FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
THE PROVISIONAL SPECIFICATION
(See section 10)
1. "A novel and improved process for the preparation of 8-nitro-2- (IH-tetrazol -5-yl)-4H-l-benzopyran-4-one from 8-nitro -2-cyano -4H-l-benzopyran-4-one and its conversion to 8-amino-2- (lH-tetrazol-5-yl)-4H-l-benzopyran-4-one hydrochloride".
2. CADILA PHARMACEUTICALS LTD., "CADILA CORPORATE CAMPUS", SARKHEJ-DHOLKA ROAD, BHAT, AHMEDABAD, 382210, GUJARAT, INDIA, AN INDIAN COMPANY.
3. THE FOLLOWING SPECIFICATION DESCRIBES AND ASCERTAINS THE NATURE OF THIS INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.

TITLE : A novel and improved process for the preparation of 8-nitro-2- (IH-tetrazol -5-yl)-4H-l-benzopyran-4-one from 8-nitro -2-cyano -4H-1-benzopyran-4-one and its conversion to 8-amino-2- (lH-tetrazol-5-yl)-4H-l-benzopyran-4-one hydrochloride

FIELD OF INVENTION
The present invention relates to a novel and improved process for preparing 8-nitro-2-(lH-tetrazol -5-yl)-4H-l-benzopyran-4-one [compound of formula-2] from 8-nitro -2-cyano -4H-1-benzopyran-4-one [ compound of formula-1] followed by its conversion to 8-amino-2- (IH-tetrazol -5-yl)-4H-l-benzopyran-4-one hydrochloride - [compound of formula-3] , an intermediate to prepare Pranlukast.
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BACKGROUND OF INVENTION
Important intermediates of pranlukast are as follows:
PRANLUKAST
Pranlukast is Leukotriene antagonist ( antiasthmatic) , first disclosed in
JP19840172570 Aug 20, 1984, assigned to ONO pharmaceutical Co. [Equivalent to
EP173516, US4780469 ] . Pranlukast has CAS RN [103177-37-3] , is chemically
known by any of the following names
[l]N-[4-Oxo-2-(lH-tetrazol-5-yl)-4H-l-benzopyran-8-yl]-4-(4-phenylbutoxy)benzamide
or
[2] 8-[4-(4-phenylbutoxy)-benzamido]-2-(tetrazol-5-yl)-4H-1 -benzopyran-4-one
or
[3] 8-[p-(4-phenylbutoxy)benzoyl]amino-2-(5-tetrazolyl)-4-oxo-4H-l-benzopyran
US4977162A [equivalent to WO9101123A2, US5082849A] describes preparation of compound of formula-2 , using sodium azide , pyridinium chloride in DMF, at 100°C for 3 hours followed by pouring the reaction mass in water , filtering the product,
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recrystallizing the product. [ according to method described in example-34 , step-2 in
US4977162A] .
The compound of formula-2 is converted to the compound of formula-3 using 5%
palladium on carbon, concentrated hydrochloric acid in methanol , and using hydrogen
at atmospheric pressure for 18 hours. The product is isolated after separation of the
catalyst after filtration and concentration of the filtrate in vacuo.
This process uses a precious metal catalyst, and involves extensive active catalyst
regeneration with possibilities of contaminating the finished product.
US5990142A [ equivalent to W09734885A1,EP888327B1] describes preparation of
compound of formula-2 from compound of formula-1 wherein the reaction comprises the
reaction of compound of formula-1 with sodium azide , ammonium chloride in N,N-
dimethylformamide, by stirring at 100°C for 1.25 hour followed by workup to provide a
yield of 69 % . The compound of formula-2 is converted to compound of formula-3 in
quantitative yield by catalytic hydrogenation using 5 % palladium on carbon in a mixture
of chloroform methanol and cone, hydrochloric acid .
According to this process, in the step of tetrazole cycle formation , extractive work up is
required and the yield of this step is low. In the next step palladium metal is used in a
mixture of solvents. These factors make the process commercially unattractive.
JP07-304773 describes preparation of compound of formula-2 from compound of formula-1[ R-CN] by reacting RCN with hydrazine to form RC(=NH)NHNH2 [amidrazone] , followed by treatment with a nitrite - compound of formula YNO2 [ Y is H, an alkali metal, an alkaline earth metal or CI-20 alkyl].
