CN103408488A - Optimal synthetic method of sorafenib - Google Patents
Optimal synthetic method of sorafenib Download PDFInfo
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- CN103408488A CN103408488A CN2013103498584A CN201310349858A CN103408488A CN 103408488 A CN103408488 A CN 103408488A CN 2013103498584 A CN2013103498584 A CN 2013103498584A CN 201310349858 A CN201310349858 A CN 201310349858A CN 103408488 A CN103408488 A CN 103408488A
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Abstract
The invention relates to an optimal synthetic method of sorafenib and belongs to the technical field of medicament synthesis. The method employs the following four specific steps to synthesize the sorafenib: preparation of 4-chlorine-2-(methyl carbamyl)-pyridine; (2) preparation of 4-(4-amino phenoxy)-2-methyl carbamyl-pyridine; (3) preparation of (4-chlorine-3-trifluoromethyl-phenyl)-phenyl carbamate; and (4) preparation of sorafenib. The preparation method has advantages of easily available raw materials, mild conditions, strong technological operability and controllability, low cost and high yield.
Description
Technical field
The invention belongs to technical field of medicine synthesis, be specifically related to a kind of synthetic method of Xarelto.
Background technology
Xarelto (sorafenib), chemistry 4-by name (the chloro-3-of 4-{3-[4-(trifluoromethyl) phenyl] urea groups } phenoxy group)-N
2-picoline-2-methane amide, molecular formula is: C
21H
16ClF
3N
4O
3Relative molecular mass is 465.This medicine is the first oral many kinase inhibitor by the research and development of German Bayer company, but targeting serine/threonine kinase acceptor and tyrosine kinase receptor in tumour cell and tumor vessel.Has dual antitumor action, both can directly suppress tumor growth by suppressing Raf/MEK/ERK signal conduction pathway, also can be by suppressing to generate with new vessel the activity of the tyrosine kinase receptor relevant with tumor growth, block tumor neovasculature generation, inhibition tumor cell growth indirectly.
The synthetic method of the Xarelto of open report mainly contains:
The method one: (US such as Riedl; 20010016659) take the 2-pyridine carboxylic acid is raw material; through chlorination, alcoholysis, amidation, obtain intermediate 4-(4-amino-benzene oxygen)-2-(methylcarbamoyl)-pyridine with p-aminophenol generation nucleophilic substitution, then obtain Xarelto with the condensation of the chloro-3-trifluoromethyl of 4-phenylisocyanate.
The method two: (WO such as Muddasani; 2009054004) with the chloro-3-trifluoromethyl of 4-phenylisocyanate, first with p-aminophenol generation condensation reaction, obtain intermediate 1-(the chloro-3-of 4-(trifluoromethyl)-phenyl)-3-(4-hydroxy phenyl)-urea, then generate Xarelto with the chloro-2-of 4-(methylcarbamoyl)-pyridine generation nucleophilic substitution reaction.
The method three: (Chinese Pharmaceutical Journal such as Sun Min; 2009; 44; 394-396) after the 2-pyridine carboxylic acid is obtained to intermediate 4-(4-amino-benzene oxygen)-2-(methylcarbamoyl)-pyridine through chlorination, amidation, with p-aminophenol generation nucleophilic substitution; re-use N; N-carbonyl dimidazoles (CDI) provides the carbonyl that forms urea, with the chloro-3-5-trifluoromethylaniline of 4-, three intermolecular condensations occurs and generates Xarelto.
The method four: (WO such as Rao, 2009034308) in order in synthetic route, to avoid using isocyanate ester compound, at first the same phenyl chloroformate of amino of the chloro-3-5-trifluoromethylaniline of 4-, trichoroacetic chloride etc. are carried out to derivatize, then react and obtain Xarelto with 4-(4-amino-benzene oxygen)-2-(methylcarbamoyl)-pyridine; Or the chloro-3-5-trifluoromethylaniline of 4-reacts and obtain 1-(the chloro-3-of 4-(trifluoromethyl)-phenyl)-3-(4-hydroxy phenyl)-urea with 1-(4-hydroxy phenyl) urea, then obtain Xarelto with the chloro-2-of 4-(methylcarbamoyl)-pyridine generation nucleophilic substitution reaction.
