CN101671299A - Method for synthesizing Nexavar - Google Patents
Method for synthesizing Nexavar Download PDFInfo
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- CN101671299A CN101671299A CN200810042730A CN200810042730A CN101671299A CN 101671299 A CN101671299 A CN 101671299A CN 200810042730 A CN200810042730 A CN 200810042730A CN 200810042730 A CN200810042730 A CN 200810042730A CN 101671299 A CN101671299 A CN 101671299A
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- xarelto
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Abstract
The invention provides a method for synthesizing Nexavar. The method comprises the following steps: a, dissolving a compound II and a compound III in an organic solvent inert to the compound III and adding appropriate base; b, performing reaction at a reaction temperature between 40 and 150 DEG C so as to generate a crude Nexavar product; and c, performing conventional post-treatment on the crudeproduct, wherein R is hydrogen, methyl, nitro or chlorine; the nitro is on site 4; the methyl or the chlorine is on site 2, 3 or 4; and the compound III is prepared through the reaction of a compoundIV and phenyl chloroformate or the phenyl chloroformate containing substituents on benzene rings in an organic reaction solvent inert to chloroformate at a temperature between 10 DEG C below zero and50 DEG C. The method has the advantages of applying to the preparation of Nexavar on an industrial scale, meeting standards in pharmaceutical industrial production, improving the purity and environmental compatibility of products and improving operability, safety and yield.
Description
Technical field
The present invention relates to the compound technical field, particularly the Xarelto preparing technical field more specifically, is meant a kind of synthetic method of Xarelto.
Background technology
Compound 4-{4-[({[4-chloro-3-(trifluoromethyl) phenyl] amino } carbonyl) amino] phenoxy group }-N-picoline-2-methane amide, also claim Xarelto, be recorded in the earliest among the patent WO0042012, molecular formula is C
21H
16ClF
3N
4O
3, its structural formula is seen formula I, molecular weight is 464.83.The disclosed report of patent WO0042012 shows that Compound I is the kinase whose inhibitor of a kind of Raf, can be as the disease of treatment such as cancer.
Patent WO0042012, WO2006034796, WO2006089150, WO2007059154, WO2007053574, US7235576 and document (Bankston etc., Organic Process Research ﹠amp; Development; 2002,6,777-781) method for preparing Compound I has been described, this method can be with following flowchart text:
In the end in the single step reaction, prior art is that Compound I I and isocyanic ester V or compound VI reaction are made Compound I.Although existing document disclosed method is preparation I compound effectively, when preparing Compound I with technical scale, the main drawback that adopts compound V is that the synthetic needs of compound V are used phosgene.Phosgene is a kind of hypertoxic gas, can only be in specific plant produced and use, so compound V synthetic has bigger dangerous and lower operability.The main drawback that adopts compound VI is that the synthetic yield of compound VI is very low.We adopt the synthetic method of document can only obtain the very compound VI of low-yield, cause the synthetic yield of this technology to have only 20-30%, and the purifying of product also needs the method for column chromatography for separation simultaneously, thereby the economy of this technology is too poor.
Summary of the invention
Main purpose of the present invention is exactly the problems and shortcomings at above existence, a kind of synthetic method of Xarelto is provided, this method is applicable to the technical scale preparation I compound, can satisfy the standard in the pharmaceutical industries production aspect, and can improve product purity and Environmental compatibility, improve operability, security and productive rate.
To achieve these goals, the technical solution used in the present invention is:
A kind of synthetic method of Xarelto is characterized in, comprises step:
A. Compound I I and compound III are dissolved in described compound III is in the organic solvent inert;
B. react 40 ℃～150 ℃ temperature of reaction then, thereby generate the thick product that contains described Xarelto;
C. described thick product is carried out conventional aftertreatment, thereby obtain described Xarelto.
Preferably, wherein R is hydrogen, methyl, nitro or chlorine, and described nitro is at 4 of phenyl ring, and described methyl or described chlorine are at 2,3 or 4 of phenyl ring; Described organic solvent is selected from DMF, DMSO, acetonitrile, acetone, toluene, chloroform, methylene dichloride, THF, 1,4-dioxane or pyridine.
More preferably, described temperature of reaction is 50 ℃～100 ℃; Described organic solvent is DMF, DMSO, acetonitrile or pyridine.
Further, described temperature of reaction is 60 ℃～80 ℃; Described organic solvent is a pyridine.
Preferably, described conventional aftertreatment comprises extremely-10 ℃～40 ℃ temperature of the described thick product of cooling, add entry, adding the organic extraction solvent then extracts, separate obtaining after the organic layer, add the described organic layer of weak acid scrubbing, isolate described organic layer once more to acid, drying, filtration, evaporate to dryness obtain containing the crude product of described Xarelto, and then recrystallization obtains the pure product of described Xarelto in suitable organic recrystallization solvent.Preferred dilute hydrochloric acid of described diluted acid or dilute sulphuric acid.
More preferably, described temperature is 0 ℃～30 ℃; Described organic extraction solvent is ethyl acetate, methyl tertiary butyl ether, isopropyl ether, methylene dichloride or chloroform; Described organic recrystallization solvent is ethyl acetate, tetrahydrofuran (THF), 1,4-dioxane, methyl tertiary butyl ether, isopropyl ether, acetone, acetonitrile or sherwood oil.
Further, described temperature is 10 ℃～25 ℃.
Preferably, described conventional aftertreatment comprises extremely-10 ℃～40 ℃ temperature of the described thick product of cooling, adds entry, separates out solid, obtain containing the crude product of described Xarelto after suction filtration, the oven dry, and then recrystallization obtains the pure product of described Xarelto in suitable organic recrystallization solvent.
More preferably, described temperature is 0 ℃～30 ℃; Described organic recrystallization solvent is selected from ethyl acetate, tetrahydrofuran (THF), 1,4-dioxane, methyl tertiary butyl ether, isopropyl ether, acetone, acetonitrile or sherwood oil.
Further, described temperature is 10 ℃～25 ℃.
Preferably, in described organic solvent, add suitable alkali.
More preferably, described alkali is selected from pyridine, salt of wormwood, yellow soda ash, saleratus, sodium bicarbonate, triethylamine or N, N-diethyl Isopropylamine.
Further, described alkali is pyridine, triethylamine, salt of wormwood or yellow soda ash.
Most preferably, described alkali is pyridine or salt of wormwood.
