RELATED APPLICATION

This application is a national phase entry under 35 USC 371 of International Patent Application No.: PCT/IB2017/051757 filed on 28 Mar. 2017, which claims priority from Indian Application No. 201621010969 filed on 30 Mar. 2016, the disclosures of which are incorporated in their entirety by reference herein.

FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of L-threo-(2S,3R)-3-(3.4-dihydroxyphenyl)serine (I), which is known as Droxidopa and its pharmaceutically acceptable salts. The present invention also relates to a novel metal chiral complex (IV) as an intermediate used for the preparation of droxidopa.

BACKGROUND OF THE INVENTION

The following discussion of the prior art is intended to present the invention in an appropriate technical context, and allows its significance to be properly appreciated. Unless clearly indicated to the contrary, reference to any prior art in this specification should not be construed as an expressed or implied admission that such art is widely known or forms part of common general knowledge in the field.

Droxidopa is chemically known as (2S,3R)-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-threo-(2S,3R)-3-(3,4-dihydroxyphenyl)serine. Droxidopa is available in the market as Northera® capsules with dosages of 100 mg, 200 mg and 300 mg for oral administration.



NORTHERA® (droxidopa) capsules, for oral use is approved in the USA and is indicated 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.

The drug 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.

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 (I), it has been observed that the L-threo enantiomer is the desired isomer having desired activity. Administration of the active L-threo enantiomer of the compound (I), substantially free of its other isomers, would essentially enable a reduction in the dose of drug. Due to the importance of the L-threo enantiomer of the compound (I) as an oral, synthetic norepinephrine precursor, there exists a need to develop an economical and efficient synthetic process for its production.

U.S. Pat. No. 3,920,728 (hereinafter US'728) provides a process for the preparation of droxidopa comprising reaction of 3,4-dibenzyloxybenzaldehyde with glycine, followed by treatment with sodium acetate trihydrate and diethylamine to obtain racemic-threo/erythro-3-(3,4-dibenzyloxyphenyl)-serine. Further, treatment of the compound with carbobenzoxy chloride to obtain racemic-threo/erythro-3-(3,4-dibenzyloxyphenyl)-N-carbobenzoxyserine and its treatment with dicyclohexylamine to give racemic-threo-3-(3,4-dibenzyloxyphenyl)-N-carbobenzox yserinedic yclohexylamine salt, which on treatment with HCl gas in the presence of ethyl acetate yields racemic-threo-3-(3,4-dibenzyloxyphenyl)-N-carbobenzoxyserine. Finally, treatment of the racemic serine compound with (+)-ephedrine to yield (+)-ephedrine salt of L-threo-3-(3,4-dibenzyloxyphenyl)-N-carbobenzoxyserine and hydrolysis of the compound to yield L-threo-3-(3,4-dibenzyloxyphenyl)-N-carbobenzoxyserine; which on subsequent reduction over Pd/C provides L-threo-3-(3,4-dibenzyloxyphenyl)-serine.

The patent EP0024210B1 describes a process for preparation of optically active (D- or L-) threo-3-(3,4-dihydroxyphenyl)serine (Droxidopa) comprising reaction of racemic threo-3-(3,4-dibenzyloxyphenyl)-N-carbobenzoxyserine with a resolving agent, followed by decomposition using hydrochloric acid to yield (−)-3-(3,4-dibenzyloxyphenyl)-N-carbobenzoxyserine.

U.S. Pat. No. 4,562,263 (hereinafter US'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-1,1-diphenyl-1-propanol and L-3-hydroxy-3-(4-nitrophenyl)-2-amino-1-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 on further deprotection by removal of phthaloyl group with hydrazine to yield L-threo-3-(3,4-dihydroxyphenyl)-serine.

Research articleJ. Am. Chem. Soc.107, 4252-59 (1985) disclosed a ‘general method of Diastereo- and Enantioselective Synthesis of beta-Hydroxy-alpha-amino acids by condensation of aldehydes and ketones with Glycine’ which involves formation of metal complex as:



TheJ. Am. Chem. Soc.107, 4252-59 (1985) further disclosed hydrolysis of the metal complex to give desired compound.



Similarly, Journal of fluorine chemistry 75, 93-101, (1995) refers to the synthesis of 2- and 6-fluoro analogues of threo-3-(3,4-dihydroxyphenyl) serine (2- and 6-fluoro-threo-DOPS) comprises treatment of aldehyde compound with Ni++followed by hydrolysis which is depicted below;



The published PCT application WO-A-2005/085178 disclosed the treatment of 1-hydroxy-1-(3,4-dibenzyloxyphenyl) glycine-Ni-D-2-[N—(N′-ben-zylprolyl) amino] benzophenone with hydrochloric acid to obtain L-threo-(2S,3R)-3-(3,4-dibenzyloxyphenyl) serine. As indicated, the said compound has both the hydroxyl group protected with benzyl group forms 3,4-dibenzyloxyphenyl compound. The product on subsequent metal catalyzed hydrogenation, predominately using Pd/C under hydrogenation pressure provides Droxidopa.

