CN102485714A - Method for synthesis of sorafenib through carbonylation - Google Patents
Method for synthesis of sorafenib through carbonylation Download PDFInfo
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- CN102485714A CN102485714A CN2011103023641A CN201110302364A CN102485714A CN 102485714 A CN102485714 A CN 102485714A CN 2011103023641 A CN2011103023641 A CN 2011103023641A CN 201110302364 A CN201110302364 A CN 201110302364A CN 102485714 A CN102485714 A CN 102485714A
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Abstract
The invention provides a method for synthesis of sorafenib through carbonylation. According to the invention, 4-(4-amiophenoxy)-pyridine-2-carboxylic acid methanamide reacts with 4-chloro-3-amino-benzotrifluoride in the presence of carbon dioxide with carbonate as a catalyst and basic solvents like N-methylpyrrolidone as a solvent; 4-(4-amiophenoxy)-pyridine-2-carboxylic acid methanamide reacts with carbon dioxide to produce carbamic acid at first, and then carbamic acid reacts with 4-chloro-3-amino-benzotrifluoride in an alkaline reagent to produce a product of substituted urea, i.e., sorafenib, wherein, the reactions are carried out under the conditions that the pressure of carbon dioxide is 5 to 30 atmospheric pressure and temperature is 50 to 200 DEG C. The synthetic method provided in the invention enables disadvantages in conventional synthesis of substituted urea products from phosgene or phosgene derivatives to be eliminated and has the advantages of simple and convenient operation, easily available raw materials, safety, environmental friendliness and stabile product quality.
Description
Technical field
The present invention relates to a kind of preparation method of precursor of synthetic tosic acid Xarelto, the method for the synthetic Suo Lafeini of particularly a kind of carbonylation.
Background technology
Xarelto is synthetic tosic acid Xarelto { [CAS]: 475207-59-1 chemical name: 4-{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-uride]-phenoxy }-pyridine-2-carboxylic acids methylamine-4-toluenesulfonate } precursor, the tosic acid Xarelto has been approved for the treatment of kidney and liver cancer.In addition, also have nearly 50 all kinds of clinical trials of using other multiple cancers of Xarelto treatment in progress at present all over the world.
The compound method of Xarelto mainly contains following several kinds at present:
(1) US 7235576, and WO 2006034796, " synthesizing of tosic acid Xarelto "; Zhao has taken advantage of, Chen Linjie etc., Chinese Journal of Pharmaceuticals; 2007,38 (9) 614-616, Sun Chao; 2011 the 1st phases of synthetic chemistry slip-stick artist of 4-chloro-3-(trifluoromethyl) benzene isocyanic ester such as Li Yanchen and verivate Suo Lafeini thereof; 63-65, report makes 4-chloro-3-(trifluoromethyl) benzene isocyanic ester with the hydrochloride and the solid phosgene (BTC) of 4-chloro-3-5-trifluoromethylaniline in reflux in toluene, and 4-chloro-3-(trifluoromethyl) benzene isocyanic ester obtains Xarelto with 4-(4-amino-benzene oxygen)-2-(methyl carbamyl) pyridine reaction again.Above document all is earlier synthetic 4-chloro-3-(trifluoromethyl) benzene isocyanic ester, and reaction process is all used phosgene or solid phosgene.
(2) WO 2004113274 documents with 4-(4-amino-benzene oxygen)-2-(methyl carbamyl) pyridine, 4-chloro-3-(trifluoromethyl) aniline 1,1 '-carbonyl dimidazoles (CDI) exists and three intermolecular condensations take place down generates Xarelto.1,1 '-carbonyl dimidazoles (CDI) costs an arm and a leg, and its synthetic use phosgene of getting back to again.
Summary of the invention
Technical problem to be solved by this invention is the deficiency to prior art, and the method for a kind of new synthetic Suo Lafeini is provided, and its raw material is easy to get, safety and environmental protection, constant product quality, and phosgenation products such as phosgene and CDI, isocyanic ester are not used in reaction.
