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The synthetic method of ritodrine hydrochloride

A technique for synthesizing ritodrine hydrochloride, which is applied in chemical instruments and methods, preparation of organic compounds, preparation of aminohydroxyl compounds, etc., can solve the problems of ritodrine achirality and complicated process, and reduce cost and process The effect of simple process and low reagent price

Inactive Publication Date: 2018-09-21
武汉茵茂特生物技术有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] At present, there are many reports on the preparation methods of ritodrine, most of which firstly prepare α-bromo-4-hydroxypropiophenone through the bromination reaction of 4-hydroxypropiophenone, and then through amination with p-hydroxyphenylethylamine in turn. And the selective reduction of carbonyl is also prepared, but its process is complex, and most of the synthesized ritodrine is achiral

Method used

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  • The synthetic method of ritodrine hydrochloride
  • The synthetic method of ritodrine hydrochloride
  • The synthetic method of ritodrine hydrochloride

Examples

Experimental program
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Embodiment 1

[0032]The whole cell of genetically engineered bacteria derived from the propiophenone synthase of Zymomonas mobilis is prepared by selecting the gene sequence of the propiophenone synthase derived from Zymomonas mobilis and artificially designing the designed gene sequence as shown in SEQ ID NO in the sequence table : shown in the nucleotide sequence shown in 1; the sequence is synthesized through the whole gene, cloned into the Nde I and Xho I restriction sites of the expression vector pET28a, and transformed into host bacteria E.coli BL21 (DE3) competent cells; After the positive transformants were picked and identified by sequencing, the recombinant expression vector was obtained; the recombinant expression vector was transferred into the E. coli BL21 (DE3) strain, and the recombinant propiophenone synthase genetically engineered bacteria capable of inducing the expression of the recombinant propiophenone synthase was obtained. Inoculate the recombinant propiophenone syntha...

Embodiment 2

[0036] Use the compound p-chlorobenzaldehyde of formula II and the compound pyruvic acid of formula III as substrates and buffer solution to form a reaction system, add catalyst and additives, react and purify to obtain compound (R)-1-(4-chlorophenyl) of formula IV -1-Hydroxypropan-2-one.

[0037] The specific reaction process is as follows: the reaction is carried out in a 1L shake flask, and the reaction system is controlled to 300mL, with the formula II compound p-chlorobenzaldehyde (29.51g, 0.21mol) and the formula III compound pyruvic acid (24.64g, 0.28mol) as substrates , using citric acid-sodium citrate buffer solution as a solvent, using whole cells of genetically engineered bacteria derived from Zymomonas mobilis propiophenone synthase and coenzyme thiamine pyrophosphate as catalysts. The concentration of whole cells of the genetically engineered bacteria controlling the phenylacetone synthase derived from Zymomonas mobilis is 100 g / L, and the concentration of the coe...

Embodiment 3

[0041] Formula IV compound (R)-1-(4-chlorophenyl)-1-hydroxypropan-2-one and ammonium formate are used as substrates, and a buffer solution is used to form a reaction system, a catalyst is added, reacted, and purified to obtain formula V Compound (1R,2S)-2-amino-1-(4-chlorophenyl)-1-propanol.

[0042] The reaction was carried out in a 1L shake flask, and the reaction system was controlled to 300mL. Compound (R)-1-(4-chlorophenyl)-1-hydroxypropan-2-one (35.06g, 0.19mol) and ammonium formate (23.94g, 0.38mol) as a substrate, using phosphate buffered saline as a solvent, breaking the enzyme liquid with the genetically engineered bacteria derived from the leucine dehydrogenase of Saccharomyces cerevisiae, and the gene of formate dehydrogenase derived from Candida boidinii Engineering bacteria cell breaking enzyme liquid and coenzyme NAD+ are catalysts. Control the broken enzyme solution concentration of the genetically engineered bacteria derived from the leucine dehydrogenase of ...

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Abstract

The invention discloses a method for synthesizing ritodrine hydrochloride. The method comprises that p-chlorobenzaldehyde and pyruvic acid as substrates undergo a catalytic reaction, the product is purified to form (R)-1-(4-chlorophenyl)-1-hydroxypropane-2-one, the (R)-1-(4-chlorophenyl)-1-hydroxypropane-2-one and ammonium formate as substrates undergo a catalytic reaction, the product is purifiedto form (1R, 2S)-2-amino-1-(4-chlorophenyl)-1-propanol, the (1R, 2S)-2-amino-1-(4-chlorophenyl)-1-propanol and LiOH. H2O undergo a reaction to produce 4-((1R, 2S)-2-amino-1-hydroxypropyl)phenol and 4-((1R, 2S)-2-amino-1-hydroxypropyl)phenol and 4-(2-chloroethanol)phenol undergo a reaction to produce ritodrine hydrochloride. The method realizes a low cost, utilizes mild reaction conditions and issuitable for industrial production.

Description

technical field [0001] The present invention relates to the preparation method of crude drug and medicine intermediate, specifically a kind of synthesis method of ritodrine hydrochloride. Background technique [0002] Litojun is a beta drug developed by Solvay in Belgium 2 Adrenergic receptor agonist, first listed in Sweden in 1973. Ritodrine stimulates β in uterine smooth muscle 2 Receptors can inhibit the frequency, intensity and duration of uterine smooth muscle contraction, thereby prolonging the pregnancy period, and increasing the maturity of the fetal heart and lungs, which is beneficial to the health of the baby. It is used for anti-premature treatment of pregnant women over 20 weeks of pregnancy. [0003] At present, there are many reports on the preparation methods of ritodrine, most of which firstly prepare α-bromo-4-hydroxypropiophenone through the bromination reaction of 4-hydroxypropiophenone, and then through amination with p-hydroxyphenylethylamine in turn....

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C215/60C07C213/02C07C213/08C12P13/00
Inventor 胡磊奚超群彭丹
Owner 武汉茵茂特生物技术有限公司
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