阅读说明：本技术 一种制备3-(3-氯丙基)-4-氧代吡咯烷-1-羧酸酯的方法 (Method for preparing 3- (3-chloropropyl) -4-oxopyrrolidine-1-carboxylic ester ) 是由 杨汉荣 李涛 王博 于 2019-12-04 设计创作，主要内容包括：本发明提出一种制备3-(3-氯丙基)-4-氧代吡咯烷-1-羧酸酯(I)的方法。该方法以甘氨酸酯或其可接受的盐(VIII)为原料,与氯甲酸酯(VII)反应生成中间体乙氧羰基甘氨酸酯(VI)；中间体(VI)再与丙烯酸酯(V)在碱性条件下环合得到吡咯烷酮中间体(IV)；中间体(IV)与1,3-卤代氯丙烷(III)反应,得到中间体(II)后,在酸性条件下脱羧,即可得到3-(3-氯丙基)-4-氧代吡咯烷-1-羧酸酯(I)。与老工艺相比,该工艺缩短了工艺步骤,简化了工艺操作,大大降低了三废的排放和成本,有利于工业化放大生产。<Image he="230" wi="458" file="DEST_PATH_IMAGE002.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention provides a method for preparing 3- (3-chloropropyl) -4-oxopyrrolidine-1-carboxylic ester (I). The method takes glycinate or acceptable salt (VIII) thereof as raw material, and reacts with chloroformate (VII) to generate intermediate ethoxycarbonyl glycinate (VI); the intermediate (VI) is cyclized with the acrylate (V) under the alkaline condition to obtain a pyrrolidone Intermediate (IV); and (3) reacting the Intermediate (IV) with 1, 3-halogenochloropropane (III) to obtain an intermediate (II), and decarboxylating under an acidic condition to obtain the 3- (3-chloropropyl) -4-oxopyrrolidine-1-carboxylic ester (I). Compared with the prior art, the process has the advantages of shortening process steps, simplifying process operation, greatly reducing the discharge of three wastes and cost, and being beneficial to industrial scale-up production.)

1. A process for the preparation of 3- (3-chloropropyl) -4-oxopyrrolidine-1-carboxylic acid ester (I), which comprises the following steps:

a) reacting glycine ester or an acceptable salt thereof (VIII) with chloroformate (VII) to produce intermediate ethoxycarbonylglycine ester (VI);

b) cyclizing the intermediate ethoxycarbonyl glycine ester (VI) and the acrylic ester (V) under the action of alkali to obtain a pyrrolidone Intermediate (IV);

c) the pyrrolidone Intermediate (IV) reacts with the 1, 3-halogenated chloropropane intermediate (III) under proper conditions to obtain an intermediate (II);

d) decarboxylation of the intermediate (II) in the presence of an acid to give 3- (3-chloropropyl) -4-oxopyrrolidine-1-carboxylic acid ester (I);

wherein, R, R₁、R₂Can respectively represent C_1~4Alkyl, benzyl.

2. The method of claim 1a, wherein said glycine ester or acceptable salt thereof (VIII) comprises the hydrochloride salt of glycine ethyl ester, the hydrochloride salt of glycine methyl ester; the chloroformate (VII) comprises methyl chloroformate and ethyl chloroformate.

3. The process of claim 1a, wherein suitable reaction conditions include toluene or alkanes as solvent or no solvent, inorganic base or triethylamine as base; the reaction temperature is 15-35^oC。

4. The method of claim 1b, wherein the acrylate (V) comprises methyl acrylate, ethyl acrylate; the alkali comprises sodium methoxide, sodium ethoxide, potassium tert-butoxide or sodium hydride.

5. The process of claim 1b, wherein suitable reaction conditions include toluene or alkanes as solvent, inorganic bases or triethylamine as base; the reaction temperature is 40-60 deg.C^oC。

6. The process according to claim 1c, characterized in that said 1, 3-halochloropropanes (III) comprise 1, 3-dichloropropane, 1-bromo-3-chloropropane, 1-iodo-3-chloropropane.

