CN104926735A - Industrial preparation method for 4-chlorine-5-fluorine-2-methyl pyrimidine - Google Patents
Industrial preparation method for 4-chlorine-5-fluorine-2-methyl pyrimidine Download PDFInfo
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- CN104926735A CN104926735A CN201510331299.3A CN201510331299A CN104926735A CN 104926735 A CN104926735 A CN 104926735A CN 201510331299 A CN201510331299 A CN 201510331299A CN 104926735 A CN104926735 A CN 104926735A
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- fluoro
- methylpyrimidine
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- fluorine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/30—Halogen atoms or nitro radicals
Abstract
The invention relates to an industrial preparation method for 4-chlorine-5-fluorine-2-methyl pyrimidine, and the problems that existing 4-chlorine-5-fluorine-2-methyl pyrimidine is not easy to amplify and low in yield coefficient are solved. According to the technical scheme, the industrial preparation method for the 4-chlorine-5-fluorine-2-methyl pyrimidine comprises the steps that 1 ethyl formate and ethyl fluoroacetate are reacted by potassium tert-butoxide in an alkali mode, and after a midbody of 2-fluorine-3-oxo, ethyl propionate sodium salt is obtained and reacted with acetamidine hydrochloride in a ring closing mode, 5-fluorine-2-methyl pyrimidine-4(3H)-ketone is obtained; 2 chlorination is conducted, phosphorus oxychloride serves as a chloride agent, organic alkali serves as an additive, and the 4-chlorine-5-fluorine-2-methyl pyrimidine is obtained in solvent through a reaction. The invention is used for the industrial preparation method for the 4-chlorine-5-fluorine-2-methyl pyrimidine.
Description
Technical field
The present invention relates to the preparation method of the fluoro-2-methylpyrimidine of the chloro-5-of 4-, particularly relate to the industrialized process for preparing of the fluoro-2-methylpyrimidine of the chloro-5-of 4-.
Background technology
The chloro-5-of 4-fluoro-2-methylpyrimidine is a kind of important pharmaceutical-chemical intermediate.WO2006072831A1 and WO2008096260A1 report is all be alkali by ethyl formate and ethyl fluoroacetate with sodium hydride, obtain 2-fluoro-3-oxopropanoate sodium salt intermediate, then close ring with acetamidine hydrochloride and obtain 5-fluoro-2-methylpyrimidine-4 (3H)-one.5-fluoro-2-methylpyrimidine-4 (3H)-one take phosphorus oxychloride as solvent, and DMA is that additive chlorination under 110 DEG C of conditions obtains the fluoro-2-methylpyrimidine of the chloro-5-of 4-.
Sodium hydride is combustible material, meets water and can discharge extremely inflammable gas, is not suitable for safety and amplifies production.Second step chlorination reaction, because phosphorus oxychloride has medium toxicity and tearing property and corrodibility, is reaction solvent with phosphorus oxychloride, does not meet the theory of Green Chemistry.
The document yield of Patents report is extremely low, the first step yield 6%(WO2008096260A1); Second step yield 10%(WO2006072831A1), 34%(WO2008096260A1), be not suitable for carrying out amplification and produce.
Summary of the invention
The object of this invention is to provide the industrialized process for preparing of the fluoro-2-methylpyrimidine of the chloro-5-of a kind of 4-, mainly solve safety issue that existing preparation method produces for alkali carries out amplifying with sodium hydrogen and phosphorus oxychloride and to there is toxicity and tearing property and corrosive technical problem for solvent load is large.
technical scheme of the present invention: the industrialized process for preparing of the fluoro-2-methylpyrimidine of the chloro-5-of a kind of 4-, comprises the following steps:
The first step, ethyl formate and ethyl fluoroacetate are alkali reaction with potassium tert.-butoxide, close ring obtain 5-fluoro-2-methylpyrimidine-4 (3H)-one after obtaining 2-fluoro-3-oxopropanoate sodium salt intermediate with acetamidine hydrochloride.
Second step chlorination, take phosphorus oxychloride as chlorination reagent, organic bases is additive, is obtained by reacting the fluoro-2-methylpyrimidine of the chloro-5-of 4-in a solvent.Phosphorus oxychloride consumption is 1.2 equivalents preferably.Reaction formula is as follows:
。
The first step ethyl formate and ethyl fluoroacetate reaction carry out in a solvent, reaction solvent including, but not limited to toluene, dimethylbenzene, tetrahydrofuran (THF), 2-methyltetrahydrofuran, isopropyl ether, preferred tetrahydrofuran (THF).Without separation after reacting completely, be directly used in ring closure reaction.React with acetamidine hydrochloride after 2-fluoro-3-oxopropanoate sodium salt intermediate and carry out in a solvent, reaction solvent including, but not limited to methyl alcohol, ethanol, n-propyl alcohol, Virahol, preferred alcohol.
Second step organic bases including, but not limited to triethylamine, DIPEA, DMA, pyridine, preferred triethylamine.Reaction solvent including, but not limited to methylene dichloride, normal heptane, 2-methyltetrahydrofuran, preferred methylene dichloride.
beneficial effect of the present invention: it is that alkali instead of sodium hydride that reaction process of the present invention have employed potassium tert.-butoxide, acted in a solvent by ethyl formate and ethyl fluoroacetate and form 2-fluoro-3-oxopropanoate sodium salt intermediate, intermediate is obtained by reacting 5-fluoro-2-methylpyrimidine-4 (3H)-one without separation and acetamidine hydrochloride.5-fluoro-2-methylpyrimidine-4 (3H)-one, in suitable solvent, take phosphorus oxychloride as chlorinating agent, under suitable organic bases effect, carries out chloro, and avoiding with phosphorus oxychloride is the aftertreatment problem that solvent brings.Present invention process safety is controlled, easy to operate, is beneficial to amplify to produce.And significantly improve yield.The first step ring closure reaction yield is 40-50%, second step chlorination yield >90%.Be that alkali replaces sodium hydride and has no patent and bibliographical information with potassium tert.-butoxide, avoid and use the potential safety hazard brought of sodium hydride.Select the low boiling point solvents such as methylene dichloride, reduce temperature of reaction, decrease the generation of related impurities.
Embodiment
The following example contributes to understanding the present invention, but is not limited to content of the present invention.
embodiment 1
5-fluoro-2-methylpyrimidine-4 (3H)-one
synthesis
Ethyl formate 109 grams and ethyl fluoroacetate 100 grams are dissolved in 300 milliliters of tetrahydrofuran (THF)s, add in potassium tert.-butoxide 114 grams and 600 milliliters of tetrahydrofuran (THF)s.Drip off rear stirred overnight at room temperature, reaction terminates, and obtains 2-fluoro-3-oxopropanoate sodium salt intermediate.Add ethanol 1200 milliliters, sodium ethylate 80 grams, acetamidine hydrochloride 97 grams, is heated to return stirring by system and spends the night, and reaction terminates.Reaction solution concentrating under reduced pressure is done, by minimum water dissolution, extracts product with 2-methyltetrahydrofuran, concentrated, add ethyl acetate, stirring at room temperature, filter and obtain 54 grams of 5-fluoro-2-methylpyrimidine-4 (3H)-one.
embodiment 2
5-fluoro-2-methylpyrimidine-4 (3H)-one
synthesis
Ethyl formate 109 grams and ethyl fluoroacetate 100 grams are dissolved in 300 milliliters of isopropyl ethers, add in potassium tert.-butoxide 114 grams and 600 milliliters of isopropyl ethers.Drip off rear stirred overnight at room temperature, reaction terminates, and obtains 2-fluoro-3-oxopropanoate sodium salt intermediate.Add methyl alcohol 1200 milliliters, sodium ethylate 80 grams, acetamidine hydrochloride 97 grams, is heated to return stirring by system and spends the night, and reaction terminates.Reaction solution concentrating under reduced pressure is done, by minimum water dissolution, extracts product with 2-methyltetrahydrofuran, concentrated, add ethyl acetate, stirring at room temperature, filter and obtain 40 grams of 5-fluoro-2-methylpyrimidine-4 (3H)-one.
embodiment 3
5-fluoro-2-methylpyrimidine-4 (3H)-one
synthesis
Ethyl formate 109 grams and ethyl fluoroacetate 100 grams are dissolved in 300 milliliters of toluene, add in potassium tert.-butoxide 114 grams and 600 milliliters of tetrahydrofuran (THF)s.Drip off rear stirred overnight at room temperature, reaction terminates, and obtains 2-fluoro-3-oxopropanoate sodium salt intermediate.Add Virahol 1200 milliliters, sodium ethylate 80 grams, acetamidine hydrochloride 97 grams, is heated to return stirring by system and spends the night, and reaction terminates.Reaction solution concentrating under reduced pressure is done, by minimum water dissolution, extracts product with 2-methyltetrahydrofuran, concentrated, add ethyl acetate, stirring at room temperature, filter and obtain 30 grams of 5-fluoro-2-methylpyrimidine-4 (3H)-one.
embodiment 4
the fluoro-2-methylpyrimidine of the chloro-5-of 4-
synthesis
30 grams of 5-fluoro-2-methylpyrimidine-4 (3H)-one are dissolved in 300 milliliters of methylene dichloride, add triethylamine 24 grams.Temperature drops to-5 DEG C, slowly instillation phosphorus oxychloride 43 grams, and in controlling, temperature is at-5 DEG C to 5 DEG C.Dropwise, be warming up to 20-30 DEG C, stirring is spent the night, and reaction terminates.Reaction solution is quenched in 150 ml waters, layering.Dichloromethane extraction aqueous phase, organic phase merges.Organic phase is washed with 300 milliliters of sodium bicarbonate aqueous solutions.Be concentrated into dry, obtain 32 grams of fluoro-2-methylpyrimidines of the chloro-5-of 4-.
embodiment 5
the fluoro-2-methylpyrimidine of the chloro-5-of 4-
synthesis
30 grams of 5-fluoro-2-methylpyrimidine-4 (3H)-one are dissolved in 300 milliliters of methylene dichloride, add DIPEA 30.27 grams.Temperature drops to-5 DEG C, slowly instillation phosphorus oxychloride 43 grams, and in controlling, temperature is at-5 DEG C to 5 DEG C.Dropwise, be warming up to 20-30 DEG C, stirring is spent the night, and reaction terminates.Reaction solution is quenched in 150 ml waters, layering.Dichloromethane extraction aqueous phase, organic phase merges.Organic phase is washed with 300 milliliters of sodium bicarbonate aqueous solutions.Be concentrated into dry, obtain 28 grams of fluoro-2-methylpyrimidines of the chloro-5-of 4-.
embodiment 6
30 grams of 5-fluoro-2-methylpyrimidine-4 (3H)-one are dissolved in 300 milliliters of methylene dichloride, add pyridine 18.52 grams.Temperature drops to-5 DEG C, slowly instillation phosphorus oxychloride 43 grams, and in controlling, temperature is at-5 DEG C to 5 DEG C.Dropwise, be warming up to 20-30 DEG C, stirring is spent the night, and reaction terminates.Reaction solution is quenched in 150 ml waters, layering.Dichloromethane extraction aqueous phase, organic phase merges.Organic phase is washed with 300 milliliters of sodium bicarbonate aqueous solutions.Be concentrated into dry, obtain 25 grams of fluoro-2-methylpyrimidines of the chloro-5-of 4-.
Claims (7)
1. an industrialized process for preparing for the fluoro-2-methylpyrimidine of the chloro-5-of 4-, is characterized in that comprising the following steps:
The first step, ethyl formate and ethyl fluoroacetate are alkali reaction with potassium tert.-butoxide, close ring obtain 5-fluoro-2-methylpyrimidine-4 (3H)-one after obtaining 2-fluoro-3-oxopropanoate sodium salt intermediate with acetamidine hydrochloride;
Second step chlorination, take phosphorus oxychloride as chlorination reagent, organic bases is additive, is obtained by reacting the fluoro-2-methylpyrimidine of the chloro-5-of 4-in a solvent.
2. the preparation method of the fluoro-2-methylpyrimidine of the chloro-5-of 4-according to claim 1, it is characterized in that the first step ethyl formate and ethyl fluoroacetate reaction are carried out in a solvent, reaction solvent selects one of the following: toluene, dimethylbenzene, tetrahydrofuran (THF), 2-methyltetrahydrofuran, isopropyl ether.
3. the preparation method of the fluoro-2-methylpyrimidine of the chloro-5-of 4-according to claim 2, is characterized in that reaction solvent is tetrahydrofuran (THF).
4. the preparation method of the fluoro-2-methylpyrimidine of the chloro-5-of 4-according to claim 1, react with acetamidine hydrochloride after it is characterized in that 2-fluoro-3-oxopropanoate sodium salt intermediate and carry out in a solvent, reaction solvent selects one of the following: methyl alcohol, ethanol, n-propyl alcohol, Virahol.
5. the preparation method of the fluoro-2-methylpyrimidine of the chloro-5-of 4-according to claim 4, is characterized in that reaction solvent is ethanol.
6. the preparation method of the fluoro-2-methylpyrimidine of the chloro-5-of 4-according to claim 1, is characterized in that one of the following selected by second step chlorination organic bases: triethylamine, DIPEA, DMA, pyridine; Reaction solvent selects one of the following: methylene dichloride, normal heptane, 2-methyltetrahydrofuran.
7. the preparation method of the fluoro-2-methylpyrimidine of the chloro-5-of 4-according to claim 6, it is characterized in that organic bases is triethylamine, reaction solvent is methylene dichloride.
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Citations (7)
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| GB983723A (en) * | 1962-01-23 | 1965-02-17 | Spofa Vereinigte Pharma Werke | 4-hydroxy-5-halogeno pyrimidines and the preparation thereof |
| US3275633A (en) * | 1966-09-27 | Hydroxy-s-fluoropyrimibine and a process for producing it and other compounds | ||
| CN101115760A (en) * | 2005-01-10 | 2008-01-30 | 辉瑞大药厂 | Pyrrolopyrazoles, potent kinase inhibitors |
| CN101646673A (en) * | 2007-02-07 | 2010-02-10 | 辉瑞大药厂 | 3-amino-pyrrolo[3,4-c] pyrazole- 5 (1h, 4h, 6h) carbaldehyde derivatives as pkc inhibitors |
| CN102887860A (en) * | 2012-09-29 | 2013-01-23 | 上海泰坦科技有限公司 | Preparation method of 4-chloro-6-trifluoromethylpyrimidine type compound |
| CN102911123A (en) * | 2012-09-29 | 2013-02-06 | 上海泰坦科技有限公司 | Preparation method of 2-chloro trifluoromethyl pyrimidine compound |
| CN103601686A (en) * | 2013-11-08 | 2014-02-26 | 大连九信生物化工科技有限公司 | Method for synthesizing fluorine-containing pyrimidine compounds by virtue of one-pot method |
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2015
- 2015-06-16 CN CN201510331299.3A patent/CN104926735A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US3275633A (en) * | 1966-09-27 | Hydroxy-s-fluoropyrimibine and a process for producing it and other compounds | ||
| GB983723A (en) * | 1962-01-23 | 1965-02-17 | Spofa Vereinigte Pharma Werke | 4-hydroxy-5-halogeno pyrimidines and the preparation thereof |
| CN101115760A (en) * | 2005-01-10 | 2008-01-30 | 辉瑞大药厂 | Pyrrolopyrazoles, potent kinase inhibitors |
| CN101646673A (en) * | 2007-02-07 | 2010-02-10 | 辉瑞大药厂 | 3-amino-pyrrolo[3,4-c] pyrazole- 5 (1h, 4h, 6h) carbaldehyde derivatives as pkc inhibitors |
| CN102887860A (en) * | 2012-09-29 | 2013-01-23 | 上海泰坦科技有限公司 | Preparation method of 4-chloro-6-trifluoromethylpyrimidine type compound |
| CN102911123A (en) * | 2012-09-29 | 2013-02-06 | 上海泰坦科技有限公司 | Preparation method of 2-chloro trifluoromethyl pyrimidine compound |
| CN103601686A (en) * | 2013-11-08 | 2014-02-26 | 大连九信生物化工科技有限公司 | Method for synthesizing fluorine-containing pyrimidine compounds by virtue of one-pot method |
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| CHUANGXING GUO,等: "A novel method to enable SNAr reaction of aminopyrrolopyrazoles", 《TETRAHEDRON LETTERS》 * |
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Effective date of registration: 20170410 Address after: 200131 Shanghai City, Pudong New Area Waigaoqiao Free Trade Zone Foote Road No. 288 Building No. 1 room 602-604 Applicant after: Shanghai STA Pharmaceutical R & D Co., Ltd. Applicant after: Shanghai SynTheAll Pharmaceutical Co., Ltd. Applicant after: CHANGZHOU HEQUAN PHARMACEUTICAL CO., LTD. Applicant after: Changzhou whole new drug research and Development Co., Ltd. Address before: 200131 Shanghai City, Pudong New Area Waigaoqiao Free Trade Zone Foote Road No. 288, building 1, room 602604 Applicant before: Shanghai STA Pharmaceutical R & D Co., Ltd. Applicant before: Shanghai SynTheAll Pharmaceutical Co., Ltd. Applicant before: CHANGZHOU HEQUAN PHARMACEUTICAL CO., LTD. |
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