CN111606836B - Preparation method of R-N-Boc-3-pyrrolidineacetic acid - Google Patents
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Abstract
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.
Description
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 ℃.
Example 1
This example provides a method for the preparation of R-N-Boc-3-pyrrolidineacetic acid.
(1) Sodium tert-butoxide (290g, 3.02mol) was dissolved in tetrahydrofuran (6L), stirred and cooled to 0 ℃. Trimethylphosphonoacetate (492g, 2.7mol) was dissolved in tetrahydrofuran (1L) and added dropwise to a solution of sodium tert-butoxide in tetrahydrofuran, after which stirring was continued at 0 ℃ for 2 h. Then adding N-Boc-3-pyrrolidone (500g, 2.7mol) dissolved in tetrahydrofuran (1L), and continuously stirring the reaction system at zero temperature for 1 h; this process can be represented by the following equation:
TLC detection of the disappearance of the starting material, 1N hydrochloric acid solution (2.5L) was added dropwise to make the pH acidic, 2L of water was added, the layers were separated, the aqueous phase was extracted twice with dichloromethane (1000mL), the organic phases were combined, dried over anhydrous sodium sulfate and concentrated to give 605g of E/Z mixed intermediate in 93.1% yield.
(2) L-proline (496g, 4.3mol) was dissolved in methanol (4L) and sodium borohydride (54g, 1.42mol) was added in one portion at-10 ℃ and stirred for 1h raising to 0 ℃ after addition. Cooling to-10 deg.C, dissolving the intermediate product (150g, 0.62mol) obtained in step (1) in dichloromethane (1L), adding dropwise into the above mixture, slowly heating to 0 deg.C, stirring for 1h, and naturally heating to room temperature overnight; this process can be represented by the following equation:
TLC showed disappearance of starting material, 1N hydrochloric acid solution (1L) was added dropwise, 2L water was added, layers were separated, the aqueous phase was extracted twice with a 1:1 mixture of petroleum ether and ethyl acetate (600mL), the organic phases were combined, dried over anhydrous sodium sulfate and concentrated to give 138g of crude product, which was directly used in the next step without further purification.
(3) The target (130g, 0.53mol) obtained in the second step was dissolved in tetrahydrofuran (700mL) and water (350mL), and lithium hydroxide (43g, 1mol) was added in one portion in ice bath; this process can be represented by the following equation:
TLC showed disappearance of starting material, water (1L) was added, layers were separated, the aqueous phase was adjusted to pH 2 with 1N hydrochloric acid and then extracted 3 times with ethyl acetate (700mL), the ethyl acetate phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to the remaining 1/4 organic phase, petroleum ether (150mL) was added, stirred at room temperature for 1h, filtered, and dried to afford 111g of the target compound in 91.3% yield.
The HPLC chromatogram of N-Boc-3-pyrrolidineacetic acid racemic mixture is shown in FIG. 1, and it can be seen that the racemic mixture shows peaks at 7.788 and 8.409min, and the peak areas are similar: the HPLC chromatogram of the target obtained in this example is shown in FIG. 2, and it has a distinct peak at 8.330 min.
Detecting to obtain the specific optical rotation [ a ] of the target object]D20-30.5(C1, MeOH); optical activity ee 99.9%;
1H NMR(400MHz,CDCl3)δ12.5(s,1H)3.70-3.55(m,1H)；3.54-3.34(m,1H)；3.36-3.22(m,1H)；2.62-2.50(m,1H)；2.48-2.40(m,2H)；2.14-2.03(m,2H)；1.63-1.52(m,1H)；1.45(s,9H)。
example 2
This example provides a method for the preparation of R-N-Boc-3-pyrrolidineacetic acid.
(1) Sodium tert-butoxide (337g, 3.51mol) was dissolved in tetrahydrofuran (6L), stirred and cooled to 0 ℃. Trimethylphosphonoacetate (590g, 3.24mol) was dissolved in tetrahydrofuran (1L) and added dropwise to a solution of sodium tert-butoxide in tetrahydrofuran, and the reaction was stirred at zero for 2 h. N-Boc-3-pyrrolidone (500g, 2.7mol) was then dissolved in tetrahydrofuran (1L) and added dropwise to the above solution.
