CN107903147A - A kind of synthesis technique of Crizotinib intermediate - Google Patents

A kind of synthesis technique of Crizotinib intermediate Download PDF

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Publication number
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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CN
China
Prior art keywords
synthesis technique
chloro
bis
chiral
crizotinib intermediate
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CN201711179894.5A
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Chinese (zh)
Inventor
徐亮
毛波
李彦雄
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Enantiotech Corp Ltd
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Enantiotech Corp Ltd
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Priority to CN201711179894.5A priority Critical patent/CN107903147A/en
Publication of CN107903147A publication Critical patent/CN107903147A/en
Priority to PCT/CN2018/102290 priority patent/WO2019100785A1/en
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    • 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

A kind of synthesis technique of Crizotinib intermediate
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.
CN201711179894.5A 2017-11-23 2017-11-23 A kind of synthesis technique of Crizotinib intermediate Pending CN107903147A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
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)

* Cited by examiner, † Cited by third party
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

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
CN103889995B (en) * 2012-09-06 2016-06-08 中山奕安泰医药科技有限公司 One class novel nitrogen-containing ligand metal ruthenium complex and its production and use
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

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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

Cited By (3)

* Cited by examiner, † Cited by third party
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
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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Application publication date: 20180413