CN110878041A - Preparation method of (S) -1-tert-butyloxycarbonyl-3-hydroxypiperidine - Google Patents
Preparation method of (S) -1-tert-butyloxycarbonyl-3-hydroxypiperidine Download PDFInfo
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Abstract
The invention discloses a preparation method of (S) -1-tert-butyloxycarbonyl-3-hydroxypiperidine, relating to the technical field of biological pharmacy and comprising the following steps of, firstly, preparing 3-hydroxypyridine (2) as a raw material; step two, preparing racemic 3-hydroxypiperidine (3) by 3-hydroxypyridine (2); step three, racemic 3-hydroxypiperidine (3) is prepared into a derivative (2S,3S) -N- (4-chlorphenyl) -2, 3-dihydroxy butyramide acid (4) by D-tartaric acid; fourthly, the derivative (2S,3S) -N- (4-chlorphenyl) -2, 3-dihydroxy butyramide acid (4) prepared from the D-tartaric acid is split to obtain (S) -hydroxypiperidine salt (5); and step five, extracting, concentrating and crystallizing the mixture to obtain the (S) -1-tert-butoxycarbonyl-3-hydroxypiperidine salt (5).
Description
Technical Field
The invention relates to the technical field of biological pharmacy, in particular to a preparation method of (S) -1-tert-butyloxycarbonyl-3-hydroxypiperidine.
Background
(S) -1-tert-butyloxycarbonyl-3-hydroxypiperidine is an important pharmaceutical intermediate, and the compound can be used for synthesizing an anti-congestive heart failure drug Carmorelin, an inhibitor Ibrutinib (Ibrutinib) for selectively inhibiting Bruton' S tyrosine kinase (BTK), natural substances of isopinorine (Isonitramine) and small fruit Nitrarine (Sibirine) and other prodrugs. Particularly ibrutinib has been approved in tandem for the treatment of rare invasive blood cancers-Mantle Cell Lymphoma (MCL), Chronic Lymphocytic Leukemia (CLL) and fahrenheit macroglobulinemia. As one of the 4 approved drugs for anti-tumor indications, ibrutinib received a 5 billion dollar sale on the market in the year. Analysts expect the drug to sell more than $ 10 billion in 2015 and $ 40 billion in 2018, and predict that annual peak sales for all indications of ibrutinib will reach approximately $ 50 billion. Therefore, the (S) -1-tert-butyloxycarbonyl-3-hydroxypiperidine can be expected to have wide market prospects.
The traditional production process of (S) -1-tert-butyloxycarbonyl-3-hydroxypiperidine has multiple preparation procedures, and the chiral resolving agent cannot be recycled after being crystallized after being acidified, so that the yield is not high.
Disclosure of Invention
The invention aims to solve the problems that in the prior art, the production process of (S) -1-tert-butyloxycarbonyl-3-hydroxypiperidine has more preparation procedures, and the chiral resolving agent cannot be recycled after being acidified and crystallized, so that the yield is not high.
In order to achieve the purpose, the invention adopts the following technical scheme:
a preparation method of (S) -1-tert-butyloxycarbonyl-3-hydroxypiperidine comprises the following steps,
step one, preparing 3-hydroxypyridine as a raw material;
step two, preparing racemic 3-hydroxypiperidine by 3-hydroxypyridine;
step three, racemic 3-hydroxypiperidine is prepared into a derivative (2S,3S) -N- (4-chlorphenyl) -2, 3-dihydroxy butyramic acid by D-tartaric acid;
fourthly, resolving the derivative (2S,3S) -N- (4-chlorphenyl) -2, 3-dihydroxy butyramide acid prepared from the D-tartaric acid to obtain (S) -hydroxypiperidine salt;
and step five, extracting, concentrating and crystallizing the mixture to obtain the (S) -1-tert-butyloxycarbonyl-3-hydroxypiperidine salt.
Preferably, the specific process of the first step is that fuming sulfuric acid is added into a dry reaction pot, pyridine is dropwise added under stirring, mercuric sulfate is added, the temperature is kept at 260 ℃ for 10-17h, the mixture is cooled to 18-28 ℃, ethanol is added, the mixture is continuously cooled to below 5 ℃, crystals are separated out and filtered, pyridine-3-sulfonic acid is obtained, the melting point is 345 ℃, the yield is 62%, sodium hydroxide and pyridine-3-sulfonic acid are added into the reaction pot, the mixture is melted at 160 ℃, the temperature is raised to 270 ℃ for 3-7h, the mixture is cooled to 100 ℃, water is added for dissolution, 30% hydrochloric acid is used for adjusting the pH to 5.2-4, the mixture is decompressed and concentrated, sodium chloride is removed by filtration, the filtrate is adjusted to the pH value of 7.4-10.9 by saturated sodium carbonate, the filtrate is cooled, filtered and dried, the yield of 3-hydroxypyridine crude product is obtained, the yield is 64%, the fine product is obtained, the melting point is 120 ℃ and 138 ℃, the content is 98 percent, and the refining yield is 80 percent.