Preferably, described compound III prepares by following method: react in chloro-formic ester being inert organic reaction solvent by containing substituent phenyl chloroformate on compound IV and phenyl chloroformate or the phenyl ring, temperature condition is-10 ℃～50 ℃, after reaction finishes, add weak acid scrubbing to acid, tell organic layer, use the salt water washing again, tell organic layer after drying, filtration, evaporate to dryness.Preferred dilute hydrochloric acid of described diluted acid or dilute sulphuric acid.
More preferably, described temperature condition is 0 ℃～40 ℃; Described organic reaction solvent is chloroform, methylene dichloride, 1,2-methylene dichloride, tetrahydrofuran (THF), 1,4-dioxane or ethyl acetate.
Further, described temperature condition is 10 ℃～25 ℃, and adds suitable alkali and react; Described organic reaction solvent is chloroform, methylene dichloride or 1, the 2-methylene dichloride.
Preferably, described alkali is pyridine, triethylamine or N, N-diethyl Isopropylamine; Described organic reaction solvent is chloroform or methylene dichloride.
More preferably, described alkali pyridine or triethylamine.
Most preferably, described alkali is pyridine.
The compound III that is obtained by aforesaid method need not to be further purified, and can directly drop into next step use.
Above-mentioned reaction is carried out under normal pressure usually, but also can (for example in the scope of 0.5-5 crust) carry out under high pressure or decompression.
The present invention comprises the combination of all preferable range equally.
Beneficial effect of the present invention is as follows:
1. the present invention generates Xarelto by Compound I I and compound III reaction, can satisfy the standard in the pharmaceutical industries production aspect, and can improve product purity and Environmental compatibility, can avoid the use of phosgene, improve the security and the operability of technology.。
2. the product that adopts synthesis technique of the present invention to obtain only needs recrystallization to get final product purifying, and productive rate can reach 75%, and is easy and simple to handle, is easy to suitability for industrialized production.
Embodiment
In order more to be expressly understood technology contents of the present invention, now further specify as follows in conjunction with the embodiments:
Embodiment 1
The preparation of (1.1 4-chloro-3-trifluoromethyl-phenyl) phenyl carbamate
In there-necked flask, add compound IV (4-chloro-3-trifluoromethyl-benzene, bright chemical plant, Gaoyou, chemical pure) 5g; add methylene dichloride (Shanghai chemical reagent company limited; chemical pure) the 50ml stirring and dissolving is complete, adds pyridine (Shanghai chemical reagent company limited, chemical pure) 4g.Drip the mixed solution of 10ml methylene dichloride and 4.2g phenyl chloroformate (Shanghai chemical reagent company limited, chemical pure) under the room temperature, react half an hour.TLC (PE: EA=3: 1) show that raw material reaction is complete, with the pickling of 1N salt once, wash three times that drying is filtered, 7.6 grams of weighing after the oven dry, molar yield 94%.
1H?NMR(CDCl
3，500MHz)：δ＝7.1(s，1H)，7.2(d，J＝7Hz，2H)，7.3(m，1H)，7.4(m，2H)，7.5(d，J＝8Hz，1H)，7.6(d，J＝8Hz，1H)，7.8(s，1H)。
MS(EI)：m/e＝315。
The preparation of (1.2 4-chloro-3-trifluoromethyl-phenyl) phenyl carbamate
In there-necked flask, add compound IV (4-chloro-3-trifluoromethyl-benzene, bright chemical plant, Gaoyou, chemical pure) 5g; add methylene dichloride (Shanghai chemical reagent company limited; chemical pure) the 50ml stirring and dissolving is complete, adds triethylamine (Shanghai chemical reagent company limited, chemical pure) 4g.Drip the mixed solution of 10ml methylene dichloride and 4.2g phenyl chloroformate (Shanghai chemical reagent company limited, chemical pure) under the room temperature, react half an hour.TLC (PE: EA=3: 1) show that raw material reaction is complete, with the pickling of 1N salt once, wash three times that drying is filtered, 7.4 grams of weighing after the oven dry, molar yield 92%.
1H?NMR(CDCl
3，500MHz)：δ＝7.1(s，1H)，7.2(d，J＝7Hz，2H)，7.3(m，1H)，7.4(m，2H)，7.5(d，J＝8Hz，1H)，7.6(d，J＝8Hz，1H)，7.8(s，1H)。
MS(EI)：m/e＝315。
The preparation of (1.3 4-chloro-3-trifluoromethyl-phenyl) phenyl carbamate
In there-necked flask, add compound IV (4-chloro-3-trifluoromethyl-benzene, bright chemical plant, Gaoyou, chemical pure) 5g; add methylene dichloride (Shanghai chemical reagent company limited; chemical pure) the 50ml stirring and dissolving is complete, adds pyridine (Shanghai chemical reagent company limited, chemical pure) 4g.-10 ℃ of mixed solutions that drip 10ml methylene dichloride and 4.2g phenyl chloroformate (Shanghai chemical reagent company limited, chemical pure) down react half an hour.TLC (PE: EA=3: 1) show that raw material reaction is complete, with the pickling of 1N salt once, wash three times that drying is filtered, 7.6 grams of weighing after the oven dry, molar yield 94%.
1H?NMR(CDCl
3，500MHz)：δ＝7.1(s，1H)，7.2(d，J＝7Hz，2H)，7.3(m，1H)，7.4(m，2H)，7.5(d，J＝8Hz，1H)，7.6(d，J＝8Hz，1H)，7.8(s，1H)。
MS(EI)：m/e＝315。
The preparation of (1.4 4-chloro-3-trifluoromethyl-phenyl) phenyl carbamate
In there-necked flask, add compound IV (4-chloro-3-trifluoromethyl-benzene, bright chemical plant, Gaoyou, chemical pure) 5g; add methylene dichloride (Shanghai chemical reagent company limited; chemical pure) the 50ml stirring and dissolving is complete, adds pyridine (Shanghai chemical reagent company limited, chemical pure) 4g.50 ℃ of mixed solutions that drip 10ml methylene dichloride and 4.2g phenyl chloroformate (Shanghai chemical reagent company limited, chemical pure) down react half an hour.TLC (PE: EA=3: 1) show that raw material reaction is complete, with the pickling of 1N salt once, wash three times that drying is filtered, 7.6 grams of weighing after the oven dry, molar yield 94%.
1H?NMR(CDCl
3，500MHz)：δ＝7.1(s，1H)，7.2(d，J＝7Hz，2H)，7.3(m，1H)，7.4(m，2H)，7.5(d，J＝8Hz，1H)，7.6(d，J＝8Hz，1H)，7.8(s，1H)。
MS(EI)：m/e＝315。
Embodiment 2
The preparation of (2.1 4-chloro-3-trifluoromethyl-phenyl) carboxylamine 4-nitro phenyl ester
In there-necked flask, add compound IV (4-chloro-3-trifluoromethyl-benzene, bright chemical plant, Gaoyou, chemical pure) 5g; add methylene dichloride (Shanghai chemical reagent company limited; chemical pure) the 50ml stirring and dissolving is complete, adds pyridine (Shanghai chemical reagent company limited, chemical pure) 4g.Drip the mixed solution of 10ml methylene dichloride and 5.1g p-nitrophenyl chloroformate ester (Shanghai chemical reagent company limited, chemical pure) under the room temperature, react half an hour.TLC (PE: EA=3: 1) show that raw material reaction is complete, with the pickling of 1N salt once, wash three times that drying is filtered, 8.4 grams of weighing after the oven dry, molar yield 92%.
1H?NMR(CDCl
3，500MHz)：δ＝7.1(d，J＝7Hz，1H)，7.2(dd，J＝7Hz，J＝3Hz，1H)，7.3(d，J＝7Hz，2H)，7.7(d，J＝3Hz，1H)，7.8(s，1H)，8.1(d，J＝7Hz，2H)。
MS(EI)：m/e＝360。
The preparation of (2.2 4-chloro-3-trifluoromethyl-phenyl) carboxylamine 4-nitro phenyl ester
In there-necked flask, add compound IV (4-chloro-3-trifluoromethyl-benzene, bright chemical plant, Gaoyou, chemical pure) 5g; add methylene dichloride (Shanghai chemical reagent company limited; chemical pure) the 50ml stirring and dissolving is complete, adds triethylamine (Shanghai chemical reagent company limited, chemical pure) 4g.Drip the mixed solution of 10ml methylene dichloride and 5.1g p-nitrophenyl chloroformate ester (Shanghai chemical reagent company limited, chemical pure) under the room temperature, react half an hour.TLC (PE: EA=3: 1) show that raw material reaction is complete, with the pickling of 1N salt once, wash three times that drying is filtered, 8.4 grams of weighing after the oven dry, molar yield 92%.
1H?NMR(CDCl
3，500MHz)：δ＝7.1(d，J＝7Hz，1H)，7.2(dd，J＝7Hz，J＝3Hz，1H)，7.3(d，J＝7Hz，2H)，7.7(d，J＝3Hz，1H)，7.8(s，1H)，8.1(d，J＝7Hz，2H)。
MS(EI)：m/e＝360。
The preparation of (2.3 4-chloro-3-trifluoromethyl-phenyl) carboxylamine 4-nitro phenyl ester
In there-necked flask, add compound IV (4-chloro-3-trifluoromethyl-benzene, bright chemical plant, Gaoyou, chemical pure) 5g; add methylene dichloride (Shanghai chemical reagent company limited; chemical pure) the 50ml stirring and dissolving is complete, adds pyridine (Shanghai chemical reagent company limited, chemical pure) 4g.-10 ℃ of mixed solutions that drip 10ml methylene dichloride and 5.1g p-nitrophenyl chloroformate ester (Shanghai chemical reagent company limited, chemical pure) down react half an hour.TLC (PE: EA=3: 1) show that raw material reaction is complete, with the pickling of 1N salt once, wash three times that drying is filtered, 8.4 grams of weighing after the oven dry, molar yield 92%.
1H?NMR(CDCl
3，500MHz)：δ＝7.1(d，J＝7Hz，1H)，7.2(dd，J＝7Hz，J＝3Hz，1H)，7.3(d，J＝7Hz，2H)，7.7(d，J＝3Hz，1H)，7.8(s，1H)，8.1(d，J＝7Hz，2H)。
MS(EI)：m/e＝360。
The preparation of (2.4 4-chloro-3-trifluoromethyl-phenyl) carboxylamine 4-nitro phenyl ester
In there-necked flask, add compound IV (4-chloro-3-trifluoromethyl-benzene, bright chemical plant, Gaoyou, chemical pure) 5g; add methylene dichloride (Shanghai chemical reagent company limited; chemical pure) the 50ml stirring and dissolving is complete, adds pyridine (Shanghai chemical reagent company limited, chemical pure) 4g.50 ℃ of mixed solutions that drip 10ml methylene dichloride and 5.1g p-nitrophenyl chloroformate ester (Shanghai chemical reagent company limited, chemical pure) down react half an hour.TLC (PE: EA=3: 1) show that raw material reaction is complete, with the pickling of 1N salt once, wash three times that drying is filtered, 8.4 grams of weighing after the oven dry, molar yield 92%.
1H?NMR(CDCl
3，500MHz)：δ＝7.1(d，J＝7Hz，1H)，7.2(dd，J＝7Hz，J＝3Hz，1H)，7.3(d，J＝7Hz，2H)，7.7(d，J＝3Hz，1H)，7.8(s，1H)，8.1(d，J＝7Hz，2H)。
MS(EI)：m/e＝360。
Embodiment 3
The preparation of (3.1 4-chloro-3-trifluoromethyl-phenyl) carboxylamine 2-nitro phenyl ester
In there-necked flask, add compound IV (4-chloro-3-trifluoromethyl-benzene, bright chemical plant, Gaoyou, chemical pure) 5g; add methylene dichloride (Shanghai chemical reagent company limited; chemical pure) the 50ml stirring and dissolving is complete, adds pyridine (Shanghai chemical reagent company limited, chemical pure) 4g.Drip the mixed solution of 10ml methylene dichloride and 5.1g chloroformic acid ortho-nitrophenyl ester (Shanghai chemical reagent company limited, chemical pure) under the room temperature, react half an hour.TLC (PE: EA=3: 1) show that raw material reaction is complete, with the pickling of 1N salt once, wash three times that drying is filtered, 8.4 grams of weighing after the oven dry, molar yield 92%.
