Synthesis method of etretinate ether

A compound, selected technology, applied in the preparation of carboxylate, chemical instruments and methods, preparation of organic compounds, etc., can solve the problems of unsafe operation, harsh reaction conditions, long reaction time, etc. mild effects

Active Publication Date: 2013-05-01
CHONGQING HUAPONT PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] 1. The reaction conditions are harsh, such as absolute anhydrous conditions;
[0004] 2. It needs extremely strong alkali, such as NaH, sodium alkoxide, etc., which is unsafe to operate;
[0005] 3. Long reaction time (11 hours);
[0006] 4. Low yield (about 40%) and high cost

Method used

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  • Synthesis method of etretinate ether
  • Synthesis method of etretinate ether

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Example 1 Synthesis of 4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]benzoate (one)

[0034] 10g [1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-ethyl]-triphenylphosphonium bromide, 4.0g p-methoxy Add carbonylbenzaldehyde to 200ml of dichloromethane, then add 200ml of 2% NaOH aqueous solution, stir at 40°C for two-phase reaction for about 1h, TLC (developing agent: methanol: chloroform = 1:5) to monitor the completion of the reaction of raw materials After the reaction, the organic layer was separated, and the organic solvent was removed after the organic layer was dried. Add 60ml of methanol to the residue, the precipitated solid is the crude product; heat dissolve the crude product in 20ml of ethyl acetate, add 60ml of ethanol, and precipitate needle-like crystals to obtain the title compound; the yield is 61.17%, and the content (HPLC) is 99.47%.

Embodiment 2

[0035] Example 2 Synthesis of 4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]benzoic acid methyl ester (two)

[0036] 10g [1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-ethyl]-triphenylphosphonium bromide, 5.8g p-methoxy Add carbonylbenzaldehyde to 300ml of dichloromethane, then add 12ml of 33% NaOH aqueous solution, stir at 40°C for two-phase reaction for about 5 hours, TLC (developing agent: methanol: chloroform = 1:5) to monitor the completion of the raw material reaction After the reaction, the organic layer was separated, and the organic solvent was removed after the organic layer was dried. 60ml of methanol was added to the residue, and the precipitated solid was the crude product. The crude product was dissolved in 20ml of ethyl acetate, and 60ml of ethanol was added to precipitate needle-like crystals to obtain the title compound with a yield of 79.93% and a content (HPLC) of 99.20%.

Embodiment 3

[0037] Example 3 Synthesis of 4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]benzoic acid methyl ester (three)

[0038] 9.3g [1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-ethyl]-triphenylphosphine chloride, 4.8g p-methyl Add oxycarbonylbenzaldehyde to 250ml of carbon tetrachloride, then add 10ml of 45% NaOH aqueous solution, stir at 70°C for two-phase reaction for about 1h, TLC (developing agent: methanol: chloroform = 1:5) to monitor the raw materials After the reaction is completed, the organic layer is separated after the reaction, and the organic solvent is removed after the organic layer is dried. 60ml of methanol was added to the residue, and a solid was precipitated to obtain a crude product. The crude product was dissolved in 20ml of ethyl acetate, and 60ml of ethanol was added to precipitate needle-like crystals to obtain the title compound. The yield was 71.24%, and the content (HPLC) was 99.30%.

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Abstract

The invention relates to a synthesis method of etretinate ether. The synthesis method adopts (1-(5, 6, 7, 8-tetrahydrophthalic-5, 5, 8, 8-tetramethyl-2-naphthyl)-ethyl)-terphenyl phosphorus halide (II) and p-eormylbenzoic acid ester (III) as raw materials, carries out two-phase reaction under the condition of adding aqueous alkali into an organic solvent, and then obtains the etretinate ether. The method has mild reaction condition, short reaction time, simple and convenient operation, low cost and high yield.

Description

technical field [0001] The present invention relates to the synthesis method of aromatic retinoic acid ester. Background technique [0002] Aromatic retinoids have high medicinal value. U.S. Patent No. 4,326,055 discloses [1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-ethyl]-triphenylphosphine halide and p-ethoxy Carbocarbonylbenzaldehyde was subjected to Wittig reaction, under the protection of inert gas, reacted for 12 hours at 65°C to obtain p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8- Tetramethyl 1-2-naphthyl) propenyl]-ethyl benzoate; CN200510020500.2 discloses the preparation method of aromatic ethyl retinoic acid ester, [1-(5,6,7,8-tetrahydro-5 , 5,8,8-tetramethyl-2-naphthyl)-ethyl]-triphenylphosphine bromide, p-ethoxycarbonylbenzaldehyde, add isopropanol, blow nitrogen, when heated to 65°C, add Ethanol and sodium metal were reacted for 11 hours, and the solvent was removed. Methanol was added to the residue, and the solid was separated to obtain the crude product...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C69/612C07C67/343
Inventor 杨华邹长忠郝光富
Owner CHONGQING HUAPONT PHARMA
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