CN104402813A - Novel method for synthesizing sorafenib - Google Patents

Novel method for synthesizing sorafenib Download PDF

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Publication number
CN104402813A
CN104402813A CN201410777342.4A CN201410777342A CN104402813A CN 104402813 A CN104402813 A CN 104402813A CN 201410777342 A CN201410777342 A CN 201410777342A CN 104402813 A CN104402813 A CN 104402813A
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Prior art keywords
xarelto
crude product
preparation
solvent
compound
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CN104402813B (en
Inventor
赵玉新
王喜军
牟春福
王硕冰
石成
刘金红
张婷婷
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Harbin Pharmaceutical Group Holding Co ltd
Medshine Discovery Inc
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PHARMACEUTICAL GENERAL FACTORY HAYAO GROUP
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention discloses a novel method for synthesizing sorafenib. The method comprises the following steps: using a (4-(4-aminophenoxy)-N-methylpyridine-2-carboxamide) compound II and a (4-chloro-3-trifluoromethylphenyl-carbamoyl-imidazole) compound III as raw materials, and reacting in an organic solvent inert to the compound III to produce a sorafenib crude product; then, dissolving the sorafenib crude product by the organic solvent and an organic or inorganic acid, and adding a solvent into which sorafenib is difficult to dissolve to enable the sorafenib to be separated out, so as to obtain a sorafenib pure product. The novel method is simple in technical process, ensures high product purity, facilitates operation and is suitable for large-scale industrial production.

Description

A kind of preparation method of Xarelto
Technical field
The present invention relates to medical compounds preparing technical field, particularly Xarelto preparing technical field, more specifically, relate to a kind of synthetic method and process for purification of Xarelto.
Background technology
Compound 4-{4-[({ [the chloro-3-of 4-(trifluoromethyl) phenyl] is amino } carbonyl) is amino] phenoxy group }-N-picoline-2-methane amide, also claim Xarelto, molecular formula is C 21h 16clF 3n 4o 3, molecular weight is 464.83, and structural formula is formula I.
Xarelto is a kind of multi-kinase inhibitor, is used for the treatment of the gastrointestinal stromal tumors and metastatic renal cell cancer that not to respond standard treatment or can not tolerate.Xarelto has dual anti-tumour effect: on the one hand, and it can by suppressing RAF/MEK/ERK signal transduction pathway, direct Tumor suppression growth; On the other hand, it blocks tumor neovasculature formation, the growth of indirect inhibition tumor cell by suppressing VEGFR and PDGFR again.
Chinese patent CN101082619 describes a kind of preparation method of Xarelto.
Its reaction needed is carried out under the condition of 90 DEG C of high temperature, and the reaction times reaches 5 hours, and the reaction that 4-used chloro-3-trifluoromethylbenzene based isocyanate carries out too acutely is difficult to control.
Chinese patent CN101671299A discloses a kind of preparation method of Xarelto, and its reaction raw materials employs deadly poisonous compound phenyl chloroformate, and industrial production danger is huge, and unfriendly to environment.
Chinese patent CN102219733A discloses a kind of method preparing Xarelto, and its reaction is for prepare Xarelto with triphosgene one kettle way.As everyone knows, triphosgene character is very active and have severe toxicity, is difficult to control triphosgene and has an effect with reaction solvent and generate various impurity, and be difficult to guarantee industrial production safety.
Chinese patent CN102875460A discloses a kind of method preparing Xarelto, and its method uses 4-chloro-3-trifluoromethylbenzene based isocyanate to be raw material equally.
Although prior art can synthesize Xarelto, ubiquity adopts pyroreaction, uses hypertoxic raw material, reacts the shortcoming such as uncontrollable.There is the feature such as excessive risk, high-risk in well-known suitability for industrialized production, mild condition, react controlled, raw material low toxicity can make industrial danger and production cost greatly reduce undoubtedly.
Summary of the invention
In order to solve the defect existed in prior art, the invention provides a kind of new Xarelto production technique, raw materials used toxicity is low, and reaction conditions is gentle, and simple to operate, product purity can reach more than 99.9%.
The present invention relates to a kind of preparation method of Xarelto, be achieved through the following technical solutions:
A preparation method for Xarelto, comprises following processing step:
(1) Xarelto crude product is prepared
With compound ii (4-(4-amino-benzene oxygen)-N-picoline-2-methane amide) and compound III (4-chloro-3-trifluoromethyl carbamyl imidazoles) for raw material, in the organic solvent to compound III being inertia, reaction generates Xarelto crude product;
(2) Xarelto crude product refining
With organic solvent and organic or inorganic acid solution Xarelto crude product, then add insoluble solvent Xarelto is separated out, obtain Xarelto sterling.
Prepare that the organic solvent that Xarelto crude product uses is ethyl acetate, the binary mixture of the unitary solvent such as methylene dichloride, acetonitrile or above-mentioned solvent; Required temperature of reaction is 25 DEG C-65 DEG C; The required reaction times is 1-3h.
The starting compound III (4-chloro-3-trifluoromethyl carbamyl imidazoles) preparing Xarelto crude product is synthesized by compounds Ⅳ (the chloro-3-5-trifluoromethylaniline of 4-) and compound V (N, N'-carbonyl dimidazoles) and obtains.
The binary mixture of the unitary solvents such as the organic solvent that Xarelto crude product refining uses is ethanol, ethyl acetate, acetonitrile, Virahol or above-mentioned solvent and water; The acid used is concentrated hydrochloric acid, acetic acid, 50% sulfuric acid, methylsulfonic acid, lactic acid etc.; Refining desired reaction temperature is 60 DEG C-90 DEG C.
Synthetic route of the present invention is:
Various compound chemistry title is as follows:
Chemical compounds I: 4-{4-[({ [the chloro-3-of 4-(trifluoromethyl) phenyl] is amino } carbonyl) is amino] phenoxy group }-N-picoline-2-methane amide
Compound ii: 4-(4-amino-benzene oxygen)-N-picoline-2-methane amide
Compound III: 4-chloro-3-trifluoromethyl carbamyl imidazoles
The chloro-3-5-trifluoromethylaniline of compounds Ⅳ: 4-
Compound V: N, N'-carbonyl dimidazoles
Compared with prior art, the present invention has the following advantages:
Existing technique is multiplex to deadly poisonous compound phenyl chloroformate or deadly poisonous compound triphosgene or 4-chloro-3-trifluoromethylbenzene based isocyanate; grave danger is brought to industrial production; the present invention's low toxicity compounds 4-chloro-3-trifluoromethyl carbamyl imidazoles instead of above-mentioned deadly poisonous compound, comparatively safe.In addition, the present invention does not use the complex operations such as rotary evaporation, extraction, backflow, and technological process is relatively simple.Reaction conditions is without the need to nitrogen protection, without high-temperature high-voltage reaction, and product purity can reach more than 99.9%.
Embodiment
Further describe the present invention by following examples, but scope of the present invention should be noted not by any restriction of these embodiments.
Embodiment 1 prepares compound III (4-chloro-3-trifluoromethyl carbamyl imidazoles)
2.0kg compounds Ⅳ (the chloro-3-5-trifluoromethylaniline of 4-) is dissolved in 17.0L 1,2-ethylene dichloride, stirs, add 2.3kg compound V (N, N'-carbonyl dimidazoles), be warming up to 50 DEG C, reaction 10h, then proceeds to room temperature reaction 1h.Filter, wash 2 times with 1,2-ethylene dichloride, be filtered dry, 40 DEG C of vacuum-dryings, obtain 1.6kg compound III (4-chloro-3-trifluoromethyl carbamyl imidazoles), purity 99.2%, yield 85%.
Embodiment 2 prepares Xarelto crude product
Ethyl acetate 200L, compound III 18.7kg is added in retort, stirring is warming up to 25 DEG C, then adds compound ii 9.8kg, keeps 25 DEG C of stirring reaction 3h, 20 DEG C of growing the grain 2h are cooled to after reaction terminates, filter, wash twice by ethyl acetate, be filtered dry, 40 DEG C of vacuum-dryings, obtain Xarelto crude product 17.2kg, purity 99.18%, yield 91.1%.
Embodiment 3 prepares Xarelto crude product
Methylene dichloride 200L, compound III 18.7kg is added in retort, stirring is warming up to 35 DEG C, then adds compound ii 9.8kg, keeps 35 DEG C of stirring reaction 2h, 20 DEG C of growing the grain 2h are cooled to after reaction terminates, filter, by washed with dichloromethane twice, be filtered dry, 40 DEG C of vacuum-dryings, obtain Xarelto crude product 16.9kg, purity 99.20%, yield 90.22%.
Embodiment 4 prepares Xarelto crude product
Acetonitrile 200L, compound III 18.7kg is added in retort, stirring is warming up to 45 DEG C, then adds compound ii 9.8kg, keeps 45 DEG C of stirring reaction 1.5h, 10 DEG C of growing the grain 2h are cooled to after reaction terminates, filter, with acetonitrile wash twice, be filtered dry, 40 DEG C of vacuum-dryings, obtain Xarelto crude product 17.9kg, purity 99.37%, yield 95.5%.
Embodiment 5 prepares Xarelto crude product
Ethyl acetate 100L, acetonitrile 100L, compound III 18.7kg is added in retort, stirring is warming up to 65 DEG C, then adds compound ii 9.8kg, keeps 65 DEG C of stirring reaction 1h, 15 DEG C of growing the grain 2h are cooled to after reaction terminates, filter, wash twice by ethyl acetate, be filtered dry, 40 DEG C of vacuum-dryings, obtain Xarelto crude product 17.4kg, purity 99.20%, yield 92.9%.
Embodiment 6 prepares Xarelto crude product
Methylene dichloride 100L, ethyl acetate 100L, compound III 18.7kg is added in retort, stirring is warming up to 50 DEG C, then adds compound ii 9.8kg, keeps 50 DEG C of stirring reaction 2h, 15 DEG C of growing the grain 2h are cooled to after reaction terminates, filter, wash twice by ethyl acetate, be filtered dry, 40 DEG C of vacuum-dryings, obtain Xarelto crude product 17.7kg, purity 99.12%, yield 94.5%.
Embodiment 7 prepares Xarelto crude product
Methylene dichloride 100L, acetonitrile 100L, compound III 18.7kg is added in retort, stirring is warming up to 50 DEG C, then adds compound ii 9.8kg, keeps 50 DEG C of stirring reaction 2h, 15 DEG C of growing the grain 2h are cooled to after reaction terminates, filter, wash twice by ethyl acetate, be filtered dry, 40 DEG C of vacuum-dryings, obtain Xarelto crude product 16.9kg, purity 99.05%, yield 90.22%.
Embodiment 8 Xarelto crude product refining
Medicinal alcohol 137.0L is added in retort, purified water 50.0L, Xarelto crude product 17.2kg (purity 98.50%), stirring is warming up to 60 DEG C, add concentrated hydrochloric acid 5.2kg, stirring makes solid all dissolve, add gac 0.2kg decolouring 30min, filter, carbon-coating is rinsed with the mixed solution of 60 DEG C of ethanol 34.0L and purified water 10.0L, filter, merging filtrate is in another crystallizer, be warming up to 60 DEG C to start to drip purified water 342.0L, drip to finish and be cooled to 10 DEG C of growing the grain 1h, filter, wash twice by purified water, be filtered dry, 40 DEG C of vacuum-dryings obtain Xarelto sterling 16.0kg, purity 99.97%, yield 93.0%.
Embodiment 9 Xarelto crude product refining
Medicinal alcohol 137.0L is added in retort, purified water 50.0L, Xarelto crude product 17.2kg (purity 98.78%), stirring is warming up to 90 DEG C, add concentrated hydrochloric acid 5.2kg, stirring makes solid all dissolve, add gac 0.2kg decolouring 30min, filter, carbon-coating is rinsed with the mixed solution of 90 DEG C of ethanol 34.0L and purified water 10.0L, filter, merging filtrate is in another crystallizer, be warming up to 90 DEG C to start to drip purified water 342.0L, drip to finish and be cooled to 10 DEG C of growing the grain 1h, filter, wash twice by purified water, be filtered dry, 40 DEG C of vacuum-dryings obtain Xarelto sterling 16.5kg, purity 99.96%, yield 95.9%.
Embodiment 10 Xarelto crude product refining
Medicinal alcohol 137.0L is added in retort, purified water 50.0L, Xarelto crude product 17.2kg (purity 98.35%), stirring is warming up to 60 DEG C, add acetic acid 5.2kg, stirring makes solid all dissolve, add gac 0.2kg decolouring 30min, filter, carbon-coating is rinsed with the mixed solution of 60 DEG C of ethanol 34.0L and purified water 10.0L, filter, merging filtrate is in another crystallizer, be warming up to 60 DEG C to start to drip purified water 342.0L, drip to finish and be cooled to 10 DEG C of growing the grain 1h, filter, wash twice by purified water, be filtered dry, 40 DEG C of vacuum-dryings, obtain Xarelto sterling 16.2kg, purity 99.96%, yield 94.2%.
Embodiment 11 Xarelto crude product refining
Medicinal alcohol 137.0L is added in retort, purified water 50.0L, Xarelto crude product 17.2kg (purity 98.67%), stirring is warming up to 60 DEG C, add 50% sulfuric acid 5.2kg, stirring makes solid all dissolve, add gac 0.2kg decolouring 30min, filter, carbon-coating is rinsed with the mixed solution of 60 DEG C of ethanol 34.0L and purified water 10.0L, filter, merging filtrate is in another crystallizer, be warming up to 60 DEG C to start to drip purified water 342.0L, drip to finish and be cooled to 10 DEG C of growing the grain 1h, filter, wash twice by purified water, be filtered dry, 40 DEG C of vacuum-dryings, obtain Xarelto sterling 15.5kg, purity 99.97%, yield 90.1%.
Embodiment 12 Xarelto crude product refining
Medicinal alcohol 137.0L is added in retort, purified water 50.0L, Xarelto crude product 17.2kg (purity 98.34%), stirring is warming up to 60 DEG C, add methylsulfonic acid 5.2kg, stirring makes solid all dissolve, add gac 0.2kg decolouring 30min, filter, carbon-coating is rinsed with the mixed solution of 60 DEG C of ethanol 34.0L and purified water 10.0L, filter, merging filtrate is in another crystallizer, be warming up to 60 DEG C to start to drip purified water 342.0L, drip to finish and be cooled to 10 DEG C of growing the grain 1h, filter, wash twice by purified water, be filtered dry, 40 DEG C of vacuum-dryings, obtain white solid 15.9kg, purity 99.98%, yield 92.4%.
Embodiment 13 Xarelto crude product refining
Medicinal Virahol 137.0L is added in retort, purified water 47.0L, Xarelto crude product 17.2kg (purity 98.52%), stirring is warming up to 70 DEG C, add concentrated hydrochloric acid 5.2kg, stirring makes solid all dissolve, add gac 0.2kg decolouring 30min, filter, carbon-coating is rinsed with the mixed solution of 60 DEG C of Virahol 34.0L and purified water 9.0L, filter, merging filtrate is in another crystallizer, be warming up to 60 DEG C to start to drip purified water 342.0L, drip to finish and be cooled to 10 DEG C of growing the grain 1h, filter, wash twice by purified water, be filtered dry, 40 DEG C of vacuum-dryings obtain Xarelto sterling 15.8kg, purity 99.95%, yield 91.8%.
The actual conditions that the product related in above embodiment detects is:
Get product prepared by the present invention and be about 22.0mg, accurately weighed, put in 100.0ml measuring bottle, add thinner appropriate, ultrasonicly make dissolving and be diluted to scale, shake up, as need testing solution; It is appropriate that precision measures need testing solution, quantitatively dilutes the solution made containing 2.2 μ g in every 1.0ml, solution in contrast with thinner.According to high performance liquid chromatography (Chinese Pharmacopoeia 2010 editions two annex VD) test, with octadecylsilane chemically bonded silica as weighting agent (Water Symmetry C18,3.5 μm, 4.6 × 150mm); (0.79g anhydrous potassium dihydrogenphosphate is got with pH 2.4 phosphate buffered saline buffer, add water and make dissolving and be diluted to 1000.0ml, with phosphoric acid adjust ph to 2.4) be mobile phase A, acetonitrile-ethanol (60:40) is Mobile phase B, flow velocity is 1.0ml/min, determined wavelength is 235nm, column temperature 40 DEG C.
Although illustrate and describe exemplary embodiments more of the present invention, but those skilled in the art should know, without departing from the principles and spirit of the present invention, can make change to these exemplary embodiments, scope of the present invention is limited by claim and equivalent thereof.

