CN104177292A - Method for industrial production of sorafenib tosylate polymorphic form I - Google Patents
Method for industrial production of sorafenib tosylate polymorphic form I Download PDFInfo
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- CN104177292A CN104177292A CN201410390897.3A CN201410390897A CN104177292A CN 104177292 A CN104177292 A CN 104177292A CN 201410390897 A CN201410390897 A CN 201410390897A CN 104177292 A CN104177292 A CN 104177292A
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention discloses a method for industrial production of a sorafenib tosylate polymorphic substance I. The method comprises the following steps: by adopting N-methyl-4-chloro-pyridine carboxamide and p-aminophenol as raw materials, adding a proper amount of alkali to obtain an intermediate 4-(4-aminophenoxy)-N-methyl-2-pyridine carboxamide by virtue of nucleophilic substitution reaction in an organic solvent, performing condensation on 4-(4-aminophenoxy)-N-methyl-2-pyridine carboxamide and 4-chloro-3-benzenyl trifluoride isocyanate to obtain free alkali of sorafenib, finally performing back-flow and salification with p-toluenesulfonic acid in a mixed solvent of acetone and acetonitrile, and cooling and crystallizing to obtain sorafenib tosylate of the polymorphic substance I. Compared with the prior art, the scheme of the method disclosed by the invention is simple and safe to operate, is mild in reaction condition, and does not need crystal form transformation steps; an obtained product is single and stable in crystal form and high in purity, and is suitable for large-scale industrial production.
Description
Technical field
The invention belongs to drug manufacture field, be specifically related to a kind of method of suitability for industrialized production Sorafenib Tosylate polymorphic I.
Background technology
4-{4-[3-(the chloro-3-trifluoromethyl of 4-) uride] phenoxy group } pyridine-2-carboxamide tosylate (Sorafenib Tosylate, Sorafenib Toyslate, trade(brand)name: Nexavar, Nexavar) be to be researched and developed by German Bayer company, can act on tumour cell and tumor vessel simultaneously.It has dual antitumor action: both can be by the blocking-up cell signaling path that mediated by RAF/MEK/ERK the direct propagation of inhibition tumor cell, also can block tumor neovasculature formation, the growth of inhibition tumor cell indirectly by suppressing VEGF and Thr6 PDGF BB (PDGF) acceptor.In December, 2005, the first-line drug listing through U.S. food bureau of drug (FDA) approval as treatment advanced renal cell cancer.In August, 2009, the Sorafenib Tosylate sheet of state food and drug administration approval Bayer Bitterfeld GmbH drugmaker formally enters Chinese liver cancer treatment market, for inoperable advanced liver cancer patient treatment.
WO0042012 discloses the synthetic method of BAY 43-9006 alkali for the first time, it is raw material that this patent be take 4-(4-amino-benzene oxygen)-N-methyl-2-pyridine carboxamide and the chloro-3-trifluoromethyl of 4-phenylisocyanate, in methylene dichloride, condensation generates Xarelto alkali, this step reaction time needs more than 16 hours, the long work industry production cost that not only increased of reaction times, has also reduced production efficiency simultaneously.
Patent WO2006034796, WO2009054004A etc. have also provided the method for preparing Xarelto free alkali, and reaction equation is as follows:
When compound 2 is prepared in compound 1 and the effect of compound V, with pyridine, the organic basess such as triethylamine promote the generation of reaction, pollute greatlyr, and cause a large amount of waste liquids, the compound 2 obtaining Virahol recrystallization, and crystallization is more than 12 hours; And the productive rate reacting during by compound VI only has 20-30%, and product need to pass through column chromatographic isolation and purification, and purge process produces a large amount of waste residues and waste liquid, and whole technique less economical is unsuitable for amplifying and produces.
WO2006034797 discloses Xarelto tosilate polymorphic I, polymorphs and polymorphic III first, and Xarelto tosilate methanol solvate compound and alcohol solvent compound.Point out that polymorphic I is stable crystal form, and polymorphs is metastable simultaneously.But polymorphic I is transformed by polymorphs, and conversion operation is very loaded down with trivial details, as: (1) polymorphs is warming up to 200 ℃ with given pace, then with given pace, is down to room temperature and obtains polymorphic I; (2) polymorphs is selected toluene, methyl alcohol, and ethanol, one or both mixed solvents of water, room temperature turns brilliant one week and obtains the methods such as polymorphic I, is unfavorable for industry's enlarging production.
Therefore, need to develop a kind of industrial method of preparing Sorafenib Tosylate polymorphic I of more economical environmental protection.
Summary of the invention
It is easily a kind of that problem to be solved by this invention is to provide, and prepares efficiently the method for Sorafenib Tosylate polymorphic I, do not need transformation of crystal, in whole step, only need a recrystallization, method is simple to operation, and last salify is directly prepared the Sorafenib Tosylate of the more much higher crystalline form I of purity, and whole piece route is simple, convenient, safety, has solved defect of the prior art, has greatly improved productivity effect, the pollution of minimizing to environment, is applicable to suitability for industrialized production.
The method of suitability for industrialized production Sorafenib Tosylate polymorphic I of the present invention, described Sorafenib Tosylate polymorphic I demonstrates to be had 2 θ values and is: 4.5, the X-ray powder diffraction collection of illustrative plates of 11.1,13.2,14.8,16.7,17.9,18.8,20.1,20.4,20.8,21.5,22.9,24.5,25.0 characteristic peak, described method comprises the steps:
1. take the chloro-pyridine carboxamide of N-methyl-4-and p-aminophenol is raw material, add suitable alkali nucleo philic substitution reaction to obtain structural formula suc as formula the compound 1 shown in II, the mol ratio of the chloro-pyridine carboxamide of starting raw material N-methyl-4-and p-aminophenol consumption is 1:(1-5), 70 ℃-130 ℃ of temperature of reaction;
2. will compound 1 with the condensation of the chloro-3-trifluoromethyl of 4-phenylisocyanate after obtain structural formula suc as formula the compound 2 shown in III, the mol ratio between the chloro-3-trifluoromethyl of compound 1 and 4-phenylisocyanate is 1:(1-5), ℃-30 ℃, temperature of reaction-5;
3. compound 2 and toluenesulphonic acids reaction salify, by cooling crystallization, obtain structural formula suc as formula the polymorphic form I of the Sorafenib Tosylate shown in I, and between compound 2 and toluenesulphonic acids, the mol ratio of consumption is 1:(1-2); Temperature of reaction is-10 ℃-70 ℃,
Reaction scheme is as follows:
Preferably,
Described step 1. in, alkali used is one or more the mixing in salt of wormwood, sodium carbonate, sodium hydroxide, potassium tert.-butoxide; Temperature of reaction is 70 ℃-110 ℃; Reaction solvent is nitrogen, one or both mixture of nitrogen-dimethyl formamide, dimethyl sulfoxide (DMSO).
Described step 2. in, temperature of reaction is-5 ℃ to 10 ℃; Solvent is toluene, methylene dichloride, methyl-sulphoxide or ethylene dichloride, and the solvent of recrystallization is one or both mixture of ethanol, acetone, acetonitrile.
Described step 3. in, reaction solvent is the mixture of acetone and acetonitrile, wherein the volume ratio of acetone and acetonitrile is (2-10): 1, temperature of reaction is 60 ℃ to 100 ℃.
Described step 3. in, described cooling crystallization method is as follows: first with cooling bath slow cooling to separating out solid, and then be cooled to and in reaction system, no longer separate out solid with water-bath.
More preferably,
Described step 1. in, alkali is sodium hydroxide, salt of wormwood or sodium carbonate, temperature of reaction is 90 ℃-110 ℃; Reaction solvent is nitrogen, nitrogen-dimethyl formamide.
Described step 2. in, reaction solvent is methylene dichloride, temperature of reaction is for being not less than 0 ℃ and lower than 20 ℃, the solvent of recrystallization is ethanol or acetonitrile.
Described step 3. in, the volume ratio of acetone and acetonitrile is (5-8): 1, temperature of reaction is 25 ℃-70 ℃.
The present invention has following technique effect:
1, method is easy.Involved in the present invention simple to post-reaction treatment, in the middle of whole route, only need primary purification operation, and simple and easy to operate.
