CN102875460A - Method for preparing sorafenib - Google Patents
Method for preparing sorafenib Download PDFInfo
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- CN102875460A CN102875460A CN2012101540224A CN201210154022A CN102875460A CN 102875460 A CN102875460 A CN 102875460A CN 2012101540224 A CN2012101540224 A CN 2012101540224A CN 201210154022 A CN201210154022 A CN 201210154022A CN 102875460 A CN102875460 A CN 102875460A
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- AKQIYQPFDSTHSS-UHFFFAOYSA-N C[N]C(c1cc(Oc(cc2)ccc2N)ccn1)=O Chemical compound C[N]C(c1cc(Oc(cc2)ccc2N)ccn1)=O AKQIYQPFDSTHSS-UHFFFAOYSA-N 0.000 description 2
- AGAGNAWDXWTDKK-UHFFFAOYSA-N C[N]C(c1nccc(Cl)c1)=O Chemical compound C[N]C(c1nccc(Cl)c1)=O AGAGNAWDXWTDKK-UHFFFAOYSA-N 0.000 description 2
- PLIKAWJENQZMHA-UHFFFAOYSA-N Nc(cc1)ccc1O Chemical compound Nc(cc1)ccc1O PLIKAWJENQZMHA-UHFFFAOYSA-N 0.000 description 2
- MLDQJTXFUGDVEO-UHFFFAOYSA-N CNC(c1nccc(Oc(cc2)ccc2NC(Nc(cc2)cc(C(F)(F)F)c2Cl)=O)c1)=O Chemical compound CNC(c1nccc(Oc(cc2)ccc2NC(Nc(cc2)cc(C(F)(F)F)c2Cl)=O)c1)=O MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 1
- FYBNFLRGZHGUDY-UHFFFAOYSA-N O=C(c1nccc(Cl)c1)Cl Chemical compound O=C(c1nccc(Cl)c1)Cl FYBNFLRGZHGUDY-UHFFFAOYSA-N 0.000 description 1
- NBJZEUQTGLSUOB-UHFFFAOYSA-N O=C=Nc(cc1)cc(C(F)(F)F)c1Cl Chemical compound O=C=Nc(cc1)cc(C(F)(F)F)c1Cl NBJZEUQTGLSUOB-UHFFFAOYSA-N 0.000 description 1
- SIOXPEMLGUPBBT-UHFFFAOYSA-N OC(c1ncccc1)=O Chemical compound OC(c1ncccc1)=O SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses a method for preparing sorafenib. 2-picolinic acid is subjected to chlorination, esterification and methylamination to form a key intermediate, namely 4-chloropyridine-N-methyl-2-formamide, the intermediate and p-aminophenol are subjected to coupled reaction under alkaline condition, and a reaction product is reacted with 4-chloro-3-trifluoromethyl phenyl isocyanate to form a target compound.
Description
Technical field
The present invention relates to a kind of 4-{4-[({[4-of preparation chloro-3-(trifluoromethyl) phenyl] amino } carbonyl) amino] phenoxy group }-method of N-picoline-2-methane amide (I).
Background technology
4-{4-[({[4-chloro-3-(trifluoromethyl) phenyl] amino } carbonyl) amino] phenoxy group }-N-picoline-2-methane amide (I) is reported among the patent WO 2000042012 the earliest, and drugmaker develops at first by Bayer Bitterfeld GmbH.Compound (I) is called as the kinase whose inhibitor of enzyme Raf, can be used for treating the diseases such as cancer.
