CN104557946A - Preparation method of ibrutinib - Google Patents
Preparation method of ibrutinib Download PDFInfo
- Publication number
- CN104557946A CN104557946A CN201510055853.XA CN201510055853A CN104557946A CN 104557946 A CN104557946 A CN 104557946A CN 201510055853 A CN201510055853 A CN 201510055853A CN 104557946 A CN104557946 A CN 104557946A
- Authority
- CN
- China
- Prior art keywords
- reaction
- preparation
- shandong
- ibrutinib
- buddhist nun
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 0 Nc1c(C(c(cc2)ccc2Oc2ccccc2)N*2)c2ncn1 Chemical compound Nc1c(C(c(cc2)ccc2Oc2ccccc2)N*2)c2ncn1 0.000 description 3
- NQRYJNQNLNOLGT-UHFFFAOYSA-N C1CCNCC1 Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
- OKRWWSHYSCHBKU-ITUIMRKVSA-N C=CC(N(CCC1)C[C@@H]1[n](c1c2c(N)ncn1)nc2-c(cc1)ccc1Oc1ccccc1)O Chemical compound C=CC(N(CCC1)C[C@@H]1[n](c1c2c(N)ncn1)nc2-c(cc1)ccc1Oc1ccccc1)O OKRWWSHYSCHBKU-ITUIMRKVSA-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
Abstract
The invention relates to a preparation method of ibrutinib. The preparation method comprises the following steps: allowing 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo [3, 4-d] pyrimidine, 1-[3(S)-hydroxy-1-piperidinyl]-2-propen-1-one, and triphenylphosphine to be dissolved in tetrahydrofuran as a reaction solvent at a temperature of -20 to 100 DEG C, and then slowly adding diisopropyl azodicarboxylate, and stirring until the reaction is finished to obtain the ibrutinib. The preparation method provided by the invention has the advantages of easy availability of raw materials, mild conditions, simple process, economy and environmental protection, and is suitable for industrial production.
Description
Technical field
The present invention relates to bulk drug preparing technical field, be specifically related to the preparation method of Yi Lu for Buddhist nun (Ibrutinib).
Background technology
According to Shandong for Buddhist nun (English name Ibrutinib, trade name IMBRUVICA), it is bruton's tyrosine kinase (BTK) inhibitor that U.S. Johnson & Johnson and U.S. Pharmacyclics Inc. research and develop jointly.This medicine and on November 13rd, 2013 are ratified to obtain and go on the market, for the treatment of lymphoma mantle cell (mantle celllymphoma, MCL).Yi Lu is called for the chemistry of Buddhist nun (Ibrutinib): 1-[3 (R)-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-base]-piperidino]-2-propylene-1-ketone, its structural formula is:
Document ChemMedChem.2007,2 (1): 58-61 report the synthetic method of Yi Lu for Buddhist nun,
The method is with 4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3; 4-d] pyrimidine is raw material; to prolong through light with 3 (S)-hydroxy piperidine-1-t-butyl formates react, Deprotection and the reaction such as acrylated, obtained according to Shandong for Buddhist nun.But this route steps is many, particularly introduce and also to experience remove-insurance and acrylated after chiral radicals, have impact on total yield, cost increases, and is unfavorable for industrialization.
China Patent Publication No. CN103121999 reports according to a kind of synthetic method of Shandong for Buddhist nun:
The method is with 4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3; 4-d] pyrimidine is raw material; with 3 (S)-hydroxy piperidine-1-t-butyl formates through mineral alkali catalyzed reaction, trifluoroacetylations such as cesium carbonates; the reactions such as Deprotection, acrylated and de-trifluoroacetyl group, obtained according to Shandong for Buddhist nun.But this route steps is many, the reaction of mineral alkali catalysis 4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine and 3 (S)-hydroxy piperidine-1-t-butyl formates, the optical purity of product can not be guaranteed; Meanwhile, also experience trifluoroacetylation, Deprotection, acrylated and de-trifluoroacetyl group, have impact on total yield after introducing chiral radicals, cost increases, and is unfavorable for that industrialization generates.
China Patent Publication No. CN103626774 reports according to Shandong another synthetic method for Buddhist nun:
The method with 4-phenoxy group Benzoyl chloride for raw material, with propane dinitrile and methyl-sulfate generation condensation and first oxidizing reaction, then obtain Yi Lu for Buddhist nun (I) with 1-[3 (R)-diazanyl-piperidino]-2-propylene-1-ketone through pyrazoles cyclisation and pyrimidine cyclization.By directly being introduced by chiral structure 1-[3 (R)-diazanyl-piperidino]-2-propylene-1-ketone, this synthetic route step is made to shorten to four steps.But this route at high temperature carries out pyrimidine cyclisation after propenyl structure being introduced, and is easily cause side reaction, causes product purity to reduce, and yield reduces, and is unfavorable for suitability for industrialized production.
