Side chain, synthesis method thereof, and method for synthesizing hydroxychloroquine sulfate from side chain

A technology of hydroxychloroquine sulfate and a synthesis method, applied in the field of medicine and chemical industry, can solve the problems of high safety risk, high impurity content and high raw material cost, and achieve the effects of low process temperature, high yield and quality, and low manufacturing cost

Active Publication Date: 2017-10-20
宜宾莱特医药化工有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0025] In summary, the current synthetic route of hydroxychloroquine sulfate mainly has two unfavorable factors: one is the preparation of the side chain of hydroxychloroquine: it needs to use ammonia gas or high-concentration liquid ammonia, which has a heavy odor and has a bad impact on the environment. High-pressure hydrogenation is required to reduce to amino groups, which has a high safety risk; the second is the preparation of hydroxychloroquine base: due to the relatively low activity of the 4-position chlorine of 4,7-dichloroquinoline, it is impossible to use only c

Method used

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  • Side chain, synthesis method thereof, and method for synthesizing hydroxychloroquine sulfate from side chain
  • Side chain, synthesis method thereof, and method for synthesizing hydroxychloroquine sulfate from side chain
  • Side chain, synthesis method thereof, and method for synthesizing hydroxychloroquine sulfate from side chain

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0105] Preparation of side chains:

[0106] (1) Condensation reaction: Add 30g of N-ethylethanolamine, 0.6g of tetrabutylammonium bromide, 25g of potassium hydroxide, 240g of chloroform, and 120g of water into the reaction flask, then control the temperature at 20-30°C, and add 38g of 5 -Chloro-2-pentanone, after the dropwise addition, stirred and reacted for 3 hours, static layered, discarded the water phase, added 24g of anhydrous sodium sulfate to the organic layer, controlled the temperature at 10-20°C, stirred and dried for 1 hour, filtered, The filtrate was the organic phase of the condensation product, and its content was detected. The condensation product was 50.2 g, the molar yield was 92% (based on 5-chloro-2-pentanone), and the GC purity was ≧98.5%.

[0107] (2) Esterification reaction: Cool the organic phase of the condensation product (condensation product 50.2g) prepared in step (1) to 0-5°C, and add 24g of acetyl chloride dropwise at heat preservation. After co...

Embodiment 2

[0111] Preparation of side chains:

[0112] (1) Condensation reaction: Add 30g of N-ethylethanolamine, 0.9g of tetrabutylammonium bromide, 25g of potassium hydroxide, 240g of chloroform, and 120g of water into the reaction flask, then control the temperature at 20-30°C, and add 38g of 5 -Chloro-2-pentanone, after the dropwise addition, stirred and reacted for 3 hours, static layered, discarded the water phase, added 24g of anhydrous sodium sulfate to the organic layer, controlled the temperature at 10-20°C, stirred and dried for 1 hour, filtered, The filtrate was the organic phase of the condensation product, and its content was detected. The condensation product was 50.8 g, the molar yield was 93.1% (based on 5-chloro-2-pentanone), and the GC purity was ≧98.5%.

[0113] (2) Esterification reaction: cool down the organic phase of the condensation product (containing 50.8 g of condensation product) prepared in step (1) to 0-5° C., add 24 g of acetyl chloride dropwise while keep...

Embodiment 3

[0117] Preparation of side chains:

[0118] (1) Condensation reaction: Add 30g of N-ethylethanolamine, 1.2g of tetrabutylammonium bromide, 25g of potassium hydroxide, 240g of chloroform, and 120g of water into the reaction flask, then control the temperature at 20-30°C, and add 38g of 5 -Chloro-2-pentanone, after the dropwise addition, stirred and reacted for 3 hours, static layered, discarded the water phase, added 24g of anhydrous sodium sulfate to the organic layer, controlled the temperature at 10-20°C, stirred and dried for 1 hour, filtered, The filtrate was the organic phase of the condensation product, and its content was detected. The condensation product was 51.7g, the molar yield was 94.7% (based on 5-chloro-2-pentanone), and the GC purity was ≧98.5%.

[0119] (2) Esterification reaction: Cool the organic phase of the condensation product (condensation product 51.7g) prepared in step (1) to 0-5°C, and add 24g of acetyl chloride dropwise at heat preservation. After c...

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Abstract

The invention discloses a side chain, a synthesis method thereof, and a method for synthesizing hydroxychloroquine sulfate from the side chain. The synthesis method of the side chain comprises the following steps: 1, condensing N-ethylethanolamine and 5-chloro-2-pentanone to obtain a condensation product; 2, esterifying the condensation product and an acetyl reagent to obtain an esterification product; 3, reducing the esterification product to obtain a reduction product; and 4, reacting the reduction product with a halogenating agent to obtain the side chain. The synthesis method of the hydroxychloroquine sulfate comprises the following steps: 1, reacting 4-amino-7-chloroquinoline with paratoluensulfonyl chloride to obtain 4-Tos-amino-7-chloroquinoline; 2, reacting the side chain with the 4-Tos-amino-7-chloroquinoline to obtain a hydroxyquine base; and 3, reacting the hydroxyquine base with sulfuric acid to obtain the hydroxychloroquine sulfate. The synthesis method of the new side chain avoids the ammonification process and the catalytic hydrogenation process, and is safe and environmentally friendly, and the hydroxychloroquine sulfate can be obtained through low-temperature condensation of the side chain, so the quality of the above products is remarkably improved, and the production flow is simplified.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a side chain and a synthesis method thereof, and a method for synthesizing hydroxychloroquine sulfate by using the side chain. Background technique [0002] Hydroxychloroquine sulfate, chemical name 2-4-(7-chloro-4-quinolyl) aminopentylethylamino-ethanol sulfate, English name: Hydroxychloroquine Sulfate, chemical structural formula is as follows: [0003] [0004] Hydroxychloroquine (Hydroxychloroquine, HCQ) is an antimalarial drug composed of 4-aminoquinoline compounds. Hydroxychloroquine sulfate was synthesized by Surrey and Hammer in 1946. It is clinically used to treat discoid lupus erythematosus and systemic lupus erythematosus, and has also been widely used in rheumatism-related diseases. [0005] Discoid lupus erythematosus (DLE) is a relatively common skin and mucous membrane connective tissue disease, 25%-35% have oral lesions, which can be s...

Claims

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Application Information

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IPC IPC(8): C07C219/06C07C213/08C07D215/46
CPCC07C219/06C07D215/46
Inventor 刘铁彭能文游洪全邓天余
Owner 宜宾莱特医药化工有限公司
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