CN105566215B - A kind of Rui Gefeini preparation method - Google Patents
A kind of Rui Gefeini preparation method Download PDFInfo
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Abstract
The invention discloses a kind of Rui Gefeini preparation method, wherein introducing noval chemical compound 4 (3 fluorophenoxy)NThe formamide of picoline 2（5）With 4 (amino-benzene oxygens of 3 fluorine 4)NThe formamide of picoline 2（6）As intermediate, a kind of have that reaction condition is gentle, post processing is simple, reaction yield and purity are high, cost is low and method more reasonably Rui Gefeini preparation method by introducing the intermediate and providing.
Description
Technical field
The invention belongs to pharmaceutical technology field, there is provided a kind of Mutiple Targets kinase inhibitor Rui Gefeini synthetic method,
More specifically to by introducing 4- (3- fluorophenoxies)-N- picoline -2- formamides (5), 4- (the fluoro- 4- nitrobenzene of 3-
Epoxide)-N- picoline -2- formamides (6) and 4- (the fluoro- 4- amino-benzene oxygens of 3-)-N- picoline -2- formamides (7) make
For the Rui Gefeini of intermediate preparation method.
Background technology
Rui Gefeini (regorafenib, 1) is researched and developed by Beyer Co., Ltd, and first is proved to can be used for treating metastatic
The small molecule Mutiple Targets kinase inhibitor of the carcinoma of the rectum (mCRC), the approval of 2012 food and medicine Surveillance Authority of the Nian9Yue U.S. (FDA)
Listing, trade name Stivarga.It can effectively block tumor cell proliferation, suppress Tumor Angiongesis, modulate tumor micro-loop
Border, there is good antitumor activity.Medicines structure and Sorafenib only have fine difference, but its to VEGFR-2, PDGFR- β,
FGFR-1 and c-Kit inhibitory action is stronger, moreover it is possible to suppresses Tie-2, has wider blood vessel formation against function.It is complete at present
Into Rui Gefeini for the two large-scale random phase of the international, multi-center III clinical examination of metastatic colorectal carcinoma and GISTs
Test, its single medicine or currently actively develop with the clinical researches of standard chemotherapeutic agents therapeutic alliance other malignant tumours.Knot
Structure formula is：
At present, the bibliography about Rui Gefeini preparation methods includes：Patent WO2005009961,
WO2008089388、WO2011130728、WO2012012404.The Rui Gefeini provided in these documents preparation method, it is
Using pyridine -2- formic acid as initiation material, Rui Gefeini is made through chloro, ammonolysis, into ether and addition reaction.
In ammonolysis reaction, these documents prepare the hydrochloride of intermediate 4 by following steps：By the brown of intermediate 4
Grease is dissolved in organic solvent, after by the way that concentrated hydrochloric acid is added dropwise into salt.This method yield is low, and compound character is bad, therefore, this
Invention is improved the salifying method of intermediate 4.
In the route reacts into ether, the method specifically reported according to above-mentioned document, although reaction only has a step, reaction
Need to carry out under solvent in nitrogen strict protection and do with DMA, side reaction is a lot, easily produces and docks with amino and phenol is oxidized
Accessory substance, post processing it is numerous and diverse, product purification it is more difficult, it is necessary to pillar layer separation purify, yield is not high, is not suitable for industrial metaplasia
Production.In consideration of it, the present invention devises new synthetic route.
The content of the invention
The purpose of the present invention is to be directed to the problems and shortcomings present on, there is provided it is a kind of prepare Rui Gefeini have efficacious prescriptions
Method, it is used as intermediate by introducing noval chemical compound 5 and 6, there is provided a kind of reaction condition milder, post processing is simpler, reacts and receives
Rate and purity is higher, cost is lower and method more reasonably Rui Gefeini preparation method.
Due to compound 4- (3- fluorophenoxies)-N- picoline -2- formamides (5) and 4- (the fluoro- 4- aminobenzenes oxygen of 3-
Base)-N- picoline -2- formamides (6) are synthesis first and are used for Rui Gefeini preparation, therefore, the present invention includes chemical combination
The synthesis of thing 5 and 6 and its application in Rui Gefeini is prepared.
The present invention synthetic route be：
The preparation method of the present invention, comprises the following steps：
1) chlorination：Pyridine -2- formic acid (2) and NaBr are added in chlorobenzene, thionyl chloride is slowly added dropwise under stirring, is risen
Temperature to 85~130 DEG C of reactions, reaction finishes, is cooled to room temperature, is concentrated under reduced pressure, and obtains the yellow oil (3) containing a small amount of solid, after
Toluene is added to it, is directly used in the next step.
2) ammonolysis reaction：Methylamine water solution is cooled to -10~0 DEG C, 3 toluene solution, control temperature are slowly added under stirring
Degree is not higher than 50 DEG C, finishes, and reacts at room temperature, and reaction finishes, separates water layer and extracted with toluene, and be concentrated under reduced pressure organic phase, thereto
The organic solvent solution of hydrogen chloride is added, filters, filter cake is dissolved in water, adjusts pH to filter to neutrality, dry, it is chloro- to obtain 4- with buck
N- picoline -2- formamides (4).
Wherein, the organic solvent is selected from dichloromethane, ether, acetone, tetrahydrofuran, dioxane, ethyl acetate, second
One or more in alcohol or methanol.
Preferable organic solvent is dioxane.
Wherein, in ammonolysis reaction, the buck be sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate,
The aqueous solution or ammoniacal liquor of saleratus or sodium acid carbonate.
It is preferred that buck is sodium hydrate aqueous solution.
3) reacted into ether：3- fluorophenols and alkali are added in organic solvent, stir 30min, it is rear to add 4- chloro-n-methyl pyrroles
Pyridine -2- formamides (4), 70~180 DEG C of reactions are warming up to, 4- (3- fluorophenoxies)-N- picoline -2- formamides (5) are made.
Wherein, the one kind or one of the organic solvent in acetonitrile, DMF, DMA, DMSO, NMP, benzene, toluene and chlorobenzene
The mixed solvent of the kind above.
Preferable organic solvent is DMF.
Wherein, the alkali is selected from hydrogen sodium, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, carbonic acid
One kind in sodium, cesium carbonate, sodium methoxide, potassium methoxide or caustic alcohol.
Preferable alkali is potassium hydroxide.
4) nitration reaction：Intermediate 5 is dissolved in the concentrated sulfuric acid, after be slowly dropped into the nitration mixture of concentrated nitric acid-concentrated sulfuric acid, control temperature
Less than 50 DEG C reactions of degree, reaction are finished, are poured into water, organic solvent extraction, merge organic phase, use saturated aqueous common salt successively
Wash, dry, filter, be concentrated under reduced pressure, obtain yellow oil (6), it is not purified to be directly used in the next step.
Wherein, the volume ratio of the concentrated nitric acid-concentrated sulfuric acid nitration mixture is 1:10~10:1, preferred volume ratio 1:3；The temperature
Degree is less than 50 DEG C, and preferable temperature is -10~0 DEG C.
Wherein, the organic solvent is selected from dichloromethane, ethyl acetate, benzene, toluene, chlorobenzene, ether, chloroform, four chlorinations
One or more kinds of mixed solvents in carbon and hexamethylene.
Preferable solvent is one or more kinds of mixed solvents in dichloromethane, ethyl acetate, toluene, ether.
5) reduction reaction：Iron powder, ammonium chloride, concentrated hydrochloric acid are added to the in the mixed solvent of organic solvent-water, are heated to reflux
30min, rear to instill step reaction grease, reaction is finished, filtered while hot, and be concentrated under reduced pressure filtrate, is dissolved added with solvent remaining
Thing, acid rinsing, water layer are extracted with organic solvent, are merged organic phase, are dried, filter, are evaporated, obtain 4- (the fluoro- 4- aminobenzenes oxygen of 3-
Base)-N- picoline -2- formamides (7).