Summary of the invention
The object of the invention is to overcome the above-mentioned shortcoming of prior art, the optimization synthesis technique of the Xarelto of a kind of mild condition, the applicable suitability for industrialized production that easy to operate, yield is high, quality is good, energy consumption is low is provided.
The objective of the invention is to reach like this, a kind of optimization synthesis technique of Xarelto, be that 2-pyridine carboxylic acid and sulfur oxychloride are synthesized to 4-chloropyridine-2-carbonyl chloride hydrochloride under Sodium Bromide catalysis, then in the mixed solvent of methyl alcohol and methylamine, react and obtain the chloro-2-of 4-(methylcarbamoyl)-pyridine; The chloro-2-of 4-(methylcarbamoyl)-pyridine is reacted under alkaline condition with p-aminophenol and obtain 4-(4-amino-benzene oxygen)-2-methylcarbamoyl-pyridine; The chloro-3-5-trifluoromethylaniline of 4-is reacted under alkaline condition with phenyl chloroformate and obtains (the chloro-3-trifluoromethyl of 4-)-phenyl-phenyl carbamate; Finally (the chloro-3-trifluoromethyl-phenyl of 4-) phenyl carbamate is reacted and obtains Xarelto with 4-(4-amino-benzene oxygen)-2-(methylcarbamoyl) pyridine.
In a specific embodiment of the present invention, the mol ratio of described 2-pyridine carboxylic acid and sulfur oxychloride is 1: 2～4; The mol ratio of 2-pyridine carboxylic acid and Sodium Bromide is 1: 0.125～0.25.
In another specific embodiment of the present invention, the volume ratio of described methyl alcohol and aqueous methylamine solution is 1: 1～2, and the reaction times is 3～6h.
In another specific embodiment of the present invention, described alkali is sodium hydride, potassium tert.-butoxide, sodium hydroxide, potassium hydroxide; The mol ratio of alkali and p-aminophenol is 1: 1～1.5, and the mol ratio of the chloro-2-of 4-(methylcarbamoyl)-pyridine and p-aminophenol is 1: 1～1.2, and the reaction times is 2～4h.
In another specific embodiment of the present invention, the mol ratio of the chloro-3-5-trifluoromethylaniline of 4-and phenyl chloroformate is 1: 1～1.5, and described alkali is saleratus or salt of wormwood; The mol ratio of alkali and phenyl chloroformate is 1: 1～1.2.
In another specific embodiment of the present invention, the mol ratio of (the chloro-3-trifluoromethyl-phenyl of 4-)-phenyl carbamate and 4-(4-amino-benzene oxygen)-2-(methylcarbamoyl)-pyridine is 1: 1～1.2; Temperature of reaction is 80～90 ℃.
Advantage of the present invention is:
1, by the conditioned reaction condition, make the consumption of 2-pyridine carboxylic acid, sulfur oxychloride, Sodium Bromide reach relatively minimum, guaranteed simultaneously yield and purity.
2, with the mixing solutions of methyl alcohol and methylamine, react, improve yield and purity.
3, adopt the synthetic chloro-2-of 4-(methylcarbamoyl) of one pot of multistep processes-pyridine, reduce reactions steps, reduced reaction cost.
4, avoid using triphosgene, and expensive carbonyl dimidazoles.
5, raw materials used cheap and easy to get, the mild condition of whole reaction, easy to operate, yield good, total recovery reaches as high as 55.6%; The reaction solvent for use is recyclable applying mechanically all, and environmental is low.
The accompanying drawing explanation
Accompanying drawing is the building-up reactions formula of Xarelto.
Embodiment
Following case study on implementation is used for the present invention is described, but is not used for limiting the scope of the invention.
Embodiment 1
The preparation of the chloro-2-of 4-(methylcarbamoyl)-pyridine (2)
4.92g (40mmol) 2-pyridine carboxylic acid (1) and 0.62g (6mmol) Sodium Bromide are joined in 10mL toluene, be heated to 85 ℃, slowly drip 10mL (140mmol), concentrating under reduced pressure after equality of temperature reaction 15h, add 10mL toluene again; The aqueous methylamine solution of 20mL methyl alcohol and 20mL30% is cooled to 5 ℃; drip above-mentioned toluene solution; dropwise all room temperatures that heats up; reaction 4h, with ethyl acetate (3*20mL) extraction, organic layer washes with water; anhydrous sodium sulfate drying; concentrating under reduced pressure, the gained crude product obtains the chloro-2-of 5.13g4-(methylcarbamoyl)-pyridine (2), yield 75% with ethyl acetate-sherwood oil recrystallization.
The preparation of the chloro-2-of 4-(methylcarbamoyl)-pyridine (2)
4.92g (40mmol) 2-pyridine carboxylic acid (1) and 0.52g (5mmol) Sodium Bromide are joined in 10mL toluene, be heated to 85 ℃, slowly drip 6mL (140mmol), concentrating under reduced pressure after equality of temperature reaction 15h, add 10mL toluene again; The aqueous methylamine solution of 20mL methyl alcohol and 20mL30% is cooled to 5 ℃; drip above-mentioned toluene solution; dropwise all room temperatures that heats up; reaction 3h, with ethyl acetate (3*20mL) extraction, organic layer washes with water; anhydrous sodium sulfate drying; concentrating under reduced pressure, the gained crude product obtains the chloro-2-of 4.95g4-(methylcarbamoyl)-pyridine (2), yield 72.4% with ethyl acetate-sherwood oil recrystallization.
The preparation of the chloro-2-of 4-(methylcarbamoyl)-pyridine (2)
4.92g (40mmol) 2-pyridine carboxylic acid (1) and 1.03g (10mmol) Sodium Bromide are joined in 10mL toluene, be heated to 85 ℃, slowly drip 10mL (140mmol), concentrating under reduced pressure after equality of temperature reaction 15h, add 10mL toluene again; The aqueous methylamine solution of 20mL methyl alcohol and 20mL30% is cooled to 5 ℃; drip above-mentioned toluene solution; dropwise all room temperatures that heats up; reaction 4h, with ethyl acetate (3*20mL) extraction, organic layer washes with water; anhydrous sodium sulfate drying; concentrating under reduced pressure, the gained crude product obtains the chloro-2-of 5.22g4-(methylcarbamoyl)-pyridine (2), yield 76.3% with ethyl acetate-sherwood oil recrystallization.
Embodiment 4
The preparation of the chloro-2-of 4-(methylcarbamoyl)-pyridine (2)
4.92g (40mmol) 2-pyridine carboxylic acid (1) and 0.62g (6mmol) Sodium Bromide are joined in 10mL toluene, be heated to 85 ℃, slowly drip 6mL (80mmol), concentrating under reduced pressure after equality of temperature reaction 15h, add 10mL toluene again; The aqueous methylamine solution of 20mL methyl alcohol and 40mL30% is cooled to 5 ℃; drip above-mentioned toluene solution; dropwise all room temperatures that heats up; reaction 6h, with ethyl acetate (3*20mL) extraction, organic layer washes with water; anhydrous sodium sulfate drying; concentrating under reduced pressure, the gained crude product obtains the chloro-2-of 5.13g4-(methylcarbamoyl)-pyridine (2), yield 69.4% with ethyl acetate-sherwood oil recrystallization.
The preparation of the chloro-2-of 4-(methylcarbamoyl)-pyridine (2)
4.92g (40mmol) 2-pyridine carboxylic acid (1) and 0.62g (6mmol) Sodium Bromide are joined in 10mL toluene, be heated to 85 ℃, slowly drip 11.4mL (160mmol), concentrating under reduced pressure after equality of temperature reaction 15h, add 10mL toluene again; The aqueous methylamine solution of 20mL methyl alcohol and 30mL30% is cooled to 5 ℃; drip above-mentioned toluene solution; dropwise all room temperatures that heats up; reaction 4h, with ethyl acetate (3*20mL) extraction, organic layer washes with water; anhydrous sodium sulfate drying; concentrating under reduced pressure, the gained crude product obtains the chloro-2-of 5.3lg4-(methylcarbamoyl)-pyridine (2), yield 77.6% with ethyl acetate-sherwood oil recrystallization.