Technical problem to be solved by this invention is to realize through following technical scheme.The present invention is the method for a kind of oxo process Suo Lafeini, is characterized in: in the presence of carbonic acid gas, use alkaline carbonate to be catalyzer with 4-(4-amino-benzene oxygen)-pyridine-2-carboxylic acids methane amide and 4-chloro-3-5-trifluoromethylaniline, adopt basic solvent; Reaction process is: 4-(4-amino-benzene oxygen)-pyridine-2-carboxylic acids methane amide generates carboxylamine with carbon dioxide reaction earlier, and this carboxylamine reacts to generate under basic solvent with 4-chloro-3-5-trifluoromethylaniline again and replaces urea product, i.e. Suo Lafeini then;
The mol ratio of 4-(4-amino-benzene oxygen)-pyridine-2-carboxylic acids methane amide and 4-chloro-3-5-trifluoromethylaniline is 1: 5～5: 1; The mol ratio of the consumption of alkaline carbonate and main reaction thing is 1: 3～3: 1; Reaction pressure is the 5-30 normal atmosphere; Temperature of reaction is 50-200 ℃; Reaction times is 2-50 hour.
In the method and technology scheme of above-described oxo process Suo Lafeini: reaction can be adopted the method for treating different things alike; Be 4-(4-amino-benzene oxygen)-pyridine-2-carboxylic acids methane amide, 4-chloro-3-5-trifluoromethylaniline, alkaline carbonate, the disposable adding of basic solvent, feed carbonic acid gas then and react.
In the method and technology scheme of above-described oxo process Suo Lafeini: reaction can also be adopted the method for fractional steps; Promptly add 4-(4-amino-benzene oxygen)-pyridine-2-carboxylic acids methane amide, N-Methyl pyrrolidone earlier; Feed carbon dioxide reaction and generate carboxylamine; Add 4-chloro-3-5-trifluoromethylaniline, alkaline carbonate and basic solvent then, generate Suo Lafeini with the carboxylamine reaction.
In the method and technology scheme of above-described oxo process Suo Lafeini: described alkaline carbonate can be alkaline carbonate conventional in the prior art, preferred Quilonum Retard, cesium carbonate and rubidium carbonate.
In the method and technology scheme of above-described oxo process Suo Lafeini: described basic solvent is preferably the N substituted pyrrolidone.Further be preferably the mixture of one or more compositions among N-Methyl pyrrolidone, N-ethyl pyrrolidone, triethylamine, the DMF.
In the compound method of the present invention; Because 4-(4-amino-benzene oxygen)-pyridine-2-carboxylic acids methane amide is stronger than the alkalescence of 4-chloro-3-5-trifluoromethylaniline; So the former more easily with carbon dioxide reaction generation carboxylamine; This carboxylamine generates with the reaction of 4-chloro-3-5-trifluoromethylaniline and replaces urea product, i.e. Suo Lafeini then.Reaction equation is following:
Midbody 4-used in the present invention (4-amino-benzene oxygen)-pyridine-2-carboxylic acids methane amide can be synthetic by following method, also can select for use commercially available prod or art methods synthetic.
Compared with prior art, do not use phosgenation products such as phosgene and CDI, isocyanic ester when compound method of the present invention is reacted, got rid of traditional method and synthesized replacement urea product drawback with phosgene or phosgene verivate.The present invention is easy and simple to handle, raw material is easy to get, safety and environmental protection, constant product quality.
Embodiment
Below further describe concrete technical scheme of the present invention,, and do not constitute restriction its right so that those skilled in the art understands the present invention further.
