CN114409505A - Preparation method of posaconazole intermediate - Google Patents
Preparation method of posaconazole intermediate Download PDFInfo
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- CN114409505A CN114409505A CN202210091159.3A CN202210091159A CN114409505A CN 114409505 A CN114409505 A CN 114409505A CN 202210091159 A CN202210091159 A CN 202210091159A CN 114409505 A CN114409505 A CN 114409505A
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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, carrying out acylation reaction on m-difluorobenzene, 3-hydroxymethyl-4-butyrolactone and a catalyst to obtain a compound IV; in a solvent B, reacting a compound IV, a carbonyl methylenation reagent and an auxiliary agent to obtain a posaconazole intermediate 2- [2- (2, 4-difluorophenyl) -2-propylene-1-yl ] -1, 3-propylene glycol. The invention takes the m-difluorobenzene as the initial raw material, and 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 wide prospect, and shows good antifungal activity in vitro and in vivo, especially against some drug-resistant strains. The medicine can be used for treating various complex rare fungal infectious diseases, has strong activity and quick response, and can be clinically used as remedial treatment of refractory 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.
The 2- [2- (2, 4-difluorophenyl) -2-propen-1-yl ] -1, 3-propanediol (I) is used as a key intermediate for synthesizing the posaconazole, has important significance for developing 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 methods for the synthesis of this intermediate from m-difluorobenzene, the synthetic routes are shown below:
according to the route, expensive trimethyl chloromethyl silane substances are used, the Grignard reaction is adopted, the reaction condition requirement is strict, the operation is difficult, the production cost is high, and the industrial production is not easy to realize; in addition, chloroacetyl chloride used in the route has strong irritation and large pollution.
Chinese patent CN105732311A discloses a method for synthesizing 2- [2- (2, 4-difluorophenyl) -2-propen-1-yl ] -1, 3-propanediol, which takes m-difluorobenzene and 1,2, 3-trichloropropane as raw materials, and obtains the product through alkylation, elimination reaction, nucleophilic reaction and reduction under the catalysis of aluminum trichloride, 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, and has harsh conditions and high cost.
At present, a preparation method of posaconazole intermediate, which has low raw material cost, high yield and is simple and easy to implement, is urgently needed.
Disclosure of Invention
The invention aims to provide a preparation method of a posaconazole intermediate, which has the advantages of cheap and easily obtained raw materials, simple and convenient process, no need of over-harsh reaction conditions, low cost, simple and efficient reaction process.
The preparation method of the posaconazole intermediate comprises the following steps:
(1) in a solvent A, carrying out acylation reaction on m-difluorobenzene, 3-hydroxymethyl-4-butyrolactone and a catalyst to obtain a compound IV;
(2) in a solvent B, reacting a compound IV, a carbonyl methylenation reagent and an auxiliary agent to obtain a posaconazole intermediate 2- [2- (2, 4-difluorophenyl) -2-propylene-1-yl ] -1, 3-propylene glycol.
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.
The mass ratio of the solvent A to the m-difluorobenzene in the step (1) is 0-15:1, and 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 the 3-hydroxymethyl-4-butyrolactone to the 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 8-14 h.
The solvent B in the step (2) is one or more of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-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 methylenation reagent in the step (2) is one of methyl triphenyl phosphine salt, Nysted reagent or Tebbe reagent.
When the carbonylation reagent is Nysted reagent, no additional solvent B is required as the Nysted reagent contains tetrahydrofuran.
The molar ratio of the carbonyl methylenation agent to the compound IV in the step (2) is 1.0-3.0:1, preferably 1.1-2.0: 1.
The assistant 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-10-40 ℃, and the reaction time is 3-10 h.
The posaconazole intermediate prepared by the invention is 2- [2- (2, 4-difluorophenyl) -2-propen-1-yl ] -1, 3-propanediol, and the structural formula is as follows:
the preparation method of the posaconazole intermediate is characterized in that m-difluorobenzene (II) and 3-hydroxymethyl-4-butyrolactone (III) are subjected to acylation reaction in a solvent A under the action of a catalyst to prepare a compound IV; in solvent B, compound IV, a carbonyl methylenation reagent and an auxiliary agent react to prepare 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;
a compound I: 2- [2- (2, 4-difluorophenyl) -2-propen-1-yl ] -1, 3-propanediol.