2, be applicable to suitability for industrialized production.Operational path of the present invention is brief, and reaction conditions is gentle, controlled, pollutes littlely, is applicable to very much suitability for industrialized production;
3, product purity is high.After end product salify, need not refine and turn brilliant, directly obtain required crystal formation, and product purity reach more than 99%.
Accompanying drawing explanation
Fig. 1 is several crystal form X-powder diagrams of Sorafenib Tosylate that prior art patent CN101065360A announces;
The X-powder diagram of the Sorafenib Tosylate polymorphic I that Fig. 2 the present invention is prepared.
Embodiment
Synthesizing of embodiment 1 Sorafenib Tosylate polymorphic I
1. compound 1 is synthetic
In 50L reactor, add 12L nitrogen, nitrogen-dimethyl formamide, by p-aminophenol 1.92kg (17.58mol), sodium hydroxide 960g, adds in reaction flask.Then under nitrogen protection, add anhydrous sodium carbonate 300g, the chloro-pyridine formyl of N-methyl-4-3.0kg (17.58mol) is added in the DMF of 12L and dissolve, in the reaction system that the DMF solution of the chloro-pyridine formyl of N-methyl-4-is added dropwise to.After dropwising, stirring at room 30min.Reaction solution is heated to 90 ℃, stirring reaction 4h, raw material reaction is complete.After having reacted, system adds 16L water, ethyl acetate extraction, and organic layer concentrate drying, sherwood oil making beating suction filtration after 1 hour, filter cake petroleum ether, forced air drying, obtains brown solid chemical compound 1,2.79kg, yield 70%.
2. compound 2 is synthetic
In 50L reactor, add the methylene dichloride of 2.5kg (10.28mol) compound 1 and 25L, reaction system is cooled to below 20 ℃, adds the chloro-3-trifluoromethyl of the 4-phenylisocyanate of 2.28kg (10.28mol).After dropwising, stir 1h.After completion of the reaction, there are a large amount of off-white color solids to separate out.Suction filtration reaction solution, filter cake eluent methylene chloride.Filter cake forced air drying, obtains 4.62kg, yield 98.3%.Thick product utilization ethyl alcohol recrystallization obtains sterling 3.00kg, yield 65.3%.
3. Sorafenib Tosylate polymorphic I is synthetic
In 100L reactor, add 2.58kg (5.55mol) compound 2, acetone 24L, acetonitrile 4L, be heated to backflow, add tosic acid 1.06kg (5.55mol), stir 2 hours, suction filtration while being cooled to room temperature, filter cake hexanaphthene drip washing, filter cake forced air drying, obtains 3.33kg I crystal formation Sorafenib Tosylate, yield is 95%, purity 99%.
1H-NMR(DMSO-d6):δ2.28(s,3H),2.79(d,J＝4.8Hz,3H),5.77(br.s,1H,SO3H),7.14(d,J＝7.9Hz,2H),7.17-7.22(m,d,J＝8.8Hz,3H),7.44(d,J＝2.0Hz,1H),7.48(d,J＝8.0Hz,2H),7.57(d,J＝8.8Hz,2H),7.63(m,1H),7.67(m,1H),8.14(d,J＝2.2Hz,1H),8.53(d,J＝5.6Hz,1H),8.87(d,J＝4.8Hz,1H),9.10(br.s,1H),9.30(br.s,1H)。
Synthesizing of embodiment 2 Sorafenib Tosylate polymorphic I
1. compound 1 is synthetic
In 50L reactor, add 12L nitrogen, nitrogen-dimethyl formamide, by the p-aminophenol of 3.84kg (35.16mol), the sodium hydroxide of 960g, adds in reaction flask.Then under nitrogen protection, the chloro-pyridine carboxamide of N-methyl-4-of 3.0kg (17.58mol) is added in the DMF of 12L and dissolve, in the reaction system that the DMF solution of the chloro-pyridine formyl of N-methyl-4-is added dropwise to.After dropwising, stirring at room 30min.Reaction solution is heated to 100 ℃, stirring reaction 4h.After having reacted, system adds 16L water, ethyl acetate extraction, and organic layer concentrate drying, sherwood oil making beating suction filtration after 1 hour, filter cake petroleum ether, forced air drying, obtains brown solid chemical compound 1,2.2kg, yield 63%.
