CN111233759A - Process for preparing apatinib - Google Patents
Process for preparing apatinib Download PDFInfo
- Publication number
- CN111233759A CN111233759A CN202010210058.4A CN202010210058A CN111233759A CN 111233759 A CN111233759 A CN 111233759A CN 202010210058 A CN202010210058 A CN 202010210058A CN 111233759 A CN111233759 A CN 111233759A
- Authority
- CN
- China
- Prior art keywords
- apatinib
- methyl
- amino
- ester
- nicotinic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention provides a method for preparing apatinib, which comprises the step of directly mixing 1- (4-aminophenyl) cyclopentyl carbonitrile with 2- [ (pyridine-4-methyl) amino ] nicotinic acid mid-alcohol ester in the presence of a catalyst to perform amidation reaction to obtain the apatinib. The invention overcomes the prejudice of the prior art, insists on exploring the amidation reaction of ester and amine, screens out a method for preparing apatinib, can directly mix and react materials, does not need to be dripped, has simple and convenient synthesis and purification, low cost and high product purity, has high yield no matter calculated by ester or amine raw materials, and can be higher by dozens of percent compared with the same prior art.
Description
Technical Field
The invention relates to a method for preparing apatinib.
Background
In the growth and metastasis of malignant tumors, the formation of new blood vessels in the tumor plays a very important role. The inhibition of tumor angiogenesis is an important means for treating tumors, and tyrosine kinase Vascular Endothelial Growth Factor (VEGF) and receptor thereof (VEGFR) have extremely important functions in tumor angiogenesis and are important targets in the blocking of tumor angiogenesis. Apatinib is a new generation tyrosine kinase inhibitor, makes up the gap of specific drugs for solid tumors in China, has gastric cancer, lung cancer and the like in clinical practice, can be used for trying to treat side effects of hemangioma due to the fact that the drug can block a tumor angiogenesis mechanism, and is combined with a PD1 antibody to treat lung cancer and the like, and related lung cancer indications are reported to be examined and approved by the national drug administration.
At present, the synthetic route of apatinib mainly comprises the following steps:
the method comprises the following steps of using 1- (4-nitrophenyl) cyclopentyl nitrile as an initial raw material, carrying out catalytic hydrogenation on palladium-carbon to obtain 1- (4-aminophenyl) cyclopentyl nitrile, carrying out amidation reaction on the 1- (4-aminophenyl) cyclopentyl nitrile and 2-chloronicotinyl chloride, carrying out substitution reaction on the 2-chloronicotinyl chloride and 4-aminomethylpyridine to prepare an apatinib crude product, and finally carrying out column chromatography purification to obtain the apatinib. Extension of the reaction route: the method comprises the steps of using benzyl cyanide as a raw material, condensing 1, 4-dibromobutane under the action of strong alkali sodium hydroxide or sodium hydride to generate 1-cyano-1-phenylcyclopentane, obtaining 1- (4-nitrophenyl) cyclopentyl nitrile through nitration reaction, using ferric trichloride to catalyze hydrazine hydrate to reduce or using iron powder and zinc powder to reduce nitro to amino to obtain 1- (4-aminophenyl) cyclopentyl nitrile, then carrying out amidation condensation with 2-chloronicotinoyl chloride to prepare N- [4- (1-cyanocyclopentyl) phenyl ] -2-chloro-3-pyridinecarboxamide, and reacting with 4-aminomethylpyridine to obtain apatinib, wherein the total yield of five-step reaction is 33.5-43.2% (calculated by benzyl cyanide).
The synthetic route has long reaction steps, and the price of the raw material 2-chloronicotinoyl chloride is higher; the ortho-position of the chlorine atom of the amidation reaction product N- [4- (1-cyanocyclopentyl) phenyl ] -2-chloro-3-pyridinecarboxamide is an amide functional group, which is not enough to activate the chlorine atom for substitution reaction, and the substitution reaction activity is low, so that the substitution reaction of N- [4- (1-cyanocyclopentyl) phenyl ] -2-chloro-3-pyridinecarboxamide and 4-aminomethyl pyridine requires higher reaction temperature and longer reaction time, more side reactions and product degradation are caused by harsher reaction conditions, the purity of the obtained apatinib is only 95-96%, the product purity guarantee and impurity control are not facilitated, and the yield is lower.
