CN111362886A - 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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- 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
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- 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, belonging to the field of pharmaceutical chemistry, which comprises the steps of preparing 1, 4-bis (4-chlorophenyl) piperazine from chlorobromobenzene and anhydrous piperazine under certain conditions; performing unilateral methyl etherification on the product generated in the step S1 to obtain 1- (4-methoxyphenyl) -4- (4-chlorophenyl) piperazine; ammoniating the product in the step S2 to obtain 1- (4-methoxyphenyl) -4- (4-aminophenyl) piperazine; demethylating the product in the step S3, recrystallizing and purifying to obtain the 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine. The raw materials used in the process are cheap, the reaction conditions are relatively simple, the method is easy to realize, the yield is high, 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, and a second-generation triazole antifungal drug marketed by FDA in 2006 is widely used for patients with increased infectious risk due to severe immunodeficiency. Posaconazole (chemical name: 4- [4- [4- [4- [ [ (3R, 5R) -5- (2, 4-difluorophenyl) -5- (1, 2, 4-triazol-1-ylmethyl) oxolan-3-yl ] methoxy ] phenyl ] piperazin-1-yl ] phenyl ] -2- [ (2S, 3S) -2-hydroxypentan-3-yl ] -1, 2, 4-triazol-3-one) having the structural formula:
1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine is one of important intermediates for synthesizing posaconazole bulk drugs, and the molecular formula is C16H19N3O, molecular weight of 269.34, structural formula
According to the descriptions of the patents of U.S. Pat. No. 4, 6355801, 1, WO 01034587 and CN101824009A, the disclosed synthesis method of 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine has the following two steps:
the first step is as follows:
or
The second step is that:
however, the price of raw materials and the price of palladium carbon used in the reported process are high, a closed space is needed for catalytic hydrogenation, the requirement on equipment is strict, the reaction operation difficulty is high, safety risks exist, byproducts are easily generated by high-pressure hydrogenation, and the purification difficulty is increased.
Disclosure of Invention
The invention aims to: the invention provides a novel preparation method of posaconazole intermediate 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine, aiming at the problems that the price of raw materials and the price of palladium-carbon catalyst in the existing preparation method are high, a closed space is needed for catalytic hydrogenation, the requirement on equipment is strict, the difficulty in reaction operation is high, safety risk exists, byproducts are easily generated by high-pressure hydrogenation, and the purification difficulty is increased.
The technical scheme adopted by the invention is as follows:
a preparation method of posaconazole intermediate 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine comprises the following steps:
s1, taking bromochlorobenzene and anhydrous piperazine as raw materials to generate 1, 4-di (4-chlorphenyl) piperazine under certain conditions;
s2, carrying out unilateral methyl etherification on the product generated in the step S1 to obtain 1- (4-methoxyphenyl) -4- (4-chlorphenyl) piperazine;
s3, ammoniating the product in the step S2 to obtain 1- (4-methoxyphenyl) -4- (4-aminophenyl) piperazine;
s4, demethylating the product obtained in the step S3 to obtain the 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine.
The reaction scheme is as follows:
preferably, the reaction to produce 1, 4-bis (4-chlorophenyl) piperazine in step S1 comprises the steps of: according to the mass ratio of 1: (3.66-5.66): (3.8-4.8) adding anhydrous piperazine, p-chlorobromobenzene and an acid-binding agent into dimethyl sulfoxide in sequence, stirring and heating to 165-190 ℃, and carrying out heat preservation reaction; after 4h, starting TLC monitoring until the anhydrous piperazine is less than 1 percent and finishing the reaction; cooling to 20-30 deg.C, and adjusting pH to 6-7 with acid; extracting and separating for at least 2 times; concentrating under reduced pressure at 50-60 deg.C to dryness, and passing through 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 to produce 1- (4-methoxyphenyl) -4- (4-chlorophenyl) piperazine in step S2 comprises the steps of: under the anhydrous condition and 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 for dissolving, and cooling to 10-15 ℃; slowly dropwise adding 0.1-0.23% by mass of sodium methoxide solution, controlling the temperature to be 8-26 ℃, carrying out 2-2.5h, after dropwise adding, carrying out heat preservation reaction at 15-20 ℃ for 2h, and then carrying out TLC monitoring until the reaction is finished; extracting at 10-20 deg.C for at least 2 times, and concentrating at 50-60 deg.C under reduced pressure to dry to obtain 1- (4-methoxyphenyl) -4- (4-chlorophenyl) piperazine.
Preferably, the solvent of the sodium methoxide solution is hexamethylphosphoric triamide, and the dropping temperature is 10-20 ℃.
Preferably, the solvent for the extraction separation liquid is toluene.
Preferably, the reaction to produce 1- (4-methoxyphenyl) -4- (4-aminophenyl) piperazine in step S3 includes the steps of: under the protection of nitrogen, according to the mass ratio of (2-3): 1: (1.6-2.5) taking 1- (4-methoxyphenyl) -4- (4-chlorphenyl) piperazine, anhydrous cupric salt and concentrated ammonia water, and sequentially adding PEG1000And (2) stirring the mixed solution 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 ℃, carrying out reduced pressure concentration, then quenching with water, slowly cooling to 20-25 ℃, carrying out heat preservation filtration, 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 PEG1000Volume ratio of DIL and tetrahydrofuran mixed solution 1: (0.8-1.2).
Preferably, the mass fraction of the concentrated ammonia water is 28%.
Preferably, the reaction to produce 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine in step S4 includes the steps of: according to the mass ratio of 1: (7-8) sequentially adding 1- (4-methoxyphenyl) -4- (4-aminophenyl) piperazine and iodocyclohexane into DMF (dimethyl formamide) for dissolving; refluxing the reaction at 82-85 ℃ and starting TLC monitoring after 3h until the content of 1- (4-methoxyphenyl) -4- (4-aminophenyl) piperazine is less than 1%; concentrating under reduced pressure at 40-50 deg.C to obtain excessive iodocyclohexane, cooling to 30 deg.C, adding concentrated solution into water, crystallizing, 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:
in the process, the raw materials of the bromochlorobenzene and the anhydrous piperazine are very cheap, the process 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 high, and the cost of a 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 detailed description and specific examples, while indicating the preferred embodiment of the invention, are intended for purposes of illustration only and are not intended to limit the scope of the invention.
A preparation method of posaconazole intermediate 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine comprises the following steps:
preparation of S1:1, 4-bis (4-chlorophenyl) piperazine M1:
taking 100ml of dimethyl sulfoxide, and adding 10g of anhydrous piperazine, 46.67g of p-chlorobromobenzene and 48g of potassium carbonate; stirring and heating to 185 ℃ of 175 and keeping the temperature for reaction; TLC monitoring was started after 4h (methanol: dichloromethane ═ 1; 4, ninhydrin colour development) and samples were taken 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 value to 6-7 by using 6N hydrochloric acid; adding 100ml of toluene, stirring for 0.5h, standing, separating, adding 50ml of toluene into the water phase, stirring for 0.5h, standing, and separating; mixing the toluene phases, adding 100ml of saturated sodium chloride solution, stirring for 0.5h, standing, and separating; vacuum concentrating at 50-60 deg.C to dryness to obtain 31.62g brown solid; passing through a silica gel column to obtain 26.04g of brown yellow solid M1 with the yield of 73.0 percent,1H NMR(400MHz，DMSO)δ7.32(d，4H)，6.70(d，4H)，3.12(d，8H)。
preparation of S2:1- (4-methoxyphenyl) -4- (4-chlorophenyl) piperazine M2:
under the anhydrous condition and under the protection of nitrogen, adding 20g M1 into 100g of hexamethylphosphoric triamide (HMPA), stirring to dissolve, and cooling to 10-15 ℃; dissolving 4.04g of sodium methoxide into 20g of hexamethylphosphoric triamide, slowly dropwise adding the sodium methoxide into an HMPA solution of M1, controlling the temperature to be 10-20 ℃ and 2-2.5 h; after the dropwise addition, the reaction is carried out for 2h at the temperature of 15-20 ℃, TLC (ethyl acetate: petroleum ether: 1: 2) is used for monitoring, and samples are taken every 0.5-1h until M1 is reacted completely; after the reaction is finished, adding 100ml of water at 10-20 ℃, stirring for 0.5h, then adding 100g of toluene, stirring for 0.5h, standing, separating, adding 50g of toluene into the water phase, stirring for 0.5h, standing, and separating; mixing the toluene phases, adding 100 saturated sodium chloride solution, stirring for 0.5h, standing, and separating; concentrating toluene at 50-60 deg.C under reduced pressure to dryness to obtain 19.13g brown solid; passing through the column to obtain 15.89g of brown yellow solid M2 with the yield of 80.6 percent,1H 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 S3:1- (4-methoxyphenyl) -4- (4-aminophenyl) piperazine M3:
