Preparation method of three-membered ring on 5, 6-dihydrocyclopentylpyridine-7-ketone compound

Abstract

The invention relates to a preparation method of a three-membered ring on a 5, 6-dihydrocyclopentylpyridine-7-ketone compound. According to the method, 5, 6-dihydrocyclopentylpyridine-7-ketone compounds as shown in a formula I and a formula II react to obtain the compound. Compared with an existing production technology, the method is simple, efficient and low in cost, the separation yield can reach 80-90%, and the industrial production requirement can be met. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical synthesis, and specifically relates to a method for preparing a three-membered ring on a 5,6-dihydrocyclopentylpyridine-7-one compound. Background Art

[0002] 5,6-Dihydrocyclopentapyridine-7-one compounds are important drug intermediates. The introduction of cyclopropane can effectively improve the metabolic stability. Currently, there are few reports on the three-membered ring of 5,6-dihydrocyclopentapyridine-7-one compounds. Patent WO2019060860 reported a similar reaction: 6,7-dihydro-5H-quinoline-8-one was prepared by using 1,2-dibromoethane, sodium hydrogen and DMF as the reaction system to form a three-membered ring. The reaction requires the use of dangerous raw materials sodium hydrogen, and the post-treatment separation yield is low at only 21%, which cannot meet the requirements of industrial production.

[0003]

[0004] This patent develops a simple, efficient and low-cost synthesis route to address the shortcomings of the existing technology. The new method uses diphenyl (vinyl) sulfonium trifluoromethanesulfonate / DBU as the reaction system, and the separation yield can reach 80-90%, which can meet the needs of industrial production. Summary of the invention

[0005] In order to prepare the three-membered ring on a 5,6-dihydrocyclopenta-pyridine-7-one compound to meet the requirements of industrial production, the present invention provides a method for preparing the three-membered ring on a 5,6-dihydrocyclopenta-pyridine-7-one compound.

[0006] In order to achieve the above object, the present invention adopts the following technical solutions:

[0007] In the first aspect, the present invention provides a method for preparing a three-membered ring of a 5,6-dihydrocyclopentylpyridine-7-one compound of formula I, which is obtained by reacting a 5,6-dihydrocyclopentylpyridine-7-one compound of formula I with a compound of formula II:

[0008]

[0009] R1, R2, R3 are selected from H, halogen or aliphatic hydrocarbon, and n is selected from 1-10;

[0010] The base is selected from potassium tert-butoxide, pyridine, triethylamine or 1,8-diazabicyclo[5,4,0]-7-undecene, preferably 1,8-diazabicyclo[5,4,0]-7-undecene; the molar ratio of the compound of formula I to the base is 1:

[0011] (1-10), preferably (1-5);

[0012] The catalyst is selected from zinc trifluoromethanesulfonate, and the molar ratio of the compound of formula I to the catalyst is 1:(1-10), preferably (1-3);

[0013] The reaction temperature is 10-30°C and the reaction time is 2-8h;

[0014] The solvent is selected from dimethylformamide, dimethylacetamide or dimethyl sulfoxide;

[0015] The post-treatment step comprises: quenching and then concentrating, then adding dichloromethane or ethyl acetate to filter, adding acid to wash and separate the layers, and then concentrating again.

[0016] In a second aspect, the present invention provides a method for preparing a three-membered ring of a 5,6-dihydrocyclopentylpyridine-7-one compound of formula I-1, which is obtained by reacting a 5,6-dihydrocyclopentylpyridine-7-one compound of formula I-1 with a compound of formula II:

[0017]

[0018] The base is selected from potassium tert-butoxide, pyridine, triethylamine or 1,8-diazabicyclo[5,4,0]-7-undecene, preferably 1,8-diazabicyclo[5,4,0]-7-undecene; the molar ratio of the compound of formula I-1 to the base is 1:

[0019] (1-10), preferably (1-5);

[0020] The catalyst is selected from zinc trifluoromethanesulfonate, and the molar ratio of the compound of formula I-1 to the catalyst is 1:

[0021] (1-10), preferably (1-3);

[0022] The reaction temperature is 10-30°C and the reaction time is 2-8h;

[0023] The solvent is selected from dimethylformamide, dimethylacetamide or dimethyl sulfoxide;

[0024] The post-treatment step comprises: quenching and then concentrating, then adding dichloromethane or ethyl acetate to filter, adding acid to wash and separate the layers, and then concentrating again.

[0025] The main advantages and features of the present invention are as follows:

[0026] First, the synthesis route of the present invention is short, and cheap and readily available chemical raw materials are used, so there is no need to synthesize it by oneself, which is conducive to reducing costs.

[0027] 2. The steps of the present invention have mild reaction conditions, high yield, low cost, high safety, and are suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Attached Figure 1 : Hydrogen spectrum of compound III-1 prepared in Example 1. DETAILED DESCRIPTION

[0029] The present invention is further defined in the following examples. It should be understood that these examples, while indicating preferred embodiments of the present invention, are given by way of illustration only and do not limit the present invention as claimed.

[0030] Example 1: Spiro(cyclopenta[b]pyridine-6,1'-cyclopropane)-7(5H)-one

[0031]

[0032] Dissolve 5,6-dihydro-7H-cyclopenta[B]pyridin-7-one (5.00 g) in dimethylformamide (150 mL), add zinc trifluoromethanesulfonate (16.38 g), dimethylformamide solution (50 mL) containing diphenyl(vinyl)sulfonium trifluoromethanesulfonate (16.33 g), and 1,8-diazabicyclo[5,4,0]-7-undecene (17.15 g) at room temperature, and keep the temperature at 10-30°C for 4 hours. After the reaction, add saturated ammonium chloride aqueous solution to quench, and concentrate under reduced pressure until a large amount of solid precipitates. After adding dichloromethane, filter first, then add dilute hydrochloric acid, separate, concentrate the organic layer, and purify by column chromatography to obtain 5.1 g of solid. The yield is 85%. 1H NMR (400MHz, CDCl3): δ8.75(d,J=4.7Hz,1H),7.86(d,J=7.8Hz,1H),7.43(dd, J=7.9,4.6Hz,1H),3.20(s,2H),1.55(q,J=3.8Hz,2H),1.20(p,J=4.1Hz,2H).

[0033] Example 2: 2-Chloro-spiro(cyclopenta[b]pyridine-6,1'-cyclopropane)-7(5H)-one

[0034]

[0035] Dissolve 2-chloro-5,6-dihydro-7H-cyclopenta[B]pyridin-7-one (5.00 g) in 120 mL dimethylformamide, add zinc trifluoromethanesulfonate (13.06 g), 40 mL dimethylformamide solution containing diphenyl(vinyl)sulfonium trifluoromethanesulfonate (13.02 g), and 1,8-diazabicyclo[5,4,0]-7-undecene (13.67 g) at room temperature, and keep the reaction at 10-30°C for 4 hours. After the reaction, add saturated ammonium chloride aqueous solution to quench, and concentrate under reduced pressure until a large amount of solid precipitates. After adding dichloromethane, filter first, then add dilute hydrochloric acid, separate, concentrate the organic layer, and purify by column chromatography to obtain 5.2 g of solid. The yield is 90%.

Claims

1. A method for preparing a three-membered ring of a 5,6-dihydrocyclopentylpyridin-7-one compound of formula I, characterized in that: The 5,6-dihydrocyclopentylpyridin-7-one compound of formula I and the compound of formula II are reacted to obtain: The R1, R2, R3 are selected from H, halogen or aliphatic hydrocarbon, and n is selected from 1-10.

2. A method for preparing a three-membered ring of a 5,6-dihydrocyclopentylpyridin-7-one compound of formula I-1, characterized in that: The 5,6-dihydrocyclopentylpyridin-7-one compound of formula I-1 and the compound of formula II are reacted to obtain:

3. The preparation method according to claim 1 or 2, characterized in that: The base is selected from potassium tert-butoxide, pyridine, triethylamine or 1,8-diazabicyclo[5,4,0]-7-undecene.

4. The preparation method according to claim 1 or 2, characterized in that: The molar ratio of the compound of formula I or formula I-1 to the base is 1:(1-10).

5. The preparation method according to claim 1 or 2, characterized in that: The catalyst is selected from zinc trifluoromethanesulfonate.

6. The preparation method according to claim 1 or 2, characterized in that: The molar ratio of the compound of formula I or formula I-1 to the catalyst is 1:(1-10).

7. The preparation method according to claim 1 or 2, characterized in that: The reaction temperature is 10-30°C.

8. The preparation method according to claim 1 or 2, characterized in that: The reaction time is 2-8h.

9. The preparation method according to claim 1 or 2, characterized in that: The solvent is selected from dimethylformamide, dimethylacetamide or dimethyl sulfoxide.

10. The preparation method according to claim 1 or 2, characterized in that: The post-treatment step comprises: quenching and then concentrating, then adding dichloromethane or ethyl acetate to filter, adding acid to wash and separate the layers, and then concentrating again.

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