CN104910068A - 2-cyano isonicotinic acid hydrazide 1.5 p-toluenesulfonate synthetic method - Google Patents
2-cyano isonicotinic acid hydrazide 1.5 p-toluenesulfonate synthetic method Download PDFInfo
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- CN104910068A CN104910068A CN201510201767.5A CN201510201767A CN104910068A CN 104910068 A CN104910068 A CN 104910068A CN 201510201767 A CN201510201767 A CN 201510201767A CN 104910068 A CN104910068 A CN 104910068A
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- cyano group
- isonicotinic acid
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- 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
- C07D213/86—Hydrazides; Thio or imino analogues thereof
Abstract
A 2-cyano isonicotinic acid hydrazide 1.5 p-toluenesulfonate synthetic method is as follows: 2-cyano methyl isonicotinate is used as a starting material for alkali hydrolysis to obtain 2-cyano isonicotinic acid, the 2-cyano isonicotinic acid is condensed with tertiary butoxy carbonyl hydrazine under the action of a condensing agent, and the condensation compound is hydrolyzed with p-toluenesulfonate monohydrate to obtain a target compound. The process does not need high temperature or low temperature reaction, and does not need an inert gas for protection, all reaction solvents do not need non-water pretreatment, an intermediate does not need purification, reaction condition is mild, operation is simple, and the method is suitable for industrial production.
Description
Technical field
The invention belongs to pharmacy field, be specifically related to a kind of synthetic method of 2-cyano group isonicotinic acid hydrazide 1.5 tosilate.
Background technology
Toby department he (Topiroxostat) is Fuji's pharmacy and three and the anti-antihyperuricemic disease drug of a new generation of chemical joint development, and 2-cyano group Isonicotinoylhydrazine 1.5 tosilate is the key intermediate (Chinese patent 2002819276.1) of synthesis Topiroxostat.Bibliographical information (Chinese patent 2002819276.1) 2-cyano group Isonicotinoylhydrazine 1.5 tosilate adopts γ-picolinic acid N-oxide compound to be that raw material is through 4 step reaction preparations; wherein; the reaction needed of γ-picolinic acid N-oxide compound and Vinyl chloroformate-15 DEG C, carry out under anhydrous, protection of inert gas, reaction conditions harsher (Fig. 1-route 1).Also can be raw material by 2-cyano group iso methyl nicotinate, directly and hydrazine reaction, obtain 2-cyano group Isonicotinoylhydrazine, but due to the high poison of hydrazine inflammable, there is potential safety hazard (Fig. 1-route 3) in industrial production.
For this reason, the present invention adopts 2-cyano group iso methyl nicotinate to be starting raw material, through alkali as the hydrolysis such as sodium carbonate, salt of wormwood obtains 2-cyano group γ-picolinic acid, at condensing agent as N, N '-dicyclohexylcarbodiimide, under the effect of 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride etc., with the condensation of tert-butoxycarbonyl hydrazine, condenses tosic acid monohydrate hydrolysis obtains target compound.Owing to there is ester bond and cyano group in 2-cyano group iso methyl nicotinate molecule simultaneously, under strongly alkaline conditions, ester bond and cyano group are hydrolyzed simultaneously, cannot obtain expection product 2-cyano group γ-picolinic acid.Through contriver's test of many times, find to adopt the hydrolysis such as sodium carbonate, salt of wormwood, expection product 2-cyano group γ-picolinic acid can be obtained easily.The condensation of 2-cyano group γ-picolinic acid and tert-butoxycarbonyl hydrazine, can adopt sulfur oxychloride that 2-cyano group γ-picolinic acid is first prepared into the different nicotinoyl chlorine of 2-cyano group, with the different nicotinoyl chlorine of 2-cyano group and the condensation of tert-butoxycarbonyl hydrazine, but be through contriver's test of many times, the method yield is very low, and environmental pollution is large, is not suitable for industrial production.
Summary of the invention
the technical problem solved:the invention provides a kind of synthetic method of 2-cyano group isonicotinic acid hydrazide 1.5 tosilate, 2-cyano group iso methyl nicotinate is adopted to be starting raw material, through 3 step reactions, obtain key intermediate 2-cyano group isonicotinic acid hydrazide 1.5 tosilate, technique after improvement does not need high temperature or low-temp reaction, and reaction conditions is gentle, and intermediate is without the need to purifying, simple to operate, be applicable to industrial production.
technical scheme: a kind of synthetic method of 2-cyano group isonicotinic acid hydrazide 1.5 tosilate, preparation process is: adopt 2-cyano group iso methyl nicotinate to be starting raw material, obtain 2-cyano group γ-picolinic acid through basic hydrolysis, under the effect of condensing agent, obtain condenses with the condensation of tert-butoxycarbonyl hydrazine; Wherein, 2-cyano group iso methyl nicotinate and the ratio of the amount of substance of alkali are 1:2-1:3,2-cyano group γ-picolinic acid is 1:1.5-1:3 with the ratio of the amount of substance of tert-butoxycarbonyl hydrazine.
Described alkali is sodium carbonate or salt of wormwood.