The preparation of the chloro-2-of 4-(methylcarbamoyl)-pyridine (2)
4.92g (40mmol) 2-pyridine carboxylic acid (1) and 1.03g (10mmol) Sodium Bromide are joined in 10mL toluene, be heated to 85 ℃, slowly drip 11.4mL (160mmol), concentrating under reduced pressure after equality of temperature reaction 15h, add 10mL toluene again; The aqueous methylamine solution of 20mL methyl alcohol and 30mL30% is cooled to 5 ℃; drip above-mentioned toluene solution; dropwise all room temperatures that heats up; reaction 4h, with ethyl acetate (3*20mL) extraction, organic layer washes with water; anhydrous sodium sulfate drying; concentrating under reduced pressure, the gained crude product obtains the chloro-2-of 5.37g4-(methylcarbamoyl)-pyridine (2), yield 78.5% with ethyl acetate-sherwood oil recrystallization.
Embodiment 7
The preparation of 4-(4-amino-benzene oxygen)-2-methylcarbamoyl-pyridine (3)
Under nitrogen protection; 4.36g (40rnmol) p-aminophenol is dissolved in the DMF of 60mL drying; add wherein 0.96g (40mmol) NaH; after room temperature reaction 2h; add the chloro-2-of 6.84 (40mmol) 4-(methylcarbamoyl)-pyridine (2); be warming up to 85 ℃, reaction 2h.Cool to room temperature; add 200mL water; by ethyl acetate (3*200mL), extract; organic phase is washed with saturated nacl aqueous solution; anhydrous sodium sulfate drying; concentrating under reduced pressure, obtain 8.54g4-(4-amino-benzene oxygen)-2-methylcarbamoyl-pyridine (3), yield 87.9% with ethyl acetate-sherwood oil recrystallization.
Embodiment 8
The preparation of 4-(4-amino-benzene oxygen)-2-methylcarbamoyl-pyridine (3)
Under nitrogen protection; 4.36g (40mmol) p-aminophenol is dissolved in the DMF of 60mL drying; add wherein 4.48g (40mmol) NaH; after room temperature reaction 2h; add the chloro-2-of 6.84 (40mmol) 4-(methylcarbamoyl)-pyridine (2); be warming up to 85 ℃, reaction 2h.Cool to room temperature; add 200mL water; by ethyl acetate (3*200mL), extract; organic phase is washed with saturated nacl aqueous solution; anhydrous sodium sulfate drying; concentrating under reduced pressure, obtain 8.32g4-(4-amino-benzene oxygen)-2-methylcarbamoyl-pyridine (3), yield 85.6% with ethyl acetate-sherwood oil recrystallization.
Embodiment 9
The preparation of 4-(4-amino-benzene oxygen)-2-methylcarbamoyl-pyridine (3)
Under nitrogen protection; 4.36g (40mmol) p-aminophenol is dissolved in the DMF of 60mL drying; add wherein 2.4g (60mmol) NaOH; after room temperature reaction 2h; add the chloro-2-of 5.47g (32mmol) 4-(methylcarbamoyl)-pyridine (2); be warming up to 85 ℃, reaction 2h.Cool to room temperature; add 200mL water; by ethyl acetate (3*200mL), extract; organic phase is washed with saturated nacl aqueous solution; anhydrous sodium sulfate drying; concentrating under reduced pressure, obtain 7.54g4-(4-amino-benzene oxygen)-2-methylcarbamoyl-pyridine (3), yield 77.6% with ethyl acetate-sherwood oil recrystallization.
