CN102553642A - Catalyst and preparation method for sorafenib intermediate - Google Patents
Catalyst and preparation method for sorafenib intermediate Download PDFInfo
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- CN102553642A CN102553642A CN2011103939018A CN201110393901A CN102553642A CN 102553642 A CN102553642 A CN 102553642A CN 2011103939018 A CN2011103939018 A CN 2011103939018A CN 201110393901 A CN201110393901 A CN 201110393901A CN 102553642 A CN102553642 A CN 102553642A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 239000003054 catalyst Substances 0.000 title claims abstract description 22
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 title abstract 2
- 239000005511 L01XE05 - Sorafenib Substances 0.000 title abstract 2
- 229960003787 sorafenib Drugs 0.000 title abstract 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 48
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims abstract description 35
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims abstract description 28
- 239000011261 inert gas Substances 0.000 claims abstract description 12
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000002156 mixing Methods 0.000 claims abstract description 7
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 32
- 238000000034 method Methods 0.000 claims description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- 239000000543 intermediate Substances 0.000 claims description 9
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- 238000006243 chemical reaction Methods 0.000 abstract description 23
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- 238000009776 industrial production Methods 0.000 abstract 1
- NBTOZLQBSIZIKS-UHFFFAOYSA-N methoxide Chemical compound [O-]C NBTOZLQBSIZIKS-UHFFFAOYSA-N 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- 239000000047 product Substances 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 239000012948 isocyanate Substances 0.000 description 12
- 150000002513 isocyanates Chemical class 0.000 description 12
- 239000012044 organic layer Substances 0.000 description 11
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 238000003810 ethyl acetate extraction Methods 0.000 description 6
- 230000007935 neutral effect Effects 0.000 description 6
- 238000012805 post-processing Methods 0.000 description 6
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 5
- 239000004202 carbamide Substances 0.000 description 5
- 239000012295 chemical reaction liquid Substances 0.000 description 5
- 230000001143 conditioned effect Effects 0.000 description 5
- 150000005686 dimethyl carbonates Chemical class 0.000 description 5
- 239000007789 gas Substances 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000000376 reactant Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
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- 239000002994 raw material Substances 0.000 description 3
- DGRVQOKCSKDWIH-UHFFFAOYSA-N 1-chloro-2-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1Cl DGRVQOKCSKDWIH-UHFFFAOYSA-N 0.000 description 2
- VIUDTWATMPPKEL-UHFFFAOYSA-N 3-(trifluoromethyl)aniline Chemical compound NC1=CC=CC(C(F)(F)F)=C1 VIUDTWATMPPKEL-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- 230000005587 bubbling Effects 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
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- -1 purity is low Substances 0.000 description 2
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 2
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- CMXLWMLABMJODV-UHFFFAOYSA-N Cc(cc1C(F)(F)F)ccc1Cl Chemical compound Cc(cc1C(F)(F)F)ccc1Cl CMXLWMLABMJODV-UHFFFAOYSA-N 0.000 description 1
- OWIKHYCFFJSOEH-UHFFFAOYSA-N Isocyanic acid Chemical compound N=C=O OWIKHYCFFJSOEH-UHFFFAOYSA-N 0.000 description 1
- OENCGIJIRMMVSY-UHFFFAOYSA-N N=C=O.FC(F)(F)c1ccccc1Cl Chemical class N=C=O.FC(F)(F)c1ccccc1Cl OENCGIJIRMMVSY-UHFFFAOYSA-N 0.000 description 1
- ASPDJZINBYYZRU-UHFFFAOYSA-N Nc(cc1C(F)(F)F)ccc1Cl Chemical compound Nc(cc1C(F)(F)F)ccc1Cl ASPDJZINBYYZRU-UHFFFAOYSA-N 0.000 description 1
- ZOIORXHNWRGPMV-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O.CC(O)=O ZOIORXHNWRGPMV-UHFFFAOYSA-N 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- XLJMAIOERFSOGZ-UHFFFAOYSA-N anhydrous cyanic acid Natural products OC#N XLJMAIOERFSOGZ-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
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- HCUYBXPSSCRKRF-UHFFFAOYSA-N diphosgene Chemical compound ClC(=O)OC(Cl)(Cl)Cl HCUYBXPSSCRKRF-UHFFFAOYSA-N 0.000 description 1
