CN107903147A - A kind of synthesis technique of Crizotinib intermediate - Google Patents
A kind of synthesis technique of Crizotinib intermediate Download PDFInfo
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- CN107903147A CN107903147A CN201711179894.5A CN201711179894A CN107903147A CN 107903147 A CN107903147 A CN 107903147A CN 201711179894 A CN201711179894 A CN 201711179894A CN 107903147 A CN107903147 A CN 107903147A
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- synthesis technique
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- chiral
- crizotinib intermediate
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- 238000000034 method Methods 0.000 title claims abstract description 27
- 239000002146 L01XE16 - Crizotinib Substances 0.000 title claims abstract description 15
- KTEIFNKAUNYNJU-GFCCVEGCSA-N crizotinib Chemical compound O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NC=1)N)=CC=1C(=C1)C=NN1C1CCNCC1 KTEIFNKAUNYNJU-GFCCVEGCSA-N 0.000 title claims abstract description 15
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 14
- 229960005061 crizotinib Drugs 0.000 title claims abstract description 14
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 14
- 239000003054 catalyst Substances 0.000 claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 9
- 239000001257 hydrogen Substances 0.000 claims abstract description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000002904 solvent Substances 0.000 claims abstract description 8
- 239000003513 alkali Substances 0.000 claims abstract description 7
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 7
- 239000002994 raw material Substances 0.000 claims abstract description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 44
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical group COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 2
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- -1 Hydrogen furans Chemical class 0.000 claims 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 1
- 239000003208 petroleum Substances 0.000 claims 1
- 229910052700 potassium Inorganic materials 0.000 claims 1
- 239000011591 potassium Substances 0.000 claims 1
- 150000003851 azoles Chemical class 0.000 abstract description 9
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 230000009286 beneficial effect Effects 0.000 abstract description 3
- 230000000087 stabilizing effect Effects 0.000 abstract description 2
- JAOYKRSASYNDGH-SCSAIBSYSA-N (1r)-1-(2,6-dichloro-3-fluorophenyl)ethanol Chemical compound C[C@@H](O)C1=C(Cl)C=CC(F)=C1Cl JAOYKRSASYNDGH-SCSAIBSYSA-N 0.000 abstract 1
- HCEKGPAHZCYRBZ-UHFFFAOYSA-N 1-(3-fluorophenyl)ethanone Chemical compound CC(=O)C1=CC=CC(F)=C1 HCEKGPAHZCYRBZ-UHFFFAOYSA-N 0.000 abstract 1
- 125000003963 dichloro group Chemical group Cl* 0.000 abstract 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical group N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 230000004224 protection Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- VZHJIJZEOCBKRA-UHFFFAOYSA-N 1-chloro-3-fluorobenzene Chemical compound FC1=CC=CC(Cl)=C1 VZHJIJZEOCBKRA-UHFFFAOYSA-N 0.000 description 1
- FPYJSJDOHRDAMT-KQWNVCNZSA-N 1h-indole-5-sulfonamide, n-(3-chlorophenyl)-3-[[3,5-dimethyl-4-[(4-methyl-1-piperazinyl)carbonyl]-1h-pyrrol-2-yl]methylene]-2,3-dihydro-n-methyl-2-oxo-, (3z)- Chemical compound C=1C=C2NC(=O)\C(=C/C3=C(C(C(=O)N4CCN(C)CC4)=C(C)N3)C)C2=CC=1S(=O)(=O)N(C)C1=CC=CC(Cl)=C1 FPYJSJDOHRDAMT-KQWNVCNZSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 150000001576 beta-amino acids Chemical class 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 229940049068 xalkori Drugs 0.000 description 1
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
- B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
- B01J31/2409—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring with more than one complexing phosphine-P atom
- B01J31/2414—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring with more than one complexing phosphine-P atom comprising aliphatic or saturated rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
- C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
- C07C29/143—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of ketones
- C07C29/145—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of ketones with hydrogen or hydrogen-containing gases
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/60—Reduction reactions, e.g. hydrogenation
- B01J2231/64—Reductions in general of organic substrates, e.g. hydride reductions or hydrogenations
- B01J2231/641—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes
- B01J2231/643—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes of R2C=O or R2C=NR (R= C, H)
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/80—Complexes comprising metals of Group VIII as the central metal
- B01J2531/82—Metals of the platinum group
- B01J2531/821—Ruthenium
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a kind of synthesis technique of Crizotinib intermediate, comprise the following steps：In the environment of alkali and solvent, with 2,6 dichloro, 3 fluoro acetophenone for raw material, use hydrogen to be reacted for reducing agent under the action of chiral catalyst, obtain (R) 1 (2,6 dichloro, 3 fluorophenyl) ethanol；Gram azoles that the technique of the present invention can settle acquisition high chiral purity at one go using above-mentioned reduction system replaces Buddhist nun's chiral intermediate, eliminate the chiral resolution process of existing process complexity, greatly shorten process cycle, production cost is low, reaction condition is gentle and process stabilizing, high conversion rate, reaction generation environment pollution is few, beneficial to realizing industrialized production.
Description
Technical field
The invention belongs to pharmaceutical-chemical intermediate to synthesize field, relates generally to a kind of synthesis work of Crizotinib intermediate
Skill.
Background technology
Gram azoles replaces Buddhist nun (Crizotinib, English trade name Xalkori), chemical name：(R) -3- [1- (bis- chloro- 3- of 2,6-
Fluoro- benzene)-ethyoxyl] -5- (- 1 hydrogen of 1- piperidines -4- alkyl-pyrazoles -4- alkyl)-pyrimidine -2- indanes are developed by Pfizer
Suppression Met/ALK/ROS the emulative Mutiple Targets kinases inhibitors of ATP.Respectively in ALK, ROS and MET kinase activity
Confirm that gram azoles has human body notable clinical efficacy for Buddhist nun in abnormal tumor patient.Gram azoles is as follows for the structural formula of Buddhist nun：
Gram azoles is one of most quick medicine in tumour medicine research and development history for Buddhist nun, cause after being listed in the U.S. within 2011 Hong
It is dynamic.Inventor is scientist doctor Cui Jingrong of Chinese origin (US patent 7858643), wins the 38th American National inventor year
Degree prize.
(R) -1- (2,6- bis- chloro- 3- fluorophenyls) ethanol is that gram azoles replaces the important chiral intermediate of Buddhist nun, prepares enantiomer-pure
(R) -1- (the chloro- 3- fluorophenyls of 2,6- bis-) ethanol be synthesis gram azoles replace Buddhist nun's committed step.(R) -1- optically active in recent years
The synthetic method of (the chloro- 3- fluorophenyls of 2,6- bis-) ethanol is increasingly subject to the concern of people.(R) -1- (the chloro- 3- fluorophenyls of 2,6- bis-)
The structural formula of ethanol is as follows：
(R) -1- (the chloro- 3- fluorophenyls of 2,6- bis-) ethanol principal synthetic routes have following several at present：
Method one is that the chloro- 3- fluoro acetophenones of 2,6- bis- obtain chirality (R) -1- through the chemical asymmetric reduction of the progress such as CBS
(2,6- bis- chloro- 3- fluorophenyls) ethanol, this method energy consumption is big, and pollution is big, and catalyst amount is big.
Method two is to carry out asymmetric reduction using enzyme 3- fluoro acetophenones chloro- to 2,6- bis-, and current this method is more difficult
Industrialization, is primarily due to the more difficult preparation of such a enzyme.
Method three is 1- (the chloro- 3- fluorobenzene of 2,6- bis- that the chloro- 3- fluoro acetophenones of 2,6- bis- obtain racemization through sodium borohydride reduction
Base) ethanol, then chiral auxiliary agent B oc-L- proline, catalyst p-methyl benzenesulfonic acid and condensing agent EDCI split to obtain chirality
(R) -1- (the chloro- 3- fluorophenyls of 2,6- bis-) ethanol.Such a method and step length, yield is low, and the chiral purity of obtained product is not
It is high.
The content of the invention
In view of the problems of the existing technology, the object of the present invention is to provide a kind of synthesis work of Crizotinib intermediate
Skill.
To achieve these goals, the present invention uses following technical scheme：
A kind of synthesis technique of Crizotinib intermediate, comprise the following steps：In the environment of alkali and solvent, with 2,
The chloro- 3- fluoro acetophenones of 6- bis- are raw material, use hydrogen to be reacted, obtained under the action of chiral catalyst for reducing agent
(R) -1- (the chloro- 3- fluorophenyls of 2,6- bis-) ethanol；The structural formula of wherein described chiral catalyst is as follows：
Abbreviation β-BIMAH (S, S-4-1a).
β-the BIMAH (S, S-4-1a) be by using beta amino acids as initial feed, amino protected with Boc after with adjacent ammonia
Base phenol condensation cyclization, then take off Boc protections with hydrochloric acid and just obtained β-BIMAH ligands, corresponding rhodium catalyst is then made again,
Just obtain β-BIMAH (S, S-4-1a).
The synthetic route of β-BIMAH (S, S-4-1a) is as follows：
Preferably, the alkali in potassium tert-butoxide, potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate at least one
Kind.
Preferably, the solvent is selected from tetrahydrofuran, dichloromethane, toluene, normal heptane, n-hexane, hexamethylene, oil
At least one of ether, methyl tertiary butyl ether(MTBE), methanol, ethanol, isopropanol and tert-butyl alcohol.
Preferably, the molar ratio of the chloro- 3- fluoro acetophenones of 2, the 6- bis- and chiral catalyst is 100000:1-100:1.
Preferably, the molar ratio of the chloro- 3- fluoro acetophenones of 2, the 6- bis- and alkali is 20000:1-2:1.
Preferably, the temperature of the reaction is 10-60 DEG C, time 10-20h.
Preferably, the pressure of the reaction is 2-50bar.
Beneficial effects of the present invention：
The present invention, for raw material, uses hydrogen as reducing agent, β-BIMAH (S, S-4-1a) with the chloro- 3- fluoro acetophenones of 2,6- bis-
For chiral catalyst, reaction obtains ee%>99% gram azoles replaces Buddhist nun's chiral intermediate, and yield is also up to 93%.
The technique of the present invention can settle gram azoles for obtaining high chiral purity at one go using above-mentioned reduction system for Buddhist nun's chirality
Intermediate, eliminates the chiral resolution process of existing process complexity, greatly shortens process cycle, and production cost is low, reaction condition
Gentle and process stabilizing, high conversion rate, reaction generation environment pollution is few, beneficial to realizing industrialized production.
Embodiment
In order to preferably explain the present invention, it is described further in conjunction with specific examples below, but the present invention is unlimited
In specific embodiment.
Embodiment 1
Take the chloro- 3- fluoro acetophenones of 2,6- bis- of 0.01mol to be dissolved with tetrahydrofuran 140ml, add the catalysis of 0.0001mol
Agent β-BIMAH (S, S-4-1a), add the potassium tert-butoxide of 0.01mol, the hydrogen of 30bar are passed through as reducing agent, at 30 DEG C
After stirring 16h, filter, revolving removes solvent and obtains the off-white powder of product (R) -1- (2,6- bis- chloro- 3- fluorophenyls) ethanol
Powder, product purity 99.5%, yield 89.9%.
Embodiment 2
Take the chloro- 3- fluoro acetophenones of 2,6- bis- of 0.01mol to be dissolved with n-hexane 140ml, add the catalyst of 0.0001mol
β-BIMAH (S, S-4-1a), add the potassium carbonate of 0.01mol, are passed through the hydrogen of 30bar as reducing agent, are stirred at 30 DEG C
After 16h, filtering, revolving removes solvent and obtains the white solid powder of product (R) -1- (2,6- bis- chloro- 3- fluorophenyls) ethanol,
Product purity 99.3%, yield 89%.
Embodiment 3
Take the chloro- 3- fluoro acetophenones of 2,6- bis- of 0.01mol molten with the mixed solvent of 100ml dichloromethane and 40ml toluene
Solution, adds the catalyst β-BIMAH (S, S-4-1a) of 0.001mol, adds the potassium hydroxide of 0.01mol, is passed through the hydrogen of 30bar
Gas after stirring 16h at 30 DEG C, filters, revolving removes solvent and obtains product (R) -1- (2,6- bis- chloro- 3- fluorine as reducing agent
Phenyl) ethanol white solid powder, product purity 99.6%, yield 93%.
The foregoing is merely the specific embodiment of the present invention, it is not intended to limit the scope of the invention, every utilization
The equivalent transformation that the present invention makees, is directly or indirectly used in other relevant technical fields, is similarly included in the present invention's
Among scope of patent protection.
Claims (7)
1. a kind of synthesis technique of Crizotinib intermediate, it is characterised in that comprise the following steps：In alkali and the environment of solvent
In, with the chloro- 3- fluoro acetophenones of 2,6- bis- for raw material, use hydrogen to be reacted for reducing agent under the action of chiral catalyst,
Obtain (R) -1- (the chloro- 3- fluorophenyls of 2,6- bis-) ethanol；The structural formula of wherein described chiral catalyst is as follows：
2. the synthesis technique of Crizotinib intermediate according to claim 1, it is characterised in that the alkali is selected from tertiary fourth
At least one of potassium alcoholate, potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate.
3. the synthesis technique of Crizotinib intermediate according to claim 1, it is characterised in that the solvent is selected from four
Hydrogen furans, dichloromethane, toluene, normal heptane, n-hexane, hexamethylene, petroleum ether, methyl tertiary butyl ether(MTBE), methanol, ethanol, isopropyl
At least one of alcohol and the tert-butyl alcohol.
4. the synthesis technique of Crizotinib intermediate according to claim 1, it is characterised in that 2, the 6- bis- is chloro-
The molar ratio of 3- fluoro acetophenones and chiral catalyst is 100000:1-100:1.
5. the synthesis technique of Crizotinib intermediate according to claim 1, it is characterised in that 2, the 6- bis- is chloro-
The molar ratio of 3- fluoro acetophenones and alkali is 20000:1-2:1.
6. the synthesis technique of Crizotinib intermediate according to claim 1, it is characterised in that the temperature of the reaction
For 10-60 DEG C, time 10-20h.
7. the synthesis technique of Crizotinib intermediate according to claim 1, it is characterised in that the pressure of the reaction
For 2-50bar.
Priority Applications (2)
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|---|---|---|---|
| CN201711179894.5A CN107903147A (en) | 2017-11-23 | 2017-11-23 | A kind of synthesis technique of Crizotinib intermediate |
| PCT/CN2018/102290 WO2019100785A1 (en) | 2017-11-23 | 2018-08-24 | Synthesis process for crizotinib intermediate |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711179894.5A CN107903147A (en) | 2017-11-23 | 2017-11-23 | A kind of synthesis technique of Crizotinib intermediate |
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| CN107903147A true CN107903147A (en) | 2018-04-13 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019100785A1 (en) * | 2017-11-23 | 2019-05-31 | 中山奕安泰医药科技有限公司 | Synthesis process for crizotinib intermediate |
| CN112552144A (en) * | 2020-12-25 | 2021-03-26 | 中山奕安泰医药科技有限公司 | Crizotinib intermediate and refining method thereof |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110105175A (en) * | 2019-06-11 | 2019-08-09 | 河南中医药大学 | A method of Buddhist nun's intermediate is replaced using supported chiral catalyst preparation gram azoles |
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| JP2015024975A (en) * | 2013-07-26 | 2015-02-05 | 関東化学株式会社 | Production method of optically active secondary alcohol |
| CN105330517A (en) * | 2015-11-23 | 2016-02-17 | 中山奕安泰医药科技有限公司 | Method for synthesizing 3,5-bis(trifluoromethyl) phenethyl alcohol |
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| WO2014036702A1 (en) * | 2012-09-06 | 2014-03-13 | 中山奕安泰医药科技有限公司 | New metal ruthenium complex having nitrogen ligand, preparation method therefor, and uses thereof |
| CN107903147A (en) * | 2017-11-23 | 2018-04-13 | 中山奕安泰医药科技有限公司 | A kind of synthesis technique of Crizotinib intermediate |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2015024975A (en) * | 2013-07-26 | 2015-02-05 | 関東化学株式会社 | Production method of optically active secondary alcohol |
| CN105330517A (en) * | 2015-11-23 | 2016-02-17 | 中山奕安泰医药科技有限公司 | Method for synthesizing 3,5-bis(trifluoromethyl) phenethyl alcohol |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2019100785A1 (en) * | 2017-11-23 | 2019-05-31 | 中山奕安泰医药科技有限公司 | Synthesis process for crizotinib intermediate |
| CN112552144A (en) * | 2020-12-25 | 2021-03-26 | 中山奕安泰医药科技有限公司 | Crizotinib intermediate and refining method thereof |
| CN112552144B (en) * | 2020-12-25 | 2023-02-28 | 中山奕安泰医药科技有限公司 | Crizotinib intermediate and refining method thereof |
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