Title of Invention	AN IMPROVED PROCESS FOR THE PREPARATION OF ISOSORBIDE-5-MONONITRATE
Abstract	ABSTRACT A safe, cheap commercial process for preparing Isosorbide-5-mononltrate is developed. Aqueous 70% D-sorbitoi is dehydrated to isosorbide and acetylated and purified to get Isosorbide-2-acetate. The latter is nitrated with acetyl nitrate and the product Isosorbide-2-acetate-5-nitrate is deacetylated by a novel process using strong ammonia. The crude Isosrobide-5-mononitrate is recrystallised from water to obtain pharmaceutical grade product.

Title of Invention

AN IMPROVED PROCESS FOR THE PREPARATION OF ISOSORBIDE-5-MONONITRATE

Abstract

ABSTRACT A safe, cheap commercial process for preparing Isosorbide-5-mononltrate is developed. Aqueous 70% D-sorbitoi is dehydrated to isosorbide and acetylated and purified to get Isosorbide-2-acetate. The latter is nitrated with acetyl nitrate and the product Isosorbide-2-acetate-5-nitrate is deacetylated by a novel process using strong ammonia. The crude Isosrobide-5-mononitrate is recrystallised from water to obtain pharmaceutical grade product.

Full Text	The present invention relates to an improved process for the preparation of Isosorbide-5-mononitrate, of formula-I given below. This is used as a vasodilator in the treatment of heart disease, such as angina pectoris. The present invention particularly relates to an improved process for preparation of isosorbide-5-mononitrate by a simple, safe and cheap method, which can be utilized for its commercial production. The present invention involves a novel hydrolysis method using strong ammonia, which is hitherto not reported for the preparation of this compound. Background of the Invention: A mixture of nitrated compounds, isosorbide-5-mononitrate (of formula-I) isosorbide-2-mononitrate (of formula-II) Formula-II and isosorbide-2,5-dinitrate (of formula-Ill) are produced when isosorbide (of formula-IV) (also known as 1,4-3,6-dianhydro-D-sorbitol) is nitrated with nitric acid (according to the method of I.G. Csizmadia and D.L.Hayward, Photochem. Photobiology 4,657 (1965). The three nitrated compounds are separated from this mixture by column chromatography. Later a number of preparative methods are reported for making Isosorbide-5-mono-nitrate (of Formula-I) and the drawbacks in these processes are highlighted. 1. According to the processes mentioned in Organic Magnetic Resonance Vol. 3, 363 (1971) and D.L.Hayward et.al.Can. J.Chem, 45, 2, 1919 (1967), the Isosorbide-2,5-dinitrate (of formula-Ill) is saponified by partial basic or acid hydrolysis and the products Isosorbide-2-mononitrate and Isosorbide-5-mononitrate are separated by subsequent column chromatography. This is a laborious and time consuming procedure and difficult to practice in plant scale. 2. According to German Patent - (2, 903, 927) Isosorbide is acetylated with a lower alkanoic acid anhydride or chloride or bromide and the acylation mixture is nitrated with nitric acid and acetic anhydride to get Isosorbide-5-acylate-2-nitrate (of formula-V), Formula - v isosorbide-2-acylate -5-nitrate (of formula-VI) and isosorbide-2,5-diacetate (of formula-VII) These are hydrolysed with methanolic sodium methoxide and the product Isosorbide-5-mononitrate is separated by crystallisation with this patent procedure we could not obtain the product in the yields claimed (86%) and the product was also not conforming to the pharmacopieal specifications with respect to clarity of the solution test. 3. According to French patent 2, 103, 906 isosorbide-5-mononitrate is prepared by reduction of isosorbide-2,5-dinitrate using hydrazine hydrate. The reduction process is not selective and will result in Isosrobide-2-mononitrate and chromatographic separation is required and it is not feasible for commercialisation. 4. According to US patent 4, 713, 466 the isosorbide-2,5-dinitrate is reduced with zinc and acetic acid to get isosorbide-5-mononitrate. The process involves chromatographic separation of isosorbide-5-mononitrate and isosorbide-2-mononitrate. This is a laborious and time consuming procedure and difficult to practice in plant scale. 5. According to German Patent 2, 951, 934, US patent 4, 065, 488 and European Patent 0045076 isosorbide is protected on 2nd position by acetyl group and is then nitrated with nitric acid and acetic anhydride on 5th position and deprotection of acetyl group on 2nd position is done by acid or alkaline hydrolysis. The reported yields are not achieved when scaled up and the product obtained fails for clarity of the solution test. We concentrated our research efforts towards the development of an improved process for the preparation of isosorbide-5-mononitrate (of formula -I) by protecting isosorbide on second position by acetyl group. This intermediate (isosorbide-2-acetate of formula-VIII) is purified and nitrated on fifth position with acetyl nitrate by using optimised mole ratios of acetic anhydride and nitric acid to obtain the intermediate, formula-VI. Finally deprotection of the 2-acetyl group is carried out by using 25% ammonia solution and the product is obtained with improved yields. The method of using strong ammonia for deacetylating isosorbide-5-acetyl-5-nitrate is novel. Over-all our method is a safe and cheap commercial process and in particular the novel method of deacetylation of isosorblde-2-acetyl-5-nttrate provides product of pharnnacopeial quality. Accordingly, present invention provides an improved process for the preparation of isosorbide-5-mononitrate, which comprises: a) dehydrating D-sorbitol by known methods to obtain isosorbide, b) acetylating the isosorbide obtained in step (a) to isosorbide-2-acetate by known methods, c) nitrating the product obtained, isosorbide-2-acetate, in step (b) using optimum quantities of acetyl nitrate (which is prepared in situ by adding fuming nitric acid to acetic anhydride) at a temperature below 20°C to obtain isosorbide-2-acetate-5-nitrate, d) deacetylating the isosorbide-2-acetate-5-nitrate obtained in step (c) by a novel process using strong ammonia at room temperature, e) isolation of isosorbide-5-nitrate by i) reducing the volume of mass by distillation of aqueous methanol under vacuum at mass temperature below 60°C. ii) treating the concentrated mass with activated carbon, iii) filtering and gradually cooling the filtrate to 50C, maintaining the mass at 5C for 3 hours. iv) filtering the crystalline product, washing the cake with chilled water and drying under vacuum at temperature below 600 C. The details of the invention are given in the examples below which are provided to illustrate the invention only and therefore should not be construed to limit the scope of the invention. Example-I. (a) Preparation of Isosorbide of the formula-IV. 820.0 gms (3.15 moles) of 70% sorbitol aqueous solution is charged into four necked 2.0 Its round bottom flask equipped with a condenser connected to receiver, a thermometer socket and an addition funnel. 8.1 gms (0.0426 mole) of p-Toluene sulphonic acid is added and the temperature is raised to 95-105°C. About 200ml of water is collected in about 12-15 hrs at mass temperature 105 - 130°C. Then further (160.0 ml) water is distilled off under vacuum with mass temperature not crossing 130°C. Then cooled to 70 - 90°C, added 5% sodium carbonate solution and adjusted mass pH to 7.0 to 8.0, then temperature is raised again to 90 - 110°C and applied vacuum to remove remaining water. The isosorbide is distilled under high vacuum (8 mm) at temperature 200°C and collected 320.0 gms (70%yield). (b) Preparation of isosorbide-2-acetate of the formula-VIII. 4.0 gms (0.06 moles) of sodium acetate anhydrous is added to 75,0 gms of isosorbide (0.514 mole) of the formula-IV prepared as above and heated to 120°C and held at 120 - 130°C for 30 min. Then 116 gms (1.137 moles) of acetic anhydride is added slowly at 115 - 120°C over a period of 3 hrs. The mixture is held at 120 - 130°C for further 3 hrs. Then cooled to 70 - 80°C and 2nd lot of isosorbide 75.0 gms (0,514moles) prepared as above is added at 70 - 80°C and raised the temperature to 120 - 130°C and maintained at 120 - 130°C for further 45 min. Acetic acid is distilled off at 125 - 135°C under mild vacuum. Then the product is fractionated by high vacuum distillation. The main fraction is allowed to crystallise by standing at room temperature. The product is filtered and the cake dissolved in methylene chloride and washed with small amount of water. The residual oil is allowed to crystallize, and is filtered. Carbon tetra chloride washing (20.0 ml) is given to the solid mass. Total yield: - 100.0 gms ( 52 % yield on theory) GC purity - 96.0% (with isosorbide content limit is NMT 1.0%) (C) Pr^pgrjitipn Qf ig9gorbi formula-VI. 22.5 gm (0.22 moles) of acetic anhydride is cooled to 10-15°C and 24.0 gm of fuming nitric add (d 1.48) is added slowly at temperature 10-15°C in 2-3 hrs. Then 30.0 gms of isosorbide-2-acetate (0.16 moles) prepared as described above is added in small lots at temperature 10-15°C in 2-3 hrs. The completion of the reaction is monitored by TLC. The reaction mixture is quenched into chilled water (200ml) and the precipitated product is filtered and is washed with water (25.0 ml), the wet product is taken for deacetylation. Wet - 40.0 gm(34.0 gm on dry basis)-(yield -91.0%) HPLC purity - 99.0 + % ( d) Preparation of isosorbide-5-mononitrate of the formula-I. 40gm (0.146 moles) of the wet isosorbide-2-acetate-5-nitrate prepared as described above is suspended in 15.0 ml of methanol. 38.0 ml of ammonia strong solution (25%) is added and stirred at room temperature for 8 hrs. Completion of the deacetylation Is monitored by TLC. Then methanol and water mixture is distilled under vacuum at temperature less than 60°C and the volume reduced to 35 - 40 ml activated carbon l.5gms is added and stirred at 50 -55°C for 20 min., filtered through hyflow and the solution is filtered through 20μ pore size filter. The clear filtrate is gradually cooled to 5°C and kept at 4 - 5°C for 3 - 4 hrs. The product is filtered and dried under vacuum at temperature not crossing 60°C. 11nd crops are taken from mother liquors by saturating with sodium chloride and is added to next batch prior to carbon treatment to obtain 24gms as 1st crop. Claims: 1. An improved process for the preparation of isosorbide-5-mononitrate, which comprises: a) dehydrating D-sorbitoi by known methods to obtain isosorbide, b) acetylating the isosorbide obtained in step (a) to isosorbide-2-acetate by known methods, c) nitrating the product obtained, isosorbide-2-acetate, in step (b) using optimum quantities of acetyl nitrate (which is prepared in situ by adding fuming nitric acid to acetic anhydride) at a temperature below 200 °C to obtain isosorbide-2-acetate-5-nitrate, d) deacetylating the isosorbide-2-acetate-5-nitrate obtained in step (c) by a novel process using strong ammonia at room temperature, e) isolation of isosorbide-5-nitrate by (i) reducing the volume of mass by distillation of aqueous methanol under vacuum at mass temperature below 600C, (ii) treating the concentrated mass with activated carbon, (iii) filtering and gradually cooling the filtrate to 5°C, maintaining the mass at 5°C for 3 hours, (iv) filtering the crystalline product, washing the cake with chilled water and drying under vacuum at temperature below 600°C. 2. An improved process for the preparation of isosorbide-5-mononitrate subsequently as herein described with reference to the example.

Full Text

The present invention relates to an improved process for the preparation of Isosorbide-5-mononitrate, of formula-I given below. This is used as a vasodilator in the treatment of heart disease, such as angina pectoris. The present invention particularly relates to an improved process for preparation of isosorbide-5-mononitrate by a simple, safe and cheap method, which can be utilized for its commercial production. The present invention involves a novel hydrolysis method using strong ammonia, which is hitherto not reported for the preparation of this compound.

Background of the Invention:
A mixture of nitrated compounds, isosorbide-5-mononitrate (of formula-I) isosorbide-2-mononitrate (of formula-II)
Formula-II

and isosorbide-2,5-dinitrate (of formula-Ill)

are produced when isosorbide (of formula-IV)

(also known as 1,4-3,6-dianhydro-D-sorbitol) is nitrated with nitric acid (according to the method of I.G. Csizmadia and D.L.Hayward, Photochem. Photobiology 4,657 (1965). The three nitrated compounds are separated from this mixture by column chromatography.
Later a number of preparative methods are reported for making Isosorbide-5-mono-nitrate (of Formula-I) and the drawbacks in these processes are highlighted.
1. According to the processes mentioned in Organic Magnetic Resonance Vol. 3, 363 (1971) and D.L.Hayward et.al.Can. J.Chem, 45, 2, 1919 (1967), the Isosorbide-2,5-dinitrate (of formula-Ill) is saponified by partial basic or acid hydrolysis and the products Isosorbide-2-mononitrate and Isosorbide-5-mononitrate are

separated by subsequent column chromatography. This is a laborious and time consuming procedure and difficult to practice in plant scale.
2. According to German Patent - (2, 903, 927) Isosorbide is acetylated with a lower alkanoic acid anhydride or chloride or bromide and the acylation mixture is nitrated with nitric acid and acetic anhydride to get Isosorbide-5-acylate-2-nitrate (of formula-V),
Formula - v

isosorbide-2-acylate -5-nitrate (of formula-VI)

and isosorbide-2,5-diacetate (of formula-VII)

These are hydrolysed with methanolic sodium methoxide and the product Isosorbide-5-mononitrate is separated by crystallisation with this patent procedure we could not obtain the product in the yields claimed (86%) and the product was also not conforming to the pharmacopieal specifications with respect to clarity of the solution test.
3. According to French patent 2, 103, 906 isosorbide-5-mononitrate is prepared by reduction of isosorbide-2,5-dinitrate using hydrazine hydrate. The reduction process is not selective and will result in Isosrobide-2-mononitrate and chromatographic separation is required and it is not feasible for commercialisation.
4. According to US patent 4, 713, 466 the isosorbide-2,5-dinitrate is reduced with zinc and acetic acid to get isosorbide-5-mononitrate. The process involves chromatographic separation of isosorbide-5-mononitrate and isosorbide-2-mononitrate. This is a laborious and time consuming procedure and difficult to practice in plant scale.

5. According to German Patent 2, 951, 934, US patent 4, 065, 488 and European Patent 0045076 isosorbide is protected on 2nd position by acetyl group and is then nitrated with nitric acid and acetic anhydride on 5th position and deprotection of acetyl group on 2nd position is done by acid or alkaline hydrolysis. The reported yields are not achieved when scaled up and the product obtained fails for clarity of the solution test.
We concentrated our research efforts towards the development of an improved process for the preparation of isosorbide-5-mononitrate (of formula -I) by protecting isosorbide on second position by acetyl group. This intermediate (isosorbide-2-acetate of formula-VIII)

is purified and nitrated on fifth position with acetyl nitrate by using optimised mole ratios of acetic anhydride and nitric acid to obtain the intermediate, formula-VI. Finally deprotection of the 2-acetyl group is carried out by using 25% ammonia solution and the product is obtained with improved yields. The method of using strong ammonia for deacetylating isosorbide-5-acetyl-5-nitrate is novel. Over-all our method is a safe and cheap commercial process

and in particular the novel method of deacetylation of isosorblde-2-acetyl-5-nttrate provides product of pharnnacopeial quality.
Accordingly, present invention provides an improved process for the preparation of isosorbide-5-mononitrate, which comprises:
a) dehydrating D-sorbitol by known methods to obtain isosorbide,
b) acetylating the isosorbide obtained in step (a) to isosorbide-2-acetate by known methods,
c) nitrating the product obtained, isosorbide-2-acetate, in step (b) using optimum quantities of acetyl nitrate (which is prepared in situ by adding fuming nitric acid to acetic anhydride) at a temperature below 20°C to obtain isosorbide-2-acetate-5-nitrate,
d) deacetylating the isosorbide-2-acetate-5-nitrate obtained in step (c) by a novel process using strong ammonia at room temperature,
e) isolation of isosorbide-5-nitrate by
i) reducing the volume of mass by distillation of aqueous methanol under vacuum at mass temperature below 60°C.
ii) treating the concentrated mass with activated carbon,
iii) filtering and gradually cooling the filtrate to 50C, maintaining the mass at 5C for 3 hours.

iv) filtering the crystalline product, washing the cake with chilled
water and drying under vacuum at temperature below 600 C.
The details of the invention are given in the examples below which are provided to illustrate the invention only and therefore should not be construed to limit the scope of the invention.
Example-I.
(a) Preparation of Isosorbide of the formula-IV.
820.0 gms (3.15 moles) of 70% sorbitol aqueous solution is charged into four necked 2.0 Its round bottom flask equipped with a condenser connected to receiver, a thermometer socket and an addition funnel. 8.1 gms (0.0426 mole) of p-Toluene sulphonic acid is added and the temperature is raised to 95-105°C. About 200ml of water is collected in about 12-15 hrs at mass temperature 105 - 130°C. Then further (160.0 ml) water is distilled off under vacuum with mass temperature not crossing 130°C. Then cooled to 70 - 90°C, added 5% sodium carbonate solution and adjusted mass pH to 7.0 to 8.0, then temperature is raised again to 90 - 110°C and applied vacuum to remove remaining water. The isosorbide is distilled under high vacuum (8 mm) at temperature 200°C and collected 320.0 gms (70%yield).
(b) Preparation of isosorbide-2-acetate of the formula-VIII.
4.0 gms (0.06 moles) of sodium acetate anhydrous is added to 75,0 gms of isosorbide (0.514 mole) of the formula-IV prepared as above and heated to 120°C and held at 120 - 130°C for 30 min. Then 116 gms (1.137 moles) of acetic anhydride is added slowly at 115 - 120°C over a period of 3 hrs. The mixture is held at 120 - 130°C for further

3 hrs. Then cooled to 70 - 80°C and 2nd lot of isosorbide 75.0 gms
(0,514moles) prepared as above is added at 70 - 80°C and raised the
temperature to 120 - 130°C and maintained at 120 - 130°C for
further 45 min. Acetic acid is distilled off at 125 - 135°C under mild vacuum. Then the product is fractionated by high vacuum distillation. The main fraction is allowed to crystallise by standing at room temperature. The product is filtered and the cake dissolved in methylene chloride and washed with small amount of water. The residual oil is allowed to crystallize, and is filtered. Carbon tetra chloride washing (20.0 ml) is given to the solid mass. Total yield: - 100.0 gms ( 52 % yield on theory) GC purity - 96.0% (with isosorbide content limit is NMT 1.0%)
(C) Pr^pgrjitipn Qf ig9gorbi formula-VI.
22.5 gm (0.22 moles) of acetic anhydride is cooled to 10-15°C and
24.0 gm of fuming nitric add (d 1.48) is added slowly at temperature
10-15°C in 2-3 hrs. Then 30.0 gms of isosorbide-2-acetate (0.16
moles) prepared as described above is added in small lots at
temperature 10-15°C in 2-3 hrs. The completion of the reaction is
monitored by TLC. The reaction mixture is quenched into chilled water
(200ml) and the precipitated product is filtered and is washed with
water (25.0 ml), the wet product is taken for deacetylation.
Wet - 40.0 gm(34.0 gm on dry basis)-(yield -91.0%)
HPLC purity - 99.0 + %
( d) Preparation of isosorbide-5-mononitrate of the formula-I.
40gm (0.146 moles) of the wet isosorbide-2-acetate-5-nitrate prepared as described above is suspended in 15.0 ml of methanol.

38.0 ml of ammonia strong solution (25%) is added and stirred at room temperature for 8 hrs. Completion of the deacetylation Is monitored by TLC. Then methanol and water mixture is distilled under vacuum at temperature less than 60°C and the volume reduced to 35 - 40 ml activated carbon l.5gms is added and stirred at 50 -55°C for 20 min., filtered through hyflow and the solution is filtered through 20μ pore size filter. The clear filtrate is gradually cooled to 5°C and kept at 4 - 5°C for 3 - 4 hrs. The product is filtered and dried under vacuum at temperature not crossing 60°C. 11nd crops are taken from mother liquors by saturating with sodium chloride and is added to next batch prior to carbon treatment to obtain 24gms as 1st crop.

Claims:
1. An improved process for the preparation of isosorbide-5-mononitrate, which comprises:
a) dehydrating D-sorbitoi by known methods to obtain isosorbide,
b) acetylating the isosorbide obtained in step (a) to isosorbide-2-acetate by known methods,
c) nitrating the product obtained, isosorbide-2-acetate, in step (b) using optimum quantities of acetyl nitrate (which is prepared in situ by adding fuming nitric acid to acetic anhydride) at a temperature below 200 °C to obtain isosorbide-2-acetate-5-nitrate,

d) deacetylating the isosorbide-2-acetate-5-nitrate obtained in step (c) by a novel process using strong ammonia at room temperature,
e) isolation of isosorbide-5-nitrate by
(i) reducing the volume of mass by distillation of aqueous methanol under vacuum at mass temperature below 600C,
(ii) treating the concentrated mass with activated carbon,
(iii) filtering and gradually cooling the filtrate to 5°C, maintaining the mass at 5°C for 3 hours,
(iv) filtering the crystalline product, washing the cake with chilled water and drying under vacuum at temperature below 600°C.
2. An improved process for the preparation of isosorbide-5-mononitrate subsequently as herein described with reference to the example.

Documents:

391-mas-1999 abstract.pdf

391-mas-1999 claims.pdf

391-mas-1999 correspondence others.pdf

391-mas-1999 description (complete).pdf

391-mas-1999 form-1.pdf

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Patent Number

187648

Indian Patent Application Number

391/MAS/1999

PG Journal Number

36/2010

Publication Date

03-Sep-2010

Grant Date

Date of Filing

06-Apr-1999

Name of Patentee

NATCO PHARMA LTD

Applicant Address

NATCO HOUSE ROAD NO.2, BANJARA HILLS, HYDERABAD 500 033, INDIA

Inventors:

#	Inventor's Name	Inventor's Address
1	SAMBASIVA RAMACHANDRAN	NATCO PHARMA LTD., NATCO HOUSE ROAD NO.2, BANJARA HILLS, HYDERABAD - 500 033, INDIA
2	TUMMALA VENKATA RAO	NATCO PHARMA LTD., NATCO HOUSE ROAD NO.2, BANJARA HILLS, HYDERABAD - 500 033, INDIA
3	KON AKANCHI. DURGA PRASAD	NATCO PHARMA LTD., NATCO HOUSE ROAD NO.2, BANJARA HILLS, HYDERABAD - 500 033, INDIA
4	TALASILA.SAMBASIVA RAO	NATCO PHARMA LTD., NATCO HOUSE ROAD NO.2, BANJARA HILLS, HYDERABAD - 500 033, INDIA
5	TADIMALLLA. VENKATA SRIHARI	NATCO PHARMA LTD., NATCO HOUSE ROAD NO.2, BANJARA HILLS, HYDERABAD - 500 033, INDIA

PCT International Classification Number

C07D493/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA