described formula a compound is 1:(0.001 ~ 0.7 with the mole dosage ratio of alkali);
The temperature of reaction of described reaction is 0 ~ 80
oc.
Concrete, described formula b compound is selected from following compounds:
，
，
Wherein R
1, R
2, R
3definition identical with above-mentioned definition.
When R is NR
1r
2time, formula a compound is specially the following compounds with a-3 structure:
Described formula a-3 formula a-1 compound and HNR
1r
2reaction prepares;
The reaction solvent of described reaction is selected from: a kind of or wherein several mixed solvent in tetrahydrofuran (THF), methylene dichloride, toluene, methyl tertiary butyl ether, dioxane, DMF, DMSO;
Described formula a-1 compound and described HNR
2r
3mole dosage ratio be: 1:1.2 ~ 1:10;
Described formula b-1 compound can be converted into formula b-2 compound as follows:
Formula b-1 compound under alkali effect with R
3y reacts, or
Formula b-1 compound obtains formula c compound under acid effect, formula c compound and R
3oNa carries out being obtained by reacting shown formula b-2 compound.
Wherein: Y is I, Br, Cl.
Described alkali is: sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium ethylate, potassium ethylate, sodium tert-butoxide, potassium tert.-butoxide, sodium amide, triethylamine, Tributylamine or N-methylmorpholine;
Described formula b-1 compound and described R
3the mole dosage ratio of Y is: 1:1.2 ~ 1:10;
Described formula b-1 compound with the mole dosage ratio of described alkali is: 1:1.2 ~ 1:5;
This step reaction solvent for use is selected from a kind of or wherein several mixed solvent in methyl alcohol, ethanol, propyl alcohol, butanols, tetrahydrofuran (THF), toluene, methyl tertiary butyl ether, dioxane, acetonitrile, DMAC, DMF, DMSO.
Described acid is: acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, methylsulfonic acid, tosic acid, para-methylbenzenepyridinsulfonate sulfonate;
Described formula b-1 compound with the mole dosage ratio of described acid is: 1:(0.1 ~ 1);
Described formula c compound and described R
3the mole dosage ratio of ONa is: 1 (0.1 ~ 1);
This reaction solvent for use is selected from: methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, tetrahydrofuran (THF), methylene dichloride.
Described formula b-2 compound is the method that provides of file conventionally, and such as Japanese publication file JP2008031131, the method provided in US Patent No. 6207822, can prepare ezetimibe.
Described formula b-3 compound is the method that provides of file conventionally, and the method such as, provided in WO2007017705, can prepare ezetimibe.
The preparation method of the ezetimibe chiral intermediate that the present invention provides, the beneficial effect had is: 1) chiral reduction agent consumption of the present invention is low, is less than 1/1000 with the mol ratio of substrate; 2) hydrogen source is hydrogen, compared with prior art environmental protection and the optical purity of product can reach more than 97%, and yield all can reach more than 95%.3) when X described in formula M structural compounds is C
1~ C
4during alkyl, the mole dosage of chiral catalyst is 1/50000 of substrate, and the optical purity of the product obtained also can reach more than 98%, and yield also can reach more than 95%; 4) in the present invention, when substrate is 5-(4-fluorophenyl)-5-carbonyl valeric acid, owing to containing hydroxy-acid group in substrate, catalyzer can be poisoned under normal circumstances, thus the yield wanting the consumption of larger catalyst just can obtain expecting and optical purity, and the mole dosage of chiral catalyst is 1/50000 of substrate 5-(4-fluorophenyl)-5-carbonyl valeric acid in the present invention, the optical purity obtaining product also can reach more than 98%, and yield also can reach more than 95.Therefore the present invention has very high using value in the industrial production of ezetimibe.
Accompanying drawing explanation
Fig. 1 be embodiment 1 prepare (
s)-5-(4-fluorophenyl)-5-hydroxypentanoic acid optical purity report (ee);
Fig. 2 be embodiment 6 prepare (
s)-5-(4-fluorophenyl)-5-hydroxyl methyl optical purity report (ee);
Fig. 3 be embodiment 8 prepare (
s)-5-(4-fluorophenyl)-5-hydroxyl-1-morpholine penta-1-ketone optical purity report (ee).