2. compound 2 is synthetic
In 50L reactor, add the compound 1 of 2.5kg (10.28mol) and the methylene dichloride of 25L, reaction system is cooled to below 20 ℃, adds the chloro-3-trifluoromethyl of the 4-phenylisocyanate of 3.4kg (15.42mol).After dropwising, stir 1h.After completion of the reaction, there are a large amount of off-white color solids to separate out.Suction filtration reaction solution, filter cake eluent methylene chloride.Filter cake forced air drying, obtains 4.48kg, yield 94.3%.Thick product utilization ethyl alcohol recrystallization obtains sterling, 2.88kg, yield 64.3%.
3. Sorafenib Tosylate polymorphic I is synthetic
In 100L reactor, add 2.58kg (5.55mol) compound 2, acetone 32L, acetonitrile 4L, be heated to backflow, add tosic acid 1.58kg (8.33mol), stir 2 hours, suction filtration while being cooled to room temperature, filter cake hexanaphthene drip washing, filter cake forced air drying, obtains 3.0kg I crystal formation Sorafenib Tosylate, yield is 72.6%, purity 99%.
1H-NMR(DMSO-d6):δ2.27(s,3H),2.79(d,J＝4.8Hz,3H),5.78(br.s,1H,SO3H),7.14(d,J＝7.9Hz,2H),7.17-7.22(m,d,J＝8.8Hz,3H),7.44(d,J＝2.0Hz,1H),7.48(d,J＝8.0Hz,2H),7.60(d,J＝8.8Hz,2H),7.63(m,1H),7.67(m,1H),8.16(d,J＝2.2Hz,1H),8.53(d,J＝5.6Hz,1H),8.87(d,J＝4.8Hz,1H),9.10(br.s,1H),9.30(br.s,1H)。
Synthesizing of embodiment 3 Sorafenib Tosylate polymorphic I
1. compound 1 is synthetic
In 50L reactor, add 12L nitrogen, nitrogen-dimethyl formamide, by the p-aminophenol of 4.80kg (43.95mol), the sodium hydroxide of 960g, adds in reaction flask.Then under nitrogen protection, add the anhydrous sodium carbonate of 300g, the chloro-pyridine carboxamide of N-methyl-4-of 3.0kg (17.58mol) is added in the DMF of 12L and dissolve, in the reaction system that the DMF solution of the chloro-pyridine formyl of N-methyl-4-is added dropwise to.After dropwising, stirring at room 30min.Reaction solution is heated to 110 ℃, stirring reaction 4h.After having reacted, system adds 16L water, ethyl acetate extraction, and organic layer concentrate drying, sherwood oil making beating suction filtration after 1 hour, filter cake petroleum ether, forced air drying, obtains brown solid chemical compound 1,2.8kg, yield 75%.
2. compound 2 is synthetic
In 50L reactor, add the compound 1 of 2.5kg (10.28mol) and the methylene dichloride of 25L, reaction system is cooled to below 10 ℃, adds the chloro-3-trifluoromethyl of the 4-phenylisocyanate of 3.87kg (17.48mol).After dropwising, stir 1h.After completion of the reaction, there are a large amount of off-white color solids to separate out.Suction filtration reaction solution, filter cake eluent methylene chloride.Filter cake forced air drying, obtains 4.63kg, yield 98.4%.Thick product utilization ethyl alcohol recrystallization obtains sterling 3.0kg, yield 65%.
3. Sorafenib Tosylate polymorphic I is synthetic
In 100L reactor, add 2.58kg (5.55mol) compound 2, acetone 40L, acetonitrile 8L, be heated to backflow, add tosic acid 2.11kg (11.10mol), stir suction filtration while being cooled to room temperature 2 hours, filter cake hexanaphthene drip washing, filter cake forced air drying, obtains 3.02kg I crystal formation Sorafenib Tosylate, and yield is 82%. purity 99%.
