CN108623602A - A method of prepare and purify and replaces Buddhist nun according to Shandong - Google Patents
A method of prepare and purify and replaces Buddhist nun according to Shandong Download PDFInfo
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- CN108623602A CN108623602A CN201810551855.1A CN201810551855A CN108623602A CN 108623602 A CN108623602 A CN 108623602A CN 201810551855 A CN201810551855 A CN 201810551855A CN 108623602 A CN108623602 A CN 108623602A
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- Prior art keywords
- shandong
- buddhist nun
- prepare
- compound
- reaction
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- 0 O[C@@]1C*CCC1 Chemical compound O[C@@]1C*CCC1 0.000 description 2
- OWHNIGPDWOERQG-UHFFFAOYSA-N C=CC(N(CCC1)CC1[n](c1ncnc(N)c11)nc1-c(cc1)ccc1[U]c1ccccc1)=O Chemical compound C=CC(N(CCC1)CC1[n](c1ncnc(N)c11)nc1-c(cc1)ccc1[U]c1ccccc1)=O OWHNIGPDWOERQG-UHFFFAOYSA-N 0.000 description 1
- NTSAEGNFPKKRLX-UHFFFAOYSA-N CC(C)(C)OC(N(CCC1)CC1[n](c1ncnc(N)c11)nc1-c(cc1)ccc1Oc1ccccc1)=O Chemical compound CC(C)(C)OC(N(CCC1)CC1[n](c1ncnc(N)c11)nc1-c(cc1)ccc1Oc1ccccc1)=O NTSAEGNFPKKRLX-UHFFFAOYSA-N 0.000 description 1
- XGIQFMWTZUKIKG-UHFFFAOYSA-N CC(c(cc1C)ccc1Oc1ccccc1)=C(C#N)C#N Chemical compound CC(c(cc1C)ccc1Oc1ccccc1)=C(C#N)C#N XGIQFMWTZUKIKG-UHFFFAOYSA-N 0.000 description 1
- DXKQJCVMSCEMBY-UHFFFAOYSA-N CC1C=CC=CC1OC1C=CC(c2n[n](C(CCC3)CN3C(CCCl)=O)c3ncnc(N)c23)=CC1 Chemical compound CC1C=CC=CC1OC1C=CC(c2n[n](C(CCC3)CN3C(CCCl)=O)c3ncnc(N)c23)=CC1 DXKQJCVMSCEMBY-UHFFFAOYSA-N 0.000 description 1
- MWTPPIZIKZHMSK-UHFFFAOYSA-N N#CC(C#N)=C(c(cc1)ccc1Oc1ccccc1)O Chemical compound N#CC(C#N)=C(c(cc1)ccc1Oc1ccccc1)O MWTPPIZIKZHMSK-UHFFFAOYSA-N 0.000 description 1
- HNIMEQCLCNSCGH-UHFFFAOYSA-N Nc([nH]nc1-c(cc2)ccc2Oc2ccccc2)c1C#N Chemical compound Nc([nH]nc1-c(cc2)ccc2Oc2ccccc2)c1C#N HNIMEQCLCNSCGH-UHFFFAOYSA-N 0.000 description 1
- GPSQYTDPBDNDGI-UHFFFAOYSA-N Nc1c(c(-c(cc2)ccc2Oc2ccccc2)n[n]2C3CNCCC3)c2ncn1 Chemical compound Nc1c(c(-c(cc2)ccc2Oc2ccccc2)n[n]2C3CNCCC3)c2ncn1 GPSQYTDPBDNDGI-UHFFFAOYSA-N 0.000 description 1
- AOOZVQGGMFGGEE-UHFFFAOYSA-N O=C(c(cc1)ccc1Oc1ccccc1)Cl Chemical compound O=C(c(cc1)ccc1Oc1ccccc1)Cl AOOZVQGGMFGGEE-UHFFFAOYSA-N 0.000 description 1
- RYAQFHLUEMJOMF-UHFFFAOYSA-N OC(c(cc1)ccc1Oc1ccccc1)=O Chemical compound OC(c(cc1)ccc1Oc1ccccc1)=O RYAQFHLUEMJOMF-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses a kind of methods prepared and purified and replace Buddhist nun according to Shandong, (R) 3 (4 Phenoxyphenyl) 1 (3 base of piperidines) 1H pyrazolos [3,4 d] pyrimidine 4 amine (II) and acryloyl chloride be condensed in the case where being acted on comprising the mixed base of organic base and metal hydroxides, generate and replace Buddhist nun (I) according to Shandong.The synthetic method post-processing operation of the present invention is simple, not will produce a large amount of floccules, product purity is high, high income, is suitble to industrialized production.