1H?NMR(CDCl
3，500MHz)：δ＝7.1(d，J＝7Hz，1H)，7.2(dd，J＝7Hz，J＝3Hz，1H)，7.3(dd，J＝7Hz，J＝3Hz，1H)，7.3(m，1H)，7.6(m，1H)，7.7(d，J＝3Hz，1H)，7.8(s，1H)，8.1(dd，J＝7Hz，J＝3Hz，1H)。
MS(EI)：m/e＝360。
The preparation of (3.2 4-chloro-3-trifluoromethyl-phenyl) carboxylamine 2-nitro phenyl ester
In there-necked flask, add compound IV (4-chloro-3-trifluoromethyl-benzene, bright chemical plant, Gaoyou, chemical pure) 5g; add methylene dichloride (Shanghai chemical reagent company limited; chemical pure) the 50ml stirring and dissolving is complete, adds triethylamine (Shanghai chemical reagent company limited, chemical pure) 4g.Drip the mixed solution of 10ml methylene dichloride and 5.1g chloroformic acid ortho-nitrophenyl ester (Shanghai chemical reagent company limited, chemical pure) under the room temperature, react half an hour.TLC (PE: EA=3: 1) show that raw material reaction is complete, with the pickling of 1N salt once, wash three times that drying is filtered, 8.4 grams of weighing after the oven dry, molar yield 92%.
1H?NMR(CDCl
3，500MHz)：δ＝7.1(d，J＝7Hz，1H)，7.2(dd，J＝7Hz，J＝3Hz，1H)，7.3(dd，J＝7Hz，J＝3Hz，1H)，7.3(m，1H)，7.6(m，1H)，7.7(d，J＝3Hz，1H)，7.8(s，1H)，8.1(dd，J＝7Hz，J＝3Hz，1H)。
MS(EI)：m/e＝360。
The preparation of (3.3 4-chloro-3-trifluoromethyl-phenyl) carboxylamine 2-nitro phenyl ester
In there-necked flask, add compound IV (4-chloro-3-trifluoromethyl-benzene, bright chemical plant, Gaoyou, chemical pure) 5g; add methylene dichloride (Shanghai chemical reagent company limited; chemical pure) the 50ml stirring and dissolving is complete, adds pyridine (Shanghai chemical reagent company limited, chemical pure) 4g.-10 ℃ of mixed solutions that drip 10ml methylene dichloride and 5.1g chloroformic acid ortho-nitrophenyl ester (Shanghai chemical reagent company limited, chemical pure) down react half an hour.TLC (PE: EA=3: 1) show that raw material reaction is complete, with the pickling of 1N salt once, wash three times that drying is filtered, 8.4 grams of weighing after the oven dry, molar yield 92%.
1H?NMR(CDCl
3，500MHz)：δ＝7.1(d，J＝7Hz，1H)，7.2(dd，J＝7Hz，J＝3Hz，1H)，7.3(dd，J＝7Hz，J＝3Hz，1H)，7.3(m，1H)，7.6(m，1H)，7.7(d，J＝3Hz，1H)，7.8(s，1H)，8.1(dd，J＝7Hz，J＝3Hz，1H)。
MS(EI)：m/e＝360。
The preparation of (3.4 4-chloro-3-trifluoromethyl-phenyl) carboxylamine 2-nitro phenyl ester
In there-necked flask, add compound IV (4-chloro-3-trifluoromethyl-benzene, bright chemical plant, Gaoyou, chemical pure) 5g; add methylene dichloride (Shanghai chemical reagent company limited; chemical pure) the 50ml stirring and dissolving is complete, adds pyridine (Shanghai chemical reagent company limited, chemical pure) 4g.50 ℃ of mixed solutions that drip 10ml methylene dichloride and 5.1g chloroformic acid ortho-nitrophenyl ester (Shanghai chemical reagent company limited, chemical pure) down react half an hour.TLC (PE: EA=3: 1) show that raw material reaction is complete, with the pickling of 1N salt once, wash three times that drying is filtered, 8.4 grams of weighing after the oven dry, molar yield 92%.
1H?NMR(CDCl
3，500MHz)：δ＝7.1(d，J＝7Hz，1H)，7.2(dd，J＝7Hz，J＝3Hz，1H)，7.3(dd，J＝7Hz，J＝3Hz，1H)，7.3(m，1H)，7.6(m，1H)，7.7(d，J＝3Hz，1H)，7.8(s，1H)，8.1(dd，J＝7Hz，J＝3Hz，1H)。
MS(EI)：m/e＝360。
Embodiment 4
4.14-{4-[({[4-chloro-3-(trifluoromethyl) phenyl] amino } carbonyl) amino] phenoxy group }-preparation of N-picoline-2-methane amide
(4-chloro-3-trifluoromethyl-phenyl) carboxylamine 4-nitro phenyl ester 2.49g of Compound I I (4-(4-amino-benzene methoxy base)-N-methyl-2-pyridine carboxamide) 1.92g and example 1 preparation is added in the there-necked flask, add pyridine 25ml stirring and dissolving.Be warming up to 80 ℃, reacted 2 hours, TLC (PE: EA=3: 1) show that raw material reaction is complete.System is concentrated into dried, is cooled to room temperature, adds entry 100ml, adds ethyl acetate (50ml * 2) extraction, with 1N hydrochloric acid (100ml * 3) washing, washing (100ml * 2), the water washing of 100ml saturated common salt.Tell organic layer and add a small amount of anhydrous sodium sulfate drying, filter, be concentrated on a small quantity, separate out white solid, suction filtration, a small amount of petroleum ether solid, oven-dried weight 2.7 grams, molar yield 75%.
M.p.206-208℃。
1H?NMR(DMSO-d
6，500MHz)：δ＝2.8(d，J＝4.4Hz，3H)，7.1(dd，J＝2.5，5.6Hz，1H)，7.2(d，J＝8.8Hz，2H)，7.4(d，J＝2.4Hz，1H)，7.6-7.7(m，4H)，8.1(d，J＝1.9Hz，1H)，8.5(d，J＝5.6Hz，1H)，8.8(d，J＝4.5Hz，1H)，9.0(br，1H)，9.2(br，1H)。
MS(ESI，CH
3CN/H
2O)：m/e＝465[M+H]
+。
4.24-{4-[({[4-chloro-3-(trifluoromethyl) phenyl] amino } carbonyl) amino] phenoxy group }-preparation of N-picoline-2-methane amide
(4-chloro-3-trifluoromethyl-phenyl) phenyl carbamate 2.49g of Compound I I (4-(4-amino-benzene methoxy base)-N-methyl-2-pyridine carboxamide) 1.92g and example 1 preparation is added in the there-necked flask, add DMF 25ml stirring and dissolving.Be warming up to 80 ℃, reacted 2 hours, TLC (PE: EA=3: 1) show that raw material reaction is complete.System is concentrated into dried, is cooled to 25 ℃, adds entry 100ml, adds ethyl acetate (50ml * 2) extraction, washes (100ml * 2) with water, the water washing of 100ml saturated common salt.Tell organic layer and add a small amount of anhydrous sodium sulfate drying, filter, be concentrated on a small quantity, separate out white solid, suction filtration, a small amount of petroleum ether solid, oven-dried weight 2.5 grams, molar yield 72%.
M.p.206-208℃。
1H?NMR(DMSO-d
6，500MHz)：δ＝2.8(d，J＝4.4Hz，3H)，7.1(dd，J＝2.5，5.6Hz，1H)，7.2(d，J＝8.8Hz，2H)，7.4(d，J＝2.4Hz，1H)，7.6-7.7(m，4H)，8.1(d，J＝1.9Hz，1H)，8.5(d，J＝5.6Hz，1H)，8.8(d，J＝4.5Hz，1H)，9.0(br，1H)，9.2(br，1H)。
MS(ESI，CH
3CN/H
2O)：m/e＝465[M+H]
+。
4.34-{4-[({[4-chloro-3-(trifluoromethyl) phenyl] amino } carbonyl) amino] phenoxy group }-preparation of N-picoline-2-methane amide
(4-chloro-3-trifluoromethyl-phenyl) carboxylamine 4-nitro phenyl ester 2.49g of Compound I I (4-(4-amino-benzene methoxy base)-N-methyl-2-pyridine carboxamide) 1.92g and example 1 preparation is added in the there-necked flask, add pyridine 25ml stirring and dissolving.Be warming up to 40 ℃, reacted 10 hours, TLC (PE: EA=3: 1) show that raw material reaction is complete.System is concentrated into dried, is cooled to-10 ℃, adds entry 100ml, adds ethyl acetate (50ml * 2) extraction, with 1N hydrochloric acid (100ml * 3) washing, washing (100ml * 2), the water washing of 100ml saturated common salt.Tell organic layer and add a small amount of anhydrous sodium sulfate drying, filter, be concentrated on a small quantity, separate out white solid, suction filtration, a small amount of petroleum ether solid, oven-dried weight 2.7 grams, molar yield 75%.
M.p.206-208℃。
1H?NMR(DMSO-d
6，500MHz)：δ＝2.8(d，J＝4.4Hz，3H)，7.1(dd，J＝2.5，5.6Hz，1H)，7.2(d，J＝8.8Hz，2H)，7.4(d，J＝2.4Hz，1H)，7.6-7.7(m，4H)，8.1(d，J＝1.9Hz，1H)，8.5(d，J＝5.6Hz，1H)，8.8(d，J＝4.5Hz，1H)，9.0(br，1H)，9.2(br，1H)。
MS(ESI，CH
3CN/H
2O)：m/e＝465[M+H]
+。
4.44-{4-[({[4-chloro-3-(trifluoromethyl) phenyl] amino } carbonyl) amino] phenoxy group }-preparation of N-picoline-2-methane amide
(4-chloro-3-trifluoromethyl-phenyl) carboxylamine 4-nitro phenyl ester 2.49g of Compound I I (4-(4-amino-benzene methoxy base)-N-methyl-2-pyridine carboxamide) 1.92g and example 1 preparation is added in the there-necked flask, add pyridine 25ml stirring and dissolving.Be warming up to 150 ℃, reacted 1 hour, TLC (PE: EA=3: 1) show that raw material reaction is complete.System is concentrated into dried, is cooled to 40 ℃, adds entry 100ml, adds ethyl acetate (50ml * 2) extraction, with 1N hydrochloric acid (100ml * 3) washing, washing (100ml * 2), the water washing of 100ml saturated common salt.Tell organic layer and add a small amount of anhydrous sodium sulfate drying, filter, be concentrated on a small quantity, separate out white solid, suction filtration, a small amount of petroleum ether solid, oven-dried weight 2.7 grams, molar yield 75%.
M.p.206-208℃。
1H?NMR(DMSO-d
6，500MHz)：δ＝2.8(d，J＝4.4Hz，3H)，7.1(dd，J＝2.5，5.6Hz，1H)，7.2(d，J＝8.8Hz，2H)，7.4(d，J＝2.4Hz，1H)，7.6-7.7(m，4H)，8.1(d，J＝1.9Hz，1H)，8.5(d，J＝5.6Hz，1H)，8.8(d，J＝4.5Hz，1H)，9.0(br，1H)，9.2(br，1H)。
MS(ESI，CH
3CN/H
2O)：m/e＝465[M+H]
+。
Embodiment 5
5.14-{4-[({[4-chloro-3-(trifluoromethyl) phenyl] amino } carbonyl) amino] phenoxy group }-preparation of N-picoline-2-methane amide
(4-chloro-3-trifluoromethyl-phenyl) carboxylamine 4-nitro phenyl ester 2.84g of Compound I I (4-(4-amino-benzene methoxy base)-N-methyl-2-pyridine carboxamide) 1.92g and example 2 preparations is added in the there-necked flask, add pyridine 25ml stirring and dissolving.Be warming up to 80 ℃, reacted 2 hours, TLC (PE: EA=3: 1) show that raw material reaction is complete.System is concentrated into dried, is cooled to 25 ℃, adds entry 100ml, adds ethyl acetate (50ml * 2) extraction, with 1N hydrochloric acid (100ml * 3) washing, washing (100ml * 2), the water washing of 100ml saturated common salt.Tell organic layer and add a small amount of anhydrous sodium sulfate drying, filter, be concentrated on a small quantity, separate out white solid, suction filtration, a small amount of petroleum ether solid, oven-dried weight 2.9 grams, molar yield 80%.
M.p.206-208℃。
1H?NMR(DMSO-d
6，500MHz)：δ＝2.8(d，J＝4.4Hz，3H)，7.1(dd，J＝2.5，5.6Hz，1H)，7.2(d，J＝8.8Hz，2H)，7.4(d，J＝2.4Hz，1H)，7.6-7.7(m，4H)，8.1(d，J＝1.9Hz，1H)，8.5(d，J＝5.6Hz，1H)，8.8(d，J＝4.5Hz，1H)，9.0(br，1H)，9.2(br，1H)。
MS(ESI，CH
3CN/H
2O)：m/e＝465[M+H]
+。
5.24-{4-[({[4-chloro-3-(trifluoromethyl) phenyl] amino } carbonyl) amino] phenoxy group }-preparation of N-picoline-2-methane amide
(4-chloro-3-trifluoromethyl-phenyl) carboxylamine 4-nitro phenyl ester 2.84g of Compound I I (4-(4-amino-benzene methoxy base)-N-methyl-2-pyridine carboxamide) 1.92g and example 2 preparations is added in the there-necked flask, add DMF 25ml stirring and dissolving.Be warming up to 80 ℃, reacted 2 hours, TLC (PE: EA=3: 1) show that raw material reaction is complete.System is concentrated into dried, is cooled to room temperature, adds entry 100ml, adds ethyl acetate (50ml * 2) extraction, washes (100ml * 2) with water, the water washing of 100ml saturated common salt.Tell organic layer and add a small amount of anhydrous sodium sulfate drying, filter, be concentrated on a small quantity, separate out white solid, suction filtration, a small amount of petroleum ether solid, oven-dried weight 2.8 grams, molar yield 77%.