W09531445 [equivalent to EP0711762B1 ] describes preparation of compound of formula-2 from compound of formula-1 as follows.
8-nitro -2-cyano -4H-l-benzopyran-4-one [compound of formula-1] [R-CN] in a mixture of toluene , triethyl amine and methanol is reacted with hydrogen sulfide to give corresponding thioamide [ RC(=S)NH2 ] , which is converted by reaction with hydrazine to amidrazone [ RC(=NH)NHNH2 ] , then reacted with nitrous acid compound of
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formula ANO2, wherein A is hydrogen atom, an alkali metal, an alkaline earth metal or a
C1-C20 alkyl group, to give corresponding tetrazole [ compound of formula-2].
This process uses a toxic gas such as hydrogen sulfide, mixture of solvents and involves
multistep extractive workup thereby making it inappropriate for industrial scale
operations.
The process involving use of zinc salt for the transformation of nitrile to tetrazole is a
safe and efficient process as reported in JOC (2001) 66 , 7945-50.The use of zinc salt for
transforming nitrile to tetrazole has also been published in W09637481 and US5502191.
Prior art processes described above suffers from any of the following drawbacks such as processes with lower yield, using toxic gas, using a precious metal catalyst, or involving multistep extractive workup.
It is a long felt need of the industry to provide a better method which is free from above-mentioned disadvantages , and hence more suitable on commercial scale.
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SUMMARY OF INVENTION
The key feature of this invention is that in both the steps water is used as a solvent, hence
it is not necessary to recover solvent, and further no purifications are required at both the
stages.
The main object of the present invention is to carry out tetrazole cycle formation from
nitrile using lewis acid such as magnesium halides like magnesium chloride, magnesium
bromide, zinc halides such as zinc chloride, zinc bromide; preferably zinc chloride along
with sodium azide using NaN3.
Another object of the invention is to carry out tetrazole cycle formation from nitrile in
water with higher yield.
Yet another object of the invention is to carry out tetrazole cycle formation from nitrile
without using toxic gas such as hydrogensulfide.
Yet another object of the invention is to carry out reduction of nitro to amino group
without using a precious metal catalyst such as palladium.
Yet another object of the invention is to carry out reduction of nitro to amino group
using a mild chemoselective reagent such as stannous chloride / aqueous HC1 in water.
Yet another object of the invention is to avoid purification such as crystallization /
chromatographic separation at both the steps and avoid multistep extractive workup.
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DETAILED DESCRIPTION
Thus in accordance with present invention 8-amino-2- (lH-tetrazol -5-yl)-4H-l-
benzopyran-4-one hydrochloride salt - compound of Formula-3 is prepared in following
steps:
Step [a] Reacting 8-nitro -2-cyano -4H-l-benzopyran-4-one [compound of Formula-1 ]
with sodium azide in presence of lewis acid such as magnesium halides like magnesium chloride, magnesium bromide, zinc halides such as zinc chloride, zinc bromide; preferably zinc chloride in water at temperature ranging from 25-100 C , preferably at 80-85°C for time sufficient to effect almost complete conversion of compound of Formula-1, followed by cooling to about 25-30°C , reacting with sodium nitrite / aqueous hydrochloric acid , stirring at about 25-30 C , and filtering mass followed by washing with dilute HC1 ,water and drying ;
Step [b] Reacting 8-nitro-2- (lH-tetrazol -5-yl)-4H-l-benzopyran-4-one [compound of Formula-2] in water , with stannous chloride dihydrate in about 30 % hydrochloric acid at about 10-50 C, preferably at 30-35 C for time sufficient to effect almost complete conversion of compound of Formula-2 to compound of Formula-3, followed by diluting with water ,stirring at 20-25 C , filtering ,washing and drying.
The present invention uses stannous chloride dihydrate / aq. Hydrochloric acid as reducing agent for reducing nitro group to amino group with high chemoselectivity in the preparation of compound of Formula-3 from compound of Formula-2. Stannous chloride is mild reducing agent, which is cheap and commercially available , and does not require organic solvent for carrying out the reduction.
In step [a] , lewis acid such as magnesium halides like magnesium chloride, magnesium bromide, zinc halides such as zinc chloride, zinc bromide can be used. The preferred reagents are zinc salts such as zinc halides such as zinc chloride, zinc bromide, more preferably zinc chloride. The solvent for the reaction is water.
The reaction is carried out at 25-100°C , preferably at 80-85°C .
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The progress of the reaction is monitored by TLC / HPLC and after 98 % conversion , the reaction mass is cooled to about 30°C, treated with sodium nitrite followed by dropwise addition of aqueous HC1 at 25-30 C over about30-45 C .The reaction mass is further stirred at 25-30 C for about 30 minutes and filtered . The solid cake is washed with IN HC1 and finally with water, and dried. The product thus obtained is sufficiently pure to take for the next step . The yield is around 87 %.
In step [b] , the reducing agent for the nitro group to amino group is stannous chloride dihydrate / aqueous hydrochloric acid. Stannous chloride dihydrate / aqueous hydrochloric acid is a mild and chemoselective reagent.
The medium for this reaction is water. Nitro compound [ compound of Formula-2 ] is taken in water and to it a solution of stannous chloride in 30 % HC1 is added with stirring at 10 to 60°C , preferably at 30-35 C , over about one hour and further stirred at this temperature for about four hours. The progress of the reaction is monitored by TLC. The reaction mass is diluted with water cooled to about 20-25 C and stirred for about one
hour. The reaction mass is filtered and washed with water and dried till % water is <0.5
% to give 8-amino -2- (lH-tetrazol -5-yl)-4H-l-benzopyran-4-one hydrochloride salt.
The present invention is illustrated with non-limiting examples as follows.
Example-1
Preparation of 8-nitro-2- (lH-tetrazol -5-yl)-4H-l-benzopyran-4-one
8-nitro -2-cyano -4H-1-benzopyran-4-one (100 gm ), ZnC12 (34.7 gm ) , sodium azide (33 gm ) and water (1.20 liter ) were charged in 2 Liter multi-necked flask equipped with mechanical stirrer , condenser, thermometer , and an oil bath with heater. The reaction mass was heated to 80°C and stirred at 80-85°C for about five hours. The progress of the reaction was monitored by TLC/HPLC. After >99% conversion of starting compound [ Formula-1] , the reaction mass was cooled to 30°C. Sodium nitrite ( 9.58 gm ) was added to it at 25-30°C. Concentrated HC1 (72 ml) was added drop wise at 25-30 C over 30 to 45 minutes. The reaction mass was stirred at 25-30°C for 30 minutes. The reaction mass was filtered and washed with 100 ml x 2 IN HC1 and finally with 100 ml x 2 water.
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The filtered product - i.e. 8-nitro-2- (lH-tetrazol -5-yl)-4H-l-benzopyran-4-one was
dried at 60°C for 24 hours Wt= 104gms [87%] Purity by HPLC > 98 %
Example-2
Preparation of 8-amino -2- (lH-tetrazol -5-yl)-4H-l-benzopyran-4-one
8-nitro-2- (lH-tetrazol -5-yl)-4H-l-benzopyran-4-one ( 100 gm ), water ( 300 ml) were charged at 25-30°C in one liter capacity three necked flask equipped with mechanical stirrer, thermometer, addition funnel and water bath. A solution of stannous chloride dihydrate ( 274 gm) in 30 % HC1 (500 ml) was added at 30-35°C over about one hour.
After the addition was over, the reaction mass was stirred at 30-35 C for four hours. The reaction mass was checked for complete conversion by taking TLC. Water ( 200 ml ) was added at 30-35°C over about 30 minutes. The reaction mass was cooled up to 25 C and stirred at 20-25UC for one hour. The reaction mass was filtered and the cake was washed with water (100 ml).The wet cake was dried at 50-55 C for 18-24 hours till the moisture content was < 0.5 %.The product obtained was 8-amino -2- (lH-tetrazol -5-yl)-4H-l-benzopyran-4-one hydrochloride salt. Wt= 64-67 gm [ yield 62 to 65 % ] Purity by HPLC > 99 %