DESC:Field of the Invention:
The present application relates to an improved process for the preparation of
Levodopa, which is represented by the following structural formula-I.
5
Formula-I
Background of the Invention:
DOPA is converted to dihydroxyphenethylamine (dopamine) through the action of aromatic
10 L-amino acid decarboxylase (AAAD), an enzyme present in most mammalian tissues in
relatively large amounts (Lovenberg et al., 1960).
DOPA stands for Dihydroxy Phenyl Alanine, is a precursor (forerunner)
of dopamine, a key neurotransmitter (messenger) in the brain. Dopa is used in the treatment
of Parkinson disease. Parkinson disease is believed to be related to low levels of dopamine in
15 certain parts of the brain. When dopa is taken by mouth, it crosses through the blood-brain
barrier. Once it has crossed from the bloodstream into the brain, it is converted to dopamine.
The resulting increase in dopamine concentrations in the brain is thought to improve nerve
conduction and to assist in lessening the movement disorders in Parkinson disease.
In 1970 the FDA (Food and Drug Administration) approved dopa in the form of
20 L-Dopa, or levodopa, for use in the US. The drug revolutionized the treatment of Parkinson
disease.
There are various processes reported for the preparation of Levodopa, using different
solvents and reagents.
Based on draw back of the prior art processes, there is a need for providing an
25 improved process for the preparation of Levodopa which involves simple experimental
procedures, well suited to industrial production, which avoids the use of column
chromatography purification, and which affords high pure Levodopa.
The present invention provides an improved process for preparation of Levodopa,
which is efficient, industrially viable and cost effective.
3
Brief Description:
The first aspect of the present invention provides an improved process for the preparation of the Levodopa.
The second aspect of the present invention provides an improved process for the preparation of the Levodopa. 5
Brief description of the drawings:
Figure 1: Illustrates the PXRD pattern of crystalline form of Levodopa obtained by example--3.
10
Detailed Description:
As used herein the term “suitable solvent” used in the present invention refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, petether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene and the like; “ether solvents” such as dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene 15 glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, 1,2-dimethoxy ethane and the like; “ester solvents” such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; “polar-aprotic solvents such as dimethyl acetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-20 methylpyrrolidone (NMP) and the like; “chloro solvents” such as dichloromethane, dichloroethane, chloroform, carbontetra chloride and the like; “ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; “nitrile solvents” such as acetonitrile, propionitrile, isobutyronitrile and the like; “alcoholic solvents” such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 25 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2-methoxyethanol, l,2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; “polar solvents” such as water or mixtures thereof.
4
As used herein the present invention the term “suitable base” refers to inorganic or
organic base. Inorganic base refers to “alkali metal carbonates” such as sodium carbonate,
potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as
sodium bicarbonate, potassium bicarbonate and the like; “alkali metal hydroxides” such as
5 sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; “alkali metal
alkoxides” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium
ethoxide, sodium tert.butoxide, potassium tert-butoxide, lithium tert-butoxide and the like;
alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the
like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like;
10 and organic bases such as like dimethylamine, diethylamine, diisopropyl amine, diisopropyl
ethylamine, diisobutylamine, triethylamine, pyridine, piperidine, 4-dimethyl amino pyridine
(DMAP), N-methyl morpholine (NMM), or mixtures thereof.
The term “reducing” agent used in the present invention refers suitable reducing reagents are
selected from Lithium aluminium hydride, sodium borohydride, BF3 etherate solution, Pd/C,
15 Ray-nickel;
The term “protecting” agent / group (PG) used in the present invention refers to a suitable
protecting reagents that are selected selected from di-tert-butyl dicarbonate, chlorobenzyl
formate, benzoylchloride, benzylbromide, benzylchloride, acetylchloride, fluorenyl
methyloxy carbonyl chloride; The term “phase transfer catalyst (PTC)” used in the present
20 invention refers are selected from triethylbenzyl ammonium chloride, tetrabutyl ammonium
bromide, tetrabutyl ammonium chloride, tetrabutyl ammonium acetate, methyl tributyl
ammonium chloride, tetrabutyl ammonium hydroxide, tributylbenzylammonium chloride;
The first aspect of the present invention provides an improved process for the
25 preparation of compound of formula-I.
Formula-I
5
Comprising of:
a) Reacting the compound of formula-1,
5 Formula-1
with suitable reagent, suitable solvent to provide compound of formula-2.
Formula-2
10
b) reacting the compound of formula-2 with suitable reagents, suitable solvents to get
compound of formula-3.
Formula-3
15
c) optionally purifying the compound obtained in step-b) with suitable reagents, suitable
solvents to provide compound of formula-I.
20 Formula-I
wherein in step-a) suitable reagents refer as acetyl chloride and aluminum chloride and the
suitable solvent is nitrobenzene; suitable temperature is 0-125°C.
6
Wherein in step-b) Suitable reagents refer as hydrogen peroxide; inorganic bases
such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; suitable
solvent refer as “chloro solvents” such as dichloromethane, dichloroethane, chloroform,
carbon tetrachloride and the like; polar and non-polar solvents” such as DMF, DMSO, NMP,
5 water or mixtures thereof; Suitable temperature is -10 to -80°C; pH- 4.0-5.0.
Wherein in step-c) suitable acid reagents refer as hydrochloric acid, hydrobromic
acid, acetic acid; sodium hydroxide, potassium hydroxide, lithium hydrochloride,
triethylamine, diisopropylamine and mixture thereof; suitable solvent refer as “ketone
solvents” such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like “ester
10 solvents” such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like.
“nitrile solvents” such as acetonitrile, propionitrile, isobutyronitrile and the like; “alcoholic
solvents” such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tbutanol,
2-nitroethanol; “polar and non-polar solvents” such as DMF, DMSO, NMP, water or
mixtures thereof; Suitable temperature is 0 to 100°C; pH-3.0-5.0;
15
The preferred embodiment of the present invention provides an improved process for the
preparation of compound of formula-I.
20 Formula-I
Comprising of:
a) Reacting the compound of formula-1,
25 Formula-1
with acetyl chloride and aluminum chloride in nitrobenzene to provide compound of
formula-2,
7
Formula-2
b) reacting the compound of formula-2 with sodium hydroxide in presence of hydrogen
5 peroxide in dichloromethane and water to get compound of formula-3,
Formula-3
10 c) reacting the compound obtained in step-b) with hydrochloric acid in water and basified
with sodium hydroxide followed by addition of acetone to provide compound of formula-I.
15 Formula-I
The present invention described as follows in a schematic representation:
20
8
The second aspect of the present invention provides an improved process for the
preparation of compound of formula-I.
5 Formula-I
a) Reacting the compound of formula-1,
Formula-1
with suitable reagent, suitable solvent to provide compound of formula-4,
10
Formula-4
b) reacting the compound of formula-4 with suitable reagents, solvents to get compound of
formula-3,
15
Formula-3
c) optionally purifying the compound obtained in step-b) with suitable reagents and solvents
to provide compound of formula-I.
20
Formula-I
Wherein in step-a) suitable reagents are selected from aq. HBr, bromine, bromine in acetic
acid, suitable temperature is 0 to 100°C.
9
Wherein in step-b) suitable reagents are selected from sodium hydroxide, potassium
hydroxide, lithium hydroxide, calcium hydroxide, potassium iodide, sodium iodide, copper
iodide and mixture thereof; suitable temperature is 10-120°C;
wherein in step-c) suitable acid refer as hydrochloric acid, hydrobromic acid, acetic
5 acid; sodium hydroxide, potassium hydroxide, lithium hydroxide, triethylamine, diiso propyl
amine and mixture thereof;
Wherein in step-a), b) and c) suitable solvent is selected from “ketone solvents” such
as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like “ether solvents” such as
diethyl ether, THF and like “ester solvents” such as methyl acetate, ethyl acetate, isopropyl
10 acetate, n-butyl acetate and the like. “nitrile solvents” such as acetonitrile, propionitrile,
isobutyronitrile and the like; “alcoholic solvents” such as methanol, ethanol, n-propanol,
isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol; poly ethylene glycol, ethylene
glycol, propylene glycol ;“ polar and non-polar solvents” such as water, DMF, DMSO, NMP
and mixtures thereof; Suitable temperature is 0-70°C; pH-3.0-4.0.
15 The preferred embodiment for the present invention provides an improved process for
the preparation of compound of formula-I.
Formula-I
20 a) Reacting the compound of formula-1,
Formula-1
with HBr solution, in acetic acid to provide compound of formula-4,
25
Formula-4
10
b) reacting the compound of formula-4 with sodium hydroxide, copper (I) iodide in water to
get compound of formula-3,
Formula-3
5
d) optionally purifying the compound obtained in step-b) in water by acidification and
basification to provide compound of formula-I.
Formula-I
10
The present invention described as follows in a schematic representation:
15
The process for the preparation of levodopa developed by the present inventors
produces highly pure levodopa with good yield. All the related substances and residual
solvents are controlled well within the limits as suggested by ICH guidelines and most of the
related substances are controlled in non-detectable levels.
20 The compound of formula-I produced by the process of the present invention is
having purity of greater than 99.5%, preferably greater than 99.7%, more preferably greater
than 99.9% by HPLC.
The process described in the present invention was demonstrated in examples
illustrated below. These examples are provided as illustration only and therefore should not
25 be construed as limitation of the scope of the invention.
11
Examples:
Example-1: Preparation of compound of formula-2.
A round bottom flask was charged with nitrobenzene (825 mL) at 25--35°C and cooled to 10--20°C, charged with aluminum chloride (275.8 g) and L--tyrosine (75 g) at same temperature and stirred for 15 min. Acetyl chloride (64.9 g) was charged to the reaction mixture at 10--5 20°C, heated to 95--105°C and stirred for 2--3 hr. Cooled the reaction mass to 25--35°C, quenched with aq. HCl solution and stirred for 3 hr. Filtered the obtained solid, washed with aq.HCl solution and dried to get wet compound. The wet compound was charged in aq. HCl solution and heated to 75--85°C, and maintained for 2 hr. Filtered the obtained solid and dried to get the title compound. 10
Yield: 79.56 g
Example-2: Preparation of compound of formula-3.
A round bottom flask was charged with compound of formula--2 (100 g), sodium hydroxide (43.9 g in 550 mL of water) and dichloromethane (200 mL) at 25--35°C and stirred for 20 min. Separated the both layers and the aqueous layer was cooled to 0--5°C and added slowly 15 hydrogen peroxide (50 mL) and hydrose (1 g) stirred for 10--15 min. The reaction mass stirred for 3 hr at 30--40°C. Cooled the reaction mixture to --5 to 5°C, pH adjusted to 4.5 with hydrochloric acid and maintained for 4 hr. Filtered the obtained solid and washed with water to get wet compound. The obtained wet compound was charged with water and heated to 65--75°C and stirred for 1 hr. Filtered the obtained solid and washed with water and dried to get 20 the title compound.
Yield: 52.0 g
Example-3: Preparation of compound of formula-I.
A round bottom flask was charged with compound of formula--3 (150 g), water (750 mL) at 25--35°C and stirred for 15 min. cooled the reaction mass to 5--10°C; hydrochloric acid (75 25 mL) was charged slowly and stirred for 30 min at 25--35°C. Charged carbon (7.5 g) to the reaction mixture and heated to 55--65°C , stirred for 1 hr. Filtered the reaction mass through hyflow bed, washed with water and the filtrate was charged with hydrose and stirred for 30 min. Filtered the reaction mass, cooled to 0--10°C and adjusted the pH to 4.5 with aqueous sodium hydroxide solution and stirred for 15 min. Charged acetone to the reaction mass at 0--30
12
10°C and stirred for 2 hr, filtered the obtained solid and washed with acetone and dried to get the title compound.
The obtained PXRD depicted in figure--1.
Yield: 48.5 g
Example-4: Preparation of compound of formula-4. 5
A round bottom flask was charged with L--tyrosine (100 g), acetic acid (1L), aq. 50 % HBr (250 g) and dimethylsulfoxide (50 mL) are heated to 60--70°C and stirred for 3 hr. The reaction mixture was distilled off, cooled the reaction to 25--35°C and charged with water (2 L) and heated to 60--75°C further stirred for 30 min. The reaction cooled, adjusted the pH to 7.0 with sodium carbonate solution and stirred for 2 hr. The obtained solid was filtered and 10 dried to get the title compound.
Yield: 94.06 g
Example-5: Preparation of compound of formula-3.
A round bottom flask was charged with compound of formula--4 (50 g), potassium hydroxide ( 37.8 g in 200 mL of water), copperiodide (7.5 g) and polyethylene glycol (5.0 gr ) heated to 15 90--100°C and stirred for 4 hr. Cooled the reaction mixture, filtered the unwanted compound, adjusted the pH to 1. 0 with hydrochloric acid (80 mL) and stirred for 15 min. The reaction mixture was charged with carbon and hydrose, stirred for 30 min. Filtered the carbon, adjusted the pH to 4.0 using triethylamine and stirred for 2 hr. Filtered the obtained solid, and washed with water and dried to get the title compound. 20
Yield: 18.70 g
Example-6: Preparation of compound of formula-I.
A round bottom flask was charged with compound of formula--3 (50 g), water (250 mL) at 25--35°C and stirred for 15 min. The reaction mass pH adjusted to 1.0 using hydrochloric acid (25 mL) and charged with carbon (5 g) stirred for 1 hr. Filtered the reaction mass through 25 hyflow bed washed with water. The filtrate was cooled to 0--10°C, and adjusted the pH to 4.0 with aqueous sodium hydroxide solution and stirred for 2 hr. Filtered the obtained solid and dried to get title compound.
Yield: 45.0 g
Example-7: Preparation of compound of formula-4. 30
13
A round bottom flask was charged with L--tyrosine (100 g), acetic acid (600 g), aq. 50 % Aq. HBr (365 g) and dimethylsulfoxide (50 mL) were heated to 60--70°C and stirred for 3 hr. The reaction mixture was cooled to 25--35°C and stirred for 5 hr. Distilled the solvent completely, charged with water and heated mass to 60--75°C, stirred for 30 min. Cooled the reaction, adjusted the pH to 7.0 with sodium bicarbonate solution and stirred for 2 hr. The obtained 5 solid was filtered to obtain the wet title compound.
Yield: 94. 0g
Example-8: Preparation of compound of formula-3.
A round bottom flask was charged with compound of formula--4 (100 g), water (1L), aq. sodium hydroxide solution and copperiodide (6.8 g) were heated to 90--100°C and stirred for 10 3 hr. Cooled the reaction mixture, filtered the unwanted compound and washed with methyltert butyl ether. Boric acid was charged to the reaction mixture and stirred at 0--10°C for 2 hr, adjusted the pH to 7.3 with hydrochloric acid and stirred for 15 min. The reaction was washed with MIBK, was charged with carbon and hydrose and stirred for 30 min. Filtered the reaction mixture, adjusted the pH to 4.0 using hydrochloric acid and stirred for 2 15 hr. The obtained solid was filtered, and washed with water and dried to get the title compound.
Yield: 18.7 g
Example-9: Preparation of compound of formula-I.
A round bottom flask was charged with compound of formula--3 (50 g), water (250 mL) at 20 25--35°C and stirred for 15 min. The reaction mass pH was adjusted to 1.0 using hydrochloric acid and charged with carbon stirred for 1 hr. Filtered the reaction mass through hyflow bed washed with water. The filtrated solution was cooled and adjusted the pH to 4.0 with aqueous sodium hydroxide solution and the resulting solution was stirred for 2 hr. Filtered the obtained solid and dried to get title compound. 25
Yield: 45.0 g ,CLAIMS:We claim:
1. A process for the preparation of levodopa
5
Formula-I
comprising of:
a) Reacting the compound of formula-1,
10 Formula-1
with suitable reagent, suitable solvent to provide compound of formula-2.
Formula-2
15
b) reacting the compound of formula-2 with suitable reagents, suitable solvents to get
compound of formula-3.
Formula-3
20
c) optionally purifying the compound obtained in step-b) with suitable reagents, suitable
solvents to provide compound of formula-I.
15
Formula-I
2. A process for preparation of levodopa as claimed in claim 1 wherein in step-a) suitable
reagents refer as acetyl chloride and 5 aluminum chloride and the suitable solvent is nitro
benzene; suitable temperature is 0-125°C. Wherein in step-b) Suitable reagents refer as
hydrogen peroxide; inorganic bases such as sodium hydroxide, potassium hydroxide, lithium
hydroxide and the like; Suitable temperature is -10 to -80°C; pH- 4.0-5.0.
Wherein in step-c) suitable acid reagents refer as hydrochloric acid, hydrobromic acid, acetic
10 acid; sodium hydroxide, potassium hydroxide, lithium hydroxide, triethylamine, diisopropyl
amine and mixture thereof;
3.A process for preparation of levodopa as claimed in claim 1, wherein suitable solvent refer
as “ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the
like “ester solvents” such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate
15 and the like. “Nitrile solvents” such as acetonitrile, propionitrile, isobutyronitrile and the like;
“alcoholic solvents” such as methanol, ethanol, n-propanol, isopropanol, n-butanol,
isobutanol, t-butanol, 2-nitroethanol; “ polar and non-polar solvents” such as DMF, DMSO,
NMP and water or mixtures thereof;
4. A process for the preparation of compound of formula-I.
20
Formula-I
Comprising of:
25 a) Reacting the compound of formula-1,
16
Formula-1
with acetyl chloride and aluminum chloride in nitrobenzene to provide compound of
formula-2,
5
Formula-2
b) reacting the compound of formula-2 with sodium hydroxide in presence of hydrogen
peroxide in dichloromethane and water to get compound of formula-3,
10
Formula-3
c) reacting the compound obtained in step-b) with hydrochloric acid in water and basified
15 with sodium hydroxide followed by addition of acetone to provide compound of formula-I.
Formula-I
5. An improved process for the preparation of compound of formula-I.
20
Formula-I
17
a) Reacting the compound of formula-1,
5 Formula-1
with suitable reagent, suitable solvent to provide compound of formula-4,
Formula-4
10 b) reacting the compound of formula-4 with suitable reagents, solvents to get compound of
formula-3,
Formula-3
15 c) optionally purifying the compound obtained in step-b) with suitable reagents and solvents
to provide compound of formula-I.
Formula-I
6. A process for preparation of levodopa as claimed in claim 5 , wherein in step-a) suitable
20 reagents are selected from aq. HBr, bromine, bromine in acetic acid, suitable temperature is 0
to 100°C; Wherein in step-b) suitable reagents are selected from sodium hydroxide,
potassium hydroxide, lithium hydroxide, calcium hydroxide, potassium iodide, sodium
iodide, copper iodide and mixture thereof; suitable temperature is 10-120°C; Wherein in
step-c) suitable acid refer as hydrochloric acid, hydrobromic acid, acetic acid; sodium
18
hydroxide, potassium hydroxide, lithium hydroxide, triethylamine, diiso propylamine and
mixture thereof;
7. A process for preparation of levodopa as claimed in claim 5 wherein the suitable solvent is
selected from “ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutyl
5 ketone and the like “ether solvents” such as diethyl ether, THF and like “ester solvents” such
as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like. “nitrile
solvents” such as acetonitrile, propionitrile, isobutyronitrile and the like; “alcoholic solvents”
such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-
nitroethanol; poly ethylene glycol, ethylene glycol, propylene glycol ; “polar & non-polar
10 solvents” such as water, DMF, DMSO, NMP and mixtures thereof; Suitable temperature is 0
to 100°C; pH: 0-11;
8. An improved process for the preparation of compound of formula-I.
15 Formula-I
a) Reacting the compound of formula-1,
Formula-1
with HBr solution, in acetic acid to provide compound of formula-4,
20
Formula-4
b) reacting the compound of formula-4 with sodium hydroxide, copper (I) iodide in water to
get compound of formula-3,
25
19
Formula-3
c) Optionally purifying the compound obtained in step-b) in water by acidification and
basification to provide compound of formula-I.
5
Formula-I
9. A compound of formula-4.
10
Formula-4
10. The compound of formula-I obtained according to any of preceding claims having
chemical purity and chiral purity > 99% by HPLC.