1H-NMR(DMSO-d6):δ2.29(s,3H),2.79(d,J＝4.8Hz,3H),5.9(br.s,1H,SO3H),7.14(d,J＝7.9Hz,2H),7.17-7.22(m,d,J＝8.8Hz,3H),7.44(d,J＝2.0Hz,1H),7.48(d,J＝8.0Hz,2H),7.61(d,J＝8.8Hz,2H),7.63(m,1H),7.67(m,1H),8.14(d,J＝2.2Hz,1H),8.53(d,J＝5.6Hz,1H),8.87(d,J＝4.8Hz,1H),9.10(br.s,1H),9.30(br.s,1H)。
Synthesizing of embodiment 4 Sorafenib Tosylate polymorphic I
1. compound 1 is synthetic
In 50L reactor, add 12L nitrogen, nitrogen-dimethyl formamide, by the p-aminophenol of 9.59Kg (87.9mol), the sodium hydroxide of 960g, adds in reaction flask.Then under nitrogen protection, add the Anhydrous potassium carbonate of 300g, the chloro-pyridine carboxamide of N-methyl-4-of 3.0kg (17.58mol) is added in the DMF of 12L and dissolve, in the reaction system that the DMF solution of the chloro-pyridine formyl of N-methyl-4-is added dropwise to.After dropwising, stirring at room 30min.Reaction solution is heated to 110 ℃, stirring reaction 4h, raw material reaction is complete.After having reacted, system adds 16L water, ethyl acetate extraction, and organic layer concentrate drying, sherwood oil making beating suction filtration after 1 hour, filter cake petroleum ether, forced air drying, obtains brown solid chemical compound 1,2.49kg, yield 60%.
m.p.114-116℃
1H-NMR(DMSO-d6):δ2.76(d,J＝4.7Hz,3H),5.21(br.s,2H),6.62-6.86(m,J＝8.6Hz,4H),7.05(dd,J＝2.4,5.4Hz,1H),7.33(d,J＝2.3Hz,1H),8.46(d,J＝5.5Hz,1H),8.78(br.d,J＝4.5Hz,1H)。
2. compound 2 is synthetic
In 50L reactor, add the compound 1 of 2.5kg (10.28mol) and the methylene dichloride of 25L, reaction system is cooled to 0 ℃, adds the chloro-3-trifluoromethyl of the 4-phenylisocyanate of 11.38kg (51.40mol).After dropwising, stir 1h.After completion of the reaction, there are a large amount of off-white color solids to separate out.Suction filtration reaction solution, filter cake eluent methylene chloride.Filter cake forced air drying, obtains 4.67kg, yield 99.3%.Thick product utilization acetone, acetonitrile recrystallization obtains sterling 2.80kg, yield 65.3%.m.p.206-208℃。
1H-NMR(DMSO-d6):δ2.77(d,J＝4.8Hz,3H),7.15(m,3H),7.35(d,J＝2.5Hz,1H),7.62(m,4H),8.11d,J＝2.5Hz,1H),8.49(d,J＝5.5Hz,1H),8.78(br.d,1H),8.99(s,1H),9.22(s,1H)
3. Sorafenib Tosylate polymorphic I is synthetic
In 100L reactor, add 2.58kg (5.55mol) compound 2, acetone 50L, acetonitrile 10L, be heated to backflow, add tosic acid 1.16kg (6.10mol), stir 2 hours, suction filtration while being cooled to room temperature, filter cake hexanaphthene drip washing, filter cake forced air drying, obtains 3.1kg I crystal formation Sorafenib Tosylate, yield is 90%, purity 99%.m.p.223-231℃；1H-NMR(DMSO-d6):δ2.29(s,3H),2.79(d,J＝4.8Hz,3H),5.9(br.s,1H,SO3H),7.14(d,J＝7.9Hz,2H),7.17-7.22(m,d,J＝8.8Hz,3H),7.44(d,J＝2.0Hz,1H),7.48(d,J＝8.0Hz,2H),7.61(d,J＝8.8Hz,2H),7.63(m,1H),7.67(m,1H),8.14(d,J＝2.2Hz,1H),8.53(d,J＝5.6Hz,1H),8.87(d,J＝4.8Hz,1H),9.10(br.s,1H),9.30(br.s,1H)。
Several crystal form X-powdery diffractometry 2 θ values of Sorafenib Tosylate that table 1 is announced for existing patent CN101065360A.X-powdery diffractometry 2 θ, d (A) value of the Sorafenib Tosylate polymorphic I that table 2 is prepared for the present embodiment.Several crystal form X-powder diagrams of Sorafenib Tosylate that Fig. 1: patent CN101065360A announces, Fig. 2 is the X-powder diagram of the Sorafenib Tosylate polymorphic I prepared of the present embodiment; From table 2 and Fig. 2, can find out, resulting according to method described in this patent is Sorafenib Tosylate polymorphic I.
