CN110218169B - Synthesis method of chiral 4- (N-benzyloxycarbonyl) pyrrolidone - Google Patents

Synthesis method of chiral 4- (N-benzyloxycarbonyl) pyrrolidone Download PDF

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CN110218169B
CN110218169B CN201910515455.XA CN201910515455A CN110218169B CN 110218169 B CN110218169 B CN 110218169B CN 201910515455 A CN201910515455 A CN 201910515455A CN 110218169 B CN110218169 B CN 110218169B
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reaction
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tetrahydrofuran
pyrrolidone
chiral
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CN110218169A (en
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李雁武
王敬
朱太勇
胡叶敏
袁建勇
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Chongqing Medical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D207/18—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 one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—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 one double bond between ring members or between a ring member and a non-ring member 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
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones 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 other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
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    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention provides a synthesis method of chiral 4- (N-benzyloxycarbonyl) pyrrolidone, which uses L-asparagine as a starting raw material to prepare the chiral 4- (N-benzyloxycarbonyl) pyrrolidone through four steps of amino protection, diazotization reaction, carbonyl reduction and cyclization.

Description

Synthesis method of chiral 4- (N-benzyloxycarbonyl) pyrrolidone
Technical Field
The invention belongs to the technical field of medicinal chemistry, and particularly relates to a synthetic method of chiral 4- (N-benzyloxycarbonyl) pyrrolidone.
Background
Chiral 4- (N-carbobenzoxy) pyrrolidone is a very important fine chemical and intermediate, and can be used for synthesizing fourth-generation quinolone antibacterial drugs moxifloxacin and pyrrolidone aniline compounds with the activity of treating endometriosis or uterine leiomyoma. However, the synthesis of chiral 4- (N-benzyloxycarbonyl) pyrrolidone in the prior art often starts with 2-pyrrolidone and is not only costly, but also requires a late chiral resolution to obtain the desired optical configuration, potentially increasing process costs. Therefore, there is a need to develop a low-cost method for synthesizing chiral 4- (N-benzyloxycarbonyl) pyrrolidone.
Figure BDA0002094874610000011
Disclosure of Invention
In order to solve the problems in the prior art, the invention aims to provide a method for synthesizing chiral 4- (N-benzyloxycarbonyl) pyrrolidone. The method takes the L-asparagine as the initial raw material, does not need chiral resolution in the synthetic route, has low process cost and is suitable for industrial production. Except for special description, the parts are parts by weight, and the percentage is mass percent.
The purpose of the invention is realized by the following technical scheme:
a synthetic method of chiral 4- (N-benzyloxycarbonyl) pyrrolidone adopts the following synthetic route:
Figure BDA0002094874610000021
in the process of preparing the compound 1 by reacting L-asparagine with benzyl chloroformate, in order to accelerate the reaction process and obtain a satisfactory yield, the reaction solvent is a mixed solvent of tetrahydrofuran and water, and the volume ratio of the tetrahydrofuran to the water is 1.5-2.5. Because the product has higher polarity and solubility in water, when a mixed solvent of tetrahydrofuran and water is adopted, in order to reduce the loss of the product during separation, hydrochloric acid is used for adjusting the pH value to 2-3 at the temperature of-5-0 ℃ in the separation process of the product.
In the process of preparing a compound 2 by reacting a compound 1 with diazomethane, N-methylnitrosourea which is a raw material for generating the diazomethane is prepared, the N-methylnitrosourea is not added into sodium hydroxide liquid too much once so as to prevent the gas from generating too violent reaction, after the introduction of the diazomethane is stopped, the reaction liquid is continuously stirred until the redundant diazomethane is volatilized, and then the solvent is distilled off, otherwise, the product is oily after the rotary drying.
In the process of preparing the compound 3 by reducing the compound 2, the yield is not ideal when a single reaction solvent is used, so that the compound solvent formed by anhydrous tetrahydrofuran and anhydrous methanol is used for reaction, and the volume ratio of the anhydrous tetrahydrofuran to the anhydrous methanol is 3-5:1. In the reaction process, the system can generate gas violently, preferably, the compound 2, sodium borohydride and anhydrous tetrahydrofuran are added firstly, the reaction is carried out for 10 to 20min at the temperature of between 5 ℃ below zero and 0 ℃, then, anhydrous methanol is added for continuous reaction for 30 to 40min, and then, the reaction system is moved to the room temperature for continuous reaction until the reaction is complete. In the post-treatment process of the reaction, the reaction liquid cannot be completely dried, otherwise, the reaction liquid is not easy to be layered in the subsequent extraction process, the extraction efficiency is influenced, and the reaction liquid is concentrated to be slurry.
In the process of preparing the compound 4 from the compound 3, a ring formation method after bromination is firstly determined, NBS or carbon tetrabromide is used as a bromine donor, tetra (triphenyl) phosphorus is used as a catalyst, a bromination product is obtained by reaction in tetrahydrofuran or dichloromethane, then the bromination product forms a ring under the condition that sodium hydride is used as alkali, but the nuclear magnetic hydrogen spectrum of the obtained product is not split, one carbonyl peak in the carbon spectrum is shifted, and the inventor later confirms by using two-dimensional spectra HMBC and HMQC that a target product is not obtained. After further exploration, the inventor adds the compound 3 and 50% sodium hydride (half of the total mass of sodium hydride) into a reaction vessel, adds tetrahydrofuran after nitrogen replacement, adds methanesulfonyl chloride, reacts for 15-20 h at room temperature, then adds the rest sodium hydride, and reacts the reaction system at 45-55 ℃ for 20-25 h to successfully prepare the compound 4 (chiral 4- (N-benzyloxycarbonyl) pyrrolidone).
The synthesis method of the chiral 4- (N-benzyloxycarbonyl) pyrrolidone comprises the following steps:
(1) Dissolving L-asparagine in a mixed solvent formed by tetrahydrofuran and water in a volume ratio of 1.5-2.5, adding benzyl chloroformate at 0 ℃, then moving a reaction system to room temperature for reaction for 6 hours, then moving the reaction system to-5-0 ℃, adding 2.4mmol/L hydrochloric acid to adjust the pH value to 2-3, filtering, and drying a filter cake to obtain a compound 1;
(2) Adding the compound 1 into a reaction vessel, adding tetrahydrofuran, stirring at room temperature, adding a proper amount of sodium hydroxide solution with the concentration of 1g/mL, and then adding N-methylnitrosourea to enable the compound 1 to react with diazomethane generated by the N-methylnitrosourea to prepare a compound 2;
(3) Adding the compound 2 and sodium borohydride into a reaction container, adding anhydrous tetrahydrofuran, reacting at-5-0 ℃ for 10-20 min, adding anhydrous methanol, continuing to react for 30-40 min, and then moving a reaction system to room temperature for continuing to react until the reaction is complete; the volume ratio of the anhydrous tetrahydrofuran to the anhydrous methanol is 3-5:1;
(4) Adding the compound 3 and 50% of sodium hydride (half of the total mass of the sodium hydride) into a reaction vessel, adding tetrahydrofuran after nitrogen replacement, adding methanesulfonyl chloride at 0 ℃, reacting for 20h at room temperature, adding the remaining 50% of sodium hydride, reacting the reaction system at 45-55 ℃ for 22h, and separating to obtain the compound 4 (chiral 4- (N-benzyloxycarbonyl) pyrrolidone).
Has the advantages that:
the invention provides a synthesis method of chiral 4- (N-benzyloxycarbonyl) pyrrolidone, which is characterized in that L-asparagine which is easy to obtain and low in price is used as an initial raw material, and the chiral 4- (N-benzyloxycarbonyl) pyrrolidone is prepared through four steps of amino protection, diazotization, carbonyl reduction and cyclization.
Detailed Description
The present invention is described in detail below with reference to specific examples, which are given for the purpose of further illustrating the invention and are not to be construed as limiting the scope of the invention, and the invention may be modified and adapted by those skilled in the art in light of the above disclosure.
Example 1
Route for the preparation of compound 1:
Figure BDA0002094874610000041
the specific process is as follows:
adding 10g (75.76 mmol) of L-asparagine and 4.55g (113.64 mmol) of magnesium oxide into a 250mL wedge flask, adding 80mL of water and 40mL of tetrahydrofuran and stirring at 0 ℃, slowly adding 14.22g (83.33 mmol) of benzyl chloroformate after 10min, moving the reaction to room temperature, monitoring by TLC (EA/MeOH = 1/1) that the raw materials are completely reacted after 6h, ending the reaction, moving the reaction to low temperature, adding hydrochloric acid (2.4 mmol/L) to adjust the pH of the reaction solution to 2-3, a large amount of white solid is precipitated, filtering, washing the filter cake with water, drying the filter cake to obtain 16.6g of white solid, and obtaining: 83.24%. MS (M/z) 267 (M + 1); 1 HNMR(400MHz,CD 3 OD)δ:7.38-7.29(m,5H), 5.10(s,2H),4.54(m,1H),2.77-2.73(m,2H).
example 2
Route to compound 2:
Figure BDA0002094874610000051
the specific process is as follows:
compound 1 15g (56.37 mmol) was charged to a 250mL wedge flask, 175m L tetrahydrofuran was added and stirred at room temperature. 100mL (1 g/mL) of the frozen sodium hydroxide solution prepared in advance was sealed with 40mL of ether, N-methylnitrosourea was added and the resulting diazomethane was passed through the reaction. And (3) stopping introducing the raw materials when the reaction liquid turns yellow and does not fade, monitoring by TLC (EA/MeOH = 5/1) until the raw materials completely react, continuously stirring until redundant diazomethane is volatilized, evaporating the solvent, and drying to obtain 13.7g of light yellow solid with the yield of 86.76%. MS (M/z) 281 (M + 1); 1 HNMR(4 00MHz,CD 3 OD)δ:7.37-7.31(m,5H),5.12(s,2H),4.58(m,1H),3.74(s,3 H),2.78-2.75(m,2H).
in the synthesis process of the compound 2, N-methyl nitrosourea which is a raw material for generating diazomethane is prepared, and the preparation process comprises the following steps: adding 140mL of methylamine solution into a 1L wedge-shaped flask, adding water to dilute the solution to 300mL, stirring the solution at the temperature of minus 15 ℃, dropwise adding 140mL of concentrated hydrochloric acid into the system, moving the reaction to room temperature after the dropwise adding is finished, adding 300g of urea, refluxing the reaction solution at the temperature of 110 ℃ for 18 to 20 hours, cooling the reaction solution, adding 110g of sodium nitrite, and stirring the solution to be clear for later use; adding 600mL of water into a 2L three-necked bottle, dripping 60mL of concentrated sulfuric acid for dilution, mechanically stirring at the temperature of minus 15 ℃, slowly adding the refluxed reaction liquid into diluted sulfuric acid, generating a large amount of light red foamy solid, performing suction filtration to obtain a light red product N-methylnitrosourea, and storing in a refrigerator for later use.
Example 3
Route for preparation of compound 3:
Figure BDA0002094874610000061
the specific process is as follows:
adding 5g (17.85 mmol) of compound 2 and 1.35g (35.65 mmol) of sodium borohydride into a 100mL wedge flask, adding 40mL of anhydrous tetrahydrofuran, inserting a nitrogen balloon on a bottle stopper, stirring at 0 ℃, adding 10mL of anhydrous methanol for 10min, generating gas vigorously by the system, gradually dissolving the raw material, and moving the reaction to room temperature after 30minThe process is carried out. After 5h TLC monitoring (EA/MeOH = 10/1) the starting material reaction was complete. The reaction was allowed to warm to low temperature, 2mL of saturated sodium bicarbonate solution was added, the reaction solution was rotary evaporated to a slurry, 45mL of ethyl acetate was added, 25mL of water was separated into layers, the aqueous layer was extracted with ethyl acetate (4 5mL X3), the organic layers were combined, dried over anhydrous sodium sulfate, and subjected to silica gel column chromatography (E A/MeOH = 10/1-5/1) to give 3.29g of a white solid with a yield of 73.11%. MS (M/z) 253 (M + 1); 1 HNMR(400MHz,CD 3 OD)δ:7.37-7.29(m,5H),5.09(s,2H),4.03(m,1H), 3.58-3.55(m,2H),2.53-2.38(m,2H).
example 4
Route for preparation of compound 4:
Figure BDA0002094874610000071
the specific process is as follows:
0.8g (3.17 mmol) of Compound 3 and 165mg (4.13 mmol) of sodium hydride were charged in a 100mL two-necked flask, and after purging with nitrogen, 60mL of dry tetrahydrofuran was added and the mixture was stirred at 0 ℃. An additional 0.68g (6.34 mmol) of methanesulfonyl chloride was added, stirring at room temperature for 20h then 165mg (4.13 mmol) of sodium hydride was added to the system and the reaction was moved to 50 ℃ and after stirring for 22h, TLC monitored (EA/MeOH = 10/1) that the starting material was essentially completely reacted. After the solvent was evaporated by rotation, 0.47g of a white solid was isolated by silica gel column chromatography (D CM/EA = 2/1-1/1) with a yield of 63.3%. MS (M/z) 235 (M + 1); 1 HNMR(400MHz,CDCl 3 )δ:7.36-7.26(m,5H),5.66(s,2H),5.08(s,2H), 4.45-4.41(m,2H),4.20(m,1H),2.77(dd,J＝16,8Hz,1H),2.41(dd,J＝16,4 Hz,1H)； 13 CNMR(100MHz,CDCl 3 )δ:175.4,155.8,135.9,128.6,128.4, 128.2,73.6,67.2 48.0,34.8。

Claims (1)

1. a synthetic method of chiral 4- (N-benzyloxycarbonyl) pyrrolidone adopts the following synthetic route:
Figure FDA0003815180710000011
the method comprises the following steps:
(1) Dissolving L-asparagine in a mixed solvent formed by tetrahydrofuran and water in a volume ratio of 1.5-2.5, adding benzyl chloroformate at 0 ℃, then moving a reaction system to room temperature for reaction for 6 hours, then moving the reaction system to-5-0 ℃, adding 2.4mmol/L hydrochloric acid to adjust the pH value to 2-3, filtering, and drying a filter cake to obtain a compound 1;
(2) Adding the compound 1 into a reaction vessel, adding tetrahydrofuran, stirring at room temperature, adding a proper amount of sodium hydroxide solution with the concentration of 1g/mL, and then adding N-methylnitrosourea to enable the compound 1 to react with diazomethane generated by the N-methylnitrosourea to prepare a compound 2;
(3) Adding the compound 2 and sodium borohydride into a reaction container, adding anhydrous tetrahydrofuran, reacting for 10-20 min at-5-0 ℃, adding anhydrous methanol, continuing to react for 30-40 min, and then moving a reaction system to room temperature for continuing to react until the reaction is complete; the volume ratio of the anhydrous tetrahydrofuran to the anhydrous methanol is 3-5:1;
(4) Adding the compound 3 and 50% sodium hydride into a reaction vessel, adding tetrahydrofuran after nitrogen replacement, adding methanesulfonyl chloride at 0 ℃, reacting at room temperature for 20h, adding the remaining 50% sodium hydride, reacting the reaction system at 45-55 ℃ for 22h, and separating to obtain chiral 4- (N-benzyloxycarbonyl) pyrrolidone.
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Publication number Priority date Publication date Assignee Title
CN101239937A (en) * 2007-02-07 2008-08-13 上海雅本化学有限公司 Method for preparing optical activity R-(-)-1-benzylcarbonyl-3-aminopyrrolidine and hydrochloride thereof
CN105175365A (en) * 2015-09-01 2015-12-23 辽宁中医药大学 Method for efficiently synthesizing beta-benzyl butyrolactone having specific configuration
CN109535035A (en) * 2019-01-08 2019-03-29 吉尔生化（上海）有限公司 A kind of preparation method of the N- benzyloxycarbonyl group -3- amino-alanine tert-butyl ester

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WO2015188369A1 (en) * 2014-06-13 2015-12-17 Merck Sharp & Dohme Corp. Purine inhibitors of human phosphatidylinositol 3-kinase delta

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101239937A (en) * 2007-02-07 2008-08-13 上海雅本化学有限公司 Method for preparing optical activity R-(-)-1-benzylcarbonyl-3-aminopyrrolidine and hydrochloride thereof
CN105175365A (en) * 2015-09-01 2015-12-23 辽宁中医药大学 Method for efficiently synthesizing beta-benzyl butyrolactone having specific configuration
CN109535035A (en) * 2019-01-08 2019-03-29 吉尔生化（上海）有限公司 A kind of preparation method of the N- benzyloxycarbonyl group -3- amino-alanine tert-butyl ester

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