The intermediate 2- [ (pyridine-4-methyl) amino ] nicotinate is a usable raw material, but as mentioned above, the influence factors of the reaction activity are many, the amidation reaction of the ester and amine usually requires high temperature, strong base or catalyst is needed for the reaction, many materials need to be added slowly, and the dropwise addition is better.
Disclosure of Invention
The invention overcomes the prejudice of the prior art, insists on exploring the amidation reaction of ester and amine, screens out a method for preparing apatinib, can directly mix and react materials, does not need to be dripped, has simple and convenient synthesis and purification, low cost and high product purity, has high yield which is calculated by ester or amine raw materials, and can reach 94.3 percent, which is higher than dozens of percent compared with the prior art.
The technical scheme adopted by the invention is as follows:
a method for preparing apatinib, which comprises directly mixing 1- (4-aminophenyl) cyclopentylcarbonitrile with 2- [ (pyridine-4-methyl) amino ] nicotinic acid mid-grade alcohol ester in the presence of a catalyst to perform amidation reaction to obtain the apatinib. The 2- [ (pyridine-4-methyl) amino ] nicotinic acid intermediate alcohol ester is an ester formed by 2- [ (pyridine-4-methyl) amino ] nicotinic acid and an intermediate alcohol, wherein the intermediate alcohol can be isoamyl alcohol or active amyl alcohol (2-methyl-1-butanol), and the ester can be purchased, customized or synthesized by referring to the conventional technology, for example, 2- [ (pyridine-4-methyl) amino ] nicotinic acid isoamyl alcohol ester or 2- [ (pyridine-4-methyl) amino ] nicotinic acid active amyl alcohol ester can be obtained by carrying out esterification reaction on N- (pyridine-4-ylmethyl) -2-amino-3-cyanopyridine and isoamyl alcohol or active amyl alcohol under the action of acid.
Optionally, the molar ratio of 1- (4-aminophenyl) cyclopentylcarbonitrile to the medium alcohol 2- [ (pyridin-4-methyl) amino ] nicotinic acid ester is 1.05-1.15:1, e.g., 1.1: 1.
Optionally, the catalyst is a Lewis acid, such as SnCl4。
Optionally, the molar ratio of the catalyst to the 2- [ (pyridin-4-methyl) amino ] nicotinic acid medium alcohol ester is 1-3:100, such as 1: 50.
Optionally, the solvent of the amidation reaction is a weak organic base, such as dimethylacetamide. The solvent is used in an amount sufficient to dissolve the starting material, and may be 1mmol of 2- [ (pyridin-4-methyl) amino ] nicotinic acid medium alcohol ester in 2-6mL of dimethylacetamide.
Optionally, the temperature of the amidation reaction is 50-150 ℃, such as 100 ℃.
Optionally, the amidation reaction time is 6-8 h.
Optionally, the post-treatment of the reaction comprises: extracting with ethyl acetate aqueous solution, and then recrystallizing with isopropanol to obtain apatinib; stirring can be used as an auxiliary agent during crystallization. In the ethyl acetate water solution, the volume ratio of ethyl acetate to water can be 1:1, and the dosage can be 2-6mL, such as 4mL, for 1 millimole of 2- [ (pyridine-4-methyl) amino ] nicotinic acid medium alcohol ester; the isopropanol crystallization can be realized by reducing the temperature to low temperature, such as crystallization at 0 ℃, and the time can be 1 h; the amount of isopropyl alcohol used may be 2-6mL, e.g., 4mL, based on 1 millimole of the medium alcohol 2- [ (pyridin-4-methyl) amino ] nicotinic acid ester.
