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Compound (e)-3-(1-methylpyrrolidin-2-yl)-acrylic acid hydrochloride and its synthesis method

A technology of acrylic acid hydrochloride and methylpyrrolidine, which is applied in the field of compound-3-acrylic acid hydrochloride and synthesis, can solve the problems of low yield, difficult next-step reaction, easy to be oxidized, etc., and achieves simplified reaction process , Improve the overall yield of the product and the effect of structural stability

Active Publication Date: 2019-04-30
SHANDONG BOYUAN PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Therefore, there are also problems such as the above-mentioned "severe synthetic conditions, low yield, easy to be oxidized and difficult to react in the next step"

Method used

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  • Compound (e)-3-(1-methylpyrrolidin-2-yl)-acrylic acid hydrochloride and its synthesis method
  • Compound (e)-3-(1-methylpyrrolidin-2-yl)-acrylic acid hydrochloride and its synthesis method
  • Compound (e)-3-(1-methylpyrrolidin-2-yl)-acrylic acid hydrochloride and its synthesis method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Example 1: Synthesis of (S, E)-3-(1-methylpyrrolidin-2-yl)-acrylic acid hydrochloride

[0055] 1) Synthesis of BOC-L-prolinaldehyde

[0056] Weigh 100g of BOC-L-prolinol into a 2L four-necked reaction flask, add 1.5L of dichloromethane, stir and dissolve at room temperature, add 15.4g of sodium bromide, 2.3g of TEMPO, cool down below -10°C, and start dripping Add sodium hypochlorite solution adjusted to pH=8~9 in advance, and keep the temperature at -5~-10°C. TLC tracking (developer ethyl acetate:petroleum ether=1:1), stop adding sodium hypochlorite solution dropwise (about 500ml) after the reaction of the raw materials is complete, static layering, leave the organic layer, and use 1% sulfuric acid solution 800ml, Wash once each with 800 ml of 5% sodium thiosulfate solution and 800 ml of saturated saline, dry the organic layer over anhydrous magnesium sulfate, filter, and evaporate to dryness to obtain 94 g of BOC-L-prolinaldehyde.

[0057] 2) Synthesis of S-pyrrolidi...

Embodiment 2

[0066] Example 2: (S,E)-N-﹛4-[3-chloro-4-(pyridin-2-ylmethoxy)-anilino]-3-cyano-7-ethoxy-quinoline Synthesis of -6-yl﹜-3-(1-methyl-pyrrolidin-2-yl)-acrylamide (Compound 1)

[0067]

[0068] Add 7.7 g of (S,E)-3-(1-methylpyrrolidin-2-yl)-acrylic acid hydrochloride obtained in Example 1 into a reaction flask with 60 ml of tetrahydrofuran, add 1 ml of DMF, and stir Add 7.6g of oxalyl chloride dropwise, control the temperature at 20-25°C, keep warm and stir for 2-3 hours; cool the reaction solution to -5-0°C with a cold pump, add 4-[4-[(2-pyridyl)formazol dropwise Oxy]-3-chloroanilino]-6-amino-3-cyano-7-ethoxyquinoline in tetrahydrofuran (4-[4-[(2-pyridyl)methoxy]-3- Chloroanilino]-6-amino-3-cyano-7-ethoxyquinoline 16.3g, tetrahydrofuran 70ml), keep the temperature below 0°C, keep it warm for 1-2h after the dropwise addition, add 24g of triethylamine dropwise, Stir at 0-5°C for 4-5 hours, add 2ml of methanol at this temperature, concentrate the reaction solution to dryness af...

Embodiment 3

[0069] Example 3: Synthesis of (R, E)-3-(1-methylpyrrolidin-2-yl)-acrylic acid hydrochloride

[0070] 1) Synthesis of BOC-D-prolinaldehyde

[0071] Weigh 100g of BOC-D-prolinol and place it in a 2L four-necked reaction flask, add 1.5L of dichloromethane, stir and dissolve at room temperature, add 15.5g of sodium bromide and 2.5g of TEMPO, lower the temperature below -10°C, and start dripping Add sodium hypochlorite solution adjusted to pH=8~9 in advance, and keep the temperature at -5~-10°C. TLC tracking (developing agent ethyl acetate:petroleum ether=1:1), after the reaction of the raw materials is complete, stop adding sodium hypochlorite solution (about 500ml dropwise), static layering, keep the organic layer, and use 1% sulfuric acid solution 800ml respectively , 800ml of 5% sodium thiosulfate solution and 800ml of saturated saline were washed once respectively, and the organic layer was dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness to obtain...

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Abstract

The invention discloses a compound (E)-3-(1-methylpyrrolidine-2-yl)-acrylic hydrochloride and a synthetic method. The compound is structurally as shown in a formula (I). The synthetic method of the compound comprises the following steps: using BOC-L-prolinol (or BOC-D-prolinol) as an initial material, and by oxidization, forming aldehyde; removing a BOC protective agent; then reacting with haloalkane; then by a Wittig reaction, synthesizing (S,E)-3-(1-methylpyrrolidine-2-yl)-ethyl acrylate; after hydrolysis, salifying to obtain (S,E)-3-(1-methylpyrrolidine-2-yl)-acrylic hydrochloride [or (R,E)-3-(1-methylpyrrolidine-2-yl)-acrylic hydrochloride]. The compound, as a medical intermediate, can be used for preparing quinazoline or quinolines medicine derivatives. The formula is shown in the description.

Description

technical field [0001] The invention relates to the field of organic synthesis, and mainly relates to compound (E)-3-(1-methylpyrrolidin-2-yl)-acrylic acid hydrochloride and a synthesis method. Background technique [0002] The clinical application of quinazoline or quinoline anticancer drug derivatives is more and more extensive, and the synthesis and innovation of its intermediates are becoming more and more important. Patent CN102020639 introduces 6-aminoquinazoline or 3-cyanoquinoline Phenyl derivatives, their preparation methods and their applications in medicine. The specific compounds involved in the above-mentioned patents are compounds 1-6 shown in Table 1 below, wherein compounds 1, 4, and 5 all involve (E)-3-(1-methylpyrrolidin-2-yl)-propene structure . [0003] Table 1 6-aminoquinazoline or 3-cyanoquinoline derivatives [0004] [0005] (S,E)-N-{4-[3-chloro-4-(pyridin-2-ylmethoxy)-anilino]-3-cyano-7-ethoxy group given in the above patent literature -Quinol...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D207/08C07D401/14
CPCC07D207/08C07D401/14
Inventor 杨铎朱义胜李彪
Owner SHANDONG BOYUAN PHARM CO LTD
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