CN114409505B - Preparation method of posaconazole intermediate - Google Patents
Preparation method of posaconazole intermediate Download PDFInfo
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- CN114409505B CN114409505B CN202210091159.3A CN202210091159A CN114409505B CN 114409505 B CN114409505 B CN 114409505B CN 202210091159 A CN202210091159 A CN 202210091159A CN 114409505 B CN114409505 B CN 114409505B
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
- C07C45/46—Friedel-Crafts reactions
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/32—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions without formation of -OH groups
Abstract
The invention belongs to the technical field of medicines, and particularly relates to a preparation method of a posaconazole intermediate. In a solvent A, performing acylation reaction on m-difluorobenzene, 3-hydroxymethyl-4-butyrolactone and a catalyst to obtain a compound IV; in the solvent B, the compound IV, a carbonyl methylene reagent and an auxiliary agent react to obtain the posaconazole intermediate 2- [2- (2, 4-difluorophenyl) -2-propylene-1-yl ] -1, 3-propanediol. The invention takes m-difluorobenzene as the initial raw material, which is cheap and easy to obtain; the reaction condition is easy to control, the operation is safe and simple, the process is green and environment-friendly, the cost is low, and the industrialization is easy to realize.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a preparation method of a posaconazole intermediate.
Background
Posaconazole (trade name: noxafil) is a broad spectrum triazole antifungal drug with broad prospects, and shows good antifungal activity in vitro and in vivo, especially against some drug-resistant strains. The medicine can be used for treating various complicated rare fungal infectious diseases, has strong activity and quick response, and can be clinically used as remedy for treating intractable invasive fungal infection. The product has ideal safety and tolerance, and low toxicity to liver and kidney, and is suitable for patients with long-term treatment.
2- [2- (2, 4-difluorophenyl) -2-propylene-1-yl ] -1, 3-propanediol (I) is used as a key intermediate for synthesizing posaconazole, has important significance for the development of posaconazole bulk drugs, and the preparation process with low cost can greatly improve the market competitiveness of the posaconazole bulk drugs.
The structural formula of 2- [2- (2, 4-difluorophenyl) -2-propen-1-yl ] -1, 3-propanediol (I) is as follows:
patents EP2789610 and WO2011144653 disclose a process for the synthesis of this intermediate from m-difluorobenzene, the synthetic route being as follows:
the method uses the expensive trimethylchloromethyl silane substance and adopts the Grignard reaction, and has the advantages of strict reaction condition requirements, difficult operation, high production cost and difficult realization of industrial production; in addition, the chloroacetyl chloride used in the route has strong irritation and larger pollution.
Chinese patent CN105732311a discloses a method for synthesizing 2- [2- (2, 4-difluorophenyl) -2-propen-1-yl ] -1, 3-propanediol, using m-difluorobenzene and 1,2, 3-trichloropropane as raw materials, and carrying out alkylation, elimination reaction, nucleophilic reaction and reduction under the catalysis of aluminum trichloride to obtain the product, wherein the reaction route is as follows:
the route uses 1,2, 3-trichloropropane as an alkylating reagent, has poor selectivity, uses sodium tert-butoxide to eliminate hydrogen chloride, has harsh conditions and has higher cost.
At present, a preparation method of posaconazole intermediate with low raw material cost, high yield, simplicity and easiness is needed to be provided.
Disclosure of Invention
The invention aims to provide a preparation method of posaconazole intermediate, which has the advantages of low-cost and easily-obtained raw materials, simple and convenient technological process, no need of too severe reaction conditions, low cost and simple and efficient reaction process.
The preparation method of the posaconazole intermediate provided by the invention comprises the following steps:
(1) In a solvent A, performing acylation reaction on m-difluorobenzene, 3-hydroxymethyl-4-butyrolactone and a catalyst to obtain a compound IV;
(2) In the solvent B, the compound IV, a carbonyl methylene reagent and an auxiliary agent react to obtain the posaconazole intermediate 2- [2- (2, 4-difluorophenyl) -2-propylene-1-yl ] -1, 3-propanediol.
The solvent A in the step (1) is one or more of dichloromethane, dichloroethane, nitromethane, nitrobenzene, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tertiary butyl ether, hexane, heptane or toluene.
The mass ratio of the solvent A to the m-difluorobenzene in the step (1) is 0-15:1, preferably 3-15:1.
