WO2005085178A1 - Method of preparing optically active serine derivative - Google Patents

Method of preparing optically active serine derivative Download PDF

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WO2005085178A1
WO2005085178A1 PCT/KR2005/000604 KR2005000604W WO2005085178A1 WO 2005085178 A1 WO2005085178 A1 WO 2005085178A1 KR 2005000604 W KR2005000604 W KR 2005000604W WO 2005085178 A1 WO2005085178 A1 WO 2005085178A1
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compound
formula
acid
preparing
alkyl
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Ho-Sung Yu
You-Hwa Hong
Do-Young Jang
Soon-Jeong Kwon
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Estechpharma Co., Ltd.
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    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
    • 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
    • C07C227/16—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 not involving the amino or carboxyl groups
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/22—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated the carbon skeleton being further substituted by oxygen atoms
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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • E04G7/306—Scaffolding bars or members with non-detachably fixed coupling elements for connecting crossing or intersecting bars or members the added coupling elements are fixed at several bars or members to connect
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    • E—FIXED CONSTRUCTIONS
    • E04—BUILDING
    • E04G—SCAFFOLDING; FORMS; SHUTTERING; BUILDING IMPLEMENTS OR AIDS, OR THEIR USE; HANDLING BUILDING MATERIALS ON THE SITE; REPAIRING, BREAKING-UP OR OTHER WORK ON EXISTING BUILDINGS
    • E04G7/00—Connections between parts of the scaffold
    • E04G7/30—Scaffolding bars or members with non-detachably fixed coupling elements
    • E04G7/34—Scaffolding bars or members with non-detachably fixed coupling elements with coupling elements using positive engagement, e.g. hooks or pins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention relates to a method of preparing an optically active serine derivative, and more particularly, to a method of preparing droxidopa, which is an optically active serine derivative, and a salt thereof, and an intermediate useful in the preparation of the derivative.
  • Droxidopa and a salt thereof are pharmacologically active in the circulatory system and the central nervous system and have efficacy as therapeutic agents for Parkinson disease, depression, peripheral orthostatic hypotension, etc.
  • Droxidopa has the chemical name L-threo-(2S,3R)-3-(3,4-dihydroxyphenyl)serine] and a structure of formula la
  • U.S. Patent No. 3,920,728 discloses a method of separating isomers, including droxidopa, from four isomeric forms. However, the maximum yield from the separation with four isometric forms cannot exceed 25%.
  • U.S. Patent No. 5,739,387 which corresponds to Japanese Patent Laid-open Nos. hei 9-031038, hei 9-301961, and hei 8-231518, discloses a method of preparing droxidopa from an N-acetyl DOPA derivative obtained from DOPA.
  • this method is costly because DOPA that is an expensive reagent is used.
  • Japanese Patent Laid-open No. 9-249626 discloses a method of preparing droxidopa by the synthesis of a chiral diol derivative and the incorporation and reduction of an azido group.
  • hei 5-239025 disclose methods of preparing droxidopa via the preparation of threo- N-phthaloyl-3-(3,4-dihydroxyphenyl)serine using a benzaldehyde derivative as a starting material.
  • a new preparation method that is commercially applicable on a large scale and results in a high yield is required in the field.
  • the reaction in a tri- ethylamine-methanol solvent mixture takes 3 days or longer, and a 1:1 to 2:1 mixture of threo form (2S,3R) and erythro form (2S,3S) and 5-20% of a (2R,3S) and (2R,3R) mixture are obtained. Therefore, the conventional methods cannot be commercially used to synthesize pure L-threo-(2S,3R)-3-(3,4-dihydroxyphenyl)serine, i.e., droxidopa. Furthermore, the aldol condensation reaction cannot take place due to two hydroxy groups in the phenyl ring. Disclosure of Invention Technical Problem
  • the present invention provides a method of preparing high optically pure droxidopa with a high yield and an intermediate obtained in the preparation of the droxidopa.
  • the present invention provides a stereoselective method of preparing droxidopa with the stereochemistry of L-threro-(2S,3R)- ⁇ -hydroxy- -amino acid with high purity and high yield, and a metal chiral complex that is a useful intermediate in the preparation of the droxidopa.
  • a method of preparing L-threo-(2S,3R)-3-(3,4-dihydroxyphenyl)serine or a salt thereof comprising: obtaining a compound of formula (lb) below by decomposing a compound of formula (2) below in a polar organic solvent using an acid; and hy- drogenating the compound of formula (lb):
  • each of R 1 and R 2 is independently selected from the group consisting of benzyl, p-nitrobenzyl, p-fluorobenzyl, p-trifluorobenzyl, C ⁇ C alkoxy C ⁇ C alkyl, 1 4 1 4 and C ⁇ C alkyl; and M is Cu 2+ , Ni 2+ , or Zn 2+ . 1 4
  • a method of preparing droxidopa, L-threo-(2S,3R)-3-(3,4-dihydroxyphenyl)serine, or a salt thereof according to an embodiment of the present invention includes: obtaining a compound of formula (lb) by decomposing a compound of formula (2) in a polar organic solvent using an acid and hydrogenating the compound of formula (lb).
  • each of R and R is independently selected from the group consisting of benzyl, p-nitrobenzyl, p-fluorobenzyl, p-trifluorobenzyl, C ⁇ C alkoxy C ⁇ C alkyl, and C ⁇ C alkyl; and M is Cu 2+ , Ni 2+ , or Zn 2+ . 1 4 1 4
  • both R 1 and R 2 are benzyl to facilitate the hydrogenation reaction.
  • the polar organic solvent can be selected from the group consisting of C ⁇ C alcohol, tetrahydrofuran, acetonitrile, dimethylformamide, and a mixture thereof, with methanol being preferred.
  • the acid used to prepare the compound of formula (lb) can be an inorganic acid or an organic acid, for example, hydrochloric acid, bromic acid, sulfuric acid, nitric acid, acetic acid, or trifluoroacetic acid, etc., with hydrochloric acid being preferred.
  • the amount of the acid can be varied according to which kind of acid is used. About 20 equivalents or more, preferably, about 30 equivalents, of an acid can be used with respect to 1 equivalent of the compound of formula (2).
  • the decomposing of the compound of formula (2) can be performed at a temperature of -10 ⁇ 100 °C , preferably, about 50 °C , for about 10 minutes to 5 hours, preferably, about 1 hour.
  • the hydrogenation of the compound of formula (lb) can be performed under common hydrogenation conditions, preferably, by adding hydrogen in the presence of a metal such as Pd/C, Pt, etc. and an acid such as HC1, HBr, etc.
  • the hydrogenation can be performed in a solvent such as a polar organic solvent described above, for example, ethanol at a temperature of -10 ⁇ 100 °C , preferably, about 20 °C .
  • the term 'hydrogenation' as used in the present invention refers to a reaction converting -OR and -OR groups of the compound of formula (lb) into -OH group of the compound of formula (la).
  • the compound of formula (2) can be prepared by reacting a compound of formula (3) and a compound of formula (4) in the presence of a base.
  • the base can be selected from the group consisting of alkali metal hydroxides, such as sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.; alkaline earth metal hydroxides, such as magnesium hydroxide, calcium hydroxide, barium hydroxide, etc.; alkali metal alkoxides, such as sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.; NHR R where each of R and R , which can be the same or different, is C ⁇ C alkyl; NH R where R is C ⁇ C alkyl; quaternary amine hydroxides, such as tetrabutylammonium hydroxide, benzyltrimethylamonium hydroxide, etc.; NaH; and NaNH , with an alkali metal alkoxide, particular, sodium methoxide, NaH, or NaNH being preferred for greater
  • the compound of formula (3) can be synthesized as follows. Initially, D- N-benzylproline is prepared by reacting D-proline and benzylchloride. D- 2-[N-(N'-benzylprolyl)amino]benzophenone is prepared by reacting the D- N-benzylproline and 2-aminobenzophenone. Finally, the D- 2+ 2-[N-(N'-benzylprolyl)amino]benzophenone, a salt containing M where M can be Cu Ni + , or Zn + ) or a hydrate of the salt, and glycine are reacted to obtain the compound of formula (3). These processes of synthesizing the compound of formula (3) are illustrated in reaction scheme (1) below
  • D-N-benzylproline D-proline and benzylchloride can be reacted in alcohol such as isoprolyl alcohol, etc. in the presence of a base such as potassium hydroxide, etc. at a temperature of about 40 °C for about 6 hours.
  • alcohol such as isoprolyl alcohol, etc.
  • base such as potassium hydroxide, etc. at a temperature of about 40 °C for about 6 hours.
  • the reacting of the D-2-[N-(N'-benzylprolyl)amino]benzophenone, a salt containing M selected from among Cu + , Ni + and Zn + or a hydrate of the salt, and glycine can be performed in an alcoholic solvent such as methanol at a temperature of 40 ⁇ 50 °C in the presence of a base such as potassium hydroxide, etc.
  • Examples of the salt containing Cu + , Ni + , or Zn + include a nitrate such as Ni(NO ) , etc., a halogenate such as NiCl , NiBr , etc., an acetate such as Ni(OAc) , etc., and a sulfate such as NiSO 2+ ⁇ .2+ 2+ , etc.
  • the hydrate of the salt containing Cu , Ni , or Zn can have any form, and preferably, can be Ni(NO ) • 6H O.
  • the present invention provides a useful intermediate obtained in the preparation of droxidopa.
  • the useful intermediate is the compound of formula (2) and/or the compound of formula (3).
  • L-threo-(2S,3R)-3-(3,4-dihydroxyphenyl)serine or a salt thereof can be prepared with high purity and high yield according to the method of the present invention.
  • the compound of formula (2) and/or the compound of formula (3) according to the present invention can be used when preparing droxidopa. Best Mode
  • the reaction mixture was cooled to 0 °C , and an aqueous sodium carbonate solution was added thereinto.
  • the product was extracted from the reaction mixture using dichloromethane, washed with distilled water and saturated salt water, and concentrated by drying using anhydrous magnesium sulfate.
  • the residual material was re- crystallized using ethanol and filtrated to obtain the subtitled compound with a yield of 74% (126 g).

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Abstract

A method of preparing L-threo-(2S,3R)-3-(3.4-dihydroxyphenyl)serine or a salt thereof and an immediate obtained in the preparation of the serine derivative are provided. The method includes decomposing an asymmetric aldol condensate of a chiral metal complex in a polar organic solvent using an acid and hydrogenating the resulting product.

Description

Description METHOD OF PREPARING OPTICALLY ACTIVE SERINE DERIVATIVE Technical Field
[1] The present invention relates to a method of preparing an optically active serine derivative, and more particularly, to a method of preparing droxidopa, which is an optically active serine derivative, and a salt thereof, and an intermediate useful in the preparation of the derivative. Background Art
[2] Droxidopa and a salt thereof are pharmacologically active in the circulatory system and the central nervous system and have efficacy as therapeutic agents for Parkinson disease, depression, peripheral orthostatic hypotension, etc. Droxidopa has the chemical name L-threo-(2S,3R)-3-(3,4-dihydroxyphenyl)serine] and a structure of formula la
Figure imgf000002_0001
...(la)
[3] U.S. Patent No. 3,920,728 discloses a method of separating isomers, including droxidopa, from four isomeric forms. However, the maximum yield from the separation with four isometric forms cannot exceed 25%.
[4] U.S. Patent No. 5,739,387, which corresponds to Japanese Patent Laid-open Nos. hei 9-031038, hei 9-301961, and hei 8-231518, discloses a method of preparing droxidopa from an N-acetyl DOPA derivative obtained from DOPA. However, this method is costly because DOPA that is an expensive reagent is used. Japanese Patent Laid-open No. 9-249626 discloses a method of preparing droxidopa by the synthesis of a chiral diol derivative and the incorporation and reduction of an azido group. Japanese Patent Laid-open No. sho 61-275254 and Japanese Patent Laid-open No. hei 5-239025 disclose methods of preparing droxidopa via the preparation of threo- N-phthaloyl-3-(3,4-dihydroxyphenyl)serine using a benzaldehyde derivative as a starting material. However, the development of a new preparation method that is commercially applicable on a large scale and results in a high yield is required in the field.
[5] A method of preparing diastereo- and enantio-selective β -hydroxy- -amino acid by condensing aldehyde and ketone with glycine is disclosed in J. Am. Chem. Soc. 107, 4252-4259, 1985. According to the method, D-threo-(2R,3S)- β -phenylserine derivative can be synthesized by reacting glycine having the following formula and a metal chiral complex with aldehyde, ketone, etc.
Figure imgf000003_0001
[6] A method of preparing a β -hydroxy- -amino acid having fluorine atom in a side chain using a chiral complex is disclosed in J. Chem. Soc. Perkin Trans. 1, 3143-3154, 1993.
[7] However, when using the method disclosed in J. Am. Chem. Soc. 107, 4252-4259, 1985 or J. Chem. Soc. Perkin Trans. 1, 3143-3154, 1993 to prepare an optically active serine derivative, D-threo-(2R,3S)-3-(3,4-dihydroxyphenyl)serine results as a major product. Therefore, it is difficult to obtain droxidopa, i.e., L- threo-(2S,3R)-3-(3,4-dihydroxyphenyl)serine, with high purity by the conventional methods. In addition, according to the conventional methods, the reaction in a tri- ethylamine-methanol solvent mixture takes 3 days or longer, and a 1:1 to 2:1 mixture of threo form (2S,3R) and erythro form (2S,3S) and 5-20% of a (2R,3S) and (2R,3R) mixture are obtained. Therefore, the conventional methods cannot be commercially used to synthesize pure L-threo-(2S,3R)-3-(3,4-dihydroxyphenyl)serine, i.e., droxidopa. Furthermore, the aldol condensation reaction cannot take place due to two hydroxy groups in the phenyl ring. Disclosure of Invention Technical Problem
[8] The present invention provides a method of preparing high optically pure droxidopa with a high yield and an intermediate obtained in the preparation of the droxidopa. The present invention provides a stereoselective method of preparing droxidopa with the stereochemistry of L-threro-(2S,3R)- β -hydroxy- -amino acid with high purity and high yield, and a metal chiral complex that is a useful intermediate in the preparation of the droxidopa. [9] According to an aspect of the present invention, there is provided a method of preparing L-threo-(2S,3R)-3-(3,4-dihydroxyphenyl)serine or a salt thereof, the method comprising: obtaining a compound of formula (lb) below by decomposing a compound of formula (2) below in a polar organic solvent using an acid; and hy- drogenating the compound of formula (lb):
Figure imgf000004_0001
• ••(2)
[10] wherein each of R 1 and R 2 is independently selected from the group consisting of benzyl, p-nitrobenzyl, p-fluorobenzyl, p-trifluorobenzyl, C ~ C alkoxy C ~ C alkyl, 1 4 1 4 and C ~ C alkyl; and M is Cu2+, Ni2+, or Zn2+. 1 4
[11] In another aspect of the present invention, there is provided a compound of formula (2) below:
• ••(2)
[12] wherein R , R , and M are the same as defined above. [13] The present invention also provides a compound of formula (3) below:
Figure imgf000005_0002
•••(3)
[14] wherein M is the same as defined above. Technical Solution
[15] A method of preparing droxidopa, L-threo-(2S,3R)-3-(3,4-dihydroxyphenyl)serine, or a salt thereof according to an embodiment of the present invention includes: obtaining a compound of formula (lb) by decomposing a compound of formula (2) in a polar organic solvent using an acid and hydrogenating the compound of formula (lb).
Figure imgf000005_0003
...(lb)
Figure imgf000006_0001
• ••(2) 1 2
[16] In formulae (lb) and (2), each of R and R is independently selected from the group consisting of benzyl, p-nitrobenzyl, p-fluorobenzyl, p-trifluorobenzyl, C ~ C alkoxy C ~ C alkyl, and C ~ C alkyl; and M is Cu2+, Ni2+, or Zn2+. 1 4 1 4
[17] In the method according to the present invention, it is preferable that both R 1 and R 2 are benzyl to facilitate the hydrogenation reaction.
[18] In the method according to the present invention, the polar organic solvent can be selected from the group consisting of C ~ C alcohol, tetrahydrofuran, acetonitrile, dimethylformamide, and a mixture thereof, with methanol being preferred. The acid used to prepare the compound of formula (lb) can be an inorganic acid or an organic acid, for example, hydrochloric acid, bromic acid, sulfuric acid, nitric acid, acetic acid, or trifluoroacetic acid, etc., with hydrochloric acid being preferred.
[19] The amount of the acid can be varied according to which kind of acid is used. About 20 equivalents or more, preferably, about 30 equivalents, of an acid can be used with respect to 1 equivalent of the compound of formula (2). The decomposing of the compound of formula (2) can be performed at a temperature of -10 ~ 100 °C , preferably, about 50 °C , for about 10 minutes to 5 hours, preferably, about 1 hour.
[20] 90% or more of D-2-[N-(N'-benzylprolyl)amino]benzophenone, which is a intermediate resulting from the decomposition of the compound of formula (2), can be recovered, does not undergo racemization, and can be used in a subsequent reaction, thereby providing an economical effect.
[21] The hydrogenation of the compound of formula (lb) can be performed under common hydrogenation conditions, preferably, by adding hydrogen in the presence of a metal such as Pd/C, Pt, etc. and an acid such as HC1, HBr, etc. The hydrogenation can be performed in a solvent such as a polar organic solvent described above, for example, ethanol at a temperature of -10 ~ 100 °C , preferably, about 20 °C . The term 'hydrogenation' as used in the present invention refers to a reaction converting -OR and -OR groups of the compound of formula (lb) into -OH group of the compound of formula (la).
[22] In the method according to the present invention, the compound of formula (2) can be prepared by reacting a compound of formula (3) and a compound of formula (4) in the presence of a base.
Figure imgf000007_0001
• ••(4) 1 2
[23] In formulae (3) and (4), R , R , and M are the same as defined above. [24] The base can be selected from the group consisting of alkali metal hydroxides, such as sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.; alkaline earth metal hydroxides, such as magnesium hydroxide, calcium hydroxide, barium hydroxide, etc.; alkali metal alkoxides, such as sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.; NHR R where each of R and R , which can be the same or different, is C ~ C alkyl; NH R where R is C ~ C alkyl; quaternary amine hydroxides, such as tetrabutylammonium hydroxide, benzyltrimethylamonium hydroxide, etc.; NaH; and NaNH , with an alkali metal alkoxide, particular, sodium methoxide, NaH, or NaNH being preferred for greater stereoselectivity. The amount of the base can be varied according to which kind of base is used. The amount of the base can be about 3 equivalents or greater, preferably, about 7 equivalents, with respect to 1 equivalent of the compound of formula (3).
[25] The compound of formula (3) and the compound of formula (4) are reacted by asymmetric aldol condensation in a polar organic solvent, preferably, methanol, for 1 hour. About 1 equivalent of the compound of formula (4) can be used with respect to 1 equivalent of the compound of formula (3). However, in consideration of that the compound of formula (4) is cheaper than the compound of formula (3), it is preferable that a larger amount of the composition of formula (4) than the composition of formula (3) is used.
[26] The compound of formula (3) can be synthesized as follows. Initially, D- N-benzylproline is prepared by reacting D-proline and benzylchloride. D- 2-[N-(N'-benzylprolyl)amino]benzophenone is prepared by reacting the D- N-benzylproline and 2-aminobenzophenone. Finally, the D- 2+ 2-[N-(N'-benzylprolyl)amino]benzophenone, a salt containing M where M can be Cu Ni +, or Zn +) or a hydrate of the salt, and glycine are reacted to obtain the compound of formula (3). These processes of synthesizing the compound of formula (3) are illustrated in reaction scheme (1) below
[27] Reaction scheme (1)
Figure imgf000009_0001
Compound of formula (3)
Figure imgf000009_0002
[28] In the preparation of D-N-benzylproline, D-proline and benzylchloride can be reacted in alcohol such as isoprolyl alcohol, etc. in the presence of a base such as potassium hydroxide, etc. at a temperature of about 40 °C for about 6 hours.
[29] In the preparation of D-2-[N-(N'-benzylprolyl)amino]benzophenone, the D- N-benzylproline and 2-aminobenzophenone can be reacted in a common organic solvent such as dichloromethane, etc., in the presence of thionylchloride (SOCl ). In particular, while maintaining a solution of D-N-benzylproline in dichloromethane at a temperature of about -20 ~ -30 °C , thionylchloride (SOCl ) is dropwise added into the solution, and 2-aminobenzophenone is slowly added thereto.
[30] In addition, the reacting of the D-2-[N-(N'-benzylprolyl)amino]benzophenone, a salt containing M selected from among Cu +, Ni + and Zn + or a hydrate of the salt, and glycine can be performed in an alcoholic solvent such as methanol at a temperature of 40 ~ 50 °C in the presence of a base such as potassium hydroxide, etc. Examples of the salt containing Cu +, Ni +, or Zn + include a nitrate such as Ni(NO ) , etc., a halogenate such as NiCl , NiBr , etc., an acetate such as Ni(OAc) , etc., and a sulfate such as NiSO 2+ τ .2+ 2+ , etc. The hydrate of the salt containing Cu , Ni , or Zn can have any form, and preferably, can be Ni(NO ) • 6H O. [31] The method of preparing droxidopa using the compound of formula (3) as a starting material according to the present invention is illustrated in reaction scheme (2) below. [32] Reaction scheme (2)
Figure imgf000010_0001
Figure imgf000010_0002
Figure imgf000010_0003
1 a
[33] In another aspect, the present invention provides a useful intermediate obtained in the preparation of droxidopa. The useful intermediate is the compound of formula (2) and/or the compound of formula (3).
Figure imgf000011_0001
•••(3) [34] In formulae (2) and (3), R , R , and M are the same as defined above. Advantageous Effects
[35] As described above, L-threo-(2S,3R)-3-(3,4-dihydroxyphenyl)serine or a salt thereof can be prepared with high purity and high yield according to the method of the present invention. In addition, the compound of formula (2) and/or the compound of formula (3) according to the present invention can be used when preparing droxidopa. Best Mode
[36] Hereinafter, the present invention will be described in greater detail with reference to the following examples. The following examples are for illustrative purposes and are not intended to limit the scope of the invention.
[37] Example 1. Synthesis of D-N-benzylproline
[38] A suspension of D-proline (115 g, 1 mol), potassium hydroxide (168.3 g, 3 mol), and isopropylalcohol (IL) was stirred at 40 °C until the suspension became transparent. Next, 137.3 g (1.1 mol) of benzylchloride was slowly added thereto and stirred at 40 °C for 6 hours. The reaction mixture was cooled to 0 ~ 5 °C and adjusted to pH 5-6 using 145 mL of cone. HC1. The reaction mixture was diluted using 3 L of chloroform and stirred for 18 hours. Potassium chloride was removed from the reaction mixture by filtration, and the filtrate was concentrated and recrystallized using acetone to obtain the subtitled compound with a yield of 79% (161.8 g).
[39] 1 H-NMR(CDC13,ppm) : δ 7.2 ~ 7.4(m, 5H), 4.0 ~ 4.4(dd, 2H), 3.8(dd,lH), 3.6 ~ 3.7(m,lH), 2.8(dd,lH), 1.8 ~ 2.4(m,4H)
[40] [α] 25 = + 28.4 (c = 1, EtOH)
[41] Melting point = 174 ~ 175 °C
[42] Example 2. Synthesis of D-2-rN-(N'-benzylprolyl) aminolbenzophenone
[43] While maintaining a solution of D-N-benzylproline (100 g, 487 mmol) in dichloromethane (500mL) at a temperature of -20 ~ -30 °C , 35.5 mL (487mmol) of thionylchloride (SOCl ) was dropwise added into the solution. The solution was stirred while maintaining the temperature at -10 °C until the solution became transparent. A solution of 2-aminobenzophenone (86.5 g, 438 mmol) in dichloromethane (250 mL) was dropwise added into the solution while maintaining the temperature of the solution at -30 °C . After confirming the consumption of acylchloride as a result of the reaction, the reaction mixture was cooled to 0 °C , and an aqueous sodium carbonate solution was added thereinto. The product was extracted from the reaction mixture using dichloromethane, washed with distilled water and saturated salt water, and concentrated by drying using anhydrous magnesium sulfate. The residual material was re- crystallized using ethanol and filtrated to obtain the subtitled compound with a yield of 74% (126 g).
[44] 1 H-NMR(CDC1 ,ppm) : δ 7.0 ~ 8.62(m, 14H), 3.6 ~ 4.0(d, 2H), 3.4(dd,lH), 3.1 ~ 1.8(m,6H)
[45] [α] 25= + 133.1 (c = 0.5, MeOH)
[46] Melting point = 100 ~ 100.5 °C
[47] Example 3. Synthesis of glvcine-Ni-D-2-rN-(N'-benzylprolyl)aminolbenzophenone
[48] D-2-[N-(N'-benzylprolyl)amino]benzophenone (60 g, 156 mmol), Ni(NO ) • 6H O (91 g, 312 mmol), glycine (58.5 g, 780 mmol) were dissolved in 600 mL of methanol. The mixture was heated to 40 ~ 50 °C until the color of the reaction mixture changed green. A solution of potassium hydroxide (61.3 g, 1.1 mol) in 250 mL of methanol was dropwise added and stirred for 1 hour while maintaining the temperature of the reaction mixture at 45 ~ 55 °C . The temperature of the reaction mixture was lowered to 10 °C , and 55 mL of acetic acid was dropwise added. The volume of the reaction mixture was adjusted to 2. 5L by adding water and stirred for 6 hours. The resulting solid was filtered and washed with water to obtain the subtitled compound with a yield of 75% (58 g). [49] 1 H-NMR(CDC1 ,ppm) : δ 8.2 ~ 6.6(m, 14H), 4.4(d, 1H), 3.68(s, 2H), 3.5(d,lH), 3.9 ~ 1.8(m,7H)
[50] [α] 25= - 2005 (c = 0.5, MeOH)
[51] Example 4. Synthesis of l-hydroxy-l-(3.4-dibenzyloxyphenyl)glycine-Ni-D-2-rN- (N'-benzylprolyl)aminolbenzophenone
[52] < Method 1 > 18.4 g (58 mmol) of 3,4-dibenzyloxybenzaldehyde, sodium methoxide (20mL 28% in MeOH, 90mmol), and 20 g (40 mmol) of glycine- Ni-D-2-[N-(N'-benzylprolyl)amino]benzophenone, and 50 mL of methanol were put into a dried flask with a nitrogen balloon and stirred for 1 hour. After confirming the completion of the reaction, 3,4-dibenzyloxybenzaldehyde which remained undissolved was removed by filtration. The filtrate was dropwise added into 40 mL of 20% acetic acid, and the resulting solid product was filtrated. The solid product was washed with water and dried to obtained the subtitled compound in red with a yield of 82% (26.8 g).
[53] 1 H-NMR(CDC1 ,ppm) : δ 8.6 ~ 6.0(m, 27H), 5.2 ~ 3.5(d, 8H), 4.6 ~ 1.4(m, 7H)
[54] [α] D 25= + 563.2 (c = 0.5, CHC13 )
[55] < Method 2 > 0.18 g (25mmol) lithium was dissolved in 10 mL of methanol, and 5 g (10 mmol) of glycine -Ni-D-2-[N-(N'-benzylprolyl)amino]benzophenone was added into the solution at room temperature in a nitrogen atmosphere. After stirring the solution for 10 minutes, 6.4 g (20 mmol) of 3,4-dibenzyloxybenzaldehyde was added into the solution and stirred for 30 minutes at 50 °C . The reaction mixture was filtrated to remove 3,4-dibenzyloxybenzaldehyde which remained undissolved. The filtrate was dropwise added into 10 mL of 20% acetic acid, and the resulting solid product was filtrated. The resulting solid product was washed with water and dried to obtain the subtitled compound in red with a yield of 80% (6.53 g).
[56] 1 H-NMR(CDC1 , ppm) : δ 8.6 ~ 6.0(m, 27H), 5.2 ~ 3.5(d, 8H), 4.6 ~ 1.4(m, 7H)
[57] [α] D 25= + 563.2 (c = 0.5, CHC13 )
[58] Example 5. Synthesis of L-threo-(2S.3R)-3-(3.4-dibenzyloxyphenyl)serine
[59] 5 g (6 mmol) of l-hydroxy-l-(3,4-dibenzyloxyphenyl)glycine-Ni-D-2-[N-(N'- ben- zylprolyl)amino]benzophenone was suspended in a mixed solvent of 75 mL of methanol and 37.5 mL of 5N-HC1 and heated to 50 °C . The reaction mixture was stirred for 1 hour. After confirming the completion of the reaction, the methanol in the reaction mixture was evaporated, and the pH of the reaction mixture was adjusted to 6.6. The resulting solid product was filtered and washed with water. The solid product was completely dried, suspended in acetone, and filtrated. The resulting solid product was dried to obtain the subtitled compound with a yield of 93 % (2.2 g).
[60] Melting point = 119.5 ~ 120.4 °C
[61] 1 H-NMR(DMSO-d ,ppm) : δ 7.25 - 6.8(m, 13H), 5.1(s, 4H), 5.0(d, 1H), 3.25(d, 6 1H) [62] Example 6. Synthesis of L-threo-(2S.3R)-3-(3.4-dihydroxyphenyl)serine)
[63] 7 g (18 mmol) of L-threo-3-(3,4-dibenzyloxyphenyl)serine was suspended in 400 mL of ethanol, and 100 mL of cone. HCl and 600 mg of 10% of Pd/C was added into the reaction mixture, and stirred under the pressure of l-2atm hydrogen. The reaction mixture was filtrated to remove Pd/C. The filtrate was concentrated, dissolved in ethanol, and adjusted to pH 5 using a mixture of diethylamine and ethanol. The reaction mixture was stirred for 24 hours at 0 °C . The resulting solid product was filtrated and washed with ethanol and ether to obtain the subtitled compound with a yield of 85% (3.16 g).
[64] 1 H-NMR(D O/NaOH,ppm) : δ 6.5(dd, 2H), 6.4(d, 1H), 4.7(d, 1H)
[65] [α] 25= -39 (c = l, 1N HC1)
[66] Melting point = 232 ~ 243 °C

Claims

Claims
[1] A method of preparing L-threo-(2S,3R)-3-(3,4-dihydroxyphenyl)serine or a salt thereof, the method comprising: obtaining a compound of formula (lb) below by decomposing a compound of formula (2) below in a polar organic solvent using an acid; and hydrogenating the compound of formula (lb):
Figure imgf000015_0001
• •(lb)
Figure imgf000015_0002
• •(2) 1 2 w vhheeπrein each of R and R is independently selected from the group consisting of benzyl, p-nitrobenzyl, p-fluorobenzyl, p-trifluorobenzyl, C ~ C alkoxy C ~ C alkyl, and C ~ C alkyl; and M is Cu 2+ , N τi-2+ , or Zn 2+ 1 4
[2] The method of claim 1, wherein both R 1 and R 2 are benzyl.
[3] The method of claim 1, wherein the polar organic solvent is selected from the group consisting of C ~ C alcohol, tetrahydrofuran, acetonitrile, dimethyl- formamide, and a mixture thereof.
[4] The method of claim 1, wherein the acid is selected from the group consisting of hydrochloric acid, bromic acid, sulfuric acid, nitric acid, acetic acid, and triflu- oroacetic acid.
[5] The method of claim 4, wherein the hydrogenating the compound of formula (lb) is performed by adding hydrogen in the presence of a metal and an acid.
[6] The method of any one of claims 1 through 5, wherein the compound of formula (2) is obtained by reacting a compound of formula (3) below and a compound of formula (4) below in the presence of a base:
Figure imgf000016_0001
•••(4) 1 2 wherein R , R , and M are the same as defined above.
[7] The method of claim 6, wherein the base is selected from the group consisting of alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal alkoxides, NHR R where each of R and R , which can be the same or different, is C 1 C 7 alkyl, NH RJ where R is C C alkyl, quaternary amine hydroxides, NaH, and J 2 1 y NaNH . 2
[8] The method of claim 6, wherein the compound of formula (3) is obtained by: preparing D-N-benzylproline by reacting D-proline and benzylchloride; preparing D-2-[N-(N'-benzylprolyl)amino]benzophenone by reacting the D- N-benzylproline and 2-aminobenzophenone; and reacting the D-2-[N-(N'-benzylprolyl)amino]benzophenone, with a salt containing M where M is Cu +, Ni +, or Zn + or a hydrate of the salt, and glycine.
[9] A compound of formula (2) below:
Figure imgf000017_0001
•••(2) , ι wherein R , R , and M are the same as defined in claim 1.
PCT/KR2005/000604 2004-03-05 2005-03-04 Method of preparing optically active serine derivative WO2005085178A1 (en)

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US8008285B2 (en) 2007-03-09 2011-08-30 Chelsea Therapeutics, Inc. Droxidopa and pharmaceutical composition thereof for the treatment of fibromyalgia
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WO2008137923A2 (en) * 2007-05-07 2008-11-13 Chelsea Therapeutics, Inc. Droxidopa and pharmaceutical composition thereof for the treatment of mood disorders, sleep disorders, or attention deficit disorders
US9364453B2 (en) 2011-05-17 2016-06-14 Lundbeck Na Ltd. Method of treating postural reflex abnormality caused by parkinson's disease
CN103086906A (en) * 2011-11-03 2013-05-08 重庆圣华曦药业股份有限公司 Droxidopa crystal and preparation method thereof
CN103086906B (en) * 2011-11-03 2015-04-01 重庆圣华曦药业股份有限公司 Droxidopa crystal and preparation method thereof
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WO2020194138A1 (en) * 2019-03-22 2020-10-01 Piramal Enterprises Limited An improved process for the preparation of eliglustat and its intermediate

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