CN109020881A - A kind of Ah pa replaces the preparation method of Buddhist nun - Google Patents
A kind of Ah pa replaces the preparation method of Buddhist nun Download PDFInfo
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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
- C07D213/82—Amides; Imides in position 3
Abstract
The present invention provides a kind of Ah pa preparation method for replacing Buddhist nun, using 2- it is halogenated-nicotinonitrile is raw material, reaction, which is substituted, with 4- aminomethyl-pyridine obtains N- (pyridin-4-yl methyl) -2- Amino 3 cyano pyridine, then N- (pyridin-4-yl methyl) -2- amino-acidum nicotinicum ester is obtained through esterification, then replaces Buddhist nun (I) through amidation process preparation Ah pa with 1- (4- aminophenyl) cyclopenta formonitrile HCN.The method of the present invention raw material is cheap and easy to get, and process flow is easy, at low cost；Waste water yield is few, safe green environmental protection；Reaction condition is easily achieved, and reactivity and selectivity are high, and side reaction is few, and few, purity and yield are high for Buddhist nun's impurity by prepared A Pa.
Description
Technical field
The present invention relates to the preparation methods that a kind of Ah pa replaces Buddhist nun, belong to technical field of medical chemistry.
Background technique
In the growth and transfer process of malignant tumour, the new vessels formation of tumour plays very important effect.Suppression
Tumor neogenetic blood vessels processed be treat tumour a kind of important means, tyrosine kinase vascular endothelial growth factor (VEGF) and its by
Body (VEGFR) has extremely important effect in the new vessels of tumour generate, and is blocked in tumor angiogenesis
Important target spot.A Pa is a kind of tyrosine kinase inhibitor of new generation for Buddhist nun, can block tumor neovasculature generation.A Pa
It is global first safely and effectively small molecule anti-angiogenesis targeted drug for being proved that late gastric cancer can be treated for Buddhist nun,
It is that can be obviously prolonged single medicine of life cycle after the failure of late gastric cancer standard chemotherapeutic.Meanwhile the medicine be in stomach cancer target drug only
A oral preparation one by one, can effectively improve the compliance of patient's treatment, and be substantially reduced medical expense.A Pa replaces Buddhist nun's mechanism of action
Are as follows: the ATP-binding site of VEGFR-2 in high selectivity competition cell blocks downstream signal transduction, inhibits the new blood of tumor tissues
Pipe generates, to treat tumour, can significantly extend the life cycle of late gastric cancer patient.A Pa is for Buddhist nun by the permanent auspicious doctor of Jiangsu Province, China
The research and development of medicine company are ratified to list, and were received in 2017 in acquisition China national Administration of Food and Drug on December 13rd, 2014
Enter medical insurance scope, there is large market.
A Pa is N- [4- (1- cyan cyclopentyl) phenyl] -2- (4- picolyl) amido -3- pyridine for Buddhist nun's chemical name
Formamide, structural formula are as follows:
Currently, Ah pa is as follows for the synthetic route key step of Buddhist nun:
Chinese patent literature CN1502608A discloses the synthetic method that a kind of Ah pa replaces Buddhist nun, with 1- (4- nitrobenzophenone) ring
Amyl nitrile be starting material, obtain 1- (4- aminophenyl) cyclopenta nitrile through palladium charcoal catalytic hydrogenation, then with 2- chloronicotinoyl chloride acyl
Aminating reaction, then reaction preparation Ah pa is substituted with 4- aminomethyl-pyridine for Buddhist nun's crude product, it eventually passes through column chromatographic purifying and obtains Ah
Pa replaces Buddhist nun.Chinese patent literature CN106243031A and " Chinese Journal of Pharmaceuticals, 2015,46 (5) 449 " have carried out reaction road
The extension of line is raw material and Isosorbide-5-Nitrae-dibromobutane in highly basic sodium hydroxide or the lower condensation generation 1- of sodium hydride effect using benzene acetonitrile
Cyano -1- phenyl pentamethylene obtains 1- (4- nitrobenzophenone) cyclopenta nitrile, ferric trichloride catalytic hydrazine hydrate reduction by nitration reaction
Or iron powder, zinc powder reduction nitro are that amino obtains 1- (4- aminophenyl) cyclopenta nitrile, are then contracted with 2- chloronicotinoyl chloride amidation
Preparation N- [4- (1- cyan cyclopentyl) phenyl] -2- chloro-3-pyridyl formamide is closed, then reacts to obtain A Pa with 4- aminomethyl-pyridine
For Buddhist nun, five step overall yield of reaction are 33.5-43.2% (in terms of benzene acetonitrile).Reaction process is described as following synthetic route 1.
