Title of Invention	A PROCESS FOR THE PREPARATION OF 2-(5-PHENYL-TETRAZOLYL)-3-FURYL-1-HYDROXY PROPANE
Abstract	A process for the preparation of 2-(5-phenyl tetrazolyl)-3-furyl-1-hydroxy propane of formula VIII wherein R=Ph, CH3 which comprises: reacting methyl-2-(5-phynyltetrazolyl)-3— furyl-propennoate of formula VI wherein R=Ph, CH3 with reducing agent of formula VII where in M=alkali in a polar solvent such as alkanal or ethernal solvent at a temperature in the range of -5° C to 40° C for a period in the range of 05 minutes to 40 minutes recovering the compound of formula VIII from the reaction mixture by conventional method.

Title of Invention

A PROCESS FOR THE PREPARATION OF 2-(5-PHENYL-TETRAZOLYL)-3-FURYL-1-HYDROXY PROPANE

Abstract

A process for the preparation of 2-(5-phenyl tetrazolyl)-3-furyl-1-hydroxy propane of formula VIII wherein R=Ph, CH3 which comprises: reacting methyl-2-(5-phynyltetrazolyl)-3— furyl-propennoate of formula VI wherein R=Ph, CH3 with reducing agent of formula VII where in M=alkali in a polar solvent such as alkanal or ethernal solvent at a temperature in the range of -5° C to 40° C for a period in the range of 05 minutes to 40 minutes recovering the compound of formula VIII from the reaction mixture by conventional method.

