CN104987337B - A kind of method for oxidation for preparing Alcaftadine - Google Patents
A kind of method for oxidation for preparing Alcaftadine Download PDFInfo
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- CN104987337B CN104987337B CN201510448367.4A CN201510448367A CN104987337B CN 104987337 B CN104987337 B CN 104987337B CN 201510448367 A CN201510448367 A CN 201510448367A CN 104987337 B CN104987337 B CN 104987337B
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- dichloromethane
- oxidation
- alcaftadine
- benzazepines
- methanol
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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Abstract
The present invention relates to one kind to prepare histamine H 1 receptor antagonist --- the new method for oxidation of Ah's catarrh (Alcaftadine), intermediate " 6; methanol of 11 dihydro 11 (piperidylidene of 1 methyl 4) 5H imidazos [2,1 b] [3] benzazepines 3 " oxidation is obtained into Alcaftadine as oxidising agent to wear this Martin reagent.The inventive method simplifies simple to operate, process environmental protection, and raw material and reagent are cheap and easy to get, high income, industrialized production preferably.
Description
Technical field
The present invention relates to a kind of novel preparation method of compound, and in particular to a kind of histamine H 1 receptor antagonist --- Ah Ka
The new method of the oxidation reaction of his fixed (Alcaftadine).
Background technology
Alcaftadine (Alcaftadine), trade name:Lastacaft, it is Weicon pharmacy (Vistakon
Pharmaceuticals a kind of) New Histamine H1 receptor antagonists of exploitation.FDA in 2010 ratifies to be used to treat anaphylaxis knot
Itch caused by film inflammation, listed in 2010.Lastacaft has been approved to be used for more than 2 years old child patient.Alcaftadine
(Alcaftadine) it is that another is used to treat after the benzene sulfonic acid Beta this (Bepreve) of ISTA drugmakers exploitation
The medicine of quick membranous conjunctivitis correlation eye itch.There is preferable potential applicability in clinical practice.
On Alcaftadine patent WO1992022551 report method for oxidation be by 6,11- dihydros -11- (1- methyl -
4- piperidylidenes) -5H- imidazos [2,1-b] [3] benzazepines -3- methanol obtains Alcaftadine, work with manganese dioxide
Skill route is as follows：
In this method, manganese dioxide is gentle oxidising agent, needs activation process before use, and feeding intake needs big serious offense
Amount, a large amount of waste residues are produced after reaction, environmental pollution is larger, makes production cost and three wastes increase.We are attempted using activation
Manganese dioxide afterwards is aoxidized, and is reacted 20 hours, conversion ratio only has 20%, and impurity is more.
Report uses silver nitrate in another patent WO2014083571A, and selenium dioxide, ammonium ceric nitrate will for oxidant
6,11- dihydros -11- (1- methyl -4- piperidylidenes) -5H- imidazos [2,1-b] [3] benzazepines -3- methanol is oxidized to Ah
Catarrh is determined.Because silver nitrate, selenium dioxide, ammonium ceric nitrate are expensive, toxicity is larger, and is found by experiment, this several oxidation
When agent aoxidizes to alcoholic extract hydroxyl group, meeting over oxidation is carboxyl, produces more carboxylic acid impurities.This several method is also not suitable for industrializing
Amplification production.
Therefore, the key technology bottleneck that safer, economic oxidation synthesis method is always Alcaftadine synthesis is found.
The content of the invention
There is the problem of above in the oxidative synthesis process based on the current Alcaftadine, We conducted research：From wearing
This-Martin reagent by 6,11- dihydros -11- (1- methyl -4- piperidylidenes) -5H- imidazos [2,1-b] [3] benzazepines -
3- methanol aoxidizes to obtain Alcaftadine, and this method high income, purity is good, simple to operate, and environmental protection.
It is a kind of convenient that the present invention provides for the oxidation reaction of Alcaftadine, and cost is low, the new method of high income.
Preparation method of the present invention is as follows：
To wear this Martin reagent as oxidising agent, in dichloromethane/tetrahydrofuran, the dichloromethane/tert-butyl alcohol, dichloromethane
By " 6,11- dihydros -11- (1- methyl -4- piperidylidenes) -5H- imidazoles in alkane/acetone, dichloromethane/butanone equal solvent system
And [2,1-b] [3] benzazepines -3- methanol " (referred to as " AT3 ") oxidation.Product, HPLC purity can be obtained in high yield>
98.0%.Our synthetic methods are as follows：
2nd, according to claim 2,4, it is a feature of the present invention that：This oxidation reaction with dichloromethane/tetrahydrofuran,
Dichloromethane/the tert-butyl alcohol, dichloromethane/acetone, dichloromethane/butanone are solvent.
5th, according to the method for claim 3,6, according to the method for claim 5, it is characterised in that：Select
Oxidant is Dai Si-Martin reagent；
(1) select Dai Si-Martin reagent and 6,11- dihydros -11- (1- methyl -4- piperidylidenes) -5H- imidazos [2,
1-b] mol ratio of [3] benzazepines -3- methanol (referred to as " AT3 ") is (1~3):1；
(2) this oxidation reaction is with dichloromethane/tetrahydrofuran, the dichloromethane/tert-butyl alcohol, dichloromethane/acetone, dichloromethane
Alkane/butanone equal solvent system is reaction dissolvent.
(3) dichloromethane/tetrahydrofuran, the dichloromethane/tert-butyl alcohol, dichloromethane/acetone, dichloromethane/butanone are each molten
The volume ratio of dichloromethane and another solvent is (1~5) in agent system：1.
(4) oxidizing reaction temperature is 10-30 DEG C.
The Alcaftadine high conversion rate according to obtained by the present invention, impurity is few, and purity is more than 98.0%, yield more than 80%.
Patent document WO1992022551 and WO2014083571A of the present invention oxidation technology compares, and has following advantages：
1) oxidising agent is easy to get.Activated manganese dioxide, manganese dioxide activation process are selected in patent WO1992022551
It is cumbersome；Silver nitrate, selenium dioxide are used in WO2014083571A, ammonium ceric nitrate is expensive and toxicity is larger；We select
Dai Si-Martin reagent is cheap and easy to get and safety and environmental protection, is able to the industrialization amplification of the committed step oxidation reaction of Alcaftadine
Realize.
2) selectivity of oxidation is good.The oxidising agent selectivity of patent WO1992022551 and WO2014083571A report
It is bad, these method for oxidation are verified by experiments to 6,11- dihydros -11- (1- methyl -4- piperidylidenes) -5H- imidazos [2,1-
B] [3] benzazepines -3- methanol (referred to as " AT3 ") is oxidized in the course of reaction of aldehyde that yield is low, impurity is more, product purity
Difference, it is difficult to realize industrialization amplification.
3) the larger reagent of the environmental pollutions such as manganese dioxide in patent document, silver nitrate, selenium dioxide is avoided, is solved
A large amount of three wastes problems in industrialized production.
4) total recovery is high, total recovery more than 85%, higher than the 60% of literature procedures.
Embodiment
The following example is used to be further discussed below the present invention, but it is not any restrictions to the scope of the present invention.Respectively
The purity testing of experiment gained sample determines on peace U3000 high performance liquid chromatographs are worn.
Embodiment 1
AT3 30.9g (0.1mol), 300mL dichloromethane, 150mL tetrahydrofurans are added in 1000mL three-necked flasks,
In 10~20 DEG C of stirring and dissolvings, Dai Si-Martin reagent 84.8g (0.2mol) is added, 20~30 DEG C are warming up to after adding and continues to stir
Mix 1-2 hours, TLC is monitored to reaction completely, is filtered, and filtrate is washed 1 time with 10% hypo solution 100mL, separated
Machine layer, then washed with the sodium bicarbonate solution 100mL of saturation 5%, organic layer is separated, adds anhydrous sodium sulfate drying, is filtered, filtrate
It is concentrated under reduced pressure.Gained grease adds the stirring of 50mL isopropanols, and cooling separates out solid, and suction filtration is dried to obtain off-white powder
27.5g, yield 89.6%.HPLC purity：98.5%.
Embodiment 2
AT3 30.9g (0.1mol), 300mL dichloromethane, the 150mL tert-butyl alcohols are added in 1000mL three-necked flasks, in
10~20 DEG C of stirring and dissolvings, Dai Si-Martin reagent 63.6g (0.15mol) is added, 20~30 DEG C are warming up to after adding and continues to stir
1-2 hours, TLC are monitored to reaction completely, filtered, and filtrate is washed 1 time with 10% hypo solution 100mL, separated organic
Layer, then washed with the sodium bicarbonate solution 100mL of saturation 5%, organic layer is separated, adds anhydrous sodium sulfate drying, is filtered, filtrate subtracts
Pressure concentration.Gained grease adds the stirring of 50mL isopropanols, and cooling separates out solid, and suction filtration is dried to obtain off-white powder 26.8g,
Yield 87.3%.HPLC purity：98.6%.
Embodiment 3
AT3 30.9g (0.1mol), 200mL dichloromethane, 200mL acetone are added in 1000mL three-necked flasks, in 10
~20 DEG C of stirring and dissolvings, Dai Si-Martin reagent 84.8g (0.2mol) is added, 20~30 DEG C are warming up to after adding and continues to stir 1-2
Hour, TLC is monitored to reaction completely, is filtered, and filtrate is washed 1 time with 10% hypo solution 100mL, separates organic layer,
Washed again with the sodium bicarbonate solution 100mL of saturation 5%, separate organic layer, add anhydrous sodium sulfate drying, filtered, filtrate decompression
Concentration.Gained grease adds the stirring of 50mL isopropanols, and cooling separates out solid, and suction filtration is dried to obtain off-white powder 26.5g, receives
Rate 86.3%.HPLC purity：98.8%.
Embodiment 4
AT3 30.9g (0.1mol), 300mL dichloromethane, 200mL butanone are added in 1000mL three-necked flasks, in 10
~20 DEG C of stirring and dissolvings, Dai Si-Martin reagent 63.6g (0.15mol) is added, 20~30 DEG C are warming up to after adding and continues to stir 1-
2 hours, TLC was monitored to reaction completely, is filtered, and filtrate is washed 1 time with 10% hypo solution 100mL, separates organic layer,
Washed again with the sodium bicarbonate solution 100mL of saturation 5%, separate organic layer, add anhydrous sodium sulfate drying, filtered, filtrate decompression
Concentration.Gained grease adds the stirring of 50mL isopropanols, and cooling separates out solid, and suction filtration is dried to obtain off-white powder 27.0g, receives
Rate 87.9%.HPLC purity：98.7%.
Embodiment 5
AT3 30.9g (0.1mol), 400mL dichloromethane, 100mL butanone are added in 1000mL three-necked flasks, in 10
~20 DEG C of stirring and dissolvings, Dai Si-Martin reagent 127.2g (0.3mol) is added, 20~30 DEG C are warming up to after adding and continues to stir 1-
2 hours, TLC was monitored to reaction completely, is filtered, and filtrate is washed 1 time with 10% hypo solution 100mL, separates organic layer,
Washed again with the sodium bicarbonate solution 100mL of saturation 5%, separate organic layer, add anhydrous sodium sulfate drying, filtered, filtrate decompression
Concentration.Gained grease adds the stirring of 50mL isopropanols, and cooling separates out solid, and suction filtration is dried to obtain off-white powder 27.9g, receives
Rate 90.9%.HPLC purity：98.6%.
Claims (1)
1. a kind of Alcaftadine intermediate as described in structural formula I --- 6,11- dihydros -11- (1- methyl -4- piperidylidenes) -
The method for oxidation of 5H- imidazos [2,1-b] [3] benzazepines -3- methanol, it is characterised in that：The intermediate structure formula is as follows：
The oxidant of selection is Dai Si-Martin reagent；Dai Si-Martin reagent of selection and 6,11- dihydros -11- (1- methyl -4-
Piperidylidene) mol ratio of -5H- imidazos [2,1-b] [3] benzazepines -3- methanol (referred to as " AT3 ") is (1~3):1；
Using dichloromethane/tetrahydrofuran, the dichloromethane/tert-butyl alcohol, dichloromethane/acetone, dichloromethane/butanone as solvent；Two
Dichloromethane in chloromethanes/tetrahydrofuran, the dichloromethane/tert-butyl alcohol, dichloromethane/acetone, each dicyandiamide solution of dichloromethane/butanone
The volume ratio of alkane and another solvent is (1~5):1；
Oxidizing reaction temperature is 10-30 DEG C；
Monitoring filters, filtrate is washed 1 time with 10% hypo solution, separates organic layer, then use saturation to reacting complete
5% sodium bicarbonate solution washs, and separates organic layer, adds anhydrous sodium sulfate drying, filters, filtrate decompression concentration；The oily
Thing adds isopropanol stirring, and cooling separates out solid, and suction filtration is dried to obtain off-white powder.
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| CN110950886A (en) * | 2019-12-13 | 2020-04-03 | 苏州莱克施德药业有限公司 | Method for synthesizing 1-methyl-imidazole-2-methyl formate derivative |
| CN114591332B (en) * | 2020-12-07 | 2023-09-08 | 武汉武药科技有限公司 | Preparation method of alcaftadine and purification method of intermediate of alcaftadine |
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| IL101850A (en) * | 1991-06-13 | 1996-01-31 | Janssen Pharmaceutica Nv | 11-(4-Piperidinyl)-imidazo (2,1-b) (3) benzazepine derivatives their preparation and pharmaceutical compositions containing them |
| WO2014080259A1 (en) * | 2012-11-21 | 2014-05-30 | Enaltec Labs Pvt. Ltd. | Novel polymorphic forms of alcaftadine |
| WO2014083571A1 (en) * | 2012-11-29 | 2014-06-05 | Neuland Laboratories Limited | A process for the preparation of alcaftadine |
| US9255105B2 (en) * | 2012-12-06 | 2016-02-09 | Enaltec Labs Private Limited | Process of preparing alcaftadine |
| US9682984B2 (en) * | 2013-03-25 | 2017-06-20 | Crystal Pharma S.A.U. | Methods for the preparation of alcaftadine |
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