Many documents and patent report there be synthesizing of compound (I).Such as CN 1721397A, US 2002165394, US2003105091, US 2003144278, US 2009068146, Organic Process Research and Development.2002,777 etc., these literature methods can represent with following scheme:
These preparation methods form intermediate 4-chloropyridine-2-formyl chloride hydrochloride (III) all take pyridine-2-formic acid (II) as initial feed after acidylate.Compound (III) changes into 4-chloro-N-picoline-2-methane amide (V) and has three kinds of methods: method one is first compound (III) to be changed into 4-chloropyridine-2-methyl-formiate hydrochloride (IV), then compound (IV) is purified out, in organic solvent, organic solution reaction with itself and methylamine generates compound (V); Method two is directly compound (III) to be made into toluene solution, with the aqueous methylamine solution reaction, generates compound (V); Method three is after compound (III) is purified, it to be reacted with the organic solution of methylamine in organic solvent, generates compound (V).The compound that obtains (V) reacts with p-aminophenol under the effect of alkali, generates 4-(4-amino-benzene oxygen)-N-picoline-2-methane amide (VI).At last the compound (VI) that obtains is generated 4-{4-[({[4-chloro-3-(trifluoromethyl) phenyl with isocyanic acid-4-chloro-3-(trifluoromethyl) phenyl ester reaction] amino } carbonyl) amino] phenoxy group }-N-picoline-2-methane amide (I).
Although can for the preparation of compound (I), there be a lot of deficiencies in prior art: operate loaded down with trivial details, yield is not high, purity is not good etc.According to prior art, in preparation compound (V), method one uses the organic solution reaction of methylamine outside obtaining compound (V), the chlorine atom of methylamine in simultaneously can attack compound (IV), thereby generate obvious impurity, in addition not only cost increase but also also unfriendly to environment of the use of a large amount of organic solvents; And method two, although used cheaply aqueous methylamine solution, hydrolysis reaction easily occurs in compound (III) in the aqueous solution, thereby causes by-product acids to occur; Method three is difficult to purify by recrystallization because the solvability of compound (III) in organic solvent is fine.According to prior art, the transformation efficiency of compound (V) preparation compound (VI) is not high, and large content of starting materials remains, and has affected yield and the purity of preparation intermediate (VI).In addition, it is on the high side to produce impurity when preparing compound (I) under the described temperature of prior art.
Summary of the invention
The present invention has overcome the defective of above-mentioned prior art, and a kind of 4-{4-[({[4-of preparation chloro-3-(trifluoromethyl) phenyl is provided] amino } carbonyl) amino] phenoxy group }-method of N-picoline-2-methane amide (I).Present method has cost advantage low, easy and simple to handle, and whole process need not any intermediate is purified, and finally obtains highly purified compound (I) with high yield.
The preparation method of compound of the present invention (I) specifically comprises the steps:
(1) pyridine-2-formic acid (II) generates 4-chloro-pyridine-2-formyl acyl chloride hydrochloride (III) with the sulfur oxychloride reaction in the presence of DMF;
(2) compound (III) generates 4-chloropyridine-2-manthanoate hydrochloride (IV) with corresponding alcohol reaction in organic solution;
(3) the water-soluble rear adding organic solvent washing of compound (IV) is removed organic layer and is divided water-yielding stratum to obtain the aqueous solution of compound (IV);
(4) reaction of the aqueous solution of compound (IV) and aqueous methylamine solution generates 4-chloro-N-picoline-2-methane amide (V);
(5) under the acting in conjunction of potassium tert.-butoxide and another part highly basic, compound (V) generates 4-(4-amino-benzene oxygen)-N-picoline-2-methane amide (VI) with the p-aminophenol reaction;
(6) compound (VI) generates 4-{4-[({[4-chloro-3-(trifluoromethyl) phenyl with isocyanic acid-4-chloro-3-(trifluoromethyl) phenyl ester reaction being lower than under 0 ℃ the temperature] amino } carbonyl) amino] phenoxy group }-N-picoline-2-methane amide (I).
Involved in the present invention to reaction can represent with following reaction formula:
R represents C in the formula
1-C
4Straight chain or alkyl or the benzyl of side chain.
Reaction from pyridine-2-formic acid (II) preparation 4-chloropyridine-2-formyl acyl chloride hydrochloride (III) of the present invention is carried out under thionyl chloride and DMF acting in conjunction.
The operating process of above-mentioned reaction from pyridine-2-formic acid (II) preparation 4-chloropyridine-2-formyl acyl chloride hydrochloride (III) is roughly as follows: add thionyl chloride and N reaction flask, dinethylformamide, add pyridine-2-formic acid (II), under suitable temperature, reacted 1～36 hour subsequently, removal of solvent under reduced pressure namely gets compound 4-chloro-pyridine-2-formyl acyl chloride hydrochloride (III), need not to process directly to carry out next step reaction.
