WO2016147133A1 - Process for the preparation of droxidopa - Google Patents

Process for the preparation of droxidopa Download PDF

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Publication number
WO2016147133A1
WO2016147133A1 PCT/IB2016/051492 IB2016051492W WO2016147133A1 WO 2016147133 A1 WO2016147133 A1 WO 2016147133A1 IB 2016051492 W IB2016051492 W IB 2016051492W WO 2016147133 A1 WO2016147133 A1 WO 2016147133A1
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formula
process according
alkyl
compound
bis
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PCT/IB2016/051492
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French (fr)
Inventor
Murali Rajappa
Arnab ROY
Amit Kumar MANDAL
Dhileepkumar Krishnamurthy
Mahesh Ramrao KULKARNI
Kamlesh Harichandra CHAVAN
Suresh Kumar SYTHANA
Sanjeev Kumar Aavula
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Piramal Enterprises Limited
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Publication of WO2016147133A1 publication Critical patent/WO2016147133A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a process for the preparation of (2S,3 ?)-2-amino-3-(3,4- dihydroxyphenyl)-3-hydroxypropanoic acid, which is known as Droxidopa, a synthetic amino acid precursor of norepinephrine.
  • Droxidopa a synthetic amino acid precursor of norepinephrine.
  • the present invention also relates to novel intermediates for the preparation of Droxidopa.
  • Droxidopa is chemically known as (2S,3 ?)-2-amino-3-(3,4-dihydroxyphenyl)-3- hydroxypropanoic acid and it is structurally represented by the following formula I. It is also known as L-i/zreo-dihydroxyphenylserine. Droxidopa is available in the market as Northera® capsules with dosages of 100 mg, 200 mg and 300 mg for oral administration.
  • Droxidopa is an orally active, synthetic norepinephrine precursor that was originally launched in 1989 in Japan by Sumitomo Dainippon Pharma for the oral treatment of frozen gait or dizziness associated with Parkinson's disease and for the treatment of orthostatic hypotension, syncope or dizziness associated with Shy-Drager syndrome and familial amyloidotic polyneuropathy.
  • Northera® is approved for the treatment of orthostatic dizziness, light headedness, or the "feeling that you are about to black out" in adult patients with symptomatic neurogenic orthostatic hypotension caused by primary autonomic failure, dopamine beta-hydroxylase deficiency, and non-diabetic autonomic neuropathy.
  • Droxidopa is a synthetic amino acid analog that is directly metabolized to norepinephrine by dopadecarboxylase, which is extensively distributed throughout the body. Chirality has acquired increasing importance for the pharmaceutical industry, as evidenced by the fact that more than 80% of the drugs developed hitherto have chiral properties. The various enantiomers may develop completely different effects in the body, so that only one of two or more enantiomeric forms administered may be effective. In the case of droxidopa, the compound of formula I, it has been observed that the h-threo enantiomer is the desired isomer having desired activity.
  • the US'728 patent also provides a process for the preparation of droxidopa comprising the steps of (i) reaction of 3,4-dibenzyloxybenzaldehyde with glycine, followed by treatment with sodium acetate trihydrate and diethylamine to obtain racemic- i zreo/er i zro-3-(3,4-dibenzyloxyphenyl)-serine; (ii) treatment of the compound obtained in step (i) with carbobenzoxy chloride to obtain racemic-threo/erythro-3-(3,4- dibenzyloxyphenyl)-N-carbobenzoxyserine; (iii) treatment of the compound obtained in step (ii) with freshly distilled dicyclohexylamine to obtain racemic-i/zreo-3-(3,4- dibenzyloxyphenyl)-N-carbobenzoxyserinedicyclohexylamine salt, which on treatment with HC1 gas in the presence of
  • US Patent No. 4,319,040 discloses a process for preparation of droxidopa comprising reaction of racemic i/zreo-3-(3,4-dibenzyloxyphenyl)-N-carbobenzoxyserine with resolving agent of formula A, followed by decomposition using hydrochloric acid to yield (-)-3-(3,4- dibenzyloxyphenyl) -N-c arbobenzoxy serine .
  • R is methyl, isopropyl or isobutyl
  • US Patent No. 4,562,263 discloses a process for preparation of droxidopa comprising optical resolution of N-phthaloyl-3-(3,4- methylenedioxyphenyl) serine using optically active amine selected from the group consisting of strychinine, cinconidine, L-norephedrine, S-2-amino-l,l-diphenyl-l-propanol and L-3-hydroxy-3-(4-nitrophenyl)-2-amino-l-propanol to yield L-N-phthaloyl-3-(3,4- methylenedioxyphenyl) serine, reacting the resulting compound with a Lewis acid selected from the group consisting of aluminium trichloride, aluminium tribromide, boron trichloride and boron tribromide to form N-phthaloyl-3-(3,4-dihydroxyphenyl)-serine;
  • the process involves use of complex agents for isomer separation, which also results in ⁇ 50 % of desired isomer.
  • the hydrazine used for the deprotection of phthaloyl group is known to be genotoxic and thus it is required to remove traces of hydrazine from the final product, droxidopa.
  • the limitation of the process described in US'263 patent is that it is unable to remove traces of hydrazine.
  • the object of this invention is to provide an alternative process for the preparation of the L-threo isomer of droxidopa, the compound represented by formula I, which is an enantioselective process.
  • the process of the present invention allows efficient large-scale synthesis by overcoming the drawbacks of the conventional resolution technique.
  • An object of the present invention is to provide a process for the preparation of L-threo- dihydroxyphenylserine (droxidopa) represented by formula I, which improves upon the limitations of the prior art process.
  • An object of the present invention is to provide a stereoselective process for the preparation of droxidopa using asymmetric induction, thereby avoiding synthetic process involving chiral resolution.
  • An object of the present invention is to provide a process for the preparation of droxidopa involving novel intermediates of formula III, formula V and formula VI.
  • An object of the present invention is to provide novel intermediates of formula III, formula V and formula VI and a process for their preparation.
  • Another object of the present invention is to provide a process for preparation of droxidopa, wherein the desired -threo isomer is obtained with selectivity > 95 %.
  • Still another object of the present invention is to provide a process for the preparation of doxidropa which is simple, efficient, cost-effective and industrially feasible process.
  • a process for the preparation of L-i/zreo-dihydroxyphenylserine (droxidopa) represented by formula I comprising the steps of: a) reacting compound of formula II with orthoformate in the presence of a solvent to yield compound of formula III; b) reacting the compound of formula III, obtained in step (a) with a compound of formula IV using a catalyst in the presence of a solvent to yield compound of formula V; c) reacting the compound of formula V, obtained in step (b) with haloacetate in the presence of a base and a solvent to yield compound of formula VI; d) reacting the compound of formula VI, obtained in step (c) with an acid in the presence of a solvent to yield the compound of formula I.
  • Ri and R 2 are independently selected from a group consisting of unsubstituted or substituted alkyl, cycloalkyl, aryl and heterocyclyl;
  • R 3 is selected from a group consisting of unsubstituted or substituted alkyl and aryl.
  • the process of the present invention overcomes the disadvantages associated with the processes described in the prior art references, which is mainly concerned with the use of a synthetic process involving chiral resolution using chiral resolving agents to obtain desired L-threo isomer, wherein the selectivity to separate the desired isomer is very low. Also, the processes described in the prior arts teach the use of genotoxic reagents; and are elaborate and tedious processes.
  • the process of the present invention is a stereoselective process utilizing asymmetric induction involving novel intermediates to obtain desired h-threo isomer in droxidopa with selectivity > 95 %, thereby making the process of the present invention simple, efficient, cost-effective and industrially applicable.
  • the present invention relates to a process for the preparation of L-threo- dihydroxyphenylserine (droxidopa) of formula I
  • R 2 is as defined herein; using a catalyst in the p ound of formula V,
  • the present invention relates to a co
  • Ri is selected from a group consisting of unsubstituted or substituted alkyl, alkoxy, cycloalkyl, aryl and heterocyclyl.
  • the present invention also relates to a process for the preparation of compound of formula in,
  • the present invention relates to a compound of formula V,
  • Ri and R 2 are independently selected from a group consisting of unsubstituted or substituted alkyl, cycloalkyl, aryl and heterocyclyl.
  • the present invention also relates to a process for the preparation of compound of formula V,
  • Ri and R 2 are as defined herein; comprising the steps of:
  • R 2 is as defined herein;
  • the present invention relates to a compound of formula VI,
  • Ri and R 2 are independently selected from a group consisting of unsubstituted or substituted alkyl, cycloalkyl, aryl and heterocyclyl;
  • R 3 is selected from a group consisting of unsubstituted or substituted alkyl and aryl.
  • the present invention also relates to a process for the preparation of compound of formula VI
  • the present invention relates to a process for the preparation of compound of formula I
  • Ri and R 2 are independently selected from a group consisting of unsubstituted or substituted alkyl, cycloalkyl, aryl and heterocyclyl.
  • the unsubstituted or substituted alkyl is (Ci-Cio)-alkyl, which may be a straight-chain or branched chain alkyl; for example, Ci-Cio for straight chain and C 3 -Cio for branched chain.
  • Suitable alkyl groups containing from one to ten carbon atoms include, but are not limited to, methyl, ethyl, n- propyl, isopropyl, n-butyl, t-butyl, iso-butyl, sec-butyl, n-pentyl, isopentyl, 2-pentyl, 3- pentyl, neo-pentyl, n-hexyl, isohexyl, 2-hexyl, 3-hexyl, n-heptyl, isoheptyl, 2-heptyl, 3- heptyl, n-octyl, isooctyl, 2-octyl, 3-octyl, n-nonyl, isononyl, 2-nonyl, 3-nonyl, n-decyl, isodecyl, 2-decyl and 3-decyl.
