CN110563627A - Preparation method of (S) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile - Google Patents
Preparation method of (S) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile Download PDFInfo
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention relates to the technical field of medicines, in particular to a preparation method of (S) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile. The preparation method at least comprises the following steps: respectively dissolving L-prolinamide, an acid-binding agent and chloroacetyl chloride in a solvent to prepare a material A, a material B and a material C, respectively introducing the material A, the material B and the material C into a microchannel reactor for reaction, collecting a first reaction solution, separating the solution, and collecting an upper organic phase; and respectively introducing the upper-layer organic phase and thionyl chloride into the microchannel reactor for reaction, collecting second reaction liquid, and performing post-treatment to obtain the (S) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile. The micro-channel reactor is used as a reaction container, so that the reaction is promoted to be rapidly carried out, the side reaction is inhibited, the reaction efficiency is improved, and the production cost is greatly reduced.
Description
Technical Field
the invention relates to the technical field of medicines, in particular to a preparation method of (S) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile.
background
Diabetes is a chronic disease characterized by hyperglycemia due to a breakdown of the mechanisms of production within the insulin body or an impaired action of insulin. If diabetes is not adequately controlled and treated, a series of acute complications can result. Vildagliptin and alagliptin are specific medicines for treating diabetes, and can obviously improve blood sugar. (S) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile is a key intermediate for synthesizing vildagliptin and alagliptin, and trifluoroacetic anhydride or cyanuric chloride is widely used as an oxidant in the existing preparation process, so that the price is high, and the environmental pollution is serious. Meanwhile, chloroacetyl chloride is used as a raw material in the existing preparation process for reaction, and in order to prevent the chloroacetyl chloride from hydrolysis reaction, a method of prolonging the reaction time at a low temperature is mostly adopted, so that the production energy consumption is high and the production efficiency is low. Therefore, the development of a new preparation process of (S) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile which is green, environment-friendly and low in production cost becomes a research hotspot.
disclosure of Invention
Aiming at the problems of high energy consumption, serious environmental pollution and the like of the existing preparation method, the invention provides a preparation method of (S) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile.
In order to achieve the purpose of the invention, the embodiment of the invention adopts the following technical scheme:
A process for the preparation of (S) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile comprising at least the steps of:
step a, respectively dissolving L-prolinamide, an acid-binding agent and chloroacetyl chloride in a solvent to prepare a material A, a material B and a material C, respectively introducing the material A, the material B and the material C into a microchannel reactor for reaction, collecting a first reaction solution, separating the solution, and collecting an upper organic phase;
and b, respectively introducing the upper-layer organic phase and thionyl chloride into the microchannel reactor for reaction, collecting second reaction liquid, and performing post-treatment to obtain the (S) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile.
The reaction formula of the preparation method provided by the application is as follows:
Compared with the prior art, the preparation method provided by the invention has the following advantages:
The method takes L-prolinamide as a raw material to react with chloroacetyl chloride in the presence of an acid-binding agent to obtain an intermediate (S) -1- (2-chloroacetyl) pyrrolidine-2-formamide (a compound I), and then the intermediate and thionyl chloride undergo an oxidation dehydration reaction to obtain (S) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile, and the preparation method is simple, the adopted raw materials are low in cost and environment-friendly, and the industrial popularization is facilitated.
The method takes the microchannel reactor as a reaction container, has a great specific surface area, and can promote the L-prolinamide and the chloroacetyl chloride to be fully mixed and promote the reaction to be carried out; the heat exchange effect is excellent, the problem that the chloroacetyl chloride is hydrolyzed due to overhigh temperature of a system caused by heat generated by the exothermic reaction of the L-prolinamide and the chloroacetyl chloride can be avoided, the reaction is promoted to be rapidly carried out, the occurrence of side reaction is inhibited, the reaction efficiency is improved, and the production cost is greatly reduced.
Preferably, the molar ratio of the L-prolinamide to the acid-binding agent to the chloroacetyl chloride is 1:1-1.2: 1-1.2.
Preferably, the molar ratio of the L-prolinamide to the thionyl chloride is 1: 4-6.
the ratio is preferably controlled so that the L-prolinamide reaction is completed, and the excess of raw materials is avoided, thereby increasing the production cost.
Preferably, the acid-binding agent is potassium carbonate, sodium carbonate or sodium bicarbonate.
Preferably, the acid-binding agent can accelerate the acylation reaction and prevent side reactions, and the potassium carbonate, the sodium carbonate or the sodium bicarbonate has low cost and stable structure, does not cause adverse effects on reactants and reaction liquid, and is beneficial to the reaction.
Preferably, the L-prolinamide is dissolved in an aprotic solvent to prepare a material A with the concentration of 1-2 mol/L.
Preferably, chloroacetyl chloride is dissolved in an aprotic solvent to prepare a material C with a concentration of 8-10 mol/L.
preferably, the acid-binding agent is dissolved in deionized water to prepare a material B with the concentration of 3-4.5 mol/L.
the concentration of the material A, the material B and the material C is preferably controlled, the full reaction can be ensured, and the reaction speed is improved.
preferably, the aprotic solvent is tetrahydrofuran, acetonitrile or ethyl acetate.
Preferably, the flow rate of the material A introduced into the microchannel reactor is 1-3 mL/min.
Preferably, the flow rate of the material B introduced into the microchannel reactor is 0.7-1.0 mL/min.
preferably, the flow rate of the material C introduced into the microchannel reactor is 0.4-0.6 mL/min.
Preferably, the flow rate of the upper organic phase entering the microchannel reactor is 2-4 mL/min.
Preferably, the flow rate of the thionyl chloride introduced into the microchannel reactor is 0.5-1.5 mL/min.
The introduction amount of each raw material is preferably controlled, so that the raw materials can be fully mixed and completely reacted in the reaction time, the reaction speed can be controlled, and the chloroacetyl chloride hydrolysis reaction caused by heat generated by the reaction is avoided.
Preferably, in step a, the reaction time is 2-6 min.
Preferably, in step b, the reaction time is 2-5 min.
the reaction time is preferably controlled, so that the full reaction can be ensured, the reaction yield is ensured, overlong time is avoided, and the production cost is increased.
Preferably, in step a, the temperature of the reaction is 25-50 ℃.
Further preferably, in step a, the temperature of the reaction is 25-35 ℃.
Preferably, in step b, the temperature of the reaction is 60-70 ℃.
Preferably, in step b, the temperature of the reaction is 50-80 ℃.
The reaction temperature is preferably controlled to promote the reaction and increase the reaction rate.
Further preferably, the post-treatment comprises the steps of:
Step A, distilling the second reaction solution under reduced pressure, and dissolving the obtained distillate in ethyl acetate to obtain a first solution;
Step B, sequentially adopting 4-6 wt% of sodium bicarbonate aqueous solution, deionized water and saturated saline solution to extract the first solution, and combining organic phases to obtain a second solution;
Step C, adding anhydrous sodium sulfate into the second solution, drying, filtering, and distilling the obtained filtrate under reduced pressure to obtain an oily substance;
and D, dissolving the oily matter in a mixed solvent of ethyl acetate and n-hexane in a volume ratio of 1:4.5-5.5, heating to reflux, dissolving, clarifying, cooling, crystallizing, filtering and drying to obtain the (S) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile.
The preferable post-treatment step can ensure that the product obtained by the reaction can be fully extracted and purified.
Preferably, in step a, the ratio of the mass of the distillate to the volume of the ethyl acetate is 20-28: 100.
In the step B, the volume ratio of the sodium bicarbonate aqueous solution, the deionized water, the saturated saline and the ethyl acetate is 10:2.5-3.5:2.5-3.5: 1.5-2.5.
in the step B, the addition amount of the anhydrous sodium sulfate is 40-60% of the mass of the L-prolinamide.
Preferably, in step A and step C, the temperature of the reduced pressure distillation is 50-70 ℃.
In the step D, the temperature is reduced to 0 +/-2 ℃ with the gradient of 5-10 ℃/h.
In the step D, the crystallization condition is crystallization for 2-4h under the condition of 200-400 rpm.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Example 1
The embodiment of the invention provides a preparation method of (S) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile, which comprises the following steps:
step a, dissolving 0.175mol of L-prolinamide in 150mL of tetrahydrofuran to obtain a material A with the concentration of 1.17 mol/L; dissolving 0.18mol of potassium carbonate in 50mL of deionized water to obtain a material B with the concentration of 3.6mol/L, and dissolving 0.180mol of chloroacetyl chloride in 20mL of tetrahydrofuran to obtain a material C with the concentration of 9 mol/L; introducing the material A, the material B and the material C into a microchannel reactor according to the introduction amount of 2mL/min, 0.81mL/min and 0.46mL/min respectively, reacting for 3.7min at 25 ℃, collecting a first reaction solution, separating liquid, and collecting an upper organic phase;
B, introducing the upper-layer organic phase and thionyl chloride into the microchannel reactor according to the introduction amount of 3mL/min and 1mL/min respectively, reacting for 3.0min at the temperature of 60 ℃, and collecting a second reaction solution;
C, distilling the second reaction solution at 60 ℃ under reduced pressure to remove unreacted thionyl chloride and a solvent, and dissolving the obtained distillate in 100mL of ethyl acetate to obtain a first solution;
Step d, sequentially adopting 30mL of 5 wt% sodium bicarbonate water solution, 20mL of deionized water and 20mL of saturated saline solution to extract the first solution, and combining organic phases to obtain a second solution;
Step e, adding 10g of anhydrous sodium sulfate into the second solution, drying for 3h, filtering, and distilling the obtained filtrate under reduced pressure at the temperature of 60 ℃ to obtain an oily substance;
And f, dissolving the oily matter in 60mL of mixed solvent of ethyl acetate and n-hexane in a volume ratio of 1:5, heating until refluxing, dissolving and clarifying, cooling to 0 ℃ according to a cooling gradient of 5 ℃/h, then crystallizing for 3h under the condition of 200rpm, filtering and drying to obtain 26.8g of (S) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile.
The model of the microchannel reactor is Chemtrix BV Protrix.
the yield of the obtained (S) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile was 88.6%, the purity by HPLC was 99.2%, and the optical purity by chiral HPLC was 99.9%.
Yield-actual yield 100%/theoretical yield
Example 2
The embodiment of the invention provides a preparation method of (S) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile, which comprises the following steps:
Step a, dissolving 0.175mol of L-prolinamide in 90mL of ethyl acetate to obtain a material A with the concentration of 1.94 mol/L; dissolving 0.21mol of sodium carbonate in 50mL of deionized water to obtain a material B with the concentration of 4.2mol/L, and dissolving 0.21mol of chloroacetyl chloride in 21mL of ethyl acetate to obtain a material C with the concentration of 10 mol/L; introducing the material A, the material B and the material C into a microchannel reactor according to the introduction amount of 1mL/min, 0.7mL/min and 0.4mL/min respectively to react for 5.7min at the temperature of 35 ℃, collecting a first reaction solution, separating liquid and collecting an upper organic phase;
b, introducing the upper-layer organic phase and thionyl chloride into the microchannel reactor according to the introduction amount of 2mL/min and 0.5mL/min respectively, reacting for 4.8min at 80 ℃, and collecting a second reaction solution;
C, distilling the second reaction solution at 70 ℃ under reduced pressure to remove unreacted thionyl chloride and a solvent, and dissolving the obtained distillate in 100mL of ethyl acetate to obtain a first solution;
Step d, sequentially adopting 35mL of 5 wt% sodium bicarbonate water solution, 25mL of deionized water and 25mL of saturated saline solution to extract the first solution, and combining organic phases to obtain a second solution;
Step e, adding 8g of anhydrous sodium sulfate into the second solution, drying for 3h, filtering, and distilling the obtained filtrate under reduced pressure at 70 ℃ to obtain an oily substance;
And f, dissolving the oily matter in 50mL of a mixed solvent of ethyl acetate and n-hexane with the volume ratio of 1:5.5, heating until refluxing, dissolving and clarifying, cooling to-2 ℃ according to a cooling gradient of 7 ℃/h, then crystallizing for 2h under the condition of 300rpm, filtering and drying to obtain 26.1g of (S) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile.
the model of the microchannel reactor is Chemtrix BV Protrix.
The yield of the obtained (S) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile was 86.2%, the purity by HPLC was 99.3%, and the optical purity by chiral HPLC was 99.9%.
Example 3
the embodiment of the invention provides a preparation method of (S) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile, which comprises the following steps:
step a, dissolving 0.175mol of L-prolinamide in 175mL of acetonitrile to obtain a material A with the concentration of 1 mol/L; dissolving 0.19mol of sodium bicarbonate in 60mL of deionized water to obtain a material B with the concentration of 3.17mol/L, and dissolving 0.19mol of chloroacetyl chloride in 20mL of acetonitrile to obtain a material C with the concentration of 9.5 mol/L; introducing the material A, the material B and the material C into a microchannel reactor according to the introduction amount of 3mL/min, 1.0mL/min and 0.6mL/min respectively, reacting for 2.6min at 50 ℃, collecting a first reaction solution, separating liquid, and collecting an upper organic phase;
b, introducing the upper-layer organic phase and thionyl chloride into the microchannel reactor according to the introduction amount of 4mL/min and 1.5mL/min respectively, reacting for 2.2min at 50 ℃, and collecting a second reaction solution;
c, distilling the second reaction solution at 50 ℃ under reduced pressure to remove unreacted thionyl chloride and a solvent, and dissolving the obtained distillate in 100mL of ethyl acetate to obtain a first solution;
Step d, sequentially adopting 25mL of 5 wt% sodium bicarbonate aqueous solution, 35mL of deionized water and 15mL of saturated saline solution to extract the first solution, and combining organic phases to obtain a second solution;
Step e, adding 12g of anhydrous sodium sulfate into the second solution, drying for 3h, filtering, and distilling the obtained filtrate under reduced pressure at 50 ℃ to obtain an oily substance;
and f, dissolving the oily matter in 50mL of a mixed solvent of ethyl acetate and n-hexane in a volume ratio of 1:4.5, heating until the oily matter is refluxed, dissolved and clarified, cooling to 2 ℃ according to a cooling gradient of 10 ℃/h, then crystallizing for 4h under the condition of 400rpm, filtering and drying to obtain 26.0g of (S) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile.
The model of the microchannel reactor is Chemtrix BV Protrix.
the yield of the obtained (S) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile was 85.9%, the purity by HPLC was 99.3%, and the optical purity by chiral HPLC was 99.9%.
the above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents or improvements made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (10)
1. A method for preparing (S) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile, which is characterized by comprising the following steps: at least comprises the following steps:
Step a, respectively dissolving L-prolinamide, an acid-binding agent and chloroacetyl chloride in a solvent to prepare a material A, a material B and a material C, respectively introducing the material A, the material B and the material C into a microchannel reactor for reaction, collecting a first reaction solution, separating the solution, and collecting an upper organic phase;
And b, respectively introducing the upper-layer organic phase and thionyl chloride into a microchannel reactor for reaction, collecting second reaction liquid, and performing post-treatment to obtain the (S) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile.
2. a process for the preparation of (S) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile according to claim 1, wherein: the molar ratio of the L-prolinamide to the acid-binding agent to the chloroacetyl chloride is 1:1-1.2: 1-1.2; and/or
The molar ratio of the L-prolinamide to the thionyl chloride is 1: 4-6; and/or
the acid-binding agent is potassium carbonate, sodium carbonate or sodium bicarbonate.
3. A process for the preparation of (S) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile according to claim 1, wherein: dissolving the L-prolinamide in an aprotic solvent to prepare a material A with the concentration of 1-2 mol/L; and/or
Dissolving chloroacetyl chloride in an aprotic solvent to prepare a material C with the concentration of 8-10 mol/L; and/or
and dissolving the acid-binding agent in deionized water to prepare a material B with the concentration of 3-4.5 mol/L.
4. a process for the preparation of (S) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile according to claim 3, wherein: the aprotic solvent is tetrahydrofuran, acetonitrile or ethyl acetate.
5. A process for producing (S) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile according to claim 1, characterized in that: the flow rate of the material A introduced into the microchannel reactor is 1-3 mL/min; and/or
The flow rate of the material B introduced into the microchannel reactor is 0.7-1.0 mL/min; and/or
the flow rate of the material C introduced into the microchannel reactor is 0.4-0.6 mL/min; and/or
The flow rate of the upper organic phase entering the microchannel reactor is 2-4 mL/min; and/or
The flow rate of the thionyl chloride introduced into the microchannel reactor is 0.5-1.5 mL/min.
6. a process for the preparation of (S) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile according to claim 1, wherein: in the step a, the reaction time is 2-6 min; and/or
in the step b, the reaction time is 2-5 min.
7. a process for the preparation of (S) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile according to claim 1, wherein: in the step a, the reaction temperature is 25-50 ℃; and/or
In the step b, the temperature of the reaction is 50-80 ℃.
8. The process for producing (S) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile according to claim 7, wherein: in the step a, the reaction temperature is 25-35 ℃; and/or
In step b, the temperature of the reaction is 60-70 ℃.
9. a process for the preparation of (S) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile according to claim 1, wherein: the post-treatment comprises the following steps:
Step A, distilling the second reaction solution under reduced pressure, and dissolving the obtained distillate in ethyl acetate to obtain a first solution;
step B, sequentially adopting 4-6 wt% of sodium bicarbonate aqueous solution, deionized water and saturated saline solution to extract the first solution, and combining organic phases to obtain a second solution;
Step C, adding anhydrous sodium sulfate into the second solution, drying, filtering, and distilling the obtained filtrate under reduced pressure to obtain an oily substance;
And D, dissolving the oily matter in a mixed solvent of ethyl acetate and n-hexane in a volume ratio of 1:4.5-5.5, heating to reflux, dissolving, clarifying, cooling, crystallizing, filtering and drying to obtain the (S) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile.
10. A process for the preparation of (S) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile according to claim 9, wherein: in the step A, the volume ratio of the mass of the distillate to the ethyl acetate is 20-28: 100; and/or
In the step B, the volume ratio of the sodium bicarbonate aqueous solution, the deionized water, the saturated saline solution and the ethyl acetate is 10:2.5-3.5:2.5-3.5: 1.5-2.5; and/or
In the step B, the addition amount of the anhydrous sodium sulfate is 40-60% of the mass of the L-prolinamide;
And/or
In the step A and the step C, the temperature of the reduced pressure distillation is 50-70 ℃; and/or
In the step D, the temperature is reduced to 0 +/-2 ℃ with the gradient of 5-10 ℃/h; and/or
In the step D, the crystallization condition is crystallization for 2-4h under the condition of 200-400 rpm.
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| CN104262227A (en) * | 2014-09-16 | 2015-01-07 | 东北制药集团股份有限公司 | Preparation method of (S)-1-(2-chloracetyl)pyrrolidine-2-carbonitrile |
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