CN104987337A - Novel oxidation method for preparing alcaftadine - Google Patents
Novel oxidation method for preparing alcaftadine Download PDFInfo
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- CN104987337A CN104987337A CN201510448367.4A CN201510448367A CN104987337A CN 104987337 A CN104987337 A CN 104987337A CN 201510448367 A CN201510448367 A CN 201510448367A CN 104987337 A CN104987337 A CN 104987337A
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- methylene dichloride
- alcaftadine
- methyl
- lastacaft
- piperidylidene
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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 invention relates to a novel oxidation method for preparing a histamine H1 receptor antagonist--alcaftadine. The method comprises the step of using a Dess-Martin periodinane as an oxidation reagent to oxidize an intermediate--6,11-dihydro-11-(1-methyl-4-piperidylidene)-5H-imidazo[2,1-b][3]benzazepine-3- methanol so as to obtain the alcaftadine. The novel oxidation method for preparing the alcaftadine is simplified and has the advantages of simple operation, environment-friendly process, cheap and easily-available raw materials and reagents, high yield and more applicability to industrial production.
Description
Technical field
The present invention relates to a kind of novel preparation method of compound, be specifically related to a kind of histamine H 1 receptor antagonist---the novel method of the oxidizing reaction of Lastacaft (Alcaftadine).
Background technology
Lastacaft (Alcaftadine), trade(brand)name: Lastacaft is a kind of New Histamine H1 receptor antagonist that Weicon pharmacy (Vistakon Pharmaceuticals) is developed.FDA approval in 2010 was used for the treatment of the itch that anaphylaxis conjunctivitis causes, in listing in 2010.Lastacaft has now got permission for more than 2 years old child patient.After the Phenylsulfonic acid Beta this (Bepreve) of Lastacaft (Alcaftadine) Shi Ji ISTA drugmaker exploitation, another is used for the treatment of the medicine of anaphylaxis conjunctivitis dependency eye itch.There is good potential applicability in clinical practice.
The method for oxidation reported about the patent WO1992022551 of Lastacaft is by 6,11-dihydro-11-(1-methyl-4-piperidylidene)-5H-imidazo [2,1-b] [3] benzazepines-3-methyl alcohol obtains Lastacaft with manganese dioxide, and operational path is as follows:
In the method, Manganse Dioxide is gentle oxidising agent, needs activation treatment before use, and feeding intake, it is greatly excessive to need, and produces a large amount of waste residue after reaction, and environmental pollution is comparatively large, and production cost and the three wastes are increased.We attempt the Manganse Dioxide after using activation and are oxidized, and react 20 hours, transformation efficiency only has 20%, and impurity is more.
In another section of patent WO2014083571A, report adopts Silver Nitrate, tin anhydride, ceric ammonium nitrate is oxygenant is Lastacaft by 6,11-dihydro-11-(1-methyl-4-piperidylidene)-5H-imidazo [2,1-b] [3] benzazepines-3-methanol oxidation.Because of Silver Nitrate, tin anhydride, ceric ammonium nitrate price is more expensive, and toxicity is comparatively large, and finds through experiment, when this several oxygenant is oxidized alcoholic extract hydroxyl group, can over oxidation is carboxyl, produces more carboxylic acid impurities.This several method is also not suitable for industrial amplification production.
Therefore, the gordian technique bottleneck that safer, economic oxidation synthesis method is Lastacaft synthesis is always found.
Summary of the invention
There is above problem in the oxidative synthesis process based on this Lastacaft current, We conducted research: select Dai Si-Martin reagent by 6,11-dihydro-11-(1-methyl-4-piperidylidene)-5H-imidazo [2,1-b] [3] benzazepines-3-methanol oxidation obtains Lastacaft, the method yield is high, purity is good, simple to operate, and environmental protection.
The oxidizing reaction that the present invention is Lastacaft provides a kind of convenient, and cost is low, the novel method that yield is high.
Preparation method of the present invention is as follows:
To wear this Martin reagent for oxidising agent, by " 6; 11-dihydro-11-(1-methyl-4-piperidylidene)-5H-imidazo [2,1-b] [3] benzazepines-3-methyl alcohol " (being called for short " AT3 ") oxidation in methylene dichloride/tetrahydrofuran (THF), methylene dichloride/trimethyl carbinol, methylene dichloride/acetone, methylene dichloride/butanone equal solvent system.Product can be obtained with high yield, HPLC purity >98.0%.Our synthetic method is as follows:
4, according to claim 2,4, the invention is characterized in: this oxidizing reaction with methylene dichloride/tetrahydrofuran (THF), methylene dichloride/trimethyl carbinol, methylene dichloride/acetone, methylene dichloride/butanone for solvent.
5, method according to claim 3,6, method according to claim 5, it is characterized in that: the oxygenant selected is Dai Si-Martin reagent;
(1) Dai Si-Martin reagent selected and 6, the mol ratio of 11-dihydro-11-(1-methyl-4-piperidylidene)-5H-imidazo [2,1-b] [3] benzazepines-3-methyl alcohol (being called for short " AT3 ") is (1 ~ 3): 1;
(2) this oxidizing reaction with methylene dichloride/tetrahydrofuran (THF), methylene dichloride/trimethyl carbinol, methylene dichloride/acetone, methylene dichloride/butanone equal solvent system for reaction solvent.
(3) in methylene dichloride/tetrahydrofuran (THF), methylene dichloride/trimethyl carbinol, methylene dichloride/acetone, each solvent system of methylene dichloride/butanone, the volume ratio of methylene dichloride and another solvent is (1 ~ 5): 1.
(4) oxidizing reaction temperature is 10-30 DEG C.
Obtained by the present invention, Lastacaft transformation efficiency is high, and impurity is few, and purity is greater than 98.0%, yield more than 80%.The oxidizing process of patent documentation WO1992022551 and WO2014083571A of the present invention compares, and has following advantages:
1) oxidising agent is easy to get.Select activated manganese dioxide in patent WO1992022551, Manganse Dioxide reactivation process is more loaded down with trivial details; Use Silver Nitrate, tin anhydride in WO2014083571A, ceric ammonium nitrate price is more expensive and toxicity is larger; We select Dai Si-Martin reagent cheap and easy to get and safety and environmental protection, the industrialization of the committed step oxidizing reaction of Lastacaft is amplified and is achieved.
2) selectivity be oxidized is good.The oxidising agent selectivity of patent WO1992022551 and WO2014083571A report is bad, confirm that these method for oxidation are to 6 through experiment, 11-dihydro-11-(1-methyl-4-piperidylidene)-5H-imidazo [2,1-b] [3] benzazepines-3-methyl alcohol (be called for short " AT3 ") is oxidized in the reaction process of aldehyde that yield is low, impurity is many, product purity is poor, is difficult to realize industrialization and amplifies.
3) avoid the reagent that the environmental pollutions such as Manganse Dioxide in patent documentation, Silver Nitrate, tin anhydride are larger, solve a large amount of three wastes problems in suitability for industrialized production.
4) total recovery is high, total recovery more than 85%, higher than 60% of literature procedures.
Embodiment
The following example is used for describing the present invention further, but it is not any restriction to scope of the present invention.The purity testing of each experiment gained sample measures wearing on peace U3000 high performance liquid chromatograph.
Embodiment 1
AT3 30.9g (0.1mol), 300mL methylene dichloride, 150mL tetrahydrofuran (THF) are added in 1000mL there-necked flask, in 10 ~ 20 DEG C of stirring and dissolving, add Dai Si-Martin reagent 84.8g (0.2mol), be warming up to 20 ~ 30 DEG C after adding to continue to stir 1-2 hour, TLC monitoring is to reacting completely, suction filtration, filtrate washs 1 time with 10% hypo solution 100mL, separate organic layer, wash with saturated 5% sodium hydrogen carbonate solution 100mL again, separate organic layer, add anhydrous sodium sulfate drying, suction filtration, filtrate reduced in volume.Gained oily matter adds 50mL Virahol and stirs, and solid is separated out in cooling, and suction filtration drying obtains off-white color solid 27.5g, yield 89.6%.HPLC purity: 98.5%.
Embodiment 2
AT3 30.9g (0.1mol), 300mL methylene dichloride, the 150mL trimethyl carbinol are added in 1000mL there-necked flask, in 10 ~ 20 DEG C of stirring and dissolving, add Dai Si-Martin reagent 63.6g (0.15mol), be warming up to 20 ~ 30 DEG C after adding to continue to stir 1-2 hour, TLC monitoring is to reacting completely, suction filtration, filtrate washs 1 time with 10% hypo solution 100mL, separate organic layer, wash with saturated 5% sodium hydrogen carbonate solution 100mL again, separate organic layer, add anhydrous sodium sulfate drying, suction filtration, filtrate reduced in volume.Gained oily matter adds 50mL Virahol and stirs, and solid is separated out in cooling, and suction filtration drying obtains off-white color solid 26.8g, yield 87.3%.HPLC purity: 98.6%.
Embodiment 3
AT3 30.9g (0.1mol), 200mL methylene dichloride, 200mL acetone are added in 1000mL there-necked flask, in 10 ~ 20 DEG C of stirring and dissolving, add Dai Si-Martin reagent 84.8g (0.2mol), be warming up to 20 ~ 30 DEG C after adding to continue to stir 1-2 hour, TLC monitoring is to reacting completely, suction filtration, filtrate washs 1 time with 10% hypo solution 100mL, separate organic layer, wash with saturated 5% sodium hydrogen carbonate solution 100mL again, separate organic layer, add anhydrous sodium sulfate drying, suction filtration, filtrate reduced in volume.Gained oily matter adds 50mL Virahol and stirs, and solid is separated out in cooling, and suction filtration drying obtains off-white color solid 26.5g, yield 86.3%.HPLC purity: 98.8%.
Embodiment 4
AT3 30.9g (0.1mol), 300mL methylene dichloride, 200mL butanone are added in 1000mL there-necked flask, in 10 ~ 20 DEG C of stirring and dissolving, add Dai Si-Martin reagent 63.6g (0.15mol), be warming up to 20 ~ 30 DEG C after adding to continue to stir 1-2 hour, TLC monitoring is to reacting completely, suction filtration, filtrate washs 1 time with 10% hypo solution 100mL, separate organic layer, wash with saturated 5% sodium hydrogen carbonate solution 100mL again, separate organic layer, add anhydrous sodium sulfate drying, suction filtration, filtrate reduced in volume.Gained oily matter adds 50mL Virahol and stirs, and solid is separated out in cooling, and suction filtration drying obtains off-white color solid 27.0g, yield 87.9%.HPLC purity: 98.7%.
Embodiment 5
AT3 30.9g (0.1mol), 400mL methylene dichloride, 100mL butanone are added in 1000mL there-necked flask, in 10 ~ 20 DEG C of stirring and dissolving, add Dai Si-Martin reagent 127.2g (0.3mol), be warming up to 20 ~ 30 DEG C after adding to continue to stir 1-2 hour, TLC monitoring is to reacting completely, suction filtration, filtrate washs 1 time with 10% hypo solution 100mL, separate organic layer, wash with saturated 5% sodium hydrogen carbonate solution 100mL again, separate organic layer, add anhydrous sodium sulfate drying, suction filtration, filtrate reduced in volume.Gained oily matter adds 50mL Virahol and stirs, and solid is separated out in cooling, and suction filtration drying obtains off-white color solid 27.9g, yield 90.9%.HPLC purity: 98.6%.
Claims (6)
1. the Lastacaft intermediate as described in structural formula I---6,11-dihydro-11-(1-methyl-4-piperidylidene)-5H-imidazo [2,1-b] method for oxidation of [3] benzazepines-3-methyl alcohol (be called for short " AT3 "), it is characterized in that: this intermediate structure formula is as follows:
2. the oxygenant selected is Dai Si-Martin reagent.
3. according to claim 2, Dai Si-the Martin reagent selected and 6, the mol ratio of 11-dihydro-11-(1-methyl-4-piperidylidene)-5H-imidazo [2,1-b] [3] benzazepines-3-methyl alcohol (being called for short " AT3 ") is (1 ~ 3): 1.
4. the invention is characterized in: this oxidizing reaction with methylene dichloride/tetrahydrofuran (THF), methylene dichloride/trimethyl carbinol, methylene dichloride/acetone, methylene dichloride/butanone for solvent.
5. method according to claim 3, in methylene dichloride/tetrahydrofuran (THF), methylene dichloride/trimethyl carbinol, methylene dichloride/acetone, each solvent system of methylene dichloride/butanone, the volume ratio of methylene dichloride and another solvent is (1 ~ 5): 1.
6. method according to claim 5, is characterized in that: oxidizing reaction temperature is 10-30 DEG C.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN114591332A (en) * | 2020-12-07 | 2022-06-07 | 武汉武药科技有限公司 | Preparation method of alcaftadine and purification method of intermediate thereof |
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 |
| 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 |
| WO2014087208A2 (en) * | 2012-12-06 | 2014-06-12 | Enaltec Labs Pvt. Ltd. | A process of preparing alcaftadine |
| WO2014154620A1 (en) * | 2013-03-25 | 2014-10-02 | Crystal Pharma S.A.U. | Methods for the preparation of alcaftadine |
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- 2015-07-28 CN CN201510448367.4A patent/CN104987337B/en active Active
Patent Citations (6)
| 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 |
| CN1142360A (en) * | 1991-06-13 | 1997-02-12 | 詹森药业有限公司 | A method for preparing a medical composition conpaining imidazo[2,1-b][3] benzo azepine dericvants |
| 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 |
| WO2014087208A2 (en) * | 2012-12-06 | 2014-06-12 | Enaltec Labs Pvt. Ltd. | A process of preparing alcaftadine |
| WO2014154620A1 (en) * | 2013-03-25 | 2014-10-02 | Crystal Pharma S.A.U. | Methods for the preparation of alcaftadine |
Non-Patent Citations (1)
| Title |
|---|
| PRAMOD B. PANSURIYA 等: "Synthesis and structural elucidation of a novel polymorph of alcaftadine", 《SPECTROCHIMICA ACTA PART A: MOLECULAR AND BIOMOLECULAR SPECTROSCOPY》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN114591332A (en) * | 2020-12-07 | 2022-06-07 | 武汉武药科技有限公司 | Preparation method of alcaftadine and purification method of intermediate thereof |
| 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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