CN104910068B - A kind of synthetic method of the tosilate of 2 cyano group isonicotinic acid hydrazide 1.5 - Google Patents

A kind of synthetic method of the tosilate of 2 cyano group isonicotinic acid hydrazide 1.5 Download PDF

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Publication number
CN104910068B
CN104910068B CN201510201767.5A CN201510201767A CN104910068B CN 104910068 B CN104910068 B CN 104910068B CN 201510201767 A CN201510201767 A CN 201510201767A CN 104910068 B CN104910068 B CN 104910068B
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cyano
isonicotinic acid
room temperature
tosilate
stirred
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CN104910068A (en
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陈冬寅
吴剑虹
李婷
熊正新
李飞
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Nanjing Medical University
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Nanjing Medical University
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D213/00Heterocyclic 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
    • C07D213/02Heterocyclic 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
    • C07D213/04Heterocyclic 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
    • C07D213/60Heterocyclic 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 heteroatoms or with carbon atoms having three bonds to hetero atoms, with at the most one to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78Carbon atoms having three bonds to hetero atoms, with at the most one to halogen, e.g. ester or nitrile radicals
    • C07D213/86Hydrazides; Thio or imino analogues thereof

Abstract

A kind of synthetic method of the tosilate of 2 cyano group isonicotinic acid hydrazide 1.5,2 cyano group iso methyl nicotinates are used for initiation material, 2 cyano group isonicotinic acid are obtained by basic hydrolysis, in the presence of condensing agent, it is condensed with tert-butoxycarbonyl hydrazine, condensation product obtains target compound with the hydrolysis of p-methyl benzenesulfonic acid monohydrate.The technique does not need high temperature or low-temp reaction, it is not necessary to inert gas shielding, and all reaction dissolvents need not be without water pretreatment, intermediate without purification, and reaction condition is gentle, simple to operate, is adapted to industrial production.

Description

A kind of synthetic method of the tosilate of 2- cyano group isonicotinic acid hydrazide 1.5
Technical field
The invention belongs to pharmaceutical field, and in particular to a kind of synthesis of the tosilate of 2- cyano group isonicotinic acid hydrazide 1.5 Method.
Background technology
Toby department he(Topiroxostat)For Fuji's pharmacy and three and chemical joint development anti-antihyperuricemic of new generation Disease drug, the tosilate of 2- cyano group isonicotinic acid hydrazide 1.5 is the key intermediate (Chinese patent for synthesizing Topiroxostat 2002819276.1).The tosilate of document report (Chinese patent 2002819276.1) 2- cyano group isonicotinic acid hydrazide 1.5 is adopted It is that raw material reacts preparation by 4 steps with isonicotinic acid N- oxides, wherein, the reaction of isonicotinic acid N- oxides and ethyl chloroformate is needed To be carried out under -15 DEG C, anhydrous, inert gas shielding, reaction condition is harsher(Fig. 1-route 1).Can also be different by 2- cyano group Methyl nicotinate is raw material, directly and hydrazine reaction, obtains 2- cyano group isonicotinic acid hydrazide, but is due to that hydrazine high poison is inflammable, and industrial production is deposited In potential safety hazard(Fig. 1-route 3).
Therefore, the present invention uses 2- cyano group iso methyl nicotinate for initiation material, hydrolyzed by alkali such as sodium carbonate, potassium carbonate etc. 2- cyano group isonicotinic acid is obtained, in condensing agent such as N, N '-dicyclohexylcarbodiimide, 1- ethyls-(3- dimethylaminopropyls) carbon In the presence of diimmonium salt hydrochlorate etc., it is condensed with tert-butoxycarbonyl hydrazine, the hydrolysis of condensation product p-methyl benzenesulfonic acid monohydrate is obtained Obtain target compound.Due to there is ester bond and cyano group, under strongly alkaline conditions, ester bond simultaneously in 2- cyano group iso methyl nicotinate molecules Hydrolyzed simultaneously with cyano group, it is impossible to obtain expected product 2- cyano group isonicotinic acid.By inventor's test of many times, discovery uses carbonic acid Sodium, potassium carbonate etc. are hydrolyzed, in that context it may be convenient to obtain expected product 2- cyano group isonicotinic acid.2- cyano group isonicotinic acid and tert-butoxycarbonyl The condensation of hydrazine, can first be prepared into the different nicotinoyl chlorine of 2- cyano group, with the different nicotinoyl of 2- cyano group using thionyl chloride by 2- cyano group isonicotinic acid Chlorine is condensed with tert-butoxycarbonyl hydrazine, but passes through inventor's test of many times, and this method yield is very low, and environmental pollution is big, Be not suitable for industrial production.
The content of the invention
The technical problem of solution:The present invention provides a kind of synthesis side of the tosilate of 2- cyano group isonicotinic acid hydrazide 1.5 Method, uses 2- cyano group iso methyl nicotinate for initiation material, is reacted by 3 steps, obtains key intermediate 2- cyano group isonicotinic acid hydrazides 1.5 tosilate, the technique after improvement does not need high temperature or low-temp reaction, and reaction condition is gentle, and intermediate need not be carried It is pure, it is simple to operate, it is adapted to industrial production.
Technical scheme:A kind of synthetic method of the tosilate of 2- cyano group isonicotinic acid hydrazide 1.5, preparation process is:Adopt It is initiation material with 2- cyano group iso methyl nicotinates, 2- cyano group isonicotinic acid is obtained by basic hydrolysis, in the presence of condensing agent, with uncle Butoxy carbonyl hydrazine is condensed to yield condensation product;Wherein, the ratio between amount of material of 2- cyano group iso methyl nicotinate and alkali is 1:2-1:3, The ratio between amount of material of 2- cyano group isonicotinic acid and tert-butoxycarbonyl hydrazine is 1:1.5-1:3.
The alkali is sodium carbonate or potassium carbonate.
The condensing agent is N, N '-dicyclohexylcarbodiimide or 1- ethyls-(3- dimethylaminopropyls) carbodiimide Hydrochloride.
A kind of synthetic method of the tosilate of 2- cyano group isonicotinic acid hydrazide 1.5, step is:2- cyano group iso methyl nicotinates In 0.05mol, tetrahydrofuran 50mL, isopropanol 50mL, water 30mL suspension, it is stirred at room temperature down and carbonic acid sodium powder is added portionwise Last 0.1mol, is finished, and room temperature continues stirring reaction 2 hours, concentrated hydrochloric acid 0.1mol is added dropwise, 70 DEG C are filtered to remove inorganic salts, filtrate Concentration, obtains white solid;2- cyano group isonicotinic acid 0.05mol, tetrahydrofuran 150mL, 1- ethyl-(3- dimethylaminopropyls) carbon Diimmonium salt hydrochlorate 0.055mol, the g of I-hydroxybenzotriazole 0.5, tert-butoxycarbonyl hydrazine 0.075mol, are stirred at room temperature 48 small When, insoluble matter is filtered to remove, filtrate concentration adds ethyl acetate 150mL, washed with water 50mL, organic layer anhydrous sodium sulfate 10.0g is dried, and filtering, filtrate adds p-methyl benzenesulfonic acid monohydrate 0.1mol, and reaction 24 hours is stirred at room temperature, and filtering obtains white Color solid.
Beneficial effect:The technique does not need high temperature or low-temp reaction, it is not necessary to inert gas shielding, all reaction dissolvents Need not be gentle without water pretreatment, reaction condition, intermediate is simple to operate without purification, is adapted to industrial production.
Brief description of the drawings
Fig. 1 is the synthetic route chart of the tosilate of 2- cyano group isonicotinic acid hydrazide 1.5.
Embodiment
The following examples can make those skilled in the art to be fully understood by the present invention, but not limit this in any way Invention.
The synthesis of the 2- cyano group isonicotinic acid of embodiment 1
2- cyano group iso methyl nicotinate 8.1g (0.05mol), tetrahydrofuran 50mL, isopropanol 50mL, water 30mL suspension In liquid, it is stirred at room temperature down and the g of powdered sodium carbonate 10.6 (0.1mol) is added portionwise, finish, room temperature continues stirring reaction 2 hours, drop Enriching hydrochloric acid 8.4mL (0.1mol), 70 DEG C are filtered to remove inorganic salts, and filtrate concentration obtains the g of white solid 7.2, 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 the 2- cyano group isonicotinic acid of embodiment 2
2- cyano group iso methyl nicotinate 8.1g (0.05mol), tetrahydrofuran 50mL, isopropanol 50mL, water 30mL suspension In liquid, it is stirred at room temperature down and the g of potassium carbonate powder 20.1 (0.15mol) is added portionwise, finish, room temperature continues stirring reaction 2 hours, Concentrated hydrochloric acid 12.8mL (0.15mol) is added dropwise, 70 DEG C are filtered to remove inorganic salts, and filtrate concentration obtains the g of white solid 7.1, 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 the tosilate of 3 2- cyano group isonicotinic acid hydrazide of embodiment 1.5
Use the gained 2- cyano group isonicotinic acid 7.4g (0.05mol) of embodiment 1 or 2, tetrahydrofuran 150mL, N, the rings of N '-two Hexyl carbodiimide 11.3g (0.055mol), the g of DMAP 0.1, tert-butoxycarbonyl hydrazine 9.9g (0.075mol), is stirred at room temperature 48 hours, is filtered to remove insoluble matter, and filtrate concentration adds ethyl acetate 150mL, uses water 50mL Washing, organic layer is dried with anhydrous sodium sulfate 10.0g, and filtering, filtrate adds p-methyl benzenesulfonic acid monohydrate 19.0g (0.1mol), is stirred at room temperature reaction 24 hours, and filtering obtains the g of white solid 15.5, yield 73.8%.Product is verified:1H-NMR (DMSO-d6) 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 the tosilate of 4 2- cyano group isonicotinic acid hydrazide of embodiment 1.5
Use the gained 2- cyano group isonicotinic acid 7.4g (0.05mol) of embodiment 1 or 2, tetrahydrofuran 150mL, 1- ethyl-(3- Dimethylaminopropyl) carbodiimide hydrochloride 10.5g (0.055mol), the g of I-hydroxybenzotriazole 0.5, tert-butoxy carbonyl Base hydrazine 19.8g (0.15mol), is stirred at room temperature 48 hours, is filtered to remove insoluble matter, and filtrate concentration adds ethyl acetate 150mL, is washed with water 50mL, and organic layer is dried with anhydrous sodium sulfate 10.0g, and filtering, filtrate adds p-methyl benzenesulfonic acid one and is hydrated Thing 19.0g (0.1mol), is stirred at room temperature reaction 24 hours, and filtering obtains the g of white solid 15.6, yield 74.3%.Product is verified :1H-NMR(DMSO-d6) 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 the tosilate of 5 2- cyano group isonicotinic acid hydrazide of embodiment 1.5
Use the gained 2- cyano group isonicotinic acid 7.4g (0.05mol) of embodiment 1 or 2, tetrahydrofuran 150mL, N, the rings of N '-two Hexyl carbodiimide 11.3g (0.055mol), tert-butoxycarbonyl hydrazine 9.9g (0.075mol), is stirred at room temperature 72 hours, mistake Insoluble matter is filtered, filtrate concentration adds ethyl acetate 150mL, washed with water 50mL, organic layer anhydrous sodium sulfate 10.0g Dry, filtering, filtrate adds p-methyl benzenesulfonic acid monohydrate 19.0g (0.1mol), reaction 24 hours is stirred at room temperature, filtering is obtained The g of white solid 15.0, yield 71.4%.Product is verified:1H-NMR(DMSO-d6) 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 (1)

1. a kind of synthetic method of the tosilate of 2- cyano group isonicotinic acid hydrazide 1.5, it is characterised in that step is:2- cyano group is different In methyl nicotinate 0.05mol, tetrahydrofuran 50mL, isopropanol 50mL, water 30mL suspension, it is stirred at room temperature down and is added portionwise Powdered sodium carbonate 0.1mol, is finished, and room temperature continues stirring reaction 2 hours, is added dropwise concentrated hydrochloric acid 0.1mol, 70 DEG C be filtered to remove it is inorganic Salt, filtrate concentration, obtains white solid 2- cyano group isonicotinic acid;2- cyano group isonicotinic acid 0.05mol, tetrahydrofuran 150mL, 1- ethyl- (3- dimethylaminopropyls) carbodiimide hydrochloride 0.055mol, the g of I-hydroxybenzotriazole 0.5, tert-butoxycarbonyl hydrazine 0.15mol, is stirred at room temperature 48 hours, is filtered to remove insoluble matter, and filtrate concentration adds ethyl acetate 150mL, washed with water 50mL Wash, organic layer is dried with anhydrous sodium sulfate 10.0g, filtering, filtrate adds p-methyl benzenesulfonic acid monohydrate 0.1mol, is stirred at room temperature Reaction 24 hours, filtering, obtains white solid.
CN201510201767.5A 2015-04-24 2015-04-24 A kind of synthetic method of the tosilate of 2 cyano group isonicotinic acid hydrazide 1.5 Expired - Fee Related CN104910068B (en)

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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
CN110981795B (en) * 2019-12-18 2021-02-12 武汉世纪久海检测技术有限公司 Method for preparing 2-aminoacyl isonicotinic acid by using methyl 2-cyanoisonicotinate

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