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Preparation method of terglazan intermediate

A Teglazan and Asana technology, which is applied in the field of preparation of Teglazan intermediates, can solve the problems of difficulty in realizing industrialized production, dangerous operation, and complicated post-processing.

Pending Publication Date: 2022-03-29
浙江四维医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0010] This route also has disadvantages such as unavailable raw materials, expensive reagents, complicated post-processing, dangerous operation, etc., and it is difficult to realize industrial production

Method used

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  • Preparation method of terglazan intermediate
  • Preparation method of terglazan intermediate
  • Preparation method of terglazan intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] Embodiment 1: the synthesis of compound III'

[0064]

[0065] Put 3-hydroxy-4-nitrobenzoic acid (183g, 1.0mol), dry acetonitrile (1.0L), DMF (3.7g, 2.0mol) into a 5L three-necked flask, start mechanical stirring, slowly heat up to 70°C, and then add Thionyl chloride (238.0 g, 2.0 mol) was slowly added dropwise, and the drop was completed within 0.5-1.0 hours, and the reaction was continued for 2 hours. Then the temperature was lowered to 0° C., dimethylamine hydrochloride (163.0 g, 2.0 mol) was dropped into the reaction solution, stirring was continued for 0.5 hour, triethylamine (405.0 g, 4.0 mol) was slowly added dropwise, and the dropwise was completed within 1.0 hour. The temperature was raised to room temperature, and the reaction was continued for 0.5 hours. Evaporate the solvent under reduced pressure at 40-50°C, add 300mL of water, adjust the pH value to 3-4 with 2N dilute hydrochloric acid, extract twice with dichloromethane (500ml x 3), discard the aqueou...

Embodiment 2

[0066] Embodiment 2: the synthesis of compound IV'

[0067]

[0068] Put 3-hydroxy-N, N-dimethyl-4-nitrobenzamide (168.2g, 0.80mol), acetone (800mL), potassium carbonate (221.1g, 0.016mol) into a 2.0L three-necked flask, start mechanical stirring, and keep warm at room temperature for 10 minutes , and then slowly drop benzyl bromide (136.8 g, 0.80 mol) into the reaction solution, and drop it within 0.5-1.0 hours. After the reaction is complete, evaporate the solvent to dryness under reduced pressure at 40-50°C, add 500mL of water, extract twice with isopropyl acetate (500ml x 2), discard the aqueous phase, combine the organic phases, and concentrate to dryness at 35-40°C under reduced pressure to obtain Yellow viscous substance (233.3 g, 0.78 mol), namely the target compound IV', yield 97.2%. 1 H NMR (400MHz, CDCl 3 )δ2.96(s, 3H), 3.09(s, 3H), 5.25(s, 2H), 7.04(d, 2H, J=8.4Hz), 7.16(s, 1H), 7.32~7.44(m, 5H ), 7.87 (d, 1H, J = 8.0 Hz). MS(ESI): m / z 301.1132[M+H] + .

Embodiment 3

[0069] Embodiment 3: the synthesis of compound V'

[0070]

[0071] Put 3-(benzyloxy)-N, N-dimethyl-4-nitrobenzamide (180.2g, 0.6mol), dichloromethane (800ml), acetic acid (180.2g, 1.8mol) into a 1.0L three-necked flask, start mechanical stirring, and stir at room temperature After 10 minutes, Zn powder (78.5 g, 1.2 mol) was added in batches in four batches, 19.6 g in each batch, with an interval of 1.5 h. The progress of the reaction was tracked by HPLC, and the reaction was complete after 7 hours. Filter, wash the filter cake with 200mL dichloromethane, add 500mL water to the filtrate, stir and separate layers, extract the water phase twice with dichloromethane (500ml x 2), discard the water phase, combine the organic phases, and reduce Concentrate to dryness under reduced pressure to obtain a yellow viscous substance (150.2 g, 0.56 mol), which is the target compound V', with a yield of 92.5%. 1 H NMR (400MHz, CDCl 3 )δ3.01(s, 6H), 4.02(s, 2H), 5.09(s, 2H), 6.68(d, 1H,...

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Abstract

The invention provides a synthesis method of a terglazan intermediate compound as shown in a formula IX, which comprises the following steps: A, carrying out halogenation reaction on a compound as shown in a formula I to prepare a compound as shown in a formula II, and carrying out condensation reaction on the compound as shown in the formula II and an amine reagent without separation to prepare a compound as shown in a formula III; b, preparing a compound as shown in a formula IV from a protecting group on the compound as shown in the formula III; c, carrying out reduction reaction on the compound in the formula IV to prepare a compound in a formula V; d, preparing a compound shown as a formula VI from the compound shown as the formula V in the presence of a catalyst; e, carrying out cyclization reaction on the compound shown in the formula VI to prepare a compound shown in a formula VII; f, reacting the compound shown in the formula VII with TsCl to prepare a compound shown in a formula VIII; g, preparing a terglazan intermediate compound as shown in a formula IX from the compound as shown in the formula VIII through a deprotecting reaction; the synthesis process is low in cost, the yield of the prepared terglazan intermediate compound shown as the formula IX is high, and the industrial large-scale production applicability is high.

Description

Background technique [0001] Tegrazan, also known as Tegprazan (Tegprazan), its chemical structure is as follows: [0002] [0003] Tegoprazan is a competitive potassium ion acid blocker (P-CAB) and hydrogen ion potassium ion exchange ATPase (H+ / K+ATPase) inhibitor approved for the treatment of gastroesophageal reflux disease and erosive esophagitis. Tegoprazan was originally developed by Pfizer, and was licensed to RaQualia Pharma (separated from Pfizer) in 2008 for joint development. In 2014, it was authorized by RaQualia Pharma to CJ. In 2015, CJ HealthCare and Shandong Luoxin Pharmaceutical signed an agreement to jointly develop related diseases in China. Tegoprazan was approved for marketing by the Korean Ministry of Food and Drug Safety (MFDS) in July 2018, and is marketed by CJ HealthCare in South Korea. [0004] Gastroesophageal reflux disease is a very common digestive tract disease with a high incidence in the population. The main symptoms are heartburn, chest pa...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D235/08C07D235/22C07C257/14C07C231/12C07C237/44C07C235/60C07C231/02C07C201/12C07C205/59
CPCC07D235/08C07D235/22C07C257/14C07C231/12C07C231/02C07C201/12C07C237/44C07C235/60C07C205/59Y02P20/55
Inventor 李红亮高照波张现毅梅义将胡剀
Owner 浙江四维医药科技有限公司
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