Embodiment 1, and the method for a kind of oxo process Suo Lafeini in the presence of carbonic acid gas, uses alkaline carbonate to be catalyzer with 4-(4-amino-benzene oxygen)-pyridine-2-carboxylic acids methane amide and 4-chloro-3-5-trifluoromethylaniline, adopts basic solvent; Reaction process is: 4-(4-amino-benzene oxygen)-pyridine-2-carboxylic acids methane amide generates carboxylamine with carbon dioxide reaction earlier, and this carboxylamine reacts to generate under basic solvent with 4-chloro-3-5-trifluoromethylaniline again and replaces urea product, i.e. Suo Lafeini then;
The mol ratio of 4-(4-amino-benzene oxygen)-pyridine-2-carboxylic acids methane amide and 4-chloro-3-5-trifluoromethylaniline is 1: 5; The mol ratio of the consumption of alkaline carbonate and main reaction thing is 1: 3; Reaction pressure is the 5-30 normal atmosphere; Temperature of reaction is 50 ℃; Reaction times is 2 hours.
Embodiment 2, and other is identical with embodiment 1, and the mol ratio of 4-(4-amino-benzene oxygen)-pyridine-2-carboxylic acids methane amide and 4-chloro-3-5-trifluoromethylaniline is 5: 1; The mol ratio of the consumption of alkaline carbonate and main reaction thing is 3: 1; Reaction pressure is 30 normal atmosphere; Temperature of reaction is 200 ℃; Reaction times is 50 hours.
Embodiment 3, and other is identical with embodiment 1, and the mol ratio of 4-(4-amino-benzene oxygen)-pyridine-2-carboxylic acids methane amide and 4-chloro-3-5-trifluoromethylaniline is 1: 2; The mol ratio of the consumption of alkaline carbonate and main reaction thing is 1: 2; Reaction pressure is 10 normal atmosphere; Temperature of reaction is 100 ℃; Reaction times is 10 hours.
Embodiment 4, and other is identical with embodiment 1, and the mol ratio of 4-(4-amino-benzene oxygen)-pyridine-2-carboxylic acids methane amide and 4-chloro-3-5-trifluoromethylaniline is 2: 1; The mol ratio of the consumption of alkaline carbonate and main reaction thing is 2: 1; Reaction pressure is 20 normal atmosphere; Temperature of reaction is 150 ℃; Reaction times is 24 hours.
Embodiment 5; In the method for any one described oxo process Suo Lafeini of embodiment 1-4: the method for treating different things alike is adopted in reaction; Be 4-(4-amino-benzene oxygen)-pyridine-2-carboxylic acids methane amide, 4-chloro-3-5-trifluoromethylaniline, alkaline carbonate, the disposable adding of basic solvent, feed carbonic acid gas then and react.
Embodiment 6; In the method for any one described oxo process Suo Lafeini of embodiment 1-4: the method for fractional steps is adopted in reaction; Promptly add 4-(4-amino-benzene oxygen)-pyridine-2-carboxylic acids methane amide, N-Methyl pyrrolidone earlier; Feed carbon dioxide reaction and generate carboxylamine, add 4-chloro-3-5-trifluoromethylaniline, alkaline carbonate and basic solvent then, generate Suo Lafeini with the carboxylamine reaction.
Embodiment 7, and in the method for any one described oxo process Suo Lafeini of embodiment 1-6: described alkaline carbonate is selected from Quilonum Retard, cesium carbonate, rubidium carbonate.
Embodiment 8, and in the method for any one described oxo process Suo Lafeini of embodiment 1-7: described basic solvent is the N substituted pyrrolidone.
Embodiment 9, and in the method for any one described oxo process Suo Lafeini of embodiment 1-7: described basic solvent is selected from the mixture of one or more compositions among N-Methyl pyrrolidone, N-ethyl pyrrolidone, triethylamine, the DMF.
Embodiment 10, the method experiment one of oxo process Suo Lafeini.