Description
Technical field
The present invention relates to a kind of methods prepared and purified and replace Buddhist nun according to Shandong.
Background technology
Buddhist nun (Ibrutinib, I), entitled 1- [(3R) -3- [4- amino -3- (4- the Phenoxyphenyls) -1H- of chemistry are replaced according to Shandong
Pyrazolo [3,4-d] pyrimidine -1- bases] -1- piperidyls] -2- propylene -1- ketone, trade name Imbruvica is that Johnson ＆ Johnson's pharmacy is public
The target anticancer new drug of department and Phar-macyclics companies R ＆ D Cooperation, in 13 U.S. Huo food and medicine pipe November in 2013
Reason office (FDA) approval listing, the medicine are used for the treatment of lymphoma mantle cell (mantle cell lympho-ma, MCL).
According to the difference of starting material, according to Shandong, for Buddhist nun, there are mainly two types of synthetic routes.Route one, such as patent
US007514444B2 reports, with 1H- pyrazolos [3,4-d] pyrimidine -4- amine for starting material, obtained after bromo or iodo
Halogenated -1H- pyrazolos [3,4-d] pyrimidine -4- amine of 3-.3- halogenated -1H- pyrazolos [3,4-d] pyrimidine -4- amine and suitably replace
Phenylboric acid carries out palladium mediated cross-coupling reaction, obtains compound (III).In diisopropyl azodiformate and resin knot
The PPh of conjunction3Under the conditions of, compound (III) is coupled by Mitsunobu reactions with N-Boc-3- hydroxy piperidines, is then gone with hydrochloric acid
Compound (II) is obtained after protection.Compound (II) is coupled with acryloyl chloride, obtains replacing Buddhist nun (I) according to Shandong.
Route two be condensed, methylates through chloro, with malononitrile and hydrazine hydrate ring using 4- phenoxy benzoic acids as raw material
It closes, compound (III) is made with formamide cyclization.Compound (III) is reacted through Mitsunobu and chemical combination is made in de- Boc protecting groups
Object (II), compound (II) are coupled with acryloyl chloride, obtain replacing Buddhist nun (I) according to Shandong.
No matter which route, final step reaction is obtained by the reaction according to Shandong for Buddhist nun with compound (II) and acryloyl chloride
(Ⅰ).It is all to use single inorganic base such as that all methods being currently known, which prepare from compound (II) and replace the reaction of Buddhist nun (I) according to Shandong,
Potassium carbonate, sodium bicarbonate, sodium hydroxide etc. or single organic base such as diisopropyl ethyl amine, triethylamine etc..It is studying
In, it has been found that in the synthesis of this step, according to single organic base, such as diisopropyl ethyl amine, triethylamine, instead
It should be able to be smoothed out, and post-processing is very simple, but in the reaction, agents useful for same acryloyl chloride is even if under cryogenic
Chlorpromazine chloride can slowly be resolved into.In the reaction, chlorpromazine chloride is very easy to react with compound (II), to form impurity
(IV), content is 0.6~1.0%.Impurity (IV) is similar for Buddhist nun's (I) structure to according to Shandong, it is difficult to remove, cause product to need more
Secondary recrystallization purification could be up to standard (single impurity is less than 0.1%).According to single inorganic base, such as potassium carbonate, sodium hydroxide
Deng for reaction efficiency than organic alkaline error, yield is relatively low.When especially with single inorganic base, post-processing will produce apparent cotton-shaped
Object, especially when system high-volume to hectogram grade when, floccule is particularly evident, causes liquid separation extremely difficult, it is difficult to be amplified production.