Preferably, the specific process of the second step is that 3-hydroxypyridine, 3-8% rhodium carbon and water are added into an autoclave, the mixture reacts for 44-60h under the condition of hydrogen pressure of 4.3-6.8MPa and 90 ℃, the mixture is cooled to room temperature, hydrogen is discharged, the rhodium carbon catalyst is filtered, the filtrate is decompressed and distilled to remove water, the residual oily matter is continuously decompressed and distilled, 60-79 ℃/26.6Pa is collected, and the mixture is cooled and solidified to obtain white solid racemic 3-hydroxypiperidine, mp45-71 ℃.
Preferably, the third step is a specific process, the D- (-) -tartaric acid, the acetic anhydride and the concentrated sulfuric acid are added into a 250ml three-necked bottle, heated to 90-108 ℃ for reaction for 1-4h, cooled to room temperature, toluene is added into the reaction liquid, solid is separated out, the reaction liquid is continuously cooled to-5 ℃, the mixture is stood still, filtered after 1-5h, the filter cake is washed by a small amount of toluene and dried under reduced pressure to obtain white powder D-diacetyl tartaric anhydride, mp 114-, precipitating solid, cooling to 0 deg.C, standing, filtering after 0.2-3h, washing filter cake with cold water, and recrystallizing with 50% ethanol to obtain colorless needle crystal derivative (2S,3S) -N- (4-chlorophenyl) -2, 3-dihydroxybutyramic acid, mp183-198 deg.C.
Preferably, the specific process of the fourth step is that racemic 3-hydroxypiperidine and the derivative (2S,3S) -N- (4-chlorophenyl) -2, 3-dihydroxy butyramide acid are added into 95% ethanol, the mixture is heated to reflux, the solution becomes clear from turbidity, the mixture is cooled to room temperature, a solid is precipitated, the mixture is continuously cooled to-5 ℃, the mixture is filtered after 0.4-2h, a filter cake is washed by cold water and dried to obtain a colorless crystalline solid (S) -hydroxypiperidine salt, and mp is 144-165 ℃.
Preferably, the racemic 3-hydroxypiperidine: the proportion parameter of the derivative (2S,3S) -N- (4-chlorphenyl) -2, 3-dihydroxy butyramide acid is 1:1.03
Preferably, the specific process of the fifth step is that (S) -hydroxypiperidine salt and triethylamine are added into methanol, the mixture is stirred at room temperature until the mixture is clear, a methanol solution containing di-tert-butyl dicarbonate is dripped after 0.3 to 1.5 hours, the mixture reacts at room temperature for 1 to 3.5 hours after dripping, reduced pressure distillation is carried out until the mixture is dry, ethyl acetate and water are added into the residue, the mixture is layered, the water phase is extracted by ethyl acetate, the organic phase is combined, reduced pressure concentration is carried out until the organic phase is dry, the mixture is added into a reaction kettle, the mixture is stirred, kept stand and separated, the organic phase is washed twice by saturated salt water and then concentrated, 30 liters of petroleum ether is added, the mixture is heated to 50 ℃ and stirred for dissolution, the temperature is reduced to-20 ℃ for crystallization, and (S.
Preferably, the (S) -hydroxypiperidine salt (5): the content ratio of triethylamine is 1:1.23, and the weight ratio of ethyl acetate: the water ratio parameter was 1.25: 1.
The invention has the beneficial effects that:
the preparation process reduces the synthesis steps, improves the yield, can utilize and recover the chiral resolving agent, and is suitable for industrial production.
Drawings
FIG. 1 is a schematic diagram of the flow of the reaction molecules of the present invention.
In the figure: 1: (S) -1-tert-butoxycarbonyl-3-hydroxypiperidine, 2: 3-hydroxypyridine, 3: racemic 3-hydroxypiperidine, 4: (2S,3S) -N- (4-chlorophenyl) -2, 3-dihydroxybutylamic acid (4, 5: (S) -hydroxypiperidine salts.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments.
