CN1324790A - Naftifine hydrochloride synthesizing process - Google Patents

Abstract

A synthesis process of naftifine hydrochloride includes the following three steps: first step: using naphthalene as initial raw material and making it and paraformaldehyde hydrochloric acid to synthesize 1-chloromethyl naphthalene crude product; second step: using 1-chloromethyl naphthalene crude product and methylamine to synthesize N-methyl-1-naphthyl methylamine; and third step: using N-methyl-1-naphthyl methylamine and cinnamyl chlorine to synthesize the invented naftifine hydrochloride. This invention is moderate in reaction condition, has no need of expensive reagent, and is high in yield.

Description

The naftifine hydrochloride new synthetic process

The invention belongs to a kind of technology of chemical synthetic drug, particularly a kind of Naftifine hydrochloride synthesizing process.

Naftifungin (Naftifm) is antifungal drugs serendipitous such as Bemey in 1974, and its chemical structure is different fully with known antifungal drug, belongs to the propylamine compound.Because this product has the constructional feature and the mechanism of action of broad-spectrum antifungal activity, novelty, has caused people's attention very soon, carried out further investigation more widely, formed new class antifungal drug a--propylamine at present.At present relevant naftifine hydrochloride synthesis technique bibliographical information has four synthetic routes.

Second:

Article three:

Article four:

A. azeotropic removes H₂O or molecular sieve; B.; NaBH₄C.NaBH₄/ CH₂O or NaH₂PO₃/ CH₂O; D.HCl/H₂O/EtOH refluxes; E.NaBH₄F.5NHCl; G.Cucl or ZnCl₂Make catalyzer, dioxane refluxes; H. diisobutyl aluminum hydrogen, toluene, 40 ℃; I.DMF.NaCO₃The NaBH of twice use costliness in the synthetic route one in these four synthetic routes₄, using NaBH simultaneously₄The time, discharge a large amount of hydrogen, the very big explosion hazard of tool, cost is high, and the suitability for industrialized production of not having is worth.Also use expensive NaBH in the synthetic route two₄, the reaction volume of final step simultaneously is huge, no industrial application value.Synthetic route three needs to use excessive two extremely expensive isobutyl aluminium hydrogen, and raw material also is difficult for obtaining, and only has the laboratory to be worth.Synthetic route four raw materials are easy to get, and react also comparatively simple, are suitable for industrial production.But synthetic line four is with the synthetic N-methyl isophthalic acid of pure 1 chloromethyl naphthalene and methylamine-naphthalene methylamine, and during the purifying 1 chloromethyl naphthalene, needs second distillation, and the cycle is long, the cost height.Prolong is easily clogged by unreacted naphthalene during distillation, careless slightlyly easily causes blast to take place.

The purpose of this invention is to provide that a kind of synthesis cycle is short, raw material is inexpensive, be easy to get, reaction conditions gentleness, safety, yield height, the Naftifine hydrochloride synthesizing process that is fit to suitability for industrialized production is to overcome the deficiency of prior art.

The object of the present invention is achieved like this, and it is with three step synthetic hydrochloric acid naftifungins, and the first step is the synthetic 1 chloromethyl naphthalene crude product of starting raw material and Paraformaldehyde 96 hydrochloric acid with the naphthalene; Second step is with 1 chloromethyl naphthalene crude product and the synthetic N-methyl isophthalic acid of methylamine-naphthalene methylamine; The 3rd step is again with N-methyl isophthalic acid-naphthalene methylamine and cinnamyl chlorine synthetic hydrochloric acid naftifungin.

The present invention adopts, and naphthalene inexpensive, that be easy to get is direct and methylamine reaction behind the directly synthetic 1 chloromethyl naphthalene crude product of raw material, salify then, to react incomplete naphthalene and separate with N-methyl isophthalic acid-chloronaphthalene methylamine, after alkalization, distillation makes pure N-methyl isophthalic acid-naphthalene methylamine to the latter again.Avoided the explosive operation steps of circuit four, simple to operateization, reflection cycle is short, and yield reaches the highest yield of circuit four reports.Cinnamyl chlorine and N-methyl isophthalic acid-when naftifungin was synthesized in the reaction of naphthalene methylamine, circuit four was to make solvent with DMF, with anhydrous Na in addition₂CO₃Be acid binding agent, this method cost is higher, and it is inconvenient in industrial use under reduced pressure to reclaim DMF.The present invention then adopts 30%NaOH to make acid binding agent, with the method for cinnamyl chlorine and N-methyl isophthalic acid-naphthalene methylamine condensation, not only greatly reduces cost in toluene, has simplified operation, shorten the reflection cycle, and the yield of naftifungin meets or exceeds circuit four.And the naftifine hydrochloride product cost that the present invention produced is 900-1100 unit/kilogram only, and is the simplest for producing this product technology so far, the technology that cost is minimum.

Below be embodiments of the invention:

The detail operations step:

(1) the first step

In reactor, press and add naphthalene 320g, Paraformaldehyde 96 110g, Glacial acetic acid 260ml, 85% phosphatase 11 65ml, concentrated hydrochloric acid 362ml, mixture is heated to 80-85 ℃ (interior temperature), vigorous stirring 6 hours, mixture is chilled to 15-20 ℃, go in the separator, add frozen water, tell lower floor's 1 chloromethyl naphthalene crude product, crude product is successively with frozen water, ice-cold 10% solution of potassium carbonate, frozen water washing.

(2) second steps

The 1 chloromethyl naphthalene crude product is dissolved in the 500ml ethanol, under agitation it slowly is poured into and uses in advance in the ice bath refrigerative 1.5L30% methylethylolamine, stirred overnight at room temperature, normal pressure boils off ethanol and excessive methylamine, in residue, add entry 1L, transfer PH to filter to strongly-acid with HCL, solid is filtered with 3 * 100ml water.Filtrate transfers to PH with 30%NaOH solution and is strong basicity, 3 * 300ml chloroform extraction, extraction liquid is used the washing of 3 * 300ml saturated common salt successively, the chloroform solution dried over anhydrous sodium carbonate reclaims chloroform, and the residue decompression is steamed and slipped, get the about 99g of product, bp:142-144 ℃/about 6mmHg, yield is calculated as 46.5% by adding naphthalene, is calculated as 64.7% by the naphthalene that reacts.

(3) the 3rd steps

In reactor, add 30% sodium hydroxide 170ml, N-methyl isophthalic acid-naphthalene methylamine 171g and toluene 1L, be heated to backflow, agitation and dropping cinnamyl chlorine 153g added in about 2 hours, continued stirring and refluxing then 5 hours, cooling, divide the sub-cloud water layer, with 2 * 500ml washing, under the ice bath cooling, in toluene layer, add concentrated hydrochloric acid and regulate PH to strongly-acid, separate out oily matter, rub to oily matter curing, filter, get naftifine hydrochloride grain product 320g after the cured article drying, yield is calculated as 39.58% by dropping into naphthalene, and calculating by the naphthalene that reacts is 55%.Use the Virahol recrystallization.

Claims (6)

1. a Naftifine hydrochloride synthesizing process is characterized in that it being with three step synthetic hydrochloric acid naftifungins, and the first step is the synthetic 1 chloromethyl naphthalene crude product of starting raw material and Paraformaldehyde 96 hydrochloric acid with the naphthalene; Second step is with 1 chloromethyl naphthalene crude product and the synthetic N-methyl isophthalic acid of methylamine-naphthalene methylamine; The 3rd step is again with N-methyl isophthalic acid-naphthalene methylamine and cinnamyl chlorine synthetic hydrochloric acid naftifungin.

2. Naftifine hydrochloride synthesizing process according to claim 1, it is characterized in that the first step is to add naphthalene 320g, Paraformaldehyde 96 110g, Glacial acetic acid 250-300ml, 85% phosphatase 11 65ml, concentrated hydrochloric acid 300-400ml in reactor, mixture is heated to 80-85 ℃ (interior temperature), vigorous stirring 6 hours, mixture is chilled to 15-20 ℃, go in the separator, add frozen water, tell lower floor's 1 chloromethyl naphthalene crude product, crude product is successively with frozen water, ice-cold 10% solution of potassium carbonate, frozen water washing.

3. Naftifine hydrochloride synthesizing process according to claim 1, it is characterized in that second step was that the 1 chloromethyl naphthalene crude product is dissolved in the 500ml ethanol, under agitation it slowly is poured into and uses in advance in the ice bath refrigerative 1.5L30% methylethylolamine, stirred overnight at room temperature, normal pressure boils off ethanol and excessive methylamine, add entry 1L in residue, transfer PH to filter to strongly-acid with HCL, solid is filtered with 3 * 100ml water.Filtrate transfers to PH with 30%NaOH solution and is strong basicity, 3 * 300ml chloroform extraction, extraction liquid is used the washing of 3 * 300ml saturated common salt successively, the chloroform solution dried over anhydrous sodium carbonate reclaims chloroform, and the residue decompression is steamed and slipped, get the about 99g of product, bp:142-144 ℃/about 6mmHg, yield is calculated as 46.5% by adding naphthalene, is calculated as 64.7% by the naphthalene that reacts.

4. Naftifine hydrochloride synthesizing process according to claim 1, it is characterized in that the 3rd step was in reactor, add 30-35% sodium hydroxide 170-200ml, N-methyl isophthalic acid-naphthalene methylamine 171g and toluene 1L, be heated to backflow, agitation and dropping cinnamyl chlorine 153g added in about 2 hours, continued stirring and refluxing then 5 hours, cooling divides the sub-cloud water layer, wash with 2 * 500ml, under the ice bath cooling, in toluene layer, add concentrated hydrochloric acid and regulate PH to strongly-acid, separate out oily matter, rub to oily matter and solidify, filter, get naftifine hydrochloride grain product 320g after the cured article drying, yield is calculated as 3958% by dropping into naphthalene, and calculating by the naphthalene that reacts is 55%.Use the Virahol recrystallization.

5. Naftifine hydrochloride synthesizing process according to claim 4 is characterized in that described N-methyl isophthalic acid-naphthalene methylamine and cinnamyl chlorine synthetic hydrochloric acid naftifungin are to make acid binding agent with NaOH, with toluene as solvent.

6-Naftifine hydrochloride synthesizing process according to claim 5, the concentration that it is characterized in that described acid binding agent NaOH is 20-40%.