CN101613325B - Process for producing 5-hydroxymethylthiazole - Google Patents
Process for producing 5-hydroxymethylthiazole Download PDFInfo
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- CN101613325B CN101613325B CN2008100316085A CN200810031608A CN101613325B CN 101613325 B CN101613325 B CN 101613325B CN 2008100316085 A CN2008100316085 A CN 2008100316085A CN 200810031608 A CN200810031608 A CN 200810031608A CN 101613325 B CN101613325 B CN 101613325B
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Abstract
The invention relates to a process for producing an intermediate of an anti-AIDS medicament Ritonavir, namely 5-hydroxymethylthiazole. 2-chloro-5-chloromethylthiazole taken as a raw material and ethanol taken as solvent are hydrolyzed to synthesize 2-chloro-5-hydroxymethylthiazole under the action of alkali; and the 2-chloro-5-hydroxymethylthiazole and ether taken as solvent are subjected to magnesium powder/ethanol reductive dechlorination to synthesize the 5-hydroxymethylthiazole. The 5-hydroxymethylthiazole produced by the production process has the characteristics of low cost, mild operation conditions, no need of non-aqueous treatment on the ether and the ethanol, recycling and mechanical application of the ether and the ethanol, easy control of hydrolysis reaction and reduction reaction, and easy industrial production.
Description
Technical field
The present invention relates to a kind of production technique of 5-hydroxymethylthiazole.
Background technology
Acquired immune deficiency syndrome (AIDS) (claims acquired immune deficiency syndrome (AIDS) again, AIDS) become the major disease that threatens human health, and number of the infected is the trend that rises year by year.AIDS patient's sum reaches more than 4,200 ten thousand people at present, if effectively prevention and control estimate that HIV the infected will reach 200,000,000 people after 20 years, therefore, the research and development of anti-AIDS drug are the focuses in drug research field, the world.Ritonavir (Ritonavir) is described as the hiv protease inhibitor of 21 century, the life cycle that it can viral interference, and the virus that HIV-1 is belonged to has very strong resistant function, is the choice drug of s-generation treatment AIDS.The 5-hydroxymethylthiazole is the important intermediate of synthetic ritonavir, therefore, seek the industrialized producing technology of a low cost, operational condition gentleness, help reducing the price of 5-hydroxymethylthiazole and treatment AIDS medicine, very significant meaning is arranged benefiting patient AIDS.The molecular formula of ritonavir is as follows:
According to raw materials used difference, the 5-hydroxymethylthiazole synthesis technique of having reported can be divided into:
1. with 1,1,3, the 3-tetramethoxy propane is raw material process bromo Synthetic 2-bromo-1, and the 3-mda closes cyclization with thioformamide again and becomes 2-amino-5-thiazole carboxaldehyde, through reduction Synthetic 2-amino-5-hydroxymethylthiazole, obtain the 5-hydroxymethylthiazole through the diazotization deaminizating at last again.Reaction formula is as follows:
2. be that the reaction of raw material and hydrogen peroxide solution generates the epoxy propionic aldehyde with the propenal, direct and thiocarbamide reaction generates 2-amino-5-hydroxymethylthiazole, through the synthetic 5-hydroxymethylthiazole of diazotization desamination reaction.Reaction formula is as follows:
3. with chloracetic acid ethyl ester and ethyl formate Synthetic 2-chloro malonaldehydic acid ethyl ester, close cyclization with thioformamide again and become the 5-thiazole ethyl formate, obtain the 5-hydroxymethylthiazole with tetrahydrochysene lithium aluminium reducing at last; Close cyclization with 2-chloro malonaldehydic acid ethyl ester and thiocarbamide and become 2-amino-5-thiazole ethyl formate, obtain the 5-thiazole ethyl formate, obtain the 5-hydroxymethylthiazole with tetrahydrochysene lithium aluminium reducing at last through Isoamyinitrite reaction deaminizating.Reaction formula is as follows:
4. with, 4-thiazole diketone be raw material through the bromo Synthetic 2,4-two bromo-5-thiazole carboxaldehydes restore Synthetic 2,4-two bromo-5-hydroxymethylthiazoles, debrominate obtains the 5-hydroxymethylthiazole through catalytic hydrogenation at last.Reaction formula is as follows:
5. 2-chloro-5-5-chloromethyl thiazole with the carboxylate salt reaction, obtains corresponding ester under the phase-transfer catalyst effect, carries out the ester hydrolysis again, and the catalytic hydrogenation dechlorination obtains the 5-hydroxymethylthiazole.2-chloro-5-5-chloromethyl thiazole and water at high temperature direct reaction Synthetic 2-chloro-5-hydroxymethylthiazole obtain the 5-hydroxymethylthiazole through the catalytic hydrogenation dechlorination again.Reaction formula is as follows:
Summary of the invention
The technical problem that the present invention need solve is: at the deficiencies in the prior art part, develop a kind of 5-hydroxymethylthiazole synthetic process of easy realization suitability for industrialized production.