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- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 238000005832 oxidative carbonylation reaction Methods 0.000 description 1
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Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a catalyst which comprises sodium methoxide, methyl formate and methanol in the ratio of mass volume ratio of 0.2g:0.2g:5mL-2g:2g:5mL. The invention also discloses a preparation method of the catalyst. The preparation method comprises the following steps of: uniformly mixing the sodium methoxide, the methyl formate and the methanol and stirring under inert gas, wherein the mass volume ratio of the odium methoxide to the methyl formate to the methanol is 0.2g:0.2g:5mL-2g:2g:5mL. The invention also discloses the preparation method of a sorafenib intermediate (formula I). The preparation method comprises the following step of: under the conditions of inert gas protection and reflow and under the action of the catalyst, with dimethyl carbonate as a solvent, carrying out reaction on the dimethyl carbonate and 4-chlorine-3-trifluoromethylaniline. The preparation method disclosed by the invention has the advantages of high conversion rate, safety, no hazard, no pollution, mild reaction condition, high yield and suitability for industrial production.
Description
Technical field
The present invention relates to its intermediates preparation of a kind of catalyst and Suo Lafeini.
Background technology
4-chloro-3-trifluoromethyl carbamate is the important intermediate of preparation 4-chloro-3-trifluoromethylbenzene based isocyanate.Isocyanates is the general name of the various esters of isocyanic acid.Isocyanates is one type of important chemical intermediate, is applied to prepare polyurethane, foam, plastics, coating, artificial rubber, elastomer, synthetic leather and medical agricultural chemicals synthetic.4-chloro-3-trifluoromethylbenzene based isocyanate is the key intermediate of synthetic anti-lung cancer liver-cancer medicine Suo Lafeini, and the purity of 4-chloro-3-trifluoromethylbenzene based isocyanate is significant for the yield of synthetic this medicine.
Many weeks, the traditional conventional method for preparing isocyanates is to use the phosgenation route, but shortcoming such as there is the serious environmental defective in this process route, and this technology exists phosgene hypertoxic, and accessory substance is to the production equipment seriously corroded, and is big for environment pollution.
All the time, chemical industry is all at the non-phosgene process route of seeking the extraordinary isocyanates of a kind of safety preparation.Developed trichloromethyl chloroformate (surpalite) route in succession; Two (trichloromethyl) carbonic ester (solid phosgene; Triphosgene) route, but these two kinds of raw materials all are in course of reaction, to be decomposed into monochromatic light gas to participate in reaction, not from solving the phosgene severe toxicity in essence; There is serious potential safety hazard in intrinsic problem such as contaminated environment.
On December 3rd, 1984, the phosgene leakage accident takes place in the insecticide factory in the rich handkerchief city of India in U.S. Union Carbide Corp (UCC), causes heavy loss.45 tons of poison gases form one dense smog, have attacked the Bhopal urban district with the speed of 5000m per hour.Dead nearly 20,000 people, more than 20 ten thousand people that are injured, 50,000 people are blind, and the pregnant woman miscarries or gives birth to the dead baby, 40 square kilometres of injured areas, thousands of livestocks die like a rat.
After this between decades, people are making unremitting effort aspect the eco-friendly isocyanates non-phosgene synthesis technique of searching exploration, and isocyanates manufacturer in countries in the world all steps up the isocyanates technology of active development non-phosgene.The reducing carbonyl method that proposes of Mitsui East Asia chemical company wherein, the oxidative carbonylation method that company of Japanese Asahi Chemical Industry proposes, and U.S. Monsanto company propose by aniline and CO
2The process route of producing MDI is the most representative.
But up to now, the present process route of developing all exists process many, and appliance arrangement is complicated; Yield is low; Perhaps various shortcomings such as catalyst cost costliness cause the non-phosgene route of isocyanates, slowly can't realize big production of commercialization industry truly.
Summary of the invention
That technical problem to be solved by this invention is is low for the complex process, operating difficulties, the yield that overcome existing preparation Suo Lafeini intermediate, purity is low, catalyst is expensive and be not suitable for the defective of suitability for industrialized production, and a kind of catalyst and Suo Lafeini intermediates preparation are provided.Method conversion ratio of the present invention is high, safety does not have harm, pollution-free, reaction condition is gentle, yield is high, product purity is high and be applicable to suitability for industrialized production.
The invention provides a kind of catalyst, it contains sodium methoxide, methyl formate and methyl alcohol; The mass volume ratio of described sodium methoxide, methyl formate and methyl alcohol is 0.2g: 0.2g: 5mL～2g: 2g: 5mL.
The preferred 1g of the mass volume ratio of described sodium methoxide, methyl formate and methyl alcohol: 1g: 5mL.
The present invention also provides above-mentioned Preparation of catalysts method, and it comprises the steps: under inert gas, with sodium methoxide, methyl formate and methyl alcohol mixing, gets final product; The mass volume ratio of described sodium methoxide, methyl formate and methyl alcohol is 0.2g: 0.2g: 5mL～2g: 2g: 5mL.
Described inert gas is this area inert gas commonly used, nitrogen.
In the described step, also can comprise airtight preservation behind the mixing.
It is a kind of suc as formula the Suo Lafeini intermediates preparation shown in the I that the present invention also provides; It comprises the steps: under inert gas shielding, the counterflow condition; With the dimethyl carbonate is solvent; Under the effect of above-mentioned catalyst, dimethyl carbonate and 4-chloro-3-5-trifluoromethylaniline are reacted, get final product;
Wherein, the mass ratio of 4-chloro-3-5-trifluoromethylaniline and sodium methoxide is 20: 1～3: 1.
The consumption of described dimethyl carbonate can be selected according to the reactant of the conventional nucleophilic substitution in this area and total consumption of reaction dissolvent; The present invention is preferred especially as follows: the mol ratio of 4-chloro-3-5-trifluoromethylaniline and dimethyl carbonate is preferably 1: 4.70～and 1: 11.74, more preferably 1: 6.99.
Preferred 8: 1～3: 1 of the mass ratio of described 4-chloro-3-5-trifluoromethylaniline and sodium methoxide, more preferably 5: 1.
The temperature of described backflow is the reflux temperature of dimethyl carbonate, preferred 85 ℃～115 ℃, and more preferably 95 ℃～105 ℃, most preferably 100 ℃.
Described inert gas is this area inert gas commonly used, nitrogen.
The process of described reaction can be monitored with TLC and LC-MS, general when disappearing with reactant as the terminal point of reaction, preferred 4h～6h.
The post-processing approach of described reaction can be the conventional post-processing approach in this area, and preferred steps is following: be cooled to room temperature (20 ℃～30 ℃), add the shrend reaction of going out; Regulation system pH uses ethyl acetate extraction to neutral, merges organic layer; Dry filter boils off solvent and gets final product.The used reagent preferred volume mark of described regulation system pH is 5%～20% aqueous hydrochloric acid solution, more preferably 10% aqueous hydrochloric acid solution; The used drier of described drying is the conventional drier in this area, preferably carries out drying with anhydrous sodium sulfate.
On the basis of this area general knowledge, above-mentioned each optimum condition, but combination in any promptly get each preferred embodiments of the present invention.
Agents useful for same of the present invention and raw material are all commercially available to be got.
Positive progressive effect of the present invention is:
(1) the Preparation of catalysts method that the present invention adopted is simple, and raw material is easy to get;
(2) high, the safety of preparation method's reaction conversion ratio of the present invention do not have harm, pollution-free, reaction condition is gentle, product yield is high, purity is high and be applicable to suitability for industrialized production;
(3) the prepared 4-chloro-of the present invention 3-trifluoromethyl carbamate can further be used for synthetic anti-lung cancer liver-cancer medicine Suo Lafeini and other and contains the compound of this structure fragment.
The specific embodiment
Mode through embodiment further specifies the present invention below, but does not therefore limit the present invention among the described scope of embodiments.The experimental technique of unreceipted actual conditions in the following example according to conventional method and condition, or is selected according to catalogue.Described method of operating is operated by the conventional method of operating in this area without specifying all.
Those skilled in the art can technical scheme according to the present invention do various changes or modification, and these equivalent form of values fall within the application's appended claims institute restricted portion equally.
Embodiment 1
In the reaction there-necked flask, add 100 gram 4-chloro-3-5-trifluoromethylanilines, 300 milliliters of dimethyl carbonates, catalyst is (under the nitrogen protection; 20 gram sodium methoxides, 20 gram methyl formates and 100 ml methanol mixings are made), the reinforced back that finishes is with nitrogen replacement and under nitrogen protection, and 100 ℃ of refluxed are after 4 to 6 hours; Be cooled to room temperature (25 ℃), add shrend and go out, post processing use volume fraction is 10% aqueous hydrochloric acid solution; Conditioned reaction liquid system pH is to neutral, and reactant liquor is with the ethyl acetate extraction of capacity, and the upper strata is an organic layer; Organic layer is fully dry with anhydrous sodium sulfate, after dry, filters, and filtrating is revolved dried; The 4-chloro-3-trifluoromethyl carbamate (formula I compound) that obtains is light yellow viscous liquid 123.8 grams, yield 95.5%, product content 97.8%.Product content is recorded by HPLC, and its flowing phase is acetonitrile: water=4: 1.The structure appraising datum of formula I compound is reported with document.
The comparative example 1
In the reaction there-necked flask, add 100 gram 4-chloro-3-5-trifluoromethylanilines, 300 milliliters of dimethyl carbonates, catalyst is (under the nitrogen protection; 20 gram sodium methoxides are dissolved in methyl alcohol to be made), the reinforced back that finishes is with nitrogen replacement and under nitrogen protection, and 100 ℃ of refluxed are after 4 to 6 hours; Be cooled to room temperature (25 ℃), add shrend and go out, the use volume fraction is 10% aqueous hydrochloric acid solution; Conditioned reaction liquid system pH is to neutral, and with the ethyl acetate extraction of capacity, the upper strata is an organic layer; Organic layer is fully dry with anhydrous sodium sulfate, after dry, filters, and filtrating is revolved dried; Obtain 101.2 gram light yellow viscous liquid 4-chloro-3-trifluoromethyl carbamates (formula I compound), yield 78%, product content 91.2%.Product content is recorded by HPLC, and its flowing phase is acetonitrile: water=4: 1.
The comparative example 2
In the reaction there-necked flask, add 100 gram 4-chloro-3-5-trifluoromethylanilines, 300 milliliters of dimethyl carbonates, catalyst (15 gram zinc acetate), the reinforced back that finishes is with nitrogen replacement and under nitrogen protection; 100 ℃ of refluxed were cooled to room temperature (25 ℃) after 4 to 6 hours, added shrend and went out, and the use volume fraction is 10% aqueous hydrochloric acid solution; Conditioned reaction liquid system pH is to neutral, and with the ethyl acetate extraction of capacity, the upper strata is an organic layer; Organic layer is fully dry with anhydrous sodium sulfate, after dry, filters, and filtrating is revolved dried; Obtain 108 gram light yellow viscous liquid 4-chloro-3-trifluoromethyl carbamates (formula I compound), yield 83.2%, product content 93.0%.Product content is recorded by HPLC, and its flowing phase is acetonitrile: water=4: 1.
The comparative example 3
In the reaction there-necked flask, add 100 gram 4-chloro-3-5-trifluoromethylanilines, 300 milliliters of dimethyl carbonates, catalyst (12 gram PbO); The reinforced back that finishes is with nitrogen replacement and under nitrogen protection, and 100 ℃ of refluxed were cooled to room temperature (25 ℃) after 4 to 6 hours; Add shrend and go out, reactant liquor filters earlier, and filtrating post processing use volume fraction is 10% aqueous hydrochloric acid solution; Conditioned reaction liquid system pH is to neutral, and with the ethyl acetate extraction of capacity, the upper strata is an organic layer; Organic layer is fully dry with anhydrous sodium sulfate, after dry, filters, and filtrating is revolved dried; Obtain 112.5 gram light yellow viscous liquid 4-chloro-3-trifluoromethyl carbamates (formula I compound), yield 86.7%, product content 94.5%.Product content is recorded by HPLC, and its flowing phase is acetonitrile: water=4: 1.
The comparative example 4
In the reaction there-necked flask, add 100 gram 4-chloro-3-5-trifluoromethylanilines, 300 milliliters of dimethyl carbonates, (the inert free gas protection is down for catalyst; 20 gram sodium methoxides, 20 gram methyl formates and 100 ml methanol mixings are made), the reinforced back that finishes is with nitrogen replacement and under nitrogen protection, and 100 ℃ of refluxed are after 4 to 6 hours; Be cooled to room temperature (25 ℃), add shrend and go out, post processing use volume fraction is 10% aqueous hydrochloric acid solution; Conditioned reaction liquid system pH is to neutral, and reactant liquor is with the ethyl acetate extraction of capacity, and the upper strata is an organic layer; Organic layer is fully dry with anhydrous sodium sulfate, after dry, filters, and filtrating is revolved dried; The 4-chloro-3-trifluoromethyl carbamate (formula I compound) that obtains is a light yellow viscous liquid, yield 47.8%, product content 91.0%.Product content is recorded by HPLC, and its flowing phase is acetonitrile: water=4: 1.
Application implementation example 1
Reaction unit: 500mL clean dried reaction there-necked flask; Join anhydrous calcium chloride drying tube, stirring, reflux condenser, thermometer, 200mL addition funnel; Condensator outlet is joined alkali and is absorbed a large amount of hydrochloric acid gases that generate, and whether condensator outlet can join the bubbling device observing response and proceed.
Course of reaction: in there-necked flask, adding 125 gram toluene and two (trichloromethyl) carbonic esters of 40 grams (being called for short BTC) stirring are dissolved entirely, and anti-BTC hurts sb.'s feelings when reinforced.
Below 20 ℃; Drip pretreated toluene solution to chlorine m-trifluoromethyl aniline (abbreviation CPA); (preparation method of the toluene solution of CPA is: restrain toluene dissolving 40 grams to chlorine m-trifluoromethyl aniline with 125) white pulpous state hydrochloride solid of very fast generation, unfavorable stirring (can mend toluene and make stirring flexibly).With the reaction system reflux.When white slurry transparent (not bubbling) is terminal point (about 3 hours to 7 hours).
After if reaction finishes, the tangible urea of generation then needs carrying out decantation (or filtration) more than 35 ℃, to remove bottom grey powder (urea that promptly generates).If urea seldom, this step also can be omitted.Otherwise desolventizing after urea will make it too much and distillation operation difficulty.
Post-processing approach: normal pressure or (decompression of cooling back) distill solvent toluene.The toluene that distills out can be applied mechanically.To carry out rectifying except that the gram of 62 after desolvating bullion, temperature in the kettle is lower than 45 ℃ before the rectifying, anti-toluene bumping.Rectifier unit is that the distillation tower head (filler is the glass spring filler) that 30 centimetres of high filled columns are joined the scalable reflux ratio notices that alkali absorbs and alkali protection pump.Use the mechanical pump rectification under vacuum, 45 ℃ of condenser cooling water temperature (anti-4-chloro-3-trifluoromethylbenzene cured with isocyanates, 4-chloro-3-trifluoromethylbenzene isocyanates is called for short CPI) as far as possible.The boiling point of product is 200 degree, and the general stable temperature of accepting positive cut is 118 degree under this mechanical pump rectification under vacuum condition.Obtaining positive cut 31 grams (theoretical yield is 56.6 grams) yield after the rectifying is 54.7%, and content is 97.9%.Positive cut is difficult for solidifying, and available refrigerator is freezing.Suggestion is frozen into solid earlier, and the finished product outward appearance is good like this.Gas leakage is arranged else if slightly, and the urea that just generates solid influences the finished product outward appearance.
