CN107903177A - The preparation method of 4 methoxyl group, 2,3 Dinitrobenzenecarbonitrile - Google Patents
The preparation method of 4 methoxyl group, 2,3 Dinitrobenzenecarbonitrile Download PDFInfo
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- CN107903177A CN107903177A CN201711257751.1A CN201711257751A CN107903177A CN 107903177 A CN107903177 A CN 107903177A CN 201711257751 A CN201711257751 A CN 201711257751A CN 107903177 A CN107903177 A CN 107903177A
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- Prior art keywords
- methoxyl groups
- dinitrobenzenecarbonitrile
- bromo
- preparation
- methoxyl group
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- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- -1 methoxyl group Chemical group 0.000 title claims abstract description 8
- WWQOAUZBUYMRDM-UHFFFAOYSA-N 2,3-dinitrobenzonitrile Chemical compound [O-][N+](=O)C1=CC=CC(C#N)=C1[N+]([O-])=O WWQOAUZBUYMRDM-UHFFFAOYSA-N 0.000 title abstract 3
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 10
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims abstract description 9
- 229910017604 nitric acid Inorganic materials 0.000 claims abstract description 9
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 claims abstract description 8
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical class CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000000034 method Methods 0.000 claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims description 8
- WDCYWAQPCXBPJA-UHFFFAOYSA-N 1,3-dinitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC([N+]([O-])=O)=C1 WDCYWAQPCXBPJA-UHFFFAOYSA-N 0.000 claims description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 abstract description 4
- 150000001875 compounds Chemical class 0.000 abstract description 2
- 238000001308 synthesis method Methods 0.000 abstract description 2
- SODQFLRLAOALCF-UHFFFAOYSA-N 1lambda3-bromacyclohexa-1,3,5-triene Chemical compound Br1=CC=CC=C1 SODQFLRLAOALCF-UHFFFAOYSA-N 0.000 abstract 3
- AGGUKALRPKAKSM-UHFFFAOYSA-N 2,5-dichloro-1,3-dinitrobenzene Chemical compound [O-][N+](=O)C1=CC(Cl)=CC([N+]([O-])=O)=C1Cl AGGUKALRPKAKSM-UHFFFAOYSA-N 0.000 abstract 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 11
- 229940049595 antibody-drug conjugate Drugs 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 239000000611 antibody drug conjugate Substances 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000003053 toxin Substances 0.000 description 2
- 231100000765 toxin Toxicity 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- IZUKQUVSCNEFMJ-UHFFFAOYSA-N 1,2-dinitrobenzene Chemical class [O-][N+](=O)C1=CC=CC=C1[N+]([O-])=O IZUKQUVSCNEFMJ-UHFFFAOYSA-N 0.000 description 1
- 229930126263 Maytansine Natural products 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229940125644 antibody drug Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 235000021463 dry cake Nutrition 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- WKPWGQKGSOKKOO-RSFHAFMBSA-N maytansine Chemical compound CO[C@@H]([C@@]1(O)C[C@](OC(=O)N1)([C@H]([C@@H]1O[C@@]1(C)[C@@H](OC(=O)[C@H](C)N(C)C(C)=O)CC(=O)N1C)C)[H])\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 WKPWGQKGSOKKOO-RSFHAFMBSA-N 0.000 description 1
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/08—Preparation of nitro compounds by substitution of hydrogen atoms by nitro groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/14—Preparation of carboxylic acid nitriles by reaction of cyanides with halogen-containing compounds with replacement of halogen atoms by cyano groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Health & Medical Sciences (AREA)
- Toxicology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to the preparation method of 4 methoxyl group, 2,3 Dinitrobenzenecarbonitrile.Mainly solve the technical problem that the compound lacks Industrialized synthesis method.The method of the present invention is divided into 2 steps：The first step, reacts to obtain 1 bromine, 4 methoxyl group, 2,3 dinitro benzene by 1 bromine, 4 methoxyl group, 2 nitrobenzene is added dropwise under the concentrated sulfuric acid and concentrated nitric acid priority low temperature；Second step, 1 bromine, 4 methoxyl group, 2,3 dinitro benzene, which is dissolved in N methyl pyrrolidones, adds cuprous cyanide pyroreaction generation 4 methoxyl group, 2,3 Dinitrobenzenecarbonitrile.
Description
Technical field
4- methoxyl group -2,3- Dinitrobenzenecarbonitriles are synthesized by the bromo- 4- methoxyl groups -2- nitrobenzenes of 1- the present invention relates to a kind of
Method.
Background technology
Molecular perspectives：Molecule and its derivative involved in the present invention are the important centres for having synthesized CHROMATOGRAPHIC FRACTIONATION AND MASS antibody drug
Body.Research shows, antibody drug conjugates（antibody drug conjugates, ADC）Realize large biological molecule and small
The combination among the strong ones of molecule toxin advantage, is considered as the important means of future tumors treatment.Maytansine and its derivative are at this stage
One of toxin that ADC is most widely used, using ADC medicine Ah mores' Herceptins of the toxoid according to ester（ATE）Listing,
The indication leukemia of ADC is successfully expanded into other entity tumors.
The content of the invention
The object of the present invention is to provide a kind of preparation method by 4- methoxyl group -2,3- Dinitrobenzenecarbonitriles.Mainly solve
The compound lacks the technical problem of Industrialized synthesis method.
Technical scheme：A kind of preparation method of 4- methoxyl groups -2,3- Dinitrobenzenecarbonitrile, including following step
Suddenly, the method for the present invention is divided into 2 steps：The first step, will be added dropwise to the bromo- 4- methoxyl groups -2- of 1- under the concentrated sulfuric acid and concentrated nitric acid priority low temperature
Nitrobenzene reacts to obtain the bromo- 4- methoxyl groups -2,3- dinitro benzenes of 1-；Second step, bromo- 4- methoxyl groups -2, the 3- dinitro benzene dissolvings of 1-
The method that cuprous cyanide pyroreaction generation 4- methoxyl group -2,3- Dinitrobenzenecarbonitriles are added in 1-methyl-2-pyrrolidinone；Instead
Answer formula as follows：
。
Low temperature described in the first step is 0 DEG C, and reaction temperature is 0 DEG C-room temperature（20-30℃）, the bromo- 4- methoxyl groups -2- nitros of 1-
Benzene and concentrated nitric acid, the molar ratio of the concentrated sulfuric acid are 1:(2~3):(2~3)；High temperature described in second step is 150 DEG C, the bromo- 4- methoxyl groups of 1--
The molar ratio of 2,3- dinitro benzenes and cuprous cyanide is 1:3~5.
The beneficial effects of the invention are as follows：Route is short, easy to operate, and cost is low, and purifying is simple, is a kind of efficient, energy saving
The method for synthesizing 4- methoxyl group -2,3- Dinitrobenzenecarbonitriles.The invention belongs to initiate, pertinent literature is had no before this and reports this molecule
Synthetic method.
Embodiment
Embodiment 1,
Step 1：
The bromo- 4- methoxyl groups -2- nitrobenzenes of 1- are first added into three-necked flask and are cooled to 0 DEG C, keep temperature that dense nitre is slowly added dropwise successively
Acid and the concentrated sulfuric acid, be warmed to room temperature reaction 1 it is small when obtain bromo- 4- methoxyl groups -2, the 3- dinitro benzenes of intermediate 1-, the bromo- 4- methoxyl groups of 1- -
2- nitrobenzenes and concentrated nitric acid, the molar ratio of the concentrated sulfuric acid are 1:2:3, reaction solution is diluted with water, and is then extracted with ethyl acetate, concentration
After add petroleum ether：Ethyl acetate=3:1 mixed solvent, is stirred 20 minutes at room temperature.Filter residue is collected by filtration and is dried to obtain
The bromo- 4- methoxyl groups -2,3- dinitro benzenes of intermediate 1-.1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 4.8 Hz
1H), 7.16 (d, J = 9.2 Hz 1H), 4.00 (s, 3H).
Step 2：
Bromo- 4- methoxyl groups -2, the 3- dinitro benzenes of 1- are dissolved in 1-methyl-2-pyrrolidinone, add cyaniding Asia ketone, 1- at room temperature
The molar ratio of bromo- 4- methoxyl groups -2,3- dinitro benzenes and cuprous cyanide is 1:4, be warming up to 150 DEG C reaction 3 it is small when generate 4- first
Epoxide -2,3- Dinitrobenzenecarbonitriles.Reaction solution is diluted with water, and is then extracted with ethyl acetate, and after concentration, uses petroleum ether:Acetic acid
Ethyl ester volume ratio=3:1 mixed solvent washing, dry cake obtain 4- methoxyl group -2,3- Dinitrobenzenecarbonitriles.MS, (M-Me
) +: 208.1; 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 9.2 Hz 1H), 7.42 (d, J =
9.2 Hz 1H), 4.10 (s, 3H)。
Embodiment 2, the bromo- 4- methoxyl groups -2- nitrobenzenes of 1- and concentrated nitric acid, the molar ratio of the concentrated sulfuric acid are 1:3:2,1- bromo- 4-
The molar ratio of methoxyl group -2,3- dinitro benzenes and cuprous cyanide is 1:3, remaining is the same as embodiment 1.