Summary of the invention
The object of the invention is to for defect of the prior art, provide a kind of and have that raw material is easy to get, concise in technology, environmental protection and economy and be applicable to the preparation method of industrialized Yi Lu for Buddhist nun's body, be applied to according to the preparation of Shandong for Buddhist nun.
The invention discloses a kind of according to the preparation method of Shandong for Buddhist nun (Ibrutinib), method of the present invention comprises: 4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine and 1-[3 (S)-hydroxyl-piperidino]-2-propylene-1-ketone prolong through light and reacts (Mitsunobu reacts) step and prepare according to Shandong for Buddhist nun.
Wherein:
The mol ratio of reaction mass is as follows, 4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine: 1-[3 (S)-hydroxyl-piperidino]-2-propylene-1-ketone: triphenylphosphine: diisopropyl azodiformate=1: 0.5 ~ 3: 0.5 ~ 3: 0.5 ~ 3.
Reaction solvent is tetrahydrofuran (THF), also can be ether, dioxane, methylene dichloride, chloroform, toluene, ethyl acetate, acetonitrile and DMF or their mixture as solvent.
Usual temperature of reaction is at-20 DEG C to 100 DEG C, especially 0 DEG C to 30 DEG C.
By 4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine and 1-[3 (S)-hydroxyl-piperidino]-2-propylene-1-ketone, triphenylphosphine or its analogue are dissolved in the middle of reaction solvent, then diisopropyl azodiformate or its analogue are slowly dripped, then stirring reaction is until reaction terminates.
Also can by triphenylphosphine or its analogue, diisopropyl azodiformate or its analogue prior to stirring in reaction solvent, again by 4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine and 1-[3 (S)-hydroxyl-piperidino]-2-propylene-1-ketone adds, and then stirring reaction is until reaction terminates.
It is triphenylphosphine that triphenylphosphine or its analogue refer to what add in reaction, can be also its analogue, comprise positive tributylphosphine, diphenyl methyl phosphine and triphenylphosphine, tributylphosphine, the Polymer-supported loadings such as diphenyl methyl phosphine.
It is diisopropyl azodiformate that diisopropyl azodiformate or its analogue refer to what can add in reaction, also can be its analogue, comprise diethyl azodiformate, tert-butyl azodicarboxylate, diphenyl azodicarboxylate, azodicarbonyldipiperidine, N, N, N ', N '-tetramethyl-Cellmic C 121.
Technique scheme can be found out, compared to prior art, Yi Lu involved in the present invention is for the preparation method of Buddhist nun, there is raw material be easy to get, the feature such as concise in technology and environmental protection and economy, produces for the industrialization of Buddhist nun's bulk drug so be beneficial to Yi Lu, promotes the development of its economic technology.
Accompanying drawing explanation
Fig. 1 is chemical equation of the present invention.
Embodiment
Be clearly and completely described the technical scheme in the embodiment of the present invention below, obviously, described embodiment is only the present invention's part embodiment, instead of whole embodiments.Based on the embodiment in the present invention, those of ordinary skill in the art, not making other embodiments all obtained under creative work prerequisite, belong to the scope of protection of the invention.
Embodiment one:
Under nitrogen atmosphere, get 30.3g 4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine and 78.6g triphenylphosphine be added to 1000mL tetrahydrofuran (THF) in, 31gl-[3 (S)-hydroxyl-piperidino]-2-propylene-1-ketone is added in mixture, then drip 60.6g diisopropyl azodiformate (DIAD), reaction solution at room temperature stirs and spends the night.After reaction terminates, reaction solution is through Rotary Evaporators concentrating under reduced pressure, and methylene dichloride dissolving, saturated nacl aqueous solution washs, dry, filters, and through recrystallisation from isopropanol after filtrate is concentrated, obtain off-white color solid, Yi Lu replaces Buddhist nun 33.2g, yield 75.4%.
Embodiment two:
Get 10.1g 4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine and 17.5g Polymer-Supported triphenylphosphine be added to 200mL tetrahydrofuran (THF) in, 10.4g (1-[3 (S)-hydroxyl-piperidino]-2-propylene-1-ketone is added in mixture, then drip 13.4g diethyl azodiformate, reaction solution stirs 6 hours at 30 DEG C.Reaction system filtered after reaction terminates, filtrate is through Rotary Evaporators concentrating under reduced pressure, and acetic acid ethyl dissolution, saturated nacl aqueous solution washs, dry, filters, and through ethyl alcohol recrystallization after filtrate is concentrated, obtains Yi Lu for Buddhist nun 7.1g, yield 48.3%.