Claims (9)

1. a preparation method for Xarelto, said method comprising the steps of:
(1) Xarelto crude product is prepared
With compound ii 4-(4-amino-benzene oxygen)-N-picoline-2-methane amide and compound III 4-chloro-3-trifluoromethyl carbamyl imidazoles for raw material, in the organic solvent to compound III being inertia, reaction generates Xarelto crude product;
(2) Xarelto crude product refining
With organic solvent and organic or inorganic acid solution Xarelto crude product, then add insoluble solvent Xarelto is separated out, obtain Xarelto sterling.
2. the preparation method of Xarelto according to claim 1, is characterized in that: prepare that the organic solvent that Xarelto crude product uses is ethyl acetate, the binary mixture of the unitary solvent such as methylene dichloride, acetonitrile or above-mentioned solvent.
3. the preparation method of Xarelto according to claim 1, is characterized in that: the temperature of reaction prepared needed for Xarelto crude product is 25 DEG C-65 DEG C.
4. the preparation method of Xarelto according to claim 1, is characterized in that: the reaction times of preparing needed for Xarelto crude product is 1-3 h.
5. the preparation method of Xarelto according to claim 1; it is characterized in that: prepare the starting compound III 4-chloro-3-trifluoromethyl carbamyl imidazoles of Xarelto crude product by the chloro-3-5-trifluoromethylaniline of compounds Ⅳ 4-and compound V N, the synthesis of N'-carbonyl dimidazoles obtains.
6. the preparation method of Xarelto according to claim 5, is characterized in that: preparation compound III solvent for use is 1,2-ethylene dichloride, methylene dichloride, ethyl acetate, acetonitrile etc.
7. the preparation method of Xarelto according to claim 1, is characterized in that: the binary mixture of the unitary solvents such as the organic solvent that Xarelto crude product refining uses is ethanol, ethyl acetate, acetonitrile, Virahol or above-mentioned solvent and water.
8. the preparation method of Xarelto according to claim 1, is characterized in that: the acid that Xarelto crude product refining uses is concentrated hydrochloric acid, acetic acid, 50% sulfuric acid, methylsulfonic acid, lactic acid etc.
9. the preparation method of Xarelto according to claim 1, is characterized in that: Xarelto crude product refining desired reaction temperature is 60 DEG C-90 DEG C.
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Cited By (2)

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CN108794392A (en) * 2018-05-14 2018-11-13 中国药科大学 A kind of method of solid-state ball milling synthesis Sorafenib

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Publication number Priority date Publication date Assignee Title
CN105330600A (en) * 2015-11-30 2016-02-17 山东罗欣药业集团股份有限公司 Preparation method for Regorafenib hydrate
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CN108794392B (en) * 2018-05-14 2021-08-10 中国药科大学 Method for synthesizing sorafenib by solid-state ball milling

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Patentee after: HARBIN PHARMACEUTICAL GROUP HOLDING Co.,Ltd.

Patentee after: MEDSHINE DISCOVERY Inc.

Address before: No.109 Xuefu Road, Nangang District, Harbin, Heilongjiang 150046, No.1 Junmin Street, Xiangfang District

Patentee before: MEDSHINE DISCOVERY Inc.