CN1740160A - Synthesis process of loratadine intermediate - Google Patents

Abstract

The synthesis process of loratadine intermediate includes: adding P2O5 in 3-20 wt% into polyphosphoric acid ester through stirring at 175-240 deg.c to obtain homogeneous system; adding 3-[2-(3-chlorophenyl) ethyl]-2-pyridyl formonitrile in 4-16 wt% into the system and reaction at 175-240 deg.c for 5-14 hr to obtain the loratadine intermediate 8-chloro-5, 6-dihydro-11H-benzyo[5, 6]cycloheptyl[1, 2-b] pyridyl-11-tone; and re-crystallizing the intermediate with mixed solvent of ethyl acetate, n-hexane and petroleum in the volume ratio of 1 to 1 to 3. The present invention has mild reaction condition, simple operation, fast reaction speed, reaction conversion rate as high as 83.7-93.1 %, product yield of 62.9-78.2 %, product purity after re-crystallization of 98-99 %, and excellent industrial application foreground.

Description

A kind of synthetic method of Loratadine intermediate

Technical field

The present invention relates to a kind of Loratadine intermediate 8-chloro-5,6-dihydro-11H-benzo [5,6] suberyl [1,2-b] pyridine-11-ketone synthetic method.

Background technology

Loratadine (loratadine), chemistry 4-(8-chloro-5,6-dihydro-11H-benzo [5,6] suberyl [1 by name, 2-b] pyridine-11 alkene)-the 1-piperidine carboxylate, be oral long-acting tricyclic antidepressants antihistaminic, it is rapid-action, effect is strong, and the periphery histamine H1-receptor is had high selectivity, be [the DuBuske L M. of antihistamine drug of new generation of a kind of long-acting, no sedative effect, no anticholinergic effect, Clin Ther.1999,21 (2), 281～285].

About synthesizing of Loratadine, the synthetic method of bibliographical information mainly is to be raw material with 3-methyl-2-cyanopyridine, respectively by (1-methyl-4-piperidyl) [3-(2-(3-chloro-phenyl-)-ethyl-)-2-pyridyl]-ketone intermediate (1) and 8-chloro-5,6-dihydro-11H-benzo [5,6] suberyl [1,2-b] pyridine-11 ketone intermediate (2) comes synthetic.

Intermediate (1) synthetic is to be raw material with 3-methyl-2-cyanopyridine, through cyano protection, the highly basic effect down with the alkylation of a benzyl chloride chlorine, again through obtaining with the form reagent react behind the deprotection reduction generation cyano group; This intermediate (1) utilizes CH then ₃SO ₃H/BF ₃, HF/BF ₃Come cyclisation etc. different cyclization reagents, last and Vinyl chloroformate refluxes and obtains product Loratadine [Doris P.Schumacher, Bruce L.Murphy, Jon E.Clark, et al., J.org.Chem.1989,54,2242～2244].The sharpest edges of this route be the yield of reaction than higher, but with top CH ₃SO ₃H/BF ₃, HF/BF ₃When making cyclization reagent, owing to itself have intensive corrodibility, make and to use specific equipment such as Te Lilong aborning, and it is also bigger to the pollution of environment, thereby the industrial cost that improves, this makes it be subjected to certain restriction when concrete production, and under the very fierce situation of market competition now, this route obviously is uneconomic.This route has been used grignard reagent in reaction simultaneously, and this can increase the cost of condition control in the reaction.

Intermediate (2) synthetic also is to be raw material with 3-methyl-2-cyanopyridine, and through cyano protection, the highly basic effect down and the alkylation of a benzyl chloride chlorine; reduction generates the cyano group posthydrolysis through deprotection again, uses sulfur oxychloride [Cannata Vincenzo, Cotarca Livius then; Michieletto Ivan; WO03/040140,2003-3-15] or oxalyl chloride [Doris P.Schumacher, Florham Park; Bruce L.Murphy; Elizabeth, et al., US4; 731; 447,1988-3-15] the preparation acyl chlorides, obtain by Fourier Dare-Kerafyrm thatch reaction; this centre physical efficiency obtains ratio defective product Loratadine [Alberto Stampa with N-Vinyl chloroformate-4-piperidone reaction under the condition of gentleness then; Pelayo Camps, Gloria Rodriguez, et al.; US6; 084,100,2000-7-4].This route has avoided using the super acid of particular device, thereby can reduce the facility investment of production, reduced pollution to environment, but a big shortcoming of this route is that the yield of reaction is low with respect to aforementioned route, as with 3-[2-(3-chloro-phenyl-) ethyl]-the 2-pyridine carbonitrile is a raw material, by hydrolysis, sulfur oxychloride prepares acyl chlorides, and then the yield that carries out the reaction of Fourier Dare-Kerafyrm thatch has only 50%.Total time of reaction is also longer, and this three-step reaction altogether need be near 30 hours, and when preparing with oxalyl chloride, though yield has 50% to bring up to 63%, the reaction times is also longer, needs 40 hours altogether.

For above-mentioned two kinds of methods, synthesize Loratadine with intermediate (1) and need use specific equipment, and can cause serious environmental pollution more, relatively low again but intermediate (2) gets yield, reaction times is very long again, and these all can cause the increase of production cost.Therefore, avoid the application of super acid, synthetic intermediate (2) is a research topic highly significant efficiently.

Summary of the invention

The synthetic method that the purpose of this invention is to provide a kind of Loratadine intermediate.