Embodiment
Content for a better understanding of the present invention, is described further below in conjunction with specific embodiment, but concrete embodiment is not the restriction done content of the present invention.Described chiral catalyst provides by Zhejiang Province Jiuzhou Pharmaceutical Co., Ltd.
embodiment 1:(
s) preparation of-5-(4-fluorophenyl)-5-hydroxypentanoic acid
Take (5.0mg, 0.005mmol) chiral catalyst M(X is 3-methyl) and (30.3g, 270mmol) potassium tert.-butoxide is in the interior pipe of reaction, pipe in reaction is put into autoclave, 500mL ethanol and (52.6g, 250mmol) 5-(4-fluorophenyl)-5-carbonyl valeric acid is added, with the gas in hydrogen exchange kettle in pipe in reaction, make hydrogen pressure keep 0.2 ~ 10MPa, be heated to 50 DEG C and react.React after 10 hours, reaction solution is concentrated.In system, add 300mL water and concentrated hydrochloric acid, adjust pH=3 ~ 4.Add 300mL ethyl acetate, separatory, organic phase saturated common salt water washing, anhydrous sodium sulfate drying.Suction filtration, concentrated light yellow solid (
s)-5-(4-fluorophenyl)-5-hydroxypentanoic acid 53.0g, yield 100%, through nucleus magnetic hydrogen spectrum analysis, raw material 5-(4-fluorophenyl)-5-carbonyl valeric acid transforms completely.The chiral HPLC of product analyzes, and its optical purity is 99.5%.
HPLC analysis condition:
Instrument: Agilent1200
Chromatographic column: ChiracelOD-H, 4.6mm ' 250mm ' 5mm
Column temperature: 35
oc
Moving phase: normal hexane: ethanol: trifluoroacetic acid: diethylamine=96:4:0.2:0.1
Flow velocity: 1.0mL/min
Wavelength: 210nm
1HNMR(400MHz,MeOD)δ7.35(dd,
J=5.6,8.4Hz,2H),7.02(t,
J=8.8Hz,2H),4.62(t,
J=6.4Hz,1H),2.17(t,
J=7.0Hz,2H),1.52-1.81(m,4H)。
embodiment 2:(
s) preparation of-5-(4-fluorophenyl)-5-hydroxypentanoic acid
Take (1.0mg, 0.001mmol) chiral catalyst M(X is H) and (606mg, 5.4mmol) potassium tert.-butoxide is in the interior pipe of reaction, pipe in reaction is put into autoclave, 5mL ethanol and (1.05g, 5mmol) 5-(4-fluorophenyl)-5-carbonyl valeric acid is added, with the gas in hydrogen exchange kettle in pipe in reaction, make hydrogen pressure keep 0.2 ~ 10MPa, be heated to 50 DEG C and react.React after 20 hours, reaction solution is concentrated.In system, add 10mL water and concentrated hydrochloric acid, adjust pH=3 ~ 4.Add 10mL ethyl acetate, separatory, organic phase saturated aqueous common salt is washed once again, anhydrous sodium sulfate drying.Suction filtration, concentrated solvent obtain light yellow solid (
s)-5-(4-fluorophenyl)-5-hydroxypentanoic acid 1.06g, yield 96.1%, through nucleus magnetic hydrogen spectrum analysis, raw material 5-(4-fluorophenyl)-5-carbonyl valeric acid transforms completely.The chiral HPLC of product analyzes, and its optical purity is 97.5%.
embodiment 3:(
s) preparation of-5-(4-fluorophenyl)-5-hydroxypentanoic acid
Take (1.0mg, 0.001mmol) chiral catalyst M(X is 4-methyl) and (40mg, 1.0mmol) potassium hydroxide is in the interior pipe of reaction, pipe in reaction is put into autoclave, 5mlDMF and (10.5g, 50mmol) 5-(4-fluorophenyl)-5-carbonyl valeric acid is added, with the gas in hydrogen exchange kettle in pipe in reaction, make hydrogen pressure keep 0.2 ~ 10MPa, be heated to 50 DEG C and react.React after 20 hours, reaction solution is concentrated.In system, add 10mL water and concentrated hydrochloric acid, adjust pH=3 ~ 4.Add 10mL ethyl acetate, separatory, organic phase saturated aqueous common salt is washed once again, anhydrous sodium sulfate drying.Suction filtration, concentrated solvent obtain light yellow solid (
s)-5-(4-fluorophenyl)-5-hydroxypentanoic acid 10.3g, yield 97.2%, through nucleus magnetic hydrogen spectrum analysis, raw material 5-(4-fluorophenyl)-5-carbonyl valeric acid transforms completely.The chiral HPLC of product analyzes, and its optical purity is 98.5%.