Product G C condition: open 60 ℃ of beginning temperature, temperature programming, final temperature is 180 ℃.No constant temperature process.Sample size 0.2 μ mL.
Claims (10)
1. a catalyst is characterized in that: contain sodium methoxide, methyl formate and methyl alcohol; The mass volume ratio of described sodium methoxide, methyl formate and methyl alcohol is 0.2g: 0.2g: 5mL～2g: 2g: 5mL.
2. catalyst as claimed in claim 1 is characterized in that: the mass volume ratio of described sodium methoxide, methyl formate and methyl alcohol is 1g: 1g: 5mL.
3. a Preparation of catalysts method according to claim 1 or claim 2 is characterized in that comprising the steps: under inert gas, with sodium methoxide, methyl formate and methyl alcohol mixing, gets final product; The mass volume ratio of described sodium methoxide, methyl formate and methyl alcohol is 0.2g: 0.2g: 5mL～2g: 2g: 5mL.
4. preparation method as claimed in claim 3 is characterized in that: described inert gas is a nitrogen.
5. preparation method as claimed in claim 3 is characterized in that: in the described step, also comprise airtight preservation behind the mixing.
6. one kind suc as formula the Suo Lafeini intermediates preparation shown in the I; It is characterized in that comprising the steps: under inert gas shielding, the counterflow condition; With the dimethyl carbonate is solvent; Under the effect of according to claim 1 or claim 2 catalyst, dimethyl carbonate and 4-chloro-3-5-trifluoromethylaniline are reacted, get final product;
Wherein, the mass ratio of described 4-chloro-3-5-trifluoromethylaniline and sodium methoxide is 20: 1～3: 1.
7. preparation method as claimed in claim 6 is characterized in that: the mol ratio of described 4-chloro-3-5-trifluoromethylaniline and dimethyl carbonate is 1: 4.70～1: 11.74.
8. preparation method as claimed in claim 6 is characterized in that: the mass ratio of described 4-chloro-3-5-trifluoromethylaniline and sodium methoxide is 8: 1～3: 1.
9. preparation method as claimed in claim 6 is characterized in that: the temperature of described backflow is 85 ℃～115 ℃.
10. preparation method as claimed in claim 6 is characterized in that: described inert gas is a nitrogen.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011103939018A CN102553642B (en) | 2011-12-01 | 2011-12-01 | Catalyst and preparation method for sorafenib intermediate |
Applications Claiming Priority (1)
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103408488A (en) * | 2013-08-13 | 2013-11-27 | 张家港威胜生物医药有限公司 | Optimal synthetic method of sorafenib |
| CN104418773A (en) * | 2013-09-02 | 2015-03-18 | 上海龙翔生物医药开发有限公司 | Synthetic method of 2,4,5-trifluoro-benzene isocyanate and intermediate thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4395565A (en) * | 1981-01-28 | 1983-07-26 | Anic S.P.A. | Preparing aromatic urethans |
| US5166414A (en) * | 1989-12-28 | 1992-11-24 | Mitsubishi Gas Chemical Company, Inc. | Process for producing isocyanate compound |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4395565A (en) * | 1981-01-28 | 1983-07-26 | Anic S.P.A. | Preparing aromatic urethans |
| US5166414A (en) * | 1989-12-28 | 1992-11-24 | Mitsubishi Gas Chemical Company, Inc. | Process for producing isocyanate compound |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103408488A (en) * | 2013-08-13 | 2013-11-27 | 张家港威胜生物医药有限公司 | Optimal synthetic method of sorafenib |
| CN104418773A (en) * | 2013-09-02 | 2015-03-18 | 上海龙翔生物医药开发有限公司 | Synthetic method of 2,4,5-trifluoro-benzene isocyanate and intermediate thereof |
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