Embodiment three:
4.4g triphenylphosphine be added to 100mL methylene dichloride in, drip 6.8g diphenyl azodicarboxylate, 5.1g 4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3 is added after stirring half an hour, 4-d] (1-[3 (S)-hydroxyl-piperidino]-2-propylene-1-ketone, then reaction solution stirs and spends the night at 0 DEG C for pyrimidine and 3.9g.Reaction solution saturated nacl aqueous solution washs, dry, filters, and through recrystallisation from isopropanol after filtrate is concentrated, obtains Yi Lu for Buddhist nun 2.7g, yield 37.0%.
The explanation of above embodiment just understands method of the present invention and core concept thereof for helping; Meanwhile, for one of ordinary skill in the art, all equivalences done according to spirit of the present invention change or modify, and all should be encompassed within protection scope of the present invention.
Claims (6)
1. one kind is replaced the preparation method of Buddhist nun (Ibrutinib) according to Shandong, it is characterized in that, 4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine (I) and 1-[3 (S)-hydroxyl-piperidino]-2-propylene-1-ketone (II) under triphenylphosphine, diisopropyl azodiformate catalysis, prolong reaction (Mitsunobu reaction) through light and prepare according to Shandong
Concrete preparation method is as follows:
(1) according to following mol ratio ready reaction material: 4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine (I): 1-[3 (S)-hydroxyl-piperidino]-2-propylene-1-ketone (II): triphenylphosphine: diisopropyl azodiformate=1: 0.5 ~ 3: 0.5 ~ 3: 0.5 ~ 3;
(2) at-20 DEG C to 100 DEG C temperature, by 4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine (I) and 1-[3 (S)-hydroxyl-piperidino]-2-propylene-1-ketone (II), triphenylphosphine dissolved is in the middle of reaction solvent tetrahydrofuran (THF), then slowly dripped by diisopropyl azodiformate, stirring reaction is until reaction terminates.
2. according to claim 1 according to the preparation method of Shandong for Buddhist nun (Ibrutinib), it is characterized in that: also can by triphenylphosphine, diisopropyl azodiformate prior to stirring in reaction solvent tetrahydrofuran (THF), again by 4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine (I) and 1-[3 (S)-hydroxyl-piperidino]-2-propylene-1-ketone (II) add, and stirring reaction is until reaction terminates.
3. according to claim 1 and 2 according to the preparation method of Shandong for Buddhist nun (Ibrutinib), it is characterized in that: reaction solvent tetrahydrofuran (THF), can respectively by ether, dioxane, methylene dichloride, chloroform, toluene, ethyl acetate, acetonitrile, N, dinethylformamide substitutes, also can by the mixture replacing of ether, dioxane, methylene dichloride, chloroform, toluene, ethyl acetate, acetonitrile, DMF.
4. according to claim 1 and 2 according to the preparation method of Shandong for Buddhist nun (Ibrutinib), it is characterized in that: triphenylphosphine can be substituted by Polymer-supported loadings such as the positive tributylphosphine of its analogue, diphenyl methyl phosphine, triphenylphosphine, tributylphosphine, diphenyl methyl phosphines.
5. according to claim 1 and 2 according to the preparation method of Shandong for Buddhist nun (Ibrutinib), it is characterized in that: diisopropyl azodiformate can by its analogue diethyl azodiformate, tert-butyl azodicarboxylate, diphenyl azodicarboxylate, azodicarbonyldipiperidine, N, N, N ', N '-tetramethyl-Cellmic C 121 substitutes.