A general method for the synthesis of enantiomerically pure beta-Hydroxy-alpha-amino acids and serine derivatives is also disclosed in theJ. Chem. Soc. Perkin Trans.1, 3143-54 (1993) and published patent application US 2015/0210667A1. U.S. Pat. No. 8,980,316 (hereinafter US'316) and published patent application US 2013/0253061A1 disclosed a composition of Droxidopa with several particle size rages in terms of 90% D (μm) values and average (μm) values.

It is evident from the above discussion that the prior art processes for the preparation of droxidopa involves multiple process steps such as resolution followed by separate deprotection method. 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 chiral resolution to obtain threo/erythro isomer results into 50% loss of the undesired isomer, which affects the overall yield of the process. Further, 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.

Thus, in view of these drawbacks there is a 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.

Inventors of the present invention have developed an improved process which is a simple, efficient and cost-effective process and provides the desired compounds in improved yield and purity and that addresses the problems associated with the processes reported in the prior art. The process of the present invention does not involve use of any toxic and/or costly solvents, also does not involve use of costlier coupling agents and reagents. Moreover, the process does not require repetitive purification steps and column chromatography. Accordingly, the present invention provides a process for the preparation of droxidopa (I), which is simple, efficient, cost effective, environmentally friendly and commercially scalable for large scale operations.

SUMMARY OF THE INVENTION

In one aspect, the present invention relates to an improved process for the preparation of L-threo-(2S,3R)-3-(3,4-dihydroxyphenyl)serine (I) or a salt thereof; comprising (a) reaction of the aldehyde compound (III) (as described herein) with Metal complex (II) (as described herein), and (b) hydrolysis of the compound (IV) obtained from step (a) in presence of acid.

In one aspect, the present invention relates to an improved process for the preparation of L-threo-(2S,3R)-3-(3,4-dihydroxyphenyl)serine (I) or a salt thereof; comprising reaction of the aldehyde compound (III) (as described herein) with Metal complex (II) (as described herein) in the presence of a metal alkoxide to obtain compound (IV), followed by its hydrolysis in presence of acid.

In an embodiment, there is provided a novel intermediate metal complex (IV);


wherein M is a metal selected from Cu2+, Ni2+, or Zn2+and R1is selected from a group consisting of hydrogen, unsubstituted or substituted alkyl, cycloalkyl, aryl, heterocyclic and protecting group;

In an embodiment, there is provided a novel intermediate Nickel complex (IVa);



In another aspect, the present invention relates to an improved process for the preparation of L-threo-(2S,3R)-3-(3,4-dihydroxyphenyl)serine (I) or a salt thereof comprising (i) reaction of the aldehyde compound (IIIa) (as described herein) with Nickel complex (IIa) (as described herein), (ii) hydrolysis of the compound (IVa) obtained from step (i) in presence of acid, and (iii) treatment of the acid salt of compound (I) obtained from step (ii) with a base.

In one aspect, the present invention relates to an improved process for the preparation of L-threo-(2S,3R)-3-(3,4-dihydroxyphenyl)serine (I) or a salt thereof; comprising hydrolysis of the compound (IV) (as described herein) in presence of acid.

In an embodiment, there is provided L-threo-(2S,3R)-3-(3,4-dihydroxyphenyl)serine (I) with more than 99% ee.

In another aspect, the invention also provides a process for the purification of L-threo-(2S,3R)-3-(3,4-dihydroxyphenyl)serine (I) comprising treatment of compound (I) or its salt with a metal hydride.

In another aspect, there is provided L-threo-(2S,3R)-3-(3,4-dihydroxyphenyl)serine (I) having particle size diameter range with a d(0.1) of between about 1 to about 20 μm.

In another aspect, there is provided L-threo-(2S,3R)-3-(3,4-dihydroxyphenyl)serine (I) having particle size diameter range with a d(0.5) of between about 5 to about 105 μm.

In another aspect, there is provided L-threo-(2S,3R)-3-(3,4-dihydroxyphenyl)serine (I) having particle size diameter range with a d(0.9) of between about 10 to about 210 μm.

In another aspect, there is provided a pharmaceutical composition comprising a therapeutically effective amount of L-threo-(2S,3R)-3-(3,4-dihydroxyphenyl)serine (I) having particle size distribution range of d(0.1) between about 1 to about 20 μm, d(0.5) between about 5 to about 105 μm, d(0.9) between about 10 to about 210 μm; or any combination thereof.

In another aspect, there is provided L-threo-(2S,3R)-3-(3,4-dihydroxyphenyl)serine (I) having specific surface area value from 0.1 to 3 m2/g.