  • alkyl groups may be unsubstituted or substituted with one or more substituents.
  • a substituted alkyl refers to a (Ci-Cio)-alkyl substituted with one or more groups, preferably 1-3 groups, independently selected from halogen, hydroxy, (Ci-C 6 )- alkoxy, nitro, cyano, amino, substituted amines, C(O) and C(0) 2 -alkyl.
  • the cycloalkyl is (C3-C 12 )- cycloalkyl, wherein a saturated or partially unsaturated cyclic hydrocarbon radical including 1, 2 or 3 rings and including a total of 3 to 12 carbon atoms forming the rings.
  • cycloalkyl includes bridged, fused and spiro ring systems.
  • cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, norbornyl, bicyclo[2.1.0]pentane, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]hept-2- ene, spiro[3.3]heptanes and l,2,3,3a-tetrahydropentalene.
  • cycloalkyl group may be unsubstituted or substituted with one or more groups, preferably 1-3 groups independently selected from halogen, hydroxy, (Ci-C 6 )- alkoxy, nitro, cyano, amino, substituted amines, C(O) and C(0) 2 -alkyl.
  • the aryl is (C 6 -Ci 4 )-aryl, which refers to monocyclic or bicyclic hydrocarbon groups having 6 to 14 ring carbon atoms, preferably 6 to 10 carbon atoms in which the carbocyclic ring(s) present have a conjugated pi electron system.
  • Examples of (C 6 -Ci 4 )-aryl residues are phenyl, naphthyl, fluorenyl and anthracenyl.
  • Aryl groups can be unsubstituted or substituted with one or more groups, for example 1, 2, 3, 4 or 5 groups independently selected from halogen, hydroxy, (Ci-C 6 )-alkoxy, nitro, cyano, amino, substituted amines, C(O) and C(0) 2 -alkyl.
  • the heterocyclyl is a 3- to 9- membered saturated or partially unsaturated monocyclic or bicyclic ring system containing one to four identical or different hetero atoms selected from a nitrogen (N), a sulphur (S) or an oxygen (O) atom.
  • Heterocyclyl includes saturated heterocyclic ring systems, which do not contain any double bond. Partially unsaturated heterocyclic ring systems containing at least one double bond, but do not form an aromatic system containing hetero atom.
  • Suitable saturated and partially unsaturated heterocyclic groups include, but are not limited to, aziridine, oxirane, oxiridine, thiirane, oxetane, azetidine, thietane, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, dihydropyran, tetrahydropyran, thio- dihydropyran, thio-tetrahydropyran, piperidine, piperazine, morpholine, 1,3-oxazinane, 1,3-thiazinane, 4,5,6-tetra hydropyrimidine, 2,3-dihydrofuran, dihydrothiene, dihydropyridine, tetrahydro pyridine, isoxazolidine, pyrazolidine, azepane, oxepane, thiepane and azocane.
  • heteroaryl refers to a 5 to 10-membered aromatic monocyclic or bicyclic ring system containing one to four identical or different hetero atoms selected from N, S or an O atom.
  • heteroaryl examples include, but are not limited to pyrrole, pyrazole, imidazole, triazole, pyrazine, furan, thiophene, oxazole, thiazole, benzimidazole, benzoxazole, benzothiazole, benzofuran, indole, indazole, isoindole, isoquinoline, isooxazole, triazine, purine, pyridine, quinoline, oxadiazole, thiene, pyridazine, pyrimidine, isothiazole, quinoxaline (benzopyrazine), tetrazole, azepine, oxepine, thiepine and azocine.
  • the oxidized form of the ring nitrogen atom of the heteroaryl to provide N-oxide is also encompassed.
  • heterocyclic group may be unsubstituted or substituted with one or more groups, preferably 1-3 groups independently selected from halogen, hydroxy, (Ci-C 6 )- alkoxy, nitro, cyano, amino, substituted amines, C(O) and C(0)2-alkyl.
  • R 3 is selected from a group consisting of unsubstituted or substituted alkyl and aryl.
  • the unsubstituted or substituted alkyl is selected from (Ci-C6)-alkyl, which may be a straight-chain or branched chain alkyl; for example, Ci-C 6 for straight chain and C 3 -C 6 for branched chain.
  • Suitable alkyl groups containing from one to ten carbon atoms include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, iso-butyl, sec-butyl, n-pentyl, isopentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, isohexyl, 2-hexyl and 3-hexyl.
  • alkyl groups may be unsubstituted or substituted with one or more substituents.
  • a substituted alkyl refers to a (Ci-C 6 )-alkyl substituted with one or more groups, preferably 1-3 groups, independently selected from halogen, hydroxy, (CrC 6 )- alkoxy, nitro, cyano, amino, substituted amines, C(O) and C(0) 2 -alkyl.
  • the aryl is (C 6 -Ci 4 )-aryl, which refers to monocyclic or bicyclic hydrocarbon groups having 6 to 14 ring carbon atoms, preferably 6 to 10 carbon atoms in which the carbocyclic ring(s) present have a conjugated pi electron system.
  • Examples of (C 6 -Ci 4 )-aryl residues are phenyl, naphthyl, fluorenyl and anthracenyl.
  • Aryl groups can be unsubstituted or substituted with one or more groups, for example 1, 2, 3, 4 or 5 groups independently selected from halogen, hydroxy, (Ci-C 6 )-alkoxy, nitro, cyano, amino, substituted amines, C(O) and C(0) 2 -alkyl.
  • step (a) of the process in the step (a) of the process the said compound of formula II is reacted with orthoformate in the presence of a solvent to yield compound of formula III.
  • the said orthoformate is an alkyl orthoformate.
  • the said alkyl orthoformate is selected from trimethyl orthoformate, triethyl orthoformate, tripropylorthoformate or tributyl orthoformate.
  • the said solvent is selected from a group consisting of ethereal solvents, amide solvents, ketonic solvents, halogenated solvents, dimethyl sulfoxide, toluene, hexane, xylene and acetonitrile or a mixture thereof.
  • the said ethereal solvent is selected from tetrahydrofuran, 2-methyl tetrahydrofuran, dimethyl ether, diethyl ether, di- isopropyl ether, di-n-butyl ether, di-iodopropyl ether, methyl-tert-butyl ether, cyclopentyl methyl ether, dimethoxyethane, diethylene glycol dimethyl ether, dioxane or anisole.
  • the said amide solvent is selected from dimethylformamide, dimethylacetamide, formamide, N-methyl-2- pyrrolidone, N-methylformamide or 2-pyrrolidone.
  • the said ketonic solvent is selected from acetone, methylethyl ketone, cyclohexanone, methyl isobutyl ketone, methyl tert-butyl ketone, diethyl ketone or methyl isopropyl ketone.
  • the said halogenated solvent is selected from dichloromethane, chloroform, carbon tetrachloride or carbon tetrabromide.
  • the reaction in the step (a) of the process, is carried out at a temperature range of 50 °C to 120 °C.
  • the reaction in the step (a) of the process is carried out at a temperature range of 50 °C to 120 °C for 6 h to 20 h.
  • step (b) of the process in the step (b) of the process, the said compound of formula III, obtained in step (a) is treated with compound of formula IV using a catalyst in the presence of a solvent to yield the compound of formula V.
  • the said catalyst is selected from a group consisting of metal alkoxides, metal oxides, metal halides and metal triflates.
  • the said metal is selected from a group consisting of transition metals and inner- transition metals.
  • metal alkoxide include, but are not limited to, aluminium alkoxide, tin alkoxide, titanium alkoxide, scandium alkoxide, zinc alkoxide, zirconium alkoxide and vanadium alkoxide.
  • metal oxides include, but are not limited to aluminium oxide, tin oxide, titanium oxide, scandium oxide, palladium oxide, iron oxide, zinc oxide, zirconium oxide and vanadium oxide.
  • metal halides include, but are not limited to aluminium halide, bismuth halide, boron halide, iron halide, manganese halide, zinc halide, titanium halide and zirconium halide.
  • the said halide of metal halides is selected from chloride, bromide, fluoride or iodide.
  • metal triflates include, but not limited to zinc triflate, ytterbium triflate, yttrium triflate and scandium triflate.
  • the said solvent is selected from a group consisting of ethereal solvents, amide solvents, ketonic solvents, halogenated solvents, dimethyl sulfoxide, toluene, hexane, xylene and acetonitrile or a mixture thereof.
  • the said ethereal solvent is selected from tetrahydrofuran, 2-methyl tetrahydrofuran, dimethyl ether, diethyl ether, di- isopropyl ether, di-n-butyl ether, di-iodopropyl ether, methyl-tert-butyl ether, cyclopentyl methyl ether, dimethoxyethane, diethylene glycol dimethyl ether, dioxane or anisole.
  • the said amide solvent is selected from dimethylformamide, dimethylacetamide, formamide, N-methyl-2- pyrrolidone, N-methylformamide or 2-pyrrolidone.
  • the said ketonic solvent is selected from acetone, methylethyl ketone, cyclohexanone, methyl isobutyl ketone, methyl tert-butyl ketone, diethyl ketone or methyl isopropyl ketone.
  • the said halogenated solvent is selected from dichloromethane, chloroform, carbon tetrachloride or carbon tetrabromide.
  • the reaction in the step (b) of the process the reaction is carried out at a temperature range of 40 °C to 80 °C.
  • the reaction in the step (b) of the process is carried out at a temperature range of 40 °C to 80 °C for 0.5 h to 8 h.
  • step (c) of the process the said compound of formula V, obtained in step (b) is treated with haloacetate in the presence of a base and a solvent to yield compound of formula VI.
  • the said haloacetate in the step (c) of the process is selected from chloroacetate, bromoacetate, fluoroacetate or iodoacetate. In accordance with an embodiment of the present invention, in the step (c) of the process the said haloacetate is selected from alkyl haloacetate having 1 to 6 carbon atoms in the ester group.
  • alkyl haloacetate examples include, but are not limited to, methyl chloroacetate, methyl bromoacetate, methyl iodoacetate, methyl fluoroacetate, ethyl chloroacetate, ethyl bromoacetate, ethyl iodoacetate, ethyl fluoroacetate, n-propyl chloroacetate, n-propyl bromoacetate, propyl iodoacetate, propyl fluoroacetate, n-butyl chloroacetate, n- butyl bromoacetate, isopropyl chloroacetate, isopropyl bromoacetate, t- butyl chloroacetate and t-butylbromoacetate.
  • the said haloacetate in the step (c) of the process is selected from aryl haloacetate having 6 to 14 carbon atoms, in which the carbocyclic ring(s) present have a conjugated pi electron system in the ester group.
  • the said aryl is unsubstituted or substituted.
  • aryl haloacetate examples include, but are not limited to, 4-phenylbutyl chloroacetate, o-butoxyphenyl chloroacetate, benzyl bromoacetate, 4-bromophenyl chloroacetate, tolyl chloroacetate, benzyl iodoacetate, 6-phenylhexyl chloroacetate, xylyl chloroacetate, 2,3-dimethylphenyl iodoacetate, 2,5-dibromophenyl chloroacetate and p- butylphenyl bromoacetate.
  • the said base is selected from a group consisting of metal silylamide, metal hydroxides and metal alkoxides.
  • the said metal silylamide is selected from lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, calcium bis[bis(trimethylsilyl)amide], magnesium bis[bis(trimethylsilyl)amide], titanium tris[bis(trimethylsilyl)amide], manganese bis[bis(trimethylsilyl)amide], manganese tris[bis(trimethylsilyl)amide], zinc bis[bis(trimethylsilyl)amide], iron bis[bis(trimethylsilyl)amide], iron tris[bis(trimethylsilyl)amide] or scandium tris[bis(trimethylsilyl)amide].
  • the said metal of metal hydroxide and metal alkoxide is selected from a group consisting of alkali metals and alkaline earth metals.
  • metal hydroxide examples include, but are not limited to, sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide and calcium hydroxide.
  • metal alkoxides include, but are not limited to, sodium alkoxide, potassium alkoxide, lithium alkoxide, magnesium alkoxide and calcium alkoxide.
  • the process for preparation of compound of formula VI from compound of formula V can optionally be carried out in the presence of a phase transfer catalyst selected from the group consisting of a quaternary ammonium salt and a quaternary phosphonium salt.
  • quaternary ammonium salt phase transfer catalyst examples include, but are not limited to benzyltriethylammonium halide, hexadecyltrimethylammonium halide, tetrabutylammonium halide, tetramethylammonium halide and tetraethylammonium halide or a mixture thereof.
  • quaternary phosphonium salt phase transfer catalyst include, but are not limited to tetra-n-butyl-phosphonium chloride, tetraphenylphosphonium bromide, tetraphenylphosphonium chloride, triphenylmethylphosphonium bromide and triphenylmethylphosphonium chloride or a mixture thereof.
  • the said solvent is selected from a group consisting of ethereal solvents, amide solvents, ketonic solvents, halogenated solvents, dimethyl sulfoxide, toluene, hexane, xylene and acetonitrile or a mixture thereof.
  • the said ethereal solvent is selected from tetrahydrofuran, 2-methyl tetrahydrofuran, dimethyl ether, diethyl ether, di- isopropyl ether, di-n-butyl ether, di-iodopropyl ether, methyl-tert-butyl ether, cyclopentyl methyl ether, dimethoxyethane, diethylene glycol dimethyl ether, dioxane or anisole.
  • the said amide solvent is selected from dimethylformamide, dimethylacetamide, formamide, N-methyl-2- pyrrolidone, N-methylformamide or 2-pyrrolidone.
  • the said ketonic solvent is selected from acetone, methylethyl ketone, cyclohexanone, methyl isobutyl ketone, methyl tert-butyl ketone, diethyl ketone or methyl isopropyl ketone.
  • the said halogenated solvent is selected from dichloromethane, chloroform, carbon tetrachloride or carbon tetrabromide.
  • the reaction in the step (c) of the process is carried out at a temperature range of -78 °C to 25 °C.
  • the reaction in the step (c) of the process is carried out at a temperature range of -78 °C to 25 °C for 0.5 h to 5 h.
  • the step (c) of the process comprises reaction of compound of formula V with haloacetate in the presence of a base to yield compound of formula VI.
  • the formation of compound of formula VI is a stereoselective reaction, wherein the desired R,R-isomer of formula VI is exclusively formed.
  • the reaction may result into a S,S-isomer to some extent.
  • the compound of formula VI, as R,R-isomer plays a crucial role in the reaction.
  • S,S-isomer may contaminate the desired isomer in the subsequent steps of the preparation of droxidopa.
  • the formation of undesired S,S-isomer in the reaction may require additional step of purification for removal and to avoid any impurities formation.
  • the said compound of formula VI, obtained in step (c) is treated with an acid in the presence of a solvent to yield compound of formula I.
  • the said acid is selected from a group consisting of inorganic acid and organic acid.
  • the said inorganic acid is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid or sulphuric acid.
  • the said organic acid is selected from acetic acid, formic acid, oxalic acid, trifluoroacetic acid, maleic acid, succinic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, mandelic acid, /?-toluenesulphonic acid, methanesulphonic acid, trifluoromethanesulphonic acid, phenylsulfinic acid, benzenesulphonic acid, benzoic acid, nitrobenzoic acid or naphthalenedisulphonic acid.
  • the acid in the step (d) of the process may be used in the acid form or as a solution of acid in a solvent.
  • the said solvent is selected from water or an organic solvent or a mixture thereof.
  • the said organic solvent is selected from alcohol, ether or a mixture thereof.
  • the ether solvent may be selected from tetrahydrofuran, 2-methyl tetrahydrofuran, dimethyl ether, diethyl ether, di-isopropyl ether, di-n-butyl ether, di-iodopropyl ether, methyl-tert-butyl ether, cyclopentyl methyl ether, dimethoxyethane, diethylene glycol dimethyl ether, dioxane or anisole or a mixture thereof.
  • the alcohol may be selected from methanol, ethanol, isopropanol or n-butanol or a mixture thereof.
  • the said solvent is selected from a group consisting of ethereal solvents, amide solvents, ketonic solvents, halogenated solvents, dimethyl sulfoxide, toluene, hexane, xylene and acetonitrile or a mixture thereof.
  • the said ethereal solvent is selected from tetrahydrofuran, 2-methyl tetrahydrofuran, dimethyl ether, diethyl ether, di- isopropyl ether, di-n-butyl ether, di-iodopropyl ether, methyl-tert-butyl ether, cyclopentyl methyl ether, dimethoxyethane, diethylene glycol dimethyl ether, dioxane or anisole.
  • the said amide solvent is selected from dimethylformamide, dimethylacetamide, formamide, N-methyl-2- pyrrolidone, N-methylformamide or 2-pyrrolidone.
  • the said ketonic solvent is selected from acetone, methylethyl ketone, cyclohexanone, methyl isobutyl ketone, methyl tert-butyl ketone, diethyl ketone or methyl isopropyl ketone.
  • the said halogenated solvent is selected from dichloromethane, chloroform, carbon tetrachloride or carbon tetrabromide.
  • the reaction in the step (d) of the process is carried out at a temperature range of 0 °C to 50 °C.
  • step (d) of the process the reaction is carried out at a temperature range of 0 °C to 50 °C for 10 h to 20 h.
  • step (d) of the process only the desired isomer is obtained in a very high yield of greater than 95 %), which is specific to the reaction condition and substrate.
  • the SN (nucleophilic substitution) aziridine ring opening reaction occurs predominantly, which depends on the reaction conditions and is substrate-specific. Therefore, step (d) of the process involves an asymmetric induction reaction and constitutes the key step in the process for the preparation of droxidopa.

Abstract

The present invention provides a novel process for the preparation of droxidopa, a synthetic amino acid precursor of norepinephrine. The process is a stereoselective process for the preparation of droxidopa using asymmetric induction and thus avoids synthetic process involving chiral resolution. The present invention also provides novel intermediates of formula III, formula V and formula VI.

Description

PROCESS FOR THE PREPARATION OF DROXIDOPA
Field of the invention
The present invention relates to a process for the preparation of (2S,3 ?)-2-amino-3-(3,4- dihydroxyphenyl)-3-hydroxypropanoic acid, which is known as Droxidopa, a synthetic amino acid precursor of norepinephrine. The present invention also relates to novel intermediates for the preparation of Droxidopa.
Background of the invention Droxidopa is chemically known as (2S,3 ?)-2-amino-3-(3,4-dihydroxyphenyl)-3- hydroxypropanoic acid and it is structurally represented by the following formula I. It is also known as L-i/zreo-dihydroxyphenylserine. Droxidopa is available in the market as Northera® capsules with dosages of 100 mg, 200 mg and 300 mg for oral administration.
Figure imgf000002_0001
Droxidopa (Formula I)
Droxidopa is an orally active, synthetic norepinephrine precursor that was originally launched in 1989 in Japan by Sumitomo Dainippon Pharma for the oral treatment of frozen gait or dizziness associated with Parkinson's disease and for the treatment of orthostatic hypotension, syncope or dizziness associated with Shy-Drager syndrome and familial amyloidotic polyneuropathy. In 2011, the product was filed for approval in the U.S. and in 2014 Northera® is approved for the treatment of orthostatic dizziness, light headedness, or the "feeling that you are about to black out" in adult patients with symptomatic neurogenic orthostatic hypotension caused by primary autonomic failure, dopamine beta-hydroxylase deficiency, and non-diabetic autonomic neuropathy. Droxidopa is a synthetic amino acid analog that is directly metabolized to norepinephrine by dopadecarboxylase, which is extensively distributed throughout the body. Chirality has acquired increasing importance for the pharmaceutical industry, as evidenced by the fact that more than 80% of the drugs developed hitherto have chiral properties. The various enantiomers may develop completely different effects in the body, so that only one of two or more enantiomeric forms administered may be effective. In the case of droxidopa, the compound of formula I, it has been observed that the h-threo enantiomer is the desired isomer having desired activity. Administration of the active h-threo enantiomer of the compound of formula I, substantially free of its other isomers, would essentially enable a reduction in the dose of drug. Due to the importance of the h-threo enantiomer of the compound of formula I as an oral, synthetic norepinephrine precursor, there exists a need to develop an economical and efficient synthetic process for its production. Droxidopa is disclosed in US Patent No. 3,920,728 (hereinafter referred to as US'728 patent). The US'728 patent also provides a process for the preparation of droxidopa comprising the steps of (i) reaction of 3,4-dibenzyloxybenzaldehyde with glycine, followed by treatment with sodium acetate trihydrate and diethylamine to obtain racemic- i zreo/er i zro-3-(3,4-dibenzyloxyphenyl)-serine; (ii) treatment of the compound obtained in step (i) with carbobenzoxy chloride to obtain racemic-threo/erythro-3-(3,4- dibenzyloxyphenyl)-N-carbobenzoxyserine; (iii) treatment of the compound obtained in step (ii) with freshly distilled dicyclohexylamine to obtain racemic-i/zreo-3-(3,4- dibenzyloxyphenyl)-N-carbobenzoxyserinedicyclohexylamine salt, which on treatment with HC1 gas in the presence of ethyl acetate yields racemic-i/zreo-3-(3,4- dibenzyloxyphenyl)-N-carbobenzoxyserine; (iv) treatment of the compound obtained in step (iii) with (+)-ephedrine to yield (+)-ephedrine salt of h-threo-3-(3,4- dibenzyloxyphenyl)-N-carbobenzoxyserine; (v) hydrolysis of the compound obtained in step (iv) to yield L-i/zreo-3-(3,4-dibenzyloxyphenyl)-N-carbobenzoxyserine and (vi) reduction of the compound obtained in step (v) over Pd/C to yield h-threo-3-(3,4- dibenzyloxyphenyl)-serine. The process disclosed in US'728 patent is an elaborate and tedious process for commercial manufacturing. Also, the chiral resolution to obtain threo/ erythro isomer results into 50% loss of the undesired isomer, which affects the overall yield of the process. The US Patent No. 4,319,040 discloses a process for preparation of droxidopa comprising reaction of racemic i/zreo-3-(3,4-dibenzyloxyphenyl)-N-carbobenzoxyserine with resolving agent of formula A, followed by decomposition using hydrochloric acid to yield (-)-3-(3,4- dibenzyloxyphenyl) -N-c arbobenzoxy serine .
Figure imgf000004_0001
Formula A wherein R is methyl, isopropyl or isobutyl
The US Patent No. 4,562,263 (hereinafter referred to as US'263 patent) discloses a process for preparation of droxidopa comprising optical resolution of N-phthaloyl-3-(3,4- methylenedioxyphenyl) serine using optically active amine selected from the group consisting of strychinine, cinconidine, L-norephedrine, S-2-amino-l,l-diphenyl-l-propanol and L-3-hydroxy-3-(4-nitrophenyl)-2-amino-l-propanol to yield L-N-phthaloyl-3-(3,4- methylenedioxyphenyl) serine, reacting the resulting compound with a Lewis acid selected from the group consisting of aluminium trichloride, aluminium tribromide, boron trichloride and boron tribromide to form N-phthaloyl-3-(3,4-dihydroxyphenyl)-serine; which is then deprotected by removal of phthaloyl group with hydrazine to yield L-threo- 3-(3,4-dihydroxyphenyl)-serine. The process involves use of complex agents for isomer separation, which also results in < 50 % of desired isomer. Also, the hydrazine used for the deprotection of phthaloyl group is known to be genotoxic and thus it is required to remove traces of hydrazine from the final product, droxidopa. However, the limitation of the process described in US'263 patent is that it is unable to remove traces of hydrazine.
The prior art processes for the preparation of droxidopa involve a resolution method involving significant processing. The use of resolving agent renders the process costly. Partial recycling of the resolving agent is feasible but such recycling is costly as it requires additional processing and is also associated with waste generation. The undesired enantiomer cannot be recycled and is discarded. The maximum theoretical yield of the key intermediate obtained is just 50 % on a laboratory scale synthesis due to loss of half of the racemate. This yield may be further reduced due to the need for high chiral purity (> 95% enantiomeric excess). Thus, there is a clear need to develop an alternative asymmetric synthesis which would provide the desired L-threo isomer in an efficient and more specific manner. The said prior art processes are therefore disadvantageous for commercial manufacturing due to non-feasibility of the reaction process owing to use of genotoxic reagents, and due to the elaborate and tedious nature of the process, providing low yield of the desired isomer.
Thus, there is a need to develop a process for preparation of droxidopa, which avoids the synthetic process involving chiral resolution to obtain desired L-threo isomer, thereby making the process of the present invention simple, efficient, cost-effective and industrially feasible process. The object of this invention is to provide an alternative process for the preparation of the L-threo isomer of droxidopa, the compound represented by formula I, which is an enantioselective process. The process of the present invention allows efficient large-scale synthesis by overcoming the drawbacks of the conventional resolution technique.
Objects of the invention
An object of the present invention is to provide a process for the preparation of L-threo- dihydroxyphenylserine (droxidopa) represented by formula I, which improves upon the limitations of the prior art process.
An object of the present invention is to provide a stereoselective process for the preparation of droxidopa using asymmetric induction, thereby avoiding synthetic process involving chiral resolution.
An object of the present invention is to provide a process for the preparation of droxidopa involving novel intermediates of formula III, formula V and formula VI. An object of the present invention is to provide novel intermediates of formula III, formula V and formula VI and a process for their preparation.
Another object of the present invention is to provide a process for preparation of droxidopa, wherein the desired -threo isomer is obtained with selectivity > 95 %.
Still another object of the present invention is to provide a process for the preparation of doxidropa which is simple, efficient, cost-effective and industrially feasible process. Summary of the invention
In accordance with an aspect of the present invention, there is provided a process for the preparation of L-i/zreo-dihydroxyphenylserine (droxidopa) represented by formula I comprising the steps of: a) reacting compound of formula II with orthoformate in the presence of a solvent to yield compound of formula III; b) reacting the compound of formula III, obtained in step (a) with a compound of formula IV using a catalyst in the presence of a solvent to yield compound of formula V; c) reacting the compound of formula V, obtained in step (b) with haloacetate in the presence of a base and a solvent to yield compound of formula VI; d) reacting the compound of formula VI, obtained in step (c) with an acid in the presence of a solvent to yield the compound of formula I.
The process of the present invention is depicted in the following scheme:
Step a Step b
Catalyst
Figure imgf000006_0001
solvent Solvent
Formula II Formula III Formula IV
Figure imgf000006_0002
Formula V
Formula VI
Figure imgf000006_0003
(Droxidopa) wherein Ri and R2 are independently selected from a group consisting of unsubstituted or substituted alkyl, cycloalkyl, aryl and heterocyclyl; and
R3 is selected from a group consisting of unsubstituted or substituted alkyl and aryl. In accordance with another aspect of the present invention, there is provided a novel intermediate of formula III,
Figure imgf000007_0001
Formula III
wherein Ri is as defined herein.
In accordance with the another aspect of the present invention, there is provided a novel intermediate of formula V,
Figure imgf000007_0002
Formula V
wherein Ri and R2 are as defined herein.
In accordance with the another aspect of the present invention, there is provided a novel intermediate of formula VI,
Figure imgf000007_0003
Formula VI
wherein Ri, R2 and R3 are as defined herein. In accordance with another aspect of the present invention, there is provided a process for the preparation of novel intermediates of formula III, formula V and formula VI.
In accordance with another aspect of the present invention, the process of the present invention overcomes the disadvantages associated with the processes described in the prior art references, which is mainly concerned with the use of a synthetic process involving chiral resolution using chiral resolving agents to obtain desired L-threo isomer, wherein the selectivity to separate the desired isomer is very low. Also, the processes described in the prior arts teach the use of genotoxic reagents; and are elaborate and tedious processes. The process of the present invention is a stereoselective process utilizing asymmetric induction involving novel intermediates to obtain desired h-threo isomer in droxidopa with selectivity > 95 %, thereby making the process of the present invention simple, efficient, cost-effective and industrially applicable.
Detailed description of the invention
The present invention relates to a process for the preparation of L-threo- dihydroxyphenylserine (droxidopa) of formula I
Figure imgf000008_0001
Formula I
comprising the steps of:
a) reacting compound of formula II
Figure imgf000008_0002
Formula II with orthoformate in the presence of a solvent to yield compound of formula III,
Figure imgf000008_0003
Formula III
wherein Ri is as defined herein; reacting the compound of formula III, obtained in step (a) with compound of formula IV
O
H2N * R2
Formula IV
wherein R2 is as defined herein; using a catalyst in the p ound of formula V,
Figure imgf000009_0001
Formula V
wherein Ri and R2 are as defined herein; reacting the compound of formula V, obtained in step (b) with haloacetate presence of a base and a solvent to yield compound of formula VI,
Figure imgf000009_0002
Formula VI
wherein Ri, R2 and R3 are as defined herein; d) reacting the compound of formula VI, obtained in step (c) with an acid in the presence of a solvent to yield compound of formula I.
The present invention relates to a co
Figure imgf000009_0003
Formula III wherein Ri is selected from a group consisting of unsubstituted or substituted alkyl, alkoxy, cycloalkyl, aryl and heterocyclyl.
The present invention also relates to a process for the preparation of compound of formula in,
Figure imgf000009_0004
Formula III wherein Ri is as defined herein; comprising reacting compound of formula II
Figure imgf000010_0001
Formula II
with orthoformate in the presence of a solvent to yield compound of formula III. The present invention relates to a compound of formula V,
Figure imgf000010_0002
Formula V
wherein Ri and R2 are independently selected from a group consisting of unsubstituted or substituted alkyl, cycloalkyl, aryl and heterocyclyl.
The present invention also relates to a process for the preparation of compound of formula V,
Figure imgf000010_0003
Formula V
wherein Ri and R2 are as defined herein; comprising the steps of:
a) reacting compound of formula II
Figure imgf000010_0004
Formula II with orthoformate in the presence of a solvent to yield compound of formula III,
Figure imgf000011_0001
Formula III
wherein Ri is as defined herein; reacting the compound of formula III, obtained in step (a) with compound of formula IV
O II
H2N * R2
Formula IV
wherein R2 is as defined herein;
using a catalyst in the presence of a solvent to yield the compound of formula V.
The present invention relates to a compound of formula VI,
Figure imgf000011_0002
Formula VI wherein Ri and R2 are independently selected from a group consisting of unsubstituted or substituted alkyl, cycloalkyl, aryl and heterocyclyl; and
R3 is selected from a group consisting of unsubstituted or substituted alkyl and aryl.
The present invention also relates to a process for the preparation of compound of formula VI
Figure imgf000011_0003
Formula VI
wherein Ri, R2 and R3 are as defined herein, comprising reacting the compound of formula V
Figure imgf000012_0001
Formula V
wherein Ri and R2 are as defined herein,
with haloacetate in the presence of a base and a solvent to yield the compound of formula VI.
The present invention relates to a process for the preparation of compound of formula I
Figure imgf000012_0002
Formula I comprising reacting the compound of formula VI
Figure imgf000012_0003
Formula VI
wherein Ri, R2 and R3 are as defined herein,
with an acid in the presence of a solvent to yield the compound of formula I.
In accordance with the embodiments of the present invention Ri and R2 are independently selected from a group consisting of unsubstituted or substituted alkyl, cycloalkyl, aryl and heterocyclyl.
In accordance with the embodiments of the present invention, the unsubstituted or substituted alkyl is (Ci-Cio)-alkyl, which may be a straight-chain or branched chain alkyl; for example, Ci-Cio for straight chain and C3-Cio for branched chain. Suitable alkyl groups containing from one to ten carbon atoms, include, but are not limited to, methyl, ethyl, n- propyl, isopropyl, n-butyl, t-butyl, iso-butyl, sec-butyl, n-pentyl, isopentyl, 2-pentyl, 3- pentyl, neo-pentyl, n-hexyl, isohexyl, 2-hexyl, 3-hexyl, n-heptyl, isoheptyl, 2-heptyl, 3- heptyl, n-octyl, isooctyl, 2-octyl, 3-octyl, n-nonyl, isononyl, 2-nonyl, 3-nonyl, n-decyl, isodecyl, 2-decyl and 3-decyl.
Furthermore, the alkyl groups may be unsubstituted or substituted with one or more substituents. A substituted alkyl refers to a (Ci-Cio)-alkyl substituted with one or more groups, preferably 1-3 groups, independently selected from halogen, hydroxy, (Ci-C6)- alkoxy, nitro, cyano, amino, substituted amines, C(O) and C(0)2-alkyl.
In accordance with the embodiments of the present invention, the cycloalkyl is (C3-C12)- cycloalkyl, wherein a saturated or partially unsaturated cyclic hydrocarbon radical including 1, 2 or 3 rings and including a total of 3 to 12 carbon atoms forming the rings. The term cycloalkyl includes bridged, fused and spiro ring systems. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, norbornyl, bicyclo[2.1.0]pentane, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]hept-2- ene, spiro[3.3]heptanes and l,2,3,3a-tetrahydropentalene.
Furthermore, the cycloalkyl group may be unsubstituted or substituted with one or more groups, preferably 1-3 groups independently selected from halogen, hydroxy, (Ci-C6)- alkoxy, nitro, cyano, amino, substituted amines, C(O) and C(0)2-alkyl.
In accordance with the embodiments of the present invention, the aryl is (C6-Ci4)-aryl, which refers to monocyclic or bicyclic hydrocarbon groups having 6 to 14 ring carbon atoms, preferably 6 to 10 carbon atoms in which the carbocyclic ring(s) present have a conjugated pi electron system. Examples of (C6-Ci4)-aryl residues are phenyl, naphthyl, fluorenyl and anthracenyl. Aryl groups can be unsubstituted or substituted with one or more groups, for example 1, 2, 3, 4 or 5 groups independently selected from halogen, hydroxy, (Ci-C6)-alkoxy, nitro, cyano, amino, substituted amines, C(O) and C(0)2-alkyl.
In accordance with the embodiments of the present invention, the heterocyclyl is a 3- to 9- membered saturated or partially unsaturated monocyclic or bicyclic ring system containing one to four identical or different hetero atoms selected from a nitrogen (N), a sulphur (S) or an oxygen (O) atom. Heterocyclyl includes saturated heterocyclic ring systems, which do not contain any double bond. Partially unsaturated heterocyclic ring systems containing at least one double bond, but do not form an aromatic system containing hetero atom. Suitable saturated and partially unsaturated heterocyclic groups include, but are not limited to, aziridine, oxirane, oxiridine, thiirane, oxetane, azetidine, thietane, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, dihydropyran, tetrahydropyran, thio- dihydropyran, thio-tetrahydropyran, piperidine, piperazine, morpholine, 1,3-oxazinane, 1,3-thiazinane, 4,5,6-tetra hydropyrimidine, 2,3-dihydrofuran, dihydrothiene, dihydropyridine, tetrahydro pyridine, isoxazolidine, pyrazolidine, azepane, oxepane, thiepane and azocane.
Further, the heterocyclyl having an aromatic ring containing heteroatom/s are herein referred to by the customary term "heteroaryl". Within the context of the present invention and as used herein, the term "heteroaryl" refers to a 5 to 10-membered aromatic monocyclic or bicyclic ring system containing one to four identical or different hetero atoms selected from N, S or an O atom. Examples of heteroaryl include, but are not limited to pyrrole, pyrazole, imidazole, triazole, pyrazine, furan, thiophene, oxazole, thiazole, benzimidazole, benzoxazole, benzothiazole, benzofuran, indole, indazole, isoindole, isoquinoline, isooxazole, triazine, purine, pyridine, quinoline, oxadiazole, thiene, pyridazine, pyrimidine, isothiazole, quinoxaline (benzopyrazine), tetrazole, azepine, oxepine, thiepine and azocine. The oxidized form of the ring nitrogen atom of the heteroaryl to provide N-oxide is also encompassed.
Furthermore, the heterocyclic group may be unsubstituted or substituted with one or more groups, preferably 1-3 groups independently selected from halogen, hydroxy, (Ci-C6)- alkoxy, nitro, cyano, amino, substituted amines, C(O) and C(0)2-alkyl.
In accordance with the embodiments of the present invention, R3 is selected from a group consisting of unsubstituted or substituted alkyl and aryl. In accordance with the embodiments of the present invention, the unsubstituted or substituted alkyl is selected from (Ci-C6)-alkyl, which may be a straight-chain or branched chain alkyl; for example, Ci-C6 for straight chain and C3-C6 for branched chain. Suitable alkyl groups containing from one to ten carbon atoms, include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, iso-butyl, sec-butyl, n-pentyl, isopentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, isohexyl, 2-hexyl and 3-hexyl.
Furthermore, the alkyl groups may be unsubstituted or substituted with one or more substituents. A substituted alkyl refers to a (Ci-C6)-alkyl substituted with one or more groups, preferably 1-3 groups, independently selected from halogen, hydroxy, (CrC6)- alkoxy, nitro, cyano, amino, substituted amines, C(O) and C(0)2-alkyl.
In accordance with the embodiments of the present invention, the aryl is (C6-Ci4)-aryl, which refers to monocyclic or bicyclic hydrocarbon groups having 6 to 14 ring carbon atoms, preferably 6 to 10 carbon atoms in which the carbocyclic ring(s) present have a conjugated pi electron system. Examples of (C6-Ci4)-aryl residues are phenyl, naphthyl, fluorenyl and anthracenyl. Aryl groups can be unsubstituted or substituted with one or more groups, for example 1, 2, 3, 4 or 5 groups independently selected from halogen, hydroxy, (Ci-C6)-alkoxy, nitro, cyano, amino, substituted amines, C(O) and C(0)2-alkyl.
In an embodiment of the present invention, in the step (a) of the process the said compound of formula II is reacted with orthoformate in the presence of a solvent to yield compound of formula III.
In accordance with an embodiment of the present invention, in the step (a) of the process the said orthoformate is an alkyl orthoformate.
In accordance with an embodiment of the present invention, the said alkyl orthoformate is selected from trimethyl orthoformate, triethyl orthoformate, tripropylorthoformate or tributyl orthoformate.In accordance with an embodiment of the present invention, in the step (a) of the process the said solvent is selected from a group consisting of ethereal solvents, amide solvents, ketonic solvents, halogenated solvents, dimethyl sulfoxide, toluene, hexane, xylene and acetonitrile or a mixture thereof.
In accordance with an embodiment of the present invention, the said ethereal solvent is selected from tetrahydrofuran, 2-methyl tetrahydrofuran, dimethyl ether, diethyl ether, di- isopropyl ether, di-n-butyl ether, di-iodopropyl ether, methyl-tert-butyl ether, cyclopentyl methyl ether, dimethoxyethane, diethylene glycol dimethyl ether, dioxane or anisole. In accordance with an embodiment of the present invention, the said amide solvent is selected from dimethylformamide, dimethylacetamide, formamide, N-methyl-2- pyrrolidone, N-methylformamide or 2-pyrrolidone.
In accordance with an embodiment of the present invention, the said ketonic solvent is selected from acetone, methylethyl ketone, cyclohexanone, methyl isobutyl ketone, methyl tert-butyl ketone, diethyl ketone or methyl isopropyl ketone. In accordance with an embodiment of the present invention, the said halogenated solvent is selected from dichloromethane, chloroform, carbon tetrachloride or carbon tetrabromide.
In accordance with an embodiment of the present invention, in the step (a) of the process, the reaction is carried out at a temperature range of 50 °C to 120 °C.
In accordance with an embodiment of the present invention, in the step (a) of the process the reaction is carried out at a temperature range of 50 °C to 120 °C for 6 h to 20 h.
In an embodiment of the present invention, in the step (b) of the process, the said compound of formula III, obtained in step (a) is treated with compound of formula IV using a catalyst in the presence of a solvent to yield the compound of formula V.
In accordance with an embodiment of the present invention, in the step (b) of the process the said catalyst is selected from a group consisting of metal alkoxides, metal oxides, metal halides and metal triflates.
In accordance with an embodiment of the present invention, the said metal is selected from a group consisting of transition metals and inner- transition metals. The examples of metal alkoxide include, but are not limited to, aluminium alkoxide, tin alkoxide, titanium alkoxide, scandium alkoxide, zinc alkoxide, zirconium alkoxide and vanadium alkoxide. The examples of metal oxides include, but are not limited to aluminium oxide, tin oxide, titanium oxide, scandium oxide, palladium oxide, iron oxide, zinc oxide, zirconium oxide and vanadium oxide. The examples of metal halides include, but are not limited to aluminium halide, bismuth halide, boron halide, iron halide, manganese halide, zinc halide, titanium halide and zirconium halide.
In accordance with an embodiment of the present invention, the said halide of metal halides is selected from chloride, bromide, fluoride or iodide.
The examples of metal triflates include, but not limited to zinc triflate, ytterbium triflate, yttrium triflate and scandium triflate. In accordance with an embodiment of the present invention, in the step (b) of the process the said solvent is selected from a group consisting of ethereal solvents, amide solvents, ketonic solvents, halogenated solvents, dimethyl sulfoxide, toluene, hexane, xylene and acetonitrile or a mixture thereof. In accordance with an embodiment of the present invention, the said ethereal solvent is selected from tetrahydrofuran, 2-methyl tetrahydrofuran, dimethyl ether, diethyl ether, di- isopropyl ether, di-n-butyl ether, di-iodopropyl ether, methyl-tert-butyl ether, cyclopentyl methyl ether, dimethoxyethane, diethylene glycol dimethyl ether, dioxane or anisole. In accordance with an embodiment of the present invention, the said amide solvent is selected from dimethylformamide, dimethylacetamide, formamide, N-methyl-2- pyrrolidone, N-methylformamide or 2-pyrrolidone.
In accordance with an embodiment of the present invention, the said ketonic solvent is selected from acetone, methylethyl ketone, cyclohexanone, methyl isobutyl ketone, methyl tert-butyl ketone, diethyl ketone or methyl isopropyl ketone.
In accordance with an embodiment of the present invention, the said halogenated solvent is selected from dichloromethane, chloroform, carbon tetrachloride or carbon tetrabromide. In accordance with an embodiment of the present invention, in the step (b) of the process the reaction is carried out at a temperature range of 40 °C to 80 °C.
In accordance with an embodiment of the present invention, in the step (b) of the process the reaction is carried out at a temperature range of 40 °C to 80 °C for 0.5 h to 8 h.
In an embodiment of the present invention, in the step (c) of the process, the said compound of formula V, obtained in step (b) is treated with haloacetate in the presence of a base and a solvent to yield compound of formula VI.
In accordance with an embodiment of the present invention, in the step (c) of the process the said haloacetate is selected from chloroacetate, bromoacetate, fluoroacetate or iodoacetate. In accordance with an embodiment of the present invention, in the step (c) of the process the said haloacetate is selected from alkyl haloacetate having 1 to 6 carbon atoms in the ester group.
The examples of said alkyl haloacetate include, but are not limited to, methyl chloroacetate, methyl bromoacetate, methyl iodoacetate, methyl fluoroacetate, ethyl chloroacetate, ethyl bromoacetate, ethyl iodoacetate, ethyl fluoroacetate, n-propyl chloroacetate, n-propyl bromoacetate, propyl iodoacetate, propyl fluoroacetate, n-butyl chloroacetate, n- butyl bromoacetate, isopropyl chloroacetate, isopropyl bromoacetate, t- butyl chloroacetate and t-butylbromoacetate.
In accordance with an embodiment of the present invention, in the step (c) of the process the said haloacetate is selected from aryl haloacetate having 6 to 14 carbon atoms, in which the carbocyclic ring(s) present have a conjugated pi electron system in the ester group. In accordance with an embodiment of the present invention, the said aryl is unsubstituted or substituted.
The examples of said aryl haloacetate include, but are not limited to, 4-phenylbutyl chloroacetate, o-butoxyphenyl chloroacetate, benzyl bromoacetate, 4-bromophenyl chloroacetate, tolyl chloroacetate, benzyl iodoacetate, 6-phenylhexyl chloroacetate, xylyl chloroacetate, 2,3-dimethylphenyl iodoacetate, 2,5-dibromophenyl chloroacetate and p- butylphenyl bromoacetate. In accordance with an embodiment of the present invention, in the step (c) of the process the said base is selected from a group consisting of metal silylamide, metal hydroxides and metal alkoxides.
In accordance with an embodiment of the present invention, the said metal silylamide is selected from lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, calcium bis[bis(trimethylsilyl)amide], magnesium bis[bis(trimethylsilyl)amide], titanium tris[bis(trimethylsilyl)amide], manganese bis[bis(trimethylsilyl)amide], manganese tris[bis(trimethylsilyl)amide], zinc bis[bis(trimethylsilyl)amide], iron bis[bis(trimethylsilyl)amide], iron tris[bis(trimethylsilyl)amide] or scandium tris[bis(trimethylsilyl)amide].
In accordance with an embodiment of the present invention, the said metal of metal hydroxide and metal alkoxide is selected from a group consisting of alkali metals and alkaline earth metals.
The examples of metal hydroxide include, but are not limited to, sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide and calcium hydroxide.
The examples of metal alkoxides include, but are not limited to, sodium alkoxide, potassium alkoxide, lithium alkoxide, magnesium alkoxide and calcium alkoxide.
The process for preparation of compound of formula VI from compound of formula V can optionally be carried out in the presence of a phase transfer catalyst selected from the group consisting of a quaternary ammonium salt and a quaternary phosphonium salt.
The examples of quaternary ammonium salt phase transfer catalyst include, but are not limited to benzyltriethylammonium halide, hexadecyltrimethylammonium halide, tetrabutylammonium halide, tetramethylammonium halide and tetraethylammonium halide or a mixture thereof. The examples of quaternary phosphonium salt phase transfer catalyst include, but are not limited to tetra-n-butyl-phosphonium chloride, tetraphenylphosphonium bromide, tetraphenylphosphonium chloride, triphenylmethylphosphonium bromide and triphenylmethylphosphonium chloride or a mixture thereof.
In accordance with an embodiment of the present invention, in the step (c) of the process the said solvent is selected from a group consisting of ethereal solvents, amide solvents, ketonic solvents, halogenated solvents, dimethyl sulfoxide, toluene, hexane, xylene and acetonitrile or a mixture thereof.
In accordance with an embodiment of the present invention, the said ethereal solvent is selected from tetrahydrofuran, 2-methyl tetrahydrofuran, dimethyl ether, diethyl ether, di- isopropyl ether, di-n-butyl ether, di-iodopropyl ether, methyl-tert-butyl ether, cyclopentyl methyl ether, dimethoxyethane, diethylene glycol dimethyl ether, dioxane or anisole.
In accordance with an embodiment of the present invention, the said amide solvent is selected from dimethylformamide, dimethylacetamide, formamide, N-methyl-2- pyrrolidone, N-methylformamide or 2-pyrrolidone.
In accordance with an embodiment of the present invention, the said ketonic solvent is selected from acetone, methylethyl ketone, cyclohexanone, methyl isobutyl ketone, methyl tert-butyl ketone, diethyl ketone or methyl isopropyl ketone. In accordance with an embodiment of the present invention, the said halogenated solvent is selected from dichloromethane, chloroform, carbon tetrachloride or carbon tetrabromide.
In accordance with an embodiment of the present invention, in the step (c) of the process the reaction is carried out at a temperature range of -78 °C to 25 °C.
In accordance with an embodiment of the present invention, in the step (c) of the process the reaction is carried out at a temperature range of -78 °C to 25 °C for 0.5 h to 5 h. The step (c) of the process comprises reaction of compound of formula V with haloacetate in the presence of a base to yield compound of formula VI. The formation of compound of formula VI is a stereoselective reaction, wherein the desired R,R-isomer of formula VI is exclusively formed. The reaction may result into a S,S-isomer to some extent. The compound of formula VI, as R,R-isomer plays a crucial role in the reaction. The presence of S,S-isomer in the reaction mixture may contaminate the desired isomer in the subsequent steps of the preparation of droxidopa. The formation of undesired S,S-isomer in the reaction may require additional step of purification for removal and to avoid any impurities formation.
In an embodiment of the present invention, in the step (d) of the process, the said compound of formula VI, obtained in step (c) is treated with an acid in the presence of a solvent to yield compound of formula I. In accordance with an embodiment of the present invention, in the step (d) of the process the said acid is selected from a group consisting of inorganic acid and organic acid.
In accordance with an embodiment of the present invention, the said inorganic acid is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid or sulphuric acid.
In accordance with an embodiment of the present invention, the said organic acid is selected from acetic acid, formic acid, oxalic acid, trifluoroacetic acid, maleic acid, succinic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, mandelic acid, /?-toluenesulphonic acid, methanesulphonic acid, trifluoromethanesulphonic acid, phenylsulfinic acid, benzenesulphonic acid, benzoic acid, nitrobenzoic acid or naphthalenedisulphonic acid.
In accordance with an embodiment of the present invention, in the step (d) of the process the acid may be used in the acid form or as a solution of acid in a solvent. The said solvent is selected from water or an organic solvent or a mixture thereof. The said organic solvent is selected from alcohol, ether or a mixture thereof.
The ether solvent may be selected from tetrahydrofuran, 2-methyl tetrahydrofuran, dimethyl ether, diethyl ether, di-isopropyl ether, di-n-butyl ether, di-iodopropyl ether, methyl-tert-butyl ether, cyclopentyl methyl ether, dimethoxyethane, diethylene glycol dimethyl ether, dioxane or anisole or a mixture thereof.
The alcohol may be selected from methanol, ethanol, isopropanol or n-butanol or a mixture thereof.
In accordance with an embodiment of the present invention, in the step (d) of the process the said solvent is selected from a group consisting of ethereal solvents, amide solvents, ketonic solvents, halogenated solvents, dimethyl sulfoxide, toluene, hexane, xylene and acetonitrile or a mixture thereof.
In accordance with an embodiment of the present invention, the said ethereal solvent is selected from tetrahydrofuran, 2-methyl tetrahydrofuran, dimethyl ether, diethyl ether, di- isopropyl ether, di-n-butyl ether, di-iodopropyl ether, methyl-tert-butyl ether, cyclopentyl methyl ether, dimethoxyethane, diethylene glycol dimethyl ether, dioxane or anisole.
In accordance with an embodiment of the present invention, the said amide solvent is selected from dimethylformamide, dimethylacetamide, formamide, N-methyl-2- pyrrolidone, N-methylformamide or 2-pyrrolidone.
In accordance with an embodiment of the present invention, the said ketonic solvent is selected from acetone, methylethyl ketone, cyclohexanone, methyl isobutyl ketone, methyl tert-butyl ketone, diethyl ketone or methyl isopropyl ketone. In accordance with an embodiment of the present invention, the said halogenated solvent is selected from dichloromethane, chloroform, carbon tetrachloride or carbon tetrabromide.
In accordance with an embodiment of the present invention, in the step (d) of the process the reaction is carried out at a temperature range of 0 °C to 50 °C.
In accordance with an embodiment of the present invention, in the step (d) of the process the reaction is carried out at a temperature range of 0 °C to 50 °C for 10 h to 20 h. In step (d) of the process, only the desired isomer is obtained in a very high yield of greater than 95 %), which is specific to the reaction condition and substrate. The SN (nucleophilic substitution) aziridine ring opening reaction occurs predominantly, which depends on the reaction conditions and is substrate-specific. Therefore, step (d) of the process involves an asymmetric induction reaction and constitutes the key step in the process for the preparation of droxidopa.
The following examples which fully illustrate the practice of the preferred embodiments of the present invention are intended to be for illustrative purpose only and should not be considered in anyway to limit the scope of the present invention.
Examples
Example 1: Preparation compound of formula III
2-ethox benzo[d][l,3]dioxole-5-carbaldehyde
Figure imgf000023_0001
In a round bottom flask was charged compound of formula II (1.0 g, 7.24 mmol); triethylorthoformate (3.0 mL, 18.06 mmol) and toluene (10 mL) under nitrogen atmosphere. The resulting reaction mixture was refluxed at a temperature of 60 °C to 80 °C for 12 h to 14 h. Then the reaction mixture was cooled to 25 °C to 35 °C and diluted with ethyl acetate (25 mL) and water (25 mL), the layers formed were separated. The organic layer was then washed with brine (25 mL) and dried over anhydrous sodium sulphate. The resulting reaction mixture evaporated under reduced pressure to yield crude product. The crude product was purified by column chromatography (silica gel, hexane: ethyl acetate; 9.7:0.3) to yield pure compound of formula III. Yield 1.0 g, 71 %; 1H-NMR (400MHz, DMSO-d6): δ (ppm) 9.84 (s, 1H), 7.61 (dd, = 8.0 Hz, 1.6 Hz, 1H), 7.43 (d, = 1.6 Hz, 1H), 7.28 (s, 1H), 7.23 (d, = 8.0 Hz, 1H), 3.75-3.70 (m, 2H), 1.18 (t, = 7.2 Hz, 3H); LCMS: RT.4.229 min., Area % 92.14, MS (ES+) m/z: 194.9 (M + 1).
Example 2: Preparation compound of formula V
(E)-N-((2-ethoxybenzo[d][l,3]dioxol-5-yl)methylene)-4-methylbenzenesulfinamide
Figure imgf000024_0001
In a round bottom flask was charged the compound of formula III (obtained in example 1) (0.8 g, 4.12 mmol) and 4-methyl-(S)-benzenesulfinamide (formula IV) (0.7 g, 4.53 mmol), which were dissolved in tetrahydrofuran (25 mL). Titanium tetraethoxide (1.78 mL, 8.24 mmole) was then added under nitrogen atmosphere to the reaction mixture and stirred at 25 °C to 35 °C for 12 h to 14 h. The resulting reaction mixture was diluted with ethyl acetate (50 mL) and water filtered through celite bed. The filtrate obtained was treated with ethyl acetate and water and the layers formed were separated. The organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure to yield crude product. The crude product was purified by column chromatography (silica gel, hexane:ethyl acetate; 1: 1) to yield pure compound of formula VI. Yield - 0.76 g, 56 %; 1H-NMR (400MHz, DMSO-d6): δ (ppm) 8.66 (d, J = 1.6Hz, 1H), 7.61 (d, J = 8.0 Hz, 2H), 7.57 (d, = 8.4 Hz, 1H), 7.51 (s, 1H), 7.40 (d, = 8.0 Hz, 2H), 7.24 (d, / = 2.0 Hz, 1H), 7.16 (d, = 8.4 Hz, 1H), 3.73-3.67 (m, 2H), 2.36 (s, 3H), 1.19-1.14 (m, 3H); LCMS: RT.5.343 min., Area % 96.87, MS (ES+) m/z: 331.9 (M + 1).
Example 3: Preparation compound of formula VI
(2R,3R)-tert-butyl 3-(2-ethoxybenzo[d] [1 ,3] dioxol-5 -yl)-l -(p-tolylsulfinyl)aziridine-2- carbox late
Figure imgf000024_0002
In a reaction flask a solution of lithium bis(trimethylsilyl)amide (LiHMDS) (3.54 mL, 2.41 mmol) in tetrahydrofuran (6 mL) at -78 °C and i-butyl bromoacetate (0.27 mL, 1.8 mmol) was charged and the resulting reaction mixture was stirred for 30 min at -78 °C. A solution of the compound of formula V (obtained in example 2) (0.6 g, 1.8 mmol) in tetrahydrofuran (1 mL) was added and stirred at the same temperature for 30 min. The reaction temperature was slowly raised to 25 °C to 30 °C and maintained at this temperature for 2.5 h. The resulting reaction mixture was then quenched by adding water. The organic layer was separated and washed with brine and dried over anhydrous sodium sulphate. The reaction mixture obtained was evaporated under reduced pressure to yield a crude product. The crude product was purified by column chromatography (silica gel, hexane:ethyl acetate; 8:2) to yield pure compound of formula VI. Yield - 0.201g, 25 %; 1H-NMR (400MHz, DMSO-d6): δ (ppm) 7.72 (d, = 7.2 Hz, 2H), 7.45 (d, = 8.0 Hz, 2H), 7.12 (s, 1H), 7.04-7.02 (m, 2H), 6.98 (d, = 8.4 Hz, 1H), 3.85(t, = 6.8 Hz, 1H), 3.67- 3.60 (m, 2H), 3.26 (dd, J = 7.6,1.2 Hz, 1H), 2.40 (s, 3H), 1.18-1.13 (m, 3H), 1.06 (s, 9H); LCMS: RT. 5.88 min., Area % 95.79, MS (ES+) m/z: 445.9 (M + 1). Example 4: Preparation compound of formula I
(2S,3R)-2-amino-3-(3,4-dihydroxyphenyl)-3-hydroxypropanoic acid
Figure imgf000025_0001
To a reaction flask, was charged compound of formula VI (obtained in example 3) (401 mg, 0.897 mmol), dichloromethane (12 mL) and 50 % aqueous trifluoroacetic acid solution (2.4 mL). The reaction mixture was then stirred at a temperature of 25 °C to 35 °C for 12 h to 14 h. After the completion of the reaction, water (1 mL) and diethyl ether (50 mL) were added. The layers formed were separated and the aqueous layer obtained was heated at a temperature of 60 °C for 10 h. The resulting reaction mixture was washed with diethyl ether (10 mL) and the pH of the reaction mixture was adjusted to ~7 by using sodium hydroxide solution at 0 °C. The precipitate formed was filtered and dried to yield the compound of formula I. 1H-NMR (400MHz, DMSO-d6): δ 6.77 (d, = 1.6 Hz, 1H), 6.66 (d, = 8 Hz, 1H), 6.61(dd, = 8, 2 Hz, 1H), 4.86 (d, = 3.6 Hz, 1H), 3.24 (d, = 3.6 Hz, 1H); LCMS: RT.4.18 min., Area % 100, MS (ES+) m/z: 214.10(M+1).

Claims

We claim:
1. A process for preparation of L-i zreo-dihydroxyphenylserine (droxidopa) of formula I;
Figure imgf000026_0001
Formula I
comprising the steps of: a) reacting compound of formula II
Figure imgf000026_0002
Formula II with orthoformate in the presence of a solvent to yield compound of formula III,
Figure imgf000026_0003
Formula III
wherein Ri is selected from a group consisting of alkyl, cycloalkyl, aryl and heterocyclyl, which are unsubstituted or substituted with one or more groups selected from halogen, hydroxy, (Ci-C6)-alkoxy, nitro, cyano, amino, substituted amines, C(O) or C(0)2-alkyl; reacting the compound of formula III, obtained in step (a) with compound of formula IV
O
II
H2N * R2
Formula IV
wherein R2 is selected from a group consisting of alkyl, cycloalkyl, aryl and heterocyclyl, which are unsubstituted or substituted with one or more groups selected from halogen, hydroxy, (Ci-C6)-alkoxy, nitro, cyano, amino, substituted
C(O) or C(0)2-alkyl;
using a catalyst in the p ound of formula V,
Figure imgf000027_0001
Formula V
wherein Ri and R2 are as defined herein; reacting the compound of formula V, obtained in step (b) with haloacetate in the presence of a base and a solvent to yield compound of formula VI,
Figure imgf000027_0002
Formula VI
wherein R3 is an alkyl or aryl, which are unsubstituted or substituted with one or more groups selected from halogen, hydroxy, (Ci-C6)-alkoxy, nitro, cyano, amino, substituted amines, C(O) or C(0)2-alkyl;
Ri and R2 are as defined herein; and reacting the compound of formula VI, obtained in step (c) with an acid in the presence of a solvent to yield compound of formula I.
The process according to claim 1, wherein in step (a), the orthoformate is an alkyl orthoformate.
The process according to claim 2, wherein the alkyl orthoformate is selected from trimethyl orthoformate, triethyl orthoformate, tripropyl orthoformate or tributyl orthoformate.
The process according to claim 1, wherein in step (a), the reaction is carried out at a temperature range of 50 °C to 120 °C.
5. The process according to claim 1, wherein in step (b), the catalyst is selected from a group consisting of metal alkoxides, metal oxides, metal halides and metal triflates.
6. The process according to claim 5, wherein the metal is selected from a group consisting of transition metals and inner-transition metals.
7. The process according to claim 1, wherein in step (b), the reaction is carried out at a temperature range of 40 °C to 80 °C.
8. The process according to claim 1, wherein in step (c), the haloacetate is selected from chloroacetate, bromoacetate, fluoroacetate or iodoacetate.
9. The process according to claim 1, wherein in step (c), the haloacetate is an alkyl haloacetate having 1 to 6 carbon atoms in the ester group.
10. The process according to claim 1, wherein in step (c), the haloacetate is an aryl haloacetate having 6 to 14 carbon atoms, in which the carbocyclic ring(s) present have a conjugated pi electron system in the ester group.
11. The process according to claim 1, wherein in step (c), the base is selected from a group consisting of metal silylamides, metal hydroxides and metal alkoxides.
12. The process according to claim 11, wherein the metal silylamide is selected from lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, calcium bis[bis(trimethylsilyl)amide], magnesium bis[bis(trimethylsilyl)amide], titanium tris[bis(trimethylsilyl)amide], manganese bis[bis(trimethylsilyl)amide], manganese tris[bis(trimethylsilyl)amide], zinc bis[bis(trimethylsilyl)amide], iron bis[bis(trimethylsilyl)amide], iron tris[bis(trimethylsilyl)amide] or scandium tris[bis(trimethylsilyl)amide].
13. The process according to claim 11, wherein the metal of metal hydroxide and metal alkoxide is selected from a group consisting of alkali metals and alkaline earth metals.
14. The process according to claim 13, wherein the metal of metal hydroxide and metal alkoxide is selected from sodium, potassium, lithium, magnesium or calcium.
15. The process according to claim 1, wherein in step (c), the process is carried out in the presence of a phase transfer catalyst selected from a group consisting of a quaternary ammonium salt and a quaternary phosphonium salt.
16. The process according to claim 15, wherein the quaternary ammonium salt phase transfer catalyst is selected from benzyltriethylammonium halide, hexadecyltrimethylammonium halide, tetrabutylammonium halide, tetramethylammonium halide and tetraethylammonium halide or a mixture thereof.
17. The process according to claim 15, wherein the quaternary phosphonium salt phase transfer catalyst is selected from tetra-n-butyl-phosphonium chloride, tetraphenylphosphonium bromide, tetraphenylphosphonium chloride, triphenylmethylphosphonium bromide and triphenylmethylphosphonium chloride or a mixture thereof.
18. The process according to claim 1, wherein in step (c), the reaction is carried out at a temperature range of -78 °C to 25 °C.
19. The process according to claim 1, wherein in step (d), the acid is selected from a group consisting of inorganic acid and organic acid. 20. The process according to claim 19, wherein the acid may be used in the acid form or as a solution of acid in a solvent selected from water or an organic solvent or a mixture thereof.
21. The process according to claim 20, wherein the organic solvent is an alcohol or an ether or a mixture thereof.
22. The process according to claim 1, wherein in step (d), the reaction is carried out at a temperature range of 0 °C to 50 °C.
23. The process according to claim 1, wherein in steps (a) to (d), the solvent is selected from a group consisting of ethereal solvents, amide solvents, ketonic solvents, halogenated solvents, dimethyl sulfoxide, toluene, hexane, xylene and acetonitrile or a mixture thereof.
24. The process according to claim 1, wherein in step (c), the compound of formula VI is obtained as R,R isomer, which leads to obtaining of greater than 95 % selectivity towards the L-threo isomer of the compound of formula I.
25. A compound of formula III,
Figure imgf000030_0001
Formula III wherein Ri is selected from a group consisting of alkyl, cycloalkyl, aryl and heterocyclyl, which are unsubstituted or substituted with one or more groups selected from halogen, hydroxy, (Ci-C6)-alkoxy, nitro, cyano, amino, substituted amines, C(O) or C(0)2-alkyl.
26. A compound of formula V,
Figure imgf000030_0002
Formula V
wherein Ri and R2 are selected from a group consisting of alkyl, cycloalkyl, aryl and heterocyclyl, which are unsubstituted or substituted with one or more groups selected from halogen, hydroxy, (Ci-C6)-alkoxy, nitro, cyano, amino, substituted amines, C(O) or C(0)2-alkyl.
27. A compound of formula VI,
Figure imgf000030_0003
Formula VI wherein Ri and R2 are selected from a group consisting of alkyl, cycloalkyl, aryl and heterocyclyl, which are unsubstituted or substituted with one or more groups selected from halogen, hydroxy, (Ci-C6)-alkoxy, nitro, cyano, amino, substituted amines, C(O) or C(0)2-alkyl; and
R3 is an alkyl or aryl, which are unsubstituted or substituted with one or more groups selected from halogen, hydroxy, (Ci-C6)-alkoxy, nitro, cyano, amino, substituted amines, C(O) or C(0)2-alkyl.
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