Invention content
It is an object of the invention in place of overcome the deficiencies in the prior art, provide a kind of synthesis side for preparing and replacing Buddhist nun according to Shandong
Method, post-processing operation is simple, high income, purity are high, is suitble to industrialized production.
The technology specifically comprises the steps of：In the presence of mixed base and appropriate solvent, (R) -3- (4- Phenoxyphenyls) -1-
With acryloyl chloride condensation reaction occurs for (piperidines -3- bases) -1H- pyrazolos [3,4-d] pyrimidine -4- amine (II), generates and replaces Buddhist nun according to Shandong
(I), wherein mixed base includes following two components, and first group is divided into organic base, and second group is divided into metal hydroxides.
The present invention relates to reaction can be indicated with following reaction equation：
Reaction of the present invention from compound (II) and acryloyl chloride prepare compound (I) is under the action of mixed base
It carries out, first group of mixed base is divided into organic base, selected from diisopropyl ethyl amine, triethylamine, DBU, DABCO, pyridine, N- first
Base morpholine；Second group is divided into metal hydroxides, selected from lithium hydroxide, sodium hydroxide, potassium hydroxide.The dosage of organic base is to change
Close 1.0~2.0 equivalents of object (II)；The dosage of metal hydroxides is 0.1~0.2 equivalent of compound (II).
Reaction of the present invention from compound (II) and acryloyl chloride prepare compound (I) be in a suitable solvent into
Capable, solvent used is selected from dichloromethane, tetrahydrofuran, 2- methyltetrahydrofurans, acetonitrile, acetone, N, N- dimethyl formyls
Amine.
It is of the present invention from the reaction of compound (II) and acryloyl chloride prepare compound (I), reaction temperature be -15~
40℃。
The operating process of reaction of the present invention from compound (II) and acryloyl chloride prepare compound (I) is substantially such as
Under：
Compound (II), solvent, organic base, metal hydroxides are added in reaction bulb, acryloyl chloride is added dropwise, -15
It is reacted 1~24 hour at~40 DEG C.After having reacted, washed with citric acid solution.Organic layer is separated, organic layer is concentrated to give oily
Object, get Yi Lu replaces Buddhist nun (I) after recrystallization.
The technical program compared with the background art, the advantage of the invention is that：It is a discovery of the invention that in metal hydroxides,
Under being acted on such as sodium hydroxide, impurity (IV) easily occurs elimination reaction and is re-converted into according to Shandong for Buddhist nun (I).
Therefore, the present invention substitutes single inorganic base or organic base using mixed base, not only high conversion rate, and in reaction
The impurity (IV) inevitably generated by chlorpromazine chloride can be fully converted to product under the effect of catalytic amount metal hydroxides,
To may refrain from the impurity in the reaction system, post-processing is simple in addition, is not in a large amount of floccules, is finally received with height
It is prepared for rate, high-purity replacing Buddhist nun (I) according to Shandong, is suitble to industrialized production.
Specific implementation mode
Present disclosure is illustrated below by embodiment：
Embodiment 1：1- [(3R) -3- [4- amino -3- (4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1-
Base] -1- piperidyls] -2- propylene -1- ketone (I) synthesis
In reaction bulb be added compound ii (115.8g, 0.3mol), diisopropyl ethyl amine (42.6g, 0.33mol),
Sodium hydroxide (1.2g, 0.03mol) and dichloromethane (1.5L).At -5 DEG C, acryloyl chloride (30.0g, 0.33mol), drop is added dropwise
3h is reacted at room temperature after complete.After the completion of reaction, 5% aqueous citric acid solution (1.5L) is added into system, extracts, separates organic layer.