embodiment 4:(
s) preparation of-5-(4-fluorophenyl)-5-hydroxypentanoic acid
Take (1.0mg, 0.001mmol) chiral catalyst M(X is 3-oxyethyl group) and (50.5mg, 0.5mmol) triethylamine is in the interior pipe of reaction, pipe in reaction is put into autoclave, 5mL ethanol and (0.2g, 1mmol) 5-(4-fluorophenyl)-5-carbonyl valeric acid is added, with the gas in hydrogen exchange kettle in pipe in reaction, make hydrogen pressure keep 0.2 ~ 10MPa, be heated to 50 DEG C and react.React after 20 hours, reaction solution is concentrated.In system, add 10mL water and concentrated hydrochloric acid, adjust pH=3 ~ 4.Add 10mL ethyl acetate, separatory, organic phase saturated aqueous common salt is washed once again, anhydrous sodium sulfate drying.Suction filtration, concentrated solvent obtain light yellow solid (
s)-5-(4-fluorophenyl)-5-hydroxypentanoic acid 0.2g, yield 100%, through nucleus magnetic hydrogen spectrum analysis, raw material 5-(4-fluorophenyl)-5-carbonyl valeric acid transforms completely.The chiral HPLC of product analyzes, and its optical purity is 98.8%.
embodiment 5:(
s) preparation of-5-(4-fluorophenyl)-5-hydroxypentanoic acid
Take (1.0mg, 0.001mmol) chiral catalyst M(X is 4-(3-p-methoxy-phenyl)) and (50.5mg, 0.5mmol) sodium tert-butoxide is in the interior pipe of reaction, pipe in reaction is put into autoclave, 5mL ethanol and (0.2g, 1mmol) 5-(4-fluorophenyl)-5-carbonyl valeric acid is added, with the gas in hydrogen exchange kettle in pipe in reaction, make hydrogen pressure keep 0.2 ~ 10MPa, be heated to 50 DEG C and react.React after 24 hours, reaction solution is concentrated.In system, add 10mL water and concentrated hydrochloric acid, adjust pH=3 ~ 4.Add 10mL ethyl acetate, separatory, organic phase saturated aqueous common salt is washed once again, anhydrous sodium sulfate drying.Suction filtration, concentrated solvent obtain light yellow solid (
s)-5-(4-fluorophenyl)-5-hydroxypentanoic acid 0.2g, yield 100%, through nucleus magnetic hydrogen spectrum analysis, raw material 5-(4-fluorophenyl)-5-carbonyl valeric acid transforms completely.The chiral HPLC of product analyzes, and its optical purity is 97.1%.
embodiment 6:(
s) preparation of-5-(4-fluorophenyl)-5-hydroxyl methyl
Take (1.0mg, 0.001mmol) chiral catalyst M(X is 3-methyl) and (44.8mg, 0.4mmol) sodium ethylate is in the interior pipe of reaction, pipe in reaction is put into autoclave, 5mL ethanol and (2.24g, 10mmol) 5-(4-fluorophenyl)-5-carbonyl methyl valerate is added, with the gas in hydrogen exchange kettle in pipe in reaction, make hydrogen pressure keep 0.2 ~ 10MPa, reaction is heated to 30 DEG C and reacts.React after 2 hours, liquid will be answered to concentrate, in system, add 10mL methyl alcohol, be heated to backflow 3 hours.By concentrated after reaction solution cooling, add 15mL water and 15mL ethyl acetate, separatory.Aqueous phase is extracted with ethyl acetate twice (10mL × 2) again, merges organic phase, washes once, anhydrous sodium sulfate drying with saturated aqueous common salt again.Suction filtration, be spin-dried for solvent obtain light yellow liquid (
s)-5-(4-fluorophenyl)-5-hydroxyl methyl 2.2g, yield 97%, through nucleus magnetic hydrogen spectrum analysis, raw material 5-(4-fluorophenyl)-5-carbonyl methyl valerate transforms completely.The chiral HPLC of product analyzes, and its optical purity is 99.3%.