Reaction from 4-chloropyridine-2-formyl acyl chloride hydrochloride (III) preparation 4-chloropyridine-2-manthanoate hydrochloride (IV) of the present invention is that compound (III) carries out in the presence of corresponding alcohol, and selected alcohol is C
1-C
1Straight chain or alcohol or the benzylalcohol of side chain, wherein be preferably methyl alcohol.
The used organic solvent of reaction from 4-chloropyridine-2-formyl acyl chloride hydrochloride (III) preparation 4-chloropyridine-2-manthanoate hydrochloride (IV) of the present invention is selected from toluene, tetrahydrofuran (THF), acetonitrile, acetone, N, dinethylformamide, methylene dichloride, wherein toluene preferably.
Direct filtration obtained compound (IV) after reaction from 4-chloropyridine-2-formyl acyl chloride hydrochloride (III) preparation 4-chloropyridine-2-manthanoate hydrochloride (IV) of the present invention finished.
The operating process of above-mentioned reaction from 4-chloropyridine-2-formyl acyl chloride hydrochloride (III) preparation 4-chloropyridine-2-methyl-formiate hydrochloride (IV) is roughly as follows: add 4-chloropyridine-2-formyl acyl chloride hydrochloride (III) and organic solvent reaction flask, under the heated and stirred, add alcohol; After reaction finishes, filter and obtain solid (IV).
The operating process of the aqueous solution of preparation 4-chloropyridine of the present invention-2-manthanoate hydrochloride (IV) is as follows: it is water-soluble to filter resulting compound (IV), add organic solvent washing, remove organic layer and separate the aqueous solution that obtains compound (IV); By simple washing with separate, impurity can be dissolved in organic phase, thereby can obtain the aqueous solution of highly purified compound (IV); Wherein used organic solvent is selected from ethyl acetate, methylene dichloride, toluene, isopropyl ether, wherein is preferably ethyl acetate.
Of the present inventionly prepare the reaction of 4-chloro-N-picoline-2-methane amide (V) from 4-chloropyridine-2-manthanoate hydrochloride (IV) aqueous solution, compound (V) is that the aqueous solution of the compound (IV) by prior preparation and aqueous methylamine solution react and obtain, wherein the concentration of selected aqueous methylamine solution is 1%～40%, wherein is preferably 30～40%.
The operating process of above-mentioned reaction from 4-chloropyridine-2-manthanoate hydrochloride (IV) preparation 4-chloro-N-picoline-2-methane amide (V) is roughly as follows: the aqueous solution of the 4-chloropyridine that will prepare in advance reaction flask-2-manthanoate hydrochloride (IV) fully mixes with aqueous methylamine solution, under suitable temperature, reacted 1～24 hour, then adding ethyl acetate extracts, separatory gets organic phase, adding saturated aqueous common salt washs, organic phase is removal of solvent under reduced pressure after drying, namely obtain 4-chloro-N-picoline-2-methane amide (V), be directly used in next step reaction.
The reaction needed for preparing 4-(4-amino-benzene oxygen)-N-picoline-2-methane amide (VI) from 4-chloro-N-picoline-2-methane amide (V) and p-aminophenol of the present invention is used potassium tert.-butoxide and highly basic, and needs minute two stages to add.The fs p-aminophenol reacts under the potassium tert.-butoxide effect and forms first mixture, and the potassium tert.-butoxide of adding and the mol ratio of p-aminophenol are between 3: 1～1: 2; Subordinate phase is added a highly basic again in said mixture, and adds compound (V), and the highly basic of adding and the mol ratio of p-aminophenol are between 1: 1～3: 1.Alkali adds at twice, and replaces the salt of wormwood that uses in the prior art with highly basic, has greatly improved speed of response.