Dichloromethane is removed under reduced pressure and obtains grease, 60% methanol aqueous solution (2L) is added, system dissolved clarification is heated to, then 5~10
It is sufficiently stirred 10h under degree.Solid is filtered out, obtains 119.1g pale asphyxias solid (I) after drying, yield 90.2%, mp 152~
153℃；HPLC purity 99.58%, list is miscellaneous to be less than 0.1%；ESI-MS(m/z):441[M+H]+；1H NMR(500MHz,DMSO-
d6)δ: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)。
Embodiment 2：1- [(3R) -3- [4- amino -3- (4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine -1-
Base] -1- piperidyls] -2- propylene -1- ketone (I) synthesis
Compound ii (115.8g, 0.3mol), triethylamine (46.8g, 0.45mol), potassium hydroxide are added in reaction bulb
(2.52g, 0.045mol) and tetrahydrofuran (1.5L).At room temperature, acryloyl chloride (30.0g, 0.33mol) is added dropwise, drips off rear chamber
Temperature reaction 1h.After the completion of reaction, concentration removes tetrahydrofuran.Ethyl acetate (1.5L) and 5% citric acid water are added into residue
Solution (1.5L), extraction, separates organic layer.Ethyl acetate is removed under reduced pressure and obtains grease, 60% methanol aqueous solution (2L) is added,
It is heated to system dissolved clarification, is then sufficiently stirred 10h under 5~10 degree.Solid is filtered out, it is solid that 112.5g pale asphyxias are obtained after drying
Body (I), yield 85.3%, HPLC purity 99.51%, list is miscellaneous to be less than 0.1%.
Claims (5)
1. a kind of preparing and purifying the method for replacing Buddhist nun according to Shandong, the specific steps are：
In the presence of mixed base and appropriate solvent, (R) -3- (4- Phenoxyphenyls) -1- (piperidines -3- bases) -1H- pyrazolos
[3,4-d] pyrimidine -4- amine (II) generates with acryloyl chloride condensation and replaces Buddhist nun (I) according to Shandong, and wherein mixed base includes following two components,
First group is divided into organic base, and second group is divided into metal hydroxides,
2. according to claim 1 prepare the method for replacing Buddhist nun according to Shandong, it is characterised in that the mixing used in prepare compound (I)
First component organic base of alkali is selected from diisopropyl ethyl amine, triethylamine, DBU, DABCO, pyridine, N-methylmorpholine；Used
The dosage of organic base is 1.0~2.0 equivalents of compound (II).
3. according to claim 1 prepare the method for replacing Buddhist nun according to Shandong, it is characterised in that the mixing used in prepare compound (I)
Second component metals hydroxide of alkali is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide；The use of metal hydroxides used
Amount is 0.1~0.2 equivalent of compound (II).
4. it is according to claim 1 prepare according to Shandong replace Buddhist nun method, it is characterised in that the reaction of prepare compound (I) be
Carried out in solvent appropriate, solvent used be selected from dichloromethane, tetrahydrofuran, 2- methyltetrahydrofurans, acetonitrile, acetone,
N,N-dimethylformamide.
5. according to claim 1 prepare the method for replacing Buddhist nun according to Shandong, it is characterised in that the reaction temperature of prepare compound (I)
It is -15~40 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810551855.1A CN108623602B (en) | 2018-05-31 | 2018-05-31 | Method for preparing and purifying ibrutinib |
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| CN201810551855.1A CN108623602B (en) | 2018-05-31 | 2018-05-31 | Method for preparing and purifying ibrutinib |
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| CN108623602A true CN108623602A (en) | 2018-10-09 |
| CN108623602B CN108623602B (en) | 2020-07-17 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115124536A (en) * | 2022-07-02 | 2022-09-30 | 浙江美诺华药物化学有限公司 | Synthesis method of ibrutinib intermediate |
| CN116063309A (en) * | 2023-03-13 | 2023-05-05 | 北京京卫燕康药物研究所有限公司 | Synthesis method of ibrutinib |
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| CN105859721A (en) * | 2015-01-22 | 2016-08-17 | 浙江京新药业股份有限公司 | Method for preparing ibrutinib |
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2018
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| 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 |
| 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 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115124536A (en) * | 2022-07-02 | 2022-09-30 | 浙江美诺华药物化学有限公司 | Synthesis method of ibrutinib intermediate |
| CN116063309A (en) * | 2023-03-13 | 2023-05-05 | 北京京卫燕康药物研究所有限公司 | Synthesis method of ibrutinib |
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| CN108623602B (en) | 2020-07-17 |
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