CN108623602B - Method for preparing and purifying ibrutinib - Google Patents

Method for preparing and purifying ibrutinib Download PDF

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CN108623602B
CN108623602B CN201810551855.1A CN201810551855A CN108623602B CN 108623602 B CN108623602 B CN 108623602B CN 201810551855 A CN201810551855 A CN 201810551855A CN 108623602 B CN108623602 B CN 108623602B
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ibrutinib
preparing
compound
reaction
base
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CN108623602A (en
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陈欢生
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XIAMEN MEDICAL COLLEGE
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XIAMEN MEDICAL COLLEGE
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D487/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by C07D451/00 - C07D477/00
    • C07D487/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04Ortho-condensed systems

Abstract

The invention discloses a method for preparing and purifying ibrutinib, wherein (R) -3- (4-phenoxyphenyl) -1- (piperidine-3-yl) -1H-pyrazolo [3,4-d ] pyrimidine-4-amine (II) and acryloyl chloride are condensed under the action of mixed base containing organic base and metal hydroxide to generate ibrutinib (I). The synthesis method has the advantages of simple post-treatment operation, no generation of a large amount of floccules, high product purity and high yield, and is suitable for industrial production.

Description

Method for preparing and purifying ibrutinib
Technical Field
The invention relates to a method for preparing and purifying ibrutinib.
Background
Ibrutinib (Ibrutinib, I), chemical name is 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one, trade name is Imbruvica, is a new targeted anticancer drug developed by Qiangsheng pharmaceutical company and Phar-macyclics company, and is approved by the United states Food and Drug Administration (FDA) to be marketed in 11/13 d 2013 for the treatment of mantle cell lymphoma (MC L).
There are mainly two synthetic routes for ibrutinib, depending on the starting materials. Route one, as reported in patent US007514444B2, with 1H-pyrazolo [3,4-d]The 3-halogeno-1H-pyrazolo [3,4-d ] is obtained by taking pyrimidine-4-amine as a starting material through bromination or iodination]Pyrimidin-4-amine. 3-halo-1H-pyrazolo [3,4-d]The pyrimidin-4-amine is subjected to a palladium mediated cross-coupling reaction with an appropriately substituted phenylboronic acid to provide compound (iii). PPh in diisopropyl azodicarboxylate resin combination3Under the conditions, the compound (III) is coupled with N-Boc-3-hydroxypiperidine through a Mitsunobu reaction, and then deprotected with hydrochloric acid to obtain a compound (II). Coupling the compound (II) with acryloyl chloride to obtain ibrutinib (I).
In the second route, 4-phenoxybenzoic acid is used as a raw material, and a compound (III) is prepared by chlorination, condensation with malononitrile, methylation, cyclization with hydrazine hydrate and cyclization with formamide. And (3) carrying out Mitsunobu reaction on the compound (III) and removing a Boc protecting group to obtain a compound (II), and coupling the compound (II) with acryloyl chloride to obtain ibrutinib (I).
In any route, the final step of reaction is to react the compound (II) with acryloyl chloride to obtain the ibrutinib (I). All the processes known to date for preparing ibrutinib (i) from compound (ii) employ a single inorganic base such as potassium carbonate, sodium bicarbonate, sodium hydroxide, etc., or a single organic base such as diisopropylethylamine, triethylamine, etc. In the research, we found that, in this synthesis, if a single organic base such as diisopropylethylamine, triethylamine, etc. is used, the reaction proceeds smoothly and the post-treatment is simple, but in the reaction, the reagent acryloyl chloride used is slowly decomposed into chloropropionyl chloride even under low temperature conditions. In the reaction, chloropropionyl chloride is very easy to react with a compound (II) so as to form an Impurity (IV), and the content of the Impurity (IV) is 0.6-1.0%. The Impurity (IV) has a structure similar to that of ibrutinib (I), and is difficult to remove, so that the product can reach the standard only by repeated recrystallization purification (the single impurity is less than 0.1%). If a single inorganic base such as potassium carbonate, sodium hydroxide and the like is adopted, the reaction efficiency is poorer than that of an organic base, and the yield is lower. Particularly, when a single inorganic base is adopted, obvious floccules are generated in the post-treatment, and particularly when the system release amount reaches a hundred gram level, the floccules are extremely obvious, so that the liquid separation is very difficult, and the large-scale production is difficult.
Disclosure of Invention
The invention aims to overcome the defects of the prior art, and provides a synthetic method for preparing ibrutinib, which has the advantages of simple post-treatment operation, high yield and high purity and is suitable for industrial production.
The method comprises the following specific steps: (R) -3- (4-phenoxyphenyl) -1- (piperidin-3-yl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine (II) is subjected to condensation reaction with acryloyl chloride in the presence of a mixed base and a suitable solvent to form ibrutinib (I), wherein the mixed base comprises the following two components, namely an organic base and a metal hydroxide.
The reaction involved in the present invention can be represented by the following reaction formula:
the reaction for preparing the compound (I) from the compound (II) and acryloyl chloride is carried out under the action of mixed base, wherein the first component of the mixed base is organic base selected from diisopropylethylamine, triethylamine, DBU, DABCO, pyridine and N-methylmorpholine; the second component is a metal hydroxide selected from the group consisting of lithium hydroxide, sodium hydroxide, and potassium hydroxide. The dosage of the organic base is 1.0-2.0 equivalent of the compound (II); the amount of the metal hydroxide is 0.1 to 0.2 equivalent to the compound (II).
The reaction for preparing compound (I) from compound (II) and acryloyl chloride according to the present invention is carried out in a suitable solvent selected from the group consisting of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, acetone, N-dimethylformamide.
In the reaction for preparing the compound (I) from the compound (II) and acryloyl chloride, the reaction temperature is-15-40 ℃.
The operation of the reaction for producing compound (I) from compound (II) and acryloyl chloride according to the present invention is roughly as follows:
adding the compound (II), a solvent, an organic base and a metal hydroxide into a reaction bottle, dropwise adding acryloyl chloride, and reacting for 1-24 hours at-15-40 ℃. After the reaction, the reaction mixture was washed with citric acid solution. Separating an organic layer, concentrating the organic layer to obtain an oily substance, and recrystallizing to obtain ibrutinib (I).
Compared with the background technology, the technical scheme of the invention has the advantages that: the invention finds that under the action of metal hydroxide, such as sodium hydroxide, the Impurity (IV) is easy to undergo elimination reaction and is converted into ibrutinib (I) again.
Therefore, the invention adopts the mixed alkali to replace single inorganic alkali or organic alkali, not only has high conversion rate, but also can completely convert the inevitable Impurity (IV) generated by chloropropionyl chloride into a product under the action of catalytic amount of metal hydroxide, thereby inhibiting the impurity in a reaction system, in addition, the post-treatment is simple, a large amount of floccule can not appear, and finally, the ibrutinib (I) is prepared with high yield and high purity, and is suitable for industrial production.
Detailed Description
The present invention will be described in detail with reference to the following examples:
example 1: synthesis of 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one (I)
Adding a compound II (115.8g, 0.3mol), diisopropylethylamine (42.6g, 0.33mol), sodium hydroxide (1.2g, 0.03mol) and dichloromethane (1.5L) into a reaction bottle at-5 ℃, dropwise adding acryloyl chloride (30.0g, 0.33mol), reacting at room temperature for 3H after dropwise adding, adding a 5% citric acid aqueous solution (1.5L) into the system after the reaction is finished, extracting, separating an organic layer, removing dichloromethane under reduced pressure to obtain an oily substance, adding a 60% methanol aqueous solution (2L), heating to dissolve the system, fully stirring at 5-10 ℃ for 10H, filtering out a solid, drying to obtain 119.1g of a pale solid (mp I), wherein the yield is 90.2%, 152-153 ℃, the HP L C purity is 99.58%, the single impurity content is less than 0.1%, and ESI-MS (M/z):441[ M + H/z: (M/z)]+1H NMR(500MHz,DMSO-d6):1.48-1.60(m 1H),1.89-1.93(m,1H),2.08-2.14(m,1H),2.25-2.30(m,1H),2.94-3.0(m,0.5H),3.18-3.25(m,1H),3.63-3.75(m,0.5H),4.02-4.11(m,0.5H),4.15-4.25(m,1H),4.49-4.60(m,0.5H),4.65-4.78(m,1H),5.57-5.73(m,1H),6.02-6.18(m,1H),6.65-6.75(m,0.5H),6.81-6.92(m,0.5H),7.12-7.20(m,5H),7.42(t,J=7.6Hz,2H),7.65(d J=8.0Hz,2H),8.25(s,1H)。
Example 2: synthesis of 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one (I)
Adding a compound II (115.8g, 0.3mol), triethylamine (46.8g, 0.45mol), potassium hydroxide (2.52g, 0.045mol) and tetrahydrofuran (1.5L) into a reaction flask, dropwise adding acryloyl chloride (30.0g, 0.33mol) at room temperature, reacting at room temperature for 1h after dropwise adding, concentrating to remove tetrahydrofuran, adding ethyl acetate (1.5L) and a 5% citric acid aqueous solution (1.5L) into the residue, extracting, separating an organic layer, removing ethyl acetate under reduced pressure to obtain an oily substance, adding a 60% methanol aqueous solution (2L), heating to clear the system, fully stirring at 5-10 ℃ for 10h, filtering out a solid, drying to obtain 112.5g of a pale solid (I), wherein the yield is 85.3%, the purity of HP L C is 99.51%, and the single impurity content is less than 0.1%.

Claims (4)

1. A method for preparing and purifying ibrutinib comprises the following specific steps:
condensing (R) -3- (4-phenoxyphenyl) -1- (piperidin-3-yl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine (II) with acryloyl chloride in the presence of a mixed base comprising an organic base and a metal hydroxide as a second component in a solvent selected from the group consisting of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, acetone, N-dimethylformamide,
2. the process for preparing ibrutinib according to claim 1, wherein the first component organic base of the mixed base used for preparing compound (i) is selected from diisopropylethylamine, triethylamine, DBU, DABCO, pyridine, N-methylmorpholine; the amount of the organic base used is 1.0 to 2.0 equivalents of the compound (II).
3. The process for preparing ibrutinib according to claim 1, wherein the second component metal hydroxide of the mixed base used for preparing compound (i) is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide; the amount of the metal hydroxide used is 0.1 to 0.2 equivalent to that of the compound (II).
4. The process for preparing ibrutinib according to claim 1, wherein the reaction temperature for preparing the compound (i) is-15 to 40 ℃.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105859721A (en) * 2015-01-22 2016-08-17 浙江京新药业股份有限公司 Method for preparing ibrutinib
CN105985343A (en) * 2015-02-12 2016-10-05 上海昶朗医药科技有限公司 Preparation method for ibrutinib
CN106146516A (en) * 2015-04-20 2016-11-23 北京睿创康泰医药研究院有限公司 The preparation method of Buddhist nun's impurity of the drug is replaced according to Shandong

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WO2016170545A1 (en) * 2015-04-22 2016-10-27 Msn Laboratories Private Limited Process for the preparation of 1-[(3r)-3-[4-amino-3-(4-phenoxyphenvl)-1h- pvrazolo[3,4-d]pyriniidin-1-y1]-1-piperidinvl]-2-propen-1-one and its polymorphs thereof

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
CN105859721A (en) * 2015-01-22 2016-08-17 浙江京新药业股份有限公司 Method for preparing ibrutinib
CN105985343A (en) * 2015-02-12 2016-10-05 上海昶朗医药科技有限公司 Preparation method for ibrutinib
CN106146516A (en) * 2015-04-20 2016-11-23 北京睿创康泰医药研究院有限公司 The preparation method of Buddhist nun's impurity of the drug is replaced according to Shandong

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