CN110183377A - A kind of synthetic method of anticancer drug Rui Gefeini - Google Patents
A kind of synthetic method of anticancer drug Rui Gefeini Download PDFInfo
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- CN110183377A CN110183377A CN201910638213.XA CN201910638213A CN110183377A CN 110183377 A CN110183377 A CN 110183377A CN 201910638213 A CN201910638213 A CN 201910638213A CN 110183377 A CN110183377 A CN 110183377A
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- pyridine
- fluorophenoxy
- methylcarbamoyl
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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
Abstract
The present invention provides the synthetic methods of anticancer drug Rui Gefeini a kind of; it should be using 3- fluoro-4-nitrophenol as raw material; 4- (4- nitro -3- fluorophenoxy) -2- (methylcarbamoyl) pyridine is obtained through condensation reaction with N- methyl -4- Chloro-2-Pyridyle formamide in the presence of alkali; catalysis restores to obtain 4- (4- amino -3- fluorophenoxy) -2- (methylcarbamoyl) pyridine, then with 4- chloro- 3- (trifluoromethyl) phenyl isocyanate condensation reaction get Rui Gefeini in tetrahydrofuran.The present invention is easy to get using raw material is relatively inexpensive, and reaction condition is mild, easy to operate and safe, product yield is higher, and product purity is high, industrial value with higher.
Description
Technical field
The invention belongs to chemical intermediate preparation method technical fields, and in particular to a kind of anticancer drug Rui Gefeini
Synthetic method.
Background technique
Rui Gefeini (I) trade name Stivarga, a kind of oral multi-kinase inhibitor developed by Bayer A.G,
It is by inhibiting multiple proteins kinases, and targeting is generated in tumour, tumor vessel occurs and other tumours driving gene is logical
Road blocks Tumor Angiongesis, inhibits tumor cell proliferation and modulate tumor microenvironment, to inhibit the proliferation of tumour and invade
It attacks.Rui Gefeini, in the granted listing in the U.S., is clinically used for previously having received the transfer of currently available therapy treatment in September, 2012
Property colorectal cancer.2, FDA has approved 1 New indication within 2013 --- it cuts off and for that cannot perform the operation to other drugs treatment nothing
The treatment of the gastrointestinal malignant stromal tumors patient of response.This product has also carried out multinomial clinical research in other solid tumors in recent years,
In April, 2017, FDA approval become FDA nearly 10 for previously receiving hepatocellular carcinoma (HCC) patient of Sorafenib treatment
The first liver cancer new drug ratified over year.
Entitled 4- [4- [[[4- chloro- 3- (trifluoromethyl) phenyl] carbamyl] the amino] -3- fluorobenzene of Rui Gefeini chemistry
Oxygroup]-N- picoline -2- formamide, chemical structure is as shown in formula I.
The disclosed document synthetic route in relation to anticancer drug Rui Gefeini is more both at home and abroad:
1), acylation reaction is occurred in DMF and is obtained using the chloro- 3- of 4- (trifluoromethyl) aniline and phenyl chloroformate by Cheng Gang et al.
N- [4- chloro- 3- (trifluoromethyl) phenyl] phenyl carbamate, reacts into urea with 4- amino -3- fluorophenol in DMF and obtains 1-
[4- chloro- 3- (trifluoromethyl) phenyl] -3- (the fluoro- 4- hydroxy phenyl of 2-) urea, then with N- methyl -4- Chloro-2-Pyridyle formamide and
Cesium carbonate is substituted into ether get Rui Gefeini in DMSO；The raw material phenyl chloroformate that this law uses has high toxicity, and unstable
It is fixed, there is certain corrosivity, the high requirements on the equipment is not suitable for industrialized production；2), Wang Yabo et al. is existed using p-aminobenzene sulfonic acid
Again with hydrochloric acid at salt after diazo-reaction in the presence of sodium carbonate and sodium nitrite, then with m fluorophenol 1mol/L hydrogen-oxygen
Change in sodium solution and obtain 4- [(the fluoro- 4- hydroxy phenyl of 2-) diazenyl] benzene sulfonic acid sodium salt through coupling reaction, then is passed through by sodium sulfite
Reduction reaction obtains 4- amino -3- fluorophenol；Then under potassium tert-butoxide effect, 4- amino -3- fluorophenol and N- methyl -4- are chloro-
2- pyridine carboxamide nucleo philic substitution reaction in n,N-dimethylacetamide obtains 4- (4- amino -3- fluorophenoxy) -2- (first
Base carbamyl) pyridine；Then again with the chloro- 3- of 4- (trifluoromethyl) aniline N'N- carbonyl dimidazoles (CDI) effect under through contracting
Urea get Rui Gefeini is synthesized, the method starting material p-aminobenzene sulfonic acid is cheap and easy to get, and reaction condition is mild, but since CDI is to sky
Air-sensitive sense is extremely easy in decomposition moist lability, chance water, and is easy to generate more difficult isolated dimer, and total recovery is relatively low, therefore uncomfortable
Close industrialized production.
Summary of the invention
The present invention provides the synthetic methods of anticancer drug Rui Gefeini a kind of, should be with 3- fluoro-4-nitrophenol (II)
Raw material obtains 4- (4- nitro -3- fluorobenzene oxygen through condensation reaction with N- methyl -4- Chloro-2-Pyridyle formamide in the presence of alkali
Base) -2- (methylcarbamoyl) pyridine (III), then (III) catalysis restores to obtain 4- (4- amino -3- fluorophenoxy) -2- (methyl
Carbamyl) pyridine (IV), then IV with the condensation reaction in tetrahydrofuran of the chloro- 3- of 4- (trifluoromethyl) phenyl isocyanate
Get Rui Gefeini (I).The present invention is easy to get using raw material is relatively inexpensive, reaction condition is mild, easy to operate and safe, product yield compared with
Height, product purity is high, industrial value with higher.
A kind of synthetic method of anticancer drug Rui Gefeini, includes the following steps:
A, 3- fluoro-4-nitrophenol, N- methyl -4- Chloro-2-Pyridyle formamide, solvent and alkali are added in reactor and are controlled
Temperature is stirred to react, and the reaction time 3~10 hours, reaction temperature was 80~180 DEG C and is condensed to obtain 4- (4- nitro -3- fluorophenoxy) -
2- (methylcarbamoyl) pyridine (III)；The solvent is selected from toluene, dimethylbenzene, diethylene glycol dimethyl ether, polyethylene glycol, second
One or several kinds of mixing of acetoacetic ester and dioxane, the alkali are selected from sodium hydroxide, potassium hydroxide, sodium methoxide, tertiary fourth
One or several kinds of mixing of potassium alcoholate, sodium carbonate, potassium carbonate and cesium carbonate, dosage are rubbing for 3- fluoro-4-nitrophenol (II)
1~3 times of amount of your equivalent；
B, by 4- obtained above (4- nitro -3- fluorophenoxy) -2- (methylcarbamoyl) pyridine (III), catalyst and
Solvent is added in reactor temperature control stirring and reacts, and is passed through hydrogen, and 0~60 DEG C of temperature control reaction temperature, the reaction time 1~5 hour
Restore to obtain 4- (4- amino -3- fluorophenoxy) -2- (methylcarbamoyl) pyridine (IV)；The catalyst be Raney's nickel or
Person's palladium carbon, dosage are the 0.1 of the molar equivalent of 4- (4- nitro -3- fluorophenoxy) -2- (methylcarbamoyl) pyridine (III)
~0.5 times of amount；The pressure of the hydrogen is 1-20atm；Described is selected from methylene chloride, chloroform, tetrahydrofuran, ethyl acetate
With the one or several kinds mixing of dioxane；
C, by 4- obtained above (4- amino -3- fluorophenoxy) -2- (methylcarbamoyl) pyridine (IV), the chloro- 3- of 4-
(trifluoromethyl) phenyl isocyanate and solvent are added to temperature control stirring in reactor and react, condensation reaction get Rui Gefeini (I)；
The solvent is selected from one or several kinds of mixing of methylene chloride, chloroform, tetrahydrofuran, ethyl acetate and dioxane；Institute
The reaction temperature for the temperature control stated is 0~60 DEG C, and being stirred to react the time is 2~8 hours；
Reaction route is as follows:
In the step (a), 90~160 DEG C of the reaction temperature, the reaction time is 6~8 hours.
In the step (b), the reaction temperature is 10~30 DEG C, and the reaction time is 2~4 hours.
In the step (c), the reaction temperature is 20~50 DEG C, and the reaction time is 3~7 hours.
The beneficial effects of the present invention are: (1) is with 3- fluoro-4-nitrophenol, N- methyl -4- Chloro-2-Pyridyle formamide and 4-
Chloro- 3- (trifluoromethyl) phenyl isocyanate is starting material, and raw material is cheap and easy to get, and route by-product is less, and yield is higher, is produced
Product overall cost is lower, and product market competition ability is strong.
(2) synthetic route is shorter and using being all the stable technique of comparative maturity, and reaction condition is mild, operation is convenient, green
Color is efficient.
Specific embodiment
The synthetic method of anticancer drug Rui Gefeini of the invention is done combined with specific embodiments below further details of
Description.
The preparation of embodiment 1:4- (4- nitro -3- fluorophenoxy) -2- (methylcarbamoyl) pyridine (III):
In four mouthfuls of 500mL closed reaction flasks, 31.4 grams of 3- fluoro-4-nitrophenols (II), 34.1 grams of N- first are added
Base -4- Chloro-2-Pyridyle formamide, 20.1 grams of sodium carbonate and 150 grams of dioxane, are heated at reflux, and are stirred to react 6 hours, TLC is anti-
It should monitor, reaction terminates 200 grams of elutriations of addition and goes out solid, filters to obtain product 4- (4- nitro -3- fluorophenoxy) -2- (methyl ammonia
Formoxyl) 49.5 grams of crude product of pyridine (III), yield 85.1%.
The preparation of embodiment 2:4- (4- nitro -3- fluorophenoxy) -2- (methylcarbamoyl) pyridine (III):
In four mouthfuls of 500mL closed reaction flasks, 31.4 grams of 3- fluoro-4-nitrophenols (II), 34.1 grams of N- first are added
Base -4- Chloro-2-Pyridyle formamide, 20.1 grams of sodium carbonate and 150 grams of diethylene glycol dimethyl ethers, are heated at reflux, it is small to be stirred to react 6
When, TLC reaction monitoring, reaction terminates 200 grams of elutriations of addition and goes out solid, filters to obtain product 4- (4- nitro -3- fluorophenoxy) -2-
55.6 grams of crude product of (methylcarbamoyl) pyridine (III), yield 95.5%.
The preparation of embodiment 3:4- (4- nitro -3- fluorophenoxy) -2- (methylcarbamoyl) pyridine (III):
In four mouthfuls of 500mL closed reaction flasks, 31.4 grams of 3- fluoro-4-nitrophenols (II), 34.1 grams of N- first are added
Base -4- Chloro-2-Pyridyle formamide, 27.8 grams of potassium carbonate and 150 grams of diethylene glycol dimethyl ethers, are heated at reflux, it is small to be stirred to react 6
When, TLC reaction monitoring, reaction terminates 200 grams of elutriations of addition and goes out solid, filters to obtain product 4- (4- nitro -3- fluorophenoxy) -2-
56.4 grams of crude product of (methylcarbamoyl) pyridine (III), yield 96.6%.
Embodiment 4:4- (4- amino -3- fluorophenoxy) -2- (methylcarbamoyl) pyridine (IV):
In 500mL closed autoclave, above-mentioned 4- (4- nitro -3- fluorophenoxy) -2- (methyl carbamyl is added
Base) 29.1 grams, 0.6 gram Raney's nickel of pyridine (III) crude product and 100 grams of methanol, it is passed through the hydrogen of 1atm, 20 DEG C of temperature control, stirring is anti-
It answers 3 hours, TLC reaction monitoring, reaction terminates that Raney's nickel is recovered by filtration, and then decompression steams methanol and obtains 4- (4- amino -3- fluorobenzene
Oxygroup) 25.8 grams of crude product of -2- (methylcarbamoyl) pyridine (IV), yield 98.9%.
Embodiment 5:4- (4- amino -3- fluorophenoxy) -2- (methylcarbamoyl) pyridine (IV):
In 500mL closed autoclave, above-mentioned 4- (4- nitro -3- fluorophenoxy) -2- (methyl carbamyl is added
Base) 29.1 grams, 0.6 gram Raney's nickel of pyridine (III) crude product and 100 grams of methanol, it is passed through the hydrogen of 2atm, 20 DEG C of temperature control, stirring is anti-
It answers 3 hours, TLC reaction monitoring, reaction terminates that Raney's nickel is recovered by filtration, and then decompression steams methanol and obtains 4- (4- amino -3- fluorobenzene
Oxygroup) 26.0 grams of crude product of -2- (methylcarbamoyl) pyridine (IV), yield 99.6%.
Embodiment 6: Rui Gefeini (I):
In four mouthfuls of 500mL closed reaction flasks, above-mentioned 4- (4- amino -3- fluorophenoxy) -2- (methyl carbamyl is added
Base) (IV) 52.3 gram of pyridine, 44.3 grams and 200 grams of tetrahydrofuran, 20 DEG C of room temperature of 4- chloro- 3- (trifluoromethyl) phenyl isocyanate
It is stirred to react 5 hours, TLC reaction monitoring, reaction terminates that 75 gram 10% of dilute hydrochloric acid is added dropwise, and solid is precipitated, filters get Rui Gefei
The hydrochloride of Buddhist nun, the free then ethyl acetate of filter cake sodium hydrate aqueous solution extract, are evaporated ethyl acetate and obtain product Rui Gefeini
78.9 grams, yield 81.7%.
Embodiment 7: Rui Gefeini (I):
In four mouthfuls of 500mL closed reaction flasks, above-mentioned 4- (4- amino -3- fluorophenoxy) -2- (methyl carbamyl is added
Base) (IV) 52.3 gram of pyridine, 44.3 grams and 200 grams of tetrahydrofuran, 20 DEG C of room temperature of 4- chloro- 3- (trifluoromethyl) phenyl isocyanate
It is stirred to react 5 hours, TLC reaction monitoring, reaction terminates that 75 gram 10% of dilute hydrochloric acid is added dropwise, and solid is precipitated, filters get Rui Gefei
The hydrochloride of Buddhist nun, the free then ethyl acetate of filter cake aqueous sodium carbonate extract, are evaporated ethyl acetate and obtain product Rui Gefeini
86.7 grams, yield 89.8%.
Most preferred embodiment 8:
In four mouthfuls of 500mL closed reaction flasks, 31.4 grams of 3- fluoro-4-nitrophenols (II), 34.1 grams of N- first are added
Base -4- Chloro-2-Pyridyle formamide, 27.8 grams of potassium carbonate and 150 grams of diethylene glycol dimethyl ethers, are heated at reflux, it is small to be stirred to react 6
When, reaction terminates 200 grams of elutriations of addition and goes out solid, filters to obtain product 4- (4- nitro -3- fluorophenoxy) -2- (methyl carbamyl
Base) 56.4 grams of crude product of pyridine (III), obtain 56.4 gram III is added in the closed autoclave of 500mL, 1.16 Cray Buddhist nuns
Nickel and 200 grams of methanol are passed through the hydrogen of 2atm, 20 DEG C of temperature control, are stirred to react 3 hours, and reaction terminates that Raney's nickel is recovered by filtration,
Decompression steams methanol and obtains 50.2 gram IV, and then 50.2 gram IV is added in four mouthfuls of closed reaction flasks of 500mL, is added 42.6
Gram chloro- 3- of 4- (trifluoromethyl) phenyl isocyanate and 200 grams of tetrahydrofurans, 20 DEG C of room temperature are stirred to react 5 hours, reaction knot
75 gram 10% of dilute hydrochloric acid is added dropwise in beam, and solid is precipitated, and filters the hydrochloride of get Rui Gefeini, and filter cake aqueous sodium carbonate is free right
Ethyl acetate extracts afterwards, is evaporated ethyl acetate and obtains 83.7 grams of product Rui Gefeini, total recovery 86.4%.
Above-described embodiment is the refinement to the technical program, and the technical solution that the invention represents is not limited to
Embodiment is stated, the data that each end in left and right refers to can also be such as supplemented, above-mentioned parameters can be according to the actual situation according in invention
The parameter mentioned in appearance carries out optimum selecting.
Claims (4)
1. a kind of synthetic method of anticancer drug Rui Gefeini, include the following steps: it is characterized by: a, by the fluoro- 4- nitro of 3-
Phenol, N- methyl -4- Chloro-2-Pyridyle formamide, solvent and alkali are added to temperature control stirring in reactor and react, and the reaction time 3~
10 hours, reaction temperature was 80~180 DEG C and is condensed to obtain 4- (4- nitro -3- fluorophenoxy) -2- (methylcarbamoyl) pyridine
(Ⅲ)；The solvent is selected from the one of toluene, dimethylbenzene, diethylene glycol dimethyl ether, polyethylene glycol, ethyl acetate and dioxane
Kind or several mixing, the alkali be selected from sodium hydroxide, potassium hydroxide, sodium methoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate and
One or several kinds of mixing of cesium carbonate, dosage are 1~3 times of amount of the molar equivalent of 3- fluoro-4-nitrophenol (II)；
B, by 4- obtained above (4- nitro -3- fluorophenoxy) -2- (methylcarbamoyl) pyridine (III), catalysts and solvents
It is added to temperature control stirring in reactor to react, is passed through hydrogen, 0~60 DEG C of temperature control reaction temperature, restored within the reaction time 1~5 hour
Obtain 4- (4- amino -3- fluorophenoxy) -2- (methylcarbamoyl) pyridine (IV)；The catalyst is Raney's nickel or palladium
Carbon, dosage are the 0.1~0.5 of the molar equivalent of 4- (4- nitro -3- fluorophenoxy) -2- (methylcarbamoyl) pyridine (III)
It measures again；The pressure of the hydrogen is 1-20atm；Described is selected from methylene chloride, chloroform, tetrahydrofuran, ethyl acetate and two
One or several kinds of mixing of six ring of oxygen；
C, by 4- obtained above (4- amino -3- fluorophenoxy) -2- (methylcarbamoyl) pyridine (IV), the chloro- 3- (trifluoro of 4-
Methyl) phenyl isocyanate and solvent be added to temperature control stirring in reactor and react, condensation reaction get Rui Gefeini (I)；It is described
Solvent be selected from one or several kinds of mixing of methylene chloride, chloroform, tetrahydrofuran, ethyl acetate and dioxane；Described
The reaction temperature of temperature control is 0~60 DEG C, and being stirred to react the time is 2~8 hours；
Reaction route is as follows:
2. the synthetic method of anticancer drug Rui Gefeini according to claim 1 a kind of, it is characterised in that: the step
(a) in, 90~160 DEG C of the reaction temperature, the reaction time is 6~8 hours.
3. the synthetic method of anticancer drug Rui Gefeini according to claim 1 a kind of, it is characterised in that: the step
(b) in, the reaction temperature is 10~30 DEG C, and the reaction time is 2~4 hours.
4. the synthetic method of anticancer drug Rui Gefeini according to claim 1 a kind of, it is characterised in that: the step
(c) in, the reaction temperature is 20~50 DEG C, and the reaction time is 3~7 hours.
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Application publication date: 20190830 |