CN105130993B - A kind of new method for oxidation for synthesizing Alcaftadine - Google Patents
A kind of new method for oxidation for synthesizing Alcaftadine Download PDFInfo
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- CN105130993B CN105130993B CN201510448368.9A CN201510448368A CN105130993B CN 105130993 B CN105130993 B CN 105130993B CN 201510448368 A CN201510448368 A CN 201510448368A CN 105130993 B CN105130993 B CN 105130993B
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- alcaftadine
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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 a kind of histamine H 1 receptor antagonist --- the new oxidation synthesis method of Alcaftadine (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 using sodium hypochlorite/TEMPO as oxidising agent.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 medicine, and in particular to a kind of histamine H 1 receptor antagonist --- Ah's catarrh
The new method of the oxidation reaction of 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.
Silver nitrate is used in another patent WO2014083571A, selenium dioxide, ammonium ceric nitrate is oxidant, by 6,
11- dihydros -11- (1- methyl -4- piperidylidenes) -5H- imidazos [2,1-b] [3] benzazepines -3- methanol is oxidized to Ah's card
He is fixed.Because silver nitrate, selenium dioxide, ammonium ceric nitrate are expensive, toxicity is larger, and is found by experiment, this several oxidant
When being aoxidized to alcoholic extract hydroxyl group, meeting over oxidation is carboxyl, produces more carboxylic acid impurities.This several method is also not suitable for industrialization and put
Big production.
Oxidation synthesis method is always the key technology bottleneck of Alcaftadine synthesis.
Therefore, it is that Alcaftadine synthesizes problem anxious to be resolved to find safer, economic oxidation synthesis method.
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 secondary
Sodium chlorate/tetramethyl piperidine nitrogen oxides (TEMPO) oxidation system by 6,11- dihydros -11- (1- methyl -4- piperidylidenes) -
5H- imidazos [2,1-b] [3] benzazepines -3- methanol aoxidizes, and obtains Alcaftadine, and this method high income, purity is good, behaviour
It is simple to make process, 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：
In catalyst presence, with sodium hypochlorite/tetramethyl piperidine nitrogen oxides (TEMPO) for oxidant, in dichloromethane
By 6,11- dihydros -11- (1- methyl -4- piperidylidenes) -5H- imidazos [2,1-b] [3] benzo a word used for translation in the dicyandiamide solution of alkane/water
Heptan is because of -3- methanol (referred to as " AT3 ") oxidation.Product, HPLC purity can be obtained in high yield>98.0%.Our synthetic methods are such as
Under：
(1) oxidant selected in method is sodium hypochlorite, tetramethyl piperidine nitrogen oxides (TEMPO)；
(2) concentration of sodium hypochlorite preferably 5~10%；
(3) sodium hypochlorite and AT3 mol ratio are 1~2:1；
(4) reaction is catalyst from KI, sodium iodide, KBr, sodium bromide；
(5) for the oxidation reaction using methylene chloride/water system as solvent, the ratio of dichloromethane and water is 10-50:1；
(6) 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
Sodium hypochlorite, tetramethyl piperidine nitrogen oxides (TEMPO) is cheap and easy to get and safety and environmental protection, make the critical oxidation of Alcaftadine
The industrialization amplification of step is achieved.
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
AT330.9g (0.1mol), TEMPO 0.16g (1mmol), 300mL dichloromethane are added into 500mL three-necked flasks
In, stirring and dissolving, add potassium bromide solution (1.19g KBrs (10mmol) are dissolved in 6mL purified waters), stirring be cooled to-
10~-5 DEG C, 10% liquor natrii hypochloritis 53mL (0.15mol) is added dropwise, drop finishes, and maintains -10~-5 DEG C of stirring 30min, is warming up to
10~20 DEG C, 30min is stirred, TLC is monitored to reaction completely, stratification, separates organic layer, organic layer 100mL bicarbonates
Sodium solution washs 2 times, separates organic layer, adds anhydrous sodium sulfate drying, filters, filtrate decompression concentration.Gained grease adds
50mL isopropanols stir, and separate out solid, and suction filtration is dried to obtain off-white powder 26.5g, yield 86.3%.HPLC purity：
98.7%.
Embodiment 2
AT330.9g (0.1mol), TEMPO 0.16g (1mmol), 300mL dichloromethane are added into 500mL three-necked flasks
In, stirring and dissolving, add sodium bromide solution (1.03g sodium bromides (10mmol) are dissolved in 15mL purified waters), stirring be cooled to-
10~-5 DEG C, 5% liquor natrii hypochloritis 106mL (0.15mol) is added dropwise, drop finishes, and maintains 20~30 DEG C of stirring 30min, is warming up to
10~20 DEG C, 30min is stirred, TLC is monitored to reaction completely, stratification, separates organic layer, organic layer 100mL bicarbonates
Sodium solution washs 2 times, separates organic layer, adds anhydrous sodium sulfate drying, filters, filtrate decompression concentration.Gained grease adds
50mL isopropanols stir, and separate out solid, and suction filtration is dried to obtain off-white powder 24.6g, yield 80.1%.HPLC purity：
98.9%.
Embodiment 3
AT330.9g (0.1mol), TEMPO 0.16g (1mmol), 300mL dichloromethane are added into 500mL three-necked flasks
In, stirring and dissolving, add liquor kalii iodide (1.66g KIs (10mmol) are dissolved in 15mL purified waters), stirring be cooled to-
10~-5 DEG C, 10% liquor natrii hypochloritis 71mL (0.2mol) is added dropwise, drop finishes, and maintains -10~-5 DEG C of stirring 30min, is warming up to
10~20 DEG C, 30min is stirred for, TLC is monitored to reaction completely, stratification, separates organic layer, organic layer 100mL carbonic acid
Hydrogen sodium solution washs 2 times, separates organic layer, adds anhydrous sodium sulfate drying, filters, filtrate decompression concentration.Gained grease adds
Enter the stirring of 50mL isopropanols, separate out solid, suction filtration is dried to obtain off-white powder 26.2g, yield 85.3%.HPLC purity：
99.0%.
Embodiment 4
AT330.9g (0.1mol), TEMPO 0.16g (1mmol), 300mL dichloromethane are added into 500mL three-necked flasks
In, stirring and dissolving, add IodineSodium Solution (1.50g KIs (10mmol) are dissolved in 30mL purified waters), stirring be cooled to-
10~-5 DEG C, 10% liquor natrii hypochloritis 71mL (0.2mol) is added dropwise, drop finishes, and maintains -10~-5 DEG C of stirring 30min, is warming up to
10~20 DEG C, 30min is stirred, TLC is monitored to reaction completely, stratification, separates organic layer, organic layer 100mL bicarbonates
Sodium solution washs 2 times, separates organic layer, adds anhydrous sodium sulfate drying, filters, filtrate decompression concentration.Gained grease adds
50mL isopropanols stir, and separate out solid, and suction filtration is dried to obtain off-white powder 27.2g, yield 88.6%.HPLC purity：
98.5%.
Claims (1)
- A kind of oxidation synthesis method of 1. histamine H 1 receptor antagonist --- Alcaftadine (Alcaftadine), it is characterised in that： In the presence of a catalyst, as the oxidizing Alcaftadine intermediate as described in structural formula I --- 6,11- dihydro -11- (1- Methyl -4- piperidylidenes) -5H- imidazos [2,1-b] [3] benzazepines -3- methanol (referred to as " AT3 ") is madeThe oxidant of selection is sodium hypochlorite/tetramethyl piperidine nitrogen oxides (TEMPO)；Using methylene chloride/water as solvent；The ratio of dichloromethane and water is 10-50:1；Oxidizing reaction temperature is -10-30 DEG C；In terms of effective chlorine, the concentration of sodium hypochlorite is 5~10%；Sodium hypochlorite and AT3 mol ratio are 1~2:1；The catalyst is KI, sodium iodide, KBr, sodium bromide.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1068118A (en) * | 1991-06-13 | 1993-01-20 | 詹森药业有限公司 | Imidazo [2,1-b] [3] benzazepine derivative, composition and usage |
| CN101906068A (en) * | 2009-06-04 | 2010-12-08 | 浙江医药股份有限公司新昌制药厂 | Preparation method of 2-pyridine carboxaldehyde |
| WO2014080259A1 (en) * | 2012-11-21 | 2014-05-30 | Enaltec Labs Pvt. Ltd. | Novel polymorphic forms of alcaftadine |
| WO2014087208A2 (en) * | 2012-12-06 | 2014-06-12 | Enaltec Labs Pvt. Ltd. | A process of preparing alcaftadine |
| CN104860888A (en) * | 2015-05-26 | 2015-08-26 | 南京华威医药科技开发有限公司 | Alcaftadine intermediate and synthetic method for alcaftadine |
-
2015
- 2015-07-28 CN CN201510448368.9A patent/CN105130993B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1068118A (en) * | 1991-06-13 | 1993-01-20 | 詹森药业有限公司 | Imidazo [2,1-b] [3] benzazepine derivative, composition and usage |
| CN101906068A (en) * | 2009-06-04 | 2010-12-08 | 浙江医药股份有限公司新昌制药厂 | Preparation method of 2-pyridine carboxaldehyde |
| WO2014080259A1 (en) * | 2012-11-21 | 2014-05-30 | Enaltec Labs Pvt. Ltd. | Novel polymorphic forms of alcaftadine |
| WO2014087208A2 (en) * | 2012-12-06 | 2014-06-12 | Enaltec Labs Pvt. Ltd. | A process of preparing alcaftadine |
| CN104860888A (en) * | 2015-05-26 | 2015-08-26 | 南京华威医药科技开发有限公司 | Alcaftadine intermediate and synthetic method for alcaftadine |
Non-Patent Citations (2)
| Title |
|---|
| 2-吡啶甲醛的合成;李小清，等;《浙江化工》;20091231;第40卷(第10期);第8-9页，第8页反应式及第9页1.4节 * |
| Synthesis and structural elucidation of a novel polymorph of alcaftadine;Pramod B. Pansuriya 等;《Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy》;20150209;第142卷;第311-319页，第312页右栏第7~15行，Scheme 1 * |
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