Of the present inventionly prepare the reaction of 4-(4-amino-benzene oxygen)-N-picoline-2-methane amide (VI) from 4-chloro-N-picoline-2-methane amide (V) and p-aminophenol, the highly basic that adds in subordinate phase is selected from potassium tert.-butoxide, sodium tert-butoxide, potassium hydroxide, sodium hydroxide and sodium hydride, wherein is preferably potassium hydroxide.
Above-mentioned to prepare the operating process of reaction of 4-(4-amino-benzene oxygen)-N-picoline-2-methane amide (VI) from 4-chloro-N-picoline-2-methane amide (V) and p-aminophenol roughly as follows: add p-aminophenol, potassium tert.-butoxide and solvent reaction flask, stirred 2 hours, add successively subsequently 4-chloro-N-picoline-2-methane amide (V), potassium hydroxide, temperature reaction 1～24 hour; After reaction finishes, add entry and ethyl acetate extracts, separatory obtains organic phase and obtains 4-(4-amino-benzene oxygen)-N-picoline-2-methane amide (VI) after the removal of solvent under reduced pressure after drying, is directly used in next step reaction.
Of the present inventionly prepare 4-{4-[({[4-chloro-3-(trifluoromethyl) phenyl from 4-(4-amino-benzene oxygen)-N-picoline-2-methane amide (VI) and isocyanic acid-4-chloro-3-(trifluoromethyl) phenyl ester] amino } carbonyl) amino] phenoxy group }-temperature of reaction of N-picoline-2-methane amide (I) is-20～0 ℃, wherein be preferably-10～0 ℃, react at low temperatures, can obviously reduce the generation of impurity.
Of the present inventionly prepare 4-{4-[({[4-chloro-3-(trifluoromethyl) phenyl from 4-(4-amino-benzene oxygen)-N-picoline-2-methane amide (VI) and isocyanic acid-4-chloro-3-(trifluoromethyl) phenyl ester] amino } carbonyl) amino] phenoxy group }-the N-picoline-reaction of 2-methane amide (I) is to carry out suitable solvent, selected solvent is selected from ethyl acetate, methylene dichloride, trichloromethane, tetrahydrofuran (THF), toluene, wherein is preferably ethyl acetate.
Above-mentionedly prepare 4-{4-[({[4-chloro-3-(trifluoromethyl) phenyl from 4-(4-amino-benzene oxygen)-N-picoline-2-methane amide (VI) and isocyanic acid-4-chloro-3-(trifluoromethyl) phenyl ester] amino } carbonyl) amino] phenoxy group }-operating process of the reaction of N-picoline-2-methane amide (I) is roughly as follows: is being lower than under 0 degree, with 4-(4-amino-benzene oxygen)-N-picoline-2-methane amide (VI) and the fully reaction in suitable solvent of isocyanic acid-4-chloro-3-(trifluoromethyl) phenyl ester, being warming up to room temperature after raw material disappears fully stirs to promote product fully to separate out again, filter, with the solid recrystallization in alcoholic solvent that obtains, namely obtain high purity 4-{4-[({[4-chloro-3-(trifluoromethyl) phenyl] amino } carbonyl) amino] phenoxy group }-N-picoline-2-methane amide (I).
The advantage of method of the present invention is by simple operation, uses cheapness and eco-friendly reagent to prepare 4-{4-[({[4-chloro-3-(trifluoromethyl) phenyl with high yield and high purity ground] amino } carbonyl) amino] phenoxy group }-N-picoline-2-methane amide (I).Particularly, the intermediate of whole piece route all need not to carry out special purification operations, only needs can directly carry out next step reaction through operations such as simple filtration and extractions, has greatly simplified operation.Than other route, this route is not only with low cost, and is simple to operate, and environmental friendliness and greatly improved product yield and purity is fit to suitability for industrialized production.
Embodiment
The below further specifies technical scheme of the present invention with specific embodiment, but protection scope of the present invention is not limited to this:
Synthesizing of embodiment one 4-chloropyridine-2-formyl acyl chloride hydrochloride (III)
With 2.7L thionyl chloride and 90mLN, dinethylformamide is added in the reaction flask, fully stirs; Add subsequently 1.5Kg pyridine-2-formic acid, be warming up to 75 ℃, reacted 24 hours, thionyl chloride is fully removed in underpressure distillation, obtains 4-chloropyridine-2-formyl acyl chloride hydrochloride (III) crude product, directly carries out next step reaction.