Embodiment 10
The preparation of 4-(4-amino-benzene oxygen)-2-methylcarbamoyl-pyridine (3)
Under nitrogen protection; 4.36g (40mmol) p-aminophenol is dissolved in the DMF of 60mL drying; add wherein 0.96g (50mmol) KOH; after room temperature reaction 2h; add the chloro-2-of 6.16 (36mmol) 4-(methylcarbamoyl)-pyridine (2); be warming up to 85 ℃, reaction 2h.Cool to room temperature; add 200mL water; by ethyl acetate (3*200mL), extract; organic phase is washed with saturated nacl aqueous solution; anhydrous sodium sulfate drying; concentrating under reduced pressure, obtain 7.84g4-(4-amino-benzene oxygen)-2-methylcarbamoyl-pyridine (3), yield 80.7% with ethyl acetate-sherwood oil recrystallization.
Embodiment 11
The preparation of (the chloro-3-trifluoromethyl-phenyl of 4-)-phenyl carbamate (5)
3.92g (20mmol) the chloro-3-5-trifluoromethylaniline of 4-(4) is added in 25mL toluene, add 2.76g (20mmol) salt of wormwood.Under ice bath, drip 3.14g (20mmol) phenyl chloroformate, dropwise, room temperature reaction 1h, pour in frozen water, with ethyl acetate (3*50mL) extraction, the washing of organic phase saturated nacl aqueous solution, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains 5.68g (the chloro-3-trifluoromethyl-phenyl of 4-)-phenyl carbamate (5), yield 89.9%.
Embodiment 12
The preparation of (the chloro-3-trifluoromethyl-phenyl of 4-)-phenyl carbamate (5)
3.92g (20mmol) the chloro-3-5-trifluoromethylaniline of 4-(4) is added in 25mL toluene, add 3.0g (30mmol) saleratus.Under ice bath, drip 4.7lg (30mmol) phenyl chloroformate, dropwise, room temperature reaction 1h, pour in frozen water, with ethyl acetate (3*50mL) extraction, the washing of organic phase saturated nacl aqueous solution, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains 5.78g (the chloro-3-trifluoromethyl-phenyl of 4-)-phenyl carbamate (5), yield 91.5%.
Embodiment 13
The preparation of (the chloro-3-trifluoromethyl-phenyl of 4-)-phenyl carbamate (5)
3.92g (20mmol) the chloro-3-5-trifluoromethylaniline of 4-(4) is added in 25mL toluene, add 3.45g (25mmol) salt of wormwood.Under ice bath, drip 3.93g (25mmol) phenyl chloroformate, dropwise, room temperature reaction 1h, pour in frozen water, with ethyl acetate (3*50mL) extraction, the washing of organic phase saturated nacl aqueous solution, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains 5.98g (the chloro-3-trifluoromethyl-phenyl of 4-)-phenyl carbamate (5), yield 94.6%.
Embodiment 14
The preparation of Xarelto (6)
By in 3.16g (10mmol) (the chloro-3-trifluoromethyl-phenyl of 4-)-phenyl carbamate (5) solution 10mL DMF; add 2.43g (10mmol) 4-(4-amino-benzene oxygen)-2-methylcarbamoyl-pyridine (3); be warmed up to 80 ℃; reaction 2h; after cooling, pour in frozen water; by ethyl acetate (3*30mL), extract; saturated nacl aqueous solution washing organic layer; anhydrous sodium sulfate drying; after concentrating under reduced pressure, add the 10mL acetonitrile; after fully stirring, filter to obtain 3.74g Xarelto (6), yield 80.4%.
Embodiment 15
The preparation of Xarelto (6)
By in 3.16g (10mmol) (the chloro-3-trifluoromethyl-phenyl of 4-)-phenyl carbamate (5) solution 10mL DMF; add 2.92g (12mmol) 4-(4-amino-benzene oxygen)-2-methylcarbamoyl-pyridine (3); be warmed up to 90 ℃; reaction 2h; after cooling, pour in frozen water; by ethyl acetate (3*30mL), extract; saturated nacl aqueous solution washing organic layer; anhydrous sodium sulfate drying; after concentrating under reduced pressure, add the 10mL acetonitrile; after fully stirring, filter to obtain 3.96g Xarelto (6), yield 85.2%.