Example 1, a method for preparing (S) -1-tert-butoxycarbonyl-3-hydroxypiperidine, comprising the steps of,
step one, preparing 3-hydroxypyridine 2 as a raw material, adding fuming sulfuric acid into a dry reaction pot, dropwise adding pyridine while stirring, adding mercuric sulfate, heating to 210 ℃, keeping the temperature for 10 hours, cooling to 18 ℃, adding into ethanol, continuously cooling to below 5 ℃, precipitating crystals, filtering to obtain pyridine-3-sulfonic acid, melting point 345 ℃, yield 62%, adding sodium hydroxide and pyridine-3-sulfonic acid into a reaction pot, melting at 160 ℃, heating to 210 ℃, keeping the temperature for 3h, cooling to 100 ℃, adding water for dissolution, adjusting the pH to 5.2 by using 30% hydrochloric acid, concentrating under reduced pressure, filtering to remove sodium chloride, adjusting the pH of filtrate to 7.4 by using saturated sodium carbonate, cooling, filtering, drying to obtain a crude product of 3-hydroxypyridine with the yield of 64%, recrystallizing by using toluene to obtain a refined product with the melting point of 120 ℃, the content of 98% and the refining yield of 80%;
step two, adding 3-hydroxypyridine, 3% rhodium carbon and water into a high-pressure kettle, reacting for 44 hours under the conditions of hydrogen pressure of 4.3MPa and 90 ℃, cooling to room temperature, evacuating hydrogen, filtering, recovering a rhodium carbon catalyst, evaporating water from the filtrate under reduced pressure, continuously distilling the residual oily matter under reduced pressure, collecting 60 ℃/26.6Pa, cooling and solidifying to obtain 3-hydroxypiperidine 3 as a white solid, wherein mp45 ℃;
step three, adding D- (-) -tartaric acid, acetic anhydride and concentrated sulfuric acid into a 250ml three-necked flask, and heating to 90 ℃ for reaction for 1-4 h. Cooling to room temperature, adding toluene into the reaction solution to precipitate a solid, continuously cooling to-5 ℃, standing, filtering after 1h, washing a filter cake with a small amount of toluene, drying under reduced pressure to obtain white powder D-diacetyl tartaric anhydride, mp114 ℃, adding D-diacetyl tartaric anhydride and p-chloroaniline into dichloromethane, heating, refluxing, stirring and reacting for 12h, cooling to room temperature, adding 2% potassium hydroxide solution, stirring for 0.1h, standing, layering, washing an organic phase with water, combining aqueous phases, stirring for 0.2h at room temperature, adding concentrated hydrochloric acid to adjust the pH to 1.0, precipitating a solid, cooling to 0 ℃, standing, filtering after 0.2h, washing a filter cake with cold water, recrystallizing with 50% ethanol to obtain a colorless acicular crystal derivative (2S,3S) -N- (4-chlorophenyl) -2, 3-dihydroxy-butyrylaminic acid 4, mp183 ℃;
step four, adding racemic 3-hydroxypiperidine 3 and derivative (2S,3S) -N- (4-chlorphenyl) -2, 3-dihydroxy butyramide acid 4 into 95% ethanol, heating to reflux, clarifying the solution from turbidity, cooling to room temperature, precipitating a solid, continuously cooling to-5 ℃, filtering after 0.4h, washing a filter cake with cold water, and drying to obtain colorless crystalline solid (S) -hydroxypiperidine salt 5, mp144 ℃;
step five, adding (S) -hydroxypiperidine salt 5 and triethylamine into methanol, stirring at room temperature until the mixture is clear, dripping into a methanol solution containing di-tert-butyl dicarbonate after 0.3h, reacting at room temperature for 1h after dripping, distilling under reduced pressure until the mixture is dry, adding ethyl acetate and water into the residue, layering, extracting the water phase with ethyl acetate, combining the organic phases, concentrating under reduced pressure until the mixture is dry, adding into a reaction kettle, stirring, standing for liquid separation, washing the organic phase with saturated saline solution twice, concentrating, adding 30 liters of petroleum ether, heating to 50 ℃, stirring for dissolving, cooling to-20 ℃ for crystallization, and filtering to obtain (S) -1-tert-butoxycarbonyl-3-hydroxypiperidine 1.