Synthesizing of embodiment two 4-chloropyridine-2-methyl-formiate hydrochloride (IV)
1L toluene is added in above compound (III) crude product, is heated to 50 ℃, under fully stirring, add 1L methyl alcohol, after dropwising, filter to get solid, purity 70%; Add 7L water and 3L ethyl acetate in solid, separatory obtains the aqueous solution of compound (IV), is directly used in next step reaction.The purity 97% of compound in the aqueous solution (IV).
Synthesizing of embodiment three 4-chloro-N-picoline-2-methane amides (V)
After the aqueous solution of above compound (IV) and 2.3Kg 30% aqueous methylamine solution fully mixed stirring at room 2 hours.Use subsequently each 5L ethyl acetate coextraction 3 secondary response liquid, separatory gets organic phase.Organic phase again with the extraction of 5L saturated aqueous common salt once, organic phase after drying, decompression is removed organic solvent and is got 1.77Kg 4-chloro-N-picoline-2-methane amide (V), is directly used in next step reaction, three-step reaction yield 85%.
Synthesizing of embodiment four 4-(4-amino-benzene oxygen)-N-picoline-2-methane amide (VI)
1.13Kg p-aminophenol and 1.16Kg potassium tert.-butoxide are added to 10LN, in the dinethylformamide, stirred 2 hours.Add embodiment three gained compounds (V), 580g potassium hydroxide, be warming up to 80 ℃ of reactions 8 hours, HPLC shows the raw material completely dissolve.Be cooled to the greenhouse, add 10L water, and the 15L ethyl acetate, separatory gets organic phase, and after anhydrous thin sour magnesium drying, removal of solvent under reduced pressure gets the brown dope 4-of 2.32Kg (4-amino-benzene oxygen)-N-picoline-2-methane amide (VI), yield 92% is directly used in next step reaction.
Embodiment five 4-{4-[({[4-chloro-3-(trifluoromethyl) phenyl] amino } carbonyl) amino] phenoxy group }-N-picoline-2-methane amide (I) synthetic
Under-10 ℃, 2.9Kg 4-(4-amino-benzene oxygen)-N-picoline-2-methane amide (VI) and 2.65Kg isocyanic acid-4-chloro-3-(trifluoromethyl) phenyl ester fully are stirred to the raw material disappearance after the dissolving in the 25L ethyl acetate; Be warming up to subsequently room temperature, stir so that product is fully separated out, filter, with the solid recrystallization in methyl alcohol that obtains, with the solid filtering of separating out, fully obtain 4.18Kg white solid 4-{4-[({[4-chloro-3-(trifluoromethyl) phenyl after the oven dry] amino } carbonyl) amino] phenoxy group }-N-picoline-2-methane amide (I), yield 75%, purity 99.6%.
Claims (10)
1. one kind prepares 4-{4-[({[4-chloro-3-(trifluoromethyl) phenyl] amino } carbonyl) amino] phenoxy group }-method of N-picoline-2-methane amide (I),
Its feature comprises:
(1) pyridine-2-formic acid (II) generates 4-chloropyridine-2-formyl chloride hydrochloride (III) with the sulfur oxychloride reaction in the presence of DMF,
(2) compound (III) generates 4-chloropyridine-2-manthanoate hydrochloride (IV) with corresponding alcohol reaction in organic solution,
R represents C in the formula
1-C
4Straight chain or alkyl or the benzyl of side chain;
(3) the water-soluble rear adding organic solvent washing of compound (IV) is removed organic layer and is divided water-yielding stratum to obtain the aqueous solution of compound (IV);
(4) reaction of the aqueous solution of compound (IV) and aqueous methylamine solution generates 4-chloro-N-picoline-2-methane amide (V),
(5) under the acting in conjunction of potassium tert.-butoxide and another part highly basic, compound (V) generates 4-(4-amino-benzene oxygen)-N-picoline-2-methane amide (VI) with the p-aminophenol reaction,
(6) compound (VI) generates 4-{4-[({[4-chloro-3-(trifluoromethyl) phenyl with isocyanic acid-4-chloro-3-(trifluoromethyl) phenyl ester reaction being lower than under 0 ℃ the temperature] amino } carbonyl) amino] phenoxy group }-N-picoline-2-methane amide (I)
2. described preparation method according to claim 1, the selected alcohol of reaction that it is characterized in that preparing compound (IV) is C
1-C
4Straight chain or alcohol or the benzylalcohol of side chain, wherein preferred alcohol is methyl alcohol.
