阅读说明：本技术 一种R-N-Boc-3-吡咯烷乙酸的制备方法 (Preparation method of R-N-Boc-3-pyrrolidineacetic acid ) 是由 史曼曼 黄龙龙 吴天俊 于 2020-06-12 设计创作，主要内容包括：本发明提供一种R-N-Boc-3-吡咯烷乙酸的制备方法,所述制备方法以N-Boc-3-吡咯烷酮和三甲基膦酰基乙酸酯为原料,经wittig反应、不对称还原氢化反应和水解反应得到所述R-N-Boc-3-吡咯烷乙酸。所述制备方法从价格低廉的混旋体N-Boc-3-吡咯烷酮出发,反应条件温和,无需使用危险性物料,且反应步骤较少,过程简单,最终能够得到单一的具有目标手性结构的产物R-N-Boc-3-吡咯烷乙酸,且产物纯度较高,其光学活性ee值＞99％,得率也较高,有利于工业化放大生产。(The invention provides a preparation method of R-N-Boc-3-pyrrolidine acetic acid, which comprises the steps of taking N-Boc-3-pyrrolidone and trimethylphosphonyl acetate as raw materials, and carrying out wittig reaction, asymmetric reduction hydrogenation reaction and hydrolysis reaction on the raw materials to obtain the R-N-Boc-3-pyrrolidine acetic acid. The preparation method starts from low-cost mixed isomer N-Boc-3-pyrrolidone, has mild reaction conditions, does not need to use dangerous materials, has fewer reaction steps and simple process, can finally obtain a single product R-N-Boc-3-pyrrolidineacetic acid with a target chiral structure, has higher product purity, has an optical activity ee value of more than 99 percent and higher yield, and is favorable for industrial amplification production.)

1. The preparation method of the R-N-Boc-3-pyrrolidine acetic acid is characterized in that N-Boc-3-pyrrolidone and trimethylphosphonyl acetate are used as raw materials, and the R-N-Boc-3-pyrrolidine acetic acid is obtained through wittig reaction, asymmetric reduction hydrogenation reaction and hydrolysis reaction.

2. The method of claim 1, comprising the steps of:

(1) N-Boc-3-pyrrolidone and trimethylphosphonoacetic ester are subjected to wittig reaction in the presence of an alkaline reagent to obtain a compound shown in the formula I, wherein the reaction process is as follows:

(2) the compound shown in the formula I is subjected to asymmetric reduction hydrogenation reaction under the action of L-proline and a reducing agent to obtain R-N-Boc-3-pyrrolidine methyl acetate, and the reaction process is as follows:

(3) and carrying out hydrolysis reaction on the R-N-Boc-3-pyrrolidine methyl acetate in the presence of an alkaline reagent to obtain the R-N-Boc-3-pyrrolidine acetic acid.

3. The method according to claim 2, wherein the molar ratio of N-Boc-3-pyrrolidone and trimethylphosphonoacetate in the step (1) is 1 (1-1.2);

preferably, the alkaline reagent of step (1) comprises sodium tert-butoxide and/or potassium tert-butoxide;

preferably, the molar ratio of the N-Boc-3-pyrrolidone to the sodium tert-butoxide is 1 (1.1-1.3).

4. The preparation method according to claim 2 or 3, wherein the temperature of the wittig reaction in the step (1) is-5 to 5 ℃;

preferably, the wittig reaction time in the step (1) is 1.5-2.5 h;

preferably, the solvent for the wittig reaction in step (1) comprises any one or a combination of at least two of tetrahydrofuran, dichloromethane, chloroform, n-hexane, acetonitrile, diethyl ether, methyl tert-butyl ether or ethyl acetate, preferably tetrahydrofuran.

5. The preparation method according to any one of claims 2 to 4, wherein the reducing agent in the step (2) comprises any one or a combination of at least two of sodium borohydride, potassium borohydride, lithium triacetoxyborohydride, sodium triacetoxyborohydride and potassium triacetoxyborohydride;

preferably, the molar ratio of the compound shown in the formula I to the reducing agent is 1 (2-3);

preferably, the temperature of the reducing agent added into the reaction solution in the step (2) is-5 ℃.

6. The production method according to any one of claims 2 to 5, wherein the L-proline in the step (2) is dissolved in methanol;

preferably, the temperature of the L-proline dissolved in the methanol in the step (2) is-15 to-8 ℃;

preferably, the molar ratio of the compound shown in the formula I to L-proline is 1 (6-8).

