CN100427473C - Synthesis method of key intermediate 2-cyanpyrazine of tuberculosis drug pyrazinamide - Google Patents
Synthesis method of key intermediate 2-cyanpyrazine of tuberculosis drug pyrazinamide Download PDFInfo
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- CN100427473C CN100427473C CNB2006101547228A CN200610154722A CN100427473C CN 100427473 C CN100427473 C CN 100427473C CN B2006101547228 A CNB2006101547228 A CN B2006101547228A CN 200610154722 A CN200610154722 A CN 200610154722A CN 100427473 C CN100427473 C CN 100427473C
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- pyrazine
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Abstract
The invention discloses a synthesizing method of 2-cyano pyrazine as key intermediate of antitubercular drugs aldinamide, which comprises the following steps: adopting alkyl benzene as reacting solvent; making 1.5-3% cuprous iodide, potassium iodide and 1-1.5% N, N'-dimethyldiamine as composite catalyst; reacting 2, 2-difluobromobenzene and sodium cyanide with molar rate at 1: 1.0-2.0 protected by nitrogen at 100-150 Deg C for 20-48h; filtering; decompressing the filtrate; fractioning to obtain the product. The invention shortens reacting flow path, which is simple to feed and dispose.
Description
Technical field
The present invention relates to the medicine intermediate preparation method, relate in particular to a kind of synthetic method of anti-tuberculosis drugs pyrazinoic acid amide intermediate 2 cyano pyrazine.
Background technology
The important source material of 2 cyano pyrazine production for treating tuberculosis drug pyrazinamide.Therefore how efficiently Synthetic 2-cyanopyrazine receives people's huge concern.Synthetic more existing bibliographical informations of 2 cyano pyrazine have been reported the research of special catalyst catalysis 2-methylpyrazine prepared by ammoxidation 2 cyano pyrazine such as document " fine chemistry industry ".Document Applied Catalsis, 1986, cyclization dehydration dehydrogenation under catalyst action is 2 monomethyl pyrazines to the 20:219-222 report with quadrol and propylene glycol earlier, the High Temperature High Pressure catalytic ammoxidation is 2 one cyanopyrazines again.Document CN1398855 has reported that by adopting with 2-methylpyrazine, ammonia and oxygen be raw material, in temperature of reaction is 300～500 ℃, in the gauge pressure reaction pressure is under-0.05～0.05MPa condition, and raw material is by with vanadium, chromium catalyst system and non-imposed interpolation phosphorus and be selected from basic metal or the technical scheme of the fluid catalyst bed that alkaline-earth metal is formed is used for the industrial production of 2 cyano pyrazine.Document CN1408711 has reported the catalyzer that a kind of 2-methylpyrazine Synthetic 2-cyanopyrazine uses, and this catalyzer adopts metavanadic acid ammonia, Vanadium Pentoxide in FLAKES, and ammonium molybdate, phosphoric acid are through flooding the loaded catalyst of preparation system.Document CN1429820 has reported that a kind of oxidation proceses of ammonia prepares the method and the special-purpose catalyst of 2 cyano pyrazine, it is to be Primary Catalysts with vanadium, titanium, and phosphorus, iron, nickel, cobalt, bismuth, manganese, chromium, molybdenum, copper, zinc, tin, boron, potassium, lithium, magnesium etc. are the multicomponent catalyst of promotor.Above-mentioned these synthesis technique Preparation of Catalyst complexity, reaction process is long cycle time, the condition harshness, or have many experimentations to relate to variety of problems such as high-temperature and high-pressure conditions, low-yield, aftertreatment complexity.Thereby under the condition of gentleness, the synthesis technique that solves 2 cyano pyrazine efficiently is very important and urgent.
Summary of the invention
The synthetic method that the purpose of this invention is to provide a kind of anti-tuberculosis drugs pyrazinoic acid amide intermediate 2 cyano pyrazine.
It is to be reaction solvent with the alkylbenzene; with cuprous iodide; potassiumiodide and N; N '-dimethyl-ethylenediamine is a combination catalyst; 2-bromo-pyrazine and sodium cyanide reacted 20～48 hours at 100～150 ℃ under nitrogen protection; subsequent filtration; the filtrate decompression fractionation obtains 2 cyano pyrazine; the molar equivalent ratio of 2-bromo-pyrazine and sodium cyanide is 1: 1.0～2.0; the consumption of cuprous iodide is 5～30% molar equivalents of 2-bromo-pyrazine; the consumption of potassiumiodide is 1.5～3 molar equivalents of cuprous iodide; N, the consumption of N '-dimethyl-ethylenediamine are 1～1.5 molar equivalent of 2-bromo-pyrazine, and reaction formula is:
Described reaction solvent alkylbenzene is toluene, ethylbenzene or dimethylbenzene.
Reaction times is preferably 20～36 hours.Temperature of reaction is preferably 100～130 ℃.The molar equivalent ratio of 2-bromo-pyrazine and sodium cyanide is preferably 1: 1.0～and 1.5; The consumption of cuprous iodide is preferably 5～20% molar equivalents of 2-bromo-pyrazine; The consumption of potassiumiodide is preferably 1.5～2.5 molar equivalents of cuprous iodide; N, the consumption of N '-dimethyl-ethylenediamine are preferably 1～1.2 molar equivalent of 2-bromo-pyrazine.
The present invention compares with existing synthetic method, has the following advantages:
1) reaction conditions gentleness;
2) the reaction process flow process is short;
3) use cheap reagent;
4) feed intake and aftertreatment all very simple, be easy to realize industrialized production.
Embodiment
The molecular formula of 2 cyano pyrazine is:
The concrete reactions steps of the synthetic method of anti-tuberculosis drugs pyrazinoic acid amide key intermediate 2 cyano pyrazine is as follows:
With the alkylbenzene is reaction solvent; with cuprous iodide, potassiumiodide and N, N '-dimethyl-ethylenediamine is a combination catalyst, and 2-bromo-pyrazine and sodium cyanide reacted 20～48 hours at 100～150 ℃ under nitrogen protection; subsequent filtration, filtrate decompression fractionation obtain high yield, highly purified 2 cyano pyrazine.Wherein the molar equivalent ratio of 2-bromo-pyrazine and sodium cyanide is 1: 1.0～2.0; The consumption of cuprous iodide is 5～30% molar equivalents of 2-bromo-pyrazine; The consumption of potassiumiodide is 1.5～3 molar equivalents of cuprous iodide; N, the consumption of N '-dimethyl-ethylenediamine are 1～1.5 molar equivalent of 2-bromo-pyrazine.Recommendation response solvent alkylbenzene is toluene, ethylbenzene, dimethylbenzene, and override is a toluene.The recommendation response time is 20～36 hours, and override is 24 hours.The recommendation response temperature is 100～130 ℃, and override is 110 ℃.Recommending the molar equivalent ratio of 2-bromo-pyrazine and sodium cyanide is 1: 1.0～1.5, and override is 1: 1.2; The consumption of cuprous iodide is 5～20% molar equivalents of 2-bromo-pyrazine, and override is 10% molar equivalent; The consumption of potassiumiodide is 1.5～2.5 molar equivalents of cuprous iodide, and override is 2 molar equivalents; N, the consumption of N '-dimethyl-ethylenediamine are 1～1.2 molar equivalent of 2-bromo-pyrazine, and override is 1 molar equivalent.
Following examples will help to understand the present invention, but be not limited to content of the present invention:
Embodiment 1
In 1 liter of three-necked bottle; add 500 milliliters of toluene under the nitrogen protection successively; 48 gram (0.3 mole) 2-bromo-pyrazines, 11.8 gram (0.36 mole, 1.2 equivalents) sodium cyanides; 5.73 gram (30 mmoles; 0.1 cuprous iodide equivalent), 10 gram potassiumiodides (60 mmoles, 0.2 equivalent); 26.4 gram N; N '-dimethyl-ethylenediamine (0.3 mole, 1.0 equivalents), under nitrogen protection 110 ℃ of stirring reactions 30 hours; finish reaction; subsequent filtration, the filtrate decompression fractionation obtains the transparent liquid 2 cyano pyrazine, productive rate 70%; purity 99% (GC), 84～87 ℃ of boiling points (18-20mmHg).
Embodiment 2
In 1 liter of three-necked bottle; add 500 milliliters of ethylbenzene under the nitrogen protection successively; 48 gram (0.3 mole) 2-bromo-pyrazines; 11.8 gram (0.36 mole, 1.2 equivalents) sodium cyanide, 5.73 gram (30 mmoles; 0.1 cuprous iodide equivalent); 10 gram potassiumiodides (60 mmoles, 0.2 equivalent), 26.4 gram N; (0.3 mole of N '-dimethyl-ethylenediamine; 1.0 equivalent), under nitrogen protection,, finish reaction 120 ℃ of stirring reactions 25 hours; subsequent filtration; the filtrate decompression fractionation obtains the transparent liquid 2 cyano pyrazine, productive rate 73%, purity 99%.
Embodiment 3
In 1 liter of three-necked bottle; add 500 milliliters of toluene under the nitrogen protection successively; 48 gram (0.3 mole) 2-bromo-pyrazines; 11.8 gram (0.36 mole, 1.2 equivalents) sodium cyanide, 5.73 gram (30 mmoles; 0.1 cuprous iodide equivalent); 11 gram potassiumiodides (66 mmoles, 0.22 equivalent), 26.4 gram N; (0.3 mole of N '-dimethyl-ethylenediamine; 1.0 equivalent), under nitrogen protection,, finish reaction 105 ℃ of stirring reactions 36 hours; subsequent filtration; the filtrate decompression fractionation obtains the transparent liquid 2 cyano pyrazine, productive rate 71%, purity 99%.
Embodiment 4
In 1 liter of three-necked bottle; add 500 milliliters of ethylbenzene under the nitrogen protection successively; 48 gram (0.3 mole) 2-bromo-pyrazines; 19.8 gram (0.6 mole, 2 equivalents) sodium cyanide, 2.83 gram (15 mmoles; 0.05 cuprous iodide equivalent); 10 gram potassiumiodides (60 mmoles, 0.3 equivalent), 39 gram N; (0.45 mole of N '-dimethyl-ethylenediamine; 1.5 equivalent), under nitrogen protection,, finish reaction 130 ℃ of stirring reactions 205 hours; subsequent filtration; the filtrate decompression fractionation obtains the transparent liquid 2 cyano pyrazine, productive rate 77%, purity 99%.
Embodiment 5
In 1 liter of three-necked bottle; add 500 milliliters of dimethylbenzene under the nitrogen protection successively; 48 gram (0.3 mole) 2-bromo-pyrazines; 11.8 gram (0.36 mole, 1.2 equivalents) sodium cyanide, 17.2 gram (90 mmoles; 0.3 cuprous iodide equivalent); 22 gram potassiumiodides (132 mmoles, 0.44 equivalent), 26.4 gram N; (0.3 mole of N '-dimethyl-ethylenediamine; 1.0 equivalent), under nitrogen protection,, finish reaction 100 ℃ of stirring reactions 48 hours; subsequent filtration; the filtrate decompression fractionation obtains the transparent liquid 2 cyano pyrazine, productive rate 72%, purity 99%.
Claims (5)
1. the synthetic method of an anti-tuberculosis drugs pyrazinoic acid amide intermediate 2 cyano pyrazine; it is characterized in that it is is reaction solvent with the alkylbenzene; with cuprous iodide; potassiumiodide and N; N '-dimethyl amine is a combination catalyst; 2-bromo-pyrazine and sodium cyanide reacted 20～48 hours at 100～150 ℃ under nitrogen protection; subsequent filtration; the filtrate decompression fractionation obtains 2 cyano pyrazine; the molar equivalent ratio of 2-bromo-pyrazine and sodium cyanide is 1: 1.0～2.0; the consumption of cuprous iodide is 5～30% molar equivalents of 2-bromo-pyrazine; the consumption of potassiumiodide is 1.5～3 molar equivalents of cuprous iodide; N; the consumption of N '-dimethyl-ethylenediamine is 1～1.5 molar equivalent of 2-bromo-pyrazine, and reaction formula is:
2. the synthetic method of a kind of anti-tuberculosis drugs pyrazinoic acid amide intermediate 2 cyano pyrazine according to claim 1 is characterized in that described reaction solvent alkylbenzene is toluene, ethylbenzene or dimethylbenzene.
3. the synthetic method of a kind of anti-tuberculosis drugs pyrazinoic acid amide intermediate 2 cyano pyrazine according to claim 1 is characterized in that the described reaction times is 20～36 hours.
4. the synthetic method of a kind of anti-tuberculosis drugs pyrazinoic acid amide intermediate 2 cyano pyrazine according to claim 1 is characterized in that described temperature of reaction is 100～130 ℃.
5. the synthetic method of a kind of anti-tuberculosis drugs pyrazinoic acid amide intermediate 2 cyano pyrazine according to claim 1, the molar equivalent ratio that it is characterized in that described 2-bromo-pyrazine and sodium cyanide is 1: 1.0～1.5; The consumption of cuprous iodide is 5～20% molar equivalents of 2-bromo-pyrazine; The consumption of potassiumiodide is 1.5～2.5 molar equivalents of cuprous iodide; N, the consumption of N '-dimethyl-ethylenediamine are 1～1.2 molar equivalent of 2-bromo-pyrazine.
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4419272A (en) * | 1981-02-28 | 1983-12-06 | Degussa Ag | Catalysts for the production of 2-cyanopyrazine |
| EP0253360A2 (en) * | 1986-07-15 | 1988-01-20 | Koei Chemical Co., Ltd. | Process for preparing nitriles |
| CN1398855A (en) * | 2001-07-20 | 2003-02-26 | 中国石油化工股份有限公司 | Ammoxidation process of preparing 2-cyano pyrazine |
| CN1398856A (en) * | 2001-07-20 | 2003-02-26 | 中国石油化工股份有限公司 | Fluidized bed catalyst for preparing 2-cyano pyrazine |
| CN1408711A (en) * | 2002-09-24 | 2003-04-09 | 天津大学 | Catalyst for synthesizing 2-cyano pyrazine from 2-methy/pyrazine and synthesizing method |
| CN1429820A (en) * | 2003-01-15 | 2003-07-16 | 邯郸市赵都精细化工厂 | Method of preparing 2-cyanopyrazine by ammonia oxidation method and its special catalyst |
| JP2005289962A (en) * | 2004-04-05 | 2005-10-20 | Ms Jubilant Organosys Ltd | Method for preparing cyanopyrazine |
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- 2006-11-21 CN CNB2006101547228A patent/CN100427473C/en not_active Expired - Fee Related
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4419272A (en) * | 1981-02-28 | 1983-12-06 | Degussa Ag | Catalysts for the production of 2-cyanopyrazine |
| EP0253360A2 (en) * | 1986-07-15 | 1988-01-20 | Koei Chemical Co., Ltd. | Process for preparing nitriles |
| CN1398855A (en) * | 2001-07-20 | 2003-02-26 | 中国石油化工股份有限公司 | Ammoxidation process of preparing 2-cyano pyrazine |
| CN1398856A (en) * | 2001-07-20 | 2003-02-26 | 中国石油化工股份有限公司 | Fluidized bed catalyst for preparing 2-cyano pyrazine |
| CN1408711A (en) * | 2002-09-24 | 2003-04-09 | 天津大学 | Catalyst for synthesizing 2-cyano pyrazine from 2-methy/pyrazine and synthesizing method |
| CN1429820A (en) * | 2003-01-15 | 2003-07-16 | 邯郸市赵都精细化工厂 | Method of preparing 2-cyanopyrazine by ammonia oxidation method and its special catalyst |
| JP2005289962A (en) * | 2004-04-05 | 2005-10-20 | Ms Jubilant Organosys Ltd | Method for preparing cyanopyrazine |
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