CN106083711A - A kind of synthetic method of Rui Gefeini - Google Patents
A kind of synthetic method of Rui Gefeini Download PDFInfo
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- CN106083711A CN106083711A CN201610370098.9A CN201610370098A CN106083711A CN 106083711 A CN106083711 A CN 106083711A CN 201610370098 A CN201610370098 A CN 201610370098A CN 106083711 A CN106083711 A CN 106083711A
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- rui gefeini
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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 present invention relates to 4 chlorine 3 (trifluoromethyl) aniline as initiation material, first with phenyl chloroformate generation amidation process, obtain intermediate, with 4 amino 3 fluorophenol generation amidation process, obtain intermediate, with starting material 4 chlorine N methyl 2 pyridine carboxamides generation alkylated reaction, acetone water recrystallization, obtains target product Rui Gefeini, and this preparation method is simple and easy to do, yield is high, quality is good, it is simple to industrialized production.
Description
Technical field:
The present invention relates to medicinal chemistry art, be specifically related to the synthetic method of a kind of Rui Gefeini.
Background technology
Rui Gefeini (regorafenib, 1) chemical entitled 4-[4-({ [4-chloro-3-(trifluoromethyl) phenyl] amino first
Acyl } amino)-3-fluorophenoxy]-N-picoline-2-Methanamide is novel the swashing of Bayer Bitterfeld GmbH medicines and health protection company research and development more
Enzyme inhibitor kind anti-cancer drugs, can suppress to promote that KIT (CD117), the PDGFR of cancerous cell and tumor vascular growth are (platelet-derived
Growth factor receptors), the kinases such as VEGFR (vascular endothelial growth factor receptor).This medicine is first and ties for treating transitivity
The oral little molecule multi-kinase inhibitor of intestinal rectal cancer.
The documents such as WO2005/009961A describe the synthetic method of a kind of Rui Gefeini, and its synthetic route is as follows:
The deficiency of this route is to have employed Carbimide. (the 4-chloro-3-(fluoroform with certain toxicity and extremely unstable
Base) phenyl) ester as initiation material, furthermore, when being alkylated reaction, amino is not protected, can produce certain
Impurity.
Technical scheme
The present invention is directed to above-mentioned document weak point, its synthetic route is redesigned, with 4-chloro-3-(trifluoro
Methyl) aniline (2) is initiation material, (2) first with phenyl chloroformate generation amidation process, obtain intermediate (3), (3) and 4-
There is amidation process in amino-3-fluorophenol (4), obtains intermediate (5), (5) and starting material 4-chloro-n-methyl-2-pyridine
There is alkylated reaction, acetone water recrystallization in carboxylic acid amides (6), obtains target product Rui Gefeini (1), and this preparation method is easy easily
Row, yield are high, and quality is good, it is simple to industrialized production, and synthetic route is as follows:
Experimental example 1, the selection of feed postition of alkali kind of three-step reaction
The selection of the alkali kind of three-step reaction, respectively potassium tert-butoxide, cesium carbonate, sodium hydrogen, Feldalat NM, compare,
Result is as shown in table 1.
1-(4-chloro-3-(trifluoromethyl) phenyl)-3-(3-fluoro-4-hydroxyl it is sequentially added in dimethyl sulfoxide (1500ml)
Base phenyl) urea (5) (150.0g), 4-chloro-n-methyl-2-pyridine carboxamides (6) (110.0g) and a certain amount of alkali, be warming up to 40
～45 DEG C, insulated and stirred 15h, after reaction terminates, in reactant liquor, add 1500ml water, stir 1h, filter, filter cake acetone water
Recrystallization, obtains Rui Gefeini.
The selection of the alkali kind of table 1 three-step reaction
| Alkali kind | Alkali consumption | Reaction condition | Conversion ratio | Yield |
| Potassium tert-butoxide | 2.5eq | 40～45 DEG C | 97% | 56% |
| Cesium carbonate | 2.5eq | 40～45 DEG C | 95% | 82% |
| Sodium hydrogen | 2.5eq | 40～45 DEG C | 81% | 63% |
| Feldalat NM | 2.5eq | 40～45 DEG C | 67% | 47% |
As can be seen from Table 1, when potassium tert-butoxide makees alkali, reaction conversion ratio is the highest, but product purity is poor, and product needs post
Chromatography purification, yield is also relatively low；When cesium carbonate makees alkali, reaction conversion ratio is higher, and product yield is higher；When sodium hydrogen makees alkali, instead
Answering conversion ratio relatively low, product purity is poor, needs column chromatography purification, and yield is also relatively low；When Feldalat NM makees alkali, reaction conversion ratio
Minimum, yield is also minimum.
The investigation of experimental example the 2, the 3rd step cesium carbonate usage amount
1-(4-chloro-3-(trifluoromethyl) phenyl)-3-(3-fluoro-4-hydroxyl it is sequentially added in dimethyl sulfoxide (1500ml)
Base phenyl) urea (5) (150.0g), 4-chloro-n-methyl-2-pyridine carboxamides (6) (110.0g) and a certain amount of cesium carbonate, heat up
To 40～45 DEG C, insulated and stirred 15h, after reaction terminates, in reactant liquor, add 1500ml water, stir 1h, filter, filter cake is with third
Ketone water recrystallization, obtains 174.5g title compound.(yield is 81.0%).
Table 2 cesium carbonate is made the reaction condition of alkali and is compared
As can be seen from Table 2,1.5eq cesium carbonate, 2.0eq cesium carbonate, 2.5eq cesium carbonate, 3.0eq cesium carbonate it are respectively adopted
When making alkali, conversion ratio is incremented by successively, but when making alkali with 2.5eq cesium carbonate, yield is the highest.
The present invention prepares that Rui Gefeini (1) purity is high, impurity is few, and stability is strong, is the good raw material of preparation, incite somebody to action this
The dosage form of the crystallization of invention makes medicine, crystallization is mixed with suitable adjuvant additive, makes preparation.
The preferred formulation of the present invention is: tablet, powder, granule, capsule, syrup, oral containing tablet, inhalant etc.
Preparation；External preparation or the notes such as suppository, ointment, Eye ointments, transdermal agent, eye drop, nasal drop, ear drop, cataplasma, lotion
Penetrate agent.
Preferably adjuvant is: excipient, binding agent, lubricant, disintegrating agent, coloring agent, taste masking rectify olfactory agent, emulsifying agent, table
Face activating agent, cosolvent, suspendible agent, isotonic agent, buffer agent, preservative, antioxidant, stabilizer, absorption enhancer etc..
Preferably excipient is: lactose, white sugar, glucose, corn starch, mannitol, Sorbitol, starch, α starch,
Dextrin, crystalline cellulose, light silicon anhydride, aluminium silicate, calcium silicates, silicic acid magnesium aluminate, calcium hydrogen phosphate etc..
Preferably binding agent is: polyvinyl alcohol, methylcellulose, ethyl cellulose, arabic gum, tragacanth gum, gelatin, worm
Glue, hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, polyvinyl pyrrolidone, Polyethylene Glycol etc..
Preferably lubricant is: magnesium stearate, calcium stearate, stearyl fumarate sodium, Talcum, Polyethylene Glycol, colloidal state two
Silicon oxide etc..
Preferably disintegrating agent is: crystalline cellulose, agar, gelatin, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, really
Glue, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethylcellulose calcium, cross-linking sodium carboxymethyl cellulose, carboxymethyl form sediment
Powder, carboxymethyl starch sodium etc..
Preferably coloring agent is: iron sesquioxide, Yellow ferric oxide, carmine, caramel, beta-carotene, oxidation
Titanium, Talcum, Riboflavin Sodium Phosphate etc..
Preferably correctives is: cocoa powder, menthol, Oleum menthae, Borneolum Syntheticum, Cortex cinnamomi japonici powder etc..
Preferably emulsifying agent or surfactant is: octadecyl triethanolamine, sodium lauryl sulphate, dodecyl ammonia
Base propanoic acid, lecithin, glyceryl monostearate, sucrose fatty acid ester, fatty acid glyceride etc..
Preferably cosolvent is: Polyethylene Glycol, propylene glycol, benzoic acid benzyl ester, ethanol, cholesterol, triethanolamine, carbonic acid
Sodium, sodium citrate, Tween 80, nicotiamide etc..
Preferably suspensoid is: polyvinyl alcohol, polyvinyl pyrrolidone, methylcellulose, hydroxymethyl cellulose, hydroxyl second
The hydrophilic macromolecules such as base cellulose, hydroxypropyl cellulose.
Preferably isotonic agent is: glucose, sodium chloride, mannitol, Sorbitol etc..
Preferably buffer agent is: the buffer such as phosphate, acetate, carbonate, citrate.
Preferably preservative is: methyl parahydroxybenzoate, propyl p-hydroxybenzoate, methaform, benzylalcohol, phenethanol,
Dehydroactic acid, sorbic acid etc..
Preferably antioxidant is: sulphite, ascorbic acid, alpha-tocopherol etc..
The synthesis of embodiment 1:N-(4-chloro-3-(trifluoromethyl) phenyl) phenyl carbamate (3)
4-chloro-3-(trifluoromethyl) aniline (2) (100g), system control is added in DMF (1000ml)
Temperature, less than 10 DEG C, is sequentially added into pyridine (81.0g) and dropping phenyl chloroformate (121.0g), is warmed to room temperature, insulated and stirred 3h, instead
After should terminating, adding 1500ml water, 2000ml dichloromethane, separate organic facies in reactant liquor, organic facies uses 200ml3N successively
Aqueous hydrochloric acid solution, 200ml saturated nacl aqueous solution, 200ml water wash, and anhydrous sodium sulfate is dried, and decompression steams solvent, n-hexane
Making beating, obtains 151.3g title compound.(yield is 93.7%).
1H-NMR (500MHz, CDCl3): 7.81 (1H, s), 7.60～7.61 (1H, d, J=5.0Hz), 7.24～7.28
(2H, m), 7.20～7.21 (1H, d, J=5.0Hz), 7.01～7.06 (3H, m).
The synthesis of embodiment 2:1-(4-chloro-3-(trifluoromethyl) phenyl)-3-(3-fluoro-4-hydroxy phenyl) urea (5)
N-(4-chloro-3-(trifluoromethyl) phenyl) phenyl carbamate is added in DMF (1500ml)
(3) (150.0g), system temperature control is less than 15 DEG C, adds 4-amino-3-fluorophenol (4) (121.0g), is warmed to room temperature, insulated and stirred
4h.After reaction terminates, adding 1500ml water, 2000ml dichloromethane, separate organic facies in reactant liquor, organic facies is used successively
300ml3N aqueous hydrochloric acid solution, 300ml saturated nacl aqueous solution, 300ml water wash, and anhydrous sodium sulfate is dried, and decompression steams molten
Agent, recrystallisation from isopropanol, obtain 152.1g title compound.(yield is 91.8%).
LC-MS316.5(M+1)。
1H-NMR (500MHz, DMSO): 9.32 (2H, s), 7.81 (1H, s), 7.59～7.60 (1H, d, J=5.0Hz),
7.49～7.50 (1H, d, J=5.0Hz), 7.21～7.22 (1H, d, J=5.0Hz), 6.51～6.52 (1H, d, J=
5.0Hz), 6.41 (1H, s), 4.87 (1H, s).
The synthesis of embodiment 3: Rui Gefeini (1)
1-(4-chloro-3-(trifluoromethyl) phenyl)-3-(3-fluoro-4-hydroxyl it is sequentially added in dimethyl sulfoxide (1500ml)
Base phenyl) urea (5) (150.0g), 4-chloro-n-methyl-2-pyridine carboxamides (6) (110.0g) and cesium carbonate (350.1g), heat up
To 40～45 DEG C, insulated and stirred 15h, after reaction terminates, in reactant liquor, add 1500ml water, stir 1h, filter, filter cake is with third
Ketone water recrystallization, obtains 174.5g title compound.(yield is 81.0%).
LC-MS 483.7(M+1-H2O)。
1H-NMR (500MHz, DMSO): 10.46 (1H, s), 9.35 (2H, s), 8.65～8.66 (1H, d, J=5.0Hz),
8.13 (1H, s), 7.83 (1H, s), 7.59～7.60 (1H, d, J=5.0Hz), 7.46～7.49 (2H, m), 7.20～7.21
(1H, d, J=5.0Hz), 6.42～6.46 (2H, m), 2.81 (3H, s).
The condition of the HPLC of embodiment 4: Rui Gefeini sample purity is:
High performance liquid chromatograph
Chromatographic column: common C8 post
Column temperature: 35 DEG C
Flow velocity: 1.0ml/min
Sample size: 10 μ l
Flowing phase: with 0.15mol/L trifluoroacetic acid aqueous solution as mobile phase A, acetonitrile is Mobile phase B, and according to the form below is washed
De-.
Detection wavelength: 235nm
| Time (minute) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 65 | 35 |
| 20 | 10 | 90 |
| 25 | 10 | 90 |
| 26 | 65 | 35 |
| 30 | 65 | 35 |
The embodiment of the present invention 3 product, standard substance flowing phased soln, takes need testing solution, takes 20 μ l and injects liquid chromatograph
Instrument, records chromatogram, and Rui Gefeini peak retention time is 19.7 minutes, and number of theoretical plate is calculated by Rui Gefeini peak and is not less than
3000, the Rui Gefeini containing compound should be the 99.7%～101.0% of labelled amount.
| The total peak area of impurity/Rui Gefeini peak area | |
| Embodiment 4 product | 0.017% |
| Commercial standard | 0.098% |
Embodiment 6
Rui Gefeini sheet is formulated by following component, by 1000 consumptions:
Its preparation method comprises the steps:
1) Rui Gefeini and pharmaceutic adjuvant are pulverized and sieved respectively, standby,
2) raw material and the pharmaceutic adjuvant physical mixed that take recipe quantity parts by weight are uniform,
3) wet granulation,
4) it is dried, granulate,
5) convert additional adjuvant, mix homogeneously, be pressed into tablet
6) Opadry uses certain solvent dissolve, be coated as coating solution.
Result of the test
Medicament contg: qualified
Disintegration: meet regulation
Embodiment 7
Rui Gefeini sheet is formulated by following component, by 1000 consumptions:
Its preparation method comprises the steps:
1) Rui Gefeini and pharmaceutic adjuvant are pulverized and sieved respectively, standby,
2) raw material and the pharmaceutic adjuvant physical mixed that take recipe quantity parts by weight are uniform,
3) wet granulation,
4) it is dried, granulate,
5) convert additional adjuvant, mix homogeneously, be pressed into tablet
6) Opadry uses certain solvent dissolve, be coated as coating solution.
Result of the test
Medicament contg: qualified
Disintegration: meet regulation
Above embodiments of the invention are described in detail, but described content have been only presently preferred embodiments of the present invention,
It is not to be regarded as the practical range for limiting the present invention.All impartial changes made according to the present patent application scope and improvement etc.,
Within all should still belonging to the patent covering scope of the present invention.
Claims (1)
1. the preparation method of Yi Zhong Rui Gefeini, it is characterised in that: with 4-chloro-3-(trifluoromethyl) aniline (2) as initiation material,
(2) elder generation and phenyl chloroformate generation amidation process, obtains intermediate (3), and (3) occur amide with 4-amino-3-fluorophenol (4)
Changing reaction, obtain intermediate (5), there is alkylated reaction with starting material 4-chloro-n-methyl-2-pyridine carboxamides (6) in (5),
Acetone water recrystallization, obtains target product Rui Gefeini (1)；
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011113368A1 (en) * | 2010-03-18 | 2011-09-22 | 苏州泽璟生物制药有限公司 | Preparation method of fluoro-substituted deuterated diphenylurea |
| WO2011113203A1 (en) * | 2010-03-18 | 2011-09-22 | 苏州泽璟生物制药有限公司 | Deuterium-substituted omega-diphenylurea and derivatives thereof and pharmaceutical compositions comprising the compounds |
| US20150175545A1 (en) * | 2012-09-18 | 2015-06-25 | Suzhou Zelgen Biopharmaceutical Co., Ltd | Preparation Method of Fluoro-Substituted Deuterated Diphenylurea |
-
2016
- 2016-05-31 CN CN201610370098.9A patent/CN106083711B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011113368A1 (en) * | 2010-03-18 | 2011-09-22 | 苏州泽璟生物制药有限公司 | Preparation method of fluoro-substituted deuterated diphenylurea |
| WO2011113203A1 (en) * | 2010-03-18 | 2011-09-22 | 苏州泽璟生物制药有限公司 | Deuterium-substituted omega-diphenylurea and derivatives thereof and pharmaceutical compositions comprising the compounds |
| US20150175545A1 (en) * | 2012-09-18 | 2015-06-25 | Suzhou Zelgen Biopharmaceutical Co., Ltd | Preparation Method of Fluoro-Substituted Deuterated Diphenylurea |
Non-Patent Citations (1)
| Title |
|---|
| 郑德强，等: "瑞戈非尼的合成", 《中国医药工业杂志》 * |
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