M.p.206-208℃。
1H?NMR(DMSO-d
6，500MHz)：δ＝2.8(d，J＝4.4Hz，3H)，7.1(dd，J＝2.5，5.6Hz，1H)，7.2(d，J＝8.8Hz，2H)，7.4(d，J＝2.4Hz，1H)，7.6-7.7(m，4H)，8.1(d，J＝1.9Hz，1H)，8.5(d，J＝5.6Hz，1H)，8.8(d，J＝4.5Hz，1H)，9.0(br，1H)，9.2(br，1H)。
MS(ESI，CH
3CN/H
2O)：m/e＝465[M+H]
+。
5.34-{4-[({[4-chloro-3-(trifluoromethyl) phenyl] amino } carbonyl) amino] phenoxy group }-preparation of N-picoline-2-methane amide
(4-chloro-3-trifluoromethyl-phenyl) carboxylamine 4-nitro phenyl ester 2.84g of Compound I I (4-(4-amino-benzene methoxy base)-N-methyl-2-pyridine carboxamide) 1.92g and example 2 preparations is added in the there-necked flask, add pyridine 25ml stirring and dissolving.Be warming up to 40 ℃, reacted 10 hours, TLC (PE: EA=3: 1) show that raw material reaction is complete.System is concentrated into dried, is cooled to 40 ℃, adds entry 100ml, adds ethyl acetate (50ml * 2) extraction, with 1N hydrochloric acid (100ml * 3) washing, washing (100ml * 2), the water washing of 100ml saturated common salt.Tell organic layer and add a small amount of anhydrous sodium sulfate drying, filter, be concentrated on a small quantity, separate out white solid, suction filtration, a small amount of petroleum ether solid, oven-dried weight 2.9 grams, molar yield 80%.
M.p.206-208℃。
1H?NMR(DMSO-d
6，500MHz)：δ＝2.8(d，J＝4.4Hz，3H)，7.1(dd，J＝2.5，5.6Hz，1H)，7.2(d，J＝8.8Hz，2H)，7.4(d，J＝2.4Hz，1H)，7.6-7.7(m，4H)，8.1(d，J＝1.9Hz，1H)，8.5(d，J＝5.6Hz，1H)，8.8(d，J＝4.5Hz，1H)，9.0(br，1H)，9.2(br，1H)。
MS(ESI，CH
3CN/H
2O)：m/e＝465[M+H]
+。
5.44-{4-[({[4-chloro-3-(trifluoromethyl) phenyl] amino } carbonyl) amino] phenoxy group }-preparation of N-picoline-2-methane amide
(4-chloro-3-trifluoromethyl-phenyl) carboxylamine 4-nitro phenyl ester 2.84g of Compound I I (4-(4-amino-benzene methoxy base)-N-methyl-2-pyridine carboxamide) 1.92g and example 2 preparations is added in the there-necked flask, add pyridine 25ml stirring and dissolving.Be warming up to 150 ℃, reacted 1 hour, TLC (PE: EA=3: 1) show that raw material reaction is complete.System is concentrated into dried, is cooled to-10 ℃, adds entry 100ml, adds ethyl acetate (50ml * 2) extraction, with 1N hydrochloric acid (100ml * 3) washing, washing (100ml * 2), the water washing of 100ml saturated common salt.Tell organic layer and add a small amount of anhydrous sodium sulfate drying, filter, be concentrated on a small quantity, separate out white solid, suction filtration, a small amount of petroleum ether solid, oven-dried weight 2.9 grams, molar yield 80%.
M.p.206-208℃。
1H?NMR(DMSO-d
6，500MHz)：δ＝2.8(d，J＝4.4Hz，3H)，7.1(dd，J＝2.5，5.6Hz，1H)，7.2(d，J＝8.8Hz，2H)，7.4(d，J＝2.4Hz，1H)，7.6-7.7(m，4H)，8.1(d，J＝1.9Hz，1H)，8.5(d，J＝5.6Hz，1H)，8.8(d，J＝4.5Hz，1H)，9.0(br，1H)，9.2(br，1H)。
MS(ESI，CH
3CN/H
2O)：m/e＝465[M+H]
+
Embodiment 6
6.14-{4-[({[4-chloro-3-(trifluoromethyl) phenyl] amino } carbonyl) amino] phenoxy group }-preparation of N-picoline-2-methane amide
(4-chloro-3-trifluoromethyl-phenyl) carboxylamine 2-nitro phenyl ester 2.84g of Compound I I (4-(4-amino-benzene methoxy base)-N-methyl-2-pyridine carboxamide) 1.92g and example 3 preparations is added in the there-necked flask, add pyridine 25ml stirring and dissolving.Be warming up to 80 ℃, reacted 2 hours, TLC (PE: EA=3: 1) show that raw material reaction is complete.System is concentrated into dried, is cooled to room temperature, adds entry 100ml, adds ethyl acetate (50ml * 2) extraction, with 1N hydrochloric acid (100ml * 3) washing, washing (100ml * 2), the water washing of 100ml saturated common salt.Tell organic layer and add a small amount of anhydrous sodium sulfate drying, filter, be concentrated on a small quantity, separate out white solid, suction filtration, a small amount of petroleum ether solid, oven-dried weight 2.9 grams, molar yield 80%.
M.p.206-208℃。
1H?NMR(DMSO-d
6，500MHz)：δ＝2.8(d，J＝4.4Hz，3H)，7.1(dd，J＝2.5，5.6Hz，1H)，7.2(d，J＝8.8Hz，2H)，7.4(d，J＝2.4Hz，1H)，7.6-7.7(m，4H)，8.1(d，J＝1.9Hz，1H)，8.5(d，J＝5.6Hz，1H)，8.8(d，J＝4.5Hz，1H)，9.0(br，1H)，9.2(br，1H)。
MS(ESI，CH
3CN/H
2O)：m/e＝465[M+H]
+。
6.24-{4-[({[4-chloro-3-(trifluoromethyl) phenyl] amino } carbonyl) amino] phenoxy group }-preparation of N-picoline-2-methane amide
(4-chloro-3-trifluoromethyl-phenyl) carboxylamine 2-nitro phenyl ester 2.84g of Compound I I (4-(4-amino-benzene methoxy base)-N-methyl-2-pyridine carboxamide) 1.92g and example 3 preparations is added in the there-necked flask, add DMF 25ml stirring and dissolving.Be warming up to 80 ℃, reacted 2 hours, TLC (PE: EA=3: 1) show that raw material reaction is complete.System is concentrated into dried, is cooled to room temperature, adds entry 100ml, adds ethyl acetate (50ml * 2) extraction, washes (100ml * 2) with water, the water washing of 100ml saturated common salt.Tell organic layer and add a small amount of anhydrous sodium sulfate drying, filter, be concentrated on a small quantity, separate out white solid, suction filtration, a small amount of petroleum ether solid, oven-dried weight 2.8 grams, molar yield 77%.
M.p.206-208℃。
1H?NMR(DMSO-d
6，500MHz)：δ＝2.8(d，J＝4.4Hz，3H)，7.1(dd，J＝2.5，5.6Hz，1H)，7.2(d，J＝8.8Hz，2H)，7.4(d，J＝2.4Hz，1H)，7.6-7.7(m，4H)，8.1(d，J＝1.9Hz，1H)，8.5(d，J＝5.6Hz，1H)，8.8(d，J＝4.5Hz，1H)，9.0(br，1H)，9.2(br，1H)。
MS(ESI，CH
3CN/H
2O)：m/e＝465[M+H]
+。
6.34-{4-[({[4-chloro-3-(trifluoromethyl) phenyl] amino } carbonyl) amino] phenoxy group }-preparation of N-picoline-2-methane amide
(4-chloro-3-trifluoromethyl-phenyl) carboxylamine 2-nitro phenyl ester 2.84g of Compound I I (4-(4-amino-benzene methoxy base)-N-methyl-2-pyridine carboxamide) 1.92g and example 3 preparations is added in the there-necked flask, add pyridine 25ml stirring and dissolving.Be warming up to 40 ℃, reacted 10 hours, TLC (PE: EA=3: 1) show that raw material reaction is complete.System is concentrated into dried, is cooled to-10 ℃, adds entry 100ml, adds ethyl acetate (50ml * 2) extraction, with 1N hydrochloric acid (100ml * 3) washing, washing (100ml * 2), the water washing of 100ml saturated common salt.Tell organic layer and add a small amount of anhydrous sodium sulfate drying, filter, be concentrated on a small quantity, separate out white solid, suction filtration, a small amount of petroleum ether solid, oven-dried weight 2.9 grams, molar yield 80%.
M.p.206-208℃。
1H?NMR(DMSO-d
6，500MHz)：δ＝2.8(d，J＝4.4Hz，3H)，7.1(dd，J＝2.5，5.6Hz，1H)，7.2(d，J＝8.8Hz，2H)，7.4(d，J＝2.4Hz，1H)，7.6-7.7(m，4H)，8.1(d，J＝1.9Hz，1H)，8.5(d，J＝5.6Hz，1H)，8.8(d，J＝4.5Hz，1H)，9.0(br，1H)，9.2(br，1H)。
MS(ESI，CH
3CN/H
2O)：m/e＝465[M+H]
+。
6.44-{4-[({[4-chloro-3-(trifluoromethyl) phenyl] amino } carbonyl) amino] phenoxy group }-preparation of N-picoline-2-methane amide
(4-chloro-3-trifluoromethyl-phenyl) carboxylamine 2-nitro phenyl ester 2.84g of Compound I I (4-(4-amino-benzene methoxy base)-N-methyl-2-pyridine carboxamide) 1.92g and example 3 preparations is added in the there-necked flask, add pyridine 25ml stirring and dissolving.Be warming up to 150 ℃, reacted 1 hour, TLC (PE: EA=3: 1) show that raw material reaction is complete.System is concentrated into dried, is cooled to 40 ℃, adds entry 100ml, adds ethyl acetate (50ml * 2) extraction, with 1N hydrochloric acid (100ml * 3) washing, washing (100ml * 2), the water washing of 100ml saturated common salt.Tell organic layer and add a small amount of anhydrous sodium sulfate drying, filter, be concentrated on a small quantity, separate out white solid, suction filtration, a small amount of petroleum ether solid, oven-dried weight 2.9 grams, molar yield 80%.
M.p.206-208℃。
1H?NMR(DMSO-d
6，500MHz)：δ＝2.8(d，J＝4.4Hz，3H)，7.1(dd，J＝2.5，5.6Hz，1H)，7.2(d，J＝8.8Hz，2H)，7.4(d，J＝2.4Hz，1H)，7.6-7.7(m，4H)，8.1(d，J＝1.9Hz，1H)，8.5(d，J＝5.6Hz，1H)，8.8(d，J＝4.5Hz，1H)，9.0(br，1H)，9.2(br，1H)。
MS(ESI，CH
3CN/H
2O)：m/e＝465[M+H]
+。
In sum, the synthetic method of Xarelto of the present invention is applicable to the technical scale preparation I compound, can satisfy the standard in the pharmaceutical industries production aspect, and can improve product purity and Environmental compatibility, improve operability, security and productive rate.
Need to prove, all quote in this application as a reference, just quoted as a reference separately as each piece document at all documents that the present invention mentions.Should understand in addition, above-described is specific embodiments of the invention and the know-why used, after having read above-mentioned teachings of the present invention, those skilled in the art can make various changes or modifications and not deviate from spirit of the present invention and scope the present invention, and these equivalent form of values fall within the scope of the invention equally.
Claims (20)
1. the synthetic method of an Xarelto is characterized in that, comprises step:
A. Compound I I and compound III are dissolved in described compound III is in the organic solvent inert;
B. react 40 ℃～150 ℃ temperature of reaction then, thereby generate the thick product that contains described Xarelto;
C. described thick product is carried out conventional aftertreatment, thereby obtain described Xarelto.
2. the synthetic method of Xarelto according to claim 1 is characterized in that, wherein R is hydrogen, methyl, nitro or chlorine, and described nitro is at 4 of phenyl ring, and described methyl or described chlorine are at 2,3 or 4 of phenyl ring; Described organic solvent is selected from DMF, DMSO, acetonitrile, acetone, toluene, chloroform, methylene dichloride, THF, 1,4-dioxane or pyridine.