The technical solution used in the present invention is may further comprise the steps:

1) Vanadium Pentoxide in FLAKES of its mass percent 3%～20% of adding in polyphosphoric acid stirs down at 175～240 ℃, becomes homogeneous phase until system;

2) add 3-[2-(3-chloro-phenyl-) ethyl of polyphosphoric acid mass percent 4%～16%]-the 2-pyridine carbonitrile is in the system of step 1), reacted 5～14 hours down at 175～240 ℃, obtain the intermediate 8-chloro-5 of Loratadine, 6-dihydro-11H-benzo [5,6] suberyl [1,2-b] pyridine-11-ketone;

3) from step 2) the Loratadine intermediate that obtains, with volume ratio be 1: 1: 3 ethyl acetate, normal hexane and sherwood oil mixed solvent carry out recrystallization, obtain purity and be 98～99% product.

The beneficial effect that the present invention has is: a kind of synthetic Loratadine intermediate (2) 8-chloro-5 is provided, 6-dihydro-11H-benzo [5,6] suberyl [1,2-b] method of pyridine-11-ketone, improve yield, shortened the time of reaction, simplified operation, thereby make that utilizing intermediate (2) to synthesize Loratadine becomes practical, avoided by CH in the synthetic Loratadine of intermediate (1) ₃SO ₃H/BF ₃, HE/BF ₃Deng the application of reagent, the requirement of the reaction pair equipment of Jiang Diing greatly makes a synthetic method with very high industrial utility value.

The method reaction conversion ratio that provides of the present invention reaches 83.7～93.1%, and product yield reaches 62.9～78.2%, and the purity of product reaches 98～99% behind the process recrystallization.

Embodiment

Below in conjunction with embodiment the present invention is further specified:

Embodiment 1:

Add Vanadium Pentoxide in FLAKES (25g) to the PPA (250g) that is heated to 240 ℃, add 3-[2-(3-chloro-phenyl-) ethyl after stirring into homogeneous phase]-2-pyridine carbonitrile (30g), and under this temperature, reacted 6.5 hours, the result of reaction is: 3-[2-(3-chloro-phenyl-) ethyl]-transformation efficiency of 2-pyridine carbonitrile reaches 87.9%, product carries out recrystallization with the mixed solvent of ethyl acetate, normal hexane and sherwood oil (1: 1: 3), and to obtain purity be 98% product, and yield is 67.4%.

Embodiment 2:

Add Vanadium Pentoxide in FLAKES (37.5g) to the PPA (250g) that is heated to 210 ℃, add 3-[2-(3-chloro-phenyl-) ethyl after stirring into homogeneous phase]-2-pyridine carbonitrile (15g), and under this temperature, reacted 7 hours, the result of reaction is: 3-[2-(3-chloro-phenyl-) ethyl]-transformation efficiency of 2-pyridine carbonitrile reaches 89.4%, product carries out recrystallization with the mixed solvent of ethyl acetate, normal hexane and sherwood oil (1: 1: 3), and to obtain purity be 98.4% product, and yield is 72.5%.

Embodiment 3:

Add Vanadium Pentoxide in FLAKES (17.5g) to the PPA (250g) that is heated to 190 ℃, add 3-[2-(3-chloro-phenyl-) ethyl after stirring into homogeneous phase]-2-pyridine carbonitrile (25g), and under this temperature, reacted 8 hours, the result of reaction is: 3-[2-(3-chloro-phenyl-) ethyl]-transformation efficiency of 2-pyridine carbonitrile reaches 93.1%, product carries out recrystallization with the mixed solvent of ethyl acetate, normal hexane and sherwood oil (1: 1: 3), and to obtain purity be 99% product, and yield is 78.2%.

Embodiment 4:

Add Vanadium Pentoxide in FLAKES (50g) to the PPA (250g) that is heated to 240 ℃, add 3-[2-(3-chloro-phenyl-) ethyl after stirring into homogeneous phase]-2-pyridine carbonitrile (20g), and under this temperature, reacted 5 hours, the result of reaction is: 3-[2-(3-chloro-phenyl-) ethyl]-transformation efficiency of 2-pyridine carbonitrile reaches 83.7%, product carries out recrystallization with the mixed solvent of ethyl acetate, normal hexane and sherwood oil (1: 1: 3), and to obtain purity be 98.7% product, and yield is 62.9%.

Embodiment 5:

Add Vanadium Pentoxide in FLAKES (7.5g) to the PPA (250g) that is heated to 175 ℃, add 3-[2-(3-chloro-phenyl-) ethyl after stirring into homogeneous phase]-2-pyridine carbonitrile (30g), and under this temperature, reacted 14 hours, the result of reaction is: 3-[2-(3-chloro-phenyl-) ethyl]-transformation efficiency of 2-pyridine carbonitrile reaches 94%, product carries out recrystallization with the mixed solvent of ethyl acetate, normal hexane and sherwood oil (1: 1: 3), and to obtain purity be 98.8% product, and yield is 77.6%.

Claims (1)

1, a kind of synthetic method of Loratadine intermediate is characterized in that may further comprise the steps:

1) Vanadium Pentoxide in FLAKES of its mass percent 3%～20% of adding in polyphosphoric acid stirs down at 175～240 ℃, becomes homogeneous phase until system;

2) add 3-[2-(3-chloro-phenyl-) ethyl of polyphosphoric acid mass percent 4%～16%]-the 2-pyridine carbonitrile is in the system of step 1), reacted 5～14 hours down at 175～240 ℃, obtain the intermediate 8-chloro-5 of Loratadine, 6-dihydro-11H-benzo [5,6] suberyl [1,2-b] pyridine-11-ketone;

3) from step 2) the Loratadine intermediate that obtains, with volume ratio be 1: 1: 3 ethyl acetate, normal hexane and sherwood oil mixed solvent carry out recrystallization, obtain purity and be 98～99% product.