CN108341770A - A kind of preparation method of Sorafenib compound - Google Patents
A kind of preparation method of Sorafenib compound Download PDFInfo
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- CN108341770A CN108341770A CN201810277140.1A CN201810277140A CN108341770A CN 108341770 A CN108341770 A CN 108341770A CN 201810277140 A CN201810277140 A CN 201810277140A CN 108341770 A CN108341770 A CN 108341770A
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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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Abstract
The invention discloses a kind of preparation methods of Sorafenib compound.The present invention, which is reacted using 2 chlorine, 55 amido benzotrifluoride with Zassol, is made compound III, and 4 bromophenols (compounds Ⅳ) are reacted with compound V is made compound VI, and compound VI reacts to obtain finished product Sorafenib (I) with compound III.The reaction is raw materials used cheap and easy to get, and process route is simple, and total recovery is high, and by-product is few, is suitble to industrialized production.
Description
Technical field
The present invention relates to the synthesis fields of drug, and in particular to the preparation method of antitumor drug Sorafenib compound.
Background technology
Sorafenib (sorafenib) is the novel signal transduction developed jointly by German Bayer and Onxy companies
Inhibitor and multiple target point antitumor drug.Sorafenib has dual antitumor action：It both can be by blocking by RAF/MEK/
Cell signal propagation pathways that ERK is mediated and directly inhibit the proliferation of tumour cell, can also inhibit new by acting on VEGFR
It the formation of angiogenic and cuts off the nutrition supply of tumour cell and achievees the purpose that contain tumour growth.
The chemical name of Sorafenib is 4- { 4- [3- (the chloro- 3- trifluoromethyl-phenyls of 4-)-uride]-phenoxy group }-pyrrole
Pyridine -2- carboxylic acid methylamines have chemical constitution shown in Formulas I：
It is as follows about Sorafenib synthetic route and preparation method report situation at present：
1, patent WO0042012, WO2006034796, WO2006089150, WO2007059154, WO2007053574,
US7235576 etc. reports that route is as follows：
In final step reaction, the prior art, which reacts compound 2 with isocyanate compound 5, is made compound 1, but
The hypertoxicities gas such as phosgene is commonly used in prepare compound 5, there are cumbersome, the reaction time is long, isolates and purifies difficulty etc.
Problem, and that there are stability is poor for isocyanate compound 5, is easy to generate symmetrical urea by-product.
Meanwhile compound 2 reacts prepare compound 1 with compound 6, the preparation of compound 6 uses N, N- carbonyl dimidazoles
(CDI) it prepares, and N, N '-carbonyl dimidazoles are unstable (CDI), very easy hydrolysis, and it is expensive, be not suitable for industry
Metaplasia is produced.
2, the synthetic route of patent CN 102875460A, US7351834 report：
The route obtains the chloro- 2- of intermediate 4- using 2- pyridine carboxylic acids as starting material, through chlorine substitution, methanol solution, amidation
(methylcarbamoyl) pyridine 7.Then 7 occur nucleophilic substitution with para-aminophenol, form the product with ethers structure
8, in this single step reaction, have one between amino and phenolic hydroxyl group in para-aminophenol structure and the nucleophilic substitution of compound 7
A competition, causes product yield to reduce.
Invention content
It is an object of the invention to overcome the deficiencies of existing technologies, a kind of new Sorafenib compound preparation side is provided
Method, the preparation method starting material is cheap and easy to get, and process route is simple, and total recovery is high, and by-product is few, is suitble to industrialized production.
Synthetic route of the present invention is as follows：
A kind of preparation method of Sorafenib compound, it is characterised in that the preparation method includes the following steps：
A, the chloro- 5- 5 amido benzotrifluorides of 2- are reacted with Zassol is made compound III；
B, 4- bromophenols (compounds Ⅳ) are reacted with compound V is made compound VI；
C, compound VI, which is reacted with compound III in catalyst, ligand, alkali and organic solvent, is made final product Suo Lafei
Buddhist nun (I).
Wherein, the molar ratio that the chloro- 5- 5 amido benzotrifluorides of 2- are reacted with Zassol in step a is 1:1-2；Reaction temperature is
20-50 DEG C, further preferred reaction temperature is 40-50 DEG C, reaction time 1-2h.
The catalyst used in step c is Pd (OAc)2Or Pd2(dba)3, used ligand is the bis- diphenylphosphines-of 4,5-
9,9- xanthphos；Used alkali is Cs2CO3、K3PO4Or sodium ethoxide；Reaction dissolvent is tetrahydrofuran, N, N- diformazans
Yl acetamide, six ring of Isosorbide-5-Nitrae-dichloro or toluene；Compound VI is 1 with compound III molar ratio:1；Catalyst rubs with compound VI
You are than being 0.01-0.025:1, ligand mole dosage is 2-3 times of catalyst, and the mole dosage of alkali is 1-2 times of compound VI.
