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Trans-3a-fluoropyrrolidine[3,4-C]benzo cyclocompound and preparation method thereof

A technology of fluoropyrrolidine and cyclic compounds, which is applied in organic chemistry, drug combination, bulk chemical production, etc. It can solve the problems of no literature reports on synthetic methods, and achieve the effect of increasing diversity and improving polarity

Active Publication Date: 2013-03-06
上海药明康德新药开发有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It mainly solves the technical problems that there are no literature reports on the synthesis method of trans-3a-fluoropyrrolidine [3,4-C] acyclic compounds and the screening of selective H3 receptor antagonistic activity

Method used

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  • Trans-3a-fluoropyrrolidine[3,4-C]benzo cyclocompound and preparation method thereof
  • Trans-3a-fluoropyrrolidine[3,4-C]benzo cyclocompound and preparation method thereof
  • Trans-3a-fluoropyrrolidine[3,4-C]benzo cyclocompound and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Example 1: Preparation of 5-benzyl-6a-fluorohexahydropyrrole[3,4-C]pyrrole-1(2hydrogen)-one 1a:

[0048]

[0049] Steps:

[0050] Add triethyl 2-fluorophosphine-2-ylacetate 2 (71.9 g, 0.297 mmol) and 1 L of anhydrous tetrahydrofuran to a separate setup of a constant-pressure dropping funnel, a cryogenic thermometer, and a three-way port filled with nitrogen. Cool the 2-liter three-necked flask to minus 78 degrees Celsius, and drop n-butyllithium (118.8 ml, 0.312 mmol) into the three-necked flask from a constant pressure dropping funnel. After the dropwise addition was completed, the reaction was maintained at minus 78 degrees Celsius for 1 hour. After dissolving tert-butyl-N-(2-oxyethyl)carbamate 3 (45 g, 0.297 mmol) in 200 ml of anhydrous tetrahydrofuran, it was dropped into the reaction flask at minus 78 degrees Celsius. After the dropwise addition was completed, the reaction was maintained at minus 78 degrees Celsius for 2 hours. The reaction was quenched with 50...

Embodiment 2

[0056] Example 2: Preparation of trans 6a-fluorohexahydropyrrole[3,4-C]pyrrol-1(2hydrogen)-one 1b:

[0057]

[0058] Steps:

[0059] Dissolve 2.9 g of trans 5-benzyl-6a-fluorohexahydropyrrole[3,4-C]pyrrol-1(2hydrogen)-one 1a in 200 ml of tetrahydrofuran, add 600 mg of palladium containing 10% by weight Wet palladium on carbon, stirred under 50 psi of hydrogen at room temperature for 48 hours. The reaction was completed, filtered, and the mother liquor was concentrated under reduced pressure. The resulting crude product was separated by column chromatography to obtain 1.5 g of trans-6a-fluorohexahydropyrrole[3,4-C]pyrrole-1(2hydrogen)-one 1b, with a yield of 84% .

[0060] HNMR (MeOD) δ: 3.97-3.92 (m, 1H), 3.82-3.74 (m, 3H), 3.47-3.24 (m, 3H).

Embodiment 3

[0061] Example 3: Preparation of trans-tert-butyl-3a-fluoro-4-oxahydropyrrole[3,4-C]pyrrole-2(1hydrogen)-carboxylate 7:

[0062]

[0063] Steps:

[0064] Dissolve 5 grams of trans-5-benzyl-6a-fluorohexahydropyrrole[3,4-C]pyrrol-1(2hydrogen)-one 1a in 300 ml of tetrahydrofuran, add 1 gram of palladium containing 10% by weight Wet palladium on carbon and 5.1 g of di-tert-butyl dicarbonate were stirred under 50 psi of hydrogen at room temperature for 24 hours. After the reaction was completed, it was filtered, and the mother liquor was concentrated under reduced pressure to obtain a white solid. The solid was washed and stirred with 50 ml of petroleum ether for 2 hours, and filtered to obtain 4.8 g of trans-tert-butyl-3a-fluoro-4-oxahydropyrrole[3,4-c]pyrrole-2(1hydrogen)-carboxylate 7. The yield is 92%.

[0065] HNMR (CDCl3) δ: 7.40-7.13 (br m, 1H), 4.01-3.94 (t, 1H), 3.78-3.66 (m, 3H), 3.53-3.38 (br s, 1H), 3.20-3.10 (m, 2H), 1.45 (s, 9H).

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Abstract

The invention relates to a trans-3a-fluoropyrrolidine[3,4-C]benzo cyclocompound and a preparation method thereof, mainly solves the technical problem that the trans-3a-fluoropyrrolidine[3,4-C]benzo cyclocompound is reported in no documents and realizes the screening on the structure-activity relationship of the medical activity of the trans-3a-fluoropyrrolidine[3,4-C]benzo cyclocompound. The structural general formula is shown in the specification, wherein n=1 or 2; G is CH2 or an N atom; R1 and R2 are hydrogen, amide, sulfamide, urea, alkyl or aryl; the preferable amide is benzamide; the preferable sulfamide is methylsulfamide; the preferable urea is methylurea; and the preferable alkyl or aryl is one of C1-4 straight-chain or substituent-side-chain-containing alkyl and substituted aryl.

Description

technical field [0001] The present invention relates to trans-3a-fluoropyrrolidine [3,4-C] ring compound and its preparation method. Background technique [0002] Tetrahydropyrrole-(3,4) acyclic compound Ia is a kind of compound developed by Arena Pharmaceuticals in the United States to treat cognitive impairment, epilepsy, brain trauma, depression, obesity, Parkinson's syndrome, dizziness, insomnia, etc. and H3 Lead compounds for diseases related to receptor disorders. Among them, some compounds have entered the stage of clinical research as a class of new drugs. (WO2007 / 061741 A2) [0003] [0004] The application principles of modern fluorine chemistry in medicinal chemistry mainly include: (1) Changing the metabolic kinetic characteristics of drugs, for example, the introduction of fluorine atoms on the α-carbon of amides can slow down the speed of drug metabolism, while aryl fluorine can hardly change While improving the physicochemical properties of the compound,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07D209/52C07D471/04A61P25/28A61P25/08A61P25/24A61P25/16A61P25/00A61P25/20A61P3/04
CPCY02P20/55
Inventor 石卫华柏祝陈先印张歆宁肖贻崧贺海鹰陈曙辉
Owner 上海药明康德新药开发有限公司
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