The catalyst in the step (1) is one of aluminum trichloride, ferric trichloride, zinc chloride, titanium tetrachloride, sulfuric acid, acetic acid, phosphoric acid or trifluoroacetic acid.
The molar ratio of the catalyst to the m-difluorobenzene in the step (1) is 0.9-2.0:1.
The molar ratio of 3-hydroxymethyl-4-butyrolactone to m-difluorobenzene in the step (1) is 1.0-2.0:1.
The acylation reaction temperature in the step (1) is 40-120 ℃, and the acylation reaction time is 8-14h.
The solvent B in the step (2) is one or more of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tertiary butyl ether, DMF or DMSO.
The mass ratio of the solvent B to the compound IV in the step (2) is 0-15:1, preferably 3-15:1.
The carbonyl methylation reagent in the step (2) is one of methyl triphenylphosphine salt, nysed reagent or Tebbe reagent.
When the carbonylmethylene reagent is a nysed reagent, since tetrahydrofuran is contained in the nysed reagent, it is not necessary to add the solvent B additionally.
The molar ratio of the carbonylmethylene reagent to the compound IV in step (2) is 1.0-3.0:1, preferably 1.1-2.0:1.
The auxiliary agent in the step (2) is alkali or titanium tetrachloride, wherein the alkali is one of sodium hydride, potassium hydride, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium amide, butyl lithium or sodium hydroxide.
The molar ratio of the auxiliary agent to the compound IV in the step (2) is 0.9-1.5:1.
The reaction temperature in the step (2) is-10 to 40 ℃ and the reaction time is 3 to 10 hours.
The posaconazole intermediate prepared by the invention is 2- [2- (2, 4-difluorophenyl) -2-propylene-1-yl ] -1, 3-propanediol, and the structural formula is as follows:
the preparation method of the posaconazole intermediate comprises the steps of preparing a compound IV through acylation reaction of m-difluorobenzene (II) and 3-hydroxymethyl-4-butyrolactone (III) in a solvent A under the action of a catalyst; in the solvent B, the compound IV, the carbonyl methylene reagent and the auxiliary agent react to prepare the compound I.
The reaction equation of the present invention is as follows:
wherein, compound II: m-difluorobenzene;
compound III: 3-hydroxymethyl-4-butyrolactone;
compound IV:2- [2- (2, 4-difluorophenyl) -2-oxo-1-yl ] -1, 3-propanediol;
compound I:2- [2- (2, 4-difluorophenyl) -2-propen-1-yl ] -1, 3-propanediol.
The beneficial effects of the invention are as follows:
1. the invention takes m-difluorobenzene as the initial raw material, which is cheap and easy to obtain; the reaction condition is easy to control, the operation is safe and simple, the process is green and environment-friendly, the cost is low, and the industrialization is easy to realize.
2. The method has the advantages of simple and efficient route and good reaction selectivity of each step, the total yield of the prepared 2- [2- (2, 4-difluorophenyl) -2-propylene-1-yl ] -1, 3-propanediol (I) is more than 74 percent, and the yield is remarkably improved compared with the yield reported in the prior literature.
3. The 2- [2- (2, 4-difluorophenyl) -2-propylene-1-yl ] -1, 3-propanediol prepared by the invention has high purity and can be used as a starting material of posaconazole.
Drawings
FIG. 1 is a diagram of compound I prepared in example 1 1 H-NMR spectrum.
FIG. 2 is a diagram of the compound I prepared in example 1 13 C-NMR spectrum.
FIG. 3 is an HPLC chart of compound I prepared in example 1.
FIG. 4 is an HPLC chart of compound I prepared in example 2.
FIG. 5 is an HPLC chart of compound I prepared in example 3.
Detailed Description
The invention is further described below with reference to examples.
The percentages in the examples are by mass unless otherwise specified.
Example 1
(1) 114g of m-difluorobenzene, 140g of 3-hydroxymethyl-4-butyrolactone and 133g of aluminum trichloride are introduced into a reaction flask equipped with a stirrer and a thermometer under nitrogen; stirring is started, the temperature is increased to 80 ℃, and the HPLC monitoring reaction is carried out until the raw material is less than 1%; stopping the reaction, cooling the reaction liquid to room temperature, pouring the reaction liquid into ice water, and extracting the reaction liquid with ethyl acetate for 3 times, wherein 1L of the reaction liquid is used each time; the organic phases were combined, washed once with saturated sodium bicarbonate and once with saturated brine; concentrating the organic phase under reduced pressure until the moisture is <0.1%; otherwise, ethyl acetate is added, and the concentration is continued until the water content is qualified, so that the compound IV (the yield of the folded purity is 90%) is obtained and is directly used for the next reaction.
(2) Under the protection of nitrogen, 1L tetrahydrofuran and 435.5g methyl triphenyl phosphine iodide are added into a reaction bottle provided with a stirrer and a thermometer, and the temperature is reduced to 0 ℃; 121.2g of potassium tert-butoxide is added, and the mixture is stirred at 0 ℃ for reaction for 1h; dissolving the compound IV obtained in the step (1) in 1L tetrahydrofuran, dropwise adding the solution into a system, slowly heating to room temperature, and stirring for reaction for 5 hours; HPLC monitor until no compound IV remains, stop the reaction; suction-filtering through diatomite, and washing the filter cake with 0.5L tetrahydrofuran; the filtrate was concentrated under reduced pressure to give 209g of crude compound I.
(3) Dissolving the crude product of the compound I in 350ml of toluene, stirring, dropwise adding 950ml of n-heptane, gradually clouding the system, precipitating solid, stirring for 1h after dripping, standing for 1h, carrying out suction filtration, and drying the filter cake in vacuum to obtain 194g of the compound I, wherein the total yield is 85% and the liquid phase purity is 99.36% calculated by m-difluorobenzene. Compound I 1 The H-NMR spectrum is shown in FIG. 1, compound I 13 The C-NMR spectrum is shown in FIG. 2, and the HPLC spectrum of the compound I is shown in FIG. 3.
Example 2
(1) To a reaction flask equipped with a stirrer and a thermometer was charged 0.5L of methylene chloride, 114g of m-difluorobenzene, 140g of 3-hydroxymethyl-4-butyrolactone and 136g of zinc chloride under nitrogen. Stirring is started, the temperature is raised to 40 ℃, and the HPLC monitoring reaction is carried out until the raw material is <1%; stopping the reaction, cooling the reaction liquid to room temperature, pouring the reaction liquid into ice water, standing for layering, and extracting the water phase with dichloromethane for 2 times, wherein 0.5L of the water phase is used each time; the organic phases were combined, washed once with saturated sodium bicarbonate and once with saturated brine; concentrating the organic phase under reduced pressure until the moisture is <0.1%; otherwise, adding dichloromethane, continuously concentrating until the water content is qualified, and obtaining the compound IV (the yield of the folded purity is 90%) which is directly used for the next reaction.
(2) To a reaction flask equipped with a stirrer and a thermometer under nitrogen protection, 900mL of Nysed reagent (containing 2M tetrahydrofuran solution) was added, and 171g of titanium tetrachloride was added at 0 to 5℃to obtain a reddish brown turbid liquid. Stirring at 25deg.C for 2 hr, cooling to 0deg.C, slowly adding compound IV, stirring at 0deg.C for 6 hr, slowly adding into vigorously stirred 2L saturated sodium bicarbonate solution, and stirring at 25deg.C for 1 hr. The mixture was filtered through celite and the filter cake was stirred with 1L of dichloromethane. The mixture was separated, and the organic phase was washed with saturated brine. The organic phase was dried over magnesium sulfate and the filtrate was concentrated under reduced pressure to give 189g of crude compound I.
(3) Dissolving the crude product of the compound I in 320ml of toluene, stirring, dropwise adding 860ml of n-heptane, gradually clouding the system, precipitating solid, stirring for 1h after dripping, standing for 1h, suction filtering, and vacuum drying a filter cake to obtain 176g of the compound I, wherein the total yield is 77.1% and the liquid phase purity is 99.29% calculated by m-difluorobenzene, and an HPLC (high performance liquid chromatography) spectrum of the compound I is shown in figure 4.
Example 3
(1) To a reaction flask equipped with a stirrer and a thermometer under nitrogen atmosphere were added 0.6L of toluene, 114g of m-difluorobenzene, 140g of 3-hydroxymethyl-4-butyrolactone and 98g of concentrated sulfuric acid. Stirring is started, the temperature is increased to 80 ℃, and the HPLC monitoring reaction is carried out until the raw material is less than 1%; stopping the reaction, cooling the reaction liquid to room temperature, pouring the reaction liquid into ice water, and regulating the pH value of the system to be neutral by liquid alkali. Standing for layering, extracting the water phase with toluene for 2 times, and 0.5L each time; the organic phases were combined and washed once with saturated brine; concentrating the organic phase under reduced pressure until the moisture is <0.1%; otherwise, toluene is added, and the concentration is continued until the water content is qualified, so that the compound IV (the yield of the folded purity is 85%) is obtained and is directly used for the next reaction.
(2) Under the protection of nitrogen, adding 0.8L tetrahydrofuran and 365.4g methyl triphenylphosphine bromide into a reaction flask with a stirrer and a thermometer, and cooling to 0 ℃; 114.4g of potassium tert-butoxide is added, and the mixture is stirred at 0 ℃ for reaction for 1h; dissolving the obtained compound IV in 1L tetrahydrofuran, dropwise adding the solution into a system, slowly heating to room temperature, and stirring for reaction for 5 hours; HPLC monitor until no compound IV remains, stop the reaction; suction-filtering through diatomite, and washing the filter cake with 0.5L tetrahydrofuran; the filtrate was concentrated under reduced pressure to give 181g of crude compound I.
(3) Dissolving the crude product of the compound I in 280ml of toluene, stirring, dropwise adding 750ml of n-heptane, gradually clouding the system, precipitating solid, stirring for 1h after dripping, standing for 1h, suction-filtering, and vacuum-drying a filter cake to obtain 169g of the compound I, wherein the total yield is 74% and the liquid phase purity is 99.01% calculated by m-difluorobenzene, and an HPLC (high performance liquid chromatography) spectrum of the compound I is shown in figure 5.
Comparative example 1
1.1, 2, 3-Trichloropropane (29.40 g,0.20 mol) was added dropwise to 1, 3-difluorobenzene (22.82 g,0.20 mol) at 0℃and the reaction mixture was stirred for a further 30min, after which 5 batches of aluminum trichloride (26.66 g,0.20 mol) were added together, and after this addition gas evolved. After the addition, the reaction was continued at 0℃for 1 hour and then at room temperature (20-35 ℃) for 6 hours. Mixing at 0deg.C after the reactionThe compound is carefully added into 200ml of hydrochloric acid solution with the concentration of 2mol/l, stirred evenly and extracted three times with dichloromethane, 200ml each time, the dichloromethane layers are combined and saturated NaHCO is used 3 The solution, water and saturated brine were washed once respectively. Anhydrous Na for organic layer 2 SO 4 After drying, filtration and rotary evaporation of dichloromethane gave 38.26g (0.17 mol) of 1, 3-dichloro-2- (2, 4-difluorophenyl) propane as an oily product in 85% yield.
2. 45.01g (0.20 mol) of 1, 3-dichloro-2- (2, 4-difluorophenyl) propane and 12.34g (0.22 mol) of potassium hydroxide were added to 150ml of t-butanol, and the mixture was refluxed for 5 hours. After the reaction, tert-butanol was distilled off under reduced pressure, 150ml of ice water was added to the resulting mixture, which was neutralized with 5mol/l hydrochloric acid at 0℃and extracted three times with 450ml of methylene chloride, and the organic layers were combined with anhydrous Na 2 SO 4 After drying, filtration and rotary evaporation of dichloromethane gave 33.95g (0.18 mol) of 1- (1-chloromethylvinyl) -2, 4-difluorobenzene as an oily product in 90% yield.
3. 37.72g (0.20 mol) of 1- (1-chloromethylvinyl) -2, 4-difluorobenzene were dissolved in 100ml of dimethyl sulfoxide, followed by addition of 12.00g (0.30 mol) of sodium hydroxide and 90.5ml (0.60 mol) of diethyl malonate, and the reaction mixture was stirred at room temperature for 8 hours. After the reaction was completed, 300ml of water was added thereto, and stirring was continued for 1 hour. The resulting solution was extracted twice with 200ml and 100ml cyclohexane respectively, the cyclohexane layers were combined, washed once with 150ml of 5% (weight to volume ratio, i.e. 5g sodium hydroxide per 100ml solution) sodium hydroxide solution, and once with 150ml water, anhydrous Na 2 SO 4 Drying, filtering, rotary evaporating to remove cyclohexane to obtain 2- [2- (2, 4-difluorophenyl) allyl as oily product]56.21g (0.18 mol) of diethyl 1, 3-malonate in 90% yield.
4. 12.48g (0.04 mol) of diethyl 2- [2- (2, 4-difluorophenyl) -2-propen-1-yl ] -1, 3-malonate were dissolved in a mixed solvent of 100ml of isopropyl alcohol and 10ml of water, 3.36g (0.08 mol) of lithium chloride and 3.04g (0.08 mol) of sodium borohydride were added after cooling to-5℃and the reaction mixture was stirred at room temperature for 20 hours. After the reaction was completed, the pH of the solution was adjusted to pH=1 with 4.0mol/l hydrochloric acid. Then adjusted to ph=10 with 20% (w/v) sodium hydroxide solution. After stirring for 1 hour, the organic layer was separated and the isopropanol was removed by rotary evaporation. 100ml of toluene and 100ml of water were added to the obtained oily substance, a toluene layer was separated, and toluene was removed by rotary evaporation to obtain 7.30g (0.032 mol) of 2- [2- (2, 4-difluorophenyl) -2-propen-1-yl ] -1, 3-propanediol as an oily product in 80% yield.
The total yield of comparative example 1 was only 55.08%, while the total yields of examples 1-3 were all above 74%, the total yields of examples 1-3 were significantly higher than that of comparative example 1.
Claims (10)
1. The preparation method of the posaconazole intermediate is characterized by comprising the following steps of:
(1) In a solvent A, performing acylation reaction on m-difluorobenzene, 3-hydroxymethyl-4-butyrolactone and a catalyst to obtain a compound IV;
(2) In a solvent B, the compound IV, a carbonyl methylene reagent and an auxiliary agent react to obtain a posaconazole intermediate 2- [2- (2, 4-difluorophenyl) -2-propylene-1-yl ] -1, 3-propanediol;
the structural formula of compound IV is as follows:
；
the carbonyl methylation reagent in the step (2) is methyl triphenylphosphine salt or Nysed reagent; when the carbonyl methylene reagent is methyl triphenylphosphine salt, the auxiliary agent is alkali; alternatively, when the carbonylmethylene reagent is an Nysed reagent, the auxiliary agent is titanium tetrachloride.
2. The preparation method of posaconazole intermediate according to claim 1, wherein the solvent A in the step (1) is one or more of dichloromethane, dichloroethane, nitromethane, nitrobenzene, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, hexane, heptane or toluene, and the mass ratio of the solvent A to m-difluorobenzene is 3-15:1.
3. The method for preparing posaconazole intermediate according to claim 1, wherein the catalyst in the step (1) is one of aluminum trichloride, ferric trichloride, zinc chloride, titanium tetrachloride, sulfuric acid, acetic acid, phosphoric acid or trifluoroacetic acid, and the molar ratio of the catalyst to m-difluorobenzene is 0.9-2.0:1.
4. The process for preparing posaconazole intermediate according to claim 1, wherein the molar ratio of 3-hydroxymethyl-4-butyrolactone to m-difluorobenzene in step (1) is 1.0-2.0:1.
5. The process for preparing posaconazole intermediate according to claim 1, wherein the acylation reaction temperature in step (1) is 40-120 ℃ and the acylation reaction time is 8-14h.
6. The preparation method of posaconazole intermediate according to claim 1, wherein the solvent B in the step (2) is one or more of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, DMF or DMSO, and the mass ratio of the solvent B to the compound IV is 3-15:1.
7. The process for the preparation of posaconazole intermediate according to claim 1, characterized in that the molar ratio of carbonyl methyleneating agent to compound IV in step (2) is 1.0-3.0:1.
8. The process for the preparation of posaconazole intermediate according to claim 1, characterized in that the molar ratio of auxiliary agent to compound IV in step (2) is 0.9-1.5:1.
9. The method for preparing posaconazole intermediate according to claim 1, wherein the base is one of sodium hydride, potassium hydride, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium amide, butyl lithium or sodium hydroxide.
10. The process for preparing posaconazole intermediate according to claim 1, wherein the reaction temperature in step (2) is-10 to 40 ℃ and the reaction time is 3 to 10 hours.
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| CN105777539A (en) * | 2016-03-30 | 2016-07-20 | 浙江大学宁波理工学院 | Synthesis method of 2-[2-(2,4-diflurophenyl)propenyl]-1,3-diethyl malonate |
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| WO2009141837A2 (en) * | 2008-05-21 | 2009-11-26 | Ind-Swift Laboratories Limited | Process for preparing posaconazole and intermediates thereof |
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