CN101824009A - Simple preparation method for posaconazole and piperazine intermediate thereof - Google Patents
Simple preparation method for posaconazole and piperazine intermediate thereof Download PDFInfo
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- CN101824009A CN101824009A CN201010184574A CN201010184574A CN101824009A CN 101824009 A CN101824009 A CN 101824009A CN 201010184574 A CN201010184574 A CN 201010184574A CN 201010184574 A CN201010184574 A CN 201010184574A CN 101824009 A CN101824009 A CN 101824009A
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Abstract
The invention discloses a method for preparing 1-(4-hydroxyphenyl)-4-(4-aminophenyl)piperazine intermediate. The piperazine intermediate has a structural formula II. The compound is a main intermediate of a novel medicament posaconazole for treating invasive fungal infection.
Description
Technical field
The present invention relates to the preparation method of 1-(4-hydroxy phenyl)-4-(4-aminophenyl) piperazine, above-claimed cpd can further be used for preparing treatment intrusive mood fungi infestation newtype drug posaconazole.
Background technology
Posaconazole (chemical name: 4-[4-[4-[4-[[(3R, 5R)-5-(2, the 4-difluorophenyl)-5-(1,2,4-triazol-1-yl methyl) oxa-penta ring-3-yl] methoxyl group] phenyl] piperazine-1-yl] phenyl]-2-[(2S, 3S)-2-hydroxyl penta-3-yl]-1,2,4-triazole-3-ketone posacaonazole), has following formula structure (seeing the formula I):
The formula I
The posaconazole has a broad antifungal spectrum, security and better tolerance are for the prevention of deep fungal infection and treatment provide a kind of new treatment to select.This medicine on September 15th, 2006 is used for refractory disease or the caused fungi infestation of other drug resistance by a kind of wide spectrum triazole antifungal agent of drugs approved by FDA.
The method for preparing posaconazole of open report has following several:
In world patent WO9517407, U.S. Pat 5710154, US5714490, European patent EP 0736030 and Chinese patent ZL94195025.5, introduced by 1-chloro-2, the 4-difluoro acetophenone obtains 2-(2 through the witting reaction, the 4-difluorophenyl) vinylcarbinol obtains product through polystep reactions such as Sharpless epoxidation, nucleophilic substitution, condensation, reduction again.This method finally obtains product through the reaction of 21 steps, mentions multistep in the patent and all adopts the mode of column chromatography that intermediate is carried out separation and purification, is unfavorable for suitability for industrialized production.
Concrete reaction formula is as follows:
In world patent WO9633178, introduced the S-ethyl lactate and protected through pyrrolidone, the benzyl protection hydroxyl, and then with the reaction of piperazine intermediate I and intermediate A, obtain posaconazole.Concrete reaction formula is as follows:
Bibliographical information (T.L, 2002,43.3359-3363) the synthetic posaconazoles, method one of obtaining of other two kinds of methods:
Method two:
In view of the therapeutic value of target compound, be necessary to seek one easy and simple to handle, yield is good, with low cost, and the also gratifying synthetic route of the quality of product.Emphasis of the present invention is sought a kind of simple synthesis and is prepared its important intermediate (seeing the formula II).
Summary of the invention
The purpose of this invention is to provide a kind of easy and simple to handle, yield is good, and preparation method's (formula II) of the also gratifying posaconazole intermediate of the quality of product 1-(4-hydroxy phenyl)-4-(4-aminophenyl) piperazine, the gained compound can be used for treating intrusive mood fungi infestation newtype drug posaconazole.
The formula II
The invention provides a kind of synthetic method of posaconazole intermediate 1-(4-hydroxy phenyl)-4-(4-aminophenyl) piperazine, be specially: with P-nethoxyaniline and N, N-two (2-haloethyl)-4-N-methyl-p-nitroaniline is a raw material, in non-protonic solvent, under alkaline condition, carry out condensation and cyclization, intermediate 1-(4-hydroxy phenyl)-4-(4-aminophenyl) piperazine (seeing the formula II) shown in last catalytic hydrogenation obtains.
Further be specially: selected N, N-two (2-haloethyl)-4-N-methyl-p-nitroaniline is N, N-two (2-bromotrifluoromethane)-4-N-methyl-p-nitroaniline, N, N-two (2-chloroethyl)-4-N-methyl-p-nitroaniline or N, N-two (1-chloro-2-bromotrifluoromethane)-4-N-methyl-p-nitroaniline.
Wherein non-protonic solvent is selected from DMF, DMAC, ethers, glycol dimethyl ether, diglyme, Propylene Glycol Dimethyl Ether, DMSO, dimethylbenzene, benzene, toluene or acetonitrile.
Wherein selected alkali is sodium hydroxide, sodium hydride, potassium hydroxide, sodium methylate or sodium amide.
Wherein the cyclized condensation reaction temperature is chosen between 80 ℃ to 140 ℃.Catalytic hydrogenation is selected the Pd/C shortening for use.
This intermediate can further carry out condensation, chiral separation easily by the method shown in the patent WO9633178, obtains anti-fungal infection medicine posaconazole, and concrete reaction scheme is as follows:
Embodiment
Following embodiment is to describe in detail the present invention, but should not be construed as limiting the invention.
Synthesizing of embodiment 1 1-(4-p-methoxy-phenyl)-4-(4-nitrophenyl) piperazine
In 3 liters there-necked flask, add 300 gram N, N-two (2-chloroethyl)-4-N-methyl-p-nitroaniline, 120 gram P-nethoxyaniline.Stir 1.5 liters of N of adding down, dinethylformamide, and add 20 gram sodium hydroxide in batches.Be heated to 100 ℃ of reactions 24 hours.Stopped reaction stirs cooling down, adds the entry dilution, uses 2 liters of chloroform extractions three times then.Organic phase adds the Anhydrous potassium carbonate drying, and suction filtration concentrates and removes chloroform.Residuum adds 1, and 4-dioxane recrystallization obtains target compound 1-(4-p-methoxy-phenyl)-4-(4-nitrophenyl) piperazine 202.4 grams, yield 87%.mp.195.4℃。
Synthesizing of embodiment 2 1-(4-p-methoxy-phenyl)-4-(4-nitrophenyl) piperazine
In 500 milliliters there-necked flask, add 52.5 gram N, N-two (2-chloroethyl)-4-N-methyl-p-nitroaniline, 18.4 gram P-nethoxyaniline.Stir 200 milliliters of toluene of adding down, and add 2 gram sodium hydroxide in batches.Be heated to back flow reaction 24 hours.Stopped reaction is cooled to 50-60 ℃ under stirring, and adds the entry dilution, separatory.Organic phase washes twice with water, adds the Anhydrous potassium carbonate drying,
Suction filtration concentrates and removes toluene.Residuum adds 1, and 4-dioxane recrystallization obtains target compound 1-(4-p-methoxy-phenyl)-4-(4-nitrophenyl) piperazine 35.2 grams, yield 88.5%.mp.194.6℃。
Synthesizing of embodiment 3 1-(4-p-methoxy-phenyl)-4-(4-nitrophenyl) piperazine
In 500 milliliters there-necked flask, add 52.5 gram N, N-two (2-chloroethyl)-4-N-methyl-p-nitroaniline, 18.4 gram P-nethoxyaniline.Stir 200 milliliters of N of adding down, dinethylformamide, and add 2 gram sodium hydroxide in batches.Be heated to 100 ℃ of reactions 24 hours.Stopped reaction is cooled to 50-60 ℃ under stirring, and adds the entry dilution, uses 450 milliliters of chloroform extractions three times then.Organic phase adds the Anhydrous potassium carbonate drying, and suction filtration concentrates and removes chloroform.Residuum adds 1, and 4-dioxane recrystallization obtains target compound 1-(4-p-methoxy-phenyl)-4-(4-nitrophenyl) piperazine 34.4 grams, yield 87%.mp.195.1℃。
Synthesizing of embodiment 4 1-(4-hydroxy phenyl)-4-(4-nitrophenyl) piperazine
In 500 milliliters there-necked flask, add 200 milliliters of tetrahydrofuran (THF)s, to wherein adding 23.2 gram 1-(4-p-methoxy-phenyl)-4-(4-nitrophenyl) piperazines.Feeding the bromize hydrogen gas reaction in reaction solution spends the night.In reaction solution, add water washing, separatory, organic phase washes twice with water, vacuum concentration.Resistates adds re-crystallizing in ethyl acetate and obtains target compound 1-(4-hydroxy phenyl)-4-(4-nitrophenyl) piperazine 12.1 grams, yield 55%.mp.174.3℃。
Synthesizing of embodiment 5:1-(4-hydroxy phenyl)-4-(4-aminophenyl) piperazine
In 500 milliliters there-necked flask, add 200 milliliters of tetrahydrofuran (THF)s, to wherein adding 23.2 gram 1-(4-p-methoxy-phenyl)-4-(4-nitrophenyl) piperazines.Feeding the bromize hydrogen gas reaction in reaction solution spends the night.In reaction solution, add water washing, separatory, organic phase washes twice with water, vacuum concentration.Resistates adds re-crystallizing in ethyl acetate and obtains target compound 1-(4-hydroxy phenyl)-4-(4-nitrophenyl) piperazine 12.1 grams, yield 55%.mp.174.3℃。
Embodiment 6:
In the 1L there-necked flask, add 50g amino alcohol (1-1), add 750ml DMSO and at room temperature stir, get 12g NaOH solution (adding 84ml water) then and stirred 5 minutes.In reaction flask, add 100g chiral intermediate (1-2).Stirring is spent the night, and adds 3L and is water-cooled to 5 ℃, stirs half an hour, filters.Filter cake normal hexane drip washing.Obtain 97.5g product (1-3).
Embodiment 7
Slowly in there-necked flask, add the 21.5ml phenyl chloroformate, add the reaction product that 85g goes up the step, add the 650ml methylene dichloride, under the room temperature stirring reaction 2-8 hour.Be cooled to 0 ℃, wash to weakly alkaline with saturated NaHCO3, separatory, the water dichloromethane extraction merges organic phase, and the evaporated under reduced pressure solvent adds 1.5L water and 2.5L normal hexane in resistates.Be cooled to 0 ℃, suction filtration obtains solid matter.Water, 50% methanol and normal hexane washing respectively then.Obtain exsiccant product (1-4) 100.5g.MS：FAB，667(M+H)。
Embodiment 8
In there-necked flask, add the finished product that obtains in the 347g example 7,137g chiral intermediate (1-5), 85g 4A molecular sieve, 0.8g DBU and 1400ml acetone are heated to 75 ℃-85 ℃ reactions 24 hours.Be warming up to 110 ℃ once more, continue reaction 48 hours.Reaction solution is cooled to 70 ℃, the 700ml hot acetone drip washing of suction filtration, filter cake.Be evaporated to 1000ml, be cooled to 40 ℃ and add the 2400ml methylene dichloride.Use the sodium hydrogen carbonate solution washing of 0.5M sodium hydroxide solution (2*800ml), 200ml water, 235ml1M hydrochloric acid soln, 200ml water and 250ml 5% successively.Normal pressure is concentrated into 1000ml, and decompression (being lower than 70 ℃) distillation obtains product (1-6) then.
Embodiment 9
The product (1-6) that the last step was obtained is cooled to 50 ℃, adds 350ml formic acid, continues to be cooled to 20 ℃, adds other 350ml formic acid.Getting 85g Pd/C adding 350ml formic acid stirs in the pulpous state adding reaction flask.Under 20 ℃, stir and spend the night, be heated to 40 ℃ of reactions 24 hours.Suction filtration, filter cake 350ml formic acid, the drip washing of 700ml methyl alcohol.The evaporated under reduced pressure solvent adds 3500ml methyl alcohol and 700ml ammoniacal liquor in resistates, be heated to backflow 1-2 hour, and a large amount of solids are separated out in cooling then, suction filtration, and filter cake is with 1: 1 methyl alcohol of 1400ml and water washing.40 ℃ of following forced air dryings obtain 300.5g end product (I).
Claims (7)
1. the preparation method of posaconazole intermediate 1-(4-hydroxy phenyl)-4-(4-aminophenyl) piperazine shown in the formula II, be specially: with P-nethoxyaniline and N, N-two (2-haloethyl)-4-N-methyl-p-nitroaniline is a raw material, in non-protonic solvent, under the alkaline condition, carry out condensation and cyclization, intermediate 1-(4-hydroxy phenyl)-4-(4-aminophenyl) piperazine shown in last catalytic hydrogenation obtains.
Formula II
2. preparation method according to claim 1, N, N-two (2-haloethyl)-4-N-methyl-p-nitroaniline is N, N-two (2-bromotrifluoromethane)-4-N-methyl-p-nitroaniline, N, N-two (2-chloroethyl)-4-N-methyl-p-nitroaniline or N, N-two (1-chloro-2-bromotrifluoromethane)-4-N-methyl-p-nitroaniline.
3. preparation method according to claim 1, non-protonic solvent is selected from DMF, DMAC, ethers, glycol dimethyl ether, diglyme, Propylene Glycol Dimethyl Ether, DMSO, dimethylbenzene, benzene, toluene or acetonitrile.
4. preparation method according to claim 1, alkali is sodium hydroxide, sodium hydride, potassium hydroxide, sodium methylate or sodium amide.
5. preparation method according to claim 1, cyclized condensation reaction temperature are chosen in 80 ℃～140 ℃.
6. preparation method according to claim 1, catalytic hydrogenation is selected the Pd/C shortening for use.
7. method for preparing posaconazole, it is characterized in that with P-nethoxyaniline and N, N-two (2-haloethyl)-4-N-methyl-p-nitroaniline is a raw material, in non-protonic solvent, under the alkaline condition, carry out condensation and cyclization, intermediate 1-(4-hydroxy phenyl)-4-(4-aminophenyl) piperazine shown in last catalytic hydrogenation obtains, carry out condensation, chiral separation, obtain anti-fungal infection medicine posaconazole.
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Cited By (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102643194A (en) * | 2012-03-27 | 2012-08-22 | 福州大学 | Preparation method of posaconazole intermediate |
| CN102731437A (en) * | 2012-06-15 | 2012-10-17 | 盛世泰科生物医药技术(苏州)有限公司 | Preparation method of 4-piperazine-3-trifluoromethylaniline hydrochloride |
| CN103086885A (en) * | 2013-02-28 | 2013-05-08 | 天津大学仁爱学院 | Preparation method of posaconazole intermediate |
| WO2013042138A3 (en) * | 2011-09-19 | 2013-05-23 | Msn Laboratories Limited | Process for preparation of triazole antifungal drug, its intermediates and polymorphs thereof |
| CN103852528A (en) * | 2012-12-07 | 2014-06-11 | 重庆莱美药业股份有限公司 | Method for detecting posaconazole |
| CN105461644A (en) * | 2014-09-05 | 2016-04-06 | 上海欣生源药业有限公司 | Preparation and separation purification methods of drug intermediate |
| CN105606736A (en) * | 2016-01-27 | 2016-05-25 | 重庆华邦制药有限公司 | Method for separation determination of posaconazole intermediate Z1 and related substances of posaconazole intermediate Z1 |
| CN105646137A (en) * | 2016-01-14 | 2016-06-08 | 宁波新凯生物科技有限公司 | Method for synthesizing 1-(1-chloromethylvinyl)-2,4-difluorobenzene |
| CN105777482A (en) * | 2016-03-30 | 2016-07-20 | 浙江大学宁波理工学院 | Synthesis method of 1-(1-chloromethylvinyl)-2,4-difluorobenzene |
| CN106699741A (en) * | 2015-07-16 | 2017-05-24 | 成都自豪药业有限公司 | New crystal form of benzyl ether posaconazole, and preparation method and use thereof |
| CN106883221A (en) * | 2017-04-17 | 2017-06-23 | 兰州大学 | A kind of amorphous posaconazole and preparation method thereof |
| WO2017147893A1 (en) * | 2016-03-04 | 2017-09-08 | 浙江奥翔药业股份有限公司 | Posaconazole, composition, intermediate, preparation method therefor, and uses thereof |
| CN108239077A (en) * | 2016-12-26 | 2018-07-03 | 昆明积大制药股份有限公司 | A kind of novel preparation method of posaconazole and its intermediate |
| CN111362886A (en) * | 2020-04-23 | 2020-07-03 | 成都百特万合医药科技有限公司 | Preparation method of posaconazole intermediate 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine |
| CN111606898A (en) * | 2020-05-23 | 2020-09-01 | 湖北扬信医药科技有限公司 | Posaconazole related substance and preparation method and application thereof |
| CN114516849A (en) * | 2020-11-18 | 2022-05-20 | 江苏恒盛药业有限公司 | Synthesis method of 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine |
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| WO2013042138A3 (en) * | 2011-09-19 | 2013-05-23 | Msn Laboratories Limited | Process for preparation of triazole antifungal drug, its intermediates and polymorphs thereof |
| US9102664B2 (en) | 2011-09-19 | 2015-08-11 | Msn Laboratories Private Limited | Process for the preparation of triazole antifungal drug, its intermediates and polymorphs thereof |
| CN102643194A (en) * | 2012-03-27 | 2012-08-22 | 福州大学 | Preparation method of posaconazole intermediate |
| CN102731437A (en) * | 2012-06-15 | 2012-10-17 | 盛世泰科生物医药技术(苏州)有限公司 | Preparation method of 4-piperazine-3-trifluoromethylaniline hydrochloride |
| CN103852528A (en) * | 2012-12-07 | 2014-06-11 | 重庆莱美药业股份有限公司 | Method for detecting posaconazole |
| CN103852528B (en) * | 2012-12-07 | 2016-02-03 | 重庆莱美药业股份有限公司 | A kind of detection method of posaconazole |
| CN103086885A (en) * | 2013-02-28 | 2013-05-08 | 天津大学仁爱学院 | Preparation method of posaconazole intermediate |
| CN103086885B (en) * | 2013-02-28 | 2015-04-01 | 天津大学仁爱学院 | Preparation method of posaconazole intermediate |
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| CN106699741A (en) * | 2015-07-16 | 2017-05-24 | 成都自豪药业有限公司 | New crystal form of benzyl ether posaconazole, and preparation method and use thereof |
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| WO2017147893A1 (en) * | 2016-03-04 | 2017-09-08 | 浙江奥翔药业股份有限公司 | Posaconazole, composition, intermediate, preparation method therefor, and uses thereof |
| US10696643B2 (en) | 2016-03-04 | 2020-06-30 | Zhejiang Ausun Pharmaceutical Co., Ltd. | Posaconazole, composition, intermediate, preparation method and use thereof |
| CN105777482A (en) * | 2016-03-30 | 2016-07-20 | 浙江大学宁波理工学院 | Synthesis method of 1-(1-chloromethylvinyl)-2,4-difluorobenzene |
| CN105777482B (en) * | 2016-03-30 | 2018-06-15 | 浙江大学宁波理工学院 | A kind of 1-（1- chloromethyl vinyl bases）The synthetic method of -2,4- difluorobenzene |
| CN108239077A (en) * | 2016-12-26 | 2018-07-03 | 昆明积大制药股份有限公司 | A kind of novel preparation method of posaconazole and its intermediate |
| CN106883221A (en) * | 2017-04-17 | 2017-06-23 | 兰州大学 | A kind of amorphous posaconazole and preparation method thereof |
| CN111362886A (en) * | 2020-04-23 | 2020-07-03 | 成都百特万合医药科技有限公司 | Preparation method of posaconazole intermediate 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine |
| CN111606898A (en) * | 2020-05-23 | 2020-09-01 | 湖北扬信医药科技有限公司 | Posaconazole related substance and preparation method and application thereof |
| CN111606898B (en) * | 2020-05-23 | 2021-06-08 | 湖北扬信医药科技有限公司 | Posaconazole related substance and preparation method and application thereof |
| CN114516849A (en) * | 2020-11-18 | 2022-05-20 | 江苏恒盛药业有限公司 | Synthesis method of 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine |
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|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| DD01 | Delivery of document by public notice |
Addressee: Dezhong Wanquan Pharmaceuticals Tech. Dev. Co., Ltd., Beijing Document name: Notification of Patent Invention Entering into Substantive Examination Stage |
|
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20100908 |