Synthetic route 1
Said synthesis route reaction step is long, and raw material 2- chloronicotinoyl chloride price is higher；Amidation process product N- [4- (1-
Cyan cyclopentyl) phenyl] -2- chloro-3-pyridyl formamide chlorine atom ortho position be amide functional group, be not enough to activate chlorine atom into
Row substitution reaction, substitution reaction activity is low, leads to N- [4- (1- cyan cyclopentyl) phenyl] -2- chloro-3-pyridyl formamide and 4-
Aminomethyl-pyridine carries out needing higher reaction temperatures and longer reaction time when substitution reaction, and more harsh reaction condition causes
More side reaction and product degradation, gained A Pa only have 95-96% for Buddhist nun's purity, are unfavorable for product purity and guarantee and impurity control
System, and yield is lower.
In conclusion design one is at low cost, step is simple, is easily achieved, be conducive to improve reactivity and selectivity
High yield, high-purity Ah pa be of great significance for the synthetic route of Buddhist nun.
Summary of the invention
In view of the deficienciess of the prior art, the present invention provides a kind of Ah pa preparation method for replacing Buddhist nun.The method of the present invention is former
Expect cheap and easy to get, process flow simplicity, it is at low cost；Waste water yield is few, safe green environmental protection；Reaction condition is easily achieved, instead
Answer activity and selectivity high, side reaction is few, and few, purity and yield are high for Buddhist nun's impurity by prepared A Pa.
Term explanation:
II compound of formula: 2- is halogenated-nicotinonitrile；
III compound of formula: N- (pyridin-4-yl methyl) -2- Amino 3 cyano pyridine；
Formula IV compound: N- (pyridin-4-yl methyl) -2- amino-acidum nicotinicum ester；
Formula V compound: 1- (4- aminophenyl) cyclopenta formonitrile HCN；
Type I compound: Ah pa replaces Buddhist nun.
Compound number and formula numbers in this specification is completely the same, reference relationship having the same, with chemical combination
Object structural formula is foundation.
Technical scheme is as follows:
A kind of Ah pa replaces the preparation method of Buddhist nun, comprising steps of
(1) reaction III compound of preparation formula is substituted by II compound of formula and 4- aminomethyl-pyridine；
Wherein, in II structural formula of compound of formula, X is chlorine or bromine；
(2) formula IV compound is converted by III compound of formula；
Wherein, in formula IV structural formula of compound, R is methyl, ethyl, propyl or butyl；
(3) by making formula IV compound and Formula V compound prepare Ah pa through amidation process for Buddhist nun (I)；
Preferred according to the present invention, in step (1), the substitution reaction of II compound of formula and 4- aminomethyl-pyridine is in solvent
It is carried out in A, under the action of acid binding agent.
Preferably, the solvent A is in n,N-Dimethylformamide, n,N-dimethylacetamide, chlorobenzene or dichloro-benzenes
A combination of one or more；The mass ratio of II compound of the solvent A and formula is (3-20): 1；It is further preferred that institute
Stating solvent A is n,N-Dimethylformamide, and the mass ratio of II compound of the solvent A and formula is (5-10): 1.
Preferably, the acid binding agent is sodium methoxide, methanol solution of sodium methylate, sodium ethoxide, alcohol sodium alcohol solution, carbonic acid
The combination of one or more of potassium, sodium carbonate or calcium carbonate；It is further preferred that the acid binding agent is potassium carbonate or carbon
Sour sodium.
Preferably, the molar ratio of II compound of the acid binding agent, 4- aminomethyl-pyridine and formula is (1.1-1.5): (1.0-
1.2):1。
, according to the invention it is preferred to, in step (1), the substitution reaction temperature is 50-130 DEG C；Preferably, described to take
It is 80-100 DEG C for reaction temperature；The substitution reaction time is 2~10 hours；Preferably, the substitution reaction time is 4-6 hours.
, according to the invention it is preferred to, in step (2), III compound of formula is in solvent B, under the action of acid, through esterification
It is converted into formula IV compound.