The technical solution used in the present invention: with 2-chloro-5-5-chloromethyl thiazole is raw material, with ethanol is solvent, hydrolysis Synthetic 2 under the effect of alkali-chloro-5-hydroxymethylthiazole, 2-chloro-5-hydroxymethylthiazole again with ether as solvent, by the synthetic 5-hydroxymethylthiazole of magnesium powder/pure reduction dechlorination; Its reaction formula is as follows:
Concrete steps are as follows:
The first step: in ethanol, dissolving alkali is heated to 70 ℃-90 ℃, and dropping 2-chloro-5-5-chloromethyl thiazole is dissolved in the solution in the ethanolic soln, and reaction 1h-3h obtains 2-chloro-5-hydroxymethylthiazole after the processing;
Second step: in ether, add 2-chloro-5-hydroxymethylthiazole and magnesium powder, be heated to backflow, drip alcohol, reaction 1h-2h obtains the 5-hydroxymethylthiazole after the processing.
Above-mentioned concentration of ethanol scope is 50%-95%, and the molar ratio range of 2-chloro-5-5-chloromethyl thiazole and alkali is between 1: 2 to 1: 8; The molar ratio range of 2-chloro-5-hydroxymethylthiazole and magnesium is between 1: 1 to 1: 4.
Above-mentioned alkali is sodium hydroxide, potassium hydroxide, sodium bicarbonate or yellow soda ash; Ether is tetrahydrofuran (THF), glycol dimethyl ether, dioxane, isopropyl ether or t-butyl methyl ether; Alcohol is methyl alcohol, ethanol, propyl alcohol or Virahol.
Beneficial effect of the present invention: the 5-hydroxymethylthiazole of producing by this production technique has that cost is low, operational condition is gentle, ether and alcohol do not need to do not have water treatment and can recovery set all control, be easy to carry out the characteristics of suitability for industrialized production easily with, hydrolysis reaction and reduction reaction.
Embodiment
Further specify the production technique of 2-chloro-5-hydroxymethylthiazole and 5-hydroxymethylthiazole below in conjunction with embodiment.
Embodiment 1
Synthesizing of 2-chloro-5-hydroxymethylthiazole
In four-hole boiling flask, add 14g potassium hydroxide and 50mL 70% ethanol, be heated to 80 ℃ under stirring.After potassium hydroxide all dissolves, drip the solution (adding in the 20min) of 20mL 95% dissolve with ethanol 8.4g 2-chloro-5-5-chloromethyl thiazole.Behind the reaction 1.5h, cooling is filtered, and reclaims ethanol.Add 50mL water, ethyl acetate extraction (50mL * 3) merges organic layer, the 50mL washing, and the 3g anhydrous magnesium sulfate drying reclaims ethyl acetate.65 ℃ of-70 ℃ of cuts are collected in the 2000Pa underpressure distillation, obtain the about 6.83g of faint yellow oily thing, and yield is 91.37%.
Embodiment 2
Synthesizing of 2-chloro-5-hydroxymethylthiazole
In four-hole boiling flask, add 6g sodium hydroxide and 50mL 80% ethanol, be heated to 75 ℃ under stirring.After sodium hydroxide all dissolves, drip the solution (adding in the 20min) of 20mL 95% dissolve with ethanol 8.4g (0.05mol) 2-chloro-5-5-chloromethyl thiazole.Behind the reaction 2.5h, cooling is filtered, and reclaims ethanol.Add 40mL water, ethyl acetate extraction (50mL * 3) merges organic layer, the 50mL washing, and the 3g anhydrous magnesium sulfate drying reclaims ethyl acetate.65 ℃ of-70 ℃ of cuts are collected in the 2000Pa underpressure distillation, obtain the about 6.67g of faint yellow oily thing, and yield is 89.23%.
Embodiment 3
Synthesizing of 2-chloro-5-hydroxymethylthiazole
In four-hole boiling flask, add 30g yellow soda ash and 60mL 60% ethanol, be heated to 85 ℃ under stirring.After yellow soda ash all dissolves, drip the solution (adding in the 20min) of 20mL 95% dissolve with ethanol 8.4g 2-chloro-5-5-chloromethyl thiazole.Behind the reaction 1h, cooling is filtered, and reclaims ethanol.Add 40mL water, ethyl acetate extraction (50mL * 3) merges organic layer, the 50mL washing, and the 3g anhydrous magnesium sulfate drying reclaims ethyl acetate.65 ℃ of-70 ℃ of cuts are collected in the 2000Pa underpressure distillation, obtain the about 6.92g of faint yellow oily thing, and yield is 92.58%.
Embodiment 4
Synthesizing of 5-hydroxymethylthiazole
In four-hole boiling flask, add 7.48g 2-chloro-5-hydroxymethylthiazole, 70mL glycol dimethyl ether and the fresh magnesium powder of 4.8g, stir 80 ℃ of heating down, drip 20mL 95% ethanol, keep the system reflux state.Add afterreaction 1h, cooling is filtered, 30mL glycol dimethyl ether washing filter residue, filtrate is reclaimed glycol dimethyl ether, adds 60mL water, ethyl acetate extraction (50mL * 3) merges organic layer, the 50mL washing, the 3g anhydrous magnesium sulfate drying merges organic layer, reclaims ethyl acetate, the 3000Pa underpressure distillation, collect 80 ℃ of-82 ℃ of cuts, obtain the about 5.12g of faint yellow oily thing, yield is 89.04%.
Embodiment 5
Synthesizing of 5-hydroxymethylthiazole
In four-hole boiling flask, add 7.48g 2-chloro-5-hydroxymethylthiazole, 100mL t-butyl methyl ether and the fresh magnesium powder of 3.6g, be heated to backflow under stirring, drip 30mL 95% ethanol, keep the system reflux state.Add afterreaction 1h, cooling is filtered, 30mL t-butyl methyl ether washing filter residue, filtrate is reclaimed t-butyl methyl ether, adds 60mL water, ethyl acetate extraction (50mL * 3) merges organic layer, the 50mL washing, the 3g anhydrous magnesium sulfate drying merges organic layer, reclaims ethyl acetate, the 3000Pa underpressure distillation, collect 80 ℃ of-82 ℃ of cuts, obtain the about 5.02g of faint yellow oily thing, yield is 87.30%.
Embodiment 6
Synthesizing of 5-hydroxymethylthiazole
In four-hole boiling flask, add 7.48g 2-chloro-5-hydroxymethylthiazole, 70mL glycol dimethyl ether and the fresh magnesium powder of 4.8g, stir 80 ℃ of heating down, drip 30mL 95% methyl alcohol, keep the system reflux state.Add afterreaction 1h, cooling is filtered, 30mL glycol dimethyl ether washing filter residue, filtrate is reclaimed glycol dimethyl ether, adds 60mL water, ethyl acetate extraction (50mL * 3) merges organic layer, the 50mL washing, the 3g anhydrous magnesium sulfate drying merges organic layer, reclaims ethyl acetate, the 3000Pa underpressure distillation, collect 80 ℃ of-82 ℃ of cuts, obtain the about 5.00g of faint yellow oily thing, yield is 86.96%.
Embodiment 7
Synthesizing of 5-hydroxymethylthiazole
In four-hole boiling flask, add 7.48g 2-chloro-5-hydroxymethylthiazole, 100mL tetrahydrofuran (THF) and the fresh magnesium powder of 3.6g, be heated to backflow under stirring, drip 20mL 95% methyl alcohol, keep the system reflux state.Add afterreaction 1h, cooling is filtered, 30mL tetrahydrofuran (THF) washing filter residue, filtrate is reclaimed tetrahydrofuran (THF), adds 60mL water, ethyl acetate extraction (50mL * 3) merges organic layer, the 50mL washing, the 3g anhydrous magnesium sulfate drying merges organic layer, reclaims ethyl acetate, the 3000Pa underpressure distillation, collect 80 ℃ of-82 ℃ of cuts, obtain the about 4.92g of faint yellow oily thing, yield is 85.57%.
Embodiment 8
Synthesizing of 5-hydroxymethylthiazole
In four-hole boiling flask, add 7.48g 2-chloro-5-hydroxymethylthiazole, 70mL glycol dimethyl ether and the fresh magnesium powder of 3.6g, stir 80 ℃ of heating down, drip the 30mL Virahol, keep the system reflux state.Add afterreaction 1h, cooling is filtered, 30mL glycol dimethyl ether washing filter residue, filtrate is reclaimed glycol dimethyl ether, adds 60mL water, ethyl acetate extraction (50mL * 3) merges organic layer, the 50mL washing, the 3g anhydrous magnesium sulfate drying merges organic layer, reclaims ethyl acetate, the 3000Pa underpressure distillation, collect 80 ℃ of-82 ℃ of cuts, obtain the about 5.18g of faint yellow oily thing, yield is 90.09%.
Embodiment 9
Synthesizing of 5-hydroxymethylthiazole
In four-hole boiling flask, add 7.48g 2-chloro-5-hydroxymethylthiazole, 70mL tetrahydrofuran (THF) and the fresh magnesium powder of 4.2g, stir reflux down, drip the 25mL Virahol, keep the system reflux state.Add afterreaction 1h, cooling is filtered, 30mL tetrahydrofuran (THF) washing filter residue, filtrate is reclaimed tetrahydrofuran (THF), adds 60mL water, ethyl acetate extraction (50mL * 3) merges organic layer, the 50mL washing, the 3g anhydrous magnesium sulfate drying merges organic layer, reclaims ethyl acetate, the 3000Pa underpressure distillation, collect 80 ℃ of-82 ℃ of cuts, obtain the about 5.12g of faint yellow oily thing, yield is 89.04%.
Embodiment 10
Synthesizing of 5-hydroxymethylthiazole
In four-hole boiling flask, add 7.48g 2-chloro-5-hydroxymethylthiazole, 70mL t-butyl methyl ether and the fresh magnesium powder of 4.8g, stir reflux down, drip the 40mL Virahol, keep the system reflux state.Add afterreaction 1h, cooling is filtered, 30mL t-butyl methyl ether washing filter residue, filtrate is reclaimed t-butyl methyl ether, adds 60mL water, ethyl acetate extraction (50mL * 3) merges organic layer, the 50mL washing, the 3g anhydrous magnesium sulfate drying merges organic layer, reclaims ethyl acetate, the 3000Pa underpressure distillation, collect 80 ℃ of-82 ℃ of cuts, obtain the about 5.25g of faint yellow oily thing, yield is 91.30%.
The structural characterization of 5-hydroxymethylthiazole
1H-NMR (CDCCl
3) δ=: 8.781 (s, 1H, C2-H), 7.787 and 7.785 (d, 1H, C4-H, J=0.6Hz), 4.923 and 4.921 (d, 2H, CH
2, J=0.6Hz), 2.128 (s, 1H, 0H).
13C-NMR(CDCCl
3)δ＝：153.590(C2)，140.835(C4)，138.776(C5)，57.257(CH
2-C)。LC-MS：M
+/z＝115。
Claims (4)
1. the production technique of a 5-hydroxymethylthiazole, it is characterized in that: with 2-chloro-5-5-chloromethyl thiazole is raw material, with ethanol is solvent, hydrolysis Synthetic 2 under the effect of alkali-chloro-5-hydroxymethylthiazole, 2-chloro-5-hydroxymethylthiazole again with ether as solvent, by the synthetic 5-hydroxymethylthiazole of magnesium powder/pure reduction dechlorination; Its reaction formula is as follows:
2. the production technique of a kind of 5-hydroxymethylthiazole according to claim 1, its concrete steps are as follows:
The first step: in ethanol, dissolving alkali is heated to 70 ℃-90 ℃, and dropping 2-chloro-5-5-chloromethyl thiazole is dissolved in the solution in the ethanolic soln, and reaction 1h-3h obtains 2-chloro-5-hydroxymethylthiazole after the processing;
Second step: in ether, add 2-chloro-5-hydroxymethylthiazole and magnesium powder, be heated to backflow, drip alcohol, reaction 1h-2h obtains the 5-hydroxymethylthiazole after the processing.
3. the production technique of a kind of 5-hydroxymethylthiazole according to claim 2 is characterized in that: the concentration of ethanol scope is 50%-95%, and the molar ratio range of 2-chloro-5-5-chloromethyl thiazole and alkali is between 1: 2 to 1: 8; The molar ratio range of 2-chloro-5-hydroxymethylthiazole and magnesium is between 1: 1 to 1: 4.
4. the production technique of a kind of 5-hydroxymethylthiazole according to claim 2 is characterized in that: alkali is sodium hydroxide, potassium hydroxide, sodium bicarbonate or yellow soda ash; Ether is tetrahydrofuran (THF), glycol dimethyl ether, dioxane, isopropyl ether or t-butyl methyl ether; Alcohol is methyl alcohol, ethanol, propyl alcohol or Virahol.
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| CN112546969B (en) * | 2020-12-07 | 2022-12-23 | 安徽贝克制药股份有限公司 | Catalytic hydrogenation continuous production device and preparation method of ritonavir intermediate |
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Owner name: CENTRAL SOUTH UNIVERSITY OF FORESTRY AND TECHNOLOG Free format text: FORMER OWNER: YE CUICENG Effective date: 20111031 Free format text: FORMER OWNER: XIAO HONGBO KUANG CHUNTAO YIN ZUOHU SUN HANZHOU |
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Effective date of registration: 20111031 Address after: 410004 Shaoshan South Road, Hunan, No. 498, No. Patentee after: Central South University of Forestry and Technology Address before: 410004 Institute of Applied Chemistry, Central South University of Forestry and Technology, Hunan, Changsha Co-patentee before: Xiao Hongbo Patentee before: Ye Cuiceng Co-patentee before: Kuang Chuntao Co-patentee before: Yin Zuohu Co-patentee before: Sun Hanzhou |
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