CN114394976A - 2- ((S) -1-phenylethyl) -6-oxa-2-azabicyclo [3.2.1] octan-7-one - Google Patents
2- ((S) -1-phenylethyl) -6-oxa-2-azabicyclo [3.2.1] octan-7-one Download PDFInfo
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Abstract
The invention discloses a 2- ((S) -1-phenethyl) -6-oxa-2-azabicyclo [3.2.1]Octane-7-one synthesized by the following steps: mixing a mixed solution of 3-buten-1-ol and alkali A and an activating reagent solution in a micro mixer, and allowing the mixed solution to flow into a first reactor for reaction to obtain an intermediate I solution; step (2) of dissolving the intermediate I in water, (b)S) Mixing the solution of-1-phenylethylamine and the solution of alkali B in a micro mixer, and allowing the mixture to flow into a second reactor for reaction to obtain an intermediate II solution; and (3) mixing the intermediate II solution with glyoxylic acid or glyoxylic acid hydrate solution in a micro mixer, and then flowing into a third reactor for reaction to obtain a target product. The intermediate steps of the process provided by the invention do not need separation and purification, the total yield is stabilized at 64-77%, and in the process, the complicated operation flow is greatly simplified, the reaction time is greatly shortened, and the generation amount and the types of wastes are obviously reduced. Therefore, the synthesis process has the advantages of low cost, simple and convenient operation, high space-time efficiency, low discharge of three wastes and the like.
Description
Technical Field
The invention relates to the field of chemical compositions, and in particular relates to 2- ((S) -1-phenethyl) -6-oxa-2-azabicyclo [3.2.1] octane-7-ketone.
Background
The structural formula of 2- ((S) -1-phenylethyl) -6-oxa-2-azabicyclo [3.2.1] octan-7-one is shown below:
the compound can be used for preparing (2S,4R) -4-hydroxypiperidine acid and derivatives thereof, and the (2S,4R) -4-hydroxypiperidine acid can be used for preparing a second-generation protease inhibitor palivir (Paritaprevir), and in addition, the (2S,4R) -4-hydroxypiperidine acid and derivatives thereof serving as drug molecular building blocks are hot spots of current research.
The preparation route of 2- ((S) -1-phenethyl) -6-oxa-2-azabicyclo [3.2.1] octane-7-ketone in the prior art: 3-butene-1-ol reacts with paratoluensulfonyl chloride in the presence of triethylamine, then undergoes nucleophilic substitution reaction with (S) -1-phenylethylamine to obtain allylamine, and finally cyclizes with glyoxylic acid to obtain 2- ((S) -1-phenylethyl) -6-oxa-2-azabicyclo [3.2.1] octane-7-one (J.Org.chem.1996,61, 2226-one 2231). The synthesis process of the 2- ((S) -1-phenethyl) -6-oxa-2-azabicyclo [3.2.1] octane-7-ketone has the advantages of yield of 60-72%, long reaction time, more byproducts, complex process, low production efficiency, large amount of waste liquid generated in the post-treatment process and large amount of whole waste liquid, and post-treatment operation is required after each step of reaction is finished.
Disclosure of Invention
An object of the present invention is to solve at least the above problems and to provide at least the advantages described later.
The invention aims to provide a synthesis process of 2- ((S) -1-phenethyl) -6-oxa-2-azabicyclo [3.2.1] octane-7-ketone, which is simple to operate, low in cost, green and efficient.
To achieve these objects and other advantages in accordance with the present invention, there is provided a 2- ((S) -1-phenylethyl) -6-oxa-2-azabicyclo [3.2.1] octan-7-one synthesized by the steps of:
mixing a mixed solution of 3-buten-1-ol and alkali A and an activating reagent solution in a micro mixer, and allowing the mixed solution to flow into a first reactor for reaction to obtain an intermediate I solution;
step (2), mixing the intermediate solution I, the (S) -1-phenylethylamine and the alkali solution B in a micro mixer, and allowing the mixture to flow into a second reactor for reaction to obtain an intermediate solution II;
step (3), mixing the intermediate II solution with glyoxylic acid or glyoxylic acid hydrate solution in a micro mixer, and allowing the mixture to flow into a third reactor for reaction to obtain a target product 2- ((S) -1-phenethyl) -6-oxa-2-azabicyclo [3.2.1] octane-7-ketone;
the chemical reaction process of the synthesis method is as follows:
preferably, in the step (1), the activating reagent is sulfonyl halide or sulfonic anhydride; the base A is one or more of triethylamine, pyridine, substituted pyridine, diisopropylethylamine and 1, 8-diazabicyclo [5.4.0] undec-7-ene.
Preferably, the activating agent is methanesulfonic anhydride.
Preferably, in the step (1), the ratio of 3-buten-1-ol: activating reagent: the molar ratio of the base A is 1.0: (1.0-1.5): (1.0-3.0), wherein the organic solvent is one or more of tetrahydrofuran, acetonitrile, dichloromethane, toluene, acetone, diethyl ether, chloroform, ethyl acetate, N-dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, dichloroethane and pyridine.
Preferably, in the step (1), the reaction temperature is 0-60 ℃, and the residence time of the reaction mixture is 1-30 minutes.
Preferably, in step (2), the alkali B solution is one of pure organic alkali, organic solution of organic alkali or aqueous solution of inorganic alkali.
Preferably, the inorganic base is one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, lithium bicarbonate, potassium bicarbonate and sodium bicarbonate; the organic base is one or more of triethylamine, pyridine, 2, 6-lutidine, 4-dimethylaminopyridine, diisopropylethylamine and 1, 8-diazabicyclo [5.4.0] undec-7-ene.
Preferably, in the step (2), the intermediate I solution: (S) -1-phenylethylamine: the molar ratio of the alkali B is 1 (1.0-1.5): (0-3.0), the reaction temperature is 60-260 ℃, and the reaction time is 10-100 minutes.
Preferably, in the step (3), the intermediate II solution: the molar ratio of the glyoxylic acid or the glyoxylic acid hydrate is 1 (1.0-3.0), the reaction temperature is 60-160 ℃, the reaction time is 10-100 minutes, and the backpressure valve is 1.0-3.0 MPa.
Preferably, the reactor in the steps (1) to (3) is any one of a microchannel reactor, a serial coil reactor and a tubular reactor, and the micromixer in the steps (1) to (3) is any one of a T-shaped micromixer, a Y-shaped micromixer, a multi-interaction thin-layer micromixer, a static micromixer, a chaotic micromixer and a dynamic micromixer.
The invention at least comprises the following beneficial effects:
1. the synthesis of 2- ((S) -1-phenethyl) -6-oxa-2-azabicyclo [3.2.1] octane-7-ketone is realized, the intermediate does not need to be separated and purified, the final product can be directly obtained, and the total yield is stabilized at 64-77%;
2. in the process, the complicated operation flow is greatly simplified, the reaction time is greatly shortened, and the generation amount and the types of waste are obviously reduced, so the synthesis process of the 2- ((S) -1-phenethyl) -6-oxa-2-azabicyclo [3.2.1] octane-7-ketone provided by the invention has the advantages of low cost, simple and convenient operation, high space-time efficiency, low three-waste discharge and the like.
Additional advantages, objects, and features of the invention will be set forth in part in the description which follows and in part will become apparent to those having ordinary skill in the art upon examination of the following or may be learned from practice of the invention.
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FIG. 1 is a synthetic scheme of the process of the present invention.
Detailed Description
The present invention is further described in detail below with reference to the attached drawings so that those skilled in the art can implement the invention by referring to the description text.
It will be understood that terms such as "having," "including," and "comprising," as used herein, do not preclude the presence or addition of one or more other elements or groups thereof.
Example 1
The synthetic route of the 2- ((S) -1-phenethyl) -6-oxa-2-azabicyclo [3.2.1] octane-7-ketone is shown in figure 1, the acetonitrile mixed solution of 3-buten-1-ol and triethylamine (alkali A) and the acetonitrile solution of methanesulfonic anhydride are respectively conveyed by a pump A and a pump B to be mixed in a T-shaped micro mixer, the mixed material then enters a series coil reactor, the total volume of the reactor is 8mL, and the reaction temperature is 30 ℃.
Adjusting the concentration of raw materials and the flow rate of a feed pump to ensure that the molar ratio of 3-buten-1-ol, methanesulfonic anhydride and triethylamine (base A) is 1:1.1:1.2, reacting for 5 minutes (namely the retention time of the mixed reaction materials in a reactor), mixing a reaction solution with an acetonitrile solution of (S) -1-phenylethylamine (pumped by a pump C) and an acetonitrile solution of triethylamine (pumped by a pump D) in a T-shaped micro mixer, then feeding the mixed materials into a series-wound coil reactor, ensuring that the total volume of the reactor is 16mL, the reaction temperature is 200 ℃, adjusting the concentration of the solution and the flow rate of the feed pump to ensure that the 3-buten-1-ol, the molar ratio of (S) -1-phenylethylamine to triethylamine (base B) was 1:1.1:1.2, the reaction was carried out for 16 minutes, and the reaction mixture was mixed with an acetonitrile solution of glyoxylic acid (pumped in by pump E) in a T-type micromixer.
The mixed material then enters a series-connected coil reactor, the total volume of the reactor is 16mL, the reaction temperature is 120 ℃, and the concentration of the glyoxylic acid solution and the flow rate of a feed pump are adjusted to ensure that the ratio of 3-butene-1-alcohol: the molar ratio of glyoxylic acid is 1:1.5, the reaction is carried out for 30 minutes, the backpressure valve is 2.0Mpa, and the acetonitrile solution of 2- ((S) -1-phenethyl) -6-oxa-2-azabicyclo [3.2.1] octane-7-ketone is obtained after a period of time.
The reaction process is as follows:
concentrating the obtained 2- ((S) -1-phenethyl) -6-oxa-2-azabicyclo [3.2.1] octane-7-ketone solution, adding saturated saline solution, adjusting the pH value to 8-9 by using sodium carbonate, extracting by using ethyl acetate, washing an organic phase by using saturated sodium bicarbonate solution, washing by using saturated saline solution, drying by using anhydrous sodium sulfate, filtering, and distilling under reduced pressure to obtain the 2- ((S) -1-phenethyl) -6-oxa-2-azabicyclo [3.2.1] octane-7-ketone with the yield of 76%.
Example 2
The overall scheme of this example is substantially the same as that of example 1, except that:
in this example, the pump a was fed with a solution of 3-buten-1-ol and diisopropylethylamine (base a) in acetonitrile, the raw material concentration and the feed pump flow rate were adjusted so that the molar ratio of 3-buten-1-ol, methanesulfonic anhydride and diisopropylethylamine was 1:1.5:2.2, the reaction temperature in the first step was 0 ℃, and the reaction was carried out for 30 minutes, whereby the product 2- ((S) -1-phenylethyl) -6-oxa-2-azabicyclo [3.2.1] octan-7-one obtained in this example was obtained in 74% yield.
Example 3
The overall scheme of this example is substantially the same as that of example 1, except that:
in the embodiment, the feed of the pump A is a mixture of 3-butene-1-alcohol and triethylamine, and no solvent is added; the raw material concentration and the flow rate of a feed pump are adjusted so that the molar ratio of 3-butene-1-1, methanesulfonic anhydride and triethylamine (base A) is 1:1.0:3.0, the reaction temperature in the first step is 60 ℃, and the reaction is carried out for 1 minute. Without pump D, base B is not required and the remainder of base A from the first step participates in the second reaction. The product, 2- ((S) -1-phenylethyl) -6-oxa-2-azabicyclo [3.2.1] octan-7-one, obtained in this example was 73% yield.
Example 4
The overall scheme of this example is substantially the same as that of example 1, except that:
in this example, pump B was fed with ethylsulfonyl chloride and the feed concentration and feed pump flow rate were adjusted so that 3-buten-1-ol: ethylsulfonyl chloride: the molar ratio of triethylamine (base A) was 1:1.1:1.5, the reaction temperature in the first step was 50 ℃ and the reaction time was 4 minutes. The product, 2- ((S) -1-phenylethyl) -6-oxa-2-azabicyclo [3.2.1] octan-7-one, obtained in this example was 71% yield.
Example 5
The overall scheme of this example is substantially the same as that of example 1, except that:
in this example, the feed to pump D was aqueous sodium hydroxide (base B) and the feed concentration and feed pump flow rate were adjusted to give 3-buten-1-ol: (S) -1-phenylethylamine: the molar ratio of the sodium hydroxide is 1:1.0:1.0, the reaction temperature in the second step is 60 ℃, the reaction time is 100 minutes, and the second micro mixer is a Y-shaped mixer. The product, 2- ((S) -1-phenylethyl) -6-oxa-2-azabicyclo [3.2.1] octan-7-one, obtained in this example was 66%.
Example 6
The overall scheme of this example is substantially the same as that of example 1, except that:
in this example, the feed of pump C was a mixed solution of (S) -1-phenylethylamine and pyridine in acetonitrile, the feed concentration and the flow rate of the feed pump were adjusted without using pump D so that the molar ratio of 3-buten-1-ol to (S) -1-phenylethylamine to pyridine was 1:1.5:3.0, the reaction temperature in the second step was 260 ℃ and the reaction was carried out for 10 minutes. The product, 2- ((S) -1-phenylethyl) -6-oxa-2-azabicyclo [3.2.1] octan-7-one, obtained in this example was 64% yield.
Example 7
The overall scheme of this example is substantially the same as that of example 1, except that:
in this example, pump a fed a solution of 3-buten-1-ol and diisopropylethylamine (base a) in acetonitrile, pump D fed a solution of diisopropylethylamine in acetonitrile, and the feed concentration and feed pump flow rate were adjusted so that the ratio of 3-buten-1-ol: (S) -1-phenylethylamine: the molar ratio of diisopropylethylamine (base B) was 1:1.2: 2.0. The product, 2- ((S) -1-phenylethyl) -6-oxa-2-azabicyclo [3.2.1] octan-7-one, obtained in this example was 76% yield.
Example 8
The overall scheme of this example is substantially the same as that of example 1, except that:
in this example, the feed concentration and the feed pump flow rate were adjusted so that the ratio of 3-buten-1-ol: the molar ratio of the glyoxylic acid is 1:1.0, the reaction temperature of the mixture of the intermediate II solution and the glyoxylic acid solution is 60 ℃, the reaction time is 100 minutes, and the back pressure of a back pressure valve is 1.0 Mpa. The product, 2- ((S) -1-phenylethyl) -6-oxa-2-azabicyclo [3.2.1] octan-7-one, obtained in this example was 75% yield.
Example 9
The overall scheme of this example is substantially the same as that of example 1, except that:
in this example, the feed concentration and the feed pump flow rate were adjusted so that the ratio of 3-buten-1-ol: the molar ratio of the glyoxylic acid is 1:3.0, the reaction temperature of the mixture of the intermediate II solution and the glyoxylic acid solution is 160 ℃, the reaction time is 10 minutes, and the backpressure valve is 3 Mpa. The product, 2- ((S) -1-phenylethyl) -6-oxa-2-azabicyclo [3.2.1] octan-7-one, obtained in this example was 69%.
Example 10
The overall scheme of this example is substantially the same as that of example 1, except that:
in the present example, the feed of pump E was N, N-dimethylacetamide solution of glyoxylic acid hydrate (pumped in by pump E), and the material concentration and the flow rate of the feed pump were adjusted so that the molar ratio of 3-buten-1-ol to glyoxylic acid hydrate was 1:1.8, the reaction temperature was 100 ℃ and the reaction time was 60 minutes. The product, 2- ((S) -1-phenylethyl) -6-oxa-2-azabicyclo [3.2.1] octan-7-one, obtained in this example was 73% yield.
Example 11
The overall scheme of this example is substantially the same as that of example 1, except that:
in this example, the feed to pump A was a solution of 3-buten-1-ol and triethylamine in N, N-dimethylacetamide, and the feed to pump B was a solution of methanesulfonic anhydride in N, N-dimethylacetamide. Pump E feed was glyoxylic acid (50% aqueous solution) with no solvent added. The product, 2- ((S) -1-phenylethyl) -6-oxa-2-azabicyclo [3.2.1] octan-7-one, obtained in this example was 71% yield.
Example 12
The overall scheme of this example is substantially the same as that of example 1, except that:
in this example, pump A was fed with a mixture of 3-buten-1-ol and triethylamine (base A) without solvent addition, and pump C was fed with a mixture of (S) -1-phenylethylamine and diisopropylethylamine (base B) without solvent addition and without pump D. Pump E feed was glyoxylic acid (50% aqueous solution) with no solvent added. The product, 2- ((S) -1-phenylethyl) -6-oxa-2-azabicyclo [3.2.1] octan-7-one, obtained in this example was 75% yield.
Example 13
The overall scheme of this example is substantially the same as that of example 1, except that:
in the present example, the pump A was fed with a mixture of 3-buten-1-ol and triethylamine (base A) without adding a solvent, the material concentration and the feed pump flow rate were adjusted so that the molar ratio of 3-buten-1-ol, methanesulfonic anhydride and triethylamine (base A) was 1:1.1:3.0, the pump C was fed with (S) -1-phenylethylamine without adding a solvent, the pump D was not used, the base B was not fed, and the first remaining base A participated in the second reaction. Pump E feed was glyoxylic acid (50% aqueous solution) with no solvent added. The product, 2- ((S) -1-phenylethyl) -6-oxa-2-azabicyclo [3.2.1] octan-7-one, obtained in this example was 72% yield.
Example 14
The overall scheme of this example is substantially the same as that of example 1, except that:
the reactor in this example is a microchannel reactor and the micromixer is a static mixer. The product obtained in this example, 2- ((S) -1-phenylethyl) -6-oxa-2-azabicyclo [3.2.1] octan-7-one, was 77% yield.
From the above, compared with the prior art, the invention provides a novel synthesis process of 2- ((S) -1-phenethyl) -6-oxa-2-azabicyclo [3.2.1] octane-7-ketone, the intermediate steps of the process provided by the invention do not need separation and purification, the total yield is stable at 64-77%, in the process, the complicated operation flow is greatly simplified, the reaction time is greatly shortened, and the generation amount and the types of waste are obviously reduced. Therefore, the synthesis process of the 2- ((S) -1-phenethyl) -6-oxa-2-azabicyclo [3.2.1] octane-7-ketone provided by the invention has the advantages of low cost, simple and convenient operation, high space-time efficiency, low three-waste discharge and the like.
While embodiments of the invention have been described above, it is not limited to the applications set forth in the description and the embodiments, which are fully applicable in various fields of endeavor to which the invention pertains, and further modifications may readily be made by those skilled in the art, it being understood that the invention is not limited to the details shown and described herein without departing from the general concept defined by the appended claims and their equivalents.
Claims (10)
1. 2- ((S) -1-phenylethyl) -6-oxa-2-azabicyclo [3.2.1] octan-7-one characterized in that said 2- ((S) -1-phenylethyl) -6-oxa-2-azabicyclo [3.2.1] octan-7-one is synthesized by the steps of:
mixing a mixed solution of 3-buten-1-ol and alkali A and an activating reagent solution in a micro mixer, and allowing the mixed solution to flow into a first reactor for reaction to obtain an intermediate I solution;
step (2), mixing the intermediate solution I, the (S) -1-phenylethylamine and the alkali solution B in a micro mixer, and allowing the mixture to flow into a second reactor for reaction to obtain an intermediate solution II;
and (3) mixing the intermediate II solution with glyoxylic acid or glyoxylic acid hydrate solution in a micro mixer, and then flowing into a third reactor for reaction to obtain a target product 2- ((S) -1-phenethyl) -6-oxa-2-azabicyclo [3.2.1] octane-7-ketone.
2. The 2- ((S) -1-phenylethyl) -6-oxa-2-azabicyclo [3.2.1] octan-7-one of claim 1 wherein in step (1) the activating agent is a sulfonyl halide or a sulfonic anhydride; the base A is one or more of triethylamine, pyridine, substituted pyridine, diisopropylethylamine and 1, 8-diazabicyclo [5.4.0] undec-7-ene.
3. 2- ((S) -1-phenylethyl) -6-oxa-2-azabicyclo [3.2.1] octan-7-one of claim 2 wherein the activating agent is methanesulfonic anhydride.
4. 2- ((S) -1-phenylethyl) -6-oxa-2-azabicyclo [3.2.1] octan-7-one according to claim 2 wherein in step (1) 3-buten-1-ol: activating reagent: the molar ratio of the base A is 1.0: (1.0-1.5): (1.0-3.0), wherein the organic solvent is one or more of tetrahydrofuran, acetonitrile, dichloromethane, toluene, acetone, diethyl ether, chloroform, ethyl acetate, N-dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, dichloroethane and pyridine.
5. The 2- ((S) -1-phenylethyl) -6-oxa-2-azabicyclo [3.2.1] octan-7-one of claim 4 wherein in step (1) the reaction temperature is 0-60 ℃ and the residence time of the reaction mixture is 1-30 minutes.
6. The 2- ((S) -1-phenylethyl) -6-oxa-2-azabicyclo [3.2.1] octan-7-one of claim 5 wherein in step (2) the base B solution is one of a neat organic base, an organic solution of an organic base, or an aqueous solution of an inorganic base.
7. The 2- ((S) -1-phenylethyl) -6-oxa-2-azabicyclo [3.2.1] octan-7-one of claim 6 wherein the inorganic base is one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, lithium bicarbonate, potassium bicarbonate, sodium bicarbonate; the organic base is one or more of triethylamine, pyridine, 2, 6-lutidine, 4-dimethylaminopyridine, diisopropylethylamine and 1, 8-diazabicyclo [5.4.0] undec-7-ene.
8. The 2- ((S) -1-phenylethyl) -6-oxa-2-azabicyclo [3.2.1] octan-7-one of claim 6 wherein in step (2) intermediate I solution: (S) -1-phenylethylamine: the molar ratio of the alkali B is 1 (1.0-1.5): (0-3.0), the reaction temperature is 60-260 ℃, and the reaction time is 10-100 minutes.
9. The 2- ((S) -1-phenylethyl) -6-oxa-2-azabicyclo [3.2.1] octan-7-one of claim 8 wherein in step (3) intermediate II solution: the molar ratio of the glyoxylic acid or the glyoxylic acid hydrate is 1 (1.0-3.0), the reaction temperature is 60-160 ℃, the reaction time is 10-100 minutes, and the backpressure valve is 1.0-3.0 MPa.
10. The 2- ((S) -1-phenylethyl) -6-oxa-2-azabicyclo [3.2.1] octan-7-one of claim 9 wherein the reactor of steps (1) - (3) is any one of a microchannel reactor, a series coil reactor, and a tubular reactor, and the micromixer of steps (1) - (3) is any one of a T-type micromixer, a Y-type micromixer, a multi-interaction thin-layer micromixer, a static micromixer, a chaotic micromixer, and a dynamic micromixer.
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