CN102321015A - Method for preparing key intermediate 2-(cyclopropylamido)-3-pyridine formic acid of anti-aids medicament Nevirapine - Google Patents
Method for preparing key intermediate 2-(cyclopropylamido)-3-pyridine formic acid of anti-aids medicament Nevirapine Download PDFInfo
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- CN102321015A CN102321015A CN201110180511A CN201110180511A CN102321015A CN 102321015 A CN102321015 A CN 102321015A CN 201110180511 A CN201110180511 A CN 201110180511A CN 201110180511 A CN201110180511 A CN 201110180511A CN 102321015 A CN102321015 A CN 102321015A
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- Prior art keywords
- nevirapine
- key intermediate
- cyclopropyl amino
- carboxylic acid
- pyridine carboxylic
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- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 title claims abstract description 44
- 229960000689 nevirapine Drugs 0.000 title claims abstract description 21
- 238000000034 method Methods 0.000 title abstract description 9
- 239000003814 drug Substances 0.000 title abstract description 3
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 title abstract 6
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 title abstract 3
- 235000019253 formic acid Nutrition 0.000 title abstract 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- QVDNJGOBMXAPSJ-UHFFFAOYSA-N 2-(cyclopropylazaniumyl)pyridine-3-carboxylate Chemical compound OC(=O)C1=CC=CN=C1NC1CC1 QVDNJGOBMXAPSJ-UHFFFAOYSA-N 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 14
- 229940124321 AIDS medicine Drugs 0.000 claims description 10
- NQVWMXLKPISDFN-UHFFFAOYSA-N 2-(cyclopropylamino)pyridine-3-carbonitrile Chemical compound N#CC1=CC=CN=C1NC1CC1 NQVWMXLKPISDFN-UHFFFAOYSA-N 0.000 claims description 9
- YYXDQRRDNPRJFL-UHFFFAOYSA-N 2-aminopyridine-3-carbonitrile Chemical compound NC1=NC=CC=C1C#N YYXDQRRDNPRJFL-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 9
- -1 chloro Trimetylene Chemical group 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 8
- 239000011230 binding agent Substances 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- 125000001475 halogen functional group Chemical group 0.000 claims description 7
- 230000007062 hydrolysis Effects 0.000 claims description 7
- 238000006460 hydrolysis reaction Methods 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- RVQXGFOIBYLZMH-UHFFFAOYSA-N Br.C1CC1 Chemical compound Br.C1CC1 RVQXGFOIBYLZMH-UHFFFAOYSA-N 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 3
- 235000015320 potassium carbonate Nutrition 0.000 claims description 3
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- ULWHHBHJGPPBCO-UHFFFAOYSA-N propane-1,1-diol Chemical class CCC(O)O ULWHHBHJGPPBCO-UHFFFAOYSA-N 0.000 claims description 2
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical class C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 abstract 1
- 239000003513 alkali Substances 0.000 abstract 1
- LKXYJYDRLBPHRS-UHFFFAOYSA-N bromocyclopropane Chemical compound BrC1CC1 LKXYJYDRLBPHRS-UHFFFAOYSA-N 0.000 abstract 1
- 230000003301 hydrolyzing effect Effects 0.000 abstract 1
- 238000001308 synthesis method Methods 0.000 abstract 1
- 238000010025 steaming Methods 0.000 description 5
- 239000003643 water by type Substances 0.000 description 5
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 239000002726 nonnucleoside reverse transcriptase inhibitor Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- JAUPUQRPBNDMDT-UHFFFAOYSA-N 2-chloropyridine-3-carbonitrile Chemical compound ClC1=NC=CC=C1C#N JAUPUQRPBNDMDT-UHFFFAOYSA-N 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 1
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 description 1
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 206010064571 Gene mutation Diseases 0.000 description 1
- 206010019695 Hepatic neoplasm Diseases 0.000 description 1
- 102000018251 Hypoxanthine Phosphoribosyltransferase Human genes 0.000 description 1
- 108010091358 Hypoxanthine Phosphoribosyltransferase Proteins 0.000 description 1
- 108700005443 Microbial Genes Proteins 0.000 description 1
- 241000607142 Salmonella Species 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000002798 bone marrow cell Anatomy 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000001010 compromised effect Effects 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 230000035558 fertility Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 231100000025 genetic toxicology Toxicity 0.000 description 1
- 230000001738 genotoxic effect Effects 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 231100000350 mutagenesis Toxicity 0.000 description 1
- 238000002703 mutagenesis Methods 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229940042402 non-nucleoside reverse transcriptase inhibitor Drugs 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 231100000101 reproductive and developmental toxicity testing Toxicity 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 229940098802 viramune Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a method for preparing a key intermediate 2-(cyclopropylamido)-3-pyridine formic acid of an anti-aids medicament Nevirapine. The synthesis method comprises the following steps of: reacting 2-amido3-cyanopyridine with chlorinated cyclopropan (or cyclopropyl bromide) to generate 2-(cyclopropylamido)-3-cyanopyridine; and hydrolyzing in alkali to generate 2-(cyclopropylamido)-3-pyridine formic acid. The invention has the advantages of simple process, easiness in operation and high product yield, and the product purity is larger than 99 percent.