Specifically, racemic 3-hydroxypiperidine (3): the proportion parameter of the derivative (2S,3S) -N- (4-chlorphenyl) -2, 3-dihydroxy butyramide acid (4) is 1:1.03
Specifically, (S) -hydroxypiperidine salt (5): the content ratio of triethylamine is 1:1.23, and the weight ratio of ethyl acetate: the water ratio parameter was 1.25: 1.
Conversion results were as follows, with each 30 liters of reaction solution received for GC testing:
| item | PH | Conversion (%) |
| Hydrochloric acid | 5.2 | 89±1 |
| Sodium carbonate | 7.4 | 89±1 |
Example 2, a method for preparing (S) -1-tert-butoxycarbonyl-3-hydroxypiperidine, comprising the steps of,
step one, preparing 3-hydroxypyridine 2 as a raw material, adding fuming sulfuric acid into a dry reaction pot, dropwise adding pyridine while stirring, adding mercuric sulfate, heating to 220 ℃, keeping the temperature for 12 hours, cooling to 20 ℃, adding into ethanol, continuously cooling to below 5 ℃, precipitating crystals, filtering to obtain pyridine-3-sulfonic acid, melting point 345 ℃, yield 62%, adding sodium hydroxide and pyridine-3-sulfonic acid into a reaction pot, melting at 160 ℃, heating to 220 ℃, keeping the temperature for 4h, cooling to 100 ℃, adding water for dissolution, adjusting the pH to 5 by using 30% hydrochloric acid, carrying out reduced pressure concentration, filtering to remove sodium chloride, adjusting the pH of filtrate to 8.3 by using saturated sodium carbonate, cooling, filtering and drying to obtain a crude product of 3-hydroxypyridine with the yield of 64%, recrystallizing by using toluene to obtain a refined product with the melting point of 124 ℃, the content of 98% and the refining yield of 80%;
step two, adding 3-hydroxypyridine, 5.5% rhodium carbon and water into a high-pressure kettle, reacting for 48 hours under the conditions of hydrogen pressure of 4.8MPa and 90 ℃, cooling to room temperature, evacuating hydrogen, filtering, recovering a rhodium carbon catalyst, evaporating water from filtrate under reduced pressure, continuously distilling residual oily matter under reduced pressure, collecting 64 ℃/26.6Pa, cooling and solidifying to obtain 3-hydroxypiperidine 3 as a white solid, wherein mp50 ℃;
step three, adding D- (-) -tartaric acid, acetic anhydride and concentrated sulfuric acid into a 250ml three-necked flask, and heating to 93 ℃ for reaction for 2 h. Cooling to room temperature, adding toluene into the reaction solution, precipitating solid, cooling to-5 deg.C, standing, filtering after 2 hr, washing the filter cake with a little toluene, drying under reduced pressure to obtain white powder D-diacetyl tartaric anhydride, mp120 deg.C, mixing D-diacetyl tartaric anhydride, adding parachloroaniline into dichloromethane, heating, refluxing, stirring and reacting for 14h, cooling to room temperature, adding 4% potassium hydroxide solution, stirring for 0.3h, standing for layering, washing an organic phase with water, combining aqueous phases, stirring at room temperature for 0.8h, adding concentrated hydrochloric acid to adjust pH to 1.0, separating out a solid, cooling to 0 ℃, standing, filtering after 1h, washing a filter cake with cold water, and recrystallizing with 50% ethanol to obtain a colorless acicular crystal derivative (2S,3S) -N- (4-chlorophenyl) -2, 3-dihydroxybutyramic acid 4, mp183-198 ℃;
step four, adding racemic 3-hydroxypiperidine 3 and derivative (2S,3S) -N- (4-chlorphenyl) -2, 3-dihydroxy butyramide acid 4 into 95% ethanol, heating to reflux, clarifying the solution from turbidity, cooling to room temperature, precipitating a solid, continuously cooling to-5 ℃, filtering after 0.8h, washing a filter cake with cold water, and drying to obtain colorless crystalline solid (S) -hydroxypiperidine salt 5, mp150 ℃;
step five, adding (S) -hydroxypiperidine salt 5 and triethylamine into methanol, stirring at room temperature until the mixture is clear, dripping into a methanol solution containing di-tert-butyl dicarbonate after 0.6h, reacting at room temperature for 1.8h after dripping, distilling under reduced pressure until the mixture is dry, adding ethyl acetate and water into the residue, layering, extracting the water phase with ethyl acetate, combining the organic phases, concentrating under reduced pressure until the mixture is dry, adding into a reaction kettle, stirring, standing for liquid separation, washing the organic phase with saturated salt water twice, concentrating, adding 30 liters of petroleum ether, heating to 50 ℃, stirring for dissolving, cooling to-20 ℃ for crystallization, and filtering to obtain (S) -1-tert-butoxycarbonyl-3-hydroxypiperidine 1.