Preparation method of the present invention about Sorafenib compound, obtains following advantageous effect：
(1) step a is reacted using the chloro- 5- 5 amido benzotrifluorides (II) of 2- with Zassol, and reaction temperature is low, after simplifying
Reason, product yield significantly improve.
(2) 4- bromophenols (compounds Ⅳ) and compound V in step b, solve and use 4-aminophenol in the prior art
The competitive reaction at ether is participated in for amino in raw material and phenolic hydroxyl group, product yield and purity greatly improve.
(3) step c is received in catalyst, ligand, alkali and organic solvent at urea, product using compound VI and compound III
The drawbacks of rate improves, while solving isocyanate compound in the prior art or N, and N '-carbonyl dimidazoles are participated in into urea.
(4) the technique starting material is cheap and easy to get, and synthetic route is simple, easy to operate, and total yield of products is high, by-product
It is few, it is suitble to industrialized production.
Specific implementation mode
The invention content of the present invention is described in further detail below by specific embodiment, but is not therefore limited
Determine present disclosure.
Embodiment 1
The preparation of compound III
6.50g Zassols are dissolved in wiring solution-forming in 80ml water；The glacial acetic acid and 20ml water of 60ml are added in reaction bulb,
2- chloro- 5- 5 amido benzotrifluorides (II) 19.56g are added under the conditions of 20 DEG C, prepared cyanic acid sodium solution in advance, control is added
Temperature is 40-50 DEG C, and is stirred continuously, and 2h is reacted, and stops reaction.Into reaction bulb plus water, filtering, filter cake are washed with water into
Property, it is dry, obtain compound III 23.2g, product yield 97.2%, purity 99.96%.
Embodiment 2
The preparation of compound III
6.51g Zassols are dissolved in wiring solution-forming in 40ml water；The glacial acetic acid and 20ml water of 60ml are added in reaction bulb,
2- chloro- 5- 5 amido benzotrifluorides (II) 19.56g are added under the conditions of 20 DEG C, prepared cyanic acid sodium solution in advance, control is added
Temperature is 20-30 DEG C, and is stirred continuously, and 3h is reacted, and stops reaction.Into reaction bulb plus water, filtering, filter cake are washed with water into
Property, it is dry, obtain compound III 19.00g, product yield 79.5%, purity 99.82%.
Embodiment 3
The preparation of compound III
13.01g Zassols are dissolved in wiring solution-forming in 80ml water；The glacial acetic acid and 10ml of 30ml are added in reaction bulb
2- chloro- 5- 5 amido benzotrifluorides (II) 19.56g are added in water under the conditions of 20 DEG C, and prepared cyanic acid sodium solution in advance is added,
It controlled at 40-50 DEG C, and is stirred continuously, reacts 1h, stop reaction.Into reaction bulb plus water, filtering, filter cake be washed with water to
Neutrality, it is dry, obtain compound III 22.80g, product yield 95.5%, purity 99.92%.
Embodiment 4
The preparation of compound VI
4- bromophenols (compounds Ⅳ) 16.82g, potassium tert-butoxide 0.1944mol, 800mlN, N- bis- are added in reaction bulb
It in methylformamide, stirs 2 hours, adds V 16.58g of compound, 0.1944mol potassium hydroxide is added, control temperature exists
80 DEG C are reacted 8 hours, and reaction is stopped, and are cooled to greenhouse, 200ml and 600ml ethyl acetate is added and is extracted, is obtained after liquid separation
Organic layer carry out revolving remove solvent obtain VI 28.73g of compound, product yield 96.2%, purity 99.96%.
Embodiment 5
The preparation of compound VI
4- bromophenols (compounds Ⅳ) 13.75g, potassium hydroxide 0.159mol, 800ml N, N- bis- are added in reaction bulb
It in methylformamide, stirs 2 hours, adds V 13.56g of compound, 0.159mol potassium hydroxide is added, control temperature is 80
DEG C reaction 8 hours, stops reaction, is cooled to greenhouse, 200ml and 600ml ethyl acetate is added and is extracted, is obtained after liquid separation
Organic layer carries out revolving removing solvent and obtains VI 22.88g of compound, product yield 93.6%, purity 99.89%.
Embodiment 6
The preparation of compound VI
4- bromophenols (compounds Ⅳ) 16.52g, potassium tert-butoxide 0.0955mol, 800mlN, N- bis- are added in reaction bulb
It in methylformamide, stirs 2 hours, adds V 16.29g of compound, 0.0955mol potassium hydroxide is added, control temperature exists
80 DEG C are reacted 8 hours, and reaction is stopped, and are cooled to greenhouse, 200ml and 600ml ethyl acetate is added and is extracted, is obtained after liquid separation
Organic layer carry out revolving remove solvent obtain VI 27.83g of compound, product yield 94.8%, purity 99.93%.
Embodiment 7
The preparation of Sorafenib (I)
Compound VI 28.72g, Pd are added in reaction bulb2(dba)3(0.0023mol), the bis- diphenylphosphine -9,9- of 4,5-
Xanthphos (0.0046mol), 19.85g K3PO4, six ring 900ml of Isosorbide-5-Nitrae-dichloro, 30min, adding is stirred at room temperature
III 22.31g of object is closed, controlled at 80-100 DEG C of reaction 1h, is monitored and is reacted with TLC, wait for cooling the temperature to room after reaction
Temperature, mixture are extracted with ethyl acetate, and purify water washing, and anhydrous sodium sulfate drying is dried in vacuo to obtain Sorafenib (I)
42.60g, yield 97.9%, purity 99.88%.
Following experimental implementation is same as Example 7, changes reaction raw materials molar ratio, catalyst type, catalyst amount, matches
Conditions, the experimental results such as body dosage, alkali type, base amount, organic solvent see the table below：
It is pointed out that the technical concepts and features of above-described embodiment only to illustrate the invention, it is ripe its object is to allow
The personage for knowing technique cans understand the content of the present invention and implement it accordingly, and the protection model of the present invention can not be limited with this
It encloses.Any equivalent change or modification in accordance with the spirit of the invention should be covered by the protection scope of the present invention.
Claims (9)
1. a kind of preparation method of Sorafenib compound, it is characterised in that the preparation method includes the following steps：
A, the chloro- 5- 5 amido benzotrifluorides of 2- are reacted with Zassol is made compound III；
B, 4- bromophenols are reacted with compound V is made compound VI；
C, compound VI, which is reacted with compound III in catalyst, ligand, alkali and organic solvent, is made final product Sorafenib
(Ⅰ)；
Its synthetic route is as follows：
2. according to the method described in claim 1, which is characterized in that the chloro- 5- 5 amido benzotrifluorides of 2- described in step a and cyanogen
The molar ratio of sour sodium reaction is 1:1-2.
3. according to the method described in claim 1, which is characterized in that the reaction temperature of step a is 20-50 DEG C, the reaction time
For 1-2h.
4. according to the method described in claim 3, which is characterized in that the reaction temperature of step a is 40-50 DEG C.
5. according to the method described in claim 1, which is characterized in that the catalyst described in step c is Pd (OAc)2Or Pd2
(dba)3, the ligand is bis- diphenylphosphine -9, the 9- xanthphos of 4,5-.
6. according to the method described in claim 1, which is characterized in that the alkali described in step c is Cs2CO3、K3PO4Or ethyl alcohol
Sodium.
7. according to the method described in claim 1, which is characterized in that organic solvent described in step c is tetrahydrofuran, N,
N- dimethylacetylamides, six ring of Isosorbide-5-Nitrae-dichloro or toluene.
8. according to the method described in claim 1, which is characterized in that compound VI is with compound III molar ratio in step c
1:1。
9. according to the method described in claim 1, which is characterized in that catalyst is with VI molar ratio of compound in step c
0.01-0.025:1, ligand mole dosage is 2-3 times of catalyst, and the mole dosage of alkali is 1-2 times of compound VI.
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| CN201810277140.1A CN108341770A (en) | 2018-03-31 | 2018-03-31 | A kind of preparation method of Sorafenib compound |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112679378A (en) * | 2020-12-31 | 2021-04-20 | 湖南兴同化学科技有限公司 | Preparation method of oxadiazon intermediate 2, 4-dichloro-5-isopropoxyphenylhydrazine |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009034308A2 (en) * | 2007-09-10 | 2009-03-19 | Cipla Limited | Process for the preparation of a raf kinase inhibitor and intermediates for use in the process |
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2018
- 2018-03-31 CN CN201810277140.1A patent/CN108341770A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009034308A2 (en) * | 2007-09-10 | 2009-03-19 | Cipla Limited | Process for the preparation of a raf kinase inhibitor and intermediates for use in the process |
Non-Patent Citations (5)
| Title |
|---|
| SIMON BREITLER ET AL.: "Synthesis of Unsymmetrical Diarylureas via Pd-Catalyzed C-N Cross-Coupling Reactions", 《ORGANIC LETTERS》 * |
| STN INTERNATIONAL: "《DATABASE REGISTRY[Online]》", 16 November 1984 * |
| 夏玉宇.: "《化验员实用手册》", 31 May 2001, 北京：化学工业出版社 * |
| 李祥高，等.: "苯脲衍生物的合成", 《化学工业与工程》 * |
| 石得中，等.: "《世界精细化工产品技术经济手册》", 31 December 1988, 化学工业部科学技术情报研究所 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112679378A (en) * | 2020-12-31 | 2021-04-20 | 湖南兴同化学科技有限公司 | Preparation method of oxadiazon intermediate 2, 4-dichloro-5-isopropoxyphenylhydrazine |
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