Description
Technical field
The present invention relates to the compound method of a kind of anti-AIDS drug nevirapine key intermediate 2-(cyclopropyl amino)-3-pyridine carboxylic acid, belong to organic chemistry and technical field of medicine synthesis.
Background technology
2-(cyclopropyl amino)-3-pyridine carboxylic acid is anti-AIDS drug nevirapine (Nevirapine) key intermediate, and nevirapine has another name called the happy life of dimension (Viramune), chemical structural formula:
Chemical structure names: 11-cyclopropyl-5,11-dihydro-4-methyl-6 hydrogen-two pyridines-[3,2-b:2,3-e] [1,4] diazepine-6-ketone, molecular formula is C15H14N4O, molecular weight is 266.3.Nevirapine be the sweet type RTI of the non-nuclear of HIV-1 (Non-Nucleoside Reverse Transcriptase Inhibitor, NNRTI).Nevirapine directly is connected with the reversed transcriptive enzyme of HIV-1 and breaks through the catalysis end that makes this enzyme to be blocked RNA and relies on the dna polymerase activity with the DNA dependence.
In carinogenicity research, nevirapine increases the incidence of the liver tumor of mouse (dosage reached for 750 mg/kg/ days) and rat (dosage reached for 35 mg/kg/ days).But these discoveries are that a more obstinate liver enzyme inducer is relevant with nevirapine probably, but can not produce genotoxicity.In following a series of bodies and in the analysis of the toxicity of in vitro tests gene, nevirapine does not demonstrate the activity of transgenation or mutagenesis.These tests comprise: (Ames: salmonella strain and Escherichia coli), mammalian cell gene mutation evaluation (CHO/HGPRT) are measured in the microbial gene sudden change, oral medication Hou utilizes the Chinese hamster ovary line cell to carry out methods such as science of heredity mensuration and the evaluation of mouse bone marrow cells micronucleus.In reproductive toxicity studies, the data suggest that in female rats receiving nevirapine to song XIAN as measured by the area under the dose to achieve full identity cloth, their fertility is compromised.This dosage is suitable with the recommended dose of this medicinal what human body.
The main method of at present synthetic this midbody is Boswell, Robert Frederick; Gupton, Bernard Franklin; Lo; The patented process of Young Sek US 20040002603; Mainly be to close at solvent from 2-chloro-3-cyanopyridine and cyclopropylamine that reaction obtains 2-(cyclopropyl amino)-3-cyanopyridine under the acid binding agent condition, obtain 2-(cyclopropyl amino)-3-pyridine carboxylic acid through hydrolysis again.
Summary of the invention
The object of the present invention is to provide a kind of technology simple, the synthetic 5-halogen 2-(cyclopropyl amino) of the different process route that yield is high-3-pyridine carboxylic acid method.
Technical solution of the present invention is: the preparation method of a kind of anti-AIDS drug nevirapine key intermediate 2-(cyclopropyl amino)-3-pyridine carboxylic acid is characterized in that: be made up of following 2 steps reaction:
Amino 3-cyanopyridine of the first step: 2-and halo Trimetylene react in the presence of solvent and acid binding agent and obtain 2-(cyclopropyl amino)-3-cyanopyridine.
Second step: the hydrolysis under alkaline condition of 2-(cyclopropyl amino)-3-cyanopyridine obtains nevirapine key intermediate 2-(cyclopropyl amino)-3-pyridine carboxylic acid.
Further, in the first step, said halo Trimetylene is meant chloro Trimetylene or cyclopropane bromide, and said solvent is meant the mixing solutions of water, alcohol or water and alcohol.
