CN111362886B - Preparation method of posaconazole intermediate 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine - Google Patents
Preparation method of posaconazole intermediate 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine Download PDFInfo
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- CN111362886B CN111362886B CN202010331114.XA CN202010331114A CN111362886B CN 111362886 B CN111362886 B CN 111362886B CN 202010331114 A CN202010331114 A CN 202010331114A CN 111362886 B CN111362886 B CN 111362886B
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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Abstract
The invention discloses a preparation method of posaconazole intermediate 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine, which belongs to the field of pharmaceutical chemistry, and 1, 4-bis (4-chlorophenyl) piperazine is generated under certain conditions by using bromochlorobenzene and anhydrous piperazine as raw materials; carrying out unilateral methylation on the product generated in the step S1 to obtain 1- (4-methoxyphenyl) -4- (4-chlorophenyl) piperazine; ammonifying the product obtained in the step S2 to obtain 1- (4-methoxyphenyl) -4- (4-aminophenyl) piperazine; and (3) demethylating the product in the step (S3), and recrystallizing and purifying to obtain the 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine. The raw materials used in the process of the invention have low price, the reaction conditions are relatively simple, the method is easy to realize, the yield is higher, and the cost of the final product can be obviously reduced.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of posaconazole intermediate 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine.
Background
Posaconazole is a derivative of itraconazole, a second-generation triazole antifungal drug marketed in the FDA in the united states in 2006, widely used in patients with increased risk of infection due to severe immunodeficiency. Posaconazole (chemical name: 4- [4- [4- [4- [ [ (3 r,5 r) -5- (2, 4-difluorophenyl) -5- (1, 2, 4-triazol-1-ylmethyl) oxapent-3-yl ] methoxy ] phenyl ] piperazin-1-yl ] phenyl ] -2- [ (2 s,3 s) -2-hydroxypent-3-yl ] -1,2, 4-triazol-3-one), structural formula:
1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine is one of important intermediates for synthesizing posaconazole bulk drug, and molecular formula C 16 H 19 N 3 O, molecular weight 269.34, structural formula
According to the description of patent US6355801B1, WO 01034587 and CN101824009A, the disclosed synthesis of 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine comprises the following two steps:
the first step:
or (b)
And a second step of:
however, the raw materials used in the reported technology and the palladium-carbon price of the catalyst are high, the catalytic hydrogenation requires a closed space, the equipment requirement is strict, the reaction operation difficulty is high, the safety risk is caused, byproducts are easy to generate in high-pressure hydrogenation, and the purification difficulty is increased.
Disclosure of Invention
The invention aims at: aiming at the problems that the raw materials of the existing preparation method and the palladium-carbon catalyst are expensive, the catalytic hydrogenation requires a closed space, the equipment requirement is strict, the reaction operation difficulty is high, the safety risk is high, byproducts are easy to generate during high-pressure hydrogenation, and the purification difficulty is increased, the invention provides a novel preparation method of posaconazole intermediate 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine.
The technical scheme adopted by the invention is as follows:
a preparation method of posaconazole intermediate 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine, which comprises the following steps:
s1, using bromochlorobenzene and anhydrous piperazine as raw materials to generate 1, 4-bis (4-chlorophenyl) piperazine under certain conditions;
s2, carrying out unilateral methylation on the product generated in the step S1 to obtain 1- (4-methoxyphenyl) -4- (4-chlorophenyl) piperazine;
s3, ammonifying the product obtained in the step S2 to obtain 1- (4-methoxyphenyl) -4- (4-aminophenyl) piperazine;
and S4, demethylating the product in the step S3 to obtain the 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine.
The reaction flow chart is as follows:
preferably, the reaction for producing 1, 4-bis (4-chlorophenyl) piperazine in step S1 comprises the steps of: the mass ratio is 1: (3.66-5.66): (3.8-4.8) taking anhydrous piperazine, p-chlorobromobenzene and an acid binding agent, sequentially adding the anhydrous piperazine, the p-chlorobromobenzene and the acid binding agent into dimethyl sulfoxide, stirring and heating to 165-190 ℃, and carrying out heat preservation reaction; after 4 hours, starting TLC monitoring until the anhydrous piperazine is less than 1%, and finishing the reaction; cooling to 20-30deg.C, and adjusting pH to 6-7 with acid; extracting and separating liquid for at least 2 times; concentrating under reduced pressure at 50-60deg.C to dry, and purifying with silica gel column to obtain 1, 4-bis (4-chlorophenyl) piperazine.
Preferably, the reaction temperature of the step S1 is 175-185 ℃.
Preferably, the acid binding agent is potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, or anhydrous trisodium phosphate.
Preferably, the reaction for producing 1- (4-methoxyphenyl) -4- (4-chlorophenyl) piperazine in step S2 comprises the steps of: under the anhydrous condition and under the protection of nitrogen, adding 1, 4-bis (4-chlorophenyl) piperazine into hexamethylphosphoric triamide solution according to the mass fraction of 0.13-0.2%, stirring and dissolving, and cooling to 10-15 ℃; slowly dropwise adding sodium methoxide solution with mass fraction of 0.1-0.23%, controlling temperature at 8-26deg.C for 2-2.5 hr, maintaining at 15-20deg.C for 2 hr, and monitoring by TLC until the reaction is completed; extracting and separating liquid at 10-20deg.C for at least 2 times, and concentrating under reduced pressure at 50-60deg.C to obtain 1- (4-methoxyphenyl) -4- (4-chlorophenyl) piperazine.
Preferably, the solvent of the sodium methoxide solution is hexamethylphosphoric triamide, and the dropwise adding temperature is 10-20 ℃.
Preferably, the solvent of the extraction fraction is toluene.
Preferably, the reaction for producing 1- (4-methoxyphenyl) -4- (4-aminophenyl) piperazine in step S3 comprises the steps of: under the protection of nitrogen, the mass ratio is (2-3): 1: (1.6-2.5) 1- (4-methoxyphenyl) -4- (4-chlorophenyl) piperazine, anhydrous copper saltConcentrated ammonia water is added into PEG in sequence 1000 And (3) stirring the mixture of DIL and tetrahydrofuran, controlling the temperature to be 75-80 ℃ for reaction, starting TLC monitoring after 4 hours until the content of 1- (4-methoxyphenyl) -4- (4-chlorophenyl) piperazine is less than 1%, cooling to 40 ℃, concentrating under reduced pressure, quenching with water, slowly cooling to 20-25 ℃, preserving heat, filtering, and drying to obtain the 1- (4-methoxyphenyl) -4- (4-aminophenyl) piperazine.
Preferably, the anhydrous copper salt is anhydrous copper sulfate or copper chloride; the PEG 1000 -volume ratio of DIL and tetrahydrofuran mixed solution is 1: (0.8-1.2).
Preferably, the mass fraction of the strong ammonia water is 28%.
Preferably, the reaction for producing 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine in step S4 comprises the steps of: the mass ratio is 1: (7-8) taking 1- (4-methoxyphenyl) -4- (4-aminophenyl) piperazine and iodo-cyclohexane, and sequentially adding the 1- (4-methoxyphenyl) piperazine and the iodo-cyclohexane into DMF for dissolution; reflux reaction at 82-85 ℃, starting TLC monitoring after 3h until 1- (4-methoxyphenyl) -4- (4-aminophenyl) piperazine is less than 1%; concentrating under reduced pressure at 40-50deg.C to obtain excessive iodinated cyclohexane, cooling to 30deg.C, adding the concentrated solution into water for crystallization, filtering, and oven drying to obtain 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine.
Compared with the prior art, the invention has the beneficial effects that:
the raw materials of the bromochlorobenzene and the anhydrous piperazine used in the process are cheap, the method is easy to realize under the action of an acid binding agent (potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate or anhydrous trisodium phosphate), the yield is higher, and the cost of the final product can be obviously reduced.
Detailed Description
The present invention will be described in further detail in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the particular embodiments described herein are illustrative only and are not intended to limit the invention, i.e., the embodiments described are merely some, but not all, of the embodiments of the invention.
A preparation method of posaconazole intermediate 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine, which comprises the following steps:
preparation of 1, 4-bis (4-chlorophenyl) piperazine M1:
100ml of dimethyl sulfoxide is taken, 10g of anhydrous piperazine, 46.67g of p-chlorobromobenzene and 48g of potassium carbonate are added; stirring and heating to 175-185 ℃, and preserving heat for reaction; TLC monitoring (methanol: dichloromethane=1; 4, ninhydrin color development) was started after 4h, sampling every 1-1.5h until anhydrous piperazine was less than 1%; after the reaction is finished, cooling to 20-30 ℃, adding 100ml of water, stirring for 0.5h, and adjusting the PH to 6-7 by using 6N hydrochloric acid; adding 100ml of toluene, stirring for 0.5h, standing, separating liquid, adding 50ml of toluene into the water phase, stirring for 0.5h, standing, and separating liquid; mixing toluene phases, adding 100ml of saturated sodium chloride solution, stirring for 0.5h, standing, and separating; concentrating under reduced pressure at 50-60deg.C to dry to give 31.62g brown solid; 26.04g of brown yellow solid M1 is obtained by passing through a silica gel column, the yield is 73.0%, 1 H NMR(400MHz，DMSO)δ7.32(d，4H)，6.70(d，4H)，3.12(d，8H)。
preparation of 1- (4-methoxyphenyl) -4- (4-chlorophenyl) piperazine M2:
under the anhydrous condition, under the protection of nitrogen, 20g of M1 is added into 100g of hexamethylphosphoric triamide (HMPA), and the mixture is stirred and dissolved and cooled to 10-15 ℃; dissolving 4.04g of sodium methoxide into 20g of hexamethylphosphoric triamide, slowly dropwise adding into the HMPA solution of M1, and controlling the temperature to 10-20 ℃ for 2-2.5h; after the dripping is finished, the reaction is carried out for 2 hours at 15-20 ℃, TLC monitoring (ethyl acetate: petroleum ether=1:2) is carried out, and sampling is carried out once every 0.5-1 hour until the reaction of M1 is finished; after the reaction is completed, adding 100ml of water at the temperature of 10-20 ℃, stirring for 0.5h, adding 100g of toluene, stirring for 0.5h, standing, separating liquid, adding 50g of toluene into a water phase, stirring for 0.5h, standing, and separating liquid; mixing toluene phases, adding 100 saturated sodium chloride solution, stirring for 0.5h, standing, and separating; concentrating toluene to dryness under reduced pressure at 50-60deg.C to obtain 19.13g brown solid; passing through a column to obtain 15.89g of brown yellow solid M2 with the yield of 80.6%, 1 H NMR(400MHz，DMSO)δ6.85(d，2H)，6.76(d，2H)，6.68(d，2H)，6.56(d，2H)，3.82(s，3H)，3.08(d，8H)。
preparation of 1- (4-methoxyphenyl) -4- (4-aminophenyl) piperazine M3:
taking 15g of M2, adding 150ml of PEG 1000 DIL,150ml tetrahydrofuran, stirred, 6.19g anhydrous copper sulfate, 12.63g ammonia (28%), nitrogen sphere; controlling the temperature to be 75-80 ℃ for reaction, starting TLC monitoring (ethyl acetate: petroleum ether=1:1) after about 4 hours until the M2 content is less than 1%, cooling to 40 ℃, and concentrating under reduced pressure to about 200 g; dripping the concentrated solution into 300ml of water with the temperature of 40 ℃ while the concentrated solution is hot, stirring for 0.5h, slowly cooling to 20-25 ℃, preserving heat, stirring for 0.5h, filtering, leaching the filter cake with 30ml of water, drying at 50-60 ℃ to obtain 12.24g brown solid M3 with the yield of 87.2%, 1 H NMR(400MHz，DMSO)δ6.82(d，2H)，6.73(d，2H)，6.66(d，2H)，6.53(d，2H)，4.82(s，2H)，3.82(s，3H)，3.07(d，8H)。
preparation of 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine M4:
10g of M3 are taken, dissolved in 10g of DMF and 74.2g of iodocyclohexane are added; reflux reaction at 82-85 ℃, after 3h TLC monitoring (ethyl acetate: petroleum ether=1:1) was started, until M3 was less than 1%; concentrating under reduced pressure at 40-50deg.C to obtain excessive iodinated cyclohexane, and cooling to 30deg.C; adding the concentrated solution into 200ml of water, crystallizing, and stirring for 0.5h; filtering, leaching a filter cake with 30ml of water, and drying at 50 ℃ after pumping to obtain 9.03g of M4 crude product;
product refinement
Adding 9.03g of 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine crude product, 100ml of dichloromethane and 100ml of methanol into a 1L three-neck flask, stirring and heating to 35 ℃ to dissolve, concentrating under reduced pressure at 30-35 ℃ to slowly precipitate solids, concentrating to about 50g, stopping concentrating, heating to 50-60 ℃, preserving heat for 1-1.5 hours, slowly cooling to 20-25 ℃, stirring for 0.5 hours, leaching a filter cake with 10ml of methanol, leaching at 40-45 ℃ and drying under vacuum for 16-20 hours at-0.08 to-0.09 MPa to obtain 8.15g of 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine refined product, yield of 85.7%, HPLC detection, purity of 99.06, single impurity of < 0.1%, 1 H NMR(400MHz，DMSO)δ8.83(s，1H)，6.83(d，2H)，6.74(d，2H)，6.67(d，2H)，6.52(d，2H)，4.61(s，2H)，3.07(d，8H)。
the foregoing examples merely represent specific embodiments of the present application, which are described in more detail and are not to be construed as limiting the scope of the present application. It should be noted that, for those skilled in the art, several variations and modifications can be made without departing from the technical solution of the present application, which fall within the protection scope of the present application.
Claims (6)
1. The preparation method of the posaconazole intermediate 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine is characterized by comprising the following steps:
s1, using bromochlorobenzene and anhydrous piperazine as raw materials to generate 1, 4-bis (4-chlorophenyl) piperazine under certain conditions, wherein the reaction for generating 1, 4-bis (4-chlorophenyl) piperazine in the step S1 comprises the following steps: the mass ratio is 1: (3.66-5.66): (3.8-4.8) taking anhydrous piperazine, p-chlorobromobenzene and an acid binding agent, sequentially adding the anhydrous piperazine, the p-chlorobromobenzene and the acid binding agent into dimethyl sulfoxide, stirring and heating to 165-190 ℃, and carrying out heat preservation reaction; after 4 hours, starting TLC monitoring until the anhydrous piperazine is less than 1%, and finishing the reaction; cooling to 20-30deg.C, and adjusting pH to 6-7 with acid; extracting and separating liquid for at least 2 times; concentrating under reduced pressure at 50-60deg.C to dry, and purifying with silica gel column to obtain 1, 4-bis (4-chlorophenyl) piperazine;
s2, carrying out unilateral methylation on the product generated in the step S1 to obtain 1- (4-methoxyphenyl) -4- (4-chlorophenyl) piperazine, wherein the reaction for generating the 1- (4-methoxyphenyl) -4- (4-chlorophenyl) piperazine in the step S2 comprises the following steps: under the anhydrous condition and under the protection of nitrogen, adding 1, 4-bis (4-chlorophenyl) piperazine into hexamethylphosphoric triamide solution according to the mass fraction of 0.13-0.2%, stirring and dissolving, and cooling to 10-15 ℃; slowly dropwise adding sodium methoxide solution with mass fraction of 0.1-0.23%, controlling temperature at 8-26deg.C for 2-2.5 hr, maintaining at 15-20deg.C for 2 hr, and monitoring by TLC until the reaction is completed; extracting and separating liquid at 10-20deg.C for at least 2 times, concentrating under reduced pressure at 50-60deg.C to obtain 1- (4-methoxyphenyl) -4- (4-chlorophenyl) piperazine;
s3, ammonifying the product in the step S2 to obtain 1- (4-methoxyphenyl) -4- (4-aminophenyl) piperazine, wherein the reaction for generating the 1- (4-methoxyphenyl) -4- (4-aminophenyl) piperazine in the step S3 comprises the following steps: under the protection of nitrogen, the mass ratio is (2-3): 1: (1.6-2.5) 1- (4-methoxyphenyl) -4- (4-chlorophenyl) piperazine and anhydrous copper salt are takenAnd concentrated ammonia water, sequentially adding into PEG 1000 Stirring the mixture of DIL and tetrahydrofuran, controlling the temperature to be 75-80 ℃ for reaction, starting TLC monitoring after 4 hours until the content of 1- (4-methoxyphenyl) -4- (4-chlorophenyl) piperazine is less than 1%, cooling to 40 ℃, concentrating under reduced pressure, quenching with water, slowly cooling to 20-25 ℃, preserving heat, filtering, and drying to obtain 1- (4-methoxyphenyl) -4- (4-aminophenyl) piperazine;
and S4, demethylating the product in the step S3, and recrystallizing and purifying to obtain the 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine, wherein the reaction for generating the 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine in the step S4 comprises the following steps: the mass ratio is 1: (7-8) taking 1- (4-methoxyphenyl) -4- (4-aminophenyl) piperazine and iodo-cyclohexane, and sequentially adding the 1- (4-methoxyphenyl) piperazine and the iodo-cyclohexane into DMF for dissolution; reflux reaction at 82-85 ℃, starting TLC monitoring after 3h until 1- (4-methoxyphenyl) -4- (4-aminophenyl) piperazine is less than 1%; concentrating under reduced pressure at 40-50deg.C to obtain excessive iodinated cyclohexane, cooling to 30deg.C, adding the concentrated solution into water for crystallization, filtering, and oven drying to obtain 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine.
2. The method for preparing posaconazole intermediate 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine according to claim 1, wherein the reaction temperature in the step S1 is 175-185 ℃.
3. The method for preparing posaconazole intermediate 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine according to claim 1, wherein the acid binding agent is potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate or anhydrous trisodium phosphate.
4. The preparation method of posaconazole intermediate 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine according to claim 1, wherein the solvent of the sodium methoxide solution is hexamethylphosphoric triamide, and the dropping temperature is 10-20 ℃.
5. The method for preparing posaconazole intermediate 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine according to claim 1, wherein the solvent of the extraction liquid fraction is toluene.
6. The method for preparing posaconazole intermediate 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine according to claim 1, wherein the anhydrous copper salt is anhydrous copper sulfate or copper chloride; the PEG 1000 -volume ratio of DIL and tetrahydrofuran mixed solution is 1: (0.8-1.2); the mass fraction of the strong ammonia water is 28%.
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| US4490530A (en) * | 1981-01-14 | 1984-12-25 | Janssen Pharmaceutica N.V. | Heterocyclic derivatives of (4-phenylpiperazin-1-yl-aryloxymethyl-1,3-dioxolan-2-yl)-methyl-1H-imidazoles and 1H-1,2,4-triazoles |
| CA1331757C (en) * | 1988-02-29 | 1994-08-30 | Janssen Pharmaceutica Naamloze Vennootschap | 5-lipoxygenase inhibiting 4-(4-phenyl-1-piperazinyl)phenols |
| US6355801B1 (en) * | 1999-11-08 | 2002-03-12 | Schering Corporation | Process for preparing N-(4-hydroxyphenyl)-N′-(4′-aminophenyl)-piperazine |
| CN101824009A (en) * | 2010-05-27 | 2010-09-08 | 北京德众万全药物技术开发有限公司 | Simple preparation method for posaconazole and piperazine intermediate thereof |
| US11028078B2 (en) * | 2011-09-07 | 2021-06-08 | The Johns Hopkins University | Itraconazole analogs and use thereof |
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| CN108003118A (en) * | 2017-12-27 | 2018-05-08 | 张家口市格瑞高新技术有限公司 | A kind of posaconazole intermediate 1-（4- hydroxy phenyls）-4-（4- aminophenyls）The preparation process of-piperazine |
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