Specifically, racemic 3-hydroxypiperidine (3): the proportion parameter of the derivative (2S,3S) -N- (4-chlorphenyl) -2, 3-dihydroxy butyramide acid (4) is 1:1.03
Specifically, (S) -hydroxypiperidine salt (5): the content ratio of triethylamine is 1:1.23, and the weight ratio of ethyl acetate: the water ratio parameter was 1.25: 1.
Conversion results were as follows, with each 30 liters of reaction solution received for GC testing:
| item | PH | Conversion (%) |
| Hydrochloric acid | 5.0 | 90.2±1 |
| Sodium carbonate | 8.3 | 90.2±1 |
Example 3, a method for preparing (S) -1-tert-butoxycarbonyl-3-hydroxypiperidine, comprising the steps of,
step one, preparing 3-hydroxypyridine 2 as a raw material, adding fuming sulfuric acid into a dry reaction pot, dropwise adding pyridine while stirring, adding mercuric sulfate, heating to 250 ℃, keeping the temperature for 15 hours, cooling to 26 ℃, adding into ethanol, continuously cooling to below 5 ℃, precipitating crystals, filtering to obtain pyridine-3-sulfonic acid, melting point 345 ℃, yield 62%, adding sodium hydroxide and pyridine-3-sulfonic acid into a reaction pot, melting at 160 ℃, heating to 260 ℃, keeping the temperature for 6 hours, cooling to 100 ℃, adding water for dissolution, adjusting the pH to 4.5 by using 30% hydrochloric acid, concentrating under reduced pressure, filtering to remove sodium chloride, adjusting the pH of filtrate to 8.9 by using saturated sodium carbonate, cooling, filtering, drying to obtain a crude product of 3-hydroxypyridine with the yield of 64%, recrystallizing by using toluene to obtain a refined product with the melting point of 133 ℃, the content of 98% and the refining yield of 80%;
step two, adding 3-hydroxypyridine, 7% rhodium carbon and water into a high-pressure kettle, reacting for 55 hours under the conditions of hydrogen pressure of 6MPa and 90 ℃, cooling to room temperature, evacuating hydrogen, filtering, recovering a rhodium carbon catalyst, evaporating water from the filtrate under reduced pressure, continuously distilling the residual oily matter under reduced pressure, collecting 75 ℃/26.6Pa, cooling and solidifying to obtain 3-hydroxypiperidine 3 as a white solid, wherein mp65 ℃;
step three, adding D- (-) -tartaric acid, acetic anhydride and concentrated sulfuric acid into a 250ml three-necked flask, and heating to 105 ℃ for reaction for 3 h. Cooling to room temperature, adding toluene into the reaction liquid to precipitate a solid, continuously cooling to-5 ℃, standing, filtering after 4h, washing a filter cake with a small amount of toluene, drying under reduced pressure to obtain white powder D-diacetyl tartaric anhydride, mp140 ℃, adding D-diacetyl tartaric anhydride and p-chloroaniline into dichloromethane, heating, refluxing, stirring and reacting for 17h, cooling to room temperature, adding 12% potassium hydroxide solution, stirring for 0.6h, standing, layering, washing an organic phase with water, combining aqueous phases, stirring for 1.6h at room temperature, adding concentrated hydrochloric acid to adjust the pH to 1.0, precipitating a solid, cooling to 0 ℃, standing, filtering after 2.2h, washing a filter cake with cold water, recrystallizing with 50% ethanol to obtain a colorless acicular crystal derivative (2S,3S) -N- (4-chlorophenyl) -2, 3-dihydroxy-butyrylaminic acid 4, mp192 ℃;
step four, adding racemic 3-hydroxypiperidine 3 and derivative (2S,3S) -N- (4-chlorphenyl) -2, 3-dihydroxybutanamic acid 4 into 95 percent ethanol, heating to reflux, clarifying the solution from turbidity, cooling to room temperature, separating out a solid, continuously cooling to-5 ℃, filtering after 1.6h, washing a filter cake with cold water, and drying to obtain a colorless crystalline solid (S) -hydroxypiperidine salt 5, mp160 ℃;
step five, adding (S) -hydroxypiperidine salt 5 and triethylamine into methanol, stirring at room temperature until the mixture is clear, dripping into a methanol solution containing di-tert-butyl dicarbonate after 1.3h, reacting at room temperature for 3h after dripping, distilling under reduced pressure until the mixture is dry, adding ethyl acetate and water into the residue, layering, extracting the water phase with ethyl acetate, combining the organic phases, concentrating under reduced pressure until the mixture is dry, adding into a reaction kettle, stirring, standing for liquid separation, washing the organic phase with saturated saline solution twice, concentrating, adding 30 liters of petroleum ether, heating to 50 ℃, stirring for dissolving, cooling to-20 ℃ for crystallization, and filtering to obtain (S) -1-tert-butoxycarbonyl-3-hydroxypiperidine 1.
