CN105503719A - Preparation method of bosutinib - Google Patents
Preparation method of bosutinib Download PDFInfo
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- CN105503719A CN105503719A CN201410546745.8A CN201410546745A CN105503719A CN 105503719 A CN105503719 A CN 105503719A CN 201410546745 A CN201410546745 A CN 201410546745A CN 105503719 A CN105503719 A CN 105503719A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 239000002145 L01XE14 - Bosutinib Substances 0.000 title claims abstract description 16
- 229960003736 bosutinib Drugs 0.000 title claims abstract description 16
- UBPYILGKFZZVDX-UHFFFAOYSA-N bosutinib Chemical compound C1=C(Cl)C(OC)=CC(NC=2C3=CC(OC)=C(OCCCN4CCN(C)CC4)C=C3N=CC=2C#N)=C1Cl UBPYILGKFZZVDX-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 39
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000000460 chlorine Substances 0.000 claims description 26
- 229910052801 chlorine Inorganic materials 0.000 claims description 26
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 20
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 15
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 12
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 claims description 12
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- VNVGDKQKDQGFAR-UHFFFAOYSA-N 3-(chloromethoxy)aniline Chemical compound NC1=CC=CC(OCCl)=C1 VNVGDKQKDQGFAR-UHFFFAOYSA-N 0.000 claims description 7
- MFESCIUQSIBMSM-UHFFFAOYSA-N I-BCP Chemical compound ClCCCBr MFESCIUQSIBMSM-UHFFFAOYSA-N 0.000 claims description 7
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 7
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 6
- YSSSPARMOAYJTE-UHFFFAOYSA-N dibenzo-18-crown-6 Chemical group O1CCOCCOC2=CC=CC=C2OCCOCCOC2=CC=CC=C21 YSSSPARMOAYJTE-UHFFFAOYSA-N 0.000 claims description 5
- 235000009518 sodium iodide Nutrition 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 4
- 239000011230 binding agent Substances 0.000 claims description 4
- 238000006482 condensation reaction Methods 0.000 claims description 4
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 4
- HSZCZNFXUDYRKD-UHFFFAOYSA-M lithium iodide Chemical compound [Li+].[I-] HSZCZNFXUDYRKD-UHFFFAOYSA-M 0.000 claims description 4
- 235000015320 potassium carbonate Nutrition 0.000 claims description 4
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 claims description 2
- BLQJIBCZHWBKSL-UHFFFAOYSA-L magnesium iodide Chemical compound [Mg+2].[I-].[I-] BLQJIBCZHWBKSL-UHFFFAOYSA-L 0.000 claims description 2
- 229910001641 magnesium iodide Inorganic materials 0.000 claims description 2
- 235000007715 potassium iodide Nutrition 0.000 claims description 2
- 229960004839 potassium iodide Drugs 0.000 claims description 2
- 229910001414 potassium ion Inorganic materials 0.000 claims description 2
- 239000003880 polar aprotic solvent Substances 0.000 claims 6
- 239000002994 raw material Substances 0.000 abstract description 7
- 239000002904 solvent Substances 0.000 abstract description 6
- 239000012043 crude product Substances 0.000 abstract description 4
- AJROJTARXSATEB-UHFFFAOYSA-N 2,4-dichloro-5-methoxyaniline Chemical compound COC1=CC(N)=C(Cl)C=C1Cl AJROJTARXSATEB-UHFFFAOYSA-N 0.000 abstract 1
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 45
- 238000003756 stirring Methods 0.000 description 24
- 239000008213 purified water Substances 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 239000007787 solid Substances 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000002798 polar solvent Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 229910000831 Steel Inorganic materials 0.000 description 5
- 239000010959 steel Substances 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000001291 vacuum drying Methods 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical group [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 0 *c(c(Cl)c1)cc(N)c1Cl Chemical compound *c(c(Cl)c1)cc(N)c1Cl 0.000 description 2
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 2
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 2
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000004576 sand Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 description 1
- BYAHOJMBKNBLIB-UHFFFAOYSA-N 4-oxo-3h-quinoline-3-carbonitrile Chemical class C1=CC=C2C(=O)C(C#N)C=NC2=C1 BYAHOJMBKNBLIB-UHFFFAOYSA-N 0.000 description 1
- BEGHZKYNLSIHIA-UHFFFAOYSA-N COc(c(OCCCCl)cc1ncc2C#N)cc1c2Cl Chemical compound COc(c(OCCCCl)cc1ncc2C#N)cc1c2Cl BEGHZKYNLSIHIA-UHFFFAOYSA-N 0.000 description 1
- ZBNZXTGUTAYRHI-UHFFFAOYSA-N Dasatinib Chemical compound C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1Cl ZBNZXTGUTAYRHI-UHFFFAOYSA-N 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 1
- 239000002067 L01XE06 - Dasatinib Substances 0.000 description 1
- 239000005536 L01XE08 - Nilotinib Substances 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 239000006004 Quartz sand Substances 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- OUUQCZGPVNCOIJ-UHFFFAOYSA-M Superoxide Chemical compound [O-][O] OUUQCZGPVNCOIJ-UHFFFAOYSA-M 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 150000003983 crown ethers Chemical class 0.000 description 1
- 229960002448 dasatinib Drugs 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 210000003298 dental enamel Anatomy 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 229960002411 imatinib Drugs 0.000 description 1
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229960001346 nilotinib Drugs 0.000 description 1
- HHZIURLSWUIHRB-UHFFFAOYSA-N nilotinib Chemical compound C1=NC(C)=CN1C1=CC(NC(=O)C=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)=CC(C(F)(F)F)=C1 HHZIURLSWUIHRB-UHFFFAOYSA-N 0.000 description 1
- 210000004214 philadelphia chromosome Anatomy 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a preparation method of bosutinib. According to the preparation method, 4-chloro-6-methoxyl-7-hydroxyl-3-quinoline formonitrile and 2,4-dichloro-5-methoxyl aniline are taken as the initial raw materials, 1-methyl-2-pyrrolidone is taken as the solvent, and a crude product of bosutinib is obtained through three steps. The preparation method has the advantages of few steps and mild conditions. The reaction conditions of the prior art are improved, the yield is prominently increased, the cost is reduced, and the preparation method is suitable for industrial production.
Description
Technical field
The invention belongs to field of medicine and chemical technology, be specifically related to a kind of preparation method of bosutinib.
Background technology
Bosutinib is a kind of potent protein kinase (Src/Abl) inhibitor.This medicine is developed by Hui Shi (Wyeth) drugmaker under Pfizer (Pfizer), go on the market for the first time on September 4th, 2012 in the U.S., be approved for the treatment of chronic myelocytic leukemia (CML) adult patients that chronic, acceleration period or acute transformation phase Philadelphia chromosome are positive, this patient had adopted one or more treatment with tyrosine kinase inhibitors in the past, and was not suitable for imatinib, nilotinib and Dasatinib.The chemical structure of bosutinib is such as formula shown in I.
Chinese patent CN101792416A discloses and generates imine derivative by adjacent manthanoate anils and itrile group acetal generation condensation reaction, and this intermediate in the basic conditions cyclization generates 4-oxo-3-quinolinecarbonitrile derivatives.The method is one of current main flow preparation method, but productive rate is lower, the productive rate particularly preparing key intermediate 4-[(the chloro-5-p-methoxy-phenyl of 2,4-bis-) is amino]-6-methoxyl group-7-(3-chlorine propoxy-)-3-quinolinecarbonitriles (formula III) only has about 50%.
Summary of the invention
The invention provides a kind of bosutinib preparation method of concise in technology, the method effectively improves productive rate by improving reaction conditions, is more suitable for suitability for industrialized production compared to existing technology.
Concrete technical scheme is as follows:
1) with the chloro-6-methoxyl group of 4--7-hydroxyl-3-quinolinecarbonitriles for starting raw material 1, in specific aprotic polar solvent, take crown ether as catalyzer, be acid binding agent containing potassium ion alkali, react alkylation with 1-bromo-3-chloropropane and generate the chloro-6-methoxyl group of 4--7-(3-chlorine propoxy-)-3-quinolinecarbonitriles (formula II).
Starting raw material 1 is preferably 1:4 to 1:1 with the mol ratio of the bromo-3-chloropropane of 1-, most preferably is 1:3;
Temperature of reaction is preferably 20 DEG C-60 DEG C;
This reaction is preferably carried out under nitrogen protection;
Specific aprotic polar solvent is selected from 1-Methyl-2-Pyrrolidone, N,N-DIMETHYLACETAMIDE and dimethyl formamide, is preferably 1-Methyl-2-Pyrrolidone;
Catalyzer is selected from 18-and is preced with-6 ethers, dibenzo-18 crown-6 ether and phenodiazine-18-hat-6 ethers, is preferably dibenzo-18 crown-6-ether;
Acid binding agent is preferably potassium hydroxide, saleratus and salt of wormwood, most preferably is salt of wormwood.
2) under pyridine hydrochloride exists, the chloro-6-methoxyl group of 4--7-(3-chlorine propoxy-)-3-quinolinecarbonitriles (formula II) and 2, condensation reaction is there is in 4-bis-chloro-5-anisidine (starting raw material 2) in specific aprotic polar solvent, obtain 4-[(the chloro-5-p-methoxy-phenyl of 2,4-bis-) is amino]-6-methoxyl group-7-(3-chlorine propoxy-)-3-quinolinecarbonitriles (formula III).
The mol ratio of formula II compound and starting raw material 2 is preferably 1:1 to 1:4, most preferably is 2:3;
Temperature of reaction is preferably 60 DEG C-120 DEG C, most preferably is 80 DEG C-110 DEG C;
This reaction is preferably carried out under nitrogen protection;
Specific aprotic polar solvent is selected from 1-Methyl-2-Pyrrolidone, N,N-DIMETHYLACETAMIDE and dimethyl formamide, is preferably 1-Methyl-2-Pyrrolidone;
3) take iodide as catalyzer, 4-[(2,4-bis-chloro-5-p-methoxy-phenyl) amino]-6-methoxyl group-7-(3-chlorine propoxy-)-3-quinolinecarbonitriles (formula III) in specific aprotic polar solvent, alkylated reaction occurs with N methyl piperazine, obtains bosutinib (formula I).
The mol ratio of formula III compound and N methyl piperazine is 1:2 to 1:8, most preferably is 1:3-1:4;
Temperature of reaction is preferably 60 DEG C-120 DEG C, most preferably is 80 DEG C-110 DEG C;
This reaction is preferably carried out in nitrogen protection;
Catalyzer is selected from potassiumiodide, sodium iodide, magnesium iodide and lithium iodide, is preferably sodium iodide;
Specific aprotic polar solvent is selected from 1-Methyl-2-Pyrrolidone, N,N-DIMETHYLACETAMIDE and dimethyl formamide, is preferably 1-Methyl-2-Pyrrolidone.
Raw materials used and the reagent suitability for industrialized production all of the present invention, wherein:
Step 2 of the present invention) improve after reaction conditions and the yield of intermediate (formula III) is brought up to 90% from 46% (CN101792416A specification sheets embodiment 4) of prior art, significantly improve the yield of product;
Prior art is with the chloro-6-methoxyl group of 4--7-(3-chlorine propoxy-)-3-quinolinecarbonitriles (formula II) and 2, when the chloro-5-anisidine of 4-bis-prepares intermediate (formula III), the ethylene glycol monoethyl ether used is as solvent, this solvent flash-point, boiling point are lower, and ingress of air or the superoxide with potential explosion hazard can be generated under illumination condition, the Ministry of Health and Chinese Ministry of Environmental Protection in succession put into effect file and criteria limit it use, and step 2 of the present invention) N-Methyl pyrrolidone that uses using, fortune and defeated storage time all safer environmental protection;
Prior art is with 4-[(2, the chloro-5-p-methoxy-phenyl of 4-bis-) amino]-6-methoxyl group-7-(3-chlorine propoxy-)-3-quinolinecarbonitriles (formula III) and N methyl piperazine prepares bosutinib time, N methyl piperazine is used to hold concurrently solvent (in CN101792416A embodiment 4, N methyl piperazine and intermediate formula III charging capacity mol ratio are 52:1) as reactant, and step 3 of the present invention) replace N methyl piperazine as solvent (N methylpiperazine and intermediate formula III charging capacity mol ratio are 10:7) with 1-methyl-2 pyrrolidone, the charging capacity of expensive raw material N methyl piperazine is decreased while keeping yield substantially constant, reduce cost,
In addition, step 2 of the present invention) use preferred N-Methyl pyrrolidone as solvent, relative to not preferred N,N-DIMETHYLACETAMIDE and dimethyl formamide, the a small amount of by product diethylamine being difficult to remove can be avoided while ensureing yield to generate, be more conducive to the control of drug standard, and N-Methyl pyrrolidone character under basic reaction conditions is more stable.
Embodiment
Below in conjunction with embodiment, further unrestriced detailed description is done to technical solution of the present invention.
The preparation of the chloro-6-methoxyl group of embodiment 1:4--7-(3-chlorine propoxy-)-3-quinolinecarbonitriles
Under nitrogen protection, in 50L enamel reaction still, add 33L1-N-methyl-2-2-pyrrolidone N-, under stirring, add 3.30kg4-chloro-6-methoxyl group-7-hydroxyl-3-quinolinecarbonitriles, 6.65kg1-bromo-3-chloropropane, 5.83kg Anhydrous potassium carbonate, 99g dibenzo-18 crown-6-ether (mol ratio of 4-chloro-6-methoxyl group-7-hydroxyl-3-quinolinecarbonitriles and the bromo-3-chloropropane of 1-is 1:3) successively; Under nitrogen protection, temperature control 30 DEG C of-40 DEG C of stirring reactions are about more than 4h, and TLC tracking monitor disappears to the chloro-6-methoxyl group of 4--7-hydroxyl-3-quinolinecarbonitriles spot; Reaction solution is transferred in 200L glassed steel reaction vessels, slowly adds 66L purified water I under temperature control 25-40 DEG C of stirring; Finish temperature control 25-35 DEG C and stir 30min; Rejection filter, gained solid washs 3 times and rejection filter by 10L purified water respectively; Gained wet product 45-55 DEG C of forced air drying 12h, obtains yellow powder 4.00kg, yield 91.4%.
The preparation of embodiment 2:4-[(the chloro-5-p-methoxy-phenyl of 2,4-bis-) is amino]-6-methoxyl group-7-(3-chlorine propoxy-)-3-quinolinecarbonitriles
Under nitrogen protection; 20L N,N-DIMETHYLACETAMIDE is added in 30L glass reaction still; 3.70kg2 is added successively under stirring; 4-bis-chloro-5-anisidine, 1.48kg pyridine hydrochloride, 4.00kg4-chloro-6-methoxyl group-7-(3-chlorine propoxy-)-3-quinolinecarbonitriles (the chloro-6-methoxyl group of 4--7-(3-chlorine propoxy-)-3-quinolinecarbonitriles and 2; the mol ratio of the chloro-5-anisidine of 4-bis-is 2:3); stirring heating temperature control 90-100 DEG C reaction more than 3h, TLC tracing and monitoring disappears to intermediate 1 spot.Reaction solution is cooled to 20-30 DEG C, be transferred to 200L glassed steel reaction vessels, add 40L ethyl acetate, 75L purified water is slowly added under stirring, add 1M hydrochloric acid (400mL concentrated hydrochloric acid and 4.5L purified water are prepared) adjust ph to 2, stir 30min, rejection filter, filter cake is respectively with 12L purified water, 12L purified water, the washing of 12L ethyl acetate; Solid adds in 20L ethyl acetate, rejection filter after stirring to pulp 30min, and solid 4L ethyl acetate is washed; Gained wet product grinds, and 35 DEG C-40 DEG C vacuum-drying 12h, obtain yellow powder 5.3kg, and yield is 88.3%.
The preparation of embodiment 3:4-[(the chloro-5-p-methoxy-phenyl of 2,4-bis-) is amino]-6-methoxyl group-7-(3-chlorine propoxy-)-3-quinolinecarbonitriles
Under nitrogen protection; 20L1-N-methyl-2-2-pyrrolidone N-is added in 30L glass reaction still; 3.70kg2 is added successively under stirring; 4-bis-chloro-5-anisidine, 1.48kg pyridine hydrochloride, 4.00kg4-chloro-6-methoxyl group-7-(3-chlorine propoxy-)-3-quinolinecarbonitriles (the chloro-6-methoxyl group of 4--7-(3-chlorine propoxy-)-3-quinolinecarbonitriles and 2; the mol ratio of the chloro-5-anisidine of 4-bis-is 2:3); stirring heating temperature control 90-100 DEG C reaction more than 3h, TLC tracing and monitoring disappears to intermediate 1 spot.Reaction solution is cooled to 20-30 DEG C, be transferred to 200L glassed steel reaction vessels, add 40L ethyl acetate, 75L purified water is slowly added under stirring, add 1M hydrochloric acid (400mL concentrated hydrochloric acid and 4.5L purified water are prepared) adjust ph to 2, stir 30min, rejection filter, filter cake is respectively with 12L purified water, 12L purified water, the washing of 12L ethyl acetate; Solid adds in 20L ethyl acetate, rejection filter after stirring to pulp 30min, and solid 4L ethyl acetate is washed; Gained wet product grinds, and 35 DEG C-40 DEG C vacuum-drying 12h, obtain yellow powder 5.4kg, and yield is 90.0%.
The preparation of embodiment 4:4-[(the chloro-5-p-methoxy-phenyl of 2,4-bis-) is amino]-6-methoxyl group-7-(3-chlorine propoxy-)-3-quinolinecarbonitriles
Under nitrogen protection; 20L dimethyl formamide is added in 30L glass reaction still; 3.70kg2 is added successively under stirring; 4-bis-chloro-5-anisidine, 1.48kg pyridine hydrochloride, 4.00kg4-chloro-6-methoxyl group-7-(3-chlorine propoxy-)-3-quinolinecarbonitriles (the chloro-6-methoxyl group of 4--7-(3-chlorine propoxy-)-3-quinolinecarbonitriles and 2; the mol ratio of the chloro-5-anisidine of 4-bis-is 2:3); stirring heating temperature control 90-100 DEG C reaction more than 3h, TLC tracing and monitoring disappears to intermediate 1 spot.Reaction solution is cooled to 20-30 DEG C, be transferred to 200L glassed steel reaction vessels, add 40L ethyl acetate, 75L purified water is slowly added under stirring, add 1M hydrochloric acid (400mL concentrated hydrochloric acid and 4.5L purified water are prepared) adjust ph to 2, stir 30min, rejection filter, filter cake is respectively with 12L purified water, 12L purified water, the washing of 12L ethyl acetate; Solid adds in 20L ethyl acetate, rejection filter after stirring to pulp 30min, and solid 4L ethyl acetate is washed; Gained wet product grinds, and 35 DEG C-40 DEG C vacuum-drying 12h, obtain yellow powder 5.2kg, and yield is 86.7%.
Embodiment 5: the preparation of bosutinib crude product
Under nitrogen protection, 16.2L1-N-methyl-2-2-pyrrolidone N-is added in 30L glass reaction still, 1.62kg sodium iodide is added successively under stirring, 4.77LN-methylpiperazine, 5.4kg4-[(2, the chloro-5-p-methoxy-phenyl of 4-bis-) amino]-6-methoxyl group-7-(3-chlorine propoxy-)-3-quinolinecarbonitriles (4-[(2, the chloro-5-p-methoxy-phenyl of 4-bis-) amino]-6-methoxyl group-7-(3-chlorine propoxy-)-3-quinolinecarbonitriles and N methyl piperazine mol ratio be 1:4), stirring heating temperature control 90 DEG C of-100 DEG C of more than stirring reaction 3h, TLC tracking monitor disappears to intermediate 2 spot, reaction solution is cooled to 20-30 DEG C, is transferred in 200L glassed steel reaction vessels, slowly adds 135L purified water under stirring, stirs 1h, rejection filter, solid washs 3 times by 10.8L purified water respectively, and rejection filter flows out to basic absence of liquid, and wet product grinds, and 40 DEG C-50 DEG C vacuum-drying 12h, obtaining bosutinib crude product is off-white color solid 5.6kg.5.6kg bosutinib crude product mixes with ethyl acetate, silica gel by equal proportion in batches, and 35 DEG C of-40 DEG C of concentrating under reduced pressure obtain sand shape thing; 28kg100-200 order silica gel fills post as stationary phase, add sand shape thing, 2.8kg quartz sand more successively, with ethyl acetate/methanol/ammoniacal liquor=300/100/1 (volume ratio, by 1080kg ethyl acetate, 320kg methyl alcohol and 4L ammoniacal liquor mixed preparing) be moving phase wash-out, TLC monitors, and collects bosutinib sterling elutriant, and 40 ~ 45 DEG C are evaporated to absence of liquid and flow out, obtain faint yellow solid 4.5kg, yield 73.3%.
Claims (10)
1. the preparation method of formula III compound, comprise: under pyridine hydrochloride exists, the chloro-6-methoxyl group of 4--7-(3-chlorine propoxy-)-3-quinolinecarbonitriles (formula II) and 2, condensation reaction is there is in 4-bis-chloro-5-anisidine in specific polar aprotic solvent, obtain 4-[(2, the chloro-5-p-methoxy-phenyl of 4-bis-) amino]-6-methoxyl group-7-(3-chlorine propoxy-)-3-quinolinecarbonitriles (formula III)
Wherein specific polar aprotic solvent is selected from 1-Methyl-2-Pyrrolidone, N,N-DIMETHYLACETAMIDE and dimethyl formamide.
2. the preparation method of claim 1, polar aprotic solvent is 1-Methyl-2-Pyrrolidone.
3. the preparation method of claim 1, the molar ratio of formula II compound and the chloro-5-anisidine of 2,4-bis-is 1:1 to 1:4, and temperature of reaction is 60 DEG C-120 DEG C.
4. the preparation method of formula II compound, comprise: under existing containing potassium ion acid binding agent and crown ether-like catalyzer, alkylated reaction is there is in 4-chloro-6-methoxyl group-7-hydroxyl-3 quinolinecarbonitriles and 1-bromo-3-chloropropane in specific polar aprotic solvent, obtain the chloro-6-methoxyl group of 4--7-(3-chlorine propoxy-)-3-quinolinecarbonitriles (formula II)
Wherein specific polar aprotic solvent is selected from 1-Methyl-2-Pyrrolidone, N,N-DIMETHYLACETAMIDE and dimethyl formamide.
5. the preparation method of claim 4, polar aprotic solvent is 1-Methyl-2-Pyrrolidone, and crown ether-like catalyzer is dibenzo-18 crown-6-ether, and acid binding agent is salt of wormwood.
6. the preparation method of claim 4-5, the molar ratio of 4-chloro-6-methoxyl group-7-hydroxyl-3 quinolinecarbonitriles and the bromo-3-chloropropane of 1-is 1:4 to 1:1, and temperature of reaction is 20 DEG C-60 DEG C.
7. a preparation method for bosutinib (formula I), comprises the following steps:
1) under dibenzo-18 crown-6-ether and salt of wormwood exist, alkylated reaction is there is in 4-chloro-6-methoxyl group-7-hydroxyl-3 quinolinecarbonitriles and the bromo-3-chloropropane of 1-in 1-Methyl-2-Pyrrolidone, obtain the chloro-6-methoxyl group of 4--7-(3-chlorine propoxy-)-3-quinolinecarbonitriles (formula II), the molar ratio of 4-chloro-6-methoxyl group-7-hydroxyl-3 quinolinecarbonitriles and the bromo-3-chloropropane of 1-is 1:4 to 1:1, and temperature of reaction is 20 DEG C-60 DEG C;
2) under pyridine hydrochloride exists, the chloro-6-methoxyl group of 4--7-(3-chlorine propoxy-)-3-quinolinecarbonitriles (formula II) and 2, condensation reaction is there is in the chloro-5-anisidine of 4-bis-in 1-Methyl-2-Pyrrolidone, obtain 4-[(2, the chloro-5-p-methoxy-phenyl of 4-bis-) amino]-6-methoxyl group-7-(3-chlorine propoxy-)-3-quinolinecarbonitriles (formula III), formula II compound and 2, the molar ratio of the chloro-5-anisidine of 4-bis-is 1:1 to 1:4, and temperature of reaction is 60 DEG C-120 DEG C;
3) under iodide exist, 4-[(2, the chloro-5-p-methoxy-phenyl of 4-bis-) amino]-6-methoxyl group-7-(3-chlorine propoxy-)-3-quinolinecarbonitriles (formula III) in 1-Methyl-2-Pyrrolidone, alkylated reaction occurs with N methyl piperazine, obtain bosutinib (formula I), described iodide are selected from potassiumiodide, sodium iodide, magnesium iodide and lithium iodide.
8. the preparation method of claim 7, wherein step 3) in iodide be sodium iodide.
9. the preparation method of claim 7-8, the molar ratio of its Chinese style III compound and N methyl piperazine is 1:2 to 1:8, and temperature of reaction is 60 DEG C-120 DEG C.
10. the preparation method of claim 1-9, respond and carry out all under nitrogen protection.
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| WO2002044166A1 (en) * | 2000-11-02 | 2002-06-06 | Astrazeneca Ab | Substituted quinolines as antitumor agents |
| CN101792416A (en) * | 2010-01-15 | 2010-08-04 | 南京医科大学 | Process for preparing bosutinib |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2002044166A1 (en) * | 2000-11-02 | 2002-06-06 | Astrazeneca Ab | Substituted quinolines as antitumor agents |
| CN101792416A (en) * | 2010-01-15 | 2010-08-04 | 南京医科大学 | Process for preparing bosutinib |
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| CN107814769A (en) * | 2016-09-14 | 2018-03-20 | 正大天晴药业集团股份有限公司 | A kind of purification process of bosutinib |
| CN107814769B (en) * | 2016-09-14 | 2021-05-07 | 正大天晴药业集团股份有限公司 | Purification method of bosutinib |
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