The reaction system was stirred at zero for 1h, TLC detected disappearance of starting material, 1N hydrochloric acid solution (2.5L) was added dropwise until pH was acidic, 2L of water was added, layers were separated, aqueous phase was extracted twice with dichloromethane (1000mL), organic phases were combined, dried over anhydrous sodium sulfate and concentrated to obtain 612g of E/Z mixed target with 94.1% yield.
(2) L-proline (570g, 4.96mol) was dissolved in methanol (4L), sodium borohydride (71g, 1.86mol) was added in one portion at-10 deg.C, and the mixture was stirred at zero temperature for 1 h. The temperature was again lowered to-10 ℃ and the target obtained in the first step (150g, 0.62mol) was dissolved in dichloromethane (1L) and added dropwise to the above mixture, slowly warmed to 0 ℃ and stirred for 1h, then naturally warmed to room temperature overnight.
TLC showed disappearance of starting material, 1N hydrochloric acid solution (1L) was added dropwise, 2L water was added, layers were separated, the aqueous phase was extracted twice with a 1:1 mixture of petroleum ether and ethyl acetate (600mL), the organic phases were combined, dried over anhydrous sodium sulfate and concentrated to give 145g of crude product, which was directly used in the next step without further purification.
(3) Dissolving the target substance (130g, 0.53mol) obtained in the second step in tetrahydrofuran (700mL) and water (350mL), adding lithium hydroxide monohydrate (55g, 1.3mol) into a next portion in ice bath, adding water (1L) after TLC shows that the raw material disappears, separating layers, adjusting the pH of the water phase to 1 by using 1N hydrochloric acid, extracting 3 times by using ethyl acetate (700mL), combining the ethyl acetate phases, drying by using anhydrous sodium sulfate, filtering, concentrating until 1/4 remains in the organic phase, adding petroleum ether (150mL), stirring for 1h at room temperature, filtering, and drying to obtain 113g of the target substance with the yield of 92.9%.
Detecting a target product: specific rotation of [ a ]]D20-30.5(C1, MeOH); the optical activity ee was 99.9%.
Example 3
This example provides a method for the preparation of R-N-Boc-3-pyrrolidineacetic acid.
(1) Potassium tert-butoxide (339g, 3.02mol) was dissolved in tetrahydrofuran (6L), stirred and cooled to 0 ℃. Trimethylphosphonoacetate (492g, 2.7mol) was dissolved in tetrahydrofuran (1L) and added dropwise to a solution of sodium tert-butoxide in tetrahydrofuran, and the reaction was stirred at zero for 2.5 h. N-Boc-3-pyrrolidone (500g, 2.7mol) was then dissolved in tetrahydrofuran (1L) and added dropwise to the above solution.
The reaction system was stirred at zero for 1h, TLC detected disappearance of starting material, 1N hydrochloric acid solution (2.5L) was added dropwise until pH was acidic, 2L of water was added, layers were separated, aqueous phase was extracted twice with dichloromethane (1000mL), organic phases were combined, dried over anhydrous sodium sulfate and concentrated to give 603g of E/Z mixed target, yield 92.8%.
(2) L-proline (428g, 3.72mol) was dissolved in methanol (4L), sodium borohydride (47g, 1.24mol) was added in one portion at-15 deg.C, and stirring was carried out at zero temperature for 0.5 h. The temperature was again lowered to-15 ℃ and the target obtained in the first step (150g, 0.62mol) was dissolved in dichloromethane (1L) and added dropwise to the above mixture, slowly warmed to 0 ℃ and stirred for 1h, then naturally warmed to room temperature overnight.
TLC showed disappearance of starting material, 1N hydrochloric acid solution (1L) was added dropwise, 2L water was added, layers were separated, the aqueous phase was extracted twice with a 1:1 mixture of petroleum ether and ethyl acetate (600mL), the organic phases were combined, dried over anhydrous sodium sulfate and concentrated to give 141g of crude product, which was directly used in the next step without further purification.
(3) Dissolving the target substance (130g, 0.53mol) obtained in the second step in tetrahydrofuran (700mL) and water (350mL), adding lithium hydroxide monohydrate (34g, 0.8mol) into a next portion in ice bath, adding water (1L) after TLC shows that the raw material disappears, separating layers, adjusting the pH of the water phase to 1 by using 1N hydrochloric acid, extracting 3 times by using ethyl acetate (700mL), combining the ethyl acetate phases, drying by using anhydrous sodium sulfate, filtering, concentrating until 1/4 remains in the organic phase, adding petroleum ether (150mL), stirring for 1h at room temperature, filtering, and drying to obtain 115g of the target substance with the yield of 94.6%.
Detecting a target product: specific rotation of [ a ]]D20-30.5(C1, MeOH); the optical activity ee was 99.9%.
Example 4
(1) Sodium tert-butoxide (290g, 3.02mol) was dissolved in tetrahydrofuran (5L), stirred and cooled to-5 ℃. Trimethylphosphonoacetate (492g, 2.7mol) was dissolved in tetrahydrofuran (1L) and added dropwise to a solution of sodium tert-butoxide in tetrahydrofuran, and stirring was continued at 5 ℃ for 2h after the addition. Then N-Boc-3-pyrrolidone (500g, 2.7mol) dissolved in tetrahydrofuran (1L) was added and the reaction was stirred at zero degrees for 1.5 h;
TLC detection of the disappearance of the starting material, 1N hydrochloric acid solution (2.5L) was added dropwise to make the pH acidic, 2L of water was added, the layers were separated, the aqueous phase was extracted twice with dichloromethane (800mL), the organic phases were combined, dried over anhydrous sodium sulfate and concentrated to give 598g of E/Z mixed intermediate in 91.9% yield.
(2) L-proline (496g, 4.3mol) was dissolved in methanol (5L) and sodium borohydride (54g, 1.42mol) was added in one portion at-8 ℃ and stirred for 1h raising to 0 ℃ after addition. Cooling to-8 ℃, dissolving the intermediate product (150g, 0.62mol) obtained in the step (1) into dichloromethane (1L), dropwise adding the mixture into the mixture, slowly heating to 0 ℃, stirring for 1h, and naturally heating to room temperature overnight;
TLC showed disappearance of starting material, 1N hydrochloric acid solution (1L) was added dropwise, 2L water was added, layers were separated, the aqueous phase was extracted twice with a 1:1 mixture of petroleum ether and ethyl acetate (600mL), the organic phases were combined, dried over anhydrous sodium sulfate and concentrated to give 135g of crude product, which was directly used in the next step without further purification.
(3) The target (130g, 0.53mol) obtained in the second step was dissolved in tetrahydrofuran (1000mL) and water (350mL), and lithium hydroxide monohydrate (43g, 1mol) was added in one portion in ice bath;
TLC showed disappearance of starting material, water (1L) was added, layers were separated, the aqueous phase was adjusted to pH 2 with 1N hydrochloric acid and then extracted 3 times with ethyl acetate (500mL), the ethyl acetate phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to the organic phase residue 1/4, petroleum ether (200mL) was added, stirred at room temperature for 1h, filtered, and dried to afford 109g of target in 89.7% yield.
Detecting a target product: specific rotation of [ a ]]D20-30.5(C1, MeOH); the optical activity ee was 99.9%.
The applicant declares that the above description is only a specific embodiment of the present invention, but the scope of the present invention is not limited thereto, and it should be understood by those skilled in the art that any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope of the present invention are within the scope and disclosure of the present invention.
Claims (24)
1. A kind ofR-N-Boc-3-pyrrolidineacetic acid preparation process characterized by the steps of:
（1）N-Boc-3-pyrrolidone and trimethylphosphonoacetate in the presence of an alkaline reagent by a wittig reaction to obtain a compound represented by 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 obtainR-N-Boc-3-pyrrolidineMethyl acetate, the reaction process is as follows:
(3) the above-mentionedR-N-Boc-3-pyrrolidineacetic acid methyl ester is obtained after hydrolysis reaction in the presence of alkaline reagentR-N-Boc-3-pyrrolidineacetic acid.
2. The method according to claim 1, wherein the step (1) is carried out in the presence of a catalystNThe molar ratio of the-Boc-3-pyrrolidone to the trimethylphosphonoacetate is 1 (1-1.2).
3. The method according to claim 1, wherein the basic agent in step (1) is sodium tert-butoxide and/or potassium tert-butoxide.
4. The method of claim 3, wherein the step of preparing the composition is carried out in the presence of a catalystNThe molar ratio of the-Boc-3-pyrrolidone to the sodium tert-butoxide is 1 (1.1-1.3).
5. The preparation method according to claim 1, wherein the temperature of the wittig reaction in the step (1) is-5 to 5 ℃.
6. The preparation method of claim 1, wherein the wittig reaction time in the step (1) is 1.5-2.5 h.
7. The preparation method according to claim 1, wherein the solvent for the wittig reaction in step (1) is 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.
8. The preparation method according to claim 7, wherein the solvent for the wittig reaction in step (1) is tetrahydrofuran.
9. The preparation method according to claim 1, wherein the reducing agent in step (2) is any one or a combination of at least two of sodium borohydride, potassium borohydride, lithium triacetoxyborohydride, sodium triacetoxyborohydride and potassium triacetoxyborohydride.
10. The preparation method according to claim 1, wherein the molar ratio of the compound shown in the formula I to the reducing agent is 1 (2-3).
11. The method according to claim 1, wherein the temperature of the reducing agent added to the reaction solution in the step (2) is-5 to 5 ℃.
12. The method according to claim 1, wherein the L-proline in the step (2) is dissolved in methanol.
13. The method according to claim 12, wherein the L-proline in the step (2) is dissolved in methanol at a temperature of-15 to-8 ℃.
14. The preparation method according to claim 1, wherein the molar ratio of the compound represented by the formula I to L-proline is 1 (6-8).
15. The method according to claim 1, wherein the conditions of the asymmetric reductive hydrogenation of step (2) comprise: reacting for 1-2 h at-5 ℃, then heating to 20-28 ℃, and reacting for 12-16 h.
16. The method according to claim 1, wherein the asymmetric reductive hydrogenation in step (2) is further performed by adjusting pH after the reaction is completed.
17. According to claim 1The preparation method is characterized in that after the asymmetric reduction hydrogenation reaction in the step (2) is finished, the asymmetric reduction hydrogenation reaction is extracted and separated to obtain the productR-N-Boc-3-pyrrolidineacetic acid methyl ester.
18. The method of claim 17, wherein the extractant is a mixture of petroleum ether and ethyl acetate.
19. The preparation method according to claim 18, wherein the volume ratio of the petroleum ether to the ethyl acetate is 1 (1-1.2).
20. The method according to claim 1, wherein the alkaline agent in the step (3) is lithium hydroxide and/or potassium hydroxide.
21. The method of claim 1, wherein the step of preparing the composition is carried out in the presence of a catalystR-NThe molar ratio of the-Boc-3-pyrrolidine methyl acetate to the alkaline reagent in the step (3) is 1 (1.5-2.5).
22. The method according to claim 1, wherein the hydrolysis reaction is followed by an operation of adjusting pH.
23. The method according to claim 22, wherein the pH is adjusted to a value of 1 to 2.
24. The method of claim 1, comprising the steps of:
(1) dissolving trimethylphosphonoacetic ester in tetrahydrofuran, adding the solution into tetrahydrofuran solution containing sodium tert-butoxide, stirring the solution for 2 hours at the temperature of between 5 ℃ below zero and 5 ℃, and adding the solutionN-Boc-3-pyrrolidone, saidNThe mole ratio of-Boc-3-pyrrolidone to sodium tert-butoxide is 1 (1.1-1.3), and the mixture is continuously stirred for 1h at the temperature of-5 ℃ to obtain a compound shown in the formula I;
(2) under the condition of-15 to-8 DEG CDissolving L-proline in methanol, adding sodium borohydride, heating to-5 ℃, stirring, cooling to-15-8 ℃, 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 (2-3), the molar ratio of the compound shown as the formula I to the L-proline is 1 (6-8), heating to-5 ℃, stirring for 1-2 h, heating to 20-28 ℃, reacting for 12-16 h, adding hydrochloric acid to adjust the pH, adding water, and extracting by using an extracting agent, wherein the volume ratio of the extracting agent is 1 (1-1.2), namely a mixed solution of petroleum ether and ethyl acetate, to obtain the L-proline-containing mixed solutionR-N-Boc-3-pyrrolidineacetic acid methyl ester;
(3) will be described inR-N-Boc-3-pyrrolidineacetic acid methyl ester is dissolved in tetrahydrofuran and water, -lithium hydroxide is added at 5-5 ℃, andR-Nthe molar ratio of-Boc-3-pyrrolidine methyl acetate to lithium hydroxide is 1 (1.5-2.5), water is added for layering, the pH of a water phase is adjusted to 1-2 by hydrochloric acid, and ethyl acetate is used for extraction to obtain the-Boc-3-pyrrolidine methyl acetate lithium hydroxideR-N-Boc-3-pyrrolidineacetic acid.
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