HPLC analysis condition:
Instrument: Agilent1200
Chromatographic column: ChiracelAD-H, 4.6mm ' 250mm ' 5mm
Column temperature: 35
oc
Moving phase: normal hexane: ethanol: trifluoroacetic acid=75:25:0.1
Flow velocity: 1.0mL/min
Wavelength: 210nm
1HNMR(400MHz,CDCl
3)δ7.33-7.29(m,2H),7.03(t,
J=8.8Hz,2H),4.67(t,
J=6.0Hz,1H),3.66(s,3H),2.34(t,
J=7.2Hz,2H),2.09(s,1H),1.60-1.83(m,4H)。
the preparation of embodiment 7:1-(4-fluorophenyl)-5-morpholine penta-1,5-diketone
In 500mL there-necked flask, add (10.5g, 50mmol) 5-(4-fluorophenyl)-5-carbonyl valeric acid, add 150mL tetrahydrofuran (THF), system is cooled to-5 DEG C, adds 16mL triethylamine.Drip pivaloyl chloride (11mL, 90mmol).Add rear maintenance and react 1 hour at such a temperature.Add DMAP (0.6mg, 5mmol) with morpholine (5.25g, 60mmol), room temperature reaction 3 hours, reacts complete, add 100mL water and 100mL ethyl acetate, separatory, aqueous phase is extracted with ethyl acetate twice (50mL × 2) again, merges organic phase, wash again once with saturated aqueous common salt, anhydrous sodium sulfate drying.Suction filtration, concentrated solvent obtains light yellow liquid 1-(4-fluorophenyl)-5-morpholine penta-1,5-diketone 12.9g, yield 92%.
1HNMR(400MHz,CDCl
3)δ8.04-7.99(m,2H),7.16-7.10(m,2H),3.69-3.61(m,6H),3.52-3.49(m,2H),3.08(t,
J=6.8Hz,2H),2.44(t,
J=7.2Hz,2H),2.10-2.05(m,2H)。
embodiment 8:(
s) preparation of-5-(4-fluorophenyl)-5-hydroxyl-1-morpholine penta-1-ketone
Take (1.0mg, 0.001mmol) chiral catalyst M(X is 3-methyl) and (22.4mg, 0.2mmol) potassium tert.-butoxide is in the interior pipe of reaction, pipe in reaction is put into autoclave, in reaction, adds 5mL ethanol and (1.4g, 5mmol) 1-(4-fluorophenyl)-5-morpholine penta-1 in pipe, 5-diketone, with the gas in hydrogen exchange kettle, make hydrogen pressure keep 0.2 ~ 10MPa, reaction is heated to 50 DEG C and reacts.React and after 10 hours, reaction solution is concentrated.15mL water and 15mL ethyl acetate is added, separatory in system.Organic phase saturated aqueous common salt is washed once again, anhydrous sodium sulfate drying.Suction filtration, concentrated light yellow liquid (
s)-5-(4-fluorophenyl)-5-hydroxyl-1-morpholine penta-1-ketone 1.4g, yield 100%, through nucleus magnetic hydrogen spectrum analysis, raw material 1-(4-fluorophenyl)-5-morpholine penta-1,5-diketone transforms completely.The chiral HPLC of product analyzes, and its optical purity is 97.8%.
HPLC analysis condition:
Instrument: Agilent1200
Chromatographic column: ChiracelAD-H, 4.6mm ' 250mm ' 5mm
Column temperature: 35
oc
Moving phase: normal hexane: ethanol: trifluoroacetic acid=75:25:0.1
Flow velocity: 1.0mL/min
Wavelength: 210nm
1HNMR(400MHz,CDCl
3)δ7.33-7.30(m,2H),7.03-6.99(m,2H),4.67(t,
J=5.6Hz,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)。
the preparation of embodiment 9:1-(4-fluorophenyl)-5-N, N-dimethyl-penten-1,5-diketone
In 500mL there-necked flask, add 5-(4-fluorophenyl)-5-carbonyl valeric acid (10.5g, 50mmol), add 150mL tetrahydrofuran (THF), system is cooled to-5 DEG C, adds 16mL triethylamine.Drip pivaloyl chloride (11mL, 90mmol).Add rear maintenance and react 1 hour at such a temperature.Add DMAP (0.6mg, 5mmol), pass into dimethylamine gas, room temperature reaction 2 hours, reacts complete, add 100mL water and 100mL ethyl acetate, separatory, aqueous phase is extracted with ethyl acetate twice (50mL × 2) again, merges organic phase, wash again once with saturated aqueous common salt, anhydrous sodium sulfate drying.Suction filtration, concentrated solvent obtains light yellow liquid 1-(4-fluorophenyl)-5-N, N-dimethyl-penten-1,5-diketone 11.1g, yield 93.2%.