Described condensing agent is N, N '-dicyclohexylcarbodiimide or 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride.
A kind of synthetic method of 2-cyano group isonicotinic acid hydrazide 1.5 tosilate, step is: in the suspension of 2-cyano group iso methyl nicotinate 0.05mol, tetrahydrofuran (THF) 50mL, Virahol 50mL, water 30mL, add powdered sodium carbonate 0.1mol under stirring at room temperature in batches, finish, room temperature continues stirring reaction 2 hours, and drip concentrated hydrochloric acid 0.1mol, 70 DEG C of mistakes filter inorganic salt, filtrate concentrates, and obtains white solid; 2-cyano group γ-picolinic acid 0.05mol, tetrahydrofuran (THF) 150mL, 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride 0.055mol, I-hydroxybenzotriazole 0.5 g, tert-butoxycarbonyl hydrazine 0.075mol, stirring at room temperature 48 hours, cross and filter insolubles, filtrate concentrates, add ethyl acetate 150mL, wash with water 50mL, organic over anhydrous sodium sulfate 10.0g is dry, filters, filtrate adds tosic acid monohydrate 0.1mol, stirring at room temperature reacts 24 hours, filters, obtains white solid.
beneficial effect: this technique does not need high temperature or low-temp reaction, does not need protection of inert gas, and all reaction solvents do not need without water pretreatment, reaction conditions gentleness, and intermediate is without the need to purifying, simple to operate, is applicable to industrial production.
Accompanying drawing explanation
Fig. 1 is the synthetic route chart of 2-cyano group Isonicotinoylhydrazine 1.5 tosilate.
Embodiment
The following examples can make those skilled in the art comprehensively can understand the present invention, but do not limit the present invention in any way.
the synthesis of embodiment 1 2-cyano group γ-picolinic acid
In the suspension of 2-cyano group iso methyl nicotinate 8.1g (0.05mol), tetrahydrofuran (THF) 50mL, Virahol 50mL, water 30mL, add powdered sodium carbonate 10.6 g (0.1mol) under stirring at room temperature in batches, finish, room temperature continues stirring reaction 2 hours, drip concentrated hydrochloric acid 8.4mL (0.1mol), 70 DEG C of mistakes filter inorganic salt, and filtrate concentrates, obtain white solid 7.2 g, yield 97.3%.Product is verified: 7.98-7.99 (d, 1H), 8.18 (s, 1H), 8.70-8.72 (d, 1H) .ESI-MS:147.0 ([M-H]-).
the synthesis of embodiment 2 2-cyano group γ-picolinic acid
In the suspension of 2-cyano group iso methyl nicotinate 8.1g (0.05mol), tetrahydrofuran (THF) 50mL, Virahol 50mL, water 30mL, add potassium carbonate powder 20.1 g (0.15mol) under stirring at room temperature in batches, finish, room temperature continues stirring reaction 2 hours, drip concentrated hydrochloric acid 12.8mL (0.15mol), 70 DEG C of mistakes filter inorganic salt, and filtrate concentrates, obtain white solid 7.1 g, yield 95.6%.Product is verified: 7.98-7.99 (d, 1H), 8.18 (s, 1H), 8.70-8.72 (d, 1H) .ESI-MS:147.0 ([M-H]-).
the synthesis of embodiment 3 2-cyano group Isonicotinoylhydrazine 1.5 tosilate
Use embodiment 1 or 2 gained 2-cyano group γ-picolinic acid 7.4g (0.05mol), tetrahydrofuran (THF) 150mL, N, N '-dicyclohexylcarbodiimide 11.3g (0.055mol), DMAP 0.1 g, tert-butoxycarbonyl hydrazine 9.9g (0.075mol), stirring at room temperature 48 hours, cross and filter insolubles, filtrate concentrates, add ethyl acetate 150mL, wash with water 50mL, organic over anhydrous sodium sulfate 10.0g is dry, filter, filtrate adds tosic acid monohydrate 19.0g (0.1mol), stirring at room temperature reacts 24 hours, filter, obtain white solid 15.5 g, yield 73.8%.Product is verified:
1h-NMR (DMSO-d
6) δ (ppm): 2.28 (s, 4.5H), 7.11-7.14 (d, 3H), 7.49-7.52 (d, 3H), 8.09-8.10 (d, 1H), 8.37 (s, 1H), 8.96-8.98 (d, 1H). ESI-MS:163.0 ([M+H]
+).
the synthesis of embodiment 4 2-cyano group Isonicotinoylhydrazine 1.5 tosilate
Use embodiment 1 or 2 gained 2-cyano group γ-picolinic acid 7.4g (0.05mol), tetrahydrofuran (THF) 150mL, 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride 10.5g (0.055mol), I-hydroxybenzotriazole 0.5 g, tert-butoxycarbonyl hydrazine 19.8g (0.15mol), stirring at room temperature 48 hours, cross and filter insolubles, filtrate concentrates, add ethyl acetate 150mL, wash with water 50mL, organic over anhydrous sodium sulfate 10.0g is dry, filter, filtrate adds tosic acid monohydrate 19.0g (0.1mol), stirring at room temperature reacts 24 hours, filter, obtain white solid 15.6 g, yield 74.3%.Product is verified:
1h-NMR (DMSO-d
6) δ (ppm): 2.28 (s, 4.5H), 7.11-7.14 (d, 3H), 7.49-7.52 (d, 3H), 8.09-8.10 (d, 1H), 8.37 (s, 1H), 8.96-8.98 (d, 1H). ESI-MS:163.0 ([M+H]
+).