In one 50 milliliters stainless steel autoclave, 4-(4-amino-benzene oxygen)-pyridine-2-carboxylic acids methane amide (2.43 grams, 10 mmoles); 4-chloro-3-5-trifluoromethylaniline (1.95 grams; 10 mmoles) and cesium carbonate (2.88 gram, 15 mmoles) be dissolved in N-Methyl pyrrolidone (10 milliliters), add stirrer; The sealing autoclave adds dioxide gas to 25 normal atmosphere.Autoclave is positioned in the silicone oil bath of 180 degree, stirred 24 hours.Be cooled to room temperature, bleed off gas.Solution is analyzed with GC (ionic flame detector) and NMR after diluting with methyl alcohol.Add entry in the solution, the product urea precipitates from solution separates out, and filtration can obtain highly purified product 2.21g, productive rate: 47.5%.Mp:210-212 ℃ of .1H NMR (DMSOd6,300MHz):
2.77 (d, J) 4.8Hz, 3H ,-NHCH3); 7.16 (m, 3H, aromatic); 7.37 (d, J) 2.5Hz, 1H, aromatic); 7.62 (m, 4H, aromatic); 8.11 (d, J) 2.5Hz, 1H, aromatic); 8.49 (d, J) 5.5Hz, 1H, aromatic); 8.77 (br d, 1H ,-NHCH3); 8.99 (s, 1H ,-NHCO-); 9.21 (s, 1H ,-NHCO-) .Massspectrum (HPLC/ES): m/e) 465 (M+1) .C
21H
16N
4ClF
3O
3Constituent content calculates: C, 54.26; H, 3.47; N, 12.05. analyzes: C, 54.11; H, 3.49; N, the 3.5min of 12.03.HPLC (ELS) purity＞98%:tR).
Embodiment 11, the method experiment two of oxo process Suo Lafeini.
In one 100 milliliters stainless steel autoclave, add 4-(4-amino-benzene oxygen)-pyridine-2-carboxylic acids methane amide (4.86 grams; 20 mmoles); Rubidium carbonate (6.93 grams, 30 mmoles) is dissolved in N-ethyl pyrrolidone (25 milliliters), adds stirrer; The sealing autoclave adds dioxide gas to 3.0Mp.Autoclave is positioned in the silicone oil bath of 200 degree, stirs and bled off gas in 20 hours, add 4-chloro-3-5-trifluoromethylaniline (3.90 grams, 20 mmoles) again and stirred 10 hours.Be cooled to room temperature, solution is analyzed with GC (ionic flame detector) and NMR after diluting with methyl alcohol.Add entry in the solution, product precipitates from solution separates out, and filtration can obtain highly purified product 4.18 grams, productive rate: 45%.C
21H
16N
4ClF
3O
3：C，54.26；H，3.47；N，12.05；Cl，7.63.Found：C，54.24；H，3.31；N，12.30；Cl，7.84.Mp：209.6℃。
Claims (6)
1. the method for an oxo process Suo Lafeini is characterized in that: in the presence of carbonic acid gas, use alkaline carbonate to be catalyzer with 4-(4-amino-benzene oxygen)-pyridine-2-carboxylic acids methane amide and 4-chloro-3-5-trifluoromethylaniline, adopt basic solvent; Reaction process is: 4-(4-amino-benzene oxygen)-pyridine-2-carboxylic acids methane amide generates carboxylamine with carbon dioxide reaction earlier, and this carboxylamine reacts to generate under basic solvent with 4-chloro-3-5-trifluoromethylaniline again and replaces urea product, i.e. Suo Lafeini then;
The mol ratio of 4-(4-amino-benzene oxygen)-pyridine-2-carboxylic acids methane amide and 4-chloro-3-5-trifluoromethylaniline is 1:5～5:1; The mol ratio of the consumption of alkaline carbonate and main reaction thing is 1:3～3:1; Reaction pressure is the 5-30 normal atmosphere; Temperature of reaction is 50-200 ℃; Reaction times is 2-50 hour.
