CN106588833B - A kind of synthetic method of Lafutidine oxidation impurities - Google Patents

A kind of synthetic method of Lafutidine oxidation impurities Download PDF

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CN106588833B
CN106588833B CN201611045884.8A CN201611045884A CN106588833B CN 106588833 B CN106588833 B CN 106588833B CN 201611045884 A CN201611045884 A CN 201611045884A CN 106588833 B CN106588833 B CN 106588833B
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lafutidine
organic layer
synthetic method
oxidation impurities
oxidation
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CN106588833A (en
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李晓曦
唐金龙
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YICHANG HEC CHANGJIANG PHARMACEUTICAL Co Ltd
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YICHANG HEC CHANGJIANG PHARMACEUTICAL Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms

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  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention belongs to technical field of chemistry, and in particular to the synthetic method of a kind of (Formulas I) of Lafutidine oxidation impurities -2- [(2- furyl methyl) sulfonyl]-N- [4- [4- (1- piperidino methyl) -2- pyridyl group] oxygen-(Z) -2- cyclobutenyl] acetamide.Its key step are as follows: 2- (2- furfuryl sulfydryl) acetic acid-(4- nitrophenol) ester (compound ii) docks (compounds Ⅳ) after peroxidating with 4- [4- (N- piperidine methyl) pyridine -2- oxygen] cis-2-butene -1- amine, and the oxidation impurities of 99.5% or more purity > are obtained after purification.Contamination levels product of the high-purity Lafutidine oxidation impurities of synthesis as finished product detection are conducive to reinforce positioning and qualitative, quality control of the raising to Lafutidine bulk pharmaceutical chemicals to the impurity.

Description

A kind of synthetic method of Lafutidine oxidation impurities
Technical field
The invention belongs to technical field of chemistry, and in particular to a kind of synthetic method of Lafutidine oxidation impurities.
Background technique
Lafutidine chemical name is -2- [(2- furyl methyl) thionyl]-N- [4- [4- (1- piperidino methyl) -2- Pyridyl group] oxygen-(Z) -2- cyclobutenyl] acetamide is New-type long-acting, potent H2Receptor antagonist (Histamine H2- Receptor antagonists), basic pharmacophoric group includes furan nucleus, alkaline piperidine methyl pyridine ether, flexible contains Four atom key of nitrogen butylene plane and sulfoxide sulphur, has second generation furan nucleus and forth generation benzyl position piperidines group concurrently and proton pump inhibits The key pharmacophore such as agent alkalinity aromatic ring pyridine ring more continues, powerful antiacid effect so having two big effects simultaneously With extremely strong mucosa.
Chemical compounds I is impurity common in Lafutidine production, will affect the quality of final products.Through retrieving, at present It without the method for synthesizing the impurity, therefore synthesizes the impurity and confirms its structure, synthesize the impurity and study its physicochemical property to add With control, and it is significant for improving Lafutidine quality to select appropriate method to effectively remove.
Summary of the invention
A kind of Lafutidine oxidation impurities -2- [(2- furyl methyl) sulfonyl]-N- [4- [4- (1- piperidino methyl) -2- Pyridyl group] oxygen-(Z) -2- cyclobutenyl] acetamide synthetic method, structure is as follows:
It is synthesized according to following route:
It is main include the following three steps:
1) using DMSO as solvent, oxidation reaction is carried out to compound ii as oxidant using IBX and obtains material 1, material 1 is added Water, methylene chloride are obtained by extraction organic layer 1, and organic layer uses water and saturated common salt water washing respectively, organic layer evaporated under reduced pressure, and use is molten Agent 1 carries out being recrystallized to give compound III；
2) compound III and compounds Ⅳ, in ethyl acetate and 2%NaHCO3It reacts under water solution system, divides after having reacted Layer, organic layer use water, 2%NaHCO respectively3, saturated common salt water washing, organic layer evaporated under reduced pressure adds 2 stirring and crystallizing of people's solvent, Crude product is obtained by filtration；
3) refine: crude product is recrystallized to give the chemical compounds I that purity is greater than 99.5% or more by solvent 3.
Preferably, the molar ratio for stating step 1) compound ii and IBX is 1:1.1-1:1.5, oxidizing reaction temperature 18-35 ℃。
Preferably, the step 1) solvent 1 is acetone, and acetone volumetric usage is 4-8 times that organic layer is spin-dried for rear weight.
Preferably, the step 2) compound III and compounds Ⅳ be molar ratio is 1:1-1.2:1.
Preferably, the step 2) ethyl acetate and 2%NaHCO3Aqueous solution volume ratio is 5:5-8:2.
Preferably, recrystallization solvent for use 2 is methyl tertiary butyl ether(MTBE), methyl tertiary butyl ether(MTBE) volumetric usage in the step 2) 8-12 times for being spin-dried for rear weight for organic layer.
Preferably, the step 3) refining solvent 3 is isopropanol, and volumetric usage is 5-10 times of crude product weight.
Beneficial effects of the present invention:
1, the synthetic method of a Lafutidine oxidation impurities: 2- (2- furfuryl sulfydryl) acetic acid-(4- nitrobenzene is provided Phenol) ester after peroxidating to 4- [4- (N- piperidine methyl) pyridine -2- oxygen] cis-2-butene -1- amine docking after obtain corresponding impurity, Overcome the disadvantage lower using Lafutidine oxidative synthesis impurity yield and purity, this method step operation simplicity and high income, Products obtained therefrom purity (being greater than 99.5%) meets contamination levels product requirement.By being conducive to reinforce to miscellaneous to its property Quality Research The qualitative and quantitative control of matter, and then improve the quality of Lafutidine bulk pharmaceutical chemicals.
2, can be by compound ii the efficient oxidation using 2- iodosobenzoic acid (IBX) this oxidant, other oxidants are anti- Long and transformation efficiency is low between seasonable, and oxidant is not thorough with few reaction, and then product colour is very poor greatly for dosage.
3, acetone improves compound III purity, removes unreacted compound ii, improves product colour.
4, ethyl acetate and 2%NaHCO3Aqueous solution promotes compound III and compounds Ⅳ reaction, 2%NaHCO3Aqueous solution Few reaction is slower, and more then compound IIIs are decomposed comparatively fast, and reaction is not thorough.
5, Lafutidine solid is precipitated in methyl tertiary butyl ether(MTBE), while effectively removing the p-nitrophenol impurity that dereaction generates, Ensure product colour.Isopropanol purification further increases product purity and content.
Detailed description of the invention
Fig. 1, the HPLC map of Lafutidine oxidation impurities
Fig. 2, Lafutidine oxidation impurities1H-NMR map
Fig. 3, Lafutidine oxidation impurities13C-NMR map
Attached drawing 4, Lafutidine oxidation impurities1H-1HCOSY map
Attached drawing 5, the HMBC map of Lafutidine oxidation impurities
Specific embodiment
The present invention is further illustrated below with reference to embodiment, but the scope of protection of present invention is not limited to implement The range of example statement.
(the synthesis of 2- (2- furfuryl sulfonyl) acetic acid-(4- nitrophenol) ester of embodiment 1
By 6.02g 2- (2- furfuryl sulfydryl) acetic acid-(4- nitrophenol) ester (compound ii, 0.02mol), 40mLDMSO is added in four-necked bottle, and 20 DEG C of temperature control stirrings are added 6.16g 2- iodosobenzoic acid (IBX, 0.22mol), control Temperature reaction 12 hours.Water 120mL, methylene chloride 80mL are added after fully reacting, is layered after stirring 0.5.Organic layer successively uses water With saturated common salt water washing, layering, organic layer is spin-dried for, and obtains grease 5.2g, and acetone 26mL recrystallization is added, after filtration drying To (2- (2- furfuryl sulfonyl) acetic acid-(4- nitrophenol) ester (compound III) 4.66g, yield 68.3%.
2 2- of embodiment [(2- furyl methyl) sulfonyl]-N- [4- [4- (1- piperidino methyl) -2- pyridyl group] oxygen - (Z) -2- cyclobutenyl] acetamide synthesis
3.14g 4- [4- (N- piperidine methyl) pyridine -2- oxygen] cis-2-butene -1- amine (compounds Ⅳ, 0.012 mol, 1eq), 30mL ethyl acetate and 20mL5%NaHCO are added to3Mixed solution in, be cooled to 0-5 DEG C, (2- (2- furans be added Methyl sulphonyl) acetic acid-(4- nitrophenol) ester (compound III) 4.3g (0.0126mol, 1.05eq) insulated and stirred 2h.Instead It is layered after answering, organic layer uses 2%NaHCO respectively3, saturated salt solution, water washing, wash and be spin-dried for organic layer, obtain light green Grease 5.5g is added 50mL methyl tertiary butyl ether(MTBE), filters, depressurize after stirring 1h after being cooled to 0-5 DEG C after 30-40 stirring 1h Drying, obtains chemical compounds I crude product 4.35g, yield 81.3%.
3 2- of embodiment [(2- furyl methyl) sulfonyl]-N- [4- [4- (1- piperidino methyl) -2- pyridyl group] oxygen - (Z) -2- cyclobutenyl] acetamide purification
4.2g crude product is added to 30mL isopropanol, is warming up to 35-40 DEG C, and gradient cooling to 5-10 DEG C, stir by heat preservation after 0.5h It is filtered after mixing 2h, decompression drying, obtains chemical compounds I fine work 3.3, yield 78.6%, purity > 99.5%.
Embodiment 4
By 6.02g 2- (2- furfuryl sulfydryl) acetic acid-(4- nitrophenol) ester (compound ii, 0.02mol), 40mLDMSO is added in four-necked bottle, and 35 DEG C of temperature control stirrings are added 8.4g 2- iodosobenzoic acid (IBX, 0.3mol), temperature control Reaction 12 hours.Water 120mL, methylene chloride 80mL are added after fully reacting, is layered after stirring 0.5.Organic layer successively use water and Saturated common salt water washing, layering, organic layer are spin-dried for, and obtain grease 5.5g, and acetone 44mL recrystallization is added, filters, dry, are obtained To (2- (2- furfuryl sulfonyl) acetic acid-(4- nitrophenol) ester (compound III) 4.1g, yield 60.1%.
Embodiment 5
3.14g 4- [4- (N- piperidine methyl) pyridine -2- oxygen] cis-2-butene -1- amine (compounds Ⅳ, 0.012 mol, 1eq), 30mL ethyl acetate and 20mL5%NaHCO are added to3Mixed solution in, be cooled to 0-5 DEG C, (2- (2- furans be added Methyl sulphonyl) acetic acid-(4- nitrophenol) ester (compound III) 4.91g (0.0144mol, 1.2eq) insulated and stirred 2h.Instead It is layered after answering, organic layer uses 2%NaHCO respectively3, saturated salt solution, water washing, wash and be spin-dried for organic layer, obtain light green Grease 5.9g is added 70mL methyl tertiary butyl ether(MTBE), filters, depressurize after stirring 1h after being cooled to 0-5 DEG C after 30-40 stirring 1h Drying, obtains chemical compounds I crude product 3.99g yield 74.6%.
The above embodiments are only the preferred technical solution of the present invention, and are not construed as limitation of the invention, this Shen Please in embodiment and embodiment in feature in the absence of conflict, can mutual any combination.Protection model of the invention The technical solution that should be recorded with claim is enclosed, the equivalent replacement side of technical characteristic in the technical solution recorded including claim Case is protection scope.Equivalent replacement i.e. within this range is improved, also within protection scope of the present invention.

Claims (5)

1. a kind of synthetic method of Lafutidine oxidation impurities, structure are as follows:
It is characterized in that, being synthesized according to following route:
Comprising the following three steps:
1) using DMSO as solvent, oxidation reaction is carried out to compound ii as oxidant using IBX and obtains material 1, material 1 be added water, Organic layer is obtained by extraction in methylene chloride, and organic layer uses water and saturated common salt water washing respectively, and organic layer evaporated under reduced pressure adds acetone weight Crystallization obtains compound III；
2) compound III and compounds Ⅳ, in ethyl acetate and 2%NaHCO3It is reacted under water solution system, layering after having reacted has Machine layer uses water, 2%NaHCO respectively3, saturated common salt water washing, organic layer evaporated under reduced pressure, add people's methyl tertiary butyl ether(MTBE) stirring analysis Crude product is obtained by filtration in crystalline substance；
3) refine: crude product is recrystallized to give the chemical compounds I that purity is greater than 99.5% by solvent 3；
Step 2) the ethyl acetate and 2%NaHCO3Aqueous solution volume ratio is 5:5-8:2；
Step 3) the refining solvent 3 is isopropanol, and dosage is 5-10 times of crude product quality, unit mL/g.
2. the synthetic method of Lafutidine oxidation impurities according to claim 1, it is characterised in that: the step 1) chemical combination The molar ratio of object II and IBX are 1:1.1-1:1.5, and oxidizing reaction temperature is 18-35 DEG C.
3. the synthetic method of Lafutidine oxidation impurities according to claim 1, it is characterised in that: the step 1) acetone Dosage is 4-8 times that organic layer is spin-dried for rear weight, unit mL/g.
4. the synthetic method of Lafutidine oxidation impurities according to claim 1, it is characterised in that: the step 2) chemical combination The molar ratio of object III and compounds Ⅳ is 1:1-1.2:1.
5. the synthetic method of Lafutidine oxidation impurities according to claim 1, it is characterised in that: first in the step 2) Base tertbutyl ether dosage is 8-12 times that organic layer is spin-dried for rear weight, unit mL/g.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103130782A (en) * 2013-03-22 2013-06-05 北京国联诚辉医药技术有限公司 Method for preparing lafutidine from hydroxylamine hydrochloride
CN104557889A (en) * 2014-12-15 2015-04-29 广东东阳光药业有限公司 Preparation method of lafutidine isomer
CN104557934A (en) * 2013-10-11 2015-04-29 南开大学 Method for synthesizing sophocarpine

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0710862A (en) * 1993-06-25 1995-01-13 Central Glass Co Ltd Production of phenyl 2-(furfurylsulfinyl) acetate derivative and phenyl 2-(furfurylsulfonyl) acetate derivative

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103130782A (en) * 2013-03-22 2013-06-05 北京国联诚辉医药技术有限公司 Method for preparing lafutidine from hydroxylamine hydrochloride
CN104557934A (en) * 2013-10-11 2015-04-29 南开大学 Method for synthesizing sophocarpine
CN104557889A (en) * 2014-12-15 2015-04-29 广东东阳光药业有限公司 Preparation method of lafutidine isomer

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ANALYTICAL TECHNIQUES FOR THE ESTIMATION OF LAFUTIDINE IN BULK AND PHARMACEUTICAL DOSAGE FORMS: A REVIEW;C.Divya Bharathi等;《World Journal of Pharmacy and Pharmaceutical Sciences》;20151231;第4卷(第8期);第497页

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