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Isotretinoin C15-triphenylphosphine chloride as well as preparation method and application thereof

A technology of triphenylphosphine chloride and tretinoin, which is applied in the field of isotretinoin C15-triphenylphosphine chloride and its preparation, and can solve the problem of low product yield and purity, and the purity and yield of isotretinoin. It is difficult to obtain the ideal degree of yield, and the content of other impurities is high, so as to achieve the effect of mild reaction conditions, easy industrial production and high purity

Active Publication Date: 2020-08-07
SHANGHAI NEW HUALIAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this patent uses the intermediate 3,3-dienolate of methyl methacrylate and β-Pyrone acetaldehyde to react to prepare the required isotretinoin, but these intermediates are in the process of preparation Among them, the yield and purity of the ubiquitous product are low, and the content of other impurities is too high, resulting in the purity and yield of isotretinoin prepared in the later stage has been difficult to obtain an ideal level

Method used

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  • Isotretinoin C15-triphenylphosphine chloride as well as preparation method and application thereof
  • Isotretinoin C15-triphenylphosphine chloride as well as preparation method and application thereof
  • Isotretinoin C15-triphenylphosphine chloride as well as preparation method and application thereof

Examples

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Effect test

Embodiment 1

[0046] Embodiment 1. A kind of preparation method of isotretinoin C15-triphenylphosphine chloride

[0047] This example mainly describes a preparation method of isotretinoin C15-triphenylphosphine chloride, comprising the following steps:

[0048] Step 1. In the reaction kettle, add 60kg vinyl-β-ionol, 9.5kg triethylamine and 60kg methanol for stirring and mixing, the stirring speed is 80rpm, and the stirring time is 10 minutes to obtain the configuration liquid; the configuration The liquid is pumped into the high-level tank, and the reaction kettle is washed twice with 20kg of methanol, and the washing liquid is pumped into the high-level tank together to obtain the high-level tank configuration liquid;

[0049] Step 2: Turn on the vacuum, and when the vacuum degree reaches -0.06~-0.07Mpa, replace the air with nitrogen in the reactor; 36kg of hydrochloric acid with a concentration of 35%, 1kg of 2,6-di-tert-butyl-p-cresol (BHT) and 71.4kg of triphenylphosphine were put into...

Embodiment 2

[0064] Embodiment 2. A kind of preparation method of isotretinoin C15-triphenylphosphine chloride

[0065] This example mainly describes a preparation method of isotretinoin C15-triphenylphosphine chloride, comprising the following steps:

[0066] Step 1. In the reaction kettle, add 55kg vinyl-β-ionol, 8kg triethylamine and 55kg methanol for stirring and mixing, the stirring speed is 75rpm, and the stirring time is 15 minutes to obtain the configuration liquid; Pump it into the head tank, wash the reactor twice with 15kg of methanol, and pump the washing liquid into the head tank together to obtain the head tank configuration liquid;

[0067] Step 2, turn on the vacuum, and when the degree of vacuum reaches -0.06Mpa, replace the air with nitrogen in the reactor; repeat the operation again, and replace the air for 2 times; Put 35% hydrochloric acid, 0.8kg 2,6-di-tert-butyl-p-cresol (BHT) and 65kg triphenylphosphine into the reaction kettle, open the reflux condenser, reduce th...

Embodiment 3

[0080] Example 3 A preparation method of isotretinoin C15-triphenylphosphine chloride

[0081] This example mainly describes a preparation method of isotretinoin C15-triphenylphosphine chloride, comprising the following steps:

[0082] Step 1. In the reaction kettle, add 65kg vinyl-β-ionol, 12kg triethylamine and 65kg methanol for stirring and mixing, the stirring speed is 90rpm, and the stirring time is 5 minutes to obtain the configuration liquid; Pump it into the head tank, wash the reactor twice with 25kg of methanol, and pump the washing liquid into the head tank together to obtain the head tank configuration liquid;

[0083] Step 2, turn on the vacuum, and when the degree of vacuum reaches -0.07Mpa, replace the air with nitrogen in the reactor; repeat the operation again, and replace the air for 2 times; Put 35% hydrochloric acid, 1.5kg 2,6-di-tert-butyl-p-cresol (BHT) and 80kg triphenylphosphine into the reaction kettle, open the reflux condenser, reduce the amount of ...

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Abstract

The invention provides isotretinoin C15-triphenylphosphine chloride and a preparation method and application thereof. The preparation method comprises the steps of: stirring and mixing vinyl-beta-ionol, triethylamine and methyl alcohol to prepare a feed liquid I; feeding nitrogen to expel oxygen, then under a vacuum condition, preparing a mixed solution of methanol, CP hydrochloric acid, 2, 6-di-tert-butyl-p-cresol and triphenylphosphine, and carrying out condensation reflux and stirring on the mixed solution to obtain a feed liquid II; dropwise adding the feed liquid II into the feed liquid Iat 30-52 DEG C to obtain a mixture; repeatedly adding ethyl acetate into the mixture, and then carrying out reduced pressure distillation to obtain a final product precursor; and carrying out cooling, cold precipitation, centrifugation and drying treatment on the final product precursor to obtain a target product. The isotretinoin C15-triphenylphosphine chloride obtained by the preparation methoddisclosed by the invention is relatively high in purity, relatively high in yield, mild in reaction condition and easy for industrial production.

Description

technical field [0001] The invention belongs to the technical field of pharmacy, and in particular relates to isotretinoin C15-triphenylphosphine chloride and its preparation method and application. Background technique [0002] Isotretinoin is a highly conjugated molecule consisting of a substituted cyclohexene moiety and a 9-carbon polyene side chain with a terminal carboxyl group, which can be used to inhibit the function and keratinization of sebaceous glands, and with For the treatment of skin diseases such as acne. In view of the important medicinal value of isotretinoin, the requirements for the quality of the intermediates in the synthesis of isotretinoin, as well as the requirements for the yield, impurity content and yield of the intermediates are also increasing day by day. [0003] Patent CN1167679C discloses a method for preparing isotretinoin in a single step, the method comprising: in a suitable solvent, making 3,3-dienolate of methyl methacrylate and β-geran...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/54A61P29/00
CPCC07F9/5442A61P29/00
Inventor 汪武训柏挺周秋火华吉涛金芳
Owner SHANGHAI NEW HUALIAN PHARMA
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