Embodiment 3, the bromo- 4- methoxyl groups -2- nitrobenzenes of 1- and concentrated nitric acid, the molar ratio of the concentrated sulfuric acid are 1:2.5:2.5,1-
The molar ratio of bromo- 4- methoxyl groups -2,3- dinitro benzenes and cuprous cyanide is 1:5, remaining is the same as embodiment 1.
Claims (7)
1. a kind of preparation method of 4- methoxyl groups -2,3- Dinitrobenzenecarbonitrile, it is characterized in that：Comprise the following steps, the first step, will
The concentrated sulfuric acid reacts to obtain the bromo- 4- methoxyl groups -2,3- of 1- with being added dropwise to the bromo- 4- methoxyl groups -2- nitrobenzenes of 1- under concentrated nitric acid priority low temperature
Dinitro benzene；Second step, bromo- 4- methoxyl groups -2, the 3- dinitro benzenes of 1-, which are dissolved in 1-methyl-2-pyrrolidinone, adds cuprous cyanide
The method that pyroreaction generates 4- methoxyl group -2,3- Dinitrobenzenecarbonitriles；Reaction equation is as follows：
。
2. the preparation method of 4- methoxyl groups -2,3- Dinitrobenzenecarbonitrile according to claim 1, it is characterized in that, the bromo- 4- of 1-
Methoxyl group -2- nitrobenzenes and concentrated nitric acid, the molar ratio of the concentrated sulfuric acid are 1:（2~3）:（2~3）.
3. the preparation method of 4- methoxyl groups -2,3- Dinitrobenzenecarbonitrile according to claim 1, it is characterized in that, the first step
The low temperature is 0 DEG C, and reaction temperature is 0 DEG C-room temperature.
4. the preparation method of 4- methoxyl groups -2,3- Dinitrobenzenecarbonitrile according to claim 1, it is characterized in that, the first step
Specially：First keep 0 DEG C and sequentially add concentrated nitric acid and the concentrated sulfuric acid dropwise into the bromo- 4- methoxyl groups -2- nitrobenzenes of 1-, heat up room temperature
React 1 it is small when obtain bromo- 4- methoxyl groups -2, the 3- dinitro benzenes of intermediate 1-.
5. the preparation method of 4- methoxyl groups -2,3- Dinitrobenzenecarbonitrile according to claim 1, it is characterized in that, the bromo- 4- of 1-
The molar ratio of methoxyl group -2,3- dinitro benzene and cuprous cyanide is 1:3~5.
6. the preparation method of 4- methoxyl groups -2,3- Dinitrobenzenecarbonitrile according to claim 1, it is characterized in that, second step
The high temperature is 150 DEG C.
7. the preparation method of 4- methoxyl groups -2,3- Dinitrobenzenecarbonitrile according to claim 1, it is characterized in that, second step
When reaction 3 is small under conditions of 150 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711257751.1A CN107903177A (en) | 2017-12-04 | 2017-12-04 | The preparation method of 4 methoxyl group, 2,3 Dinitrobenzenecarbonitrile |
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|---|---|---|---|
| CN201711257751.1A CN107903177A (en) | 2017-12-04 | 2017-12-04 | The preparation method of 4 methoxyl group, 2,3 Dinitrobenzenecarbonitrile |
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| CN107903177A true CN107903177A (en) | 2018-04-13 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201711257751.1A Pending CN107903177A (en) | 2017-12-04 | 2017-12-04 | The preparation method of 4 methoxyl group, 2,3 Dinitrobenzenecarbonitrile |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101648890A (en) * | 2009-09-16 | 2010-02-17 | 常州工程职业技术学院 | Synthesis method of 2-fluoro-4-nitrobenzonitrile |
| CN102199144A (en) * | 2004-01-14 | 2011-09-28 | 诺瓦提斯公司 | Benzimidazole derivatives |
-
2017
- 2017-12-04 CN CN201711257751.1A patent/CN107903177A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102199144A (en) * | 2004-01-14 | 2011-09-28 | 诺瓦提斯公司 | Benzimidazole derivatives |
| CN101648890A (en) * | 2009-09-16 | 2010-02-17 | 常州工程职业技术学院 | Synthesis method of 2-fluoro-4-nitrobenzonitrile |
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Application publication date: 20180413 |