1HNMR(400MHz,CDCl
3)δ8.04-7.99(m,2H),7.16-7.10(m,2H),3.69-3.61(m,6H),3.52-3.49(m,2H),3.08(t,
J=6.8Hz,2H),2.44(t,
J=7.2Hz,2H),2.10-2.05(m,2H)。
embodiment 10:(
s)-5-(4-fluorophenyl)-5-hydroxy-n, the preparation of N-dimethyl-penten acid amides
Take (1.0mg, 0.001mmol) chiral catalyst M(X is 3-methyl) and (22.4mg, 0.2mmol) potassium tert.-butoxide is in the interior pipe of reaction, and pipe in reaction is put into autoclave, in reaction, add 5mL ethanol and (1.2g in pipe, 5mmol) 1-(4-fluorophenyl)-5-N, N-dimethyl-penten-1,5-diketone, with the gas in hydrogen exchange kettle, make hydrogen pressure keep 0.2 ~ 10MPa, reaction is heated to 50 DEG C and reacts.React and after 8 hours, reaction solution is concentrated.15mL water and 15mL ethyl acetate is added, separatory in system.Organic phase saturated aqueous common salt is washed once again, anhydrous sodium sulfate drying.Suction filtration, concentrated light yellow liquid (
s)-5-(4-fluorophenyl)-5-hydroxy-n, N-dimethyl-penten acid amides 1.2g, yield 100%, through nucleus magnetic hydrogen spectrum analysis, raw material 1-(4-fluorophenyl)-5-morpholine penta-1,5-diketone transforms completely.The chiral HPLC of product analyzes, and its optical purity is 98.2%.
embodiment 11:(
s) preparation of-5-(4-fluorophenyl)-valerolactone
Add in 250mL bis-mouthfuls of bottles (
s)-5-(4-fluorophenyl)-5-hydroxypentanoic acid (14.0g, 66mmol), add 120mL methylene dichloride, system is cooled to 0 DEG C.Drip trifluoroacetic acid (3.4mL, 45mmol).React 2 hours under adding rear room temperature.TLC monitoring reacts completely, and add 100mL saturated sodium bicarbonate, separatory, aqueous phase uses dichloromethane extraction twice (50mL × 2) again, merges organic phase, washes once, anhydrous sodium sulfate drying with saturated aqueous common salt again.Suction filtration, be spin-dried for solvent obtain white solid (
s)-5-(4-fluorophenyl)-valerolactone 12.2g, yield 95%.
1HNMR(400MHz,CDCl
3)δ7.35-7.31(m,2H),7.10-7.04(m,2H),5.33(dd,J=3.2,10.8Hz,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)。
embodiment 12:(
s) preparation of-5-(4-fluorophenyl)-5-hydroxyl methyl
Add in 250mL bis-mouthfuls of bottles (
s)-5-(4-fluorophenyl)-valerolactone (27.7g, 142.6mmol) and sodium methylate (1.54g, 28.5mmol), system is replaced as nitrogen atmosphere.Add 100mL methyl alcohol, react 6 hours under adding rear room temperature.TLC monitoring reacts completely.Revolve and steam removing methyl alcohol, add 100mL methylene dichloride, separatory, aqueous phase uses dichloromethane extraction twice (50mL × 2) again, merges organic phase, washes once, anhydrous sodium sulfate drying with saturated aqueous common salt again.Suction filtration, be spin-dried for solvent obtain light yellow liquid (
s)-5-(4-fluorophenyl)-5-hydroxyl methyl 29.0g, yield 90%.
1HNMR(400MHz,CDCl
3)δ7.33-7.29(m,2H),7.03(t,
J=8.8Hz,2H),4.67(t,
J=6.0Hz,1H),3.66(s,3H),2.34(t,
J=7.2Hz,2H),2.09(s,1H),1.60-1.83(m,4H)。
embodiment 13:(
s) preparation of-5-(4-fluorophenyl)-5-hydroxyl methyl
Add in 250mL round-bottomed bottle (
s)-5-(4-fluorophenyl)-5-hydroxypentanoic acid (10.6g, 50mmol), salt of wormwood (9.0g, 65mmol) and DMF50mL, stir to obtain a suspension liquid.Add methyl iodide (4.4mL, 70mmol), react 2 hours under adding rear room temperature.TLC monitoring reacts completely.Add 300mL water and 100mL methyl tertiary butyl ether, separatory, aqueous phase uses methyl tertiary butyl ether extracting twice (100mL × 2) again, merges organic phase, washes once, anhydrous sodium sulfate drying with saturated aqueous common salt again.Suction filtration, be spin-dried for solvent obtain light yellow liquid (
s)-5-(4-fluorophenyl)-5-hydroxyl methyl 10.4g, yield 92%.
1HNMR(400MHz,CDCl
3)δ7.33-7.29(m,2H),7.03(t,
J=8.8Hz,2H),4.67(t,
J=6.0Hz,1H),3.66(s,3H),2.34(t,
J=7.2Hz,2H),2.09(s,1H),1.60-1.83(m,4H)。
embodiment 14:(
s) preparation of-5-(4-fluorophenyl)-5-hydroxypentanoic acid benzyl ester
Add in 100mL round-bottomed bottle (10.6g, 50mmol) (
s)-5-(4-fluorophenyl)-5-hydroxypentanoic acid, salt of wormwood (9.0g, 65mmol) and dimethyl formamide 25mL, stir to obtain a suspension liquid.Add benzyl bromine (12g, 70mmol), react 3 hours under adding rear room temperature.TLC monitoring reacts completely.Add 300mL water and 100mL methyl tertiary butyl ether, separatory, aqueous phase uses methyl tertiary butyl ether extracting twice (100mL × 2) again, merges organic phase, washes once, anhydrous sodium sulfate drying with saturated aqueous common salt again.Suction filtration, be spin-dried for solvent obtain light yellow liquid (
s)-5-(4-fluorophenyl)-5-hydroxypentanoic acid benzyl ester 20g, yield 95.2%.
embodiment 15:(
s) preparation of-5-(4-fluorophenyl)-5-hydroxypentanoic acid propyl ester
Add in 100mL round-bottomed bottle (10.6g, 50mmol) (
s)-5-(4-fluorophenyl)-5-hydroxypentanoic acid, (9.0g, 65mmol) salt of wormwood and 25mLDMF, stir to obtain a suspension liquid.Add (7.9g, 100mmol) chloropropane, to add at post-heating to 60 DEG C reaction 10 hours.TLC monitoring reacts completely.Add 300mL water and 100mL methyl tertiary butyl ether, separatory, aqueous phase uses methyl tertiary butyl ether extracting twice (100mL × 2) again, merges organic phase, washes once, anhydrous sodium sulfate drying with saturated aqueous common salt again.Suction filtration, be spin-dried for solvent obtain light yellow liquid (
s)-5-(4-fluorophenyl)-5-hydroxypentanoic acid propyl ester 10.9g, yield 86%.
1HNMR(400MHz,CDCl
3)δ7.35-7.29(m,2H),7.04(t,
J=8.8Hz,2H),4.67(t,
J=5.6Hz,1H),4.02(t,
J=6.8Hz,2H),2.38-2.30(m,2H),2.19(s,1H),1.82-1.59(m,6H),0.93(t,
J=7.2Hz,3H)。
embodiment 16:(
s) preparation of-5-(4-fluorophenyl)-5-hydroxypentanoic acid benzyl ester
Add in 250mL bis-mouthfuls of bottles (
s)-5-(4-fluorophenyl)-valerolactone (27.7g, 142.6mmol) and benzylalcohol sodium (2.65g, 20.4mmol), system is replaced as nitrogen atmosphere.Add 100mL methyl alcohol, react 10 hours under adding rear room temperature.TLC monitoring reacts completely.Revolve and steam removing methyl alcohol, add 100mL methylene dichloride, separatory, aqueous phase uses dichloromethane extraction twice (50mL × 2) again, merges organic phase, washes once, anhydrous sodium sulfate drying with saturated aqueous common salt again.Suction filtration, be spin-dried for solvent obtain light yellow liquid (
s)-5-(4-fluorophenyl)-5-hydroxypentanoic acid benzyl ester 39.6g, yield 92.0%.