taking M215 g, adding 150ml PEG1000DIL, 150ml tetrahydrofuran, stirring, then adding 6.19g anhydrous copper sulfate, 12.63g ammonia (28%), nitrogen ball protection; controlling the temperature to be 75-80 ℃ for reaction, starting TLC monitoring (ethyl acetate: petroleum ether is 1:1) for about 4 hours until the content of M2 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 a filter cake with 30ml of water, drying at the temperature of 50-60 ℃ to obtain 12.24g of brown solid M3 with the yield of 87.2 percent,1H 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)。
s4 preparation of 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine M4:
dissolving 10g M3 in 10g DMF, and adding 74.2g iodocyclohexane; reflux reaction at 82-85 ℃ and start TLC monitoring after 3h (ethyl acetate: petroleum ether ═ 1:1) to M3 less than 1%; concentrating under reduced pressure at 40-50 deg.C to obtain excessive iodocyclohexane, and cooling to 30 deg.C; dropwise adding the concentrated solution into 200ml of water, crystallizing, and stirring for 0.5h after the addition; filtering, leaching a filter cake with 30ml of water, draining, and drying at 50 ℃ to obtain 9.03g of M4 crude product;
product refinement
Adding 9.03g of crude 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine, 100ml of dichloromethane and 100ml of methanol into a 1L three-neck flask, stirring and heating to 35 ℃ for dissolving, concentrating under reduced pressure at 30-35 ℃, slowly separating out 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 hour, performing suction filtration, leaching a filter cake with 10ml of methanol, drying under vacuum at 40-45 ℃ and-0.08 to-0.09 MPa for 16-20 hours to obtain 8.15g of refined 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine with the yield of 85.7 percent, the purity of 99.06 and the single impurity content of less than 0.1 percent,1HNMR(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 above-mentioned embodiments only express the specific embodiments of the present application, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present application. It should be noted that, for those skilled in the art, without departing from the technical idea of the present application, several changes and modifications can be made, which are all within the protection scope of the present application.
Claims (10)
1. A preparation method of posaconazole intermediate 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine is characterized by comprising the following steps:
s1, taking bromochlorobenzene and anhydrous piperazine as raw materials to generate 1, 4-di (4-chlorphenyl) piperazine under certain conditions;
s2, carrying out unilateral methyl etherification on the product generated in the step S1 to obtain 1- (4-methoxyphenyl) -4- (4-chlorphenyl) piperazine;
s3, ammoniating the product in the step S2 to obtain 1- (4-methoxyphenyl) -4- (4-aminophenyl) piperazine;
s4, demethylating the product in the step S3, recrystallizing and purifying to obtain the 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 for forming 1, 4-bis (4-chlorophenyl) piperazine in step S1 comprises the following steps: according to the mass ratio of 1: (3.66-5.66): (3.8-4.8) adding anhydrous piperazine, p-chlorobromobenzene and an acid-binding agent into dimethyl sulfoxide in sequence, stirring and heating to 165-190 ℃, and carrying out heat preservation reaction; after 4h, starting TLC monitoring until the anhydrous piperazine is less than 1 percent and finishing the reaction; cooling to 20-30 deg.C, and adjusting pH to 6-7 with acid; extracting and separating for at least 2 times; concentrating under reduced pressure at 50-60 deg.C to dryness, and passing through silica gel column to obtain 1, 4-bis (4-chlorophenyl) piperazine.
3. The method for preparing posaconazole intermediate 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine according to claim 2, wherein the reaction temperature in step S1 is 175-185 ℃.
4. The method for preparing posaconazole intermediate 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine according to claim 2, wherein the acid-binding agent is potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate or anhydrous trisodium phosphate.
5. The method for preparing posaconazole intermediate 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine according to claim 1, wherein the reaction for producing 1- (4-methoxyphenyl) -4- (4-chlorophenyl) piperazine in step S2 comprises the following steps: under the anhydrous condition and 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 for dissolving, and cooling to 10-15 ℃; slowly dropwise adding 0.1-0.23% by mass of sodium methoxide solution, controlling the temperature to be 8-26 ℃, carrying out 2-2.5h, after dropwise adding, carrying out heat preservation reaction at 15-20 ℃ for 2h, and then carrying out TLC monitoring until the reaction is finished; extracting at 10-20 deg.C for at least 2 times, and concentrating at 50-60 deg.C under reduced pressure to dry to obtain 1- (4-methoxyphenyl) -4- (4-chlorophenyl) piperazine.
6. The method for preparing posaconazole intermediate 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine according to claim 4, wherein the solvent of the sodium methoxide solution is hexamethylphosphoric triamide, and the dropping temperature is 10-20 ℃.
7. The method for preparing posaconazole intermediate 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine according to claim 2 or 5, wherein the solvent for extracting the separated liquid is toluene.
8. The method for preparing posaconazole intermediate 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine according to claim 1, wherein the reaction for producing 1- (4-methoxyphenyl) -4- (4-aminophenyl) piperazine in step S3 comprises the following steps: under the protection of nitrogen, according to the mass ratio of (2-3): 1: (1.6-2.5) taking 1- (4-methoxyphenyl) -4- (4-chlorphenyl) piperazine, anhydrous cupric salt and concentrated ammonia water, and sequentially adding PEG1000And (2) stirring the mixed solution 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 ℃, carrying out reduced pressure concentration, then quenching with water, slowly cooling to 20-25 ℃, carrying out heat preservation filtration, and drying to obtain the 1- (4-methoxyphenyl) -4- (4-aminophenyl) piperazine.
9. The method for preparing posaconazole intermediate 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine according to claim 8, wherein the anhydrous copper salt is anhydrous copper sulfate or copper chloride; the PEG1000Volume ratio of DIL and tetrahydrofuran mixed solution 1: (0.8-1.2); the mass fraction of the strong ammonia water is 28 percent.
10. The method for preparing posaconazole intermediate 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine according to claim 1, wherein the reaction for producing 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine in step S4 comprises the following steps: according to the mass ratio of 1: (7-8) sequentially adding 1- (4-methoxyphenyl) -4- (4-aminophenyl) piperazine and iodocyclohexane into DMF (dimethyl formamide) for dissolving; refluxing the reaction at 82-85 ℃ and starting TLC monitoring after 3h until the content of 1- (4-methoxyphenyl) -4- (4-aminophenyl) piperazine is less than 1%; concentrating under reduced pressure at 40-50 deg.C to obtain excessive iodocyclohexane, cooling to 30 deg.C, adding concentrated solution into water, crystallizing, filtering, and oven drying to obtain 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine.
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| CN113717128A (en) * | 2021-09-28 | 2021-11-30 | 北京京宇合成科技有限责任公司 | Process for preparing 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine |
| 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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| MICHAEL HEPPERLE等: "Sequential mono-N-arylation of piperazine nitrogens. Part 1: A simplified method and its application to the preparation of a key N,N"-biaryl piperazine antifungal intermediate", 《TETRAHEDRON LETTERS》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN113717128A (en) * | 2021-09-28 | 2021-11-30 | 北京京宇合成科技有限责任公司 | Process for preparing 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine |
| CN113717128B (en) * | 2021-09-28 | 2023-08-22 | 北京京宇复瑞科技集团有限责任公司 | Process for preparing 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine |
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