3. described preparation method according to claim 1, it is characterized in that preparing the used solvent of the reaction of compound (IV) for being selected from: toluene, tetrahydrofuran (THF), acetonitrile, acetone, N, dinethylformamide, methylene dichloride, wherein preferred solvent is toluene.
4. described preparation method according to claim 1, it is characterized in that the used reaction solvent of step (6) is for being selected from: ethyl acetate, methylene dichloride, trichloromethane, tetrahydrofuran (THF), toluene, wherein preferred solvent is ethyl acetate.
5. method for preparing the aqueous solution of 4-chloropyridine-2-manthanoate hydrochloride (IV),
Its feature comprises:
(1) compound (III) reacts with alcohol in the organic agent solvent;
(2) direct filtration obtained compound (IV) after reaction finished;
(3) compound (IV) of gained is water-soluble, add organic solvent washing, remove organic layer and divide water-yielding stratum to obtain the aqueous solution of compound (IV).
6. described preparation method according to claim 5, the organic solvent that it is characterized in that using in the step (3) is for being selected from: ethyl acetate, methylene dichloride, toluene, isopropyl ether, wherein preferably solvent is ethyl acetate.
7. method for preparing 4-chloro-N-picoline-2-methane amide (V) is characterized in that compound (V) is that the aqueous solution of compound (IV) and aqueous methylamine solution react and obtain.
8. one kind prepares the method that the p-aminophenol reaction generates 4-(4-amino-benzene oxygen)-N-picoline-2-methane amide (VI), and its feature comprises:
(1) p-aminophenol reacts under the potassium tert.-butoxide effect and forms first mixture;
(2) add a highly basic in said mixture again, and add compound (V), reaction generates 4-(4-amino-benzene oxygen)-N-picoline-2-methane amide (VI).
9. according to claim 1,8 described preparation methods, it is characterized in that described highly basic is for being selected from: potassium tert.-butoxide, sodium tert-butoxide, potassium hydroxide, sodium hydroxide and sodium hydride, wherein preferred highly basic is potassium hydroxide.
10. described preparation method according to claim 8 is characterized in that the mol ratio of potassium tert.-butoxide and p-aminophenol in the step (1) at 3: 1～1: 2, and wherein preferred mol ratio is 1: 1; The highly basic that adds in the step (2) and the mol ratio of p-aminophenol were at 1: 1～3: 1, and wherein preferred mol ratio is 1: 1.
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| CN105085388A (en) * | 2015-09-06 | 2015-11-25 | 合肥华方医药科技有限公司 | Synthesis method for sorafenib intermediate |
| CN114957111A (en) * | 2022-07-19 | 2022-08-30 | 扬州市普林斯医药科技有限公司 | Preparation method of N-methyl-4-chloropyridine-2-formamide |
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| CN105085388A (en) * | 2015-09-06 | 2015-11-25 | 合肥华方医药科技有限公司 | Synthesis method for sorafenib intermediate |
| CN105085388B (en) * | 2015-09-06 | 2018-07-13 | 合肥华方医药科技有限公司 | A kind of synthetic method of Sorafenib intermediate |
| CN114957111A (en) * | 2022-07-19 | 2022-08-30 | 扬州市普林斯医药科技有限公司 | Preparation method of N-methyl-4-chloropyridine-2-formamide |
| CN114957111B (en) * | 2022-07-19 | 2024-02-09 | 扬州市普林斯医药科技有限公司 | Preparation method of N-methyl-4-chloropyridine-2-formamide |
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