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6-cyano-1,1(1,3-subpropyldioxy)-7-[1'-(carbalkoxy)-propyl]-5-oxo-delta6(8)-tetrahydro indolizine compound preparation method

A technology of propylenedioxy and alkoxycarbonyl, which is applied in the field of organic chemistry, can solve problems such as difficult large-scale preparation and difficult solvent recovery, and achieve the effects of low cost, high product purity and mild reaction conditions

Inactive Publication Date: 2007-08-01
FUDAN UNIV
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  • Abstract
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AI Technical Summary

Problems solved by technology

But above-mentioned these methods have all used more than four times the amount of expensive, easy-to-decompose ethyl iodide and difficult solvent recovery etc., are difficult for large-scale preparation

Method used

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  • 6-cyano-1,1(1,3-subpropyldioxy)-7-[1'-(carbalkoxy)-propyl]-5-oxo-delta6(8)-tetrahydro indolizine compound preparation method
  • 6-cyano-1,1(1,3-subpropyldioxy)-7-[1'-(carbalkoxy)-propyl]-5-oxo-delta6(8)-tetrahydro indolizine compound preparation method
  • 6-cyano-1,1(1,3-subpropyldioxy)-7-[1'-(carbalkoxy)-propyl]-5-oxo-delta6(8)-tetrahydro indolizine compound preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Example 1: 6-cyano-1,1-(2,2-dimethyl-1,3-propylenedioxy)-7-[1'-(methoxycarbonyl)-propyl]-5 -Oxo-Δ 6(8) -Preparation of Tetrahydroindolizine (I)

[0030] 6-cyano-1,1-(2,2-dimethyl-1,3-propylenedioxy)-7-[(methoxycarbonyl)-methyl]-5-oxo-Δ 6(8) -Tetrahydroindolizine (90g, 0.27mol), anhydrous potassium carbonate (55.9g, 0.405mol), bromoethane (44.1g, 0.405mol) and acetonitrile (650mL) were placed in a dry reaction flask, heated and stirred to reflux 4h. After the reaction was completed, filter, recover the solvent under reduced pressure, and cool to room temperature. Dichloroethane (600 mL) was added to the residue, stirred to dissolve, and then washed with water (130 mL) and saturated brine (45 mL) successively. The solvent was recovered under reduced pressure, and the solid was precipitated by cooling. Recrystallized with methanol to obtain dark green powder I (R 1 = R 2 =CH 3 , 91.0g, 92.8%), mp 178.6-179.2°C. Purity > 98.5% (HPLC).

[0031] 1 H NMR (CDCl 3 ):...

Embodiment 2

[0033]Example 2: 6-cyano-1,1-(2,2-dimethyl-1,3-propylenedioxy)-7-[1'-(methoxycarbonyl)-propyl]-5 -Oxo-Δ 6(8) -Preparation of Tetrahydroindolizine (I)

[0034] 6-cyano-1,1-(2,2-dimethyl-1,3-propylenedioxy)-7-[(methoxycarbonyl)-methyl]-5-oxo-Δ 6(8) -Tetrahydroindolizine (90g, 0.27mol), potassium hydroxide (30.3g, 0.54mol), diethyl sulfate (67.6g, 0.54mol) and N,N-dimethylformamide (800mL) were dried In the reaction flask, heat and stir to reflux for 7h. After the reaction was completed, filter, recover the solvent under reduced pressure, and cool to room temperature. Dichloromethane (600 mL) was added to the residue, stirred to dissolve, and then washed with water (150 mL) and saturated brine (55 mL) successively. The solvent was recovered under reduced pressure, and the solid was precipitated by cooling. Recrystallized with methanol to obtain dark green powder I (R 1 = R 2 =CH 3 , 88.2g, 90%), mp 177.0-179.1°C. Purity > 98.4% (HPLC). 1 Both H NMR and MS are consistent...

Embodiment 3

[0035] Example 3: 6-cyano-1,1-(2,2-dimethyl-1,3-propylenedioxy)-7-[1'-(methoxycarbonyl)-propyl]-5 -Oxo-Δ 6(8) -Preparation of Tetrahydroindolizine (I)

[0036] 6-cyano-1,1-(2,2-dimethyl-1,3-propylenedioxy)-7-[(methoxycarbonyl)-methyl]-5-oxo-Δ 6(8) - Tetrahydroindolizine (90g, 0.27mol), anhydrous potassium carbonate (55.9g, 0.405mol), bromoethane (44.1g, 0.405mol), acetonitrile (700mL) and triethylbenzyl ammonium chloride ( 1.23g, 5.4mmol) in a dry reaction flask, heated and stirred to reflux for 2h. After the reaction was completed, filter, recover the solvent under reduced pressure, and cool to room temperature. Dichloromethane (800 mL) was added to the residue, stirred to dissolve, and then washed with water (200 mL) and saturated brine (100 mL) successively. The solvent was recovered under reduced pressure, and the solid was precipitated by cooling. Recrystallized with methanol to obtain dark green powder I (R 1 = R 2 =CH 3 , 91.2g, 93%), mp 178-180°C. Purity > 98....

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Abstract

The invention belongs to organic chemistry field, which in detail relates to a process of preparing 6- cyano-1, 1 (1, 3- dioxypropylidene)-7- [1' (alkoxycarbonyl)- propyl ]- 5- oxo-Delt6 (8)- tetrahydrochysene indolizine (I). The 6- cyano-1, 1 (1, 3- dioxypropylidene)-7- [ (carbomethoxyl group)- methyl ]- 5- oxo-Delt6 (8)- tetrahydrochysene indolizine (II) and haloethane reacts with each other for ethylization with existence of alkali and organic solution with or without phase transversion catalyst, and produces mentioned product. The invention is characterized by temperatate reaction condition, easy operation, low cost, high-purity product and suitability for industrial production.

Description

technical field [0001] The invention belongs to the technical field of organic chemistry, and specifically relates to a 6-cyano-1,1-(1,3-propylenedioxy)-7-[1'-(alkoxycarbonyl)-propyl]-5 -Oxo-Δ 6(8) -tetrahydroindolizine compound (I) preparation method. [0002] [0003] where R 1 = H, C 1 -C 4 Alkyl, R 2 =C 1 -C 4 alkyl. Background technique [0004] 6-cyano-1,1-(1,3-propylenedioxy)-7-[1′-(alkoxycarbonyl)-propyl]-5-oxo-Δ 6(8) -Tetrahydroindolizine compounds (I) are synthetic 20(S)-camptothecins [20(S)-Camptothecins] antitumor drugs such as camptothecins (Camptothecin), hydroxycamptothecin (20( S)-10-Hydroxycamptothecin), Topotecan (Topotecan), Irinotecan (Irinotecan), etc. and important intermediates of biologically active natural products. [0005] In the presence of a base, 6-cyano-1,1-(1,3-propylenedioxy)-7-[(methoxycarbonyl)-methyl]- The alkoxycarbonyl ethyl of 5-oxo-Δ6(8)-tetrahydroindolizine compounds (II) is monoethylated to prepare 6-cyano-1,1-(1,3-prop...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/20
Inventor 陈芬儿赵磊张立鹏
Owner FUDAN UNIV
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