Several crystal form X-powdery diffractometry 2 θ values of Sorafenib Tosylate that the existing patent CN101065360A of table 1 announces
Table 2 is synthetic polymorphous diffraction 2 θ of Sorafenib Tosylate of the method for embodiment 4 and dA
0value
| 2θ | dA 0 | 2θ | dA 0 | 2θ | dA 0 | 2θ | dA 0 | 2θ | dA 0 | 2θ | dA 0 |
| 3.6 | 24.5 | 13.2 | 6.66 | 19.4 | 4.57 | 24.5 | 3.62 | 28.5 | 3.11 | 33.8 | 2.64 |
| 4.5 | 19.5 | 14.8 | 5.96 | 20.0 | 4.41 | 25.0 | 3.55 | 29.6 | 3.01 | 34.2 | 2.61 |
| 6.8 | 13.0 | 15.9 | 5.54 | 20.4 | 4.33 | 25.4 | 3.50 | 29.9 | 2.98 | 35.7 | 2.51 |
| 10.7 | 8.21 | 16.4 | 5.36 | 20.8 | 4.24 | 26.0 | 3.42 | 30.8 | 2.89 | 37.0 | 2.42 |
| 11.1 | 7.93 | 16.7 | 5.29 | 21.5 | 4.12 | 26.6 | 3.34 | 31.1 | 2.86 | 38.4 | 2.33 |
| 11.6 | 7.59 | 17.6 | 5.00 | 22.9 | 3.87 | 26.9 | 3.30 | 31.6 | 2.82 | 39.2 | 2.29 |
| 12.2 | 7.20 | 17.9 | 4.94 | 23.4 | 3.79 | 27.3 | 3.25 | 32.0 | 2.79 | 40.7 | 2.21 |
| 12.8 | 6.87 | 18.8 | 4.70 | 23.7 | 3.74 | 28.1 | 3.16 | 33.1 | 2.70 | ? | ? |
Claims (8)
1. the method for a suitability for industrialized production Sorafenib Tosylate polymorphic I, described Sorafenib Tosylate polymorphic I demonstrates to be had 2 θ values and is: 4.5, the X-ray powder diffraction collection of illustrative plates of 11.1,13.2,14.8,16.7,17.9,18.8,20.1,20.4,20.8,21.5,22.9,24.5,25.0 characteristic peak, it is characterized in that, described method comprises the steps:
1. take the chloro-pyridine carboxamide of N-methyl-4-and p-aminophenol is raw material, add suitable alkali nucleo philic substitution reaction to obtain structural formula suc as formula the compound 1 shown in II, the mol ratio of the chloro-pyridine carboxamide of starting raw material N-methyl-4-and p-aminophenol consumption is 1:(1-5), 70 ℃-130 ℃ of temperature of reaction;
2. will compound 1 with the condensation of the chloro-3-trifluoromethyl of 4-phenylisocyanate after obtain structural formula suc as formula the compound 2 shown in III, the mol ratio between the chloro-3-trifluoromethyl of compound 1 and 4-phenylisocyanate is 1:(1-5), ℃-30 ℃, temperature of reaction-5;
3. compound 2 and toluenesulphonic acids reaction salify, by cooling crystallization, obtain structural formula suc as formula the polymorphic form I of the Sorafenib Tosylate shown in I, and between compound 2 and toluenesulphonic acids, the mol ratio of consumption is 1:(1-2); Temperature of reaction is-10 ℃-70 ℃,
Reaction scheme is as follows:
2. method according to claim 1, is characterized in that, described step 1. in, alkali used is one or more the mixing in salt of wormwood, sodium carbonate, sodium hydroxide, potassium tert.-butoxide; Temperature of reaction is 70 ℃-110 ℃; Reaction solvent is nitrogen, one or both mixture of nitrogen-dimethyl formamide, dimethyl sulfoxide (DMSO).
3. method according to claim 1, is characterized in that, described step 2. in, temperature of reaction is-5 ℃ to 10 ℃; Solvent is toluene, methylene dichloride, methyl-sulphoxide or ethylene dichloride, and the solvent of recrystallization is one or both mixture of ethanol, acetone, acetonitrile.
4. method according to claim 1, is characterized in that, described step 3. in, reaction solvent is the mixture of acetone and acetonitrile, wherein the volume ratio of acetone and acetonitrile is (2-10): 1, temperature of reaction is 60 ℃ to 100 ℃.
5. method according to claim 1, is characterized in that, described step 3. in, described cooling crystallization method is as follows: first with cooling bath slow cooling to separating out solid, and then be cooled to and in reaction system, no longer separate out solid with water-bath.
6. method according to claim 2, is characterized in that, described step 1. in, alkali is sodium hydroxide, salt of wormwood or sodium carbonate, temperature of reaction is 90 ℃-110 ℃; Reaction solvent is nitrogen, nitrogen-dimethyl formamide.
7. method according to claim 3, is characterized in that, described step 2. in, reaction solvent is methylene dichloride, temperature of reaction is for being not less than 0 ℃ and lower than 20 ℃, the solvent of recrystallization is ethanol or acetonitrile.
8. method according to claim 4, is characterized in that, described step 3. in, the volume ratio of acetone and acetonitrile is (5-8): 1, temperature of reaction is 25 ℃-70 ℃.
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104888228A (en) * | 2015-05-29 | 2015-09-09 | 连云港杰瑞药业有限公司 | Sorafenib tosylate solid dispersion body and preparation method thereof |
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| CN109810051A (en) * | 2019-03-07 | 2019-05-28 | 福建南方济民医药研发中心有限公司 | A method of preparing targeting antineoplastic medicine object Sorafenib Tosylate salt |
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| CN105777625A (en) * | 2014-12-24 | 2016-07-20 | 浙江海正药业股份有限公司 | Preparation method for 4-(4-amino-3-fluorophenoxyl)-N-methylpyridine-2-methanamide |
| CN105777625B (en) * | 2014-12-24 | 2020-05-22 | 浙江海正药业股份有限公司 | Method for preparing 4- (4-amino-3-fluorophenoxy) -N-methylpyridine-2-formamide |
| CN104888228A (en) * | 2015-05-29 | 2015-09-09 | 连云港杰瑞药业有限公司 | Sorafenib tosylate solid dispersion body and preparation method thereof |
| 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 |
| CN107759517A (en) * | 2016-08-23 | 2018-03-06 | 广州白云山医药集团股份有限公司白云山制药总厂 | A kind of preparation method of Sorafenib Tosylate crystal formation I |
| CN106748996A (en) * | 2017-01-14 | 2017-05-31 | 山东裕欣药业有限公司 | A kind of Sorafenib Tosylate crystal-form compound and preparation method thereof |
| CN106748996B (en) * | 2017-01-14 | 2020-03-20 | 山东裕欣药业有限公司 | Sorafenib tosylate crystal compound and preparation method thereof |
| CN110105386A (en) * | 2018-02-01 | 2019-08-09 | 浙江瑞博制药有限公司 | Application of the serialization micro passage reaction in pharmaceutical synthesis |
| CN110105386B (en) * | 2018-02-01 | 2024-06-25 | 浙江瑞博制药有限公司 | Application of continuous microchannel reactor in drug synthesis |
| CN109810051A (en) * | 2019-03-07 | 2019-05-28 | 福建南方济民医药研发中心有限公司 | A method of preparing targeting antineoplastic medicine object Sorafenib Tosylate salt |
| CN113773249A (en) * | 2020-06-10 | 2021-12-10 | 杭州中美华东制药有限公司 | Sorafenib free base crystal Form X and preparation method thereof |
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