Full Text	This invention relates to a process for the preparation of 2-(5-phenyl tetrazolyl)-3-furyl-1 -hydroxy propane. This is useful as an antibacterial agent. Tetrazoles have long been of interest to the medicinal chemist as possible choice when carboxylic acid mimics were described. Frequently these compounds have been similar in activity to the present acids invitro but have shown different invivo profiles. Recently, LY 171883 [Agents Action 1987, 21 (3-4) 275-7 (Eng.)], a leukotriene antagonist of formula a of the drawing accompanying this specification which shows enhanced potency and selectivity both invitro and invivo as compared to its parent LY 171883 is currently in phase II clinical evaluation. The use of this antagonist has led to interesting clinical observations. Compound, DPU 753 of formula b [JOC, 56, 1991 (7-8)] is the first neopeptid angiotensin II receptor antagonists currently in clinical trials for the treatment of hypertension. This molecule is one example of an increasing number of drugs containing a tetrozole ring that functions as a more metabolically stable isostere for the carboxilic acid group. Apart from the tetrazolyl compounds there are many furan derivatives which are known as antibacterial compounds and some of them are used in medicine eg. (5-nitrofurfurylidenamino) carbamide (furacin) of formula I [Acta chemica scandinavica 26, 1972, 266-274] and 1-(5-nitrofurfuryl idenamino) imidazolidinedione (2,4) (furadantin/Nitrofurantoin) of formula II . [Eur. Pat. Appl. EP 66, 934 (cl. C07D405/12), 15 Dec. 1982, LU Appl. 83, 422, 09 Jan 1981, 18 pp. The salts of formula II are used as antiseptics of the urinary system moreover 1-alkyl and 1-aryl-5-(5-nitro-2-furyl) tetrazoles of formula III are known to posses a high antibacterial activity [Acta. Chemica. Scandinavica 26, 1972, 266-274]. In view of the high biological action of these compounds a new target was thought of which contains both tetrazole and furanmoieties. The present invention helps to explore the potentialities of new molecules containing two pharmacophoric group viz. furan and tetrazole for their biological actions. The main object of the invention is to provide a process for the preparation of 2-(5-phenyl tetrazolyl)-3-furyl-1-hydroxy propane useful as antibacterial agent. Another object of the invention is to provide a process for the molecule containing tetrazole and furan moiety of biological action. Accordingly the present invention provides a process for the preparation of 2-(5-phenyl tetrazolyl)-3-furyl-1-hydroxy propane of formula Vlll as shown in the drawing accompanying this specification wherein R=Ph, CH3 which comprises: reacting methyl-2-(5-phenyltetrazolyl)-3-furyl-propenoate of formula VI wherein R=Ph, CH3 with reducing agent of formula VII where in M=alkali metal in a polar solvent such as alkanal or ethernal solvent at a temperature in the range of -5°C to 40°C for a period in the range of 05 minutes to 40 minutes recovering the compound of formula VIII from the reaction mixture by conventional method. In an embodiment of the invention the reducing agent used may be such as alkali metal borohydride, LiBH4, NaBH4/l2. In other embodiment of the invention the polar solvent used may be such as MeOH, EtOH, THF, n-Butanol, n-Propanol. In still another embodiment of the invention the reducing agent used may be in the range of 1 to 5 equivalent per equivalent of compound of formula VI. The present invention envisages a process for a new tetrazolyl molecule with a furan moiety involving acid catalysed reaction of aziactone which can be converted to the desired molecule in a few steps. A process for the preparation of novel tetrazolyl-propanol with furan moiety at the B carbon of the formula VIII accompanying the specification which comprises reaction VI with a reducing agent of the formula VII. Compound VI is not reported ,it was prepared from the corresponding acid using standard organic preparation method such as MeOH/HC1. However, the reagent LAH is not suitable as it gives tetrazole cleavage problem or partially reduced product. Catalytic hydrogenation gives only saturated acrylic acid. 5-(4H)-oxazolone (Erlenmeyer.H.Ann.275, 1893, 3) of the formula IV in the presence of sodium azide