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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- nitroaniline
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- piperazine
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- RAGOYPUPXAKGKH-XAKZXMRKSA-N posaconazole Chemical compound O=C1N([C@H]([C@H](C)O)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@H]3C[C@@](CN4N=CN=C4)(OC3)C=3C(=CC(F)=CC=3)F)=CC=2)C=C1 RAGOYPUPXAKGKH-XAKZXMRKSA-N 0.000 title claims abstract description 15
- 229960001589 posaconazole Drugs 0.000 title claims abstract description 15
- 238000002360 preparation method Methods 0.000 title claims description 10
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 title abstract description 8
- WZIJMPVPOMTRNM-UHFFFAOYSA-N 4-[4-(4-aminophenyl)piperazin-1-yl]phenol Chemical compound C1=CC(N)=CC=C1N1CCN(C=2C=CC(O)=CC=2)CC1 WZIJMPVPOMTRNM-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000000034 method Methods 0.000 claims abstract description 8
- 239000003814 drug Substances 0.000 claims abstract description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 238000009833 condensation Methods 0.000 claims description 6
- 230000005494 condensation Effects 0.000 claims description 6
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 5
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- 206010017533 Fungal infection Diseases 0.000 claims description 3
- 208000031888 Mycoses Diseases 0.000 claims description 3
- 230000000843 anti-fungal effect Effects 0.000 claims description 3
- 239000002994 raw material Substances 0.000 claims description 3
- 238000007363 ring formation reaction Methods 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- LEEANUDEDHYDTG-UHFFFAOYSA-N 1,2-dimethoxypropane Chemical compound COCC(C)OC LEEANUDEDHYDTG-UHFFFAOYSA-N 0.000 claims description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 2
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 238000006482 condensation reaction Methods 0.000 claims description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 claims description 2
- 150000002170 ethers Chemical class 0.000 claims description 2
- 238000004904 shortening Methods 0.000 claims description 2
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 8
- 208000037026 Invasive Fungal Infections Diseases 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 26
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 239000000047 product Substances 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- 238000000967 suction filtration Methods 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 230000002194 synthesizing effect Effects 0.000 description 5
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 235000019253 formic acid Nutrition 0.000 description 4
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 3
- BNHYDULILNJFFY-UHFFFAOYSA-N 4-[4-(4-nitrophenyl)piperazin-1-yl]phenol Chemical compound C1=CC(O)=CC=C1N1CCN(C=2C=CC(=CC=2)[N+]([O-])=O)CC1 BNHYDULILNJFFY-UHFFFAOYSA-N 0.000 description 3
- 241000233866 Fungi Species 0.000 description 3
- 206010061217 Infestation Diseases 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 2
- 229940121375 antifungal agent Drugs 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000036651 mood Effects 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 150000004885 piperazines Chemical class 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 206010059866 Drug resistance Diseases 0.000 description 1
- 208000032826 Ring chromosome 3 syndrome Diseases 0.000 description 1
- 238000006202 Sharpless epoxidation reaction Methods 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 150000001414 amino alcohols Chemical class 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- YDVNLQGCLLPHAH-UHFFFAOYSA-N dichloromethane;hydrate Chemical compound O.ClCCl YDVNLQGCLLPHAH-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940116333 ethyl lactate Drugs 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 208000037922 refractory disease Diseases 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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 (17)
| 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 |
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