CN102311384A - Preparation method for sorafenib - Google Patents
Preparation method for sorafenib Download PDFInfo
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- CN102311384A CN102311384A CN2010102120391A CN201010212039A CN102311384A CN 102311384 A CN102311384 A CN 102311384A CN 2010102120391 A CN2010102120391 A CN 2010102120391A CN 201010212039 A CN201010212039 A CN 201010212039A CN 102311384 A CN102311384 A CN 102311384A
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Abstract
The invention discloses a preparation method for sorafenib. In the preparation method, 4-(4-amino phenoxyl)-N-methylpyridine-2-formamide or a salt thereof and phenyl-4-chloro-3-trifluoromethyl phenylcarbamate or 4-chloro-3-trifluoromethylphenyl isocyanate are used for preparing sorafenib base in the presence of a base and an organic solvent; and further, the sorafenib base is prepared into the sorafenib. The preparation method is convenient to operate, has the characteristic of easiness in purity and recovery of intermediates, also has the advantages of high yield, low cost and high quality and therefore has commercial value.
Description
Technical field
The present invention relates to a kind of preparation method of Xarelto.
Background technology
Sorafenib (Sorafenib) is chemistry 4-{4-[({[4-chloro-3-(trifluoromethyl by name (I)) phenyl] amino } carbonyl) amino] phenoxy group }-N-picoline-2-formamide; By the research and development of Bayer (Bayer) company, obtained food and drug administration (FDA) and ratify in 2005.Commodity are called Lei Shawa (Nexavar).This product is oral many SU11752 (multi-linaseinhibitor), clinically is used to treat liver cancer and kidney.
Synthetic world patent WO 0042012, WO 0041698, WO 2006034796, WO 2007/059154A2, CN 101052619A, WO2007/053574A2, the WO 2009/034308A2 etc. of being disclosed in of relevant Xarelto.Utilize 4-(4-amino-benzene oxygen)-N-picoline-2-methane amide (suc as formula II)
Under organic solvent, can make Xarelto alkali with 4-chloro-3-trifluoromethyl isocyanide ester (4-chloro-3-trifluoromethylphenyl isocyanate); Or utilize compound I I and 4-chloro-5-trifluoromethylaniline 1; 1-carbonyl dimidazoles (CDI; 1,1-carbonyldiimidazole) and organic solvent have down that reaction can make Xarelto alkali.
Based on considering on the above cost, we propose one and have more the preparation method that economic benefit is synthesized Xarelto alkali (Sorafenib base).
Summary of the invention
The object of the invention provides the preparation method of a kind of Xarelto compound and metilsulfate thereof; This method is to utilize compound I I or compound I I hydrochlorate and phenyl-4-chloro-3-trifluoromethyl phenyl carbamate (phenyl-4-chloro-3-trifluoromethylphenylcarbamate is like formula III) reaction in alkali and suitable organic solvent can make Xarelto alkali.Allied compound (III) is disclosed in periodical (Eur.J.of Med.Chem., 19,3 (1984) p.261) or world patent WO 2005/121147A1, WO 2009/034308A2 etc. already.
The preparation method of compound III 4-chloro-capable of using 3-5-trifluoromethylaniline (4-chloro-3-trifluoromethyl-aniline) reacts in organic solvent and inorganic alkaline water mixed solution with phenyl chloroformate (phenylchloroformate); Employed organic solvent is ETHYLE ACETATE, methylene dichloride, toluene etc., and the mineral alkali that uses is sodium hydrogencarbonate (NaHCO
3), yellow soda ash (Na
2CO
3), saleratus (KHCO
3) or salt of wormwood (K
2CO
3), temperature of reaction is good with 10-50 ℃ particularly at 0-100 ℃, the reaction times is 1-10 hour.