and glacial acetic acid at 90°C to produce tetrazolyl acrylic acid of the formula V [Acta Chemica scandinavica, 26, 1972, 266-274], Methanolysis of the compound formula V with methanolic hydrochloride to give tetrazolyl methyl acrylate of the formula VI with the compound of formula VII by reduction to produce the compound of the formula VIII. The following examples are given by way of illustration of the present invention and should not be construed to limit the scope of the present invention. Example 1 Sodium borohydride (0.07g, 1.89 m.mole) was dissolved in freshly distilled methanol (10 ml) at -5°C. To this, methyl-2-tetrazolyl-3-furyl propenoate (0.5 g, 1.68 m.mole) was added slowly. The reaction was monitored by TLC. After 20 min. methanol was removed under reduced pressure, extracted into DCM and washed with water. Organic layer dried over anhydrous sodium sulphate/anhydrous magnesium sulphate concentrated to give colour less solid of compound VIII in (0.272 g) 60% yield, M.P. 70°C. Example 2 Sodium borohydride (0.07g, 1.89 m.mole) was dissolved in freshly distilled MeOH at 28°C. To this methyl-2-tetrazolyl-3-furyl propenoate (0.5 g, 1.68 m. mole) was added portion wise. The reaction was monitored by TLC. After 5 min. MeOH was removed under reduced pressure. The reaction mixture was taken into DCM and washed with water. The DCM layer was dried over anhydrous sodium sulphate/anhydrous magnesium sulphate and concentrated to give colour less solid of compound VIII in (0.181 g) 40% yield. Purified by crystallisation from hexane/benzene mixture. Example 3 Sodium borohydride (0.191 g, 5 m. mole) was dissolved in methanol at -5°C and the methyl ester (0.5g, 1.68 m. mole) was added. The reaction was monitored by TLC. After 35 min. methanol was removed under reduced pressure and the reaction mixture was taken into dichloromethane and then washed with water. The organic layer was dried over anhydrous sodium sulphate/anhydride magnesium sulphate and concentrated to give white solid, crystallised from benzaine/hexane mixture, in (0.435 g) 96% yield. Example 4 Sodium borohydride (0.125 g, 3.3 m. mole) was added to the chilled methanol and the reaction contents were brought to room temperature. To this methyle ester (0.5 g, 1.68 m. mole) was added. The reaction mixture was monitored by TLC. After one and half hour stirring, methanol was removed under reduced pressure. The mixture was taken dichloromethane then washed with water. The organic layer was dried over anhydrous sodium sulphate/anhydrous MgSO4 which was concentrated to give white solid. Pure 2-(5-phenyltrazolyl)-3-furyl-1-hydroxy propane was obtained in (0.408g) 90% yield on crystallisation from mixed solvent (MeOH:H2O; EtOAc:Hexane). The 2-(5-phenyl tetrazolyl)-3-furyl-1 -hydroxy propane is made in a single step process from the ester and in a one pot reaction. The said process will have considerable economic gains. Advantages of the invention are : 1. It is a single step reaction. 2. No usage of hazardous chemicals. 3. Raw materials are easily accessible. 4. Very high yield. 5. High purity. 6. Very short reaction time. We Claim : 1. A process for the preparation of 2-(5-phenyl tetrazolyl)-3-furyl-1 -hydroxy propane of formula VIII as shown in the drawing accompanying this specification wherein R=Ph, CH3 which comprises: reacting methyl-2-(5-phenyltetrazolyl)-3-furyl-propenoate of formula VI wherein R=Ph, CH3 with reducing agent of formula Vll where in M=alkali metal in a polar solvent such as alkanal or ethernal solvent at a temperature in the range of -5°C to 40°C for a period in the range of 05 minutes to 40 minutes recovering the compound of formula VIM from the reaction mixture by conventional method. 2. A process as claimed in claim 1 where in the reducing agent used is such as alkali metal in reducing agent is Li, Na, l2. 3. A process as claimed in claims 1-2 where in the polar solvent used such as MeOH, EtOH, THF, n-Propanol. 4. A process as claimed in claims 1-3, where in the reducing agent used is in the range of 1 to 5 equivalent for one equivalent of compounds of formula III. 5. A process for the preparation of 2-(5-phenyl tetrazolyl)-3-furyl-1 -hydroxy propane substantially as here in described with reference to the examples.

Full Text

This invention relates to a process for the preparation of 2-(5-phenyl tetrazolyl)-3-furyl-1 -hydroxy propane. This is useful as an antibacterial agent.
Tetrazoles have long been of interest to the medicinal chemist as possible choice when carboxylic acid mimics were described. Frequently these compounds have been similar in activity to the present acids invitro but have shown different invivo profiles.
Recently, LY 171883 [Agents Action 1987, 21 (3-4) 275-7 (Eng.)], a leukotriene antagonist of formula a of the drawing accompanying this specification which shows enhanced potency and selectivity both invitro and invivo as compared to its parent LY 171883 is currently in phase II clinical evaluation. The use of this antagonist has led to interesting clinical observations.
Compound, DPU 753 of formula b [JOC, 56, 1991 (7-8)] is the first neopeptid angiotensin II receptor antagonists currently in clinical trials for the treatment of hypertension. This molecule is one example of an increasing number of drugs containing a tetrozole ring that functions as a more metabolically stable isostere for the carboxilic acid group.
Apart from the tetrazolyl compounds there are many furan derivatives which are known as antibacterial compounds and some of them are used in medicine eg. (5-nitrofurfurylidenamino) carbamide (furacin) of formula I [Acta
chemica scandinavica 26, 1972, 266-274] and 1-(5-nitrofurfuryl idenamino) imidazolidinedione (2,4) (furadantin/Nitrofurantoin) of formula II . [Eur. Pat. Appl. EP 66, 934 (cl. C07D405/12), 15 Dec. 1982, LU Appl. 83, 422, 09 Jan 1981, 18 pp.
The salts of formula II are used as antiseptics of the urinary system moreover 1-alkyl and 1-aryl-5-(5-nitro-2-furyl) tetrazoles of formula III are known to posses a high antibacterial activity [Acta. Chemica. Scandinavica 26, 1972, 266-274].
In view of the high biological action of these compounds a new target was thought of which contains both tetrazole and furanmoieties. The present invention helps to explore the potentialities of new molecules containing two pharmacophoric group viz. furan and tetrazole for their biological actions.
The main object of the invention is to provide a process for the preparation of 2-(5-phenyl tetrazolyl)-3-furyl-1-hydroxy propane useful as antibacterial agent.
Another object of the invention is to provide a process for the molecule containing tetrazole and furan moiety of biological action.
Accordingly the present invention provides a process for the preparation of 2-(5-phenyl tetrazolyl)-3-furyl-1-hydroxy propane of formula Vlll as shown in the
drawing accompanying this specification wherein R=Ph, CH3 which comprises: reacting methyl-2-(5-phenyltetrazolyl)-3-furyl-propenoate of formula VI wherein R=Ph, CH3 with reducing agent of formula VII where in M=alkali metal in a polar solvent such as alkanal or ethernal solvent at a temperature in the range of -5°C to 40°C for a period in the range of 05 minutes to 40 minutes recovering the compound of formula VIII from the reaction mixture by conventional method.
In an embodiment of the invention the reducing agent used may be such as alkali metal borohydride, LiBH4, NaBH4/l2.
In other embodiment of the invention the polar solvent used may be such as MeOH, EtOH, THF, n-Butanol, n-Propanol.
In still another embodiment of the invention the reducing agent used may be in the range of 1 to 5 equivalent per equivalent of compound of formula VI.
The present invention envisages a process for a new tetrazolyl molecule with a furan moiety involving acid catalysed reaction of aziactone which can be converted to the desired molecule in a few steps.
A process for the preparation of novel tetrazolyl-propanol with furan moiety at the B carbon of the formula VIII accompanying the specification which comprises reaction VI with a reducing agent of the formula VII.
Compound VI is not reported ,it was prepared from the corresponding acid using standard organic preparation method such as MeOH/HC1.
However, the reagent LAH is not suitable as it gives tetrazole cleavage problem or partially reduced product. Catalytic hydrogenation gives only saturated acrylic acid.
5-(4H)-oxazolone (Erlenmeyer.H.Ann.275, 1893, 3) of the formula IV in the presence of sodium azide and glacial acetic acid at 90°C to produce tetrazolyl acrylic acid of the formula V [Acta Chemica scandinavica, 26, 1972, 266-274],
Methanolysis of the compound formula V with methanolic hydrochloride to give tetrazolyl methyl acrylate of the formula VI with the compound of formula VII by reduction to produce the compound of the formula VIII.
The following examples are given by way of illustration of the present invention and should not be construed to limit the scope of the present invention.
Example 1
Sodium borohydride (0.07g, 1.89 m.mole) was dissolved in freshly distilled methanol (10 ml) at -5°C. To this, methyl-2-tetrazolyl-3-furyl propenoate (0.5 g, 1.68 m.mole) was added slowly. The reaction was monitored by TLC. After 20 min. methanol was removed under reduced pressure, extracted into DCM and
washed with water. Organic layer dried over anhydrous sodium sulphate/anhydrous magnesium sulphate concentrated to give colour less solid of compound VIII in (0.272 g) 60% yield, M.P. 70°C.
Example 2
Sodium borohydride (0.07g, 1.89 m.mole) was dissolved in freshly distilled MeOH at 28°C. To this methyl-2-tetrazolyl-3-furyl propenoate (0.5 g, 1.68 m. mole) was added portion wise. The reaction was monitored by TLC. After 5 min. MeOH was removed under reduced pressure. The reaction mixture was taken into DCM and washed with water. The DCM layer was dried over anhydrous sodium sulphate/anhydrous magnesium sulphate and concentrated to give colour less solid of compound VIII in (0.181 g) 40% yield. Purified by crystallisation from hexane/benzene mixture.
Example 3
Sodium borohydride (0.191 g, 5 m. mole) was dissolved in methanol at -5°C and the methyl ester (0.5g, 1.68 m. mole) was added. The reaction was monitored by TLC. After 35 min. methanol was removed under reduced pressure and the reaction mixture was taken into dichloromethane and then washed with water. The organic layer was dried over anhydrous sodium sulphate/anhydride magnesium sulphate and concentrated to give white solid, crystallised from benzaine/hexane mixture, in (0.435 g) 96% yield.
Example 4
Sodium borohydride (0.125 g, 3.3 m. mole) was added to the chilled methanol and the reaction contents were brought to room temperature. To this methyle ester (0.5 g, 1.68 m. mole) was added. The reaction mixture was monitored by TLC. After one and half hour stirring, methanol was removed under reduced pressure. The mixture was taken dichloromethane then washed with water. The organic layer was dried over anhydrous sodium sulphate/anhydrous MgSO4 which was concentrated to give white solid. Pure 2-(5-phenyltrazolyl)-3-furyl-1-hydroxy propane was obtained in (0.408g) 90% yield on crystallisation from mixed solvent (MeOH:H2O; EtOAc:Hexane).
The 2-(5-phenyl tetrazolyl)-3-furyl-1 -hydroxy propane is made in a single step process from the ester and in a one pot reaction. The said process will have considerable economic gains. Advantages of the invention are :
1. It is a single step reaction.
2. No usage of hazardous chemicals.
3. Raw materials are easily accessible.
4. Very high yield.
5. High purity.
6. Very short reaction time.