the synthesis of embodiment 5 2-cyano group Isonicotinoylhydrazine 1.5 tosilate
Use embodiment 1 or 2 gained 2-cyano group γ-picolinic acid 7.4g (0.05mol), tetrahydrofuran (THF) 150mL, N, N '-dicyclohexylcarbodiimide 11.3g (0.055mol), tert-butoxycarbonyl hydrazine 9.9g (0.075mol), stirring at room temperature 72 hours, cross and filter insolubles, filtrate concentrates, add ethyl acetate 150mL, wash with water 50mL, organic over anhydrous sodium sulfate 10.0g is dry, filter, filtrate adds tosic acid monohydrate 19.0g (0.1mol), stirring at room temperature reacts 24 hours, filter, obtain white solid 15.0 g, yield 71.4%.Product is verified:
1h-NMR (DMSO-d
6) δ (ppm): 2.28 (s, 4.5H), 7.11-7.14 (d, 3H), 7.49-7.52 (d, 3H), 8.09-8.10 (d, 1H), 8.37 (s, 1H), 8.96-8.98 (d, 1H). ESI-MS:163.0 ([M+H]
+).
Claims (4)
1. the synthetic method of 2-cyano group isonicotinic acid hydrazide 1.5 tosilate, it is characterized in that preparation process is: adopt 2-cyano group iso methyl nicotinate to be starting raw material, obtain 2-cyano group γ-picolinic acid through basic hydrolysis, under the effect of condensing agent, obtain condenses with the condensation of tert-butoxycarbonyl hydrazine; Wherein, 2-cyano group iso methyl nicotinate and the ratio of the amount of substance of alkali are 1:2-1:3,2-cyano group γ-picolinic acid is 1:1.5-1:3 with the ratio of the amount of substance of tert-butoxycarbonyl hydrazine.
2. the synthetic method of a kind of 2-cyano group isonicotinic acid hydrazide 1.5 tosilate according to claim 1, is characterized in that described alkali is sodium carbonate or salt of wormwood.
3. the synthetic method of a kind of 2-cyano group isonicotinic acid hydrazide 1.5 tosilate according to claim 1, it is characterized in that described condensing agent is N, N '-dicyclohexylcarbodiimide or 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride.
4. the synthetic method of a kind of 2-cyano group isonicotinic acid hydrazide 1.5 tosilate according to claim 1, it is characterized in that step is: in the suspension of 2-cyano group iso methyl nicotinate 0.05mol, tetrahydrofuran (THF) 50mL, Virahol 50mL, water 30mL, add powdered sodium carbonate 0.1mol under stirring at room temperature in batches, finish, room temperature continues stirring reaction 2 hours, and drip concentrated hydrochloric acid 0.1mol, 70 DEG C of mistakes filter inorganic salt, filtrate concentrates, and obtains white solid; 2-cyano group γ-picolinic acid 0.05mol, tetrahydrofuran (THF) 150mL, 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride 0.055mol, I-hydroxybenzotriazole 0.5 g, tert-butoxycarbonyl hydrazine 0.075mol, stirring at room temperature 48 hours, cross and filter insolubles, filtrate concentrates, add ethyl acetate 150mL, wash with water 50mL, organic over anhydrous sodium sulfate 10.0g is dry, filters, filtrate adds tosic acid monohydrate 0.1mol, stirring at room temperature reacts 24 hours, filters, obtains white solid.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106124662A (en) * | 2016-07-15 | 2016-11-16 | 江苏悦兴医药技术有限公司 | The high performance liquid chromatography method for detecting purity that a kind of 2 cyano group 4 pyridinecarboxylate are kept completely separate with its major impurity |
| CN110981795A (en) * | 2019-12-18 | 2020-04-10 | 武汉世纪久海检测技术有限公司 | Method for preparing 2-amido isonicotinic acid by using methyl 2-cyanoisonicotinate |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106124662A (en) * | 2016-07-15 | 2016-11-16 | 江苏悦兴医药技术有限公司 | The high performance liquid chromatography method for detecting purity that a kind of 2 cyano group 4 pyridinecarboxylate are kept completely separate with its major impurity |
| CN110981795A (en) * | 2019-12-18 | 2020-04-10 | 武汉世纪久海检测技术有限公司 | Method for preparing 2-amido isonicotinic acid by using methyl 2-cyanoisonicotinate |
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Inventor after: Chen Dongyin Inventor after: Wu Jianhong Inventor after: Li Ting Inventor after: Xiong Zhengxin Inventor after: Li Fei Inventor before: Chen Dongyin Inventor before: Li Fei Inventor before: Li Ting Inventor before: Xiong Zhengxin |
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