7. The production method according to any one of claims 2 to 6, wherein the conditions for the asymmetric reductive hydrogenation in the step (2) include: reacting for 1-2 h at-5 ℃, then heating to 20-28 ℃, and reacting for 12-16 h;

preferably, the asymmetric reduction hydrogenation reaction in the step (2) further comprises an operation of adjusting pH after finishing.

8. The preparation method according to any one of claims 2 to 7, wherein after the asymmetric reductive hydrogenation reaction in the step (2) is completed, the R-N-Boc-3-pyrrolidine methyl acetate is obtained by extraction and separation;

preferably, the extractant is a mixed solution of petroleum ether and ethyl acetate;

preferably, the volume ratio of the petroleum ether to the ethyl acetate is 1 (1-1.2).

9. The method according to any one of claims 2 to 8, wherein the alkaline reagent of step (3) comprises lithium hydroxide and/or potassium hydroxide;

preferably, the molar ratio of the R-N-Boc-3-pyrrolidine methyl acetate to the alkaline reagent in the step (3) is 1 (1.5-2.5);

preferably, the hydrolysis reaction also comprises the operation of adjusting pH;

preferably, the pH value is 1-2.

10. The method according to any one of claims 1 to 9, characterized by comprising the steps of:

(1) dissolving trimethyl phosphono acetate in tetrahydrofuran, adding the tetrahydrofuran solution containing sodium tert-butoxide, stirring for 2 hours at the temperature of-5 ℃, adding N-Boc-3-pyrrolidone, wherein the molar ratio of the N-Boc-3-pyrrolidone to the sodium tert-butoxide is 1 (1.1-1.3), the molar ratio of the compound shown in the formula I to a reducing agent is 1 (2-3), and continuously stirring for 1 hour at the temperature of-5 ℃ to obtain the compound shown in the formula I;

(2) dissolving L-proline in methanol at the temperature of-15 to-8 ℃, adding sodium borohydride, heating to-5 to 5 ℃, stirring, cooling to-15 to-8 ℃, adding a compound shown as a formula I dissolved in dichloromethane, wherein the molar ratio of the compound shown as the formula I to the sodium borohydride is 1 (2 to 3), the molar ratio of the compound shown as the formula I to the L-proline is 1 (6 to 8), heating to-5 to 5 ℃, stirring for 1 to 2 hours, heating to 20 to 28 ℃, reacting for 12 to 16 hours, adding hydrochloric acid to adjust the pH, adding water, and extracting by using an extracting agent, wherein the extracting agent is a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 1 (1 to 1.2), so as to obtain R-N-Boc-3-pyrrolidine methyl acetate;

(3) dissolving the R-N-Boc-3-pyrrolidine methyl acetate in tetrahydrofuran and water, adding lithium hydroxide at the temperature of-5 ℃, wherein the molar ratio of the R-N-Boc-3-pyrrolidine methyl acetate to the lithium hydroxide is 1 (1.5-2.5), adding water for layering, adjusting the pH value of a water phase to 1-2 by hydrochloric acid, and extracting by using ethyl acetate to obtain the R-N-Boc-3-pyrrolidine acetic acid.

Technical Field

The invention belongs to the field of fine chemical engineering, and relates to a preparation method of R-N-Boc-3-pyrrolidine acetic acid.

Background

R-N-Boc-3-pyrrolidineacetic acid (R-N-tert-butyloxycarbonyl-3-tetrahydropyrroleacetic acid) is an important medical synthetic intermediate. The known synthetic route starts from R-N-Boc-3-hydroxypyrrolidine, and the R-N-Boc-3-pyrrolidineacetic acid is obtained after four-step reactions of methane sulfonylation, nucleophilic substitution, hydrolysis and decarboxylation, and the specific reaction route is shown as follows:

however, this synthesis method uses relatively expensive starting materials, and in the first step, methanesulfonyl chloride, which is a highly toxic reagent, is used; in the second step, large excess diethyl propionate is used, the usage amount of the diethyl propionate is 4 equivalents of the raw materials, otherwise, the reaction can not completely occur; meanwhile, the large excess of diethyl propionate causes that a large excess of strong base (16 equivalents of potassium hydroxide) must be used in the third hydrolysis step, and then a large amount of acid is needed for neutralization to be acidic, so that a large amount of waste water and waste acid are generated. The synthetic route has large pollution and is not suitable for industrial amplification.

Therefore, the development of a process synthetic route with easily available raw materials, simple process route and higher safety to realize the industrial production of the R-N-Boc-3-pyrrolidine acetic acid is a problem to be solved in the field.

Disclosure of Invention

In view of the problems in the prior art, the invention provides the preparation method of the R-N-Boc-3-pyrrolidine acetic acid, and the preparation method has the advantages of cheap and easily-obtained raw materials, simple preparation process, high total yield and easy industrial production.

In order to achieve the purpose, the invention adopts the following technical scheme:

the invention provides a preparation method of R-N-Boc-3-pyrrolidine acetic acid, which comprises the steps of taking N-Boc-3-pyrrolidone and trimethylphosphonyl acetate as raw materials, and carrying out wittig reaction, asymmetric reduction hydrogenation reaction and hydrolysis reaction on the raw materials to obtain the R-N-Boc-3-pyrrolidine acetic acid.

According to the preparation method, starting from N-Boc-3-pyrrolidone of a cheaper mixed cyclone, firstly, wittig reaction is carried out on the N-Boc-3-pyrrolidone and trimethyl phosphono acetate to directly convert aldehyde into olefin, new carbon atoms are introduced, and then asymmetric reduction hydrogenation reaction is carried out, so that carbon-carbon double bonds are converted into carbon-carbon single bonds through catalytic hydrogenation, asymmetric reduction is also realized to obtain single chiral R-N-Boc-3-pyrrolidine methyl acetate, and finally R-N-Boc-3-pyrrolidine acetic acid is obtained through a simple hydrolysis step, so that the reaction condition is mild, the process is simple, the total yield is higher, and industrial production is easy.

As a preferred technical scheme of the invention, the preparation method comprises the following steps:

(1) N-Boc-3-pyrrolidone and trimethylphosphonoacetic ester are subjected to wittig reaction in the presence of an alkaline reagent to obtain a compound shown in the formula I, wherein the reaction process is as follows:

(2) the compound shown in the formula I is subjected to asymmetric reduction hydrogenation reaction under the action of L-proline and a reducing agent to obtain R-N-Boc-3-pyrrolidine methyl acetate, and the reaction process is as follows:

(3) and carrying out hydrolysis reaction on the R-N-Boc-3-pyrrolidine methyl acetate in the presence of an alkaline reagent to obtain the R-N-Boc-3-pyrrolidine acetic acid.

The overall reaction process can be represented by the following equation:

in a preferred embodiment of the present invention, the molar ratio of N-Boc-3-pyrrolidone and trimethylphosphonoacetate in step (1) is 1 (1 to 1.2), and may be, for example, 1:1, 1:1.05, 1:1.08, 1:1.1, 1:1.12, 1:1.14, 1:1.15, 1:1.18 or 1: 1.2.

Preferably, the alkaline agent of step (1) comprises sodium tert-butoxide and/or potassium tert-butoxide.

Preferably, the molar ratio of the N-Boc-3-pyrrolidone to sodium tert-butoxide is 1 (1.1 to 1.3), and may be, for example, 1:1.1, 1:1.15, 1:1.18, 1:1.2, 1:1.22, 1:1.24, 1:1.25, 1:1.28, or 1: 1.3.

Preferably, the temperature of the wittig reaction in the step (1) is-5 to 5 ℃, for example, -5 ℃, -4 ℃, -3 ℃, -2 ℃, -1 ℃, 0 ℃, 1 ℃, 2 ℃, 3 ℃, 4 ℃ or 5 ℃ and the like.

Preferably, the wittig reaction time in the step (1) is 1.5-2.5 h, for example, 1.5h, 1.6h, 1.7h, 1.8h, 1.9h, 2h, 2.1h, 2.2h, 2.3h, 2.4h or 2.5h, etc.

Preferably, the solvent for the wittig reaction in step (1) comprises any one or a combination of at least two of tetrahydrofuran, dichloromethane, chloroform, n-hexane, acetonitrile, diethyl ether, methyl tert-butyl ether or ethyl acetate, preferably tetrahydrofuran.

As a preferred technical scheme of the invention, the reducing agent in the step (2) comprises sodium borohydride and/or potassium borohydride.

Preferably, the molar ratio of the compound represented by the formula I to the reducing agent is 1 (2-3), and may be, for example, 1:2, 1:2.2, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, or 1: 3.

Preferably, the temperature of the reducing agent added to the reaction solution in the step (2) is-5 to 5 ℃, and may be, for example, -5 ℃, -4 ℃, -3 ℃, -2 ℃, -1 ℃, 0 ℃, 1 ℃, 2 ℃, 3 ℃, 4 ℃ or 5 ℃.

Preferably, the L-proline of step (2) is dissolved in methanol.

Preferably, the L-proline in step (2) is dissolved in methanol at a temperature of-15 to-8 ℃, and may be, for example, -15 ℃, -14 ℃, -13 ℃, -12 ℃, -11 ℃, -10 ℃, -9 ℃ or-8 ℃.

Preferably, the molar ratio of the compound represented by the formula I to L-proline is 1 (6-8), and may be, for example, 1:6, 1:6.2, 1:6.4, 1:6.6, 1:6.8, 1:7, 1:7.2, 1:7.4, 1:7.5, 1:7.6, 1:7.8 or 1: 8.

Preferably, the conditions of the asymmetric reductive hydrogenation reaction in the step (2) are as follows: reacting for 1 to 2 hours (for example, 1 hour, 1.2 hours, 14 hours, 1.5 hours, 1.6 hours, 1.8 hours, or 2 hours) at-5 to 5 ℃ (for example, -5 ℃, -4 ℃, -2 ℃, -1 ℃, 0 ℃, 1 ℃, 2 ℃, 4 ℃ or 5 ℃, and the like), further heating to 20 to 28 ℃ (for example, 20 ℃, 22 ℃, 24 ℃, 25 ℃, 26 ℃, or 28 ℃, and the like), and reacting for 12 to 16 hours (for example, 12 hours, 12.5 hours, 13 hours, 13.5 hours, 14 hours, 14.5 hours, 15 hours, 15.5 hours, or 16 hours).

Preferably, the asymmetric reduction hydrogenation reaction in the step (2) further comprises an operation of adjusting pH after finishing.

Preferably, after the asymmetric reductive hydrogenation reaction in the step (2) is finished, the R-N-Boc-3-pyrrolidine methyl acetate is obtained by extraction and separation.

Preferably, the extractant is a mixed solution of petroleum ether and ethyl acetate.

Preferably, the volume ratio of the petroleum ether to the ethyl acetate is 1 (1-1.2), and may be, for example, 1:1, 1:1.05, 1:1.08, 1:1.1, 1:1.12, 1:1.14, 1:1.15, 1:1.18, or 1: 1.2.

As a preferred technical scheme of the invention, the alkaline reagent in the step (3) comprises lithium hydroxide and/or potassium hydroxide.

Preferably, the molar ratio of the R-N-Boc-3-pyrrolidineacetic acid methyl ester to the basic reagent is 1 (1.5-2.5), and may be, for example, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4, or 1: 1.5.

Preferably, the hydrolysis reaction further comprises an operation of adjusting the pH.

Preferably, the pH adjustment value is 1 to 2, and may be, for example, 1, 1.2, 1.4, 1.5, 1.6, 1.8, 2, or the like.

As a preferred technical scheme of the invention, the preparation method comprises the following steps:

(1) dissolving trimethyl phosphono acetate in tetrahydrofuran, adding the tetrahydrofuran solution containing sodium tert-butoxide, stirring for 2 hours at the temperature of-5 ℃, adding N-Boc-3-pyrrolidone, wherein the molar ratio of the N-Boc-3-pyrrolidone to the sodium tert-butoxide is 1 (1.1-1.3), the molar ratio of the compound shown in the formula I to a reducing agent is 1 (2-3), and continuously stirring for 1 hour at the temperature of-5 ℃ to obtain the compound shown in the formula I;

(2) dissolving L-proline in methanol at the temperature of-15 to-8 ℃, adding sodium borohydride, heating to-5 to 5 ℃, stirring, cooling to-15 to-8 ℃, adding a compound shown as a formula I dissolved in dichloromethane, wherein the molar ratio of the compound shown as the formula I to the sodium borohydride is 1 (2 to 3), the molar ratio of the compound shown as the formula I to the L-proline is 1 (6 to 8), heating to-5 to 5 ℃, stirring for 1 to 2 hours, heating to 20 to 28 ℃, reacting for 12 to 16 hours, adding hydrochloric acid to adjust the pH, adding water, and extracting by using an extracting agent, wherein the extracting agent is a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 1 (1 to 1.2), so as to obtain R-N-Boc-3-pyrrolidine methyl acetate;

(3) dissolving the R-N-Boc-3-pyrrolidine methyl acetate in tetrahydrofuran and water, adding lithium hydroxide at the temperature of-5 ℃, wherein the molar ratio of the R-N-Boc-3-pyrrolidine methyl acetate to the lithium hydroxide is 1 (1.5-2.5), adding water for layering, adjusting the pH value of a water phase to 1-2 by hydrochloric acid, and extracting by using ethyl acetate to obtain the R-N-Boc-3-pyrrolidine acetic acid.

Illustratively, the preparation method provided by the invention comprises the following steps:

(1) sodium tert-butoxide is dissolved in tetrahydrofuran, stirred and cooled to 0 ℃. Dissolving trimethyl phosphono acetic ester in tetrahydrofuran, dropwise adding into tetrahydrofuran solution containing sodium tert-butoxide, and stirring at zero temperature for 2 hr. Then, N-Boc-3-pyrrolidone was dissolved in tetrahydrofuran and added dropwise to the above solution.

The reaction was stirred at zero degrees for 1h, TLC detected disappearance of starting material, 1N hydrochloric acid (where N represents the equivalent concentration, i.e. 1L of solution containing gram equivalents of solute, 1N ═ 1mol/L for hydrochloric acid) was added dropwise to the acidic pH, water was added, layers were separated, the aqueous phase was extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate and concentrated to give the E/Z mixed target.

(2) Dissolving L-proline in methanol, adding sodium borohydride into one part of the solution at the temperature of-10 ℃, and stirring the solution for 1 hour after the solution is completely added until the temperature is zero. And cooling to-10 ℃, dissolving the target substance obtained in the first step into dichloromethane, dropwise adding the dichloromethane into the mixture, slowly heating to 0 ℃, stirring for 1h, and naturally heating to room temperature overnight.

TLC shows that the raw material disappears, 1N hydrochloric acid solution is dripped, water is added, layers are separated, the water phase is extracted by mixed liquid of petroleum ether and ethyl acetate in a ratio of 1:1, the organic phases are combined, anhydrous sodium sulfate is dried and concentrated to obtain a crude product which is not further purified and is directly used in the next step.

(3) Dissolving the target substance obtained in the second step in tetrahydrofuran and water, adding lithium hydroxide monohydrate into one part in ice bath, adding water after TLC shows that the raw materials disappear, carrying out layering, adjusting the pH of the water phase to 1-2 by using 1N hydrochloric acid, then extracting by using ethyl acetate, combining ethyl acetate phases, drying by using anhydrous sodium sulfate, filtering, concentrating until the organic phase is remained 1/4, adding petroleum ether, stirring for 1h at room temperature, filtering, and drying to obtain the target substance.

The recitation of numerical ranges herein includes not only the above-recited values, but also any values between any of the above-recited numerical ranges not recited, and for brevity and clarity, is not intended to be exhaustive of the specific values encompassed within the range.

Compared with the prior art, the invention has at least the following beneficial effects:

the preparation method of the R-N-Boc-3-pyrrolidine acetic acid provided by the invention is characterized in that N-Boc-3-pyrrolidone and trimethylphosphonyl acetate are used as raw materials, and the R-N-Boc-3-pyrrolidine acetic acid is obtained through wittig reaction, asymmetric reduction hydrogenation reaction and hydrolysis reaction, the method starts from N-Boc-3-pyrrolidone of a cheaper mixed cyclone, has mild reaction conditions, does not need to use dangerous materials, has simple process, fewer reaction steps and higher yield of each step of reaction, wherein the yield of the wittig reaction is 91.9-94.1%, the product obtained after the asymmetric reduction hydrogenation reaction can be directly applied to the hydrolysis reaction without purification, and the yield of the hydrolysis reaction is 89.7-94.6%, so the method is beneficial to industrial amplification production, and finally the R-N-Boc-3-pyrrolidine acetic acid with single conformation can be obtained The product has high purity, the ee value of the optical activity is more than 99 percent, the total yield is higher, and the industrial production is easy to realize.

Drawings

FIG. 1 is a high performance liquid chromatogram of N-Boc-3-pyrrolidineacetic acid mixed isomer.

FIG. 2 is a high performance liquid chromatogram of the product R-N-Boc-3-pyrrolidineacetic acid obtained in example 1.

Detailed Description

The technical solutions of the present invention are further described in the following embodiments with reference to the drawings, but the following examples are only simple examples of the present invention and do not represent or limit the scope of the present invention, which is defined by the claims.

In the following examples, the room temperature was 25 ℃.