Specifically, racemic 3-hydroxypiperidine (3): the proportion parameter of the derivative (2S,3S) -N- (4-chlorphenyl) -2, 3-dihydroxy butyramide acid (4) is 1:1.03
Specifically, (S) -hydroxypiperidine salt (5): the content ratio of triethylamine is 1:1.23, and the weight ratio of ethyl acetate: the water ratio parameter was 1.25: 1.
Conversion results were as follows, with each 30 liters of reaction solution received for GC testing:
example 4, a method for preparing (S) -1-tert-butoxycarbonyl-3-hydroxypiperidine, comprising the steps of,
step one, preparing 3-hydroxypyridine 2 as a raw material, adding fuming sulfuric acid into a dry reaction pot, dropwise adding pyridine while stirring, adding mercuric sulfate, heating to 260 ℃, keeping the temperature for 17 hours, cooling to 28 ℃, adding into ethanol, continuously cooling to below 5 ℃, precipitating crystals, filtering to obtain pyridine-3-sulfonic acid, melting point 345 ℃, yield 62%, adding sodium hydroxide and pyridine-3-sulfonic acid into a reaction pot, melting at 160 ℃, heating to 270 ℃, keeping the temperature for 7h, cooling to 100 ℃, adding water for dissolution, adjusting the pH to 4 by using 30% hydrochloric acid, concentrating under reduced pressure, filtering to remove sodium chloride, adjusting the pH of filtrate to 10.9 by using saturated sodium carbonate, cooling, filtering, drying to obtain a crude product of 3-hydroxypyridine with the yield of 64%, recrystallizing by using toluene to obtain a refined product with the melting point of 138 ℃, the content of 98% and the refining yield of 80%;
step two, adding 3-hydroxypyridine, 8% rhodium carbon and water into a high-pressure kettle, reacting for 60 hours under the conditions of hydrogen pressure of 6.8MPa and 90 ℃, cooling to room temperature, evacuating hydrogen, filtering, recovering a rhodium carbon catalyst, evaporating water from the filtrate under reduced pressure, continuously distilling the residual oily matter under reduced pressure, collecting 79 ℃/26.6Pa, cooling and solidifying to obtain 3-hydroxypiperidine 3 as a white solid, wherein mp71 ℃;
step three, adding D- (-) -tartaric acid, acetic anhydride and concentrated sulfuric acid into a 250ml three-necked flask, and heating to 108 ℃ for reaction for 4 h. Cooling to room temperature, adding toluene into the reaction liquid to precipitate a solid, continuously cooling to-5 ℃, standing, filtering after 5h, washing a filter cake with a small amount of toluene, drying under reduced pressure to obtain white powder D-diacetyl tartaric anhydride, mp145 ℃, adding D-diacetyl tartaric anhydride and p-chloroaniline into dichloromethane, heating, refluxing, stirring and reacting for 20h, cooling to room temperature, adding 15% potassium hydroxide solution, stirring for 0.8h, standing, layering, washing an organic phase with water, combining an aqueous phase, stirring for 2h at room temperature, adding concentrated hydrochloric acid to adjust the pH to 1.0, precipitating a solid, cooling to 0 ℃, standing, filtering after 3h, washing a filter cake with cold water, recrystallizing with 50% ethanol to obtain a colorless acicular crystal derivative (2S,3S) -N- (4-chlorophenyl) -2, 3-dihydroxy butanamic acid 4, mp198 deg.C;
step four, adding racemic 3-hydroxypiperidine 3 and derivative (2S,3S) -N- (4-chlorphenyl) -2, 3-dihydroxy butyramide acid 4 into 95% ethanol, heating to reflux, clarifying the solution from turbidity, cooling to room temperature, precipitating a solid, continuously cooling to-5 ℃, filtering after 2h, washing a filter cake with cold water, and drying to obtain colorless crystalline solid (S) -hydroxypiperidine salt 5, mp165 ℃;
step five, adding (S) -hydroxypiperidine salt 5 and triethylamine into methanol, stirring at room temperature until the mixture is clear, dripping into a methanol solution containing di-tert-butyl dicarbonate after 1.5h, reacting at room temperature for 3.5h after dripping, distilling under reduced pressure until the mixture is dry, adding ethyl acetate and water into the residue, layering, extracting the water phase with ethyl acetate, combining the organic phases, concentrating under reduced pressure until the mixture is dry, adding into a reaction kettle, stirring, standing for liquid separation, washing the organic phase with saturated salt water twice, concentrating, adding 30 liters of petroleum ether, heating to 50 ℃, stirring for dissolving, cooling to-20 ℃ for crystallization, and filtering to obtain (S) -1-tert-butoxycarbonyl-3-hydroxypiperidine 1.