It should be noted that all documents mentioned in the present invention are quoted as a reference in this application, just quoted separately as a reference as each section of document.In addition should understand, the above-described know-why being specific embodiments of the invention and using, after having read foregoing of the present invention, those skilled in the art can make various changes or modifications the present invention and not deviate from spirit of the present invention and scope, and these equivalent form of values fall within the scope of the invention equally.
Claims (12)
1. a preparation method for the compound of formula b structure, comprises the steps: that formula a structural compounds is at chiral catalyst, namely obtains formula b structural compounds under alkali and hydrogen effect;
Wherein: R is NR
1r
2, OR
3or OH;
R
1and R
2be independently alkyl or R separately
1with R
2cyclization can become piperidines;
R
3for C
1~ C
6alkyl or benzyl;
Described chiral catalyst is the compound with following formula M structure:
Wherein DTB is:
X is H, C
1~ C
8alkyl, C
1~ C
8alkoxyl group.
2. preparation method according to claim 1, wherein said X is C
1~ C
4alkyl.
3. preparation method according to claim 2, wherein said X is methyl.
4. preparation method according to claim 1, wherein said alkali is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium ethylate, potassium ethylate, sodium tert-butoxide, potassium tert.-butoxide, sodium amide, triethylamine, Tributylamine or N-methylmorpholine.
5. preparation method according to claim 1, described formula a compound is 1:(0.001 ~ 0.00002 with the mole dosage ratio of described chiral catalyst).
6. preparation method according to claim 1, described formula a compound is 1:(0.001 ~ 0.7 with the mole dosage ratio of described alkali).
7. preparation method according to claim 1, this reaction is carry out within the scope of 0 ~ 80 DEG C in temperature.
8. preparation method according to claim 1, wherein said formula b compound is selected from following compounds:
Wherein R
1, R
2, R
3definition identical with the definition of claim 1.
9. preparation method according to claim 8, wherein said formula b-1 compound can be converted into formula b-2 compound as follows:
Formula b-1 compound under alkali effect with R
3y reacts, or
Formula b-1 compound obtains formula c compound under acid effect, formula c compound and R
3oNa carries out being obtained by reacting described formula b-2 compound,
Wherein: Y is I, Br or Cl; R
3definition identical with claim 1.
10. preparation method according to claim 9, wherein said alkali is sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium ethylate, potassium ethylate, sodium tert-butoxide, potassium tert.-butoxide, sodium amide, triethylamine, Tributylamine or N-methylmorpholine; Described acid is acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, methylsulfonic acid or tosic acid.
11. preparation methods according to claim 8, wherein said b-3 compound is that raw material prepares by following formula a-3 compound:
Wherein R
1with R
2definition identical with claim 1.
12. preparation methods according to claim 11, comprise step further: formula a-1 compound and HNR
1r
2reaction prepares described formula a-3 compound;
Wherein R
1, R
2definition identical with the definition of claim 1.
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| CN104326959B (en) * | 2014-11-11 | 2016-05-25 | 武汉武药科技有限公司 | A kind of preparation method of Ezetimibe isomers |
| CN107089920A (en) * | 2017-04-25 | 2017-08-25 | 武汉理工大学 | L 3 N, N dibenzyl amino 1（3 cyclohexyl methoxies）Phenyl）The preparation method of the third 1 alcohol |
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| CN101423511A (en) * | 2007-11-05 | 2009-05-06 | 中山奕安泰医药科技有限公司 | Ezetimible intermediate and synthetic method of ezetimible |
| 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 (en) * | 2008-04-25 | 2009-10-28 | 南开大学 | Application of iridium complex in asymmetry catalytic hydrogenation of unsaturated carboxylic acid |
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| CN101423511A (en) * | 2007-11-05 | 2009-05-06 | 中山奕安泰医药科技有限公司 | Ezetimible intermediate and synthetic method of ezetimible |
| 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 (en) * | 2008-04-25 | 2009-10-28 | 南开大学 | Application of iridium complex in asymmetry catalytic hydrogenation of unsaturated carboxylic acid |
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