Further, said alcohol is that carbon 1 is to carbon 6 alcohol, terepthaloyl moietie, propandiols material.
Further, in the first step, said acid binding agent is meant triethylamine, diethylamine, ethamine class amine salt and salt of wormwood, yellow soda ash class carbonate.
Further, the temperature of reaction in the first step is 10～100 degree; The amino 3-cyanopyridine of 2-: halo Trimetylene: acid binding agent: solvent (mol ratio)=1:0.2～5:0.2～5:1～100.
Further, said hydrolysis is under the condition of alkaline condition sodium hydroxide or Pottasium Hydroxide existence, to react.
The invention has the advantages that: technology is simple, and is easy to operate, and product yield is high.
Below in conjunction with embodiment the present invention is described further:
Embodiment:
Reaction of the present invention is specific as follows:
Generate 2-(cyclopropyl amino)-3-cyanopyridine by amino 3-cyanopyridine of 2-and chloro Trimetylene (or cyclopropane bromide reaction), generate 2-(cyclopropyl amino)-3-pyridine carboxylic acid through basic hydrolysis again, reaction formula is following:
The amino 3-cyanopyridine of 2-: halo Trimetylene: acid binding agent: react under 10-100 degree condition up to transforming fully solvent (mol ratio)=1:0.2～5:0.2～5:1～100; The pressure reducing and steaming solvent adds entry; Be cooled to-5 to 30 degree, agitation and filtration obtains product 2-(cyclopropyl amino)-3-cyanopyridine; Then with 2-(cyclopropyl amino)-3-cyanopyridine in doubly hydrolysis in sodium hydroxide or the potassium hydroxide solution of mole of 1-6, add water after boiling off solvent, transfer PH to acid, filter and obtain product.
Embodiment 1:
In there-necked flask, add 120 amino-3 cyanopyridines of gram 2-and 140 milliliters of ethanol, add 138 gram salt of wormwood and 200 ml waters under stirring; Slowly add the chloro Trimetylene of 80 grams again, added afterreaction 24 hours, HPLC analyzes up to reacting completely; The pressure reducing and steaming solvent adds 400 ml waters; Be cooled to the 0-5 degree, filter and obtain 115 gram products, content is more than 98.0%.
Embodiment 2:
In there-necked flask, add 120 amino-3 cyanopyridines of gram 2-and 140 milliliters of ethanol, add 220 gram triethylamines under stirring; Slowly add the chloro Trimetylene of 80 grams again, added afterreaction 24 hours, HPLC analyzes up to reacting completely; The pressure reducing and steaming solvent adds 300 ml waters; Be cooled to the 0-5 degree, filter and obtain 140 gram products, content is more than 98.5%.
Embodiment 3:
In there-necked flask, add 120 amino-3 cyanopyridines of gram 2-and 140 milliliters of ethanol, add 220 gram triethylamines under stirring; Slowly add the cyclopropane bromide of 123 grams again, added afterreaction 24 hours, HPLC analyzes up to reacting completely; The pressure reducing and steaming solvent adds 300 ml waters; Be cooled to the 0-5 degree, filter and obtain 150 gram products, content is more than 98.5%.
Embodiment 4:
In there-necked flask, add 135 gram 2-(cyclopropyl amino)-3-cyanopyridine and 300 milliliters of ethanol, stir the 350 gram potassium hydroxide solutions of adding down; Heat to backflow, HPLC analyzes up to reacting completely, and the pressure reducing and steaming solvent adds 300 ml waters; Be cooled to the 0-5 degree, add hydrochloric acid and transfer PH, filter to 2-3; Water washing obtains 135 gram products, and content is more than 99%.
Claims (6)
1. the preparation method of an anti-AIDS drug nevirapine key intermediate 2-(cyclopropyl amino)-3-pyridine carboxylic acid is characterized in that: be made up of following 2 steps reaction:
Amino 3-cyanopyridine of the first step: 2-and halo Trimetylene react in the presence of solvent and acid binding agent and obtain 2-(cyclopropyl amino)-3-cyanopyridine;
Second step: the hydrolysis under alkaline condition of 2-(cyclopropyl amino)-3-cyanopyridine obtains nevirapine key intermediate 2-(cyclopropyl amino)-3-pyridine carboxylic acid
be X=Cl or Br wherein.
2. the preparation method of a kind of anti-AIDS drug nevirapine key intermediate 2-according to claim 1 (cyclopropyl amino)-3-pyridine carboxylic acid; It is characterized in that: in the first step; Said halo Trimetylene is meant chloro Trimetylene or cyclopropane bromide, and said solvent is meant the mixing solutions of water, alcohol or water and alcohol.
3. the preparation method of a kind of anti-AIDS drug nevirapine key intermediate 2-according to claim 2 (cyclopropyl amino)-3-pyridine carboxylic acid is characterized in that: said alcohol is that carbon 1 is to carbon 6 alcohol, terepthaloyl moietie, propandiols material.
4. according to the preparation method of the said a kind of anti-AIDS drug nevirapine key intermediate 2-of claim 1 (cyclopropyl amino)-3-pyridine carboxylic acid; It is characterized in that: in the first step, said acid binding agent is meant triethylamine, diethylamine, ethamine class amine salt and salt of wormwood, yellow soda ash class carbonate.
5. the preparation method of a kind of anti-AIDS drug nevirapine key intermediate 2-according to claim 1 (cyclopropyl amino)-3-pyridine carboxylic acid is characterized in that: the temperature of reaction of the first step is 10～100 degree; The amino 3-cyanopyridine of 2-: halo Trimetylene: acid binding agent: solvent (mol ratio)=1:0.2～5:0.2～5:1～100.
6. the preparation method of a kind of anti-AIDS drug nevirapine key intermediate 2-according to claim 1 (cyclopropyl amino)-3-pyridine carboxylic acid is characterized in that: hydrolysis is under the condition of alkaline condition sodium hydroxide or Pottasium Hydroxide existence, to react.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110180511A CN102321015A (en) | 2011-06-30 | 2011-06-30 | Method for preparing key intermediate 2-(cyclopropylamido)-3-pyridine formic acid of anti-aids medicament Nevirapine |
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| CN201110180511A CN102321015A (en) | 2011-06-30 | 2011-06-30 | Method for preparing key intermediate 2-(cyclopropylamido)-3-pyridine formic acid of anti-aids medicament Nevirapine |
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| CN102321015A true CN102321015A (en) | 2012-01-18 |
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| CN201110180511A Pending CN102321015A (en) | 2011-06-30 | 2011-06-30 | Method for preparing key intermediate 2-(cyclopropylamido)-3-pyridine formic acid of anti-aids medicament Nevirapine |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116675640A (en) * | 2023-06-02 | 2023-09-01 | 中科苏州药物研究院 | A kind of preparation method of nevirapine intermediate 2-(cyclopropylamino) nicotinic acid |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1653065A (en) * | 2002-06-28 | 2005-08-10 | 贝林格尔英格海姆化学公司 | Improved method for making nevirapine |
| CN101405002A (en) * | 2005-12-29 | 2009-04-08 | 詹森药业有限公司 | Prokineticin 2 receptor antagonists |
| CN101448836A (en) * | 2006-05-23 | 2009-06-03 | 霍夫曼-拉罗奇有限公司 | Pyridopyrimidinone derivatives |
| CN101585836A (en) * | 2008-05-25 | 2009-11-25 | 浙江华海药业股份有限公司 | Novel method for preparing Nevirapine |
-
2011
- 2011-06-30 CN CN201110180511A patent/CN102321015A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1653065A (en) * | 2002-06-28 | 2005-08-10 | 贝林格尔英格海姆化学公司 | Improved method for making nevirapine |
| CN1280293C (en) * | 2002-06-28 | 2006-10-18 | 贝林格尔英格海姆化学公司 | Improved method for preparing nevirapine |
| CN101405002A (en) * | 2005-12-29 | 2009-04-08 | 詹森药业有限公司 | Prokineticin 2 receptor antagonists |
| CN101448836A (en) * | 2006-05-23 | 2009-06-03 | 霍夫曼-拉罗奇有限公司 | Pyridopyrimidinone derivatives |
| CN101585836A (en) * | 2008-05-25 | 2009-11-25 | 浙江华海药业股份有限公司 | Novel method for preparing Nevirapine |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116675640A (en) * | 2023-06-02 | 2023-09-01 | 中科苏州药物研究院 | A kind of preparation method of nevirapine intermediate 2-(cyclopropylamino) nicotinic acid |
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Application publication date: 20120118 |