Specifically, racemic 3-hydroxypiperidine (3): the proportion parameter of the derivative (2S,3S) -N- (4-chlorphenyl) -2, 3-dihydroxy butyramide acid (4) is 1:1.03
Specifically, (S) -hydroxypiperidine salt (5): the content ratio of triethylamine is 1:1.23, and the weight ratio of ethyl acetate: the water ratio parameter was 1.25: 1.
Conversion results were as follows, with each 30 liters of reaction solution received for GC testing:
analysis of the experimental data from example 1, example 2, example 3 and example 4 gave a yield of 97%, a GC purity of 99.8%, and 99.9% ee.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered to be within the technical scope of the present invention, and the technical solutions and the inventive concepts thereof according to the present invention should be equivalent or changed within the scope of the present invention.
Claims (8)
1. A preparation method of (S) -1-tert-butyloxycarbonyl-3-hydroxypiperidine is characterized by comprising the following steps: comprises the following steps of (a) carrying out,
step one, preparing 3-hydroxypyridine (2) as a raw material;
step two, preparing racemic 3-hydroxypiperidine (3) by 3-hydroxypyridine (2);
step three, racemic 3-hydroxypiperidine (3) is prepared into a derivative (2S,3S) -N- (4-chlorphenyl) -2, 3-dihydroxy butyramide acid (4) by D-tartaric acid;
fourthly, the derivative (2S,3S) -N- (4-chlorphenyl) -2, 3-dihydroxy butyramide acid (4) prepared from the D-tartaric acid is split to obtain (S) -hydroxypiperidine salt (5);
and step five, extracting, concentrating and crystallizing the mixture to obtain the (S) -1-tert-butyloxycarbonyl-3-hydroxypiperidine salt (1).
2. The method as claimed in claim 1, wherein the step one comprises adding oleum into a dry reaction vessel, dropwise adding pyridine under stirring, adding mercuric sulfate, heating to 260 deg.C, maintaining the temperature for 10-17h, cooling to 18-28 deg.C, adding ethanol, cooling to below 5 deg.C, precipitating crystals, filtering to obtain pyridine-3-sulfonic acid, melting point 345 deg.C, yield 62%, adding sodium hydroxide and pyridine-3-sulfonic acid into the reaction vessel, melting at 160 deg.C, heating to 270 deg.C, maintaining the temperature for 3-7h, cooling to 100 deg.C, dissolving in water, adjusting pH to 5.2-4 with 30% hydrochloric acid, concentrating under reduced pressure, filtering to remove sodium chloride, adjusting pH of the filtrate to 7.4-10.9 with saturated sodium carbonate, cooling, filtering and drying to obtain crude 3-hydroxypyridine product with yield of 64%, re-crystallizing with toluene to obtain refined product with melting point of 120-.
3. The method for preparing (S) -1-tert-butoxycarbonyl-3-hydroxypiperidine according to claim 1, wherein the specific process of the second step is to add 3-hydroxypyridine, 3-8% rhodium carbon and water into an autoclave, react for 44-60h under the conditions of 4.3-6.8MPa of hydrogen pressure and 90 ℃, cool to room temperature, evacuate hydrogen, filter, recover the rhodium carbon catalyst, evaporate water from the filtrate under reduced pressure, continue vacuum distillation of the remaining oily substance, collect 60-79 ℃/26.6Pa, cool and solidify to obtain racemic 3-hydroxypiperidine as a white solid, mp45-71 ℃.
4. The preparation method of (S) -1-tert-butoxycarbonyl-3-hydroxypiperidine as claimed in claim 1, wherein the third step comprises adding D- (-) -tartaric acid, acetic anhydride and concentrated sulfuric acid into a 250ml three-necked flask, heating to 90-108 deg.C for reaction for 1-4h, cooling to room temperature, adding toluene into the reaction solution, precipitating solid, further cooling to-5 deg.C, standing for 1-5h, filtering, washing the filter cake with a small amount of toluene, drying under reduced pressure to obtain white powder D-diacetyl tartaric anhydride, mp 114-, stirring for 0.1-0.8h, standing for layering, washing the organic phase with water, combining the water phases, stirring at room temperature for 0.2-2h, adding concentrated hydrochloric acid to adjust pH to 1.0, precipitating solid, cooling to 0 ℃, standing, filtering after 0.2-3h, washing the filter cake with cold water, and recrystallizing with 50% ethanol to obtain colorless acicular crystal derivative (2S,3S) -N- (4-chlorophenyl) -2, 3-dihydroxy butyramide acid (4), mp183-198 ℃.
5. The method for preparing (S) -1-tert-butoxycarbonyl-3-hydroxypiperidine according to claim 1, wherein the specific process of step four is to add racemic 3-hydroxypiperidine (3) and derivative (2S,3S) -N- (4-chlorophenyl) -2, 3-dihydroxybutanoic acid (4) into 95% ethanol, heat to reflux, clear the solution from turbidity, cool to room temperature, precipitate a solid, continue to cool to-5 ℃, filter after 0.4-2h, wash the filter cake with cold water, oven dry to obtain colorless crystalline solid (S) -hydroxypiperidine salt (5), mp144-165 ℃.
6. The process according to claim 5, wherein the ratio of racemic 3-hydroxypiperidine (3): the proportion parameter of the derivative (2S,3S) -N- (4-chlorphenyl) -2, 3-dihydroxy butyramide acid (4) is 1: 1.03.
7. The process for producing (S) -1-tert-butoxycarbonyl-3-hydroxypiperidine according to claim 1, characterized in that the concrete process of the fifth step is that (S) -hydroxypiperidine salt (5) and triethylamine are added into methanol, stirring at room temperature until the mixture is clear, dripping a methanol solution containing di-tert-butyl dicarbonate after 0.3-1.5h, reacting at room temperature for 1-3.5h after dripping, distilling under reduced pressure until the mixture is dry, adding ethyl acetate and water into the residue together, layering, extracting a water phase with ethyl acetate, combining organic phases, concentrating under reduced pressure until the mixture is dry, adding the mixture into a reaction kettle, stirring, standing, separating the liquid, washing the organic phase with saturated saline solution twice, concentrating, adding 30L of petroleum ether, heating to 50 ℃, stirring and dissolving, cooling to-20 ℃, crystallizing, and filtering to obtain (S) -1-tert-butoxycarbonyl-3-hydroxypiperidine (1).
8. The process for producing (S) -1-tert-butoxycarbonyl-3-hydroxypiperidine according to claim 6, wherein the ratio of the (S) -hydroxypiperidine salt (5): the content ratio of triethylamine is 1:1.23, and the weight ratio of ethyl acetate: the water ratio parameter was 1.25: 1.
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| GB834248A (en) * | 1956-06-18 | 1960-05-04 | Lakeside Lab Inc | Improvements in or relating to process of reducing 3-hydroxypyridine and derivatives thereof |
| CN103664760A (en) * | 2013-12-06 | 2014-03-26 | 常熟市联创化学有限公司 | Preparation method of 3-hydroxypyridine |
| CN108220358A (en) * | 2018-01-09 | 2018-06-29 | 上海应用技术大学 | The preparation method of one kind (S) -1- tertbutyloxycarbonyl -3- hydroxy piperidines |
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| GB834248A (en) * | 1956-06-18 | 1960-05-04 | Lakeside Lab Inc | Improvements in or relating to process of reducing 3-hydroxypyridine and derivatives thereof |
| CN103664760A (en) * | 2013-12-06 | 2014-03-26 | 常熟市联创化学有限公司 | Preparation method of 3-hydroxypyridine |
| CN108220358A (en) * | 2018-01-09 | 2018-06-29 | 上海应用技术大学 | The preparation method of one kind (S) -1- tertbutyloxycarbonyl -3- hydroxy piperidines |
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