Synthesis mode as for compound I I then utilizes 4-amido phenol and 4-chloro-N-methyl-2-pyridine carboxamide (4-chloro-N-methyl-2-pyridine carboxamide) under mineral alkali and organic solvent, to react; Employed mineral alkali is potassium tert.-butoxide (potassiumt-butoxide), salt of wormwood, yellow soda ash etc.; Employed organic solvent is N; Dinethylformamide (DMF), DMAC N,N (DMA) isopolarity solvent, temperature of reaction is 0-200 ℃; Be good with 25-150 ℃ particularly, the reaction times is 1-10 hour.Prepared compound I I organic acid capable of using or mineral acid make compound I I hydrochlorate in being fit to organic solvent, employed organic solvent is THF (THF), ETHYLE ACETATE, propyl alcohol, contain 1 to 4 carbon (C
1-C
4) alcohol, acetone, acetonitrile, toluene, methylene dichloride etc., employed mineral acid is hydrochloric acid, sulfuric acid, phosphoric acid etc., employed organic acid is acetic acid, formic acid, phenylformic acid, toxilic acid etc.
Utilize compound I I and phenyl-4-chloro-3-trifluoromethyl phenyl carbamate under alkali and organic solvent, can make Xarelto alkali.This reacts employed organic bases is triethylamine (Et
3N), pyridine, 4-Dimethylamino pyridine (DMAP) etc., employed organic solvent is ETHYLE ACETATE, acetonitrile, methylene dichloride, THF etc., this range of reaction temperature is 0-200 ℃, particularly normal temperature to 100 ℃ is good, the reaction times is 1-10 hour.
Utilize compound I I hydrochlorate and phenyl-4-chloro-3-trifluoromethyl phenyl carbamate under alkali and organic solvent, can make Xarelto alkali.This reacts employed organic bases is triethylamine (Et
3N), pyridine, 4-Dimethylamino pyridine (DMAP) etc., employed organic solvent is ETHYLE ACETATE, acetonitrile, methylene dichloride, THF etc., this range of reaction temperature is 0-100 ℃, particularly normal temperature to 80 ℃ is good, the reaction times is 1-10 hour.
Preparing method's 4-chloro-capable of using 3-5-trifluoromethylaniline (4-chloro-3-trifluoromethyl aniline) as for phenyl-4-chloro-3-trifluoromethyl phenyl carbamate reacts at organic solvent and alkaline aqueous solution with phenyl chloroformate (phenyl chloroformate); Thereafter layering; Get organic layer and directly make Xarelto with compound I I or the reaction of compound I I hydrochlorate, this method condition is with aforementioned identical and on operating, make things convenient for many.
Compound I I hydrochlorate and 4-chloro-3-trifluoromethylbenzene based isocyanate (4-chloro-3-trifluoromethyl phenyl isocyanate) also can make Xarelto alkali under alkali and organic solvent in addition.This reacts employed organic bases is triethylamine, pyridine, 4-Dimethylamino pyridine etc.; Employed organic solvent is ETHYLE ACETATE, acetonitrile, methylene dichloride, THF etc.; This range of reaction temperature is 0-100 ℃; Particularly be that normal temperature to 80 ℃ is advisable, and 25 ℃-70 ℃ be good, the reaction times is 1-10 hour.
Comprehensive the above, the preparation method of the disclosed Xarelto of the present invention has operation convenience, and the characteristic of easy purifying of midbody and recovery, has high yield, low cost and high-quality advantage in addition, causes the present invention to have business-like value.
Embodiment
Below make the condition that specifies each reactions step:
(1) preparation method of compound I I
Take by weighing compound 4-chloro-N-methyl-2-pyridine carboxamide (4-chloro-N-methyl-2-pyridine carboxamide, 2 grams, 11.72mmol), 4-amido phenol (4-Aminophenol; 2 the gram, 18.33mmol) and potassium tert.-butoxide (potassium-t-butoxide, 2.7 the gram; 24.06mmol) place 100 milliliters of single neck bottles; At room temperature logical nitrogen adds 15 milliliters of N, and dinethylformamide (DMF) moves to 90 ℃ of following reacting by heating 2 hours.From temperature, add 65 milliliters water, and, merge organic layer and clean with saturated sodium-chloride with ETHYLE ACETATE (20 milliliters of x2) extraction, get organic layer and add 2 gram anhydrous magnesium sulfate (MgSO
4) drying, to filter, filtrating concentrates, and drying gets 2.69 gram Vandyke brown fluid cpds II.
(2) preparation method of compound I I hydrochloride
Take by weighing compound 4-chloro-N-methyl-2-pyridine carboxamide (18.8 grams, 110.02mmol), 4-amido phenol (18.8 grams, 172.27mmol) and potassium tert.-butoxide (25.35 grams 225.91mmol) place 1 liter of single neck bottle, at room temperature logical nitrogen (N
2), add 141DMF and move to 90 ℃ of following reacting by heating 2 hours.Leave temperature, reduce to 30 ℃, under nitrogen, add 176 milliliters of technical grade acetone, move to and splash into 10 milliliters of concentrated hydrochloric acids under 5 ℃, filter, solid filters again with the technical grade acetone, the dry filbert solid chemical compound II hydrochloride of 30 grams that gets.
1H-NMR(DMSO)：
2.78(d，J＝4.7Hz，3H)，7.22(m，1H)，7.39(dd，J＝2.0Hz，8.8Hz，2H)，
7.50(d，J＝2.4Hz，2H)，7.57(dd，J＝2.0Hz，8.8Hz，2H)，
8.56(d，J＝5.6Hz，1H)，8.95(br?d，1H)。
(3) preparation method of compound III
Take by weighing compound 4-chloro-3-5-trifluoromethylaniline (4-chloro-3-trifluoromethylaniline, 25 grams 127.83mmol) place 1 liter of single neck bottle, at room temperature logical nitrogen; Add 200 milliliters of acetic acid ethyl dissolutions it, adding 250 milliliters of saturated sodium bicarbonate aqueous solutions, splash into phenyl chloroformate (phenylchloroformate; 24.01 gram 153.4mmol) stirs standing demix; Water layer merges organic layer and adds 250 milliliter of 5% sodium hydroxide (NaOH) stirring 1 hour more again with 250 milliliters of ethyl acetate extractions, gets organic layer and adds 20 gram anhydrous magnesium sulfate dryings; Filter, filtrating is concentrated into dried, and solid drying gets 32.62 gram white solid compound III.
1H-NMR(DMSO)：
7.26(m，3H)，7.43(m，2H)，7.68(d，J＝8.8Hz，1H)，
7.77(dd，J＝2.4Hz，8.8Hz，1H)，8.06(d，J＝2.4Hz，1H)，
10.72(br?s，1H)。
(4) preparation method of compound III
Take by weighing compound 4-chloro-3-5-trifluoromethylaniline (8.3 grams; 42.61mmol) placing single neck bottle, logical nitrogen adds 85 milliliters of methylene dichloride and 2 milliliters of triethylamines (triethyl amine) under room temperature; (12 grams 76.7mmol) at room temperature react 2 hours to splash into phenyl chloroformate at last.Reaction finishes to add the entry standing demix, and water layer is again with 100 milliliters of ethyl acetate extractions, and the merging organic layer is concentrated into dried, gets the white solid compound.Add 100 milliliters of methylene dichloride dissolvings (water white transparency clear liquor); Adding 100 milliliter of 5% sodium hydroxide again stirred 1 hour; Get organic layer and add 20 gram anhydrous magnesium sulfate dryings; Filter, filtrating is concentrated into dried, and solid drying gets 11.02 white solid compound III (phenyl-4-chloro-3-trifluoromethyl phenyl carbamate).
(5) preparation method of Xarelto alkali
Take by weighing compound I I hydrochloride (3.28 grams, 11.72mmol) and compound III (3.70 grams 11.72mmol), place 250 milliliters of single neck bottles, and logical nitrogen under room temperature added 65 milliliters of ETHYLE ACETATE and 2 milliliters of triethylamine heating reflux reactions 3-5 hour.From temperature, cool off and place the water termination reactions of 65 milliliters of 5 ℃ of following addings, and extract with ETHYLE ACETATE (100 milliliters of x2); Merge organic layer and clean, get organic layer and add 3.28 gram anhydrous magnesium sulfate dryings, filter with saturated sodium-chloride (65 milliliters of x2); Filtrating concentrates; Get the Vandyke brown fluid cpds, solid drying 16 hours gets the khaki solid Xarelto alkali of 3.63 grams.
1H-NMR(DMSO)：
2.78(d，J＝4.8Hz，3H)，7.13(m，1H)，
7.16(d，J＝8.9Hz，2H)，7.37(d，J＝2.5Hz，1H)，
7.58(d，J＝8.9Hz，2H)，7.59(m，1H)，7.64(m，1H)，
8.11(d，J＝2.4Hz?1H)，8.49(d，J＝5.6Hz，1H)，
8.76(br?d，1H)，8.99(s，1H)，9.21(s，1H)。
(6) preparation method of Xarelto alkali
Take by weighing compound I I hydrochloride (3 grams, 10.72mmol) and compound III (3.39 grams 10.72mmol), place 250 milliliters of single neck bottles, and at room temperature logical nitrogen adds 30 milliliters of methylene dichloride and 3.0ml triethylamine, moves to 40 ℃ of following heating reflux reactions 10 hours.From temperature, cool off and place 5 ℃ of water termination reactions that add down 30 milliliters, separate, water layer merges organic layer with 5% sodium hydroxide (60 milliliters of x2) extraction again with 30 milliliters of dichloromethane extractions, gets organic layer and is concentrated into dried, dry weak coffee look solid chemical compound.Add 30 milliliters of methylene dichloride reflux 1 hour (insoluble) again, be stirred to room temperature from temperature, filter, solid cleans with 30 milliliters of methylene dichloride again, filters, and solid drying (70 ℃) 16 hours gets the newborn pale solid Xarelto alkali of 3.2 grams.
(7) preparation method of Xarelto alkali
Take by weighing compound I I hydrochloride (1.36 the gram, 5.59mmol) and compound III (1.94 the gram, 6.15mmol); Place 250 milliliters of single neck bottles; At room temperature logical nitrogen adds 13.6 milliliters of ETHYLE ACETATE and 1.0 milliliters of triethylamines, moves to 80 ℃ of following heating reflux reactions 3 hours (Vandyke brown clear liquor).From temperature, cool off and place 5 ℃ to stir 2 hours down, filter, solid drying gets 1.9 gram pale pink solid Xarelto alkali.
(8) preparation method of Xarelto alkali
The same embodiment of implementation method (five) only can get 2.0 gram pink solid Xarelto alkali with compound I I substitution compound II hydrochloride.
(9) preparation method of Xarelto
Take by weighing compound I I hydrochloride (3.2 grams; 11.72mmol) and 4-chloro-3-trifluoromethylbenzene based isocyanate (4-chloro-3-trifluoromethylphenyl isocyanate, 2.60 grams, 11.71mmol); Place 250 milliliters of single neck bottles; At room temperature logical nitrogen adds 70 milliliters of ETHYLE ACETATE and milliliter triethylamine, heating reflux reaction 5 hours.From temperature, cool off and place the water termination reactions of 70 milliliters of 5 ℃ of following addings, and extract with ETHYLE ACETATE (100 milliliters of x2); Merging organic layer cleans with saturated sodium-chloride (65 milliliters of x2); Get organic layer and add 3.28 gram anhydrous magnesium sulfate dryings, filter, filtrating concentrates; Dry 16 hours, get the khaki solid Xarelto alkali of 3.80 grams.
(10) building-up reactions of Xarelto
Take by weighing Xarelto alkali (3.57 grams; 7.68mmol) placing 500 milliliters of single neck bottles, at room temperature logical nitrogen adds 125 ml methanol reflux to complete dissolve (tawny clear liquor); Splash into p-methyl benzenesulfonic acid (p-toluene sulfonic acid; 1.46 gram is 7.68mmol) in 15 ml methanol, 70 ℃ of following heating reflux reactions 1 hour.From temperature, cool off and place under the room temperature logical nitrogen to stir 16 hours, filter, solid cleans with ETHYLE ACETATE (20 milliliters) again, filter, solid drying (70 ℃) 16 hours, salts such as the light colour of skin solid Xarelto of 3.9 grams.
1H-NMR(DMSO)：
2.28(s，3H)，2.81(d，J＝4.7Hz，3H)，
7.13(d，J＝8.4Hz，2H)，7.18(d，J＝9.0Hz，2H)，7.25(m，1H)，
7.52(d，J＝8.1Hz，2H)，7.60(d，J＝8.1Hz，2H)，
7.59-7.68(m，3H)，8.12(d，J＝2.5Hz，1H)，8.56(d，J＝6.0Hz，1H)，
9.00(br?d，1H)，9.22(s，1H)，9.41(s，1H)。
But above-mentioned embodiment is exemplary, is to be the restriction that this patent is comprised scope in order better to make those skilled in the art can understand this patent, can not to be interpreted as; So long as according to spirit that this patent discloses done anyly be equal to change or modify, all fall into the scope that this patent comprises.
Claims (9)
1. the preparation method of an Xarelto, said Xarelto chemical formula is following:
It is characterized in that: the preparation method of said Xarelto comprises following steps:
4-amido phenol and 4-chloro-N-methyl-2-pyridine carboxamide react under alkali and organic solvent and make compound I I, or further make compound I I hydrochlorate;
Utilize 4-chloro-3-5-trifluoromethylaniline and phenyl chloroformate in organic solvent and inorganic alkaline mixing solutions, to react and make phenyl-4-chloro-3-trifluoromethyl phenyl carbamate;
Compound I I or compound I I hydrochlorate under organic bases and organic solvent, add phenyl-4-chloro-3-trifluoromethyl phenyl carbamate or 4-chloro-3-trifluoromethylbenzene based isocyanate makes Xarelto alkali; Or utilize 4-chloro-3-5-trifluoromethylaniline and phenyl chloroformate after organic solvent and alkaline aqueous solution reaction; Layering is got organic solvent and is directly reacted with compound I I or compound I I hydrochlorate and make Xarelto alkali;
Utilize Xarelto alkali further to make the Xarelto that belongs to salt.
2. preparation method according to claim 1 is characterized in that: in the preparation of said compound I I, employed mineral alkali is potassium tert.-butoxide, salt of wormwood or yellow soda ash; Employed organic solvent is N, dinethylformamide or DMAC N,N; Employed TR is 25-150 ℃, and the reaction times is 1-10 hour.
3. preparation method according to claim 2 is characterized in that: described compound I I can
Utilize organic acid or mineral acid being fit to be prepared into said compound I I hydrochlorate under the organic solvent.
4. preparation method according to claim 3 is characterized in that: in the preparation of said compound I I hydrochlorate, employed organic acid is formic acid, acetic acid, benzoic acid or maleic acid; Employed inorganic acid is hydrochloric acid, sulfuric acid or phosphoric acid; Employed organic solvent is oxolane, ethyl acetate, acetone, contain alcohol, acetonitrile, toluene or the carrene of 1 to 4 carbon.
5. preparation method according to claim 1 is characterized in that: in the preparation of said phenyl-4-chloro-3-trifluoromethyl phenyl carbamate, employed organic solvent is ETHYLE ACETATE, methylene dichloride or toluene; Employed mineral alkali is sodium hydrogencarbonate, yellow soda ash, saleratus or salt of wormwood; Employed temperature of reaction is 0-100 ℃, and the reaction times is 1-10 hour.
6. preparation method according to claim 1; It is characterized in that: described compound I I and phenyl-4-chloro-3-trifluoromethyl phenyl carbamate can make Xarelto alkali under organic bases and organic solvent, wherein employed organic bases is triethylamine, pyridine or 4-Dimethylamino pyridine; Employed organic solvent is ETHYLE ACETATE, acetonitrile, methylene dichloride or THF; This range of reaction temperature is 0-200 ℃, and the reaction times is 1-10 hour.
7. preparation method according to claim 1; It is characterized in that: said compound I I hydrochlorate and phenyl-4-chloro-3-trifluoromethyl phenyl carbamate can make Xarelto alkali under organic bases and organic solvent, wherein employed organic bases is triethylamine, pyridine or 4-Dimethylamino pyridine; Employed organic solvent is ETHYLE ACETATE, acetonitrile, methylene dichloride or THF; This range of reaction temperature is 0-100 ℃, and the reaction times is 1-10 hour.
8. preparation method according to claim 1; It is characterized in that: said compound I I hydrochlorate and 4-chloro-3-trifluoromethylbenzene based isocyanate can make Xarelto alkali under organic bases and organic solvent, wherein employed organic bases is triethylamine, pyridine or 4-Dimethylamino pyridine; Employed organic solvent is ETHYLE ACETATE, acetonitrile, methylene dichloride or THF; This range of reaction temperature is 0-100 ℃, and the reaction times is 1-10 hour.
9. preparation method according to claim 1 is characterized in that: see through the interpolation of p-methyl benzenesulfonic acid, further to make the Xarelto that belongs to salt.
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Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102875460A (en) * | 2012-05-17 | 2013-01-16 | 上海奥博生物医药技术有限公司 | Method for preparing sorafenib |
| WO2013175483A1 (en) * | 2012-05-23 | 2013-11-28 | Shilpa Medicare Limited | Process for preparing crystalline sorafenib tosylate |
| CN104672129A (en) * | 2013-11-26 | 2015-06-03 | 广东东阳光药业有限公司 | Preparation method of urea compound |
| CN104761492A (en) * | 2014-01-03 | 2015-07-08 | 正大天晴药业集团股份有限公司 | Crystal form of sorafenib tosylate, and preparation method thereof |
| CN105272911A (en) * | 2015-11-30 | 2016-01-27 | 山东罗欣药业集团股份有限公司 | Preparation method of sorafenib tosylate |
| CN105330600A (en) * | 2015-11-30 | 2016-02-17 | 山东罗欣药业集团股份有限公司 | Preparation method for Regorafenib hydrate |
| CN105646341A (en) * | 2016-01-29 | 2016-06-08 | 杭州华东医药集团新药研究院有限公司 | Sorafenib compound |
| CN105924390A (en) * | 2016-05-19 | 2016-09-07 | 广州南新制药有限公司 | Synthesis method of metafenib |
| CN108164459A (en) * | 2016-12-07 | 2018-06-15 | 上海创诺制药有限公司 | The preparation method of Sorafenib Tosylate crystal form III |
| CN109796400A (en) * | 2017-11-16 | 2019-05-24 | 四川科伦药物研究院有限公司 | A kind of toluenesulfonic acid Sorafenib crystal form and preparation method thereof |
| CN111848506A (en) * | 2020-08-21 | 2020-10-30 | 中国药科大学 | Biphenyl urea compound and pharmaceutical composition, preparation method and application thereof |
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| CN102875460A (en) * | 2012-05-17 | 2013-01-16 | 上海奥博生物医药技术有限公司 | Method for preparing sorafenib |
| WO2013175483A1 (en) * | 2012-05-23 | 2013-11-28 | Shilpa Medicare Limited | Process for preparing crystalline sorafenib tosylate |
| CN104672129A (en) * | 2013-11-26 | 2015-06-03 | 广东东阳光药业有限公司 | Preparation method of urea compound |
| CN104672129B (en) * | 2013-11-26 | 2019-06-25 | 广东东阳光药业有限公司 | A kind of preparation method of carbamide compounds |
| CN104761492A (en) * | 2014-01-03 | 2015-07-08 | 正大天晴药业集团股份有限公司 | Crystal form of sorafenib tosylate, and preparation method thereof |
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| CN105272911A (en) * | 2015-11-30 | 2016-01-27 | 山东罗欣药业集团股份有限公司 | Preparation method of sorafenib tosylate |
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| CN105646341B (en) * | 2016-01-29 | 2018-10-16 | 杭州华东医药集团新药研究院有限公司 | sorafenib compound |
| CN105924390A (en) * | 2016-05-19 | 2016-09-07 | 广州南新制药有限公司 | Synthesis method of metafenib |
| CN108164459A (en) * | 2016-12-07 | 2018-06-15 | 上海创诺制药有限公司 | The preparation method of Sorafenib Tosylate crystal form III |
| CN108164459B (en) * | 2016-12-07 | 2021-07-27 | 上海创诺制药有限公司 | Preparation method of sorafenib tosylate crystal form III |
| CN109796400A (en) * | 2017-11-16 | 2019-05-24 | 四川科伦药物研究院有限公司 | A kind of toluenesulfonic acid Sorafenib crystal form and preparation method thereof |
| CN109796400B (en) * | 2017-11-16 | 2022-07-29 | 四川科伦药物研究院有限公司 | Sorafenib tosylate crystal form and preparation method thereof |
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| CN111848506B (en) * | 2020-08-21 | 2023-01-31 | 中国药科大学 | Biphenyl urea compound and pharmaceutical composition, preparation method and application thereof |
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