PROCESS FOR THE PREPARATION OF ATROPINE AND ITS CRYSTALLINE QUATERNARY SALTS THERE OF
FIELD OF INVENTION
The present invention relates generally to a novel process for the preparation of quaternary tropine derivatives. The invention is more especially concerned with a novel process for the preparation of atropine and its crystalline quaternary salts of the formula as given below. The aim of the present invention is to provide an improved industrial method of synthesis which enables the compounds of general formula mentioned in figure I&II, to be synthesized more easily with high yield and good quality, trouble free operations, low cost and scalable for production.
BACKGROUND OF THE INVENTION
Atropine is an alkaloid drug, exists in racemic mixture i.e D-hyoscyamine and L-hyoscyamine. However, in both forms; L- hyoscyamine shows more physiological effects. The patent US 2276677 describes the usage of Atropine for treatment of affections of the central nervous system. Further, the pharmacological effects are exhibited due to its binding to muscarinic acetylcholine receptors and also it is an anti-muscarinic agent.
Chemically atropine is known as 8-methyl-8-azabicyclo [3.2.1] oct-3-yl) 3-hydroxy-2-phenyl propionate (Figure –I)
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OHOONH3CFigure-I
Human vision has developed the ability to commercial preparation and utilization of atropine for a variety of medical purposes like preventing heart slowing during anesthesia; dilating pupils of the eye for ophthalmology; providing symptomatic relief of colds and asthma; treating bradycardia (extremely slow heart rate) and heart block; serving as an antidote to certain poisons, such as nerve gas; and acting as an antispasmodic. The most common atropine compound used in medicine is atropine sulfate (C17H23NO3)2·H2SO4·H2O, the full chemical name endo (±)-alpha-Hydroxymethyl benzeneacetic acid 8-methyl-8-azabicyclo3, 2, 1] oct-3-yl ester sulphate monohydrate (Figure-II)
OHOONH3CFigure-II2H2SO4H2O
CN 104402877A patent discloses that the process for the preparation of atropine in pure form, where in Alpha-formyloxy phenyl acetic acid reacted with tropine and hydrolyzed by potassium borohydride in a mixture of chloroform and alcohol.
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Shortcoming of the application to reach the masses is use of costly material.
CN 104341414A patent discloses that, where in the method for the synthesis of atropine sulfate, which is synthesized by hydrolysis of phenyl acetate to get phenyl acetic acid. Which is the chlorinated by Thionyl chloride and then condensed with tropine. Further the condensed product reacted with paraformaldehyde in high boiler solvent to get Atropine is in lowerside yield as compare to present novel process.
WO 2014/102829 patent discloses that the crystalline polymorphs form of atropine sulphate and there preparation by reacting alpha-formyloxy phenyl acetic acid with tropine. Major drawbacks of these patent includes use carcinogenic reagents and multiple stage synthesis.
The document SU 199149 discloses the reaction of tropine derivative with amylgdalic acid in the presence of HCI.
In current innovation, all the developed process parameters are feasible with effective control measures and most importantly the process is robust and cost effective. Critical process parameters have been identified during this phase of development which affects the critical quality attribute of API.
SUMMARY OF THE INVENTION
In accordance with the present invention, there is provided a process for the preparation of atropine and its crystalline quaternary salt. The steps involved in the process are as follows:-
Brief Process Details
DL-Tropic acid reacted with acetyl chloride in presence of methylene chloride to get Acetyl DL-tropic acid in Methylene chloride. In-situ Thionyl chloride added in it in
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presence of catalytic amount of DMF to get Acid chloride of Acetyl DL-Tropic acid. Reaction mass is distilled off in inert atmosphere to get solvent free as well as Thionyl chloride and acetyl chloride free reaction mass, which is further reacted with tropine hydrochloride to get acetyl protected atropine which is further hydrolyzed by dilute Hydrochloric acid to get pure form of atropine in acetonitrile.
Pure atropine charcoalized in acetonitrile and sulphuric acid is added in it to get atropine sulphate monohydrate which is further purified in isopropyl alcohol to get pure form of crystalline atropine sulphate monohydrate.
OHOHOOHOOH3COClOOH3COCH3COClMDCSOCl2DMFNOHCH3HCl+NOCH3OOOCH3HClNOCH3OOHNOCH3OOH2H2SO4.H2OHCl/H2OH2SO4/ ACNMDCIPAFigure-IIFigure-IFigure-IVFigure-IIIFigure-VIFigure-V
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, this invention provides the process in which DL-Tropic acid of formula of figure V is reacted with Acetyl chloride in the presence halogenated organic solvent at room temperature.
On completion of reaction, in-situ reaction mass (Figure VI) is reacted with Thionyl chloride in presence of catalytic amount of DMF at room temperature under inert atmosphere.
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After completion of reaction, organic solvent is distilled off atmospherically and lastly under vacuum to distill off traces of organic solvent and traces of acetyl chloride, Thionyl chloride to obtain freshly prepared acid chloride (Figure III) which is used as such for next reaction.
The organic solvent used are halogenated aliphatic hydrocarbon such as methylene chloride, ethylene chloride , chloroform , aliphatic ester such as ethyl acetate, butyl acetate, aromatic hydrocarbon such as toluene , xylene or aliphatic ether such as diethyl ether , di-isopropyl ether. The most preferably used is methylene chloride.
Freshly prepared figure III reacted with tropine hydrochloride (Figure IV) in halogenated organic solvent at room temperature for 16.0 hrs. Organic solvent is distilled off to obtained oily mass of acetyl atropine hydrochloride.
Acetyl atropine hydrochloride is hydrolyzed by using dil. Hydrochloric acid at room temperature for 8.0 to 12.0 hrs to comply the HPLC. After completion of reaction, washing is done my using halogenated hydrocarbons to remove unreacted acetyl atropine hydrochloride and unwanted impurities.
Aqueous reaction mass is basified by using inorganic base to extract the product in organic solvent and combined layer washed with water to remove unwanted tropine and any other water soluble impurities.
The aqueous solutions of inorganic base used are alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, alkali metal carbonate and bicarbonate such as sodium carbonate, sodium bicarbonate, potassium carbonate. The most preferably used is liquor ammonia.
After basification, material extraction and crystallization is in organic solvent to obtained pure atropine base. (Figure I)
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The organic solvent used for material extraction and crystallization are halogenated aliphatic hydrocarbon such as methylene chloride, ethylene chloride, chloroform, aliphatic ester such as ethyl acetate, butyl acetate, and aromatic hydrocarbon such as toluene, xylene or aliphatic ether such as diethyl ether, di-isopropyl ether. Aliphatic hydrocarbon pentane, hexane, heptane, alcohol based methanol, ethanol, propanol, butanol, ketone based acetone, methyl ethyl ketone, nitrile based Acetonitrile. The most preferably used product extraction from aq. layer is methylene chloride and for product isolation and purification is Acetonitrile.
Pure atropine base is charcoalized in organic solvent at 45-500C and quaternized by sulphuric acid at 35-400C to get crude atropine sulphate monohydrate at 75-800C, which is further purified in organic solvent at 35-450C.
The organic solvent used for charcoalization and quaternarization are halogenated aliphatic hydrocarbon such as methylene chloride, ethylene chloride, chloroform, aliphatic ester such as ethyl acetate, butyl acetate, and aromatic hydrocarbon such as toluene, xylene or aliphatic ether such as diethyl ether, di-isopropyl ether. Aliphatic hydrocarbon pentane, hexane, heptane, alcohol based methanol, ethanol, propanol, butanol, ketone based acetone, methyl ethyl ketone, nitrile based Acetonitrile. The most preferably used for charcoalization and quaternarization is Acetonitrile and for purification is Isopropyl alcohol.
Pure material is dried for 8.0 hrs under vacuum at 60-650C to obtained Atropine sulphate monohydrate. (Figure-II)
XRD, DSC and TGA Characterization data indicates that product is in crystalline and monohydrate in form. (Diagram-I, II and III)
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Diagram-I XRD of Atropine sulphate Monohydrate.
Diagram II- DSC of Atropine sulphate monohydrate.
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Diagram III- TGA of Atropine sulphate monohydrate.
Experimental part:
Stage-01:- Preparation of Acid chloride of acetyl DL-Tropic acid (Figure-III)
111.0 gm DL tropic acid (Figure V) reacted with 77.0 gm of acetyl chloride in presence of 500.0 ml methylene chloride for a 5.0 hrs at room temperature. On completion of reaction confirmed by TLC, the reaction mass is cooled down to temperature up to 0-100C in inert atmosphere. 2.0 ml DMF is added followed by slow addition of 100.0 gm Thionyl chloride in it. Reaction is maintained for 18.0 hrs at room temperature to elevate the HCl gas completely. After 18.0 hrs methylene chloride is distilled off then temperature is raised up to 500C and excess of Thionyl chloride and acetyl chloride is distilled out. Degass it well to completely remove acetyl chloride and Thionyl chloride to get 150.0 gm Acid chloride of acetyl DL-Tropic acid. (Figure-III)
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Stage-02:- Preparation of Atropine. (Figure I).
100.0 gm Tropine hydrochloride (Figure-IV) is refluxed by azeotrope for 2.0 hrs in 450.0 ml methylene chloride to remove traces of water content from tropine hydrochloride. Temperature of reaction mass is cooled down up to 100C and freshly prepared 150.0 gm acid chloride of Acetyl DL-Tropic acid with 50.0 ml methylene chloride is added in reaction in inert atmosphere. Reaction was stirred at room temperature for 18.0 hrs and 2.0 hrs at room temperature to elevate all HCL gas. Methylene chloride is distilled off and degassed well to get acetyl atropine as an oily mass. Further a solution of 50.0 ml hydrochloric acid and 200.0 ml water is added in oily mass and maintained for 8.0 hrs at 25-350C, reaction was monitored by HPLC up to below 5.0% unreacted acetyl atropine obtained.
After completion of reaction, unreacted acetyl atropine and unwanted impurities are removed by washing with 2X100.0 ml methylene chloride. Product contained in aq. layer is cooled down up to 0-100C and basify the mass (9-10 pH) by liquor ammonia. Product is extracted with 3X200.0 ml methylene dichloride. Combined methylene chloride layer washed with 2X50.0 ml of water to remove unreacted tropine. Methylene chloride layer dried through sodium sulphate and distilled out completely to get crude atropine. 200.0 ml Acetonitrile is added in it and heat it up to 55-650C to get clear solution. Maintained it for 30.0 min then cooled down up to RT and 0-50C. After 2.0 hrs cooling, reaction mass was filtered and washed with 50.0 ml of chilled acetonitrile to get 100.0 -110 gm pure atropine (Figure-I) after drying.
Out Put 100-110.0 gm
HPLC purity: NLT 99.70%
Single highest impurity NMT 0.2%
Theoretical yield 1.62 w/w from tropine hydrochloride
Practical Yield: 1.0 to 1.10 w/w
Practical % yield 70.0%
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Stage-03:- Preparation of Atropine sulphate monohydrate (Figure II).
100.0 gm of pure atropine (Figure-I) dissolved in 1200.0 ml acetonitrile to get clear solution at 45-500C. Clear reaction mass is stirred for 30.0 min in 1.0% charcoal. After hyflow filtration the clear colorless reaction mass is cooled down up to 30-350C under inert atmosphere. Sulphuric acid LR grade 18.0 gm is added in clear reaction mass within 2.0 to 3.0 hrs and maintaining temperature 30-400C. After complete addition reaction is maintained for 1.0 hr at 30-400C and 2.0 hrs at 75-800C, further reaction mass is cooled down up to RT then 0-50C. Filtration is done after 2.0 hrs maintaining and washed with 100.0 ml chilled acetonitrile. Wet cake is dried at 60-650C for 6.0 hrs under vacuum to get 115.0 gm crude atropine sulphate monohydrate.
Out Put 110-115.0 gm
HPLC purity: NLT 99.50%
Water content 2.0 to 4.0%
Single highest impurity NMT 0.2%
Theoretical yield 1.23 w/w
Practical Yield: 1.10 to 1.15 w/w
Practical % yield 94.0%
Stage-04:- Purification of Atropine sulphate monohydrate (Figure II).
115.0 gm atropine sulphate stirred in 345.0 ml of isopropyl alcohol for 30.0 min at 25-350C then 3.0 hrs at 40-450C. Cool down the temperature of reaction up to 25-350C and maintained for 2.0 hrs. Filter the material and washed with 57.0 ml of isopropyl alcohol. Wet cake is dried at 60-650C for 6.0 to 8.0 hrs under vacuum to get 109.0 gm pure atropine sulphate monohydrate
Out Put 105-109.0 gm
HPLC purity: NLT 99.90%
Water content 2.0 to 4.0%
Theoretical yield 1.0w/w
Practical Yield: 0.90 to 0.95 w/w
Practical % yield 95.0%
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We Claim:
1. A process for preparing the atropine and its quaternary salts of formula of figure I and II by reacting acetyl protected DL-tropic acid chloride of formula of figure III with tropine hydrochloride of formula of figure IV in an organic solvent at preferable temperature, and hydrolysis at elevated temperature by using H+ ion to produce atropine base of formula of figure-I after basification of hydrolyzed aq. Layer. Which is then quaternized to give its quaternary salts of atropine sulphate of formula of figure II, as shown below: OO H
O
N
H3C
Figure-I
OHOONH3CFigure-II2H2SO4H2O
ClOOH3COFigure-III
NOHCH3H ClFigure-IV
OHOHOFigure-V
OH3COOHOFigure-VI
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2. A process for preparing of formula of figure VI by reacting DL tropic acid of formula of figure V with acid chloride in organic solvent at inert atmosphere to get formula of figure VI.
3. A process for preparing of formula of figure III by reacting of formula of figure VI with chlorinating agent in organic solvent at inert atmosphere to get formula of figure III.
4. A process for preparing the atropine and its quaternary salts of formula of Figure I to VI as claimed in claim 1 to 3, wherein the organic solvent used for the reaction, extraction, crystallization and purification is aliphatic straight chain or branched chain C6 -C12 hydrocarbon such as hexane, heptane, aromatic hydrocarbon such as toluene, xylene, Aliphatic halogenated hydrocarbon such as Methylene chloride, chloroform, ethylene dichloride, aliphatic ester such as ethyl acetate, butyl acetate, aliphatic ether such as diethyl ether, di-isopropyl ether, alcohol based solvent such as methanol, ethanol, propanol, ketone based solvent such as acetone, methyl ethyl ketone, and nitrile based solvent Acetonitrile.
5. A process for preparing the atropine and its quaternary salts of formula of Figure I as claimed in claim 1, wherein the H+ ion for hydrolysis in presence of water is organic or inorganic acids such as hydrochloric acid, sulphuric acid, nitric acid, phosphoric acid, perchloric acid, acetic acid, substituted sulphonic acids.
6. A process for preparing the atropine and its quaternary salts of formula of Figure I and II as claimed in claim 4, wherein the organic solvent is preferably Methylene chloride.
7. A process for preparing the formula of figure VI as claimed in claim 2, the hydroxyl group protection of DL-Tropic acid of formula of figure-V by reacting with acid chlorides such as formyl chloride, acetyl chloride, propionyl chloride benzoyl chloride, benzyl chloride or any other chloroformates.
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8. A process for preparing the formula of figure VI as claimed in claim 7, the hydroxyl group protection of DL-Tropic acid of formula of figure-V by reacting with acid chloride, wherein the preferably acid chloride is acetyl chloride.
9. A process for preparing the formula of figure III as claimed in claim 3, the chlorination of the hydroxy protected DL-Tropic acid formula of figure VI reacted with chlorinating agent such as Thionyl chloride, oxalyl chloride, phosphoryl chloride, phosphorus penta chloride, phosphorus trichloride etc. at inert atmosphere.
10. A process for preparing the formula of figure III as claimed in claim 9, the suitable chlorinating agent is Thionyl chloride.
11. A process for preparing the atropine and its quaternary salts of formula of Figure I as claimed in claim 4, wherein the organic solvent used is preferably Methylene chloride for reaction and Acetonitrile for crystallization.
12. A process for preparing the atropine and its quaternary salts of formula of Figure VI as claimed in claim 4, wherein the organic solvent used is preferably Methylene chloride for reaction.
13. A process for preparing the atropine and its quaternary salts of formula of Figure III as claimed in claim 4, wherein the organic solvent used is preferably in-situ Methylene chloride reaction mass of formula VI.
14. A process for preparing the atropine and its quaternary salts of formula of Figure I as claimed in claim 4, wherein the organic solvent used for the isolation, crystallization and purification is preferably acetonitrile.
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15. A process for preparing the atropine and its quaternary salts of formula of figure I as claimed in claim 1, wherein the base used for basification is the aqueous solution of alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, alkali metal carbonate and bicarbonate such as sodium carbonate, sodium bicarbonate, potassium carbonate, liquor ammonia organic base like triethyl amine, pyridine.
16. A process for preparing the atropine and its quaternary salts of formula of figure I as claimed in claim 15, wherein the base most preferably used is liquor ammonia.
17. A process for preparing the atropine and its quaternary salts of formula of Figure II as claimed in claim 4, wherein the preferable organic solvent is acetonitrile.
18. A process for preparing the atropine and its quaternary salts of formula of Figure II as claimed in claim 4, wherein the preferable organic solvent is isopropyl alcohol.
19. A process for preparing the atropine and its monohydrate quaternary salts of formula of Figure II as claimed in claim 4, wherein the preferable organic solvent is isopropyl alcohol for crystalline monohydrate form.