The invention has the beneficial effects that:
the invention overcomes the prejudice of the prior art, insists on exploring the amidation reaction of ester and amine, screens out a method for preparing apatinib, can directly mix and react materials, does not need to be dripped, has simple and convenient synthesis and purification, low cost and high product purity, has high yield which is calculated by ester or amine raw materials, and can reach 94.3 percent, which is dozens of percent higher than that of the prior art.
Detailed Description
Example 1:
adding 52.5mmol of 1- (4-aminophenyl) cyclopentyl carbonitrile into a flask with a stirrer and a thermometer, adding 100mL of N, N-dimethylacetamide, heating to dissolve 1- (4-aminophenyl) cyclopentyl carbonitrile, heating to 100 deg.C, maintaining the temperature, and directly adding 2- [ (pyridine-4-methyl) amino group]50mmol of isoamyl nicotinate, SnCl is added41mmol, continuously keeping constant temperature and stirring for reaction for 6h, then cooling to room temperature, adding 200ml of ethyl acetate aqueous solution for extraction (wherein the volume ratio of ethyl acetate to water is 1:1), concentrating the organic layer obtained by extraction to dryness, adding into 200ml of isopropanol, heating to 60 ℃ for uniform dissolution, then cooling to 0 ℃, stirring for 1h for full precipitation of crystals, filtering, and drying to obtain 17.1g of white solid, which is identified as apatinib and has the HPLC purity of 97.6%.
MS：398.3(M+H)；
1H NMR(DMSO-d6)：δ10.34(s,1H),8.47(d,2H),8.46(br,1H),8.17-8.16(d,1H),8.12-8.10(d,1H),7.80-7.76(d,2H),7.51-7.49(d,2H),7.32-7.28(d,2H),6.71-
6.68(d,1H),4.74-4.69(d,2H),2.41-2.38(m,2H),2.07-2.03(m,2H),1.89-1.87(m,4H)。
Example 2:
adding 52.5mmol of 1- (4-aminophenyl) cyclopentyl carbonitrile into a flask with a stirrer and a thermometer, adding 100mL of N, N-dimethylacetamide, heating to dissolve 1- (4-aminophenyl) cyclopentyl carbonitrile, heating to 100 deg.C, maintaining the temperature, and directly adding 2- [ (pyridine-4-methyl) amino group]50mmol of nicotinic acid active amyl alcohol ester, adding SnCl41mmol, continuously keeping constant temperature and stirring for reaction for 6h, then cooling to room temperature, adding 200ml of ethyl acetate aqueous solution for extraction (wherein the volume ratio of ethyl acetate to water is 1:1), concentrating the organic layer obtained by extraction to dryness, adding into 200ml of isopropanol, heating to 60 ℃ for uniform dissolution, then cooling to 0 ℃, stirring for 1h for full precipitation of crystals, filtering, and drying to obtain 15.6g of apatinib white solid with the apatinib HPLC purity of 90.5%.
Example 3:
adding 55mmol of 1- (4-aminophenyl) cyclopentyl carbonitrile into a flask with a stirrer and a thermometer, adding 100mL of N, N-dimethylacetamide, heating to dissolve 1- (4-aminophenyl) cyclopentyl carbonitrile, heating to 100 deg.C, maintaining the temperature, and directly adding 2- [ (pyridine-4-methyl) amino group]50mmol of isoamyl nicotinate, SnCl is added41mmol, continuously keeping constant temperature and stirring for reaction for 6h, then cooling to room temperature, adding 200ml of ethyl acetate aqueous solution for extraction (wherein the volume ratio of ethyl acetate to water is 1:1), concentrating the organic layer obtained by extraction to dryness, adding into 200ml of isopropanol, heating to 60 ℃ for uniform dissolution, then cooling to 0 ℃, stirring for 1h for full precipitation of crystals, filtering, and drying to obtain 18.8g of apatinib white solid with the purity of 99.6% by HPLC.
Example 4:
to a burner connected with a stirrer and a thermometerAdding 57.5mmol of 1- (4-aminophenyl) cyclopentyl carbonitrile into a bottle, adding 100mL of N, N-dimethylacetamide, heating to dissolve 1- (4-aminophenyl) cyclopentyl carbonitrile, heating to 100 ℃, keeping constant temperature, and directly adding 2- [ (pyridine-4-methyl) amino group]50mmol of isoamyl nicotinate, SnCl is added41mmol, continuously keeping constant temperature and stirring for reaction for 6h, then cooling to room temperature, adding 200ml of ethyl acetate aqueous solution for extraction (wherein the volume ratio of ethyl acetate to water is 1:1), concentrating the organic layer obtained by extraction to dryness, adding into 200ml of isopropanol, heating to 60 ℃ for uniform dissolution, then cooling to 0 ℃, stirring for 1h for full precipitation of crystals, filtering, and drying to obtain 17.6g of apatinib white solid with the apatinib HPLC purity of 96.1%.
Comparative example:
adding 1- (4-aminophenyl) -1-cyanocyclopentane (20.1g) into methanol (250ml), slowly adding sodium methoxide (8.1g) in batches, stirring at room temperature for 30min, cooling in an ice bath to 5-10 ℃, slowly adding methyl 2- [ (pyridine-4-methyl) amino ] nicotinate (20.3g) in batches, heating to 65 ℃, reacting for 12h, cooling to 5-10 ℃, dropwise adding 1N hydrochloric acid to adjust to neutrality, carrying out reduced pressure rotary evaporation to remove an organic solvent, adding dichloromethane and water for extraction, separating an organic phase, washing with water and saturated salt in sequence, drying with anhydrous sodium sulfate, carrying out reduced pressure rotary evaporation and concentration to dryness, and recrystallizing the obtained crude product with ethanol to obtain apatinib, 25.7g of a white solid, wherein the yield is 77.5%, and the purity is 98.6%.
Claims (10)
1. A process for preparing apatinib, comprising directly mixing 1- (4-aminophenyl) cyclopentylcarbonitrile with a medium alcohol 2- [ (pyridine-4-methyl) amino ] nicotinic acid ester in the presence of a catalyst for amidation reaction to obtain apatinib.
2. The method of claim 1, wherein the 2- [ (pyridin-4-methyl) amino ] nicotinic acid mid-alcohol ester is 2- [ (pyridin-4-methyl) amino ] nicotinic acid isoamyl alcohol ester or 2- [ (pyridin-4-methyl) amino ] nicotinic acid reactive amyl alcohol ester.
3. The process of claim 1, wherein the molar ratio of 1- (4-aminophenyl) cyclopentylcarbonitrile to the ester of a medium-grade alcohol in 2- [ (pyridin-4-methyl) amino ] nicotinic acid is 1.05-1.15: 1.
4. The process of claim 1, wherein the molar ratio of 1- (4-aminophenyl) cyclopentylcarbonitrile to the ester of a medium-grade alcohol in 2- [ (pyridin-4-methyl) amino ] nicotinic acid is 1.1: 1.
5. The method of claim 1, wherein the catalyst is a lewis acid catalyst.
6. The method of claim 1, wherein the catalyst is SnCl4。
7. A process according to any preceding claim, wherein the molar ratio of catalyst to medium alcohol 2- [ (pyridin-4-methyl) amino ] nicotinate is from 1 to 3:100, such as 1: 50.
8. The process according to any of the preceding claims, characterized in that the solvent of the amidation reaction is a weak organic base.
9. The method of claim 8, wherein the solvent is dimethylacetamide.
10. The method of any preceding claim, wherein the post-treatment of the reaction comprises: extracting with ethyl acetate aqueous solution, and recrystallizing with isopropanol to obtain apatinib.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010210058.4A CN111233759A (en) | 2020-03-23 | 2020-03-23 | Process for preparing apatinib |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010210058.4A CN111233759A (en) | 2020-03-23 | 2020-03-23 | Process for preparing apatinib |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN111233759A true CN111233759A (en) | 2020-06-05 |
Family
ID=70868101
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010210058.4A Pending CN111233759A (en) | 2020-03-23 | 2020-03-23 | Process for preparing apatinib |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111233759A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108467360A (en) * | 2018-06-22 | 2018-08-31 | 江苏美迪克化学品有限公司 | A kind of Ah pa replaces the Preparation Method And Their Intermediate of Buddhist nun |
| CN109020881A (en) * | 2018-06-28 | 2018-12-18 | 新发药业有限公司 | A kind of Ah 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 |
-
2020
- 2020-03-23 CN CN202010210058.4A patent/CN111233759A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108467360A (en) * | 2018-06-22 | 2018-08-31 | 江苏美迪克化学品有限公司 | A kind of Ah pa replaces the Preparation Method And Their Intermediate of Buddhist nun |
| CN109020881A (en) * | 2018-06-28 | 2018-12-18 | 新发药业有限公司 | A kind of Ah 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 |
Non-Patent Citations (2)
| Title |
|---|
| X. TONG, Z. REN, X. QU, Q. YANG, W. ZHANG: "Efficient amide formation from arylamines and esters promoted by AlCl3/Et3N: an experimental and computational investigation", 《RES CHEM INTERMED》 * |
| 姚英明: "稀土/碱金属化合物催化酯和胺的交换反应", 《硕士学位论文》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109020881B (en) | Preparation method of apatinib | |
| JP5273587B2 (en) | Process for producing phenylalanine derivative having quinazolinedione skeleton and production intermediate | |
| TWI697494B (en) | Synthesis of copanlisib and its dihydrochloride salt | |
| KR102482289B1 (en) | Novel synthesis method of deuterated amides and deuterated sulfonamides | |
| JP2014133745A (en) | Processes for preparing n-heteroaryl-n-aryl-amine by reacting n-aryl carbamic acid ester with halo-heteroaryl, and analogous processes | |
| JP2008538777A (en) | Acetylene derivatives | |
| JP2006517235A5 (en) | ||
| WO2016145990A1 (en) | Method of preparation for ledipasvir and derivative thereof, and intermediate compound for preparation of ledipasvir | |
| CN104311536A (en) | Method for preparing lenalidomide | |
| RU2742234C1 (en) | Coumarin-like cyclic compound as mek inhibitor and use thereof | |
| CN111925381A (en) | Synthesis method of baroxavir key intermediate | |
| CN107739335A (en) | A kind of pleasure cuts down the synthetic method for Buddhist nun | |
| CN107056695A (en) | It is a kind of to treat the synthetic method that gastric cancer medicament Ah handkerchief replaces Buddhist nun | |
| Gao et al. | Design, synthesis and biological evaluation of benzyloxyphenyl-methylaminophenol derivatives as STAT3 signaling pathway inhibitors | |
| CN110903253B (en) | Quinazolinone compound and preparation method and application thereof | |
| CN108546253A (en) | The method that multistep synthesizes 2- benzyl -1,5- dihydrobenzos [e] [1,4] oxygen azatropylidene | |
| CA2894826C (en) | Asymmetric synthesis of a substituted pyrrolidine-2-carboxamide | |
| CN109836412A (en) | A kind of preparation method of dabigatran etexilate methanesulfonate | |
| WO2015158244A1 (en) | Hydroxamic acid compound and use thereof in preparing medications for inhibiting cancer cell proliferation and/or treating cancers | |
| CN111233759A (en) | Process for preparing apatinib | |
| CN108409647B (en) | Preparation method of apatinib | |
| US20090023925A1 (en) | N'-(2-halobenzylidene)sulfonylhydrazides as intermediates in the manufacture of arylsulfonylindazoles | |
| EP3318550B1 (en) | Method for preparing a benzoic acid amide compound | |
| CN112390781B (en) | Diaryl-substituted 1,1-ethylene compound, preparation method and application | |
| CN109810052B (en) | Simple and convenient preparation method of high-selectivity apatinib |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20200605 |