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Chemical-enzyme synthesis method of atomoxetine

A compound and coenzyme technology, applied in the field of chemical-enzymatic synthesis of atomoxetine, can solve the problems of low catalytic activity, difficult to meet industrial production, low substrate concentration, etc.

Pending Publication Date: 2021-04-27
SHANGHAI INST OF PHARMA IND CO LTD +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0015] The existing industrial preparation method for preparing atomoxetine mainly adopts the traditional resolution method, which is limited by the theoretical yield of only 50%, and the carbonyl reductase catalytic activity reported in the existing biological preparation method is low, The concentration of the substrate is low, and the chiral purity of the product is only 98%, which is difficult to meet the requirements of industrial production

Method used

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  • Chemical-enzyme synthesis method of atomoxetine
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preparation example Construction

[0096] The present invention provides a kind of preparation method of compound (S)-3, comprising steps:

[0097] (a) In a liquid reaction system, the compound of formula 2 is used as a substrate, and in the presence of a coenzyme, under the catalysis of a carbonyl enzyme, an asymmetric reduction reaction is carried out to form formula (S)-3-chlorophenylpropanol;

[0098]

[0099] and

[0100] (b) optionally separating (S)-3-chlorophenylpropanol from the reaction system after the reaction in the previous step.

[0101] In the present invention, the above reaction can be coupled or not coupled with the coenzyme regeneration system.

[0102] Preferably, the above reaction is adding (coupling) a coenzyme regeneration method (system) in the same system, so as to further improve production efficiency, reduce production cost and increase tolerance to substrates.

[0103] In addition, various preferred features or combinations thereof described in the first aspect of the present ...

Embodiment 1

[0124] The preparation of embodiment 1.(S)-3-chlorophenylpropanol [(S)-3]

[0125]

[0126] Phosphate buffer (28mL, 100mM / L, pH=8.0), dimethylsulfoxide (12mL), glucose (4.2g), ketone 2 (4.0g, 0.012mol), NAD + (0.02g), carbonyl reductase wet cells (8.0g) of the present invention, and glucose dehydrogenase (4.0g) were sequentially added to a 250mL reaction bottle, and reacted for 24h in an oil bath at 45°C and mechanically stirred at 200rpm. Sampling was carried out, and the reaction process was monitored by HPLC, and the reaction of the raw materials was complete. The reaction solution was extracted three times with dichloromethane (200mL×3), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give light yellow solid (S)-3, 3.6g, the crude product yield was 87.8%, HPLC Purity 84.56%, ee value: >99.9%.

[0127] 1 HNMR (600MHz, CDCl 3 ):δ=7.37(d,J=4.2Hz,4H),7.33-7.29(m,1H), 4.96-4.94(m,1H),3.77-3.73(m,1H),3....

Embodiment 2

[0141] Example 2. Synthesis of (R)-1-chloro-3-phenyl-3-(2-methylphenoxy)propanol (4)

[0142]

[0143] In a 100mL three-necked flask, (S)-3 (1.7g, 0.010mol) was dissolved in 20mL of anhydrous tetrahydrofuran, and triphenylphosphine (3.4g, 0.013mol), o-cresol (1.4g, 0.013 mol), N 2 protection, slowly added diethyl azodicarboxylate (DEAD) (2.3 g, 0.013 mol) at 0°C. After dropping, stir at room temperature for 24h. Add 50mL of petroleum ether and stir for 1h, a large amount of white solids are produced, filter, wash the filtered solution with water (50mL×2), dry over anhydrous sodium sulfate, filter, concentrate the filtrate, and obtain the following column chromatography (petroleum ether) without Color oily liquid 4, 7 2.4g, yield 92.31%, HPLC purity: 88.63%.

[0144] 1 H NMR (600MHz, CDCl 3 ):δ=7.44-7.39(m,4H),7.33(t,J=7.2Hz,1H),7.19(d,J=7.8Hz,1H),7.04(t,J=7.8Hz,1H),6.86 (t,J=7.5Hz,1H),6.71(d,J=7.8Hz,1H),5.48-5.45(m,1H),3.89-3.85(m,1H),3.71-3.67(m,1H), 2.59-2.53(m,1H)...

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Abstract

The invention provides a chemical-enzyme synthesis method of atomoxetine. A preparation method comprises the following steps: by using 3-chloropropiophenone as a raw material, performing asymmetric reduction reaction under the catalysis of a carbonyl reductase and a coenzyme to obtain (S)-3-chlorophenylpropanol with chiral purity ee value of 99.9%, performing light delay reaction and methylation reaction, and performing salifying with hydrochloric acid to obtain the atomoxetine. The preparation method can significantly reduce the production cost, is green and environment-friendly, and has potential industrial application value.

Description

technical field [0001] The invention belongs to the technical field of medicine, in particular to a chemical-enzyme synthesis method of atomoxetine. Background technique [0002] The trade name of atomoxetine hydrochloride is Strattera, the Chinese chemical name is (R)-N-methyl-3-(2-methylphenoxy)amphetamine hydrochloride, and the English name is (R) )-N-Methyl-3-(2-methylphenoxy)benzenepropanamine hydrochloride, the molecular formula is C 17 h 22 ClNO, relative molecular weight 291.82, CAS registration number 82248-59-7, dosage form is capsule (10mg; 18mg; 25mg; 40mg), indication is attention deficit hyperactivity disorder. [0003] [0004] Atomoxetine hydrochloride was developed by Eli Lily (Eli Lily), and was approved for marketing in the United States in 2003. Atomoxetine, the first non-central excitatory ADHD drug approved by the FDA, is a highly selective norepinephrine reuptake inhibitor (SNRI). The representative synthetic route of atomoxetine hydrochloride i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P7/22C12N9/04C12N15/53C07C41/09C07C43/225C07C213/02C07C213/08C07C217/48
CPCC12P7/22C12N9/0006C12Y101/01184C07C41/09C07C213/02C07C213/08C07C43/225C07C217/48
Inventor 张福利陈少欣倪国伟邹杰汤佳伟江锣斌陈一波王宏毅晏海军
Owner SHANGHAI INST OF PHARMA IND CO LTD
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