Embodiment 16
The preparation of Xarelto (6)
By in 3.16g (10mmol) (the chloro-3-trifluoromethyl-phenyl of 4-)-phenyl carbamate (5) solution 10mL DMF; add 2.67g (11mmol) 4-(4-amino-benzene oxygen)-2-methylcarbamoyl-pyridine (3); be warmed up to 85 ℃; reaction 2h; after cooling, pour in frozen water; by ethyl acetate (3*30mL), extract; saturated nacl aqueous solution washing organic layer; anhydrous sodium sulfate drying; after concentrating under reduced pressure, add the 10mL acetonitrile; after fully stirring, filter to obtain 3.87g Xarelto (6), yield 83.2%.
Claims (8)
1. the optimization synthetic method of an Xarelto, it is characterized in that 2-pyridine carboxylic acid and sulfur oxychloride are synthesized to 4-chloropyridine-2-carbonyl chloride hydrochloride under Sodium Bromide catalysis, then in the mixed solvent of methyl alcohol again and methylamine, react and obtain the chloro-2-of 4-(methylcarbamoyl)-pyridine; The chloro-2-of 4-(methylcarbamoyl)-pyridine is reacted under alkaline condition with p-aminophenol and obtain 4-(4-amino-benzene oxygen)-2-methylcarbamoyl-pyridine; The chloro-3-5-trifluoromethylaniline of 4-is reacted under alkaline condition with phenyl chloroformate and obtains (the chloro-3-trifluoromethyl of 4-)-phenyl-phenyl carbamate; Finally (the chloro-3-trifluoromethyl-phenyl of 4-) phenyl carbamate is reacted and obtains Xarelto with 4-(4-amino-benzene oxygen)-2-(methylcarbamoyl) pyridine.
2. the synthetic method of Xarelto according to claim 1, the mol ratio that it is characterized in that described 2-pyridine carboxylic acid and sulfur oxychloride is 1: 2～4; The mol ratio of 2-pyridine carboxylic acid and Sodium Bromide is 1: 0.125～0.25.
3. the synthetic method of Xarelto according to claim 1, the volume ratio that it is characterized in that described methyl alcohol and aqueous methylamine solution is 1: 1～2, the reaction times is 3～6h.
4. the synthetic method of Xarelto according to claim 1, is characterized in that described alkali is sodium hydride, potassium tert.-butoxide, sodium hydroxide, potassium hydroxide; The mol ratio of alkali and p-aminophenol is 1: 1～1.5.
5. the synthetic method of Xarelto according to claim 1, the mol ratio that it is characterized in that the chloro-2-of described 4-(methylcarbamoyl)-pyridine and p-aminophenol is 1: 1～1.2, the reaction times is 2～4h.
6. the synthetic method of Xarelto according to claim 1, is characterized in that the mol ratio of the chloro-3-5-trifluoromethylaniline of described 4-and phenyl chloroformate is 1: 1～1.5.
7. the synthetic method of Xarelto according to claim 1, is characterized in that described alkali is saleratus or salt of wormwood; The mol ratio of alkali and phenyl chloroformate is 1: 1～1.2.
8. the synthetic method of Xarelto according to claim 1, is characterized in that the mol ratio of described (the chloro-3-trifluoromethyl-phenyl of 4-)-phenyl carbamate and 4-(4-amino-benzene oxygen)-2-(methylcarbamoyl)-pyridine is 1: 1～1.2; Temperature of reaction is 80～90 ℃.
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| 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 |
| CN110229099A (en) * | 2018-03-05 | 2019-09-13 | 连云港恒运药业有限公司 | A method of preparing Sorafenib key intermediate |
| CN110229099B (en) * | 2018-03-05 | 2023-02-21 | 连云港恒运药业有限公司 | Method for preparing sorafenib key intermediate |
| CN114957111A (en) * | 2022-07-19 | 2022-08-30 | 扬州市普林斯医药科技有限公司 | Preparation method of N-methyl-4-chloropyridine-2-formamide |
| CN114957111B (en) * | 2022-07-19 | 2024-02-09 | 扬州市普林斯医药科技有限公司 | Preparation method of N-methyl-4-chloropyridine-2-formamide |
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