Wherein, the mixed solvent system has alcohol-water, methanol-water, tetrahydrofuran-water, acetone-water, toluene-water, institute
Volume ratio is stated as 1:5~5:1.
Preferable mixed solvent is alcohol-water, preferred volume ratio 4:3.
Wherein, the organic solvent is selected from dichloromethane, ethyl acetate, benzene, toluene, chlorobenzene, ether, chloroform, four chlorinations
One or more kinds of mixed solvents in carbon and hexamethylene.
Preferable solvent is one or more kinds of mixed solvents in dichloromethane, ethyl acetate, toluene, ether.
Wherein, selected sour water be hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, oxalic acid, acetic acid, ammonium sulfate or ammonium chloride in one kind or
More than one mixed solvent；Sour water pH 2~6.It is preferred that sour water is 10% hydrochloric acid.
6) carbonylation：Solid phosgene is dissolved in organic solvent, is cooled to -10~0 DEG C, the chloro- 3- trifluoros of 4- are added portionwise
Methylaniline (9), back flow reaction 1h, it is evaporated under reduced pressure, collects the 120 DEG C/0.1MPa chloro- 3- trifluoromethylbenzenes isocyanic acids of cut 4-
Ester (8).
7) addition reaction：Intermediate 7 and the chloro- 3- trifluoromethyls phenylisocyanates (8) of 4- are dissolved in organic solvent, room temperature is anti-
30min is answered, is filtered, washs filter cake, dries, obtains target compound 4- (4- (3- (the chloro- 3- trifluoromethyls of 4-) urea groups) -3-
Fluorophenoxy)-N- picoline -2- formamides (1)；
The present invention prepares Rui Gefeini by introducing intermediate 5 and 6, significantly reduces side reaction, improves product purity
And yield, reach the purpose for reducing production cost and shortening reaction time, in particular, simplify post processing, this is in industrialized production
In it is critically important.
On the basis of the above, according to the ordinary technical knowledge and customary means of this area, the present invention is not being departed from
Under the premise of above-mentioned basic fundamental thought, the modification, replacement or change of diversified forms can also be made.
Embodiment
By the description of detailed description below, the above of the present invention is described in further detail.For
For those skilled in the art, the scope that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to following method description；
All technologies realized based on the above of the present invention belong to the scope of the present invention.
1st, the synthesis of 4- Chloro-2-Pyridyles formyl chloride hydrochloride (3)
30.0g (244mmol) pyridine -2- formic acid (2) and 4.0g (39mmol) NaBr are added in 40mL chlorobenzenes, under stirring
70mL thionyl chlorides are slowly added dropwise, finish, are warming up to 85 DEG C, react 23h.It is cooled to room temperature, is concentrated under reduced pressure, obtains containing a small amount of solid
Yellow oil.Backward its adds 120mL toluene, is directly used in the next step.
2nd, the synthesis of 4- chloro-n-methyls pyridine-2-carboxamide (4)
97mL 40% (826mmol) methylamine water solution is added in 75mL water, is cooled to 0 DEG C, is slowly added under stirring above-mentioned
3 toluene solution, controlling reaction temperature are less than 50 DEG C, finished, and react at room temperature 7h, separate water layer and extracted with toluene, merge organic
Phase, it is concentrated under reduced pressure, the dioxane solution of 150mL hydrogen chloride is added to residue, 1h is stirred at room temperature, filters.Filter cake is dissolved in
In 150mL water, pH is adjusted to filter to neutrality, dry, obtain yellow powder (4) with the 20%NaOH aqueous solution.Two-step reaction total recovery
88.3%, (the literature value of purity 99.5%：Two-step reaction total recovery 67%, purity is about 96%).MS m/z:171.1,172.1,
173.1[M+H]+,193.1[M+Na]+.1H NMR(400MHz,DMSO-d6)δ:8.87 (s, 1H), 8.63 (d, J=5.3Hz,
1H), 8.03 (d, J=2.1Hz, 1H), 7.77 (dd, J=2.1,5.3Hz, 1H), 2.84 (d, J=4.8Hz, 3H)
3rd, the synthesis of 4- (3- fluorophenoxies)-N- picoline -2- formamides (5)
8.5g (76mmol) 3- fluorophenols and 7.8g (141mmol) potassium hydroxide are added in 100mL DMF, are stirred at room temperature
30min, 10.0g (59mmol) intermediate 4 is added afterwards, is warming up to 100 DEG C of reactions.Reaction finishes, and is cooled to room temperature, is poured into
In 800mL water, stirring and crystallizing, filter, dry, obtain off-white color crystal (5).Yield 81.3%, purity 99.2%, mp 197~
198℃。MS m/z:247.2[M+H]+,269.0[M+Na]+,285.0[M+K]+.1H NMR(600MHz,DMSO)δ:8.79(d,
J=4.4Hz, 1H), 8.55 (d, J=5.6Hz, 1H), 7.56 (dd, J=15.1,8.1Hz, 1H), 7.45 (d, J=2.5Hz,
1H), 7.28-7.11 (m, 3H), 7.10 (dd, J=8.1,1.7Hz, 1H), 2.80 (d, J=4.9Hz, 3H)
4th, the synthesis of 4- (the fluoro- 4-nitrophenoxys of 3-)-N- picoline -2- formamides (6)
6.0g (25mmol) intermediate 5 is dissolved in the 30mL concentrated sulfuric acids, after be slowly added dropwise into 2.5mL concentrated nitric acids-concentrated sulfuric acid
(volume ratio 1:3) nitration mixture, control temperature -10~0 DEG C reaction 1.5h.It is poured into 700mL water, ethyl acetate extraction, closes
And organic phase, saturated common salt water washing, dry, filter, be evaporated, obtain yellow oil (6), not purified to be directly used in lower step anti-
Should.MS m/z:292.0[M+H]+,314.0[M+Na]+,330.0[M+K]+,605.0[2M+Na]+.
5th, the synthesis of 4- (the fluoro- 4- amino-benzene oxygens of 3-)-N- picoline -2- formamides (7)
6.3g (113mmol) iron powder, 0.75g (14mmol) ammonium chlorides and 1.7mL (42mmol) concentrated hydrochloric acid are added into 40mL
Alcohol-water (volume ratio 4:3) in the mixed solvent, temperature rising reflux 30min.Add the grease of intermediate 6, back flow reaction 1h.Take advantage of
Heat filters, and is evaporated filtrate, adds ethyl acetate dissolving residue, 10% salt acid elution, aqueous layer with ethyl acetate extraction, is associated with
Machine phase, saturated common salt washing, anhydrous magnesium sulfate are dried, filter, be evaporated filtrate, obtain brick-red solid (7).Two-step reaction total recovery
76.6%, (the literature value of purity 99.8%：Yield 47%).MS m/z:261.9[M+H]+,283.9[M+Na]+.1H NMR
(400MHz,DMSO-d6)δ:8.80 (q, J=4.7Hz, 1H), 8.50 (d, J=5.6Hz, 1H), 7.40 (d, J=2.4Hz,
1H), 7.13 (dd, J=2.8,5.6Hz, 1H), 7.08 (dd, J=2.4,12Hz, 1H), 6.98 (t, J=8.8Hz, 1H), 6.85
(dd, J=2.8,8.4Hz, 1H), 5.50 (brs, 2H), 2.80 (d, J=4.8Hz, 3H)
6th, the synthesis of the chloro- 3- trifluoromethyls phenylisocyanates (8) of 4-
It is stirred at room temperature down, by 12.0g (40mmol)) solid phosgene (BTC) is dissolved in 120mL ethyl acetate, it is cooled to 0 DEG C, point
Criticize and add the chloro- 3- 5-trifluoromethylanilines (9) of 20.0g 4-, be warming up to 80 DEG C, back flow reaction 1h, be evaporated under reduced pressure, 120 DEG C of collection/
0.1MPa cuts, white crystal is obtained after solidification.Yield 94.3%, purity 98.9%.1H NMR(400MHz,CDCl3)δ:7.48
(d, J=8.5Hz, 1H), 7.44 (d, J=2.4Hz, 1H), 7.22 (dd, J=2.3,8.5Hz, 1H)
7th, 4- (4- (3- (the chloro- 3- trifluoromethyls of 4-) urea groups) -3- fluorophenoxies)-N- picoline -2- formamides
(1) synthesis
3.0g (11mmol) intermediate 7 is dissolved in 20mL ethyl acetate, adds 3.5g (16mmol)) the chloro- 3- fluoroforms of 4-
Base phenylisocyanate (8), 30min is reacted at room temperature, filter, filter cake is washed with 50mL ether, filtered, dried, obtain lightpink powder
(1).Yield 94.5%, purity 99.8%.MS m/z:480.9,481.7,482.9 [M-H]-,504.9,505.8,506.9[M
+Na]+.1H NMR(400MHz,DMSO-d6)δ:9.55 (s, 1H), 8.79 (q, J=4.8Hz, 1H), 8.75 (d, J=2.3Hz,
1H), 8.53 (d, J=5.6Hz, 1H), 8.16 (t, J=9.0Hz, 1H), 8.13 (t, J=1.5Hz, 1H), 7.63 (d, J=
1.5Hz, 2H), 7.43 (d, J=2.6Hz, 1H), 7.34 (dd, J=11.6,2.7Hz, 1H), 7.21-7.17 (m, 1H), 7.08
(ddd, J=8.9,2.8,1.3Hz, 1H), 2.80 (d, J=4.8Hz, 3H).
Claims (18)
1. a kind of preparation method of Rui Gefeini (1), including chloro, ammonolysis, into ether, nitrification, reduction, addition reaction, its feature
It is, by following steps：
1) chlorination：Under NaBr catalytic action, compound 4-chloro -2- pyrroles are made with thionyl chloride in pyridine -2- formic acid (2)
The hydrochloride (3) of pyridine formyl chloride；
2) ammonolysis reaction：The hydrochloride (3) of 4- Chloro-2-Pyridyle formyl chlorides reacts with methylamine water solution, obtains 4- chloro-n-methyl pyrroles
Pyridine -2- formamides (4)；
3) reacted into ether：In the presence of alkali, 4- (3- fluorine is made with 3- fluorophenols in 4- chloro-n-methyls pyridine-2-carboxamide (4)
Phenoxy group)-N- picoline -2- formamides (5)；
4) nitration reaction：4- (3- fluorophenoxies)-N- picoline -2- formamides (5) react with concentrated nitric acid-concentrated sulfuric acid nitration mixture,
Obtain 4- (the fluoro- 4-nitrophenoxys of 3-)-N- picoline -2- formamides (6)；
5) reduction reaction：4- (the fluoro- 4-nitrophenoxys of 3-)-N- picoline -2- formamides (6) reduce through ferrous acid, and 4- is made
(the fluoro- 4- amino-benzene oxygens of 3-)-N- picoline -2- formamides (7)；
6) addition reaction：4- (the fluoro- 4- amino-benzene oxygens of 3-)-N- picoline -2- formamides (7) and the chloro- 3- trifluoromethyls of 4-
Phenylisocyanate (8) react, obtain target compound 4- (4- (3- (the chloro- 3- trifluoromethyls of 4-) urea groups) -3- fluorophenoxies) -
N- picoline -2- formamides (1).
2. preparation method according to claim 1, it is characterised in that
The chloro- 3- trifluoromethyls phenylisocyanates (8) of 4- described in step 6) are by the chloro- 3- 5-trifluoromethylanilines (9) of 4- with consolidating
Body phosgene reaction obtains.
3. preparation method according to claim 1 or 2, it is characterised in that
Step 3) reacts as follows into ether：3- fluorophenols and alkali are added in organic solvent, stir 30min, it is rear to add the chloro- N- of 4-
Picoline -2- formamides (4), 70~180 DEG C of reactions are warming up to, 4- (3- fluorophenoxies)-N- picoline -2- formyls are made
Amine (5).
4. according to the preparation method described in claim 1-2 any one, it is characterised in that
Step 4) nitration reaction is as follows：4- (3- fluorophenoxies)-N- picoline -2- formamides (5) are dissolved in the concentrated sulfuric acid, after
The nitration mixture of concentrated nitric acid-concentrated sulfuric acid, less than the 50 DEG C reactions of control temperature are slowly dropped into, reaction is finished, is poured into water, You Jirong
Agent extract, merge organic phase, saturated sodium-chloride water solution washing, dry, filter, filtrate be evaporated yellow oil 4- (3- is fluoro-
4-nitrophenoxy)-N- picoline -2- formamides (6), it is not purified to be directly used in the next step.
5. preparation method according to claim 3, it is characterised in that
Step 4) nitration reaction is as follows：4- (3- fluorophenoxies)-N- picoline -2- formamides (5) are dissolved in the concentrated sulfuric acid, after
The nitration mixture of concentrated nitric acid-concentrated sulfuric acid, less than the 50 DEG C reactions of control temperature are slowly dropped into, reaction is finished, is poured into water, You Jirong
Agent extract, merge organic phase, saturated sodium-chloride water solution washing, dry, filter, filtrate be evaporated yellow oil 4- (3- is fluoro-
4-nitrophenoxy)-N- picoline -2- formamides (6), it is not purified to be directly used in the next step.
6. according to the preparation method described in claim 1,2 or 5 any one, it is characterised in that
Step 5) reduction reaction is as follows：Iron powder, ammonium chloride, concentrated hydrochloric acid are added to the in the mixed solvent of organic solvent-water, heated back
30min is flowed, rear to instill grease 4- (the fluoro- 4-nitrophenoxys of 3-)-N- picoline -2- formamides (6), reaction finishes, and takes advantage of
Heat filters, and be concentrated under reduced pressure filtrate, dissolves residue added with solvent, with acid rinsing, water layer is extracted with organic solvent, is associated with
Machine phase, dry, filter, filtrate is evaporated, and obtains 4- (the fluoro- 4- amino-benzene oxygens of 3-)-N- picoline -2- formamides (7).
7. preparation method according to claim 3, it is characterised in that
Step 5) reduction reaction is as follows：Iron powder, ammonium chloride, concentrated hydrochloric acid are added to the in the mixed solvent of organic solvent-water, heated back
30min is flowed, rear to instill grease 4- (the fluoro- 4-nitrophenoxys of 3-)-N- picoline -2- formamides (6), reaction finishes, and takes advantage of
Heat filters, and be concentrated under reduced pressure filtrate, dissolves residue added with solvent, with acid rinsing, water layer is extracted with organic solvent, is associated with
Machine phase, dry, filter, filtrate is evaporated, and obtains 4- (the fluoro- 4- amino-benzene oxygens of 3-)-N- picoline -2- formamides (7).
8. preparation method according to claim 4, it is characterised in that
Step 5) reduction reaction is as follows：Iron powder, ammonium chloride, concentrated hydrochloric acid are added to the in the mixed solvent of organic solvent-water, heated back
30min is flowed, rear to instill grease 4- (the fluoro- 4-nitrophenoxys of 3-)-N- picoline -2- formamides (6), reaction finishes, and takes advantage of
Heat filters, and be concentrated under reduced pressure filtrate, dissolves residue added with solvent, with acid rinsing, water layer is extracted with organic solvent, is associated with
Machine phase, dry, filter, filtrate is evaporated, and obtains 4- (the fluoro- 4- amino-benzene oxygens of 3-)-N- picoline -2- formamides (7).
9. according to the preparation method described in any one of claim 1,2,5,7,8, it is characterised in that
Described ammonolysis reaction is as follows：Methylamine water solution is cooled to -10~0 DEG C, 4- Chloro-2-Pyridyle formyls are slowly added under stirring
The toluene solution of the hydrochloride (3) of chlorine, control temperature are not higher than 50 DEG C, finished, react at room temperature, and reaction finishes, and separate water layer use
Toluene extracts, and be concentrated under reduced pressure organic phase, adds the organic solvent solution of hydrogen chloride thereto, filters, filter cake is dissolved in into water, uses alkali
Water adjusts pH to filter to neutrality, dry, obtain 4- chloro-n-methyls pyridine-2-carboxamide (4)；Wherein, the organic solvent is selected from two
Chloromethanes, ether, acetone, tetrahydrofuran, dioxane, ethyl acetate, ethanol and methanol, the organic solvent of the hydrogen chloride are molten
Liquid is the corresponding hydrogen chloride solution of above-mentioned organic solvent；The buck is sodium hydroxide, potassium hydroxide, calcium hydroxide, carbonic acid
Sodium, potassium carbonate, the aqueous solution or ammoniacal liquor of saleratus or sodium acid carbonate.
10. preparation method according to claim 3, it is characterised in that
Described ammonolysis reaction is as follows：Methylamine water solution is cooled to -10~0 DEG C, 4- Chloro-2-Pyridyle formyls are slowly added under stirring
The toluene solution of the hydrochloride (3) of chlorine, control temperature are not higher than 50 DEG C, finished, react at room temperature, and reaction finishes, and separate water layer use
Toluene extracts, and be concentrated under reduced pressure organic phase, adds the organic solvent solution of hydrogen chloride thereto, filters, filter cake is dissolved in into water, uses alkali
Water adjusts pH to filter to neutrality, dry, obtain 4- chloro-n-methyls pyridine-2-carboxamide (4)；Wherein, the organic solvent is selected from two
Chloromethanes, ether, acetone, tetrahydrofuran, dioxane, ethyl acetate, ethanol and methanol, the organic solvent of the hydrogen chloride are molten
Liquid is the corresponding hydrogen chloride solution of above-mentioned organic solvent；The buck is sodium hydroxide, potassium hydroxide, calcium hydroxide, carbonic acid
Sodium, potassium carbonate, the aqueous solution or ammoniacal liquor of saleratus or sodium acid carbonate.
11. preparation method according to claim 4, it is characterised in that
Described ammonolysis reaction is as follows：Methylamine water solution is cooled to -10~0 DEG C, 4- Chloro-2-Pyridyle formyls are slowly added under stirring
The toluene solution of the hydrochloride (3) of chlorine, control temperature are not higher than 50 DEG C, finished, react at room temperature, and reaction finishes, and separate water layer use
Toluene extracts, and be concentrated under reduced pressure organic phase, adds the organic solvent solution of hydrogen chloride thereto, filters, filter cake is dissolved in into water, uses alkali
Water adjusts pH to filter to neutrality, dry, obtain 4- chloro-n-methyls pyridine-2-carboxamide (4)；Wherein, the organic solvent is selected from two
Chloromethanes, ether, acetone, tetrahydrofuran, dioxane, ethyl acetate, ethanol and methanol, the organic solvent of the hydrogen chloride are molten
Liquid is the corresponding hydrogen chloride solution of above-mentioned organic solvent；The buck is sodium hydroxide, potassium hydroxide, calcium hydroxide, carbonic acid
Sodium, potassium carbonate, the aqueous solution or ammoniacal liquor of saleratus or sodium acid carbonate.
12. preparation method according to claim 6, it is characterised in that
Described ammonolysis reaction is as follows：Methylamine water solution is cooled to -10~0 DEG C, 4- Chloro-2-Pyridyle formyls are slowly added under stirring
The toluene solution of the hydrochloride (3) of chlorine, control temperature are not higher than 50 DEG C, finished, react at room temperature, and reaction finishes, and separate water layer use
Toluene extracts, and be concentrated under reduced pressure organic phase, adds the organic solvent solution of hydrogen chloride thereto, filters, filter cake is dissolved in into water, uses alkali
Water adjusts pH to filter to neutrality, dry, obtain 4- chloro-n-methyls pyridine-2-carboxamide (4)；Wherein, the organic solvent is selected from two
Chloromethanes, ether, acetone, tetrahydrofuran, dioxane, ethyl acetate, ethanol and methanol, the organic solvent of the hydrogen chloride are molten
Liquid is the corresponding hydrogen chloride solution of above-mentioned organic solvent；The buck is sodium hydroxide, potassium hydroxide, calcium hydroxide, carbonic acid
Sodium, potassium carbonate, the aqueous solution or ammoniacal liquor of saleratus or sodium acid carbonate.
13. preparation method according to claim 3, it is characterised in that：In being reacted into ether, the organic solvent is selected from second
Nitrile, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, dimethyl sulfoxide (DMSO), 1-METHYLPYRROLIDONE, benzene, toluene and chlorobenzene
In one or more kinds of mixed solvents；The alkali is selected from hydrogen sodium, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, hydroxide
Lithium, potassium carbonate, sodium carbonate, cesium carbonate, sodium methoxide, potassium methoxide and caustic alcohol.
14. according to the preparation method any one of claim 5,7,10, it is characterised in that：It is described in being reacted into ether
Organic solvent be selected from acetonitrile, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, dimethyl sulfoxide (DMSO), 1-METHYLPYRROLIDONE,
One or more kinds of mixed solvents in benzene, toluene and chlorobenzene；The alkali is selected from hydrogen sodium, potassium tert-butoxide, sodium hydroxide, hydrogen
Potassium oxide, lithium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, sodium methoxide, potassium methoxide and caustic alcohol.
15. preparation method according to claim 4, it is characterised in that：In nitration reaction, reaction temperature is less than 50 DEG C；Institute
The volume ratio for stating concentrated nitric acid-concentrated sulfuric acid nitration mixture is 1:10~10:1；The organic solvent be selected from dichloromethane, ethyl acetate, benzene,
One or more kinds of mixed solvents in toluene, chlorobenzene, ether, chloroform, carbon tetrachloride and hexamethylene.
16. according to the preparation method any one of claim 8,11, it is characterised in that：In nitration reaction, reaction temperature
Degree is less than 50 DEG C；The volume ratio of the concentrated nitric acid-concentrated sulfuric acid nitration mixture is 1:10~10:1；The organic solvent is selected from dichloromethane
One or more kinds of mixing in alkane, ethyl acetate, benzene, toluene, chlorobenzene, ether, chloroform, carbon tetrachloride and hexamethylene are molten
Agent.
17. preparation method according to claim 6, it is characterised in that：In reduction reaction, the mixed solvent system has：
Alcohol-water, methanol-water, tetrahydrofuran-water, acetone-water and toluene-water, volume ratio 1:5~5:1；The organic solvent choosing
One or more from dichloromethane, ethyl acetate, benzene, toluene, chlorobenzene, ether, chloroform, carbon tetrachloride and hexamethylene
Mixed solvent；Selected sour water is one kind or one in hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, oxalic acid, acetic acid, ammonium sulfate or ammonium chloride
The aqueous solution of the kind above；Sour water pH 2~6.
18. according to the preparation method any one of claim 7,8, it is characterised in that：In reduction reaction, the mixing
Dicyandiamide solution has：Alcohol-water, methanol-water, tetrahydrofuran-water, acetone-water and toluene-water, volume ratio 1:5~5:1；It is described
The one kind of organic solvent in dichloromethane, ethyl acetate, benzene, toluene, chlorobenzene, ether, chloroform, carbon tetrachloride and hexamethylene
Or more than one mixed solvent；Selected sour water is in hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, oxalic acid, acetic acid, ammonium sulfate or ammonium chloride
One or more kinds of aqueous solution；Sour water pH 2~6.
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| CN110229099B (en) * | 2018-03-05 | 2023-02-21 | 连云港恒运药业有限公司 | Method for preparing sorafenib key intermediate |
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