The invention has the following beneficial effects:
1. the invention takes the m-difluorobenzene as the initial raw material, and 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 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 over 74 percent, and the yield is obviously 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 method has high purity and can be used as a starting material of posaconazole.
Drawings
FIG. 1 is a drawing of Compound I from example 11H-NMR spectrum.
FIG. 2 is a drawing of Compound I from example 113C-NMR spectrum.
FIG. 3 is an HPLC chromatogram of Compound I prepared in example 1.
FIG. 4 is an HPLC chromatogram of Compound I prepared in example 2.
FIG. 5 is an HPLC chromatogram of Compound I prepared in example 3.
Detailed Description
The present invention is further described below with reference to examples.
In the examples,% s are by mass unless otherwise specified.
Example 1
(1) Under the protection of nitrogen, 114g of m-difluorobenzene, 140g of 3-hydroxymethyl-4-butyrolactone and 133g of aluminum trichloride are added into a reaction flask provided with a stirrer and a thermometer; starting stirring, heating to 80 ℃, and monitoring the reaction by HPLC until the raw material is less than 1%; stopping reaction, cooling the reaction solution to room temperature, pouring into ice water, and extracting with ethyl acetate for 3 times, 1L each time; the organic phases are combined, washed once with saturated sodium bicarbonate and once with saturated brine; concentrating the organic phase under reduced pressure until the water content is less than 0.1%; and on the contrary, ethyl acetate is supplemented, and the concentration is continued until the water content is qualified, so that a compound IV (the purity yield is 90%) is obtained and is directly used for the next reaction.
(2) Adding 1L of tetrahydrofuran and 435.5g of methyl triphenyl phosphine iodide into a reaction bottle provided with a stirrer and a thermometer under the protection of nitrogen, and cooling to 0 ℃; adding 121.2g of potassium tert-butoxide, and stirring and reacting for 1h at 0 ℃; 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; monitoring by HPLC until no compound IV remains, and stopping the reaction; suction filtration through celite and washing of 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 getting turbid and separating out solid, stirring for 1h after dropwise adding, standing for 1h, performing suction filtration, and performing vacuum drying on a filter cake to obtain 194g of the compound I, wherein the total yield is 85% and the liquid phase purity is 99.36% calculated on m-difluorobenzene. Of the Compound I1The H-NMR spectrum is shown in figure 1, of compound I13The C-NMR spectrum is shown in FIG. 2, and the HPLC spectrum of Compound I is shown in FIG. 3.
Example 2
(1) To a reaction flask equipped with a stirrer and a thermometer, under a nitrogen blanket, were added 0.5L of dichloromethane, 114g of m-difluorobenzene, 140g of 3-hydroxymethyl-4-butyrolactone and 136g of zinc chloride. Starting stirring, heating to 40 ℃, and monitoring the reaction by HPLC until the raw material is less than 1%; stopping the reaction, cooling the reaction solution to room temperature, pouring the reaction solution into ice water, standing and layering, and extracting the water phase with dichloromethane for 2 times, wherein each time is 0.5L; the organic phases are combined, washed once with saturated sodium bicarbonate and once with saturated brine; concentrating the organic phase under reduced pressure until the water content is less than 0.1%; and on the contrary, adding dichloromethane, and continuously concentrating until the water content is qualified to obtain a compound IV (the purity yield is 90 percent), and directly using the compound IV in the next reaction.
(2) Under the protection of nitrogen, 900mL of Nysted reagent (containing 2M tetrahydrofuran solution) is added into a reaction bottle provided with a stirrer and a thermometer, and 171g of titanium tetrachloride is added at 0-5 ℃ to obtain a brownish red turbid liquid. Stirring at 25 deg.C for 2h, cooling to 0 deg.C, slowly adding compound IV, stirring at 0 deg.C for 6h, slowly adding into 2L of saturated sodium bicarbonate solution, and stirring at 25 deg.C for 1 h. After filtration through celite, the filter cake is stirred with 1L of dichloromethane. The organic phase was washed with 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 getting turbid, separating out solid, stirring for 1h after dropwise adding, standing for 1h, performing suction filtration, and performing vacuum drying on 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 on m-difluorobenzene, and an HPLC spectrogram of the compound I is shown in figure 4.
Example 3
(1) To a reaction flask equipped with a stirrer and a thermometer, under a nitrogen atmosphere, were added 0.6L of toluene, 114g of m-difluorobenzene, 140g of 3-hydroxymethyl-4-butyrolactone and 98g of concentrated sulfuric acid. Starting stirring, heating to 80 ℃, and monitoring the reaction by HPLC until the raw material is less than 1%; and stopping the reaction, cooling the reaction liquid to room temperature, pouring the reaction liquid into ice water, and adjusting the pH value of the system to be neutral by using liquid alkali. Standing for layering, and extracting the water phase with toluene for 2 times, each time for 0.5L; the organic phases were combined and washed once with saturated brine; concentrating the organic phase under reduced pressure until the water content is less than 0.1%; and on the contrary, supplementing toluene, and continuously concentrating until the water content is qualified to obtain a compound IV (the purity yield is 85 percent), which is directly used for the next reaction.
(2) Under the protection of nitrogen, adding 0.8L of tetrahydrofuran and 365.4g of methyl triphenyl phosphonium bromide into a reaction bottle provided with a stirrer and a thermometer, and cooling to 0 ℃; adding 114.4g of potassium tert-butoxide, stirring and reacting for 1h at 0 ℃; dissolving the obtained compound IV in 1L tetrahydrofuran, dropwise adding into the system, slowly heating to room temperature, and stirring for reaction for 5 h; monitoring by HPLC until no compound IV remains, and stopping the reaction; suction filtration through celite and washing of 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 leading the system to be turbid, separating out solid, stirring for 1h after dropwise adding, standing for 1h, carrying out suction filtration, and carrying out vacuum drying on a filter cake to obtain 169g of the compound I, wherein the total yield is 74 percent, the liquid phase purity is 99.01 percent, and an HPLC spectrogram of the compound I is shown in figure 5.
Comparative example 1
1.1, 2, 3-trichloropropane (29.40g, 0.20mol) was added dropwise to 1, 3-difluorobenzene (22.82g,0.20mol) at 0 ℃ and the reaction mixture was stirred for 30min and then aluminum trichloride (26.66g, 0.20mol) was added in 5 portions in total, with evolution of gas upon addition. After the addition, the reaction is carried out for 1 hour at 0 ℃, and then the reaction is continued for 6 hours at room temperature (20-35 ℃). After the reaction is complete, the mixture is carefully added to 200ml of 2mol/l hydrochloric acid solution at 0 ℃, after stirring uniformly, the mixture is extracted three times with 200ml of dichloromethane each time, the dichloromethane layers are combined and saturated NaHCO is used3The solution, water and saturated saline solution were washed once. Anhydrous Na for organic layer2SO4After drying, filtration and rotary evaporation to remove dichloromethane, 38.26g (0.17mol) of 1, 3-dichloro-2- (2, 4-difluorophenyl) propane was obtained as an oily product in 85% yield.
2. 1, 3-dichloro-2- (2, 4-difluorophenyl) propane 45.01g (0.20mol) potassium hydroxide 12.34g (0.22mol) was added to 150ml t-butanol, and the mixture was refluxed for 5 hours. Distilling under reduced pressure to remove tert-butanol after reaction, adding 150ml ice water into the obtained mixture, neutralizing with 5mol/l hydrochloric acid at 0 deg.C to neutrality, extracting with 450ml dichloromethane for three times, combining organic layers, and adding anhydrous Na2SO4After drying, filtration and rotary evaporation to remove dichloromethane, 33.95g (0.18mol) of 1- (1-chloromethylvinyl) -2, 4-difluorobenzene were obtained as an oily product with a yield of 90%.
3. 37.72g (0.20mol) of 1- (1-chloromethylvinyl) -2, 4-difluorobenzene were dissolved in 100ml of dimethyl sulfoxide, and then 12.00g (0.30mol) of sodium hydroxide and 90.5ml (0.60mol) of diethyl malonate were added to stir the reaction mixture at room temperature for 8 hours. After the reaction, 300ml of water was added and stirring was continued for 1 hour. The resulting solution was extracted twice with 200ml and 100ml cyclohexane respectively, the cyclohexane layers were combined and 150ml of 5% (w/v, i.e. 10% each)0ml solution containing 5g sodium hydroxide) sodium hydroxide solution, and then 150ml water, anhydrous Na2SO4Drying, filtering, rotary evaporating to remove cyclohexane to obtain oily product 2- [2- (2, 4-difluorophenyl) allyl]56.21g (0.18mol) of diethyl 1, 3-malonate, yield 90%.
4. 12.48g (0.04mol) of diethyl 2- [2- (2, 4-difluorophenyl) -2-propen-1-yl ] -1, 3-malonate was dissolved in a mixed solvent of 100ml of isopropanol and 10ml of water, and after cooling to-5 ℃, 3.36g (0.08mol) of lithium chloride and 3.04g (0.08mol) of sodium borohydride were added, and the reaction mixture was stirred at room temperature for 20 hours. After the reaction was completed, 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 to separate a toluene layer, and toluene was removed by rotary evaporation to obtain 7.30g (0.032mol) 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 is only 55.08%, while the total yields of examples 1-3 are all above 74%, with the total yields of examples 1-3 being significantly higher than that of comparative example 1.
Claims (10)
1. A preparation method of a posaconazole intermediate is characterized by comprising the following steps:
(1) in a solvent A, carrying out acylation reaction on m-difluorobenzene, 3-hydroxymethyl-4-butyrolactone and a catalyst to obtain a compound IV;
(2) in a solvent B, reacting a compound IV, a carbonyl methylenation reagent and an auxiliary agent to obtain a posaconazole intermediate 2- [2- (2, 4-difluorophenyl) -2-propylene-1-yl ] -1, 3-propylene glycol.
2. The method for preparing posaconazole intermediate according to claim 1, wherein the solvent A in 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 the m-difluorobenzene is 0-15: 1.
3. The method for preparing posaconazole intermediate according to claim 1, wherein the catalyst in 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 the preparation of posaconazole intermediate as claimed in claim 1, wherein the molar ratio of 3-hydroxymethyl-4-butyrolactone to m-difluorobenzene in step (1) is from 1.0 to 2.0: 1.
5. The process for preparing posaconazole intermediate according to claim 1, wherein the acylation reaction temperature in the step (1) is 40-120 ℃ and the acylation reaction time is 8-14 h.
6. The method for preparing 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 0-15: 1.
7. The method for preparing posaconazole intermediate according to claim 1, wherein the carbonylmethylenation reagent in step (2) is one of methyltriphenylphosphine salt, Nysted reagent or Tebbe reagent, and the molar ratio of the carbonylmethylenation reagent to the compound IV is 1.0-3.0: 1.
8. The method for preparing posaconazole intermediate according to claim 1, wherein the auxiliary in step (2) is alkali or titanium tetrachloride, and the molar ratio of the auxiliary to the compound IV is 0.9-1.5: 1.
9. The process for preparing posaconazole intermediate according to claim 8, 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, butyllithium 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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| WO2009141837A2 (en) * | 2008-05-21 | 2009-11-26 | Ind-Swift Laboratories Limited | Process for preparing posaconazole and intermediates thereof |
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| CN105622413A (en) * | 2016-01-14 | 2016-06-01 | 宁波新凯生物科技有限公司 | Synthesis method of diethyl 2-[2-(2,4-difluorophenyl)allyl]-1,3-malonate |
| 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 |
| CN102643194A (en) * | 2012-03-27 | 2012-08-22 | 福州大学 | Preparation method of posaconazole intermediate |
| CN103086885A (en) * | 2013-02-28 | 2013-05-08 | 天津大学仁爱学院 | Preparation method of posaconazole intermediate |
| CN104650013A (en) * | 2015-03-17 | 2015-05-27 | 新发药业有限公司 | Simple and convenient preparation method of highly selective (S)-beta-hydroxy-gamma-butyrolactone |
| CN105622413A (en) * | 2016-01-14 | 2016-06-01 | 宁波新凯生物科技有限公司 | Synthesis method of diethyl 2-[2-(2,4-difluorophenyl)allyl]-1,3-malonate |
| 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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