6. according to claim 1 and 2 according to the preparation method of Shandong for Buddhist nun (Ibrutinib), it is characterized in that: temperature of reaction especially 0 DEG C to 30 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510055853.XA CN104557946A (en) | 2015-02-04 | 2015-02-04 | Preparation method of ibrutinib |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510055853.XA CN104557946A (en) | 2015-02-04 | 2015-02-04 | Preparation method of ibrutinib |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104557946A true CN104557946A (en) | 2015-04-29 |
Family
ID=53075109
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510055853.XA Pending CN104557946A (en) | 2015-02-04 | 2015-02-04 | Preparation method of ibrutinib |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104557946A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105440040A (en) * | 2015-12-23 | 2016-03-30 | 浙江京新药业股份有限公司 | Ibrutinib purification method |
| CN107286163A (en) * | 2016-03-30 | 2017-10-24 | 上海星泰医药科技有限公司 | It is a kind of that novel crystal forms of Buddhist nun and preparation method thereof are replaced according to Shandong |
| CN114276355A (en) * | 2022-01-26 | 2022-04-05 | 江苏阿尔法药业股份有限公司 | Preparation method of ibrutinib |
| 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 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010009342A2 (en) * | 2008-07-16 | 2010-01-21 | Pharmacyclics, Inc. | Inhibitors of bruton's tyrosine kinase for the treatment of solid tumors |
| WO2013003629A2 (en) * | 2011-06-28 | 2013-01-03 | Pharmacyclics, Inc. | Methods and compositions for inhibition of bone resorption |
| CN103121999A (en) * | 2012-08-29 | 2013-05-29 | 苏州迪飞医药科技有限公司 | Method for synthesizing tyrosine kinase inhibitor PCI-32765 |
-
2015
- 2015-02-04 CN CN201510055853.XA patent/CN104557946A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010009342A2 (en) * | 2008-07-16 | 2010-01-21 | Pharmacyclics, Inc. | Inhibitors of bruton's tyrosine kinase for the treatment of solid tumors |
| WO2013003629A2 (en) * | 2011-06-28 | 2013-01-03 | Pharmacyclics, Inc. | Methods and compositions for inhibition of bone resorption |
| CN103121999A (en) * | 2012-08-29 | 2013-05-29 | 苏州迪飞医药科技有限公司 | Method for synthesizing tyrosine kinase inhibitor PCI-32765 |
Non-Patent Citations (1)
| Title |
|---|
| ZHENGYING PAN，等: "Discovery of Selective Irreversible Inhibitors for Bruton’s Tyrosine Kinase", 《CHEMMEDCHEM》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105440040A (en) * | 2015-12-23 | 2016-03-30 | 浙江京新药业股份有限公司 | Ibrutinib purification method |
| CN105440040B (en) * | 2015-12-23 | 2018-03-13 | 浙江京新药业股份有限公司 | The purification process of Buddhist nun is replaced according to Shandong |
| CN107286163A (en) * | 2016-03-30 | 2017-10-24 | 上海星泰医药科技有限公司 | It is a kind of that novel crystal forms of Buddhist nun and preparation method thereof are replaced according to Shandong |
| CN114276355A (en) * | 2022-01-26 | 2022-04-05 | 江苏阿尔法药业股份有限公司 | Preparation method of ibrutinib |
| 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 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104557946A (en) | Preparation method of ibrutinib | |
| CN102863487B (en) | Process for preparing 20,23-bi-piperidyl-5-O-carbon mould amine glycosyl-tylosin lactone | |
| CN102584795B (en) | Preparing method of crizotinib | |
| CN102757431B (en) | A kind of novel method of synthesizing sitagliptin | |
| CN102321038B (en) | Improved valsartan preparation method | |
| CN105063120B (en) | A kind of preparation method of Levetiracetam | |
| CN103232370A (en) | Preparation method of fmoc chloride glutamic acid-4-tert-butyl ester | |
| CN104557583B (en) | A kind of method synthesizing γ-aminobutyric acid class chipal compounds | |
| CN101544682B (en) | 11-keto-16,17-epoxyprogesterone and industrial production method | |
| CN101747278A (en) | Method for synthesizing 1-chloroformyl-3-methyl sulfonyl-2-imidazo flavanone | |
| CN103788010B (en) | Febuxostat intermediate and preparation method thereof | |
| CN104098462B (en) | The method for splitting of the diphenyl-propionic acid racemoid of 2 hydroxyl, 3 methoxyl group 3,3 | |
| CN108409589B (en) | Preparation method of chiral beta-amino acid ester | |
| CN103058956A (en) | Preparation method of 5-amino-1,2,3-thiadiazole | |
| CN103351386B (en) | A kind of synthetic method of Azasetron hydrochloride | |
| CN106518865A (en) | Method for preparing 1-alkenyl indolizine derivative | |
| CN107673984B (en) | Preparation method of levetiracetam key intermediate (S) -2-aminobutanamide salt | |
| CN102786440A (en) | Preparation method of trifluoroacetamidine | |
| CN103102280B (en) | The preparation method of optical voidness 1-(alpha-amido benzyl)-beta naphthal | |
| CN107849003A (en) | Prepare the new method of chromanol derivative | |
| CN105037348B (en) | A kind of Retapamulin synthetic method | |
| CN104876856A (en) | Method for preparing (R)-(+)-3-piperidinamine dihydrochloride by using resolution method | |
| CN102977104A (en) | Synthesis of 2,4-dichloro-7-hydroxy-pyrrolo(2,3)pyrimidine | |
| CN103755582A (en) | Preparation method according to D-serine through splitting method | |
| CN114591187B (en) | Preparation method of 1,3-bis (tris (hydroxymethyl) methylamino) propane |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20150429 |