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Preparation method of naftifine hydrochloride

A technology of naftifine hydrochloride and naftifine, which is applied in the preparation of carboxylic acid amides, organic compounds, amino compounds, etc., can solve the problems of difficult product structure diversification, limited sources, and numerous steps, and achieve improved Yield, simplification of reaction, and reduction of production cost

Inactive Publication Date: 2014-03-26
NORTHWEST NORMAL UNIVERSITY
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  • Abstract
  • Description
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Problems solved by technology

From these methods, it can be seen that the first two methods all need to use more expensive transition metals or hydrogenation reagents, and the substrates used need special preparation methods, and the sources of substrates such as allyl alcohol or aldehydes are limited; the latter There are many steps in the method, the process is complicated, and it is difficult to realize the diversification of product structure

Method used

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Examples

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Embodiment 1

[0022] (1) N-methyl-1-naphthylamide 2 Synthesis of: reference preparation ( Eur. J. Org. Chem. 2003, 2132-2137): N 2 Atmosphere, stirring at room temperature, the SOCl 2 (4.00 mL, 548.0 mmol) was added dropwise to 1-naphthoic acid 1 (45.6 mmol), the resulting mixture was heated to 80 ° C for 2 h; after the reaction, unreacted SOCl was removed under reduced pressure 2 , the residue was dissolved in dichloromethane (4 mL); an aqueous solution of methylamine (46.8 mmol) was added, stirred at room temperature for 12 h, and then the reaction solution was poured into saturated NaHCO 3 (500 mL) solution, dichloromethane extraction (3 × 150 mL), combined organic phase, MgSO 4 Drying and concentration gave N-methyl-1-naphthylamide 2 with a yield of 92% and mp 159-160°C. 1 H NMR: CDCl 3 , 400 MHz. δ (ppm): 8.20 (m, 1 H), 7.81 (m, 2 H), 7.82-7.31 (m, 4 H), 6.37 (br, 1 H), 2.93 (s, 3 H) ; 13 C NMR: CDCl 3 , 100 MHz. δ (ppm): 170.2, 134.3, 133.4, 130.2, 129.9, 128.1, 126.8, 126...

Embodiment 2

[0027] (1) N-methyl-1-naphthylamide 2 Synthesis: with embodiment 1.

[0028] (2) N-methyl-N-allyl substituted-1-naphthylcarboxamide 3 Synthesis of : Catalyst is FeCl 3 (20% mmol), the solvent xylene was changed to THF (50 mL), the reaction temperature was 140° C., and the reaction time was 5 h. Others were the same as in Example 1. N-methyl-N-allyl substituted-1-naphthylcarboxamide 3 The yield was 83%.

[0029] (3) Naftifine 4 Synthesis: react at 80°C and heat for 5h; distill off unreacted hydrazine hydrate, raise the temperature to 180-210°C, and continue the reaction for 1h, and the others are the same as in Example 1.

[0030] (4) Naftifine hydrochloride 5 Synthesis: with embodiment 1. The total yield of naftifine hydrochloride is 60.8%.

Embodiment 3

[0032] (1) N-methyl-1-naphthylamide 2 Synthesis: with embodiment 1.

[0033] (2) N-methyl-N-allyl substituted-1-naphthylcarboxamide 3 Synthesis of : Catalyst is BF 3 ·OEt 2 (20% mmol), the solvent xylene was changed to dioxane (50 mL), the reaction temperature was 50° C., and the reaction time was 24 h. Others were the same as in Example 1. N-methyl-N-allyl substituted-1-naphthylcarboxamide 3 The yield was 85.5%.

[0034] (3) Naftifine 4 Synthesis of hydrazine hydrate: KOH: 20 mmol), 85% hydrazine hydrate dropwise 2.0 mL (65 mmol), react at 95 °C for 3 h; distill unreacted hydrazine hydrate, raise the temperature to 190-200 °C, and continue the reaction for 3 h , other with embodiment 1.

[0035] (4) Synthesis of Naftifine Hydrochloride 5: Same as Example 1. The total yield of naftifine hydrochloride is 62.5%.

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Abstract

The invention provides a preparation method of naftifine hydrochloride, and belongs to the technical field of drug chemical synthesis. The preparation method comprises the following steps: taking 1-naphthoic acid as a starting raw material, in the presence of SOCl2 (Sulfoxide Chloride), reacting with a methylamine water solution to prepare N-methyl-1-naphthamide, enabling the N-methyl-1-naphthamide to react with formaldehyde and styrene in catalysis of Lewis acid in a multicomponent reaction manner to prepare carbonylated naftifine, performing hydrazine hydrate-KOH (Potassium Hydroxide) reduction, acidizing with hydrochloric acid, and separating the compound to obtain the naftifine hydrochloride. Through the cheap Lewis acid catalyzed amine, formaldehyde and styrene three-component one-pot method, the allyl structure unit is constructed in a single step, so that the reaction is greatly simplified, and the yield is improved; the preparation method is free from a noble metal catalyst, so that the production cost of the naftifine hydrochloride is reduced; the raw materials and various reagents are cheap and easy to get, the operation process is simple, the postprocessing procedures are simple, and the preparation method creates good conditions for industrial scale production and commercialization.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, and relates to a preparation method of naftifine hydrochloride, in particular to a method for synthesizing naftifine hydrochloride with 1-naphthoic acid as a starting material. Background technique [0002] Naftifine hydrochloride, chemical name: 3-phenyl-2-propene-N-methyl-1-naphthylmethylamine or cinnaphthylmethylamine; English name: English name: Naftifine hydrochloride, 1-Naphthalenemethanamine hydrochloride; CAS: 65472 -88-0; Molecular formula: C 21 h 21 N, molecular weight: 287.40, mp 177°C. It was developed by Naftifine Hydrochloride MERZ PHARMS in the United States, and it was listed in the United States in the late 1980s. It is an allylamine topical antifungal drug. It is suitable for skin fungal diseases caused by sensitive fungi, such as tinea corporis, tinea manuum, tinea capitis, tinea unguium, tinea versicolor, and superficial candidiasis. Its chemical structural formula is as...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C209/00C07C211/30C07C231/08C07C233/65
Inventor 权正军胡旺华张彰王喜存
Owner NORTHWEST NORMAL UNIVERSITY
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