CN104478884A - Preparation method of intermediate - Google Patents
Preparation method of intermediate Download PDFInfo
- Publication number
- CN104478884A CN104478884A CN201410734636.9A CN201410734636A CN104478884A CN 104478884 A CN104478884 A CN 104478884A CN 201410734636 A CN201410734636 A CN 201410734636A CN 104478884 A CN104478884 A CN 104478884A
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- China
- Prior art keywords
- compound
- methane amide
- reaction
- organic solvent
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- 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
- YYVUOZULIDAKRN-UHFFFAOYSA-N Nc1c(c(-c(cc2)ccc2Oc2ccccc2)n[nH]2)c2ncn1 Chemical compound Nc1c(c(-c(cc2)ccc2Oc2ccccc2)n[nH]2)c2ncn1 YYVUOZULIDAKRN-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
Abstract
The invention relates to a preparation method of an intermediate for preparing ibrutinib, belonging to the field of pharmaceutical technology. The method comprises the following steps: reacting the raw materials with formamide at a certain temperature in an organic solvent in the condition of adding a catalyst, and after the reaction, collecting the solid to obtain the product, wherein the catalyst is one or more of phosphoryl chloride, phosphorus pentachloride, phosphorus pentoxide, phosphorus trichloride, polyphosphoric acid, aluminum chloride anhydrous and sulfonyl chloride. The method can be used for solving the problem of high-temperature long-time reaction in the prior art; and moreover, the method is simple and convenient and can be applied to industrial production.
Description
Technical field
The present invention relates to a kind of for the preparation of according to the preparation method of Shandong for the intermediate of Buddhist nun, belong to pharmaceutical technology sectors.
Background technology
According to Shandong for Buddhist nun (Ibrutinib), chemistry 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-base]-piperidino]-2-propylene-1-ketone by name; A kind of irreversible bruton's tyrosine kinase (BTK, Bruton's tyrosine kinase) inhibitor, the propagation of malignant B cell, existence can be suppressed, can be used for the diseases such as treatment chronic lymphocytic leukemia (CLL) and minicell lymphocytic lympboma.
Replace in the process of Buddhist nun according to Shandong in preparation, need first to prepare midbody compound 3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-amine, its structure is such as formula shown in (02):
In prior art, be typically employed in high temperature 180 DEG C and react to prepare compound (02) for a long time; This method temperature of reaction is high, long reaction time, causes production cost high, and because long-time pyroreaction, easily produces more impurity, and make the product purification difficulty obtained, yield is low; And bring larger potential safety hazard, be unsuitable for suitability for industrialized production.
Summary of the invention
Summary of the invention
The invention provides the preparation method of a kind of compound (02), which solve the problem that high temperature of the prior art reacts for a long time, and product purity is high, yield is high, method is easy, and cost is low, is suitable for suitability for industrialized production.
Detailed Description Of The Invention
Contriver finds, compound (01) and methane amide react adding under catalysts conditions in organic solvent, are conducive to reducing temperature of reaction, reduce impurity and produce, improve product purity.
Thus, the invention provides the method that one prepares compound (02), it comprises: compound (01) and methane amide are in organic solvent, adding under catalysts conditions, in certain temperature reaction, after completion of the reaction, solid is collected, obtain compound (02), be shown below:
Described catalyzer is phosphorus oxychloride, phosphorus pentachloride, Vanadium Pentoxide in FLAKES, phosphorus trichloride, polyphosphoric acid, aluminum trichloride (anhydrous), one or more in SULPHURYL CHLORIDE.
The molar ratio of described catalyzer and compound (01) be 1:1-5:1. in some embodiments, the molar ratio of described catalyzer and compound (01) is 1.5:1-2.5:1.
In some embodiments, described catalyzer is phosphorus oxychloride.In some embodiments, described catalyzer is phosphorus pentachloride.
Described organic solvent is methane amide, N, one or more in dinethylformamide (DMF), N,N-dimethylacetamide (DMA), ethylene glycol monomethyl ether, glycol dimethyl ether (DME), tetrahydrofuran (THF), 2-methyltetrahydrofuran.In some embodiments, described organic solvent is methane amide.In some embodiments, described organic solvent is 2-methyltetrahydrofuran.
Described consumption of organic solvent, according to the Mass Calculation of compound (01), each g of compound (01), consumption of organic solvent is 3 milliliters-20 milliliters.In some embodiments, each g of compound (01), consumption of organic solvent is 5 milliliters-15 milliliters.In some embodiments, each g of compound (01), consumption of organic solvent is 7 milliliters-14 milliliters.
Compound (01) and methane amide are 0 DEG C-60 DEG C adding the temperature of reaction of reacting under catalysts conditions.In some embodiments, compound (01) and methane amide are 15 DEG C-40 DEG C adding the temperature of reaction of reacting under catalysts conditions.In some embodiments, compound (01) and methane amide are 20 DEG C-35 DEG C adding the temperature of reaction of reacting under catalysts conditions.
In some embodiments, the molar ratio of methane amide and compound (01) is 1.2:1-2.5:1.In some embodiments, the molar ratio of described methane amide and compound (01) is 1.5:1-2.2:1.
Described compound (01) and methane amide are 10 hours-30 hours adding the reaction times of reacting under catalysts conditions.In some embodiments, described compound (01) and methane amide are 10 hours-20 hours adding the reaction times of reacting under catalysts conditions.In some embodiments, described compound (01) and methane amide are 13 hours-18 hours adding the reaction times of reacting under catalysts conditions.
Compound (01) and methane amide react adding under catalysts conditions, after completion of the reaction, reaction mixture can be reduced to certain temperature, then through solid-liquid separation, obtain product.In some embodiments, after completion of the reaction, reaction mixture is reduced to-5 DEG C-30 DEG C.In some embodiments, after completion of the reaction, reaction mixture is reduced to 0 DEG C-5 DEG C.In some embodiments, after completion of the reaction, reaction mixture is reduced to-5 DEG C-0 DEG C.In some embodiments, after completion of the reaction, reaction mixture is reduced to 10 DEG C-20 DEG C.In some embodiments, after completion of the reaction, reaction mixture is reduced to 20 DEG C-25 DEG C.
After solid-liquid separation, gained solid crude product can be passed through the operations such as washing, making beating, purifying, crystallization to improve its purity Coriolis mass further.
Gained solid product can be passed through dry to remove desolventizing, and the drying means that can adopt has vacuum-drying, the conventional drying methods such as forced air drying.In some embodiments, gained solid is 40 DEG C of-100 DEG C of vacuum-dryings.In some embodiments, gained solid is 50 DEG C of-80 DEG C of vacuum-dryings.
In some embodiments, the method that one prepares compound (02) comprises: compound (01) and methane amide are in methyltetrahydrofuran, adding under phosphorus oxychloride condition, 15 DEG C-40 DEG C reactions 10 hours-20 hours, after completion of the reaction, collect solid, obtain compound (02); Wherein, each g of compound (01), 2-methyltetrahydrofuran consumption is 5 liters-15 liters, and the molar ratio of phosphorus oxychloride and compound (01) is 1.5:1-2.5:1.
In some embodiments, the method that one prepares compound (02) comprises: compound (01) and methane amide are in organic solvent, adding under phosphorus oxychloride condition, 20 DEG C-35 DEG C reactions 13 hours-18 hours, after completion of the reaction, be cooled to-5 DEG C-30 DEG C, collect solid, obtain compound (02); Wherein, each g of compound (01), 2-methyltetrahydrofuran consumption is 7 milliliters-14 milliliters, and the molar ratio of phosphorus oxychloride and compound (01) is 1.5:1-2.5:1.
Method of the present invention, by adding catalyzer and controlling other reaction conditions, temperature of reaction is reduced, and impurity is less, and method is easy, can be used for suitability for industrialized production.
Embodiment
In order to make those skilled in the art understand technical scheme of the present invention better, below disclose further some non-limiting embodiments the present invention is described in further detail.
Reagent used in the present invention all can be buied from the market or can be obtained by method described in the invention preparation.
In the present invention, g represents gram, and mL represents milliliter.
Embodiment 1
In reactor, add 3-amino-5-(4-Phenoxyphenyl)-4-cyano group-1H-pyrazoles 10.00g, methane amide 3.26g and 100mL 2-methyltetrahydrofuran, stir, then add phosphorus oxychloride 11.10g.At 30 DEG C, stirring reaction 15 hours, then filters, filter cake 2-methyltetrahydrofuran 20mL drip washing, gained solid is extremely dry 60 DEG C of vacuum-dryings, obtain 3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-amine 9.89g, purity: 99.11%; Mass spectrum MS:304.90; Nuclear-magnetism
1h NMR:(600MHz, DMSO) δ 13.55 (s, 1H), 8.22 (s, 1H), 7.67 (d, J=8.5Hz, 2H), 7.44 (t, J=7.8Hz, 2H), 7.16 (ddd, J=21.5,13.8,7.7Hz, 5H).
Embodiment 2
In reactor, add 3-amino-5-(4-Phenoxyphenyl)-4-cyano group-1H-pyrazoles 10.00g, methane amide 4.89g and 150mL 2-methyltetrahydrofuran, stir, then add phosphorus oxychloride 16.65g.At 20 DEG C, stirring reaction 20 hours, then filters, filter cake 2-methyltetrahydrofuran 20mL drip washing, gained solid is extremely dry 60 DEG C of vacuum-dryings, obtain 3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-amine 9.83g, purity: 99.12%.
Embodiment 3
In reactor, add 3-amino-5-(4-Phenoxyphenyl)-4-cyano group-1H-pyrazoles 10.00g, methane amide 3.26g and 80mL 2-methyltetrahydrofuran, stir, then add phosphorus oxychloride 11.10g.Stirring reaction 15 hours at 30 DEG C, then reaction mixture is cooled to 10 DEG C-15 DEG C, filter, filter cake methyltetrahydrofuran 20mL drip washing, gained solid is extremely dry 60 DEG C of vacuum-dryings, obtain 3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-amine 9.91g, purity: 99.14%.
Method of the present invention is described by preferred embodiment, and related personnel obviously can change methods and applications as herein described or suitably change and combination in content of the present invention, spirit and scope, realizes and applies the technology of the present invention.Those skilled in the art can use for reference present disclosure, and suitable improving technique parameter realizes.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the art, they are all deemed to be included in the present invention.
Claims (9)
1. prepare a method for compound (02),
Comprise: compound (01) and methane amide in organic solvent, react adding under catalysts conditions, after completion of the reaction, collect solid, obtain compound (02),
Wherein, described catalyzer is phosphorus oxychloride, phosphorus pentachloride, Vanadium Pentoxide in FLAKES, phosphorus trichloride, polyphosphoric acid, one or more in aluminum trichloride (anhydrous) or SULPHURYL CHLORIDE.
2. method according to claim 1, described organic solvent is one or more in methane amide, DMF, N,N-dimethylacetamide, ethylene glycol monomethyl ether, glycol dimethyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran.
3. method according to claim 1, each g of compound (01), consumption of organic solvent is 5 milliliters-15 milliliters.
4. method according to claim 1, the molar ratio of described catalyzer and compound (01) is 1.5:1-2.5:1.
5. method according to claim 1, the molar ratio of methane amide and compound (01) is 1.2:1-2.5:1.
6. method according to claim 1, compound (01) and methane amide in organic solvent, are adding under catalysts conditions, 0 DEG C-60 DEG C reactions to reacting complete.
7. method according to claim 1, compound (01) and methane amide in organic solvent, were adding under catalysts conditions, 15 DEG C-40 DEG C reactions 10 hours-30 hours.
8. method according to claim 1, after completion of the reaction, is cooled to-5 DEG C-30 DEG C by reaction mixture.
9. according to the arbitrary described method of claim 1-8, reaction mixture, in 2-methyltetrahydrofuran, 15 DEG C-40 DEG C reactions 10 hours-20 hours, is then cooled to-5 DEG C-30 DEG C by compound (01) and methane amide, collect solid, obtain compound (02).
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| CN201410734636.9A CN104478884A (en) | 2014-12-05 | 2014-12-05 | Preparation method of intermediate |
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| CN201410734636.9A CN104478884A (en) | 2014-12-05 | 2014-12-05 | Preparation method of intermediate |
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002155082A (en) * | 2000-11-17 | 2002-05-28 | Nippon Soda Co Ltd | Method for producing adenine derivative |
| CN1390219A (en) * | 1999-09-17 | 2003-01-08 | 艾博特股份有限两合公司 | Pyrazolopyrimidines as therapeutic agents |
| WO2008054827A2 (en) * | 2006-11-03 | 2008-05-08 | Pharmacyclics, Inc. | Bruton's tyrosine kinase activity probe and method of using |
| CN101610676A (en) * | 2006-09-22 | 2009-12-23 | 药品循环公司 | The inhibitor of bruton's tyrosine kinase |
| CN102159214A (en) * | 2008-07-16 | 2011-08-17 | 药品循环公司 | Inhibitors of bruton's tyrosine kinase for treatment of solid tumors |
| WO2013003629A2 (en) * | 2011-06-28 | 2013-01-03 | Pharmacyclics, Inc. | Methods and compositions for inhibition of bone resorption |
-
2014
- 2014-12-05 CN CN201410734636.9A patent/CN104478884A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1390219A (en) * | 1999-09-17 | 2003-01-08 | 艾博特股份有限两合公司 | Pyrazolopyrimidines as therapeutic agents |
| JP2002155082A (en) * | 2000-11-17 | 2002-05-28 | Nippon Soda Co Ltd | Method for producing adenine derivative |
| CN101610676A (en) * | 2006-09-22 | 2009-12-23 | 药品循环公司 | The inhibitor of bruton's tyrosine kinase |
| WO2008054827A2 (en) * | 2006-11-03 | 2008-05-08 | Pharmacyclics, Inc. | Bruton's tyrosine kinase activity probe and method of using |
| CN102159214A (en) * | 2008-07-16 | 2011-08-17 | 药品循环公司 | Inhibitors of bruton's tyrosine kinase for treatment of solid tumors |
| WO2013003629A2 (en) * | 2011-06-28 | 2013-01-03 | Pharmacyclics, Inc. | Methods and compositions for inhibition of bone resorption |
Non-Patent Citations (1)
| Title |
|---|
| TAKASHI HIROTA,等: "Polycyclic N-Hetero compounds.XVI Reactions of Benzyl Ketones with Formamide or Acetamide", 《CHEM.PHARM.BULL.》 * |
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Application publication date: 20150401 |