CN103159687A - Synthesis method of 2-aminopyrazinyl-5-formic acid - Google Patents
Synthesis method of 2-aminopyrazinyl-5-formic acid Download PDFInfo
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- CN103159687A CN103159687A CN2013101258092A CN201310125809A CN103159687A CN 103159687 A CN103159687 A CN 103159687A CN 2013101258092 A CN2013101258092 A CN 2013101258092A CN 201310125809 A CN201310125809 A CN 201310125809A CN 103159687 A CN103159687 A CN 103159687A
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- formic acid
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- trimethyl carbinol
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Abstract
The invention discloses a novel synthesis method of 2-aminopyrazinyl-5-formic acid, which comprises the following steps: carrying out hydrazinolysis reaction on accessible 2,5-ethyl diformate pyrazine to hydrazinolyze the monoester, reacting with a sodium nitrate solution, refluxing in toluene and tert-butyl alcohol to obtain a key intermediate 2-ethyl formate-5-Boc-amino-pyrazine, and refluxing in hydrochloric acid to obtain the 2-aminopyrazinyl-5-formic acid. The method has the advantages of mild and simple reaction conditions, low cost and high yield, is simple to operate and suitable for industrial production, and has great economic significance.
Description
Technical field
The present invention relates to the new synthesis process of a kind of 2-amido pyrazine-5-formic acid, belong to medicine, chemical technology field.
Background technology
Pyrazine and derivative thereof are the important intermediate of forming a connecting link between chemical industry and medicinal industry, are widely used in the fields such as medicine, agricultural chemicals, dyestuff, tensio-active agent, thiofide, oxidation inhibitor, sanitas.
2-amido pyrazine-5-formic acid is a kind of pyrazines derivatives, can be used for synthetic treatment diabetes medicine (JMC2012,55,1318-1333); Also can be used for synthesizing the medicine (WO2012027322) for the treatment of allergy, inflammation and cardiovascular disorder.
The synthetic method of bibliographical information has as follows:
Route A (JACS1949,71,2798-2800)
Route B (Helvetica Chimica Acta1964,47,873-6)
Route C (Rec.trav.chim.1962,81,282-286)
In route A, the final step reaction needed is used the potassium cyanide of severe toxicity, reaction high temperature (175 ℃), and 16 hours reaction times, to send out and answer product complicated, productive rate is low.
In route B, raw material is not easy to obtain, and need use oxidant potassium permanganate, final step depickling reaction needed high temperature, and productive rate is on the low side.
In route C, raw material is difficult for preparation, when Deprotection Cbz, needs to use Pd/C, and cost is high, and is easily on fire.
Comprehensively more above-mentioned three routes, find reagent severe toxicity or strong oxidizing property used, and are big for environment pollution, and reaction needed high temperature is wayward, and starting raw material is difficult for preparation, need with precious metal etc., and cost is high, is not suitable for amplifying producing.
Summary of the invention
The present invention seeks to select a new synthetic route to prepare 2-amido pyrazine-5-formic acid, this route raw material is easy to get, inexpensive, and productive rate is high, and reaction conditions is gentle, is suitable for industrial production, has extremely strong economic implications.
Synthetic route is as follows:
The synthetic method of 2-amido pyrazine of the present invention-5-formic acid, in synthetic 2-ethyl formate-5-formyl hydrazine pyrazine (compound 2): two ethyl esters are arranged in due to raw material, easily dibasic acid esters is by hydrazinolysis, obtain by product, therefore hydrazine hydrate needs slowly to drip, reaction solvent is including but not limited to dehydrated alcohol, anhydrous tetrahydro furan, dioxane, Virahol, propyl carbinol and acetonitrile etc., wherein take dehydrated alcohol as good; Temperature of reaction can be at 0 ℃ to room temperature.
The synthetic method of 2-amido pyrazine of the present invention-5-formic acid, in synthetic 2-ethyl formate-5-formyl nitrine pyrazine (compound 3): diazotization reaction occurs with Sodium Nitrite water liquid and 6N hydrochloric acid at 0 to 5 ℃ in the hydrazides of above-mentioned reaction gained, need use immediately dichloromethane extraction after having reacted, also can be with chloroform or ethylene dichloride.
The synthetic method of 2-amido pyrazine of the present invention-5-formic acid, in synthetic 2-ethyl formate-5-Boc-amido-pyrazine (compound 4): the Curtius rearrangement reaction occurs, and reaction solvent is including but not limited to the trimethyl carbinol, toluene-trimethyl carbinol, dimethylbenzene-trimethyl carbinol or benzene-trimethyl carbinol; Temperature of reaction is at 70 to 110 ℃.
The synthetic method of 2-amido pyrazine of the present invention-5-formic acid, in synthetic 2-amido pyrazine-5-formic acid: be mainly esterlysis and take off Boc, reaction can reflux in hydrochloric acid soln and carry out; Also can first use alkali (NaOH or KOH) heating esterlysis, then room temperature reaction is sloughed Boc in trifluoroacetic acid.
The present invention compared with prior art has following beneficial effect:
1, to adopt 2,5-dioctyl phthalate ethyl ester pyrazine be raw material in the present invention, and its price is low, be easy to get, thereby reduced cost.
2, key intermediate 2-ethyl formate-5-Boc-amido-pyrazine has good stability, easy purifying, and the impurity that enters next step reaction is few, and the purity of synthetic the finished product 2-amido pyrazine-5-formic acid is high.
3, whole reaction scheme mild condition need not silica gel column chromatography and separates, and has shortened production process, is suitable for suitability for industrialized production.
Embodiment
Embodiment 1: synthetic 2-ethyl formate-5-formyl hydrazine pyrazine (compound 2)
2,5-dioctyl phthalate ethyl ester pyrazine (85g, 0.38 mole) be dissolved in dehydrated alcohol (1500 milliliters), under condition of ice bath, slowly drip 85% hydrazine hydrate (22.3g, 0.38 mole), finish at room temperature to stir and spend the night, suction filtration is with dehydrated alcohol (100 milliliters) washing, vacuum-drying gets white solid compound (2) 60g, productive rate: 75.3%.mp：142-143℃
HNMR(DMSO-d6，400MHz)：δ9.47(1H，s)，9.23(1H，s)，8.84(1H，s)，4.55(2H，m)，4.16(2H，m)，1.47(3H，t).
Embodiment 2: synthetic 2-ethyl formate-5-formyl nitrine pyrazine (compound 3)
2-ethyl formate-5-formyl hydrazine pyrazine (37g, 0.18 mole) adds methylene dichloride (600 milliliters), water (600 milliliters), Sodium Nitrite (60g, 0.87 mole), under frozen water is cooling, drip 6N HCl (250 milliliters), after adding, water merges organic phase, anhydrous magnesium sulfate drying with methylene dichloride (200 milliliters of x3) extraction, filter, under room temperature, water pump is evaporated to driedly, gets off-white color solid chemical compound (3) 33g, productive rate: 82.9%.
Embodiment 3: synthetic 2-ethyl formate-5-Boc-amido-pyrazine (compound 4)
2-ethyl formate-5-formyl nitrine pyrazine (100g, 0.45 mole), add toluene (600 milliliters) and t-BuOH (100 milliliters), be heated to reflux, reacted 1 hour, be chilled to room temperature, suction filtration, toluene (50 milliliters) washing, dry white solid compound (4) 110g, the productive rate: 91.6% of getting.mp：162-163℃
HNMR(DMSO-d6，400MHz)：δ9.40(1H，s)，8.95(1H，s)，4.49(2H，m)，1.57(9H，s)，1.44(3H，t).
Embodiment 4: synthetic 2-amido pyrazine-5-formic acid (compound 5)
2-ethyl formate-5-Boc-amido-pyrazine (30g, 0.11 mole) adds 4N HCl (750 milliliters), reflux 3 hours, cooling, be concentrated into dried, add entry (40 milliliters), transfer to PH3, suction filtration with 2N NaOH solution, the gained solid is dissolved in hot water, adds activated carbon (0.5g), refluxed 5 minutes, suction filtration boils off most of water, and solid is separated out, dry off-white color solid 2-amido pyrazine-5-formic acid 11g, the productive rate: 71.8% of getting of suction filtration.mp：283℃(d)HNMR(DMSO-d6，400MHz)：δ12.55(1H，s)，8.49(1H，s)，7.87(1H，s)，7.25(2H，s)。
Claims (5)
1. the invention discloses to be easy to get 2,5-dioctyl phthalate ethyl ester pyrazine generation hydrazinolysis is sent out should, with the sodium nitrite solution reaction, then reflux in toluene and the trimethyl carbinol and obtain key intermediate 2-ethyl formate-5-Boc-amido-pyrazine again, then the 2-amido pyrazine-5-formic acid that refluxes in hydrochloric acid to get.
2. the synthetic method the first step of 2-amido pyrazine-5-formic acid as claimed in claim, it is characterized in that: due to two ethyl esters being arranged in raw material, be very easy to dibasic acid esters by hydrazinolysis, obtain by product, that monoesters is by hydrazinolysis and we need, therefore hydrazine hydrate needs slowly to drip, and reaction solvent is including but not limited to dehydrated alcohol, anhydrous tetrahydro furan, dioxane, Virahol, propyl carbinol and acetonitrile etc.; Temperature of reaction at 0 ℃ to room temperature.
3. the synthetic method second step of 2-amido pyrazine-5-formic acid as claimed in claim, it is characterized in that: the hydrazides of the first step reaction gained is with Sodium Nitrite water liquid and hydrochloric acid generation diazotization reaction, and temperature of reaction is at 0 to 5 ℃.
4. the synthetic method the 3rd of 2-amido pyrazine-5-formic acid goes on foot as claimed in claim, and it is characterized in that: the Curtius rearrangement reaction occurs, and reaction solvent is including but not limited to the trimethyl carbinol, toluene-trimethyl carbinol, dimethylbenzene-trimethyl carbinol and benzene-trimethyl carbinol; Temperature of reaction is at 70 to 110 ℃.
5. the synthetic method the 4th of 2-amido pyrazine-5-formic acid step as claimed in claim, it is characterized in that: esterlysis and take off Boc, reaction can be carried out in hydrochloric acid soln; Also can first use alkali (NaOH or KOH) esterlysis, then room temperature reaction is sloughed Boc in trifluoroacetic acid.
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| CN2013101258092A CN103159687A (en) | 2013-04-12 | 2013-04-12 | Synthesis method of 2-aminopyrazinyl-5-formic acid |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009024550A1 (en) * | 2007-08-20 | 2009-02-26 | N.V. Organon | N-benzyl, n' -arylcarbonylpiperazine derivatives as lxr modulators |
| CN101460468A (en) * | 2006-06-19 | 2009-06-17 | 霍夫曼-拉罗奇有限公司 | 2-pyrazinecarboxamide derivatives |
| US20090264416A1 (en) * | 2007-08-20 | 2009-10-22 | N.V. Organon And Pharmacopeia, Inc. | N-benzyl,n'-arylcarbonylpiperazine derivatives |
| EP2145879A1 (en) * | 2008-07-11 | 2010-01-20 | Mallinckrodt Inc. | Pyrazine derivatives, methods of use, and methods for preparing same |
| CN102977009A (en) * | 2012-11-09 | 2013-03-20 | 杭州澳赛诺化工有限公司 | Synthesizing method of 2-trifluoromethyl-3-fluoropyridin |
-
2013
- 2013-04-12 CN CN2013101258092A patent/CN103159687A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101460468A (en) * | 2006-06-19 | 2009-06-17 | 霍夫曼-拉罗奇有限公司 | 2-pyrazinecarboxamide derivatives |
| WO2009024550A1 (en) * | 2007-08-20 | 2009-02-26 | N.V. Organon | N-benzyl, n' -arylcarbonylpiperazine derivatives as lxr modulators |
| US20090264416A1 (en) * | 2007-08-20 | 2009-10-22 | N.V. Organon And Pharmacopeia, Inc. | N-benzyl,n'-arylcarbonylpiperazine derivatives |
| EP2145879A1 (en) * | 2008-07-11 | 2010-01-20 | Mallinckrodt Inc. | Pyrazine derivatives, methods of use, and methods for preparing same |
| CN102977009A (en) * | 2012-11-09 | 2013-03-20 | 杭州澳赛诺化工有限公司 | Synthesizing method of 2-trifluoromethyl-3-fluoropyridin |
Non-Patent Citations (1)
| Title |
|---|
| VON E.FELDER等: "For the manufacture of 2-amino-5-pyrazinecarboxylic acid and derivatives", 《HELVETICA CHIMICA ACTA》, vol. 47, 31 December 1964 (1964-12-31) * |
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Application publication date: 20130619 |