Preparation method of prucalopride intermediate

A technology for prucalopride and intermediates, which is applied in the field of preparation of prucalopride intermediates, can solve problems such as unsuitable for industrial scale production, difficult to obtain, cumbersome steps, etc., and avoid heavy metal reagents and highly toxic reagents , suitable for large-scale industrial production, mild reaction conditions

CN104529960AInactive Publication Date: 2015-04-22CHENGDU BAIYU PHARMA CO LTD
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Patent Information

Authority / Receiving Office
CN · China
Current Assignee / Owner
Publication Date
2015-04-22
Estimated Expiration
Not applicable · inactive patent

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Abstract

The invention discloses a preparation method of a prucalopride intermediate. The preparation method comprises the following steps: step a, protecting t amino group of a compound I by using trifluoroacetic anhydride to obtain a compound II; step b, under the protection of nitrogen gas, enabling the compound II, chloroacetyl chloride, anhydrous aluminium chloride, nitrobenzene and a halocarbon solvent to react to obtain a compound III; step c, enabling the compound III, an alcohol solvent and sodium acetate to have a reflux reaction to obtain a compound IV; step d, enabling the compound IV, the alcohol solvent, raney nickel and nitrogen with the pressure of 3.0Mpa to react to obtain a compound V; step e, enabling the compound V and N-chloro-succinimide to have a substitution reaction to obtain a compound VI; step f, removing an amino protective group from the compound VI to obtain a compound VII. The method disclosed by the invention has the advantages that initial raw materials are easily available, is simple and convenient to operate, is relatively mild in reaction condition, is capable of avoiding the use of heavy metal reagents and high-toxicity reagents, is high in yield and is quite suitable for large-scale industrial production.
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Description

technical field

[0001] The invention relates to a preparation method of a prucalopride intermediate, in particular to a preparation method of 4-amino-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid. Background technique

[0002] Prucalopride (also known as prucalopride), its chemical name is 4-amino-5-chloro-2,3-dihydro-N-[1-(3-methoxypropyl)-4- Piperidinyl]-7-benzofurancarboxamide (CAS: 179474-81-8), its succinate (CAS: 179474-85-2), is commonly used clinically, and is a highly selective 5-HT4 receptor agonist It can increase gastrointestinal motility and improve constipation symptoms.

[0003] 4-Amino-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid is an important intermediate for the synthesis of prucalopride. Currently, the following 4-amino-5-chloro-2 , the preparation method of 3-dihydrobenzofuran-7-carboxylic acid:

[0004] (1) The synthetic route reported by Chem.Pharm.Bull 46(1), 42-52(1998) and Pharmacy and Clinical Research 2011(4)306-307 is:

[0005] [...

Examples

Embodiment 1

[0064] 1. Preparation of Compound II

[0065] Compound I (167.1g, 1mol), triethylamine (111.1g, 1.1mol) and dichloromethane (1040g) were added into the reaction flask, the temperature was lowered to 5°C under nitrogen protection, and trifluoroacetic anhydride (220.5g, 1.05mol) / dichloromethane (150g) solution, keep the temperature at 5-15°C throughout the whole process, after dropping, react at room temperature for 3 hours, monitor the reaction with TLC (DCM:MeOH=25:1) until the reaction is complete; Pour into ice water (560g), stir for 20 minutes, let stand to separate the layers, separate the water phase, wash the organic phase with saturated aqueous sodium bicarbonate (100g); wash with 1M hydrochloric acid (110g), and then wash with saturated brine (200g) Washed, dried over magnesium sulfate (40 g), filtered and concentrated to obtain compound II (250.1 g), yield: 95.2%.

[0066] 2. Preparation of Compound III

[0067] Chloroacetyl chloride (101.7g, 0.9mol), nitrobenzene (...