Preferably, the solvent B is the group of one or more of water, methanol, ethyl alcohol, isopropanol or tert-butyl alcohol
It closes；The mass ratio of III compound of the solvent B and formula is (5-20): 1；It is further preferred that the solvent B is methanol or second
Alcohol；The mass ratio of III compound of the solvent B and formula is (5-10): 1.
Preferably, the acid is the aqueous solution or alcoholic solution of hydrogen chloride, the aqueous solution or alcoholic solution of sulfuric acid or hydrogen bromide
Aqueous solution or alcoholic solution；The molar ratio of contained acid and III compound of formula is (1.0-3.0): 1；It is further preferred that the acid is
Mass concentration is hydrochloride aqueous solution, hydrogen chloride methanol solution or the ethanol solution of hydrogen chloride of 20-40%；Most preferably, described
Acid is the hydrochloride aqueous solution that mass concentration is 30-35%.
Preferably, the esterification reaction temperature is 20-100 DEG C；It is further preferred that the esterification reaction temperature is 50-
80℃.Reaction time of esterification is 2-10 hours；It is further preferred that reaction time of esterification is 4-6 hours.
Preferred according to the present invention, in step (3), the amidation process of formula IV compound and Formula V compound is in solvent C
In, carry out under the action of catalyst.
Preferably, the solvent C is n,N-Dimethylformamide, n,N-dimethylacetamide, toluene, dimethylbenzene, chlorobenzene
Or the combination of one or more of dichloro-benzenes；The mass ratio of IV compound of the solvent C and formula is (5-25): 1；Into one
Step is preferred, and the mass ratio of IV compound of the solvent C and formula is (8-15): 1.
Preferably, the catalyst is lewis acid catalyst or organic alkali catalyst, and lewis acid catalyst is selected from chlorine
Change ammonium, zinc chloride, iron chloride or stannous chloride；Organic alkali catalyst is selected from 4-dimethylaminopyridine or piperidines；The catalyst
Quality be IV compound quality of formula 1.0-3.0%.
Preferably, formula IV compound and Formula V compound prepare Ah pa through amidation process and replace the method for Buddhist nun comprising steps of inciting somebody to action
Solvent C, catalyst and Formula V compound are uniformly mixed, and formula IV compound are added dropwise at 60-150 DEG C, drop finishes within 0.5-3 hours, then
Amidation process is carried out at 60-150 DEG C.
, according to the invention it is preferred to, the molar ratio of IV compound of Formula V compound described in step (3) and formula is (1.0-
1.5):1；It is further preferred that the molar ratio of IV compound of the Formula V compound and formula is (1.1-1.3): 1.
, according to the invention it is preferred to, in step (3), the amidation process temperature is 60-150 DEG C；Preferably, described
Amidation process temperature is 90-130 DEG C.The amidation process time is 2-10 hours；Preferably, the amidation process time is
4-6 hours.
Preferred according to the present invention, the A Pa is white solid for Buddhist nun (I), and fusing point is 158-160 DEG C, and liquid phase purity is big
In equal to 99.9%.
Reaction process of the invention is described as following synthetic route 2:
Synthetic route 2
Wherein, in II structural formula of compound of formula, X is chlorine or bromine；In formula IV structural formula of compound, R is methyl, ethyl, third
Base or butyl.
Technical characterstic of the invention and the utility model has the advantages that
1, the present invention provides the preparation method that a kind of new Ah pa replaces Buddhist nun, using 2- it is halogenated-nicotinonitrile as raw material, and
4- aminomethyl-pyridine is substituted reaction and obtains N- (pyridin-4-yl methyl) -2- Amino 3 cyano pyridine, then through esterification
N- (pyridin-4-yl methyl) -2- amino-acidum nicotinicum ester is obtained, then with 1- (4- aminophenyl) cyclopenta formonitrile HCN through amide
Change reaction preparation Ah pa and replaces Buddhist nun (I).
2, the present invention has fully considered the structure of raw material to design suitable reaction route, utilizes the halogenated -3- cyanogen of raw material 2-
The ortho para position activating effect of the cyano of yl pyridines so that 2- it is halogenated-substitution reaction of nicotinonitrile and 4- aminomethyl-pyridine is easy
In progress, and react single-minded.N- is prepared through esterification by gained N- (pyridin-4-yl methyl) -2- Amino 3 cyano pyridine
(pyridin-4-yl methyl) -2- amino-acidum nicotinicum ester and subsequent amidation process are classical reaction, and operation is stablized,
Reaction site is single-minded, product yield high.The specific raw material of the present invention and reaction route make reaction selectivity of the invention high, secondary
Product is few, product purity and high income.