2. according to the method for the described oxo process Suo Lafeini of claim 1; It is characterized in that: the method for treating different things alike is adopted in reaction; Be 4-(4-amino-benzene oxygen)-pyridine-2-carboxylic acids methane amide, 4-chloro-3-5-trifluoromethylaniline, alkaline carbonate, the disposable adding of basic solvent, feed carbonic acid gas then and react.
3. according to the method for the described oxo process Suo Lafeini of claim 1; It is characterized in that: the method for fractional steps is adopted in reaction; Promptly add 4-(4-amino-benzene oxygen)-pyridine-2-carboxylic acids methane amide, N-Methyl pyrrolidone earlier; Feed carbon dioxide reaction and generate carboxylamine, add 4-chloro-3-5-trifluoromethylaniline, alkaline carbonate and basic solvent then, generate Suo Lafeini with the carboxylamine reaction.
4. according to the method for any one described oxo process Suo Lafeini of claim 1-3, it is characterized in that: described alkaline carbonate is selected from Quilonum Retard, cesium carbonate, rubidium carbonate.
5. according to the method for any one described oxo process Suo Lafeini of claim 1-3, it is characterized in that: described basic solvent is the N substituted pyrrolidone.
6. according to the method for any one described oxo process Suo Lafeini of claim 1-3, it is characterized in that: described basic solvent is selected from the mixture of one or more compositions among N-Methyl pyrrolidone, N-ethyl pyrrolidone, triethylamine, the DMF.
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Cited By (5)
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| CN103896833A (en) * | 2012-12-27 | 2014-07-02 | 上海创诺制药有限公司 | Sorafenib tosylate solvate polymorphs and manufacturing method and application thereof |
| CN104402813A (en) * | 2014-12-15 | 2015-03-11 | 哈药集团制药总厂 | Novel method for synthesizing sorafenib |
| CN105399668A (en) * | 2015-12-29 | 2016-03-16 | 开封制药(集团)有限公司 | Method for preparing sorafenib through one-pot process |
| CN105801475A (en) * | 2016-04-25 | 2016-07-27 | 华润双鹤利民药业（济南）有限公司 | Method for preparing sorafenib tosylate |
| CN110878070A (en) * | 2018-09-06 | 2020-03-13 | 中国科学院化学研究所 | Method for preparing asymmetric urea compound |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103896833A (en) * | 2012-12-27 | 2014-07-02 | 上海创诺制药有限公司 | Sorafenib tosylate solvate polymorphs and manufacturing method and application thereof |
| CN103896833B (en) * | 2012-12-27 | 2016-12-28 | 上海创诺制药有限公司 | Sorafenib p-methyl benzenesulfonic acid salt/solvate polymorph and preparation method thereof and purposes |
| CN104402813A (en) * | 2014-12-15 | 2015-03-11 | 哈药集团制药总厂 | Novel method for synthesizing sorafenib |
| CN105399668A (en) * | 2015-12-29 | 2016-03-16 | 开封制药(集团)有限公司 | Method for preparing sorafenib through one-pot process |
| CN105399668B (en) * | 2015-12-29 | 2018-11-16 | 开封制药(集团)有限公司 | A kind of method that " one kettle way " prepares Sorafenib |
| CN105801475A (en) * | 2016-04-25 | 2016-07-27 | 华润双鹤利民药业（济南）有限公司 | Method for preparing sorafenib tosylate |
| CN105801475B (en) * | 2016-04-25 | 2018-01-12 | 华润双鹤利民药业（济南）有限公司 | A kind of preparation method of Sorafenib Tosylate |
| CN110878070A (en) * | 2018-09-06 | 2020-03-13 | 中国科学院化学研究所 | Method for preparing asymmetric urea compound |
| CN110878070B (en) * | 2018-09-06 | 2021-08-31 | 中国科学院化学研究所 | Method for preparing asymmetric urea compound |
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