CN103265482A - Preparation method of bosutinib - Google Patents
Preparation method of bosutinib Download PDFInfo
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- CN103265482A CN103265482A CN 201310236253 CN201310236253A CN103265482A CN 103265482 A CN103265482 A CN 103265482A CN 201310236253 CN201310236253 CN 201310236253 CN 201310236253 A CN201310236253 A CN 201310236253A CN 103265482 A CN103265482 A CN 103265482A
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- YVLMARQGAFPBMI-UHFFFAOYSA-N CN1CCN(CCCOC(C(C2)O)=Cc(nc3)c2c(N)c3C#N)CC1 Chemical compound CN1CCN(CCCOC(C(C2)O)=Cc(nc3)c2c(N)c3C#N)CC1 YVLMARQGAFPBMI-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses a preparation method of bosutinib (I). The preparation method comprises the step that 6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]-4-amino-3-quinolinecarbonitrile (II) and 2,4-dichloro-5-methoxybenzaldehyde (III) carry out condensation and reduction reactions to obtain bosutinib (I). The preparation method is easy in obtainment of raw materials, concise in process, economical and environment-friendly and suitable for industrial production.
Description
Technical field
The invention belongs to organic synthesis highway route design and bulk drug thereof and intermediate preparation technical field, particularly a kind of preparation method of bosutinib.
Background technology
Bosutinib (Bosutinib) is a kind of potent protein kinase (Src/Abl) inhibitor, can suppress the autonomous phosphorylation of Src albumen in the various human tumour cell, also can suppress the phosphorylation process of Src and Abl substrate.This medicine is developed by Hui Shi (Wyeth) drugmaker under the Pfizer (Pfizer), in on September 4th, 2012 in U.S.'s Initial Public Offering, be approved for the treatment of chronic myelocytic leukemia (CML) adult patients that chronic phase, acceleration period or acute transformation phase Philadelphia chromosome be positive, commodity are called Bosulif.
The chemistry of bosutinib is by name: 4-[(2,4-two chloro-5-p-methoxy-phenyls) amino]-6-methoxyl group-7-[3-(4-methyl isophthalic acid-piperazine) propoxy-]-3-quinoline formonitrile HCN, its structural formula is:
Relevant bosutinib preparation method studies existing report, removes the method for transformation of side chain functionalities and transforms outside order updates, and mainly contains following several route of synthesis for the research of 3-quinoline formonitrile HCN parent nucleus Cheng Huan:
World patent WO2003/093241 number, WO2004/075898 number, WO2002/44166 number, United States Patent (USP) US99/0406573 number and Chinese patent CN101012225A etc. have reported that with anils (IV) be starting raw material, through carrying out condensation and cyclization with (Z)-3-oxyethyl group-2-itrile group-ethyl propenoate (Va) or ethoxy methylene diethyl malonate (Vb), make 4-oxo-3-quinoline 6-carbonitrile derivatives (VI), intermediate (VI) and phosphorus oxychloride, the chlorination of chlorizating agent such as phosphorus trichloride or thionyl chloride generates 4-chloro-3-quinoline 6-carbonitrile derivatives (VII), chloro intermediate (VII) and 2, the replacement of 4-two chloro-5-anisidines (VIII) prepares bosutinib (I).This synthetic route is the main stream approach for preparing bosutinib at present; characteristics with reaction classics and process stabilizing; but because cyclization needs high temperature and long-time the backflow; chlorination reaction need use phosphorus oxychloride or thionyl chloride etc. to influence the danger product of environment, has limited the industrialization prospect of this technology.
World patent has also been reported the similar preparation method of a kind of and above-mentioned technology for WO2003/093241 number, difference is that adjacent manthanoate anils (IX) is raw material, elder generation and DMF-DMA condensation generate intermediate (X), and intermediate (X) becomes ring to generate 4-chloro-3-quinoline 6-carbonitrile derivatives (VI) under the effect of organo-metallic lithium reagent.Because the reaction needed of organo-metallic lithium reagent is carried out under very low temperature (78 ℃), there is the use of dangerization product such as phosphorus oxychloride equally in follow-up chlorination, makes the more difficult industrialization of its preparation method.
World patent has been reported a kind of one-tenth ring method for WO2009/149622 number: be raw material with o-aminoacetophenone derivative (XI), replace (XIII) and the DMF-DMA cyclic condensation obtains 4-oxo-3-quinoline 6-carbonitrile derivatives (VI) through bromination (XII), itrile group.This method advantage is that raw material is easy to get, but step is more, can not avoid the use of dangerization product such as phosphorus oxychloride equally.
World patent has been reported the operational path of another kind of preparation bosutinib for WO2005/019201 number: with 2; 4-two chloro-5-anisidine (VIII) aniline are raw material; generate N-(2 with itrile group acetic acid acidylate; 4-two chloro-5-p-methoxy-phenyls)-2-itrile group ethanamide (IXV); intermediate (IXV) generates imines condenses (XV) with anils (IV) condensation; annulation taking place behind intermediate (XV) and the phosphorus oxychloride chloro again obtain the amino replacement-3-quinoline 6-carbonitrile derivatives (XVI) of 4-, (XVI) passes through side chain R again
1And R
2Functional group conversion make bosutinib (I).This synthetic route is that condensation and substitution reaction are united two into one, and has simplified reactions steps, but because the chlorination annulation must use chlorizating agents such as phosphorus oxychloride, still bigger for environmental influence.
What Chinese patent was reported for CN101792416A number is to generate imine derivative (XVII) by adjacent manthanoate anils (IX) and itrile group acetal generation condensation reaction, and intermediate (XVII) cyclization under alkaline condition generates 4-oxo-3-quinoline 6-carbonitrile derivatives (VI).This method technology is succinct, but raw material is difficult for acquisition, and danger product such as while phosphorus oxychloride still can't be avoided.
Summary of the invention
The objective of the invention is at defective of the prior art, provide a kind of and have that raw material is easy to get, technology is succinct and the preparation method of the bosutinib of environmental protection and economy.
For achieving the above object, the present invention has adopted following main technical schemes: the preparation method of a kind of bosutinib (I),
Its preparation process comprises: 6-methoxyl group-7-[3-(4-methyl isophthalic acid-piperazine) propoxy-]-4-amino-3-quinoline formonitrile HCN (II) and 2,4-two chloro-5-methoxybenzaldehydes (III) carry out condensation, reduction reaction obtains bosutinib (I).
In addition, the present invention also proposes following attached technical scheme:
The acid binding agent of described condensation reaction is salt of wormwood, saleratus, potassium hydroxide, yellow soda ash, sodium bicarbonate, sodium hydroxide, sodium methylate, potassium tert.-butoxide, triethylamine, diisopropylamine, pyridine, N-methylpyrrole, N-methyl piperidine or N-methylmorpholine, preferred triethylamine or pyridine.
The reductive agent of described reduction reaction is sodium borohydride, POTASSIUM BOROHYDRIDE, sodium cyanoborohydride, acetoxyl group sodium borohydride or catalytic hydrogenation reaction, preferred sodium borohydride or POTASSIUM BOROHYDRIDE.
Described catalytic hydrogenation reaction is normal pressure hydrogenation, and the catalyzer of its catalytic hydrogenation can be selected palladium charcoal, palladium calcium carbonate or Raney's nickel, preferred palladium calcium carbonate.
Described raw material 6-methoxyl group-7-[3-(4-methyl isophthalic acid-piperazine) propoxy-]-chemical structure of 4-amino-3-quinoline formonitrile HCN is suc as formula shown in (II),
Its preparation process comprises: 3-[3-(4-methyl isophthalic acid-piperazine) propoxy-]-4-anisidine (IIa), triethyl orthoformate (IIb) and the third two eyeballs (IIc) carry out the condensation and cyclization reaction and make 6-methoxyl group-7-[3-(4-methyl isophthalic acid-piperazine) propoxy-]-4-amino-3-quinoline formonitrile HCN (II).
The feed ratio of described condensation and cyclization reaction is 3-[3-(4-methyl isophthalic acid-piperazine) propoxy-]-4-anisidine (IIa): triethyl orthoformate (IIb): the third two eyeballs (IIc) are 1: 0.5-2: 0.5-2, preferred 1: 1.1: 1.2.
Described condensation and cyclization reaction catalyst system therefor is lewis acid catalyst, specifically can be the fluoroform sulphonate of aluminum chloride, zinc chloride, iron trichloride, boron trifluoride, columbium pentachloride or Indium-111 chloride or lanthanon, preferred aluminum chloride.
Described raw material 2, the preparation process of 4-two chloro-5-methoxybenzaldehydes (III) comprising: 3-methoxyl group benzylalcohol (IIIa) obtains 2 through chlorination reaction, 4-two chloro-5-methoxyl group benzylalcohols (IIIb), intermediate (IIIb) obtains 2,4-, two chloro-5-methoxybenzaldehydes (III) through oxidizing reaction.
The chlorizating agent of described chlorination reaction is chlorine, sulfuryl chloride, thionyl chloride, phosphorus trichloride or phosphorus pentachloride, preferred sulfuryl chloride.
The oxidizer system of described oxidizing reaction is activated manganese dioxide, pyridinium chlorochromate (PCC), chlorine dichromic acid pyridine (PDC), methyl-sulphoxide/oxalyl chloride (Swern), 2-iodoxy phenylformic acid (IBX), Dai Si-Martin's oxygenant (Dess-Martin Periodinane), sulphur trioxide/pyridine complex (Collins oxidation) or tetramethyl piperidine oxide compound (TEMPO), preferred activated manganese dioxide or pyridinium chlorochromate (PCC).
Than prior art, the preparation method of bosutinib involved in the present invention has that raw material is easy to get, technology is succinct and characteristics such as environmental protection and economy, so be beneficial to the suitability for industrialized production of this bulk drug, promotes the development of its economic technology.
Embodiment
Below in conjunction with several preferred embodiments technical solution of the present invention is done further nonrestrictive detailed description.
Embodiment one:
In three neck reaction flasks, add 6-methoxyl group-7-[3-(4-methyl isophthalic acid-piperazine) propoxy-]-4-amino-3-quinoline formonitrile HCN (II) (3.55g, 10mmol), triethylamine (1.5g, 15mmol) with methyl alcohol 25mL, be warming up to 50-55 ℃, be stirred to system dissolving homogeneous.(2.45g, methanol solution 12mmol) dripped off to reaction solution in about 1 hour slowly to drip 2,4-, two chloro-5-methoxybenzaldehydes (III).Keep this temperature to continue reaction 3 hours, the TLC detection reaction finishes.Be cooled to 0-5 ℃, add sodium borohydride (1.9g 50mmol), added in about 1 hour in batches.Keep room temperature to continue reaction 2 hours, the TLC detection reaction finishes.Add dilute hydrochloric acid cancellation reaction.Be evaporated to 1/3rd of cumulative volume, the cooling crystallization, crude product dehydrated alcohol recrystallization gets off-white color solid bosutinib (I) 4.2g, yield 79.4%.
Embodiment two:
Under dry and nitrogen atmosphere, in three mouthfuls of reaction flasks, add 3-[3-(4-methyl isophthalic acid-piperazine) propoxy-]-4-anisidine (IIa) (2.8g, 10mmol), triethyl orthoformate (IIb) (1.63g, 11mmol) and the third two eyeball (IIc) (0.80g, 12mmol) with dehydrated alcohol 25mL, reflux 3 hours.Crystallisation by cooling, machine product N, after the dinethylformamide 25mL dissolving, (5.32g 40mmol), is heated to 140 ℃, insulation reaction 2 hours to add aluminum chloride.Cooling with reaction system impouring frozen water, has solid to separate out.Filter, filtrate is used dichloromethane extraction, concentrates, and the machine product obtain white solid 6-methoxyl group-7-[3-(4-methyl isophthalic acid-piperazine) propoxy-with ethyl alcohol recrystallization]-4-amino-3-quinoline formonitrile HCN (II) 3.1g, yield 87.3%.
Embodiment three:
(1.4g 10mmol) and acetic acid 25mL, is cooled to 0 ℃, stirs to drip sulfuryl chloride down (4.0g 30mmol), drips and finishes room temperature reaction 3 hours to add 3-methoxyl group benzylalcohol (IIIa) in three mouthfuls of reaction flasks.Be warming up to 70-80 ℃, continue reaction 0.5 hour, do not overflow to there being hydrogenchloride.Removal of solvent under reduced pressure, resistates obtains 2,4-, two chloro-5-methoxyl group benzylalcohols (IIIb) with ethyl alcohol recrystallization.The gained resistates dissolves with methylene dichloride 25mL, and adding pyridinium chlorochromate (PCC) (3.25g, 15mmol), room temperature reaction 2 hours.Add the 25mL anhydrous diethyl ether, continue reaction 2 hours.Filter, filter residue washs with ether, merges organic phase, removal of solvent under reduced pressure, and residuum gets light yellow solid 2 with re-crystallizing in ethyl acetate, 4-two chloro-5-methoxybenzaldehyde (III) 1.2g, yield is 58.8%.
It is pointed out that above-described embodiment only is explanation technical conceive of the present invention and characteristics, its purpose is to allow the personage who is familiar with this technology can understand content of the present invention and enforcement according to this, can not limit protection scope of the present invention with this.All equivalences that spirit is done according to the present invention change or modify, and all should be encompassed within protection scope of the present invention.
Claims (10)
1. the preparation method of a bosutinib (I),
It is characterized in that described preparation method, its preparation process comprises: 6-methoxyl group-7-[3-(4-methyl isophthalic acid-piperazine) propoxy-]-4-amino-3-quinoline formonitrile HCN (II) and 2,4-two chloro-5-methoxybenzaldehydes (III) carry out condensation, reduction reaction obtains bosutinib (I).
2. the preparation method of bosutinib (I) according to claim 1, it is characterized in that: the acid binding agent of described condensation reaction is salt of wormwood, saleratus, potassium hydroxide, yellow soda ash, sodium bicarbonate, sodium hydroxide, sodium methylate, potassium tert.-butoxide, triethylamine, diisopropylamine, pyridine, N-methylpyrrole, N-methyl piperidine or N-methylmorpholine.
3. the preparation method of bosutinib (I) according to claim 1, it is characterized in that: the reductive agent of described reduction reaction is sodium borohydride, POTASSIUM BOROHYDRIDE, sodium cyanoborohydride, acetoxyl group sodium borohydride or catalytic hydrogenation reaction.
4. as the preparation method of bosutinib (I) as described in the claim 3, it is characterized in that: described catalytic hydrogenation reaction is normal pressure hydrogenation, and catalyzer is palladium charcoal, palladium calcium carbonate or Raney's nickel.
5. the preparation method of bosutinib (I) according to claim 1 is characterized in that: described raw material 6-methoxyl group-7-[3-(4-methyl isophthalic acid-piperazine) propoxy-]-chemical structure of 4-amino-3-quinoline formonitrile HCN is suc as formula shown in (II),
6. as the preparation method of bosutinib (I) as described in the claim 5, it is characterized in that: described raw material 6-methoxyl group-7-[3-(4-methyl isophthalic acid-piperazine) propoxy-]-preparation process of 4-amino-3-quinoline formonitrile HCN (II) comprising: 3-[3-(4-methyl isophthalic acid-piperazine) propoxy-]-4-anisidine (IIa), triethyl orthoformate (IIb) and the third two eyeballs (IIc) carry out the condensation and cyclization reaction and make described 6-methoxyl group-7-[3-(4-methyl isophthalic acid-piperazine) propoxy-]-4-amino-3-quinoline formonitrile HCN (II).
7. as the preparation method of bosutinib (I) as described in the claim 6, it is characterized in that: the molar ratio of described condensation and cyclization reaction is 3-[3-(4-methyl isophthalic acid-piperazine) propoxy-]-4-anisidine (IIa): triethyl orthoformate (IIb): the third two eyeballs (IIc) are 1: 0.5-2: 0.5-2.
8. as the preparation method of bosutinib (I) as described in the claim 6, it is characterized in that: described condensation and cyclization reaction catalyst system therefor is the fluoroform sulphonate of aluminum chloride, zinc chloride, iron trichloride, boron trifluoride, columbium pentachloride or Indium-111 chloride or lanthanon.
9. the preparation method of bosutinib (I) according to claim 1, it is characterized in that: described raw material 2, the preparation process of 4-two chloro-5-methoxybenzaldehydes (III) comprising: 3-methoxyl group benzylalcohol (IIIa) obtains 2 through chlorination reaction, 4-two chloro-5-methoxyl group benzylalcohols (IIIb), described 2,4-two chloro-5-methoxyl group benzylalcohols (IIIb) obtain 2,4-, two chloro-5-methoxybenzaldehydes (III) through oxidizing reaction.
10. as the preparation method of bosutinib (I) as described in the claim 9, it is characterized in that: the oxidizer system of described oxidizing reaction is activated manganese dioxide, pyridinium chlorochromate, chlorine dichromic acid pyridine, methyl-sulphoxide/oxalyl chloride, 2-iodoxy phenylformic acid, Dai Si-Martin's oxygenant, sulphur trioxide/pyridine complex or tetramethyl piperidine oxide compound.
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| CN 201310236253 CN103265482A (en) | 2013-06-14 | 2013-06-14 | Preparation method of bosutinib |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015123758A1 (en) * | 2014-02-20 | 2015-08-27 | Apotex Inc. | Bosutinib forms and preparation methods thereof |
| CN104876865A (en) * | 2014-02-27 | 2015-09-02 | 南京正荣医药化学有限公司 | Preparation technology of bosutinib |
| WO2015198249A1 (en) * | 2014-06-27 | 2015-12-30 | Shilpa Medicare Limited | Process for preparation of bosutinib |
| CN105646345A (en) * | 2016-03-16 | 2016-06-08 | 浙江海正药业股份有限公司 | Novel crystal forms of bosutinib and preparation method thereof |
| CN109180578A (en) * | 2018-10-19 | 2019-01-11 | 山东创新药物研发有限公司 | A kind of preparation method of bosutinib |
-
2013
- 2013-06-14 CN CN 201310236253 patent/CN103265482A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015123758A1 (en) * | 2014-02-20 | 2015-08-27 | Apotex Inc. | Bosutinib forms and preparation methods thereof |
| US9776970B2 (en) | 2014-02-20 | 2017-10-03 | Apotex Inc. | Bosutinib forms and preparation methods thereof |
| CN104876865A (en) * | 2014-02-27 | 2015-09-02 | 南京正荣医药化学有限公司 | Preparation technology of bosutinib |
| WO2015198249A1 (en) * | 2014-06-27 | 2015-12-30 | Shilpa Medicare Limited | Process for preparation of bosutinib |
| CN105646345A (en) * | 2016-03-16 | 2016-06-08 | 浙江海正药业股份有限公司 | Novel crystal forms of bosutinib and preparation method thereof |
| CN109180578A (en) * | 2018-10-19 | 2019-01-11 | 山东创新药物研发有限公司 | A kind of preparation method of bosutinib |
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Application publication date: 20130828 |