Alcaftadine intermediate and synthetic method for alcaftadine

A kind of technology of alcaftadine and synthesis method, applied in the field of synthesis of alcaftadine intermediate and alcaftadine, can solve problems such as unsuitable for industrial production, high reaction temperature, long reaction time, etc., to avoid dihydroxy Effects of methylated by-products, high synthesis yield, and short reaction cycle

Active Publication Date: 2015-08-26
NANJING HUAWE MEDICINE TECH DEV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0020] In summary, compound VII is the key intermediate for the synthesis of alcaftadine in the prior art, and because imidazole is an electron-rich aromatic compound, it is easy to occur Electrophilic substitution reaction at C-4 and C-5, which leads to uncontrollable imidazole C-4 and C-5 bis-methylolation in the process of selective monomethylolation reaction of key intermediate VII By-products, and formaldehyde that pollutes the environment is used in the reaction process, the reaction temperature is too high, the reaction time is too long, the reaction yield is too low, the requirements for equipment are high, and it is not suitable for industrial production

Method used

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  • Alcaftadine intermediate and synthetic method for alcaftadine
  • Alcaftadine intermediate and synthetic method for alcaftadine
  • Alcaftadine intermediate and synthetic method for alcaftadine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] 5-(Trimethylsilyloxymethylene)-1 H -imidazole compound formula III Synthesis

[0048]

[0049] (1 H -Imidazol-5-yl)methanol (9.9g, 0.1mol) was added to dichloromethane (100mL), and stirred evenly. DIPEA (38.8 g, 0.3 mol) was added and stirring was continued for 30 min. Then cool to 0~5°C, add trimethylchlorosilane (TMSCl, 17.4g, 0.16mol) dropwise, stir at the same temperature for 1~2h after dropping, and concentrate the reaction solution to dryness to obtain an oil compound III .

Embodiment 2

[0051] 1-Phenylethyl-5-trimethylsilylmethylene-1 H -imidazole compound formula IV Synthesis

[0052]

[0053] The formula of the compound prepared in the previous step III and potassium carbonate (16.5g, 0.12mol) were added into acetonitrile (150mL), and stirred evenly. The temperature was raised to 75°C, and β-phenethyl bromide (18.5 g, 0.1 mol) was slowly added dropwise. After the dropwise addition, the reaction was continued for 5h. Cool to room temperature, filter with suction, concentrate the filtrate to dryness, dissolve the remaining oil in a mixed solvent of dichloromethane and water, add concentrated hydrochloric acid dropwise to pH=3~4, separate the liquids after standing still, take the water layer, and add sodium bicarbonate Solid, to pH=7~8, and no bubbles, dichloromethane extracted 3 times, the organic phase was concentrated to dryness, and the oil was purified by column to obtain the compound formula IV (14.5g, 85 % ). 1 H-NMR (300 MHz, DMSO-d 6 , ...

Embodiment 3

[0055] (5-(Hydroxymethyl)-1-phenyl-1 H -imidazol-2-yl)(1-methylpiperidin-4-yl)methanol compound formula V Synthesis

[0056]

[0057] Compound formula IV (13.7g, 0.05mol) and triethylamine (12.3g, 0.12mol) were added into acetonitrile (200mL), and stirred evenly. Cool to 0-5°C, and slowly add 1-methylpiperidine-4-carbonyl chloride hydrochloride (13.8 g, 0.07 mol) newly prepared in advance in batches. After the addition was complete, it was transferred to room temperature for 20 h. Add dropwise 40% aqueous sodium hydroxide solution to pH=9~10, then concentrate to dryness. Dissolve the remaining solid in water and ethyl acetate, add concentrated hydrochloric acid dropwise to pH = 3~4, separate the liquid after standing still, take the water layer, add solid sodium bicarbonate until pH = 7~8, and no bubbles are generated. Stir and crystallize at 5°C for 4~5h, filter with suction, and wash the filter cake with water. The obtained filter cake is dried to obtain the compou...

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Abstract

The invention belongs to the field of medicinal chemistry and particularly relates to an alcaftadine intermediate and a synthetic method for alcaftadine. The method comprises the following steps: taking (1H-imidazo-5-yl)methanol (as shown in a formula II) as a raw material, and producing a hydroxyl protection reaction, a substitution reaction with beta-phenylethyl bromide, an electrophilic substitution with 1-methylpiperidine-4-carbonyl chloride hydrochloride, a cyclization reaction and an oxidation reaction to synthesize alcaftadine (as shown in a formula I). The method provided by the invention does not relate to an imidazole ring hydroxymethylation reaction, and hydroxymethyl in the alcaftadine structure is introduced from a starting material, so that the use of high-temperature condition and a toxic reagent, namely formaldehyde is reduced, the production of bis(hydroxymethyl) byproducts in a hydroxymethylation process is avoided, and the cost is reduced. The alcaftadine intermediate is low in production cost, good in product quality and suitable for industrialized production, and the synthetic raw materials are low in price and easily available.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to an alcatadine intermediate and a synthesis method of alcatadine. Background technique [0002] Alcaftadine, the Chinese chemical name is: 11-(1-methyl-4-piperidinylidene)-6, 11-dihydro-5H-imidazole[2, 1-b]- [3] Benzazepine-3-carbaldehyde, the English chemical name is: 11-(1-methyl-4-piperidinylidene)-6, 11-dihydro-5H-imidazo[2, 1-b] [3]benzazepine-3 –carbaldehyde , the chemical formula is C 19 h 21 N 3 O, the relative molecular mass is 307.39. Structural formula is shown in formula I: [0003] [0004] Alcaftadine (alcaftadine) is a new type of histamine H1 receptor antagonist developed by Vistakon Pharmaceuticals. In July 2010, it was approved by the US FDA for marketing, and the trade name was Lastacaft. This medicine is an eye drop indicated for the treatment of ocular itching associated with allergic conjunctivitis in people over 2 years of a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D233/64C07D401/06C07D487/04C07F7/18
CPCC07D233/64C07D401/06C07D487/04C07F7/1804
Inventor 李龙霞刘宝巫凯包金远蒋玉伟张孝清
Owner NANJING HUAWE MEDICINE TECH DEV
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