7. The process of claim 1c, wherein suitable reaction conditions include toluene or alkanes as solvent, or solvent-free reaction; inorganic base or triethylamine is used as base; the reaction temperature is 10-30 deg.C^oC。

8. The method of claim 1d, wherein the acid comprises hydrochloric acid or sulfuric acid.

9. The method of claim 1d, wherein the suitable reaction conditions comprise using alcohol, water or a mixture of alcohol and water as a solvent; the reaction temperature is 40-60 deg.C^oC。

Technical Field

The invention relates to the technical field of synthesis of moxifloxacin intermediates, in particular to the technical field of synthesis of 3- (3-chloropropyl) -4-oxopyrrolidine-1-carboxylic ester.

Background

Moxifloxacin (Moxifloxacin) (shown as a formula (A)) is an artificially synthesized quinolone antibacterial drug, Moxifloxacin (Moxifloxacin) is a third-generation quinolone spectrum antibacterial drug, and is marketed in 1999 till now and widely applied to treatment of respiratory tract infection such as acquired pneumonia, acute attack of chronic bronchitis, acute bacterial sinusitis and the like in clinic. Has the advantages of strong antibacterial property, wide antibacterial spectrum, difficult generation of drug resistance, effectiveness to common drug-resistant bacteria, long half-life period, less adverse reaction and the like.

Wherein (4aS,7aS) -octahydro-1H-pyrrolo [3,4-B ] pyridine (B) is a key intermediate for synthesizing moxifloxacin. For the synthesis of intermediate B, the early method was to use 3, 4-dipicolinic acid as the starting material, close the ring with amines, then hydrogenate the pyridine ring under high pressure, reduce the carbonyl group of amides, and finally split the product. This process is less and less used because of the high equipment requirements for high pressure hydrogenation, the use of expensive reducing reagents for reducing the amide, and the chiral resolution involved.

The patent of 3- (3-chloropropyl) -4-oxopyrrolidine-1-carboxylic ester (I) synthesis is reported for the first time to be CN103044418B, the method takes 1-benzyl-3-ethoxycarbonyl-4-oxopyrrolidine 3 as a raw material, and reacts with 1-iodine-3-chloropropane in the presence of alkali to obtain an intermediate 1-benzyl-3-ethoxycarbonyl-3- (3-chloropropyl) -4-oxopyrrolidine 4, then decarboxylates to obtain 1-benzyl-3- (3-chloropropyl) -4-oxopyrrolidine 5, finally substitutes the benzyl with the ethoxycarbonyl to obtain a product 3- (3-chloropropyl) -4-oxopyrrolidine-1-carboxylic ester (I), is used for synthesizing (4aS,7aS) -octahydro-1H-pyrrolo [3,4-B ] pyridine (B). Wherein, the synthesis of the intermediate 1-benzyl-3-ethoxycarbonyl-4-oxopyrrolidine 3 takes ethyl acrylate as a raw material, the ethyl acrylate is connected with benzylamine to obtain an intermediate 1, then the intermediate 1 reacts with ethyl chloroacetate to obtain an intermediate 2, and then the intermediate 3 is obtained by Dickmann ester condensation.

The route has long steps, needs 6 steps to finish the process, and has unstable intermediate and difficult purification, so that the intermediate is difficult to purify

The industrial production is difficult to control, and the produced waste is more.

Subsequently, patent CN108863886A reports on another synthesis method of 3- (3-chloropropyl) -4-oxopyrrolidine-1-carboxylic acid ester (I). According to the method, ethyl acrylate and ethyl glycinate are used as raw materials, an intermediate 6 is obtained through splicing, an intermediate 7 is obtained through direct protection of ethoxycarbonyl without benzyl, then an intermediate 3 is obtained through condensation of Dickmann ester, the intermediate 3 reacts with 1-bromo-3-chloropropane to obtain an intermediate 9, and finally decarboxylation is carried out to obtain a product of ethyl 3- (3-chloropropyl) -4-oxopyrrolidine-1-carboxylate (I).

The steps of the route are reduced to 5 steps, the benzyl protection is omitted, and the route has certain improvement compared with the route of CN 103044418B. However, the intermediate 9 is decarboxylated under alkaline conditions, and the product ethyl 3- (3-chloropropyl) -4-oxopyrrolidine-1-carboxylate (I) reacts with itself under alkaline conditions, so that a large amount of by-products are easily generated.

Disclosure of Invention

In order to avoid the disadvantages of the production process described above, the present invention further improves the synthesis process. The invention takes glycinate or acceptable salt (VIII) thereof as raw material, and reacts with chloroformate (VII) to generate ethoxycarbonyl glycinate intermediate (VI); the intermediate (VI) and the acrylic ester (V) are cyclized under the alkaline condition, and simultaneously, Dickmann ester condensation is carried out to obtain a pyrrolidone Intermediate (IV); and (3) reacting the Intermediate (IV) with 1, 3-halogenochloropropane (III) to obtain an intermediate (II), and decarboxylating under an acidic condition to obtain the 3- (3-chloropropyl) -4-oxopyrrolidine-1-carboxylic ester (I).

Wherein, R, R₁、R₂Can respectively represent C_1~4Alkyl, benzyl.

Compared with the prior art, the process further shortens the reaction steps to 4 steps, simplifies the process operation, greatly reduces the discharge of three wastes and the cost, and is beneficial to industrial scale-up production.

The method comprises the following steps:

step 1: reacting glycine ester or an acceptable salt thereof (VIII) with chloroformate (VII) to produce intermediate (VI);

step 2: cyclizing the intermediate ethoxycarbonyl glycine ester (VI) and the acrylic ester (V) under the action of alkali to obtain a pyrrolidone Intermediate (IV);

and step 3: reacting the Intermediate (IV) with the 1, 3-halogenated chloropropane intermediate (III) under a proper condition to obtain an intermediate (II);

and 4, step 4: the intermediate (II) is decarboxylated in the presence of an acid to give the 3- (3-chloropropyl) -4-oxopyrrolidine-1-carboxylic acid ester (I).

The glycine ester or acceptable salt thereof (VIII) in step 1 comprises hydrochloride of glycine ethyl ester, hydrochloride of glycine methyl ester. Chloroformate (VII) comprises methyl chloroformate, ethyl chloroformate.

Preferably, glycine ethyl ester hydrochloride is used.

Preferably, the reaction conditions in step 1 include toluene or an alkane as a solvent.

Preferably, the reaction conditions in step 1 are inorganic base or triethylamine as base; the inorganic base comprises potassium carbonate or sodium carbonate.

Preferably, the reaction temperature in step 1 is 15-35%^oC。

The acrylate (V) in the step 2 comprises methyl acrylate and ethyl acrylate;

preferably, it is ethyl acrylate.

The alkali in the step 2 comprises sodium methoxide, sodium ethoxide, potassium tert-butoxide or sodium hydride;

sodium methoxide and sodium ethoxide are preferred.

Preferably, the reaction temperature in step 2 is 40-60%^oC。

In the step 3, the 1, 3-halogenated chloropropane comprises 1, 3-dichloropropane, 1-bromo-3-chloropropane and 1-iodo-3-chloropropane;

preferably, it is 1-bromo-3-chloropropane.

The reaction conditions in the step 3 comprise that toluene or alkane is used as a solvent, or solvent-free reaction is carried out;

preferably, toluene or a solvent-free reaction is used.

Preferably, inorganic base or triethylamine is used as base in the step 3; the inorganic base comprises potassium carbonate or sodium carbonate.

Preferably, the reaction temperature in step 3 is 10-30%^oC。

The acid in the step 4 comprises hydrochloric acid and sulfuric acid;

preferably, sulfuric acid.

In the step 4, alcohol, water or a mixed system of alcohol and water is used as a solvent;

preferably, a mixed system of alcohol and water is used.

Preferably, the reaction temperature in step 4 is 40-60%^oC。

The invention has the advantages that:

1. compared with the prior art, the synthesis sequence for preparing the intermediate (III) is adjusted, the glycine ester (VIII) reacts with the chloroformate (VII) and then reacts with the acrylate (V), so that excessive alkylation can be avoided, and the yield and the purity of the intermediate are improved.

2. The invention can test the conversion from the intermediate (VI) to the intermediate (II) in one step, combines the splicing reaction and the Dickmann ester condensation reaction, reduces the reaction steps and improves the production efficiency.

3. The invention adopts sulfuric acid for catalysis when the intermediate (II) is hydrolyzed and decarboxylated, which not only can reduce the occurrence of side reactions, but also can reuse the sulfuric acid aqueous solution for a plurality of times, thereby reducing the discharge of three wastes.

4. The invention has high total yield which is improved from 50 percent to more than 70 percent, reduces the production cost and is beneficial to industrial production.

Detailed Description

For a better understanding of the present invention, reference will now be made to the following examples. It should be understood that the following specific examples are illustrative of the invention only and are not limiting.