3, the method for the present invention raw material is cheap and easy to get, at low cost without using higher raw materials of prices such as 2- chloronicotinoyl chlorides；Do not make
With the high raw material of the risk such as sodium hydride, safe operation height；Only need three steps that final product, process flow letter can be prepared
Just, reaction condition is mild, is easily achieved；The method of the present invention waste water yield is few, safe green environmental protection；The present invention is specifically prepared
Method makes reaction selectivity high, and high income, side reaction is few, and by-product is easy to remove, and post-processing is simple, prepared A Pa
It is (liquid phase purity is up to 99.96%) with high purity for Buddhist nun, be conducive to the industrialized production that Ah pa replaces Buddhist nun.
Specific embodiment
The present invention is described in detail with reference to embodiments, but the present invention is not only limited to this.
Embodiment is raw materials used and reagent is commercial product." % " in embodiment is mass percent, is illustrated
Except.
Yield in embodiment is molar yield.
The preparation of embodiment 1:N- (pyridin-4-yl methyl) -2- Amino 3 cyano pyridine (III)
To be connected to stirring, thermometer, vacuum distillation apparatus 500 milliliters of four-hole boiling flasks in, 180 grams of N, N- dimethyl is added
Formamide, 27.7 grams of chloro- nicotinonitriles of (0.2 mole) 2- (II 1), 34.5 grams of (0.25 mole) potassium carbonate, 22.0 gram (0.2
Mole) 4- aminomethyl-pyridine, 95 to 100 DEG C are stirred to react 4 hours, are cooled to 20-25 DEG C, filter, filter cake 30 grams of N, N- bis-
Methylformamide washing, merging filtrate, vacuum distillation recovered solvent, residue are recrystallized with methyl tertiary butyl ether, obtain 38.9 grams
N- (pyridin-4-yl methyl) -2- Amino 3 cyano pyridine (III), yield 92.6%, liquid phase purity 99.72%.
The preparation of embodiment 2:N- (pyridin-4-yl methyl) -2- Amino 3 cyano pyridine (III)
To be connected to stirring, thermometer, vacuum distillation apparatus 500 milliliters of four-hole boiling flasks in, 200 grams of N, N- dimethyl is added
Formamide, 36.6 grams of bromo- nicotinonitriles of (0.2 mole) 2- (II 2), 34.5 grams of (0.25 mole) potassium carbonate, 22.0 gram (0.2
Mole) 4- aminomethyl-pyridine, 80 to 85 DEG C are stirred to react 5 hours, are cooled to 20-25 DEG C, filter, filter cake 30 grams of N, N- diformazan
The washing of base formamide, merging filtrate, vacuum distillation recovered solvent, residue are recrystallized with methyl tertiary butyl ether, obtain 39.3 grams of N-
(pyridin-4-yl methyl) -2- Amino 3 cyano pyridine (III), yield 93.6%, liquid phase purity 99.65%.
The preparation of embodiment 3:N- (pyridin-4-yl methyl) -2- amino-acidum nicotinicum methyl esters (IV 1)
To be connected to stirring, thermometer, reflux condensing tube 500 milliliters of four-hole boiling flasks in, be added 160 grams of methanol, 21.0 grams
N- (pyridin-4-yl methyl) -2- Amino 3 cyano pyridine (III) of (0.1 mole) embodiment 1 preparation, 22.0 grams of 35wt% are dense
Hydrochloric acid, 60 to 65 DEG C are stirred to react 5 hours, are cooled to 20-25 DEG C, and 100 grams of water, 150 grams of toluene, with 5wt% sodium carbonate are added
Aqueous solution regulation system pH value is 7.0-8.0, is layered, and water layer is extracted twice with toluene, and 50 grams of toluene, combining methylbenzene are organic every time
Layer, 30 grams of saturated sodium-chloride water solutions washed once, and air-distillation recycling methanol and toluene, residue are tied again with methyl tertiary butyl ether
Crystalline substance obtains 21.6 grams of N- (pyridin-4-yl methyl) -2- amino-acidum nicotinicum methyl esters (IV 1), yield 88.9%, liquid phase purity
99.85%.
The preparation of embodiment 4:N- (pyridin-4-yl methyl) -2- amino-acidum nicotinicum ethyl ester (IV 2)
To be connected to stirring, thermometer, reflux condensing tube 500 milliliters of four-hole boiling flasks in, be added 180 grams of ethyl alcohol, 21.0 grams
N- (pyridin-4-yl methyl) -2- Amino 3 cyano pyridine (III) of (0.1 mole) embodiment 2 preparation, 22.5 grams of 35wt% are dense
Hydrochloric acid, 70 to 75 DEG C are stirred to react 5 hours, are cooled to 20-25 DEG C, and 100 grams of water, 150 grams of toluene, with 5wt% sodium carbonate are added
Aqueous solution regulation system pH value is 7.0-8.0, is layered, and water layer is extracted twice with toluene, and 50 grams of toluene, combining methylbenzene are organic every time
Layer, 30 grams of saturated sodium-chloride water solutions washed once, and air-distillation recycling ethyl alcohol and toluene, residue are tied again with methyl tertiary butyl ether
Crystalline substance obtains 23.2 grams of N- (pyridin-4-yl methyl) -2- amino-acidum nicotinicum ethyl ester (IV 2), yield 90.3%, liquid phase purity
99.93%.
Embodiment 5: Ah pa replaces the preparation of Buddhist nun (I)
Into 500 milliliters of four-hole boiling flasks for being connected to blender, thermometer and Distallation systm, 100 grams of N, N- dimethyl is added
Formamide, 11.2 grams of (0.06 mole) 1- (4- aminophenyl) cyclopenta formonitrile HCNs (V), 0.2 gram of stannous chloride keep interior temperature 95-
Between 100 DEG C, N- (pyridin-4-yl methyl) -2- amino -3- pyridine first of 12.2 grams of (0.05 mole) embodiments 3 preparation is added dropwise
The solution of sour methyl esters (IV 1) and 30 grams of n,N-Dimethylformamide, drop finishes within about 1 hour, hereafter 100-105 DEG C to be stirred to react 4 small
When, while the methanol of generation is steamed, end of reaction is cooled to 20-25 DEG C, filters, 20 grams of n,N-Dimethylformamide of filter cake
Washing, merging filtrate, vacuum distillation recycling n,N-Dimethylformamide, residue are recrystallized with methyl tertiary butyl ether, are filtered, done
It is dry, 18.3 grams of white solid powder Ah pas are obtained for Buddhist nun (I), yield 92.2%, liquid phase purity 99.96%, fusing point 158.5-
160.0℃。
The nuclear magnetic data of product is as follows:
1H NMR(400MHz,DMSO-d6):δ
9.86(s,1H),8.47(d,2H),8.38(br,1H),8.15-8.18(d,1H),8.09-8.11(d,1H),
7.72-7.75(d,2H),7.44-7.47(d,2H),7.28-7.31(d,2H),6.67-6.70(dd,1H),4.67-4.71(d,
2H),2.37-2.41(m,2H),2.02-2.05(m,2H),1.82-1.85(m,4H)。
Embodiment 6: Ah pa replaces the preparation of Buddhist nun (I)
Into 500 milliliters of four-hole boiling flasks for being connected to blender, thermometer and Distallation systm, it is added 100 grams of toluene, 11.2 grams
(0.06 mole) 1- (4- aminophenyl) cyclopenta formonitrile HCN (V), 0.25 gram of 4-dimethylaminopyridine keep interior 95-105 DEG C of temperature
Between, N- (pyridin-4-yl methyl) -2- amino-acidum nicotinicum ethyl ester of 12.9 grams of (0.05 mole) embodiments 4 preparation is added dropwise
The solution of (IV 2) and 30 grams of toluene, drop finishes within about 2 hours, is hereafter stirred to react 5 hours for 110-115 DEG C, while steaming the second of generation
Alcohol, end of reaction are cooled to 20-25 DEG C, and filtering, filter cake is washed with 20 grams of toluene, merging filtrate, vacuum distillation recycling toluene,
Residue is recrystallized with methyl tertiary butyl ether, is filtered, dry, obtains 18.1 grams of white solid powder Ah pas for Buddhist nun (I), yield
91.2%, liquid phase purity 99.92%, fusing point is 158.5-160.0 DEG C.
Comparative example 1: Ah pa replaces the preparation of Buddhist nun (I)
Into 500 milliliters of four-hole boiling flasks for being connected to blender, thermometer and Distallation systm, 130 grams of N, N- dimethyl is added
Formamide, N- (pyridin-4-yl methyl) -2- amino-acidum nicotinicum methyl esters of 12.2 grams of (0.05 mole) embodiments 3 preparation
(IV 1), 11.2 grams of (0.06 mole) 1- (4- aminophenyl) cyclopenta formonitrile HCNs (V), 0.2 gram of stannous chloride, 100-105 DEG C is stirred
Reaction 4 hours is mixed, while steaming the methanol of generation, end of reaction is cooled to 20-25 DEG C, filters, filter cake 20 grams of N, N- diformazan
The washing of base formamide, merging filtrate, vacuum distillation recycling n,N-Dimethylformamide, residue are recrystallized with methyl tertiary butyl ether,
Filtering, it is dry, 13.2 grams of white solid powder Ah pas are obtained for Buddhist nun (I), yield 66.5%, liquid phase purity 97.28%.
Show that IV compound of formula is added dropwise into reaction system by the present invention by the comparison of this comparative example, advantageously reduces the change of formula IV
The amidation process for closing object itself reduces the generation of by-product to reduce side reaction, improves the purity and receipts of final product
Rate.
Claims (10)
1. a kind of Ah pa replaces the preparation method of Buddhist nun, comprising steps of
(1) reaction III compound of preparation formula is substituted by II compound of formula and 4- aminomethyl-pyridine；
Wherein, in II structural formula of compound of formula, X is chlorine or bromine；
(2) formula IV compound is converted by III compound of formula；
Wherein, in formula IV structural formula of compound, R is methyl, ethyl, propyl or butyl；
(3) by making formula IV compound and Formula V compound prepare Ah pa through amidation process for Buddhist nun (I)；
2. Ah pa according to claim 1 replace Buddhist nun preparation method, which is characterized in that in step (1), II compound of formula and
The substitution reaction of 4- aminomethyl-pyridine is carried out in solvent A, under the action of acid binding agent.
3. the preparation method that Ah pa according to claim 2 replaces Buddhist nun, which is characterized in that including one in the following conditions or
It is multinomial:
A, the solvent A is one or both of N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, chlorobenzene or dichloro-benzenes
Above combination；The mass ratio of II compound of the solvent A and formula is (3-20): 1；It is further preferred that the solvent A is N,
Dinethylformamide, the mass ratio of II compound of the solvent A and formula are (5-10): 1；
B, the acid binding agent be sodium methoxide, methanol solution of sodium methylate, sodium ethoxide, alcohol sodium alcohol solution, potassium carbonate, sodium carbonate or
The combination of one or more of calcium carbonate；It is further preferred that the acid binding agent is potassium carbonate or sodium carbonate；
C, the molar ratio of II compound of the acid binding agent, 4- aminomethyl-pyridine and formula is (1.1-1.5): (1.0-1.2): 1.
4. the preparation method that Ah pa according to claim 1 replaces Buddhist nun, which is characterized in that in step (1), the substitution reaction
Temperature is 50-130 DEG C；Preferably, the substitution reaction temperature is 80-100 DEG C.
5. Ah pa according to claim 1 replace Buddhist nun preparation method, which is characterized in that in step (2), III compound of formula in
In solvent B, under the action of acid, formula IV compound is converted into through esterification.
6. the preparation method that Ah pa according to claim 5 replaces Buddhist nun, which is characterized in that including one in the following conditions or
It is multinomial:
A, the solvent B is the combination of one or more of water, methanol, ethyl alcohol, isopropanol or tert-butyl alcohol；The solvent
The mass ratio of III compound of B and formula is (5-20): 1；It is further preferred that the solvent B is methanol or ethyl alcohol；The solvent B
Mass ratio with III compound of formula is (5-10): 1；
B, the acid is the aqueous solution or alcoholic solution of hydrogen chloride, the aqueous solution or alcoholic solution of sulfuric acid or the aqueous solution of hydrogen bromide or
Alcoholic solution；The molar ratio of contained acid and III compound of formula is (1.0-3.0): 1；It is further preferred that the acid is mass concentration
For the hydrochloride aqueous solution, hydrogen chloride methanol solution or ethanol solution of hydrogen chloride of 20-40%；Most preferably, the acid is quality
Concentration is the hydrochloride aqueous solution of 30-35%；
C, the esterification reaction temperature is 20-100 DEG C；It is further preferred that the esterification reaction temperature is 50-80 DEG C.
7. Ah pa according to claim 1 replace Buddhist nun preparation method, which is characterized in that in step (3), formula IV compound and
The amidation process of Formula V compound is carried out in solvent C, under the action of catalyst.
8. the preparation method that Ah pa according to claim 7 replaces Buddhist nun, which is characterized in that including one in the following conditions or
It is multinomial:
A, the solvent C is in N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, toluene, dimethylbenzene, chlorobenzene or dichloro-benzenes
A combination of one or more；The mass ratio of IV compound of the solvent C and formula is (5-25): 1；It is further preferred that
The mass ratio of IV compound of the solvent C and formula is (8-15): 1；
B, the catalyst is lewis acid catalyst or organic alkali catalyst, and lewis acid catalyst is selected from ammonium chloride, chlorination
Zinc, iron chloride or stannous chloride；Organic alkali catalyst is selected from 4-dimethylaminopyridine or piperidines；The quality of the catalyst is formula
The 1.0-3.0% of IV compound quality；
C, formula IV compound and Formula V compound through amidation process preparation Ah pa for Buddhist nun method comprising steps of by solvent C, urging
Agent and Formula V compound are uniformly mixed, and formula IV compound are added dropwise at 60-150 DEG C, drop finishes within 0.5-3 hours, then in 60-150
Amidation process is carried out at DEG C.
9. the preparation method that Ah pa according to claim 1 replaces Buddhist nun, which is characterized in that in step (3), including the following conditions
In it is one or more:
A, the molar ratio of IV compound of the Formula V compound and formula is (1.0-1.5): 1；It is further preferred that the Formula V chemical combination
The molar ratio of IV compound of object and formula is (1.1-1.3): 1；
B, the amidation process temperature is 60-150 DEG C；Preferably, the amidation process temperature is 90-130 DEG C.
10. the preparation method that Ah pa according to claim 1 replaces Buddhist nun, which is characterized in that the A Pa is white for Buddhist nun (I)
Solid, fusing point are 158-160 DEG C, and liquid phase purity is more than or equal to 99.9%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810685580.0A CN109020881B (en) | 2018-06-28 | 2018-06-28 | Preparation method of apatinib |
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| CN109879805A (en) * | 2019-04-22 | 2019-06-14 | 苏州富士莱医药股份有限公司 | A Pa replaces the preparation method of Buddhist nun |
| CN110003101A (en) * | 2019-04-22 | 2019-07-12 | 苏州富士莱医药股份有限公司 | A kind of Ah pa is for Buddhist nun's intermediate and preparation method thereof |
| CN110637010A (en) * | 2017-08-15 | 2019-12-31 | 江苏恒瑞医药股份有限公司 | VEGFR inhibitor crystal form and preparation method thereof |
| CN111233759A (en) * | 2020-03-23 | 2020-06-05 | 烟台市烟台山医院 | Process for preparing apatinib |
| CN111484525A (en) * | 2019-01-25 | 2020-08-04 | 新发药业有限公司 | Vitamin A ester intermediate C15 and preparation method of vitamin A ester |
| CN113024550A (en) * | 2021-03-26 | 2021-06-25 | 浙江天宇药业股份有限公司 | Impurity of apatinib mesylate and preparation method thereof |
| CN116199625A (en) * | 2023-01-19 | 2023-06-02 | 上海昱菘医药科技有限公司 | Preparation method of nicotinic acid ester compound |
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| CN111233759A (en) * | 2020-03-23 | 2020-06-05 | 烟台市烟台山医院 | Process for preparing apatinib |
| CN113024550A (en) * | 2021-03-26 | 2021-06-25 | 浙江天宇药业股份有限公司 | Impurity of apatinib mesylate and preparation method thereof |
| CN116199625A (en) * | 2023-01-19 | 2023-06-02 | 上海昱菘医药科技有限公司 | Preparation method of nicotinic acid ester compound |
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