3. the synthetic method of Xarelto according to claim 2 is characterized in that, described temperature of reaction is 50 ℃～100 ℃; Described organic solvent is DMF, DMSO, acetonitrile or pyridine.
4. the synthetic method of Xarelto according to claim 3 is characterized in that, described temperature of reaction is 60 ℃～80 ℃; Described organic solvent is a pyridine.
5. the synthetic method of Xarelto according to claim 1, it is characterized in that, described conventional aftertreatment comprises extremely-10 ℃～40 ℃ temperature of the described thick product of cooling, add entry, adding the organic extraction solvent then extracts, separate and obtain after the organic layer, add the described organic layer of weak acid scrubbing to acid, isolate described organic layer once more, drying, filtration, evaporate to dryness obtain containing the crude product of described Xarelto, and then recrystallization obtains the pure product of described Xarelto in suitable organic recrystallization solvent.
6. the synthetic method of Xarelto according to claim 5 is characterized in that, described temperature is 0 ℃～30 ℃; Described organic extraction solvent is ethyl acetate, methyl tertiary butyl ether, isopropyl ether, methylene dichloride or chloroform; Described organic recrystallization solvent is ethyl acetate, tetrahydrofuran (THF), 1,4-dioxane, methyl tertiary butyl ether, isopropyl ether, acetone, acetonitrile or sherwood oil.
7. the synthetic method of Xarelto according to claim 6 is characterized in that, described temperature is 10 ℃～25 ℃.
8. the synthetic method of Xarelto according to claim 1, it is characterized in that, described conventional aftertreatment comprises extremely-10 ℃～40 ℃ temperature of the described thick product of cooling, add entry, separate out solid, obtain containing the crude product of described Xarelto after suction filtration, the oven dry, and then recrystallization obtains the pure product of described Xarelto in suitable organic recrystallization solvent.
9. the synthetic method of Xarelto according to claim 8 is characterized in that, described temperature is 0 ℃～30 ℃; Described organic recrystallization solvent is selected from ethyl acetate, tetrahydrofuran (THF), 1,4-dioxane, methyl tertiary butyl ether, isopropyl ether, acetone, acetonitrile or sherwood oil.
10. the synthetic method of Xarelto according to claim 9 is characterized in that, described temperature is 10 ℃～25 ℃.
11. the synthetic method of Xarelto according to claim 1 is characterized in that, adds suitable alkali in described organic solvent.
12. the synthetic method of Xarelto according to claim 11 is characterized in that, described alkali is selected from pyridine, salt of wormwood, yellow soda ash, saleratus, sodium bicarbonate, triethylamine or N, N-diethyl Isopropylamine.
13. the synthetic method of Xarelto according to claim 12 is characterized in that, described alkali is pyridine, triethylamine, salt of wormwood or yellow soda ash.
14. the synthetic method of Xarelto according to claim 13 is characterized in that, described alkali is pyridine or salt of wormwood.
15. the synthetic method of Xarelto according to claim 1, it is characterized in that, described compound III prepares by following method: react in chloro-formic ester being inert organic reaction solvent by containing substituent phenyl chloroformate on compound IV and phenyl chloroformate or the phenyl ring, temperature condition is-10 ℃～50 ℃, after reaction finishes, add weak acid scrubbing, tell organic layer to acid, use the salt water washing again, tell organic layer after drying, filtration, evaporate to dryness.
16. the synthetic method of Xarelto according to claim 15 is characterized in that, described temperature condition is 0 ℃～40 ℃; Described organic reaction solvent is chloroform, methylene dichloride, 1,2-methylene dichloride, tetrahydrofuran (THF), 1,4-dioxane or ethyl acetate.
17. the synthetic method of Xarelto according to claim 16 is characterized in that, described temperature condition is 10 ℃～25 ℃, and adds suitable alkali and react; Described organic reaction solvent is chloroform, methylene dichloride or 1, the 2-methylene dichloride.
18. the synthetic method of Xarelto according to claim 17 is characterized in that, described alkali is pyridine, triethylamine or N, N-diethyl Isopropylamine; Described organic reaction solvent is chloroform or methylene dichloride.
19. the synthetic method of Xarelto according to claim 18 is characterized in that, described alkali is pyridine or triethylamine.
20. the synthetic method of Xarelto according to claim 19 is characterized in that, described alkali is pyridine.
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| CN102311384A (en) * | 2010-06-29 | 2012-01-11 | 翔真生物科技股份有限公司 | Preparation method for sorafenib |
| WO2014012480A1 (en) * | 2012-07-18 | 2014-01-23 | 苏州泽璟生物制药有限公司 | Polymorphs of deuterated omega-diphenylurea or salts thereof |
| CN103664771A (en) * | 2012-09-19 | 2014-03-26 | 齐鲁制药有限公司 | Crystal form A of Sorafenib and preparation method thereof |
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2008
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| CN102311384A (en) * | 2010-06-29 | 2012-01-11 | 翔真生物科技股份有限公司 | Preparation method for sorafenib |
| WO2014012480A1 (en) * | 2012-07-18 | 2014-01-23 | 苏州泽璟生物制药有限公司 | Polymorphs of deuterated omega-diphenylurea or salts thereof |
| CN103570613A (en) * | 2012-07-18 | 2014-02-12 | 苏州泽璟生物制药有限公司 | Polymorphic substance of deuterated omega-diphenylcarbamide or its salt |
| CN103570613B (en) * | 2012-07-18 | 2016-06-15 | 苏州泽璟生物制药有限公司 | The polymorphic form of deuterated ω-diphenyl urea or its salt |
| US9573900B2 (en) | 2012-07-18 | 2017-02-21 | Suzhou Zelgen Biopharmaceutical Co., Ltd. | Polymorphs of deuterated omega-diphenylurea or salts thereof |
| US9889123B2 (en) | 2012-07-18 | 2018-02-13 | Suzhou Zelgen Biopharmaceutical Co., Ltd. | Polymorphs of deuterated omega-diphenylurea or salts thereof |
| CN103664771A (en) * | 2012-09-19 | 2014-03-26 | 齐鲁制药有限公司 | Crystal form A of Sorafenib and preparation method thereof |
| CN103664771B (en) * | 2012-09-19 | 2016-03-30 | 齐鲁制药有限公司 | Crystal form A of Xarelto 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 |
| CN105272911B (en) * | 2015-11-30 | 2018-11-06 | 山东罗欣药业集团恒欣药业有限公司 | A kind of preparation method of Sorafenib Tosylate |
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