We Claim :
1. A process for the preparation of 2-(5-phenyl tetrazolyl)-3-furyl-1 -hydroxy propane of formula VIII as shown in the drawing accompanying this specification wherein R=Ph, CH3 which comprises: reacting methyl-2-(5-phenyltetrazolyl)-3-furyl-propenoate of formula VI wherein R=Ph, CH3 with reducing agent of formula Vll where in M=alkali metal in a polar solvent such as alkanal or ethernal solvent at a temperature in the range of -5°C to 40°C for a period in the range of 05 minutes to 40 minutes recovering the compound of formula VIM from the reaction mixture by conventional method.
2. A process as claimed in claim 1 where in the reducing agent used is such as alkali metal in reducing agent is Li, Na, l2.
3. A process as claimed in claims 1-2 where in the polar solvent used such as MeOH, EtOH, THF, n-Propanol.
4. A process as claimed in claims 1-3, where in the reducing agent used is in the range of 1 to 5 equivalent for one equivalent of compounds of formula III.
5. A process for the preparation of 2-(5-phenyl tetrazolyl)-3-furyl-1 -hydroxy propane substantially as here in described with reference to the examples.

Documents:

2133-del-1997-abstract.pdf

2133-del-1997-claims.pdf

2133-del-1997-complete specification (granted).pdf

2133-del-1997-correspondence-others.pdf

2133-del-1997-correspondence-po.pdf

2133-del-1997-description (complete).pdf

2133-del-1997-drawings.pdf

2133-del-1997-form-1.pdf

2133-del-1997-form-2.pdf

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Patent Number

186727

Indian Patent Application Number

2133/DEL/1997

PG Journal Number

43/2001

Publication Date

27-Oct-2001

Grant Date

31-May-2002

Date of Filing

31-Jul-1997

Name of Patentee

COUNCIL OF SCIENTIFIC AND INDUSTRIAL RESEARCH

Applicant Address

RAFI, MARG, NEW DELHI-110 001, INDIA.

Inventors:

#	Inventor's Name	Inventor's Address
1	SAKTIMAYEE MITRA ROY	INDIAN INSTITUTE OF CHEMICAL TECHNOLOGY, HYDERABAD 500 007 AP, INDIA.
2	DIVI SARANGAPANI IYENGAR	INDIAN INSTITUTE OF CHEMICAL TECHNOLOGY, HYDERABAD 500 007 AP, INDIA.
3	UDAY TRIAMBAKRAJ BHALERAO	INDIAN INSTITUTE OF CHEMICAL TECHNOLOGY, HYDERABAD 500 007 AP, INDIA.

PCT International Classification Number

A61K 31/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA