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WO2022157633A1 - Enantiomerically pure desglymidodrine and process for preparation thereof - Google Patents

Enantiomerically pure desglymidodrine and process for preparation thereof Download PDF

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Publication number
WO2022157633A1
WO2022157633A1 PCT/IB2022/050432 IB2022050432W WO2022157633A1 WO 2022157633 A1 WO2022157633 A1 WO 2022157633A1 IB 2022050432 W IB2022050432 W IB 2022050432W WO 2022157633 A1 WO2022157633 A1 WO 2022157633A1
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WO
WIPO (PCT)
Prior art keywords
desglymidodrine
acid
pharmaceutically acceptable
enantiomerically pure
solvate
Prior art date
Application number
PCT/IB2022/050432
Other languages
French (fr)
Inventor
Kumar Kamlesh SINGH
Sanjay Jagdish Desai
V Tadikonda PRATAP
Mahesh Laljibhai Rupapara
Rajesh Amrutlal PANDYA
Original Assignee
Cadila Healthcare Limited
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Filing date
Publication date
Application filed by Cadila Healthcare Limited filed Critical Cadila Healthcare Limited
Publication of WO2022157633A1 publication Critical patent/WO2022157633A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/64—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms
    • C07C217/66—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms with singly-bound oxygen atoms and six-membered aromatic rings bound to the same carbon atom of the carbon chain
    • C07C217/70—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms with singly-bound oxygen atoms and six-membered aromatic rings bound to the same carbon atom of the carbon chain linked by carbon chains having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
    • 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 invention relates to enantiomerically pure desglymidodrine and process for preparation thereof.
  • the invention relates to enantiomerically pure desglymidodrine or a pharmaceutically acceptable salt, solvate or a hydrate, thereof.
  • the invention relates to individual enantiomers of desglymidodrine in chirally pure form or a pharmaceutically acceptable salt, solvate or a hydrate, thereof.
  • the invention also relates to the process for their preparation, pharmaceutical compositions comprising the same and use thereof in eliciting vasopressor or antihypotensive effect in mammals.
  • Midodrine a vasopressor/antihypotensive agent
  • desglymidodrine which is chemically 1-(2,5-dimethoxyphenyl)-2-aminoethanol and can be represented by the following structure, Desglymidodrine being an active me .tabolite of midodrine and having a chiral centre, there have been attempts to obtain individual enantiomers of desglymidodrine, to investigate the biological activities of the racemic compound and the individual enantiomers.
  • an enantiomerically pure (R)-(-)- desglymidodrine compound or a pharmaceutically acceptable salt, solvate or a hydrate, thereof.
  • an enantiomerically pure (R)-(-)- desglymidodrine having a chiral purity of 98.5% or more, and free of its (S)-(+)- isomer, by area percentage of HPLC, or a pharmaceutically acceptable salt, solvate or a hydrate, thereof.
  • an enantiomerically pure (R)-(-)- desglymidodrine having a chemical purity of 98% or more, by area percentage of HPLC, or a pharmaceutically acceptable salt, solvate or a hydrate, thereof.
  • (R)-(-)-desglymidodrine having chemical purity of 98.5% or more by area percentage of HPLC, or pharmaceutically acceptable salt, solvate or hydrate, thereof.
  • an acid addition salt of desglymidodrine with a chiral auxiliary there is provided a composition comprising an enantiomerically pure (R)-(-)-desglymidodrine having a chemical purity of 98 % or more and a chiral purity of 98.5% or more, by area percentage of HPLC, or pharmaceutically acceptable salt, solvate or a hydrate, thereof.
  • a pharmaceutical composition comprising enantiomerically pure (R)-(-)-desglymidodrine, or a pharmaceutically acceptable salt, solvate or a hydrate thereof and a pharmaceutically acceptable carrier, excipient or diluent.
  • a pharmaceutical composition comprising an enantiomerically pure (R)-(-)-desglymidodrine having a chiral purity of about 98.5% or more, and free of its (S)-(+)-isomer, or a pharmaceutically acceptable salt, solvate or hydrate, thereof; and a pharmaceutically acceptable carrier, excipient or diluent.
  • a pharmaceutical composition comprising an enantiomerically pure (R)-(-)-desglymidodrine having a chemical purity of about 98% or more, or a pharmaceutically acceptable salt, solvate or a hydrate, thereof and a pharmaceutically acceptable carrier, excipient or diluent.
  • FIG. 1 Shows chemical purity by area percentage of HPLC of R-(-)- desglymidodrine in batch-1 of Table-1.
  • FIG.2 Shows chiral purity by area percentage of HPLC of R-(-)-desglymidodrine in batch-1 of Table-1.
  • FIG. 3 Shows chemical purity by area percentage of HPLC of R-(-)- desglymidodrine in batch-2 of Table-1.
  • FIG.4 Shows chiral purity by area percentage of HPLC of R-(-)-desglymidodrine in batch-2 of Table-1.
  • FIG. 5 Shows chemical purity by area percentage of HPLC of R-(-)- desglymidodrine in batch-3 of Table-1.
  • FIG.6 Shows chiral purity by area percentage of HPLC of R-(-)-desglymidodrine in batch-3 of Table-1.
  • solution does not necessarily mean only a clear solution or the one wherein the solute is completely soluble in the solvent, all the intermediate phases of mixture of components, starting from a state wherein the solute has just started getting dissolved in the solvent to a state wherein the solute has completely dissolved in the solvent, are also included within the expression ‘solution’.
  • the ranges recited herein also include the values denoted as the limits thereof.
  • the numerical values recited as the limits are not to be construed as absolute values. Any value outside the recited ranges, wherein the difference between the values is insignificant considering the nature or the property of the variable to which the limit is applied, including any analytical variation in measuring those values, are also considered to be included within those ranges.
  • Undissolved solid and/or foreign particles, if any, can be removed before solid formation and/or solvent removal.
  • a suitable technique useful for removal of solids can be selected from, but not limited to, filtration, decantation and centrifugation.
  • the terms ‘isolating’, ‘obtaining’ and ‘purifying’ are generally interchangeable, and include but not specifically limited to decantation, extraction, filtration, evaporation, lyophilisation, spray drying, crystallization, recrystallization or chromatographic operations.
  • enantiomerically pure or “in enantiomerically pure form” as used herein in relation to desglymidodrine, relates to a composition of desglymidodrine comprising at least 98% of the one individual enantiomer and less than 2% of the other enantiomer – e.g.
  • enantiomerically pure desglymidodrine comprises more than 98% of (R)-(-)-enantiomer and less than 2% of (S)-(+)-enantiomer of desglymidodrine, or more than 98.5% of (R)-(-)-enantiomer and less than 1.5% of (S)-(+)-enantiomer of desglymidodrine, or more than 99% of (R)-(-)-enantiomer and less than 1% of (S)-(+)-enantiomer of desglymidodrine, or even more than 99.5% of (R)-(-)-enantiomer and less than 0.5% of (S)-(+)-enantiomer of desglymidodrine, by area percentage of HPLC.
  • chirally pure or “in chirally pure form” as used herein in connection to individual enantiomers of desglymidodrine, relates to a composition of desglymidodrine comprising at least 98.5% of one of the respective (R)-(+)- or (S)-(- )-enantiomer and less than 1.5% of the other enantiomer, or at least 99% of one of the respective R)-(+)- or (S)-(-)-enantiomer and less than 1% of the other enantiomer, or at least 99.5% of one of the respective (R)-(+)- or (S)-(-)- enantiomer and less than 0.5% of the other enantiomer, by area percentage of HPLC.
  • n% chiral purity as used herein in connection to individual enantiomers of desglymidodrine, denotes that a composition of desglymidodrine comprises at least n% of the respective individual enantiomer and (100-n)% or less of the other enantiomer – e.g. “(R)-(-)-desglymidodrine is in more than 98.5% chiral purity” relates to a composition of desglymidodrine comprising at least 98.5% of (R)- (-)-enantiomer and 1.5% or less of the (S)-(+)-enantiomer of desglymidodrine.
  • composition as used herein means a physical mixture of two or more components.
  • composition means a drug product comprising the active ingredient(s) & pharmaceutically acceptable excipient(s), as well as any product, which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients including an active ingredient.
  • the product(s) obtained may further be converted to any other physical forms thereof which includes but not specifically limited to salt(s), solvate(s), hydrate(s), co- crystal(s) and solid dispersion(s) in either crystalline or amorphous forms and/or subjected to further physical processing like milling, shifting or other suitable powder processing techniques to adjust the particle size of the product to desired levels.
  • an enantiomerically pure desglymidodrine compound In one general aspect, there is provided an enantiomerically pure desglymidodrine compound. In another general aspect, there is provided an enantiomerically pure (R)-(-)- desglymidodrine compound, or a pharmaceutically acceptable salt, solvate or a hydrate thereof. In another general aspect, there is provided an enantiomerically pure (R)-(-)- desglymidodrine having a chiral purity of 98.5% or more by area percentage of HPLC, or a pharmaceutically acceptable salt, solvate or a hydrate, thereof.
  • an enantiomerically pure (R)-(-)- desglymidodrine having a chiral purity of 98.5% or more, and free of its (S)-(+)- isomer, by area percentage of HPLC, or a pharmaceutically acceptable salt, solvate or a hydrate, thereof.
  • an enantiomerically pure (R)-(-)- desglymidodrine having a chemical purity of 98% or more, by area percentage of HPLC, or a pharmaceutically acceptable salt, solvate or a hydrate, thereof.
  • an enantiomerically pure (R)-(-)- desglymidodrine having a chemical purity of 98.5% or more, by area percentage of HPLC, or a pharmaceutically acceptable salt, solvate or a hydrate, thereof.
  • (R)-(-)-desglymidodrine having a chiral purity of 98.5% or more, by area percentage of HPLC, or pharmaceutically acceptable salt, solvate or a hydrate, thereof.
  • there is provided (R)-(-)-desglymidodrine having a chemical purity of 98.5% or more, by area percentage of HPLC, or pharmaceutically acceptable salt, solvate or a hydrate, thereof.
  • an acid addition salt of desglymidodrine with a chiral auxiliary in another general aspect, there is provided a composition comprising an enantiomerically pure (R)-(-)-desglymidodrine having a chemical purity of 98% or more; a chiral purity of 98.5% or more, by area percentage of HPLC, or pharmaceutically acceptable salt, solvate or hydrate, thereof.
  • a pharmaceutical composition comprising enantiomerically pure (R)-(-)-desglymidodrine, or a pharmaceutically acceptable salt, solvate or hydrate, thereof and a pharmaceutically acceptable carrier, excipient or diluent.
  • a pharmaceutical composition comprising an enantiomerically pure (R)-(-)-desglymidodrine having a chiral purity of about 98.5% or more, and free of its (S)-(+)-isomer, or a pharmaceutically acceptable salt, solvate or hydrate, thereof; and a pharmaceutically acceptable carrier, excipient or diluent.
  • a pharmaceutical composition comprising an enantiomerically pure (R)-(-)-desglymidodrine having a chemical purity of about 98.5% or more, or a pharmaceutically acceptable salt, solvate or hydrate, thereof; and a pharmaceutically acceptable carrier, excipient or diluent.
  • a process for the preparation of an enantiomerically pure (R)-(-)-desglymidodrine or a pharmaceutically acceptable salt, solvate or hydrate, thereof Desglymidodrine
  • a desglymidodrine compound in enantiomerically pure form there is provided a desglymidodrine compound in enantiomerically pure form and a chemical purity of 98% or more, by area percentage of HPLC.
  • (R)-(-)-desglymidodrine In another general aspect, there is provided (R)-(-)-desglymidodrine having a chiral purity of 98.5% or more, by area percentage of HPLC. In another general aspect, there is provided (R)-(-)-desglymidodrine having a chiral purity of 99% or more, by area percentage of HPLC. In another general aspect, there is provided (R)-(-)-desglymidodrine having a chiral purity of 99.5% or more, by area percentage of HPLC.
  • (R)-(-)-desglymidodrine having a chiral purity of 98.5% or more, and a chemical purity of 98% or more, by area percentage of HPLC.
  • (R)-(-)-desglymidodrine having a chiral purity of 98.5% or more, and a chemical purity of 98.5% or more, by area percentage of HPLC.
  • (R)-(-)-desglymidodrine having a chiral purity of 98.5% or more, and a chemical purity of 99% or more, by area percentage of HPLC.
  • (R)-(-)-desglymidodrine having a chiral purity of 99% or more, and a chemical purity of 99% or more, by area percentage of HPLC.
  • (R)-(-)-desglymidodrine having a chiral purity of 99% or more, and a chemical purity of 99.5% or more, by area percentage of HPLC.
  • (R)-(-)-desglymidodrine having a chiral purity of 99.5% or more, and a chemical purity of 99.5% or more, by area percentage of HPLC.
  • (R)-(-)-desglymidodrine having a chiral purity of 99.8% or more, and a chemical purity of 99.8% or more, by area percentage of HPLC.
  • (S)-(+)-desglymidodrine having a chiral purity of 98.5% or more, by area percentage of HPLC.
  • (S)-(+)-desglymidodrine having a chiral purity of 99% or more, by area percentage of HPLC.
  • (S)-(+)-desglymidodrine having a chiral purity of 99.5% or more, by area percentage of HPLC.
  • (S)-(+)-desglymidodrine having a chiral purity of 98.5% or more, and a chemical purity of 98% or more, by area percentage of HPLC.
  • (S)-(+)-desglymidodrine having a chiral purity of 98.5% or more, and a chemical purity of 98.5% or more, by area percentage of HPLC.
  • (S)-(+)-desglymidodrine having a chiral purity of 98.5% or more, and a chemical purity of 99% or more, by area percentage of HPLC.
  • (S)-(+)-desglymidodrine having a chiral purity of 99% or more, and a chemical purity of 99% or more, by area percentage of HPLC.
  • (S)-(+)-desglymidodrine having a chiral purity of 99% or more, and a chemical purity of 99.5% or more, by area percentage of HPLC.
  • (S)-(+)-desglymidodrine having a chiral purity of 99.5% or more, and a chemical purity of 99.5% or more, by area percentage of HPLC.
  • (S)-(+)-desglymidodrine having a chiral purity of 99.8% or more, and a chemical purity of 99.8% or more, by area percentage of HPLC.
  • desglymidodrine compound can be obtained in enantiomerically pure form by preparing a diastereomeric salt form thereof.
  • desglymidodrine compound can be obtained in enantiomerically pure form by reacting desglymidodrine compound with a chiral auxiliary comprising one or more of a resolving acid selected from (+) and (-) - tartaric acid, (+) and (-)-di-p-tolyl-tartaric acid, (+) and (-)-mandelic acid and (+) and (-)-camphor sulphonic acid or an amino acid selected from D and L-glutamic acid, D and L-aspartic acid, and D and L-pyroglutamic acid.
  • a resolving acid selected from (+) and (-) - tartaric acid, (+) and (-)-di-p-tolyl-tartaric acid, (+) and (-)-mandelic acid and (+) and (-)-camphor
  • the neutralization of the diastereomeric salt can be performed using a base in the presence of one or more solvents.
  • the bases can be selected from one or more of sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate and potassium carbonate.
  • the solvent can be selected from one or more of water, ethyl acetate, tetrahydrofuran, acetone, and methyl ethyl ketone.
  • the desglymidodrine is reacted with L-(+)-tartaric acid to obtain L-(+)-tartaric acid salt of desglymidodrine, which upon neutralization provides (S)-(+)-desglymidorine in enantiomerically pure form.
  • desglymidodrine is reacted with D-(-)-tartaric acid to obtain D-(-)-tartaric acid salt of desglymidodrine, which upon neutralization provides (R)-(-)-desglymidorine in enantiomerically pure form.
  • desglymidodrine is reacted with S-(+)-mandelic acid to obtain S-(+)-mandelic acid salt of desglymidodrine, which upon neutralization provides (S)- (+)-desglymidorine in enantiomerically pure form.
  • desglymidodrine is reacted with R-(-)-mandelic acid to obtain R-(-)-mandelic acid salt of desglymidodrine, which upon neutralization provides (R)-(-)-desglymidorine in enantiomerically pure form.
  • desglymidodrine is reacted with Boc-L-glutamic acid to obtain Boc-L-Glutamic acid salt of desglymidodrine, which upon neutralization provides (R)-(-)-desglymidorine in enantiomerically pure form.
  • desglymidodrine is reacted with Boc-L-serine to obtain Boc-L-serine salt of desglymidodrine, which upon neutralization provides desglymidorine in enantiomerically pure form.
  • desglymidodrine is reacted with L-Pyroglutamic acid to obtain L-Pyroglutamic acid salt of desglymidodrine, which upon neutralization provides (S)- (+)-desglymidorine in enantiomerically pure form.
  • a diastereomeric salt of desglymidodrine there is provided a mandelic acid salt of desglymidodrine.
  • R-(-)-mandelic acid salt of desglymidodrine there is provided S-(+)-mandelic acid salt of desglymidodrine.
  • R-(-)-mandelic acid salt of desglymidodrine In another general aspect, there is provided R-(-)-mandelic acid salt of desglymidodrine. In another general aspect, there is provided S-(+)-mandelic acid salt of (S)-(+)- desglymidodrine. In another general aspect, there is provided a process for the preparation of desglymidodrine in enantiomerically pure form comprising neutralising a diastereomeric salt of desglymidodrine.
  • a process for the preparation of a diastereomeric salt of desglymidodrine comprising reacting a racemic desglymidodrine with a chiral resolving acid to obtain a diastereomeric salt of desglymidodrine.
  • the chiral resolving acid is selected from the group comprising one or more of (+) and (-)-tartaric acid, (+) and (-)-di-p-tolyl-tartaric acid, (+) and (-)- mandelic acid and (+) and (-)-camphor sulphonic acid or an amino acid selected from D and L-glutamic acid, D and L-aspartic acid, and D and L-pyroglutamic acid.
  • the solvent can be selected from one or more of water, ethyl acetate, tetrahydrofuran, acetone and methyl ethyl ketone.
  • a process for the preparation of enantiomerically pure (R)-(-)-desglymidodrine comprising: (a) reacting a racemic desglymidodrine with a chiral resolving acid to obtain a diastereomeric salt; and (b) neutralizing the diastereomeric salt to obtain (R)-(-)-desglymidodrine.
  • the chiral resolving acid at stage (a) is selected from (+) and (-) -tartaric acid, (+) and (-)-di-p-tolyl-tartaric acid, (+) and (-)-mandelic acid and (+) and (-)- camphor sulphonic acid or an amino acid selected from D and L-glutamic acid, D and L-aspartic acid, and D and L-pyroglutamic acid.
  • a process for the preparation of enantiomerically pure (S)-(+)-desglymidodrine comprising: (a) reacting a racemic desglymidodrine with chiral resolving acid to obtain a diastereomeric salt; and (b) neutralizing the salt to obtain (S)-(+)-desglymidodrine.
  • the chiral resolving acid at stage (a) is selected from (+) and (-) -tartaric acid, (+) and (-)-di-p-tolyl-tartaric acid, (+) and (-)-mandelic acid and (+) and (-)- camphor sulphonic acid or an amino acid selected from D and L-glutamic acid, D and L-aspartic acid, and D and L-pyroglutamic acid.
  • the neutralization of the diastereomeric salt can be performed using a base in the presence of one or more solvents.
  • the base can be selected from sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, and potassium carbonate.
  • the solvent can be selected from one or more of water, ethyl acetate, tetrahydrofuran, acetone and methyl ethyl ketone.
  • desglymidodrine compound can be obtained in enantiomerically pure form by chiral reduction of a compound of Formula I to obtain a compound of Formula II, and converting the compound of Formula II to desglymidodrine, wherein, X is -Cl, -Br, -F, -I, -NR 1 R 2 , or -OSO 2 R; and * denotes the chiral center, and, wherein, each of R 1 and R 2 is individually -H, -substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted aryl; or R 1 and R 2 together with the N atom to which they are attached form a monocyclic or bicyclic hetero
  • the compound of Formula I is reduced in the presence of a chiral reducing agent to obtain the compound of Formula II.
  • a chiral reducing agent can be selected from a group comprising borane; catecholborane; chiral oxazaborolidine; a chiral diamine or chiral amino alcohol in presence of a ruthenium, iridinium or rhodium catalyst; and Pd/phosphine complex in 2,2,2-trifluoroethanol.
  • the compound of Formula I wherein X is –Cl, -Br or -I, is reacted with R-(+)-methyl-CBS-oxaborolidine and borane-dimethyl sulfide to obtain corresponding compound of Formula II, which is treated with ammonia, or with potassium phthalimide followed by hydrolysis, to obtain (R)-(-)-desglymidodrine in enantiomerically pure form.
  • the compound of Formula I is reduced in the presence of a suitable carbonyl reductases enzyme, optionally in the presence of cofactors NADH or NADPH, to obtain the compound of Formula II.
  • the carbonyl reductases enzyme can be an isolated enzyme, which may be immobilized on a solid support; a whole cell microorganism; or cultured cells from plant or animal.
  • the carbonyl reductases enzyme can be selected from a group comprising S1 from Candida magnolia, KaCR from Kluyveromyces aestuarii, and PsCR I from Pichia stipites.
  • the whole cell microorganism can be selected from Saccharomyces cerevisiae, Penicillium citrinum, Aspergillus sclerotiorum, Aspergillus sydowii, Geotrichum candidum and Rhodotorula rubra.
  • the “substantially free” herein means, the N-acetyl impurity is present to the level of 0.05% or less, particularly to the level of 0.03% or less, more particular to the level of 0.01% or less, are area percentage of HPLC.
  • the “substantially free” herein means, the 2,5-dimethoxybenzaldehyde impurity is present to the level of 0.15% or less, more particular to the level of 0.1% or less, more particularly to the level of 0.05% or less, by area percentage of HPLC.
  • HPLC method for related substance and chemical purity Related substance HPLC method is carried out into a waters HPLC system. with photodiode array detector using a Kromasil C18 (250 x 4.6) mm, 5.0 ⁇ m column.
  • Mobile phase-A 100 % of 10 mM dipotassium hydrogen phosphate in water (pH adjusted to 3.5 ⁇ 0.05 using diluted orthophosphoric acid),
  • Mobile phase-B Mixture of Acetonitrile and Water in the ratio of 80: 20 (%v/v) Flow rate: 1.0 ml/minute at 225 nm.
  • HPLC method of chiral purity S-Isomer method is carried out into a waters HPLC System with photodiode array detector using a CHIRALPAK AGP (150 x 4.0) mm, 5.0 ⁇ m column.
  • Mobile phase A mixture of 1000 ml of 10 mM Ammonium acetate in water (pH adjusted to 5.8 ⁇ 0.05 using diluted acetic acid) and 20 ml of acetonitrile.
  • Flow rate 0.5 ml/minute at 210 nm.
  • Column oven temperature is 25°C. Sample concentration injected 500 ⁇ g/ml. Examples: The embodiments of the invention can further be illustrated by following examples.
  • Example-1 (R)-(-)-Mandelic Acid Salt of (R)-(-)-Desglymidodrine
  • 100 g desglymidodrine and 38.6 g R-(-)-mandelic acid were stirred in a mixture of 300 mL isopropyl alcohol and 500 mL methyl t-butyl ether for 30-60 min at 55-65 °C, followed by 2-3 hours at 25-35 °C.
  • Example-2 (R)-(-)-Mandelic Acid Salt of (R)-(-)-Desglymidodrine
  • 100 g Desglymidodrine and 38.6 g R-(-)-mandelic acid were stirred in a mixture of 300 mL isopropyl alcohol and 500 mL methyl t-butyl ether for 30-60 min at 55-65 °C and cooled to 30-35 °C.
  • Example-3 (R)-(-)-Desglymidodrine Part-A: (R)-2-chloro-1-(2,5-dimethoxyphenyl) ethan-1-ol: Borane–dimethyl sulfide in Tetrahydrofuran (2M, 14 ml) was added to a stirring solution of (R)-(+)-Methyl- CBS-oxazaborolidine in Toluene (1M, 4.65 mL) and 25 mL Tetrahydrofuran at 0-10 °C and stirred for 15-30.
  • Part-B (R)-(-)-Desglymidodrine: 250 mL aqueous ammonia was added to a stirring mixture of 10 g (R)-2-chloro-1-(2,5-dimethoxyphenyl) ethan-1-ol in 125 mL methanol and stirred for 32-38 h at 20-30 °C. After reaction completion, the solvent volume was reduced by distillation at reduced pressure. Aqueous sodium hydroxide was added to the resultant mass at 0-10 °C under stirring. The resultant solid was filtered, washed with chilled water and dried to obtain (R)-(-)-Desglymidodrine (5 g).
  • Example-4 (R)-(-)-Desglymidodrine
  • 60 g Sodium hydroxide in 300 mL water was added to a stirring mixture of 100 g (R)-(-)-mandelic acid salt of (R)-(-)-Desglymidodrine in 500 mL water and stirred for 30-45 min at 25-35 °C followed by 1-2 hours at 0-10 °C.
  • the resultant mass was filtered, washed with water and dried to obtain 51 g (R)- (-)- Desglymidodrine.
  • Example-5 Preparation of (R)-(-)-desglymidodrine
  • 1000 mL ethyl acetate, 100 g racemic-desglymidodrine and 38.57 g R-(-)-mandelic acid were taken and stirred at 25 to 30 °C for 6 to 7 hours.
  • the solid was filtered to obtain a wet cake.
  • the wet cake was again stirred with 400 mL ethyl acetate at 60 to 70 °C and cooled and filtered to obtain a mandelate salt compound of Formula (II).

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Abstract

The invention relates to enantiomerically pure desglymidodrine and process for preparation thereof. In particular, the invention relates to enantiomerically pure desglymidodrine or a pharmaceutically acceptable salt, solvate or a hydrate, thereof. More particularly, the invention relates to individual enantiomers of desglymidodrine in chirally pure form or a pharmaceutically acceptable salt, solvate or a hydrate, thereof. The invention also relates to the process for their preparation, pharmaceutical compositions comprising the same and use thereof in eliciting vasopressor or antihypotensive effect in mammals.

Description

ENANTIOMERICALLY PURE DESGLYMIDODRINE AND PROCESS FOR PREPARATION THEREOF FIELD OF THE INVENTION The invention relates to enantiomerically pure desglymidodrine and process for preparation thereof. In particular, the invention relates to enantiomerically pure desglymidodrine or a pharmaceutically acceptable salt, solvate or a hydrate, thereof. More particularly, the invention relates to individual enantiomers of desglymidodrine in chirally pure form or a pharmaceutically acceptable salt, solvate or a hydrate, thereof. The invention also relates to the process for their preparation, pharmaceutical compositions comprising the same and use thereof in eliciting vasopressor or antihypotensive effect in mammals. BACKGROUND OF THE INVENTION The following discussion of background is intended to present the invention in an appropriate technical context and allow its significance to be properly appreciated. Midodrine, a vasopressor/antihypotensive agent, is a prodrug that, after oral administration, is converted to its active metabolite desglymidodrine which is chemically 1-(2,5-dimethoxyphenyl)-2-aminoethanol and can be represented by the following structure,
Figure imgf000002_0001
Desglymidodrine being an active me .tabolite of midodrine and having a chiral centre, there have been attempts to obtain individual enantiomers of desglymidodrine, to investigate the biological activities of the racemic compound and the individual enantiomers. Many approaches have been reported in the art to obtain chirally pure enantiomers of desglymidodrine, e.g by resolution of midodrine into its individual enantiomers followed by hydrolysis or through derivatization of midodrine or desglymidodrine with a chiral auxiliary. Methods are also reported in art for chromatographic separation and/or determination of chiral purity of desglymidodrine samples. Quaglia et. al. (Chirality 16:356–362 (2004)) reported that (+)-enantiomer of desglymidodrine is practically inactive, while at the same concentration, racemic desglymidodrine and its (-)-enantiomer gave maximum effect. Therefore, it is desirable to obtain individual enantiomers of desglymidodrine with higher levels of chiral purities. Though multiple approaches and methods are reported in the art, none has been able to provide desglymidodrine enantiomers in chirally pure form as required in the field of the pharmaceuticals, suitable for making medicaments for human consumption, e.g. Christine (WO 94/00593) could obtain the dextro- enantiomer in 96.5% chiral purity through chemical transformations; while Quaglia et. al., after obtaining individual enantiomers of midodrine by resolution, hydrolysis of the same to obtain individual enantiomers followed by purification using controlled capillary electrophoresis involving a chiral selector, could obtain individual enantiomers of desglymidodrine in 98% and 95.2% chiral purities only. Therefore, there is an unmet need to obtain the individual enantiomers of desglymidodrine in enantiomerically pure form. SUMMARY OF THE INVENTION In one general aspect, there is provided an enantiomerically pure desglymidodrine compound. In another general aspect, there is provided an enantiomerically pure (R)-(-)- desglymidodrine compound, or a pharmaceutically acceptable salt, solvate or a hydrate, thereof. In another general aspect, there is provided an enantiomerically pure (R)-(-)- desglymidodrine having a chiral purity of 98.5% or more by area percentage of HPLC, or a pharmaceutically acceptable salt, solvate or a hydrate, thereof. In another general aspect, there is provided an enantiomerically pure (R)-(-)- desglymidodrine having a chiral purity of 98.5% or more, and free of its (S)-(+)- isomer, by area percentage of HPLC, or a pharmaceutically acceptable salt, solvate or a hydrate, thereof. In another general aspect, there is provided an enantiomerically pure (R)-(-)- desglymidodrine having a chemical purity of 98% or more, by area percentage of HPLC, or a pharmaceutically acceptable salt, solvate or a hydrate, thereof. In another general aspect, there is provided (R)-(-)-desglymidodrine having chemical purity of 98.5% or more by area percentage of HPLC, or pharmaceutically acceptable salt, solvate or hydrate, thereof. In another general aspect, there is provided an acid addition salt of desglymidodrine with a chiral auxiliary. In another general aspect, there is provided a composition comprising an enantiomerically pure (R)-(-)-desglymidodrine having a chemical purity of 98 % or more and a chiral purity of 98.5% or more, by area percentage of HPLC, or pharmaceutically acceptable salt, solvate or a hydrate, thereof. In another general aspect, there is provided a pharmaceutical composition comprising enantiomerically pure (R)-(-)-desglymidodrine, or a pharmaceutically acceptable salt, solvate or a hydrate thereof and a pharmaceutically acceptable carrier, excipient or diluent. In another general aspect, there is provided a pharmaceutical composition comprising an enantiomerically pure (R)-(-)-desglymidodrine having a chiral purity of about 98.5% or more, and free of its (S)-(+)-isomer, or a pharmaceutically acceptable salt, solvate or hydrate, thereof; and a pharmaceutically acceptable carrier, excipient or diluent. In another general aspect, there is provided a pharmaceutical composition comprising an enantiomerically pure (R)-(-)-desglymidodrine having a chemical purity of about 98% or more, or a pharmaceutically acceptable salt, solvate or a hydrate, thereof and a pharmaceutically acceptable carrier, excipient or diluent. In another general aspect, there is provided a process for the preparation of an enantiomerically pure (R)-(-)-desglymidodrine or a pharmaceutically acceptable salt, solvate or a hydrate, thereof. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1: Shows chemical purity by area percentage of HPLC of R-(-)- desglymidodrine in batch-1 of Table-1. FIG.2: Shows chiral purity by area percentage of HPLC of R-(-)-desglymidodrine in batch-1 of Table-1. FIG. 3: Shows chemical purity by area percentage of HPLC of R-(-)- desglymidodrine in batch-2 of Table-1. FIG.4: Shows chiral purity by area percentage of HPLC of R-(-)-desglymidodrine in batch-2 of Table-1. FIG. 5: Shows chemical purity by area percentage of HPLC of R-(-)- desglymidodrine in batch-3 of Table-1. FIG.6: Shows chiral purity by area percentage of HPLC of R-(-)-desglymidodrine in batch-3 of Table-1. DETAILED DESCRIPTION OF THE INVENTION The invention can be further understood in light of the description of the embodiments provided herein after. It is to be understood that the description, in no way, is intended to limit the scope of the invention to the expressly specified embodiments only. The equivalents and variants thereof or trivial modifications thereof which are apparently obvious to those skilled in the art, are also intended to be included within the scope of the present invention. Detailed description of routine and conventional unit operations, which are easily understood by the skilled artisan, are not included herein. Such routine unit operations are to be construed as ordinarily understood and as routinely practiced by the person skilled in the field of the invention, unless otherwise specifically described. The term “solution” as used herein, unless described otherwise, does not necessarily mean only a clear solution or the one wherein the solute is completely soluble in the solvent, all the intermediate phases of mixture of components, starting from a state wherein the solute has just started getting dissolved in the solvent to a state wherein the solute has completely dissolved in the solvent, are also included within the expression ‘solution’. The ranges recited herein also include the values denoted as the limits thereof. The numerical values recited as the limits are not to be construed as absolute values. Any value outside the recited ranges, wherein the difference between the values is insignificant considering the nature or the property of the variable to which the limit is applied, including any analytical variation in measuring those values, are also considered to be included within those ranges. Undissolved solid and/or foreign particles, if any, can be removed before solid formation and/or solvent removal. A suitable technique useful for removal of solids can be selected from, but not limited to, filtration, decantation and centrifugation. The terms ‘isolating’, ‘obtaining’ and ‘purifying’ are generally interchangeable, and include but not specifically limited to decantation, extraction, filtration, evaporation, lyophilisation, spray drying, crystallization, recrystallization or chromatographic operations. The term “enantiomerically pure” or “in enantiomerically pure form” as used herein in relation to desglymidodrine, relates to a composition of desglymidodrine comprising at least 98% of the one individual enantiomer and less than 2% of the other enantiomer – e.g. enantiomerically pure desglymidodrine comprises more than 98% of (R)-(-)-enantiomer and less than 2% of (S)-(+)-enantiomer of desglymidodrine, or more than 98.5% of (R)-(-)-enantiomer and less than 1.5% of (S)-(+)-enantiomer of desglymidodrine, or more than 99% of (R)-(-)-enantiomer and less than 1% of (S)-(+)-enantiomer of desglymidodrine, or even more than 99.5% of (R)-(-)-enantiomer and less than 0.5% of (S)-(+)-enantiomer of desglymidodrine, by area percentage of HPLC. The term “chirally pure” or “in chirally pure form” as used herein in connection to individual enantiomers of desglymidodrine, relates to a composition of desglymidodrine comprising at least 98.5% of one of the respective (R)-(+)- or (S)-(- )-enantiomer and less than 1.5% of the other enantiomer, or at least 99% of one of the respective R)-(+)- or (S)-(-)-enantiomer and less than 1% of the other enantiomer, or at least 99.5% of one of the respective (R)-(+)- or (S)-(-)- enantiomer and less than 0.5% of the other enantiomer, by area percentage of HPLC. The term “having n% chiral purity” as used herein in connection to individual enantiomers of desglymidodrine, denotes that a composition of desglymidodrine comprises at least n% of the respective individual enantiomer and (100-n)% or less of the other enantiomer – e.g. “(R)-(-)-desglymidodrine is in more than 98.5% chiral purity” relates to a composition of desglymidodrine comprising at least 98.5% of (R)- (-)-enantiomer and 1.5% or less of the (S)-(+)-enantiomer of desglymidodrine. The term “chemical purity” as used herein in connection to desglymidodrine or individual enantiomers thereof, relate to chemical purity of respective sample of desglymidodrine or individual enantiomer thereof measured by area percentage by HPLC - e.g. desglymidodrine in more than 98% chemical purity, relates to a composition of desglymidodrine comprising more than 98% desglymidodrine compound by area percentage of HPLC. The term "pharmaceutically acceptable" as used herein means useful in preparing a pharmaceutical composition that is generally non-toxic and is not biologically undesirable, and is acceptable for veterinary or human pharmaceutical use. The term "composition" as used herein means a physical mixture of two or more components. The term "pharmaceutical composition" as used herein means a drug product comprising the active ingredient(s) & pharmaceutically acceptable excipient(s), as well as any product, which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients including an active ingredient. The product(s) obtained may further be converted to any other physical forms thereof which includes but not specifically limited to salt(s), solvate(s), hydrate(s), co- crystal(s) and solid dispersion(s) in either crystalline or amorphous forms and/or subjected to further physical processing like milling, shifting or other suitable powder processing techniques to adjust the particle size of the product to desired levels. In one general aspect, there is provided an enantiomerically pure desglymidodrine compound. In another general aspect, there is provided an enantiomerically pure (R)-(-)- desglymidodrine compound, or a pharmaceutically acceptable salt, solvate or a hydrate thereof. In another general aspect, there is provided an enantiomerically pure (R)-(-)- desglymidodrine having a chiral purity of 98.5% or more by area percentage of HPLC, or a pharmaceutically acceptable salt, solvate or a hydrate, thereof. In another general aspect, there is provided an enantiomerically pure (R)-(-)- desglymidodrine having a chiral purity of 98.5% or more, and free of its (S)-(+)- isomer, by area percentage of HPLC, or a pharmaceutically acceptable salt, solvate or a hydrate, thereof. In another general aspect, there is provided an enantiomerically pure (R)-(-)- desglymidodrine having a chemical purity of 98% or more, by area percentage of HPLC, or a pharmaceutically acceptable salt, solvate or a hydrate, thereof. In another general aspect, there is provided an enantiomerically pure (R)-(-)- desglymidodrine having a chemical purity of 98.5% or more, by area percentage of HPLC, or a pharmaceutically acceptable salt, solvate or a hydrate, thereof. In another general aspect, there is provided (R)-(-)-desglymidodrine having a chiral purity of 98.5% or more, by area percentage of HPLC, or pharmaceutically acceptable salt, solvate or a hydrate, thereof. In another general aspect, there is provided (R)-(-)-desglymidodrine having a chemical purity of 98.5% or more, by area percentage of HPLC, or pharmaceutically acceptable salt, solvate or a hydrate, thereof. In another general aspect, there is provided an acid addition salt of desglymidodrine with a chiral auxiliary. In another general aspect, there is provided a composition comprising an enantiomerically pure (R)-(-)-desglymidodrine having a chemical purity of 98% or more; a chiral purity of 98.5% or more, by area percentage of HPLC, or pharmaceutically acceptable salt, solvate or hydrate, thereof. In another general aspect, there is provided a pharmaceutical composition comprising enantiomerically pure (R)-(-)-desglymidodrine, or a pharmaceutically acceptable salt, solvate or hydrate, thereof and a pharmaceutically acceptable carrier, excipient or diluent. In another general aspect, there is provided a pharmaceutical composition comprising an enantiomerically pure (R)-(-)-desglymidodrine having a chiral purity of about 98.5% or more, and free of its (S)-(+)-isomer, or a pharmaceutically acceptable salt, solvate or hydrate, thereof; and a pharmaceutically acceptable carrier, excipient or diluent. In another general aspect, there is provided a pharmaceutical composition comprising an enantiomerically pure (R)-(-)-desglymidodrine having a chemical purity of about 98.5% or more, or a pharmaceutically acceptable salt, solvate or hydrate, thereof; and a pharmaceutically acceptable carrier, excipient or diluent. In another general aspect, there is provided a process for the preparation of an enantiomerically pure (R)-(-)-desglymidodrine or a pharmaceutically acceptable salt, solvate or hydrate, thereof. Desglymidodrine In one general aspect, there is provided a desglymidodrine compound in enantiomerically pure form. In another general aspect, there is provided a desglymidodrine compound in enantiomerically pure form and a chemical purity of 98% or more, by area percentage of HPLC. (R)-(-)-desglymidodrine In another general aspect, there is provided (R)-(-)-desglymidodrine having a chiral purity of 98.5% or more, by area percentage of HPLC. In another general aspect, there is provided (R)-(-)-desglymidodrine having a chiral purity of 99% or more, by area percentage of HPLC. In another general aspect, there is provided (R)-(-)-desglymidodrine having a chiral purity of 99.5% or more, by area percentage of HPLC. In another general aspect, there is provided (R)-(-)-desglymidodrine having a chiral purity of 98.5% or more, and a chemical purity of 98% or more, by area percentage of HPLC. In another general aspect, there is provided (R)-(-)-desglymidodrine having a chiral purity of 98.5% or more, and a chemical purity of 98.5% or more, by area percentage of HPLC. In another general aspect, there is provided (R)-(-)-desglymidodrine having a chiral purity of 98.5% or more, and a chemical purity of 99% or more, by area percentage of HPLC. In another general aspect, there is provided (R)-(-)-desglymidodrine having a chiral purity of 99% or more, and a chemical purity of 99% or more, by area percentage of HPLC. In another general aspect, there is provided (R)-(-)-desglymidodrine having a chiral purity of 99% or more, and a chemical purity of 99.5% or more, by area percentage of HPLC. In another general aspect, there is provided (R)-(-)-desglymidodrine having a chiral purity of 99.5% or more, and a chemical purity of 99.5% or more, by area percentage of HPLC. In another general aspect, there is provided (R)-(-)-desglymidodrine having a chiral purity of 99.8% or more, and a chemical purity of 99.8% or more, by area percentage of HPLC. (S)-(+)-desglymidodrine In another general aspect, there is provided (S)-(+)-desglymidodrine having a chiral purity of 98.5% or more, by area percentage of HPLC. In another general aspect, there is provided (S)-(+)-desglymidodrine having a chiral purity of 99% or more, by area percentage of HPLC. In another general aspect, there is provided (S)-(+)-desglymidodrine having a chiral purity of 99.5% or more, by area percentage of HPLC. In another general aspect, there is provided (S)-(+)-desglymidodrine having a chiral purity of 98.5% or more, and a chemical purity of 98% or more, by area percentage of HPLC. In another general aspect, there is provided (S)-(+)-desglymidodrine having a chiral purity of 98.5% or more, and a chemical purity of 98.5% or more, by area percentage of HPLC. In another general aspect, there is provided (S)-(+)-desglymidodrine having a chiral purity of 98.5% or more, and a chemical purity of 99% or more, by area percentage of HPLC. In another general aspect, there is provided (S)-(+)-desglymidodrine having a chiral purity of 99% or more, and a chemical purity of 99% or more, by area percentage of HPLC. In another general aspect, there is provided (S)-(+)-desglymidodrine having a chiral purity of 99% or more, and a chemical purity of 99.5% or more, by area percentage of HPLC. In another general aspect, there is provided (S)-(+)-desglymidodrine having a chiral purity of 99.5% or more, and a chemical purity of 99.5% or more, by area percentage of HPLC. In another general aspect, there is provided (S)-(+)-desglymidodrine having a chiral purity of 99.8% or more, and a chemical purity of 99.8% or more, by area percentage of HPLC. Process In another general aspect, there is provided process(es) for the preparation of - desglymidodrine compound in enantiomerically pure form, and desglymidodrine compound in enantiomerically pure form and in more than 98% chemical purity. In another general aspect, desglymidodrine compound can be obtained in enantiomerically pure form by preparing a diastereomeric salt form thereof. In another general aspect, desglymidodrine compound can be obtained in enantiomerically pure form by reacting desglymidodrine compound with a chiral auxiliary comprising one or more of a resolving acid selected from (+) and (-) - tartaric acid, (+) and (-)-di-p-tolyl-tartaric acid, (+) and (-)-mandelic acid and (+) and (-)-camphor sulphonic acid or an amino acid selected from D and L-glutamic acid, D and L-aspartic acid, and D and L-pyroglutamic acid. In general, the neutralization of the diastereomeric salt can be performed using a base in the presence of one or more solvents. In general, the bases can be selected from one or more of sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate and potassium carbonate. In general, the solvent can be selected from one or more of water, ethyl acetate, tetrahydrofuran, acetone, and methyl ethyl ketone. In another general aspect, the desglymidodrine is reacted with L-(+)-tartaric acid to obtain L-(+)-tartaric acid salt of desglymidodrine, which upon neutralization provides (S)-(+)-desglymidorine in enantiomerically pure form. In another general aspect, desglymidodrine is reacted with D-(-)-tartaric acid to obtain D-(-)-tartaric acid salt of desglymidodrine, which upon neutralization provides (R)-(-)-desglymidorine in enantiomerically pure form. In one general aspect, desglymidodrine is reacted with S-(+)-mandelic acid to obtain S-(+)-mandelic acid salt of desglymidodrine, which upon neutralization provides (S)- (+)-desglymidorine in enantiomerically pure form. In another general aspect, desglymidodrine is reacted with R-(-)-mandelic acid to obtain R-(-)-mandelic acid salt of desglymidodrine, which upon neutralization provides (R)-(-)-desglymidorine in enantiomerically pure form. In another general aspect, desglymidodrine is reacted with Boc-L-glutamic acid to obtain Boc-L-Glutamic acid salt of desglymidodrine, which upon neutralization provides (R)-(-)-desglymidorine in enantiomerically pure form. In another general aspect, desglymidodrine is reacted with Boc-L-serine to obtain Boc-L-serine salt of desglymidodrine, which upon neutralization provides
Figure imgf000015_0001
desglymidorine in enantiomerically pure form. In another general aspect, desglymidodrine is reacted with L-Pyroglutamic acid to obtain L-Pyroglutamic acid salt of desglymidodrine, which upon neutralization provides (S)- (+)-desglymidorine in enantiomerically pure form. In another general aspect, there is provided a diastereomeric salt of desglymidodrine. In one general aspect, there is provided a mandelic acid salt of desglymidodrine. In one general aspect, there is provided R-(-)-mandelic acid salt of desglymidodrine. In another general aspect, there is provided S-(+)-mandelic acid salt of desglymidodrine. In another general aspect, there is provided R-(-)-mandelic acid salt of
Figure imgf000015_0002
desglymidodrine. In another general aspect, there is provided S-(+)-mandelic acid salt of (S)-(+)- desglymidodrine. In another general aspect, there is provided a process for the preparation of desglymidodrine in enantiomerically pure form comprising neutralising a diastereomeric salt of desglymidodrine. In another general aspect, there is provided a process for the preparation of a diastereomeric salt of desglymidodrine, the process comprising reacting a racemic desglymidodrine with a chiral resolving acid to obtain a diastereomeric salt of desglymidodrine. In general, the chiral resolving acid is selected from the group comprising one or more of (+) and (-)-tartaric acid, (+) and (-)-di-p-tolyl-tartaric acid, (+) and (-)- mandelic acid and (+) and (-)-camphor sulphonic acid or an amino acid selected from D and L-glutamic acid, D and L-aspartic acid, and D and L-pyroglutamic acid. In general, the solvent can be selected from one or more of water, ethyl acetate, tetrahydrofuran, acetone and methyl ethyl ketone. In another general aspect, there is provided a process for the preparation of enantiomerically pure (R)-(-)-desglymidodrine, the process comprising: (a) reacting a racemic desglymidodrine with a chiral resolving acid to obtain a diastereomeric salt; and (b) neutralizing the diastereomeric salt to obtain (R)-(-)-desglymidodrine. In general, the chiral resolving acid at stage (a) is selected from (+) and (-) -tartaric acid, (+) and (-)-di-p-tolyl-tartaric acid, (+) and (-)-mandelic acid and (+) and (-)- camphor sulphonic acid or an amino acid selected from D and L-glutamic acid, D and L-aspartic acid, and D and L-pyroglutamic acid. In another general aspect, there is provided a process for the preparation of enantiomerically pure (S)-(+)-desglymidodrine, comprising: (a) reacting a racemic desglymidodrine with chiral resolving acid to obtain a diastereomeric salt; and (b) neutralizing the salt to obtain (S)-(+)-desglymidodrine. In general, the chiral resolving acid at stage (a) is selected from (+) and (-) -tartaric acid, (+) and (-)-di-p-tolyl-tartaric acid, (+) and (-)-mandelic acid and (+) and (-)- camphor sulphonic acid or an amino acid selected from D and L-glutamic acid, D and L-aspartic acid, and D and L-pyroglutamic acid. In general, the neutralization of the diastereomeric salt can be performed using a base in the presence of one or more solvents. In general, the base can be selected from sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, and potassium carbonate. In general, the solvent can be selected from one or more of water, ethyl acetate, tetrahydrofuran, acetone and methyl ethyl ketone. In another general aspect, desglymidodrine compound can be obtained in enantiomerically pure form by chiral reduction of a compound of Formula I to obtain a compound of Formula II, and converting the compound of Formula II to desglymidodrine,
Figure imgf000017_0001
wherein, X is -Cl, -Br, -F, -I, -NR1R2, or -OSO2R; and * denotes the chiral center, and, wherein, each of R1 and R2 is individually -H, -substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted aryl; or R1 and R2 together with the N atom to which they are attached form a monocyclic or bicyclic heterocyclic ring which may further be substituted with one or more of carbonyl, nitro, cyano, alkyl, cycloalkyl or aryl groups, and wherein R is alkyl, phenyl, substituted alkyl and substituted phenyl. In another general aspect, the compound of Formula I is reduced in the presence of a chiral reducing agent to obtain the compound of Formula II. In general, the chiral reducing agent can be selected from a group comprising borane; catecholborane; chiral oxazaborolidine; a chiral diamine or chiral amino alcohol in presence of a ruthenium, iridinium or rhodium catalyst; and Pd/phosphine complex in 2,2,2-trifluoroethanol. In another general aspect, the compound of Formula I, wherein X is –Cl, -Br or -I, is reacted with R-(+)-methyl-CBS-oxaborolidine and borane-dimethyl sulfide to obtain corresponding compound of Formula II, which is treated with ammonia, or with potassium phthalimide followed by hydrolysis, to obtain (R)-(-)-desglymidodrine in enantiomerically pure form. In another general aspect, the compound of Formula I is reduced in the presence of a suitable carbonyl reductases enzyme, optionally in the presence of cofactors NADH or NADPH, to obtain the compound of Formula II. In another general aspect, the carbonyl reductases enzyme can be an isolated enzyme, which may be immobilized on a solid support; a whole cell microorganism; or cultured cells from plant or animal. In general, the carbonyl reductases enzyme can be selected from a group comprising S1 from Candida magnolia, KaCR from Kluyveromyces aestuarii, and PsCR I from Pichia stipites. The whole cell microorganism can be selected from Saccharomyces cerevisiae, Penicillium citrinum, Aspergillus sclerotiorum, Aspergillus sydowii, Geotrichum candidum and Rhodotorula rubra. Table-1: Analytical summary of levo-desglymidodrine {(R)-(-)-desglymidodrine}
Figure imgf000018_0001
Figure imgf000019_0001
N-Acetyl impurity: N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl] acetamide Aldehyde impurity: 2,5-dimethoxy benzaldehyde S-Isomer: (1S)-2-amino-1-(2,5-dimethoxyphenyl) ethan-1-ol *ND: Not Detected In another general aspect, there is provided an enantiomerically pure (R)-(-)- desglymidodrine compound, or a pharmaceutically acceptable salt, solvate or a hydrate thereof, substantially free from N-acetyl impurity, by area percentage of HPLC. In general, the “substantially free” herein means, the N-acetyl impurity is present to the level of 0.05% or less, particularly to the level of 0.03% or less, more particular to the level of 0.01% or less, are area percentage of HPLC. In another general aspect, there is provided an enantiomerically pure (R)-(-)- desglymidodrine compound, or a pharmaceutically acceptable salt, solvate or a hydrate thereof, substantially free from 2,5-dimethoxy benzaldehyde impurity, by area percentage of HPLC. In general, the “substantially free” herein means, the 2,5-dimethoxybenzaldehyde impurity is present to the level of 0.15% or less, more particular to the level of 0.1% or less, more particularly to the level of 0.05% or less, by area percentage of HPLC. HPLC method for related substance and chemical purity: Related substance HPLC method is carried out into a waters HPLC system. with photodiode array detector using a Kromasil C18 (250 x 4.6) mm, 5.0µm column. Mobile phase-A: 100 % of 10 mM dipotassium hydrogen phosphate in water (pH adjusted to 3.5 ± 0.05 using diluted orthophosphoric acid), Mobile phase-B: Mixture of Acetonitrile and Water in the ratio of 80: 20 (%v/v) Flow rate: 1.0 ml/minute at 225 nm. Column oven temperature: 50 °C. Gradient composition: Time (min.)/ MP B (%); 0/5; 25/15; 37/38; 52/80; 55/90; 60/90; 62/5; 75/5. Sample concentration injected 1500 µg/ml. HPLC method of chiral purity: S-Isomer method is carried out into a waters HPLC System with photodiode array detector using a CHIRALPAK AGP (150 x 4.0) mm, 5.0µm column. Mobile phase: A mixture of 1000 ml of 10 mM Ammonium acetate in water (pH adjusted to 5.8 ± 0.05 using diluted acetic acid) and 20 ml of acetonitrile. Flow rate: 0.5 ml/minute at 210 nm. Column oven temperature is 25°C. Sample concentration injected 500 µg/ml. Examples: The embodiments of the invention can further be illustrated by following examples. Example-1: (R)-(-)-Mandelic Acid Salt of (R)-(-)-Desglymidodrine In a 1 L round bottom flask, 100 g desglymidodrine and 38.6 g R-(-)-mandelic acid were stirred in a mixture of 300 mL isopropyl alcohol and 500 mL methyl t-butyl ether for 30-60 min at 55-65 °C, followed by 2-3 hours at 25-35 °C. The resultant solid was filtered, washed with mixture of isopropyl alcohol and methyl t-butyl ether and dried to obtain (R)-(-)-Mandelic Acid Salt of (R)-(-)-Desglymidodrine. [Chiral Purity: 98.89%] Example-2: (R)-(-)-Mandelic Acid Salt of (R)-(-)-Desglymidodrine In a 1 L round bottom flask, 100 g Desglymidodrine and 38.6 g R-(-)-mandelic acid were stirred in a mixture of 300 mL isopropyl alcohol and 500 mL methyl t-butyl ether for 30-60 min at 55-65 °C and cooled to 30-35 °C. The resultant mass was seeded with 0.05 g of (R)-(-)-mandelic acid salt of (R)-(-)-desglymidodrine and stirred for 2-3 h at 25-35 °C. The resultant solid was filtered, washed with mixture of isopropyl alcohol and methyl t-butyl ether and dried to obtain R)-(-)-mandelic acid salt of (R)- (-)-desglymidodrine. (38 g). Example-3: (R)-(-)-Desglymidodrine Part-A: (R)-2-chloro-1-(2,5-dimethoxyphenyl) ethan-1-ol: Borane–dimethyl sulfide in Tetrahydrofuran (2M, 14 ml) was added to a stirring solution of (R)-(+)-Methyl- CBS-oxazaborolidine in Toluene (1M, 4.65 mL) and 25 mL Tetrahydrofuran at 0-10 °C and stirred for 15-30. The temperature was raised to 20-25 °C and a solution of 10 g 2-chloro-1-(2,5-dimethoxyphenyl) ethan-1-one in 50 ml Tetrahydrofuran was added and stirred for 2-3 h. After reaction completion, 10 mL methanol was added to the mixture, stirred for 15-30 min, and the mass was distilled at reduced pressure below 50 °C. The obtained residue was dissolved in toluene and extracted with aqueous HCl solution followed by water. The organic layer was evaporated to obtain (R)-2-chloro-1-(2,5-dimethoxyphenyl) ethan-1-ol (12g). Part-B: (R)-(-)-Desglymidodrine: 250 mL aqueous ammonia was added to a stirring mixture of 10 g (R)-2-chloro-1-(2,5-dimethoxyphenyl) ethan-1-ol in 125 mL methanol and stirred for 32-38 h at 20-30 °C. After reaction completion, the solvent volume was reduced by distillation at reduced pressure. Aqueous sodium hydroxide was added to the resultant mass at 0-10 °C under stirring. The resultant solid was filtered, washed with chilled water and dried to obtain (R)-(-)-Desglymidodrine (5 g). Example-4: (R)-(-)-Desglymidodrine In a 1 L round bottom flask, 60 g Sodium hydroxide in 300 mL water was added to a stirring mixture of 100 g (R)-(-)-mandelic acid salt of (R)-(-)-Desglymidodrine in 500 mL water and stirred for 30-45 min at 25-35 °C followed by 1-2 hours at 0-10 °C. The resultant mass was filtered, washed with water and dried to obtain 51 g (R)- (-)- Desglymidodrine. [Chiral Purity: 99.83%, HPLC Purity: 99.85%] Example-5: Preparation of (R)-(-)-desglymidodrine In a 2L round bottom flask, 1000 mL ethyl acetate, 100 g racemic-desglymidodrine and 38.57 g R-(-)-mandelic acid were taken and stirred at 25 to 30 °C for 6 to 7 hours. The solid was filtered to obtain a wet cake. The wet cake was again stirred with 400 mL ethyl acetate at 60 to 70 °C and cooled and filtered to obtain a mandelate salt compound of Formula (II). This wet cake and 210 mL water were taken in another flask and sodium hydroxide solution was added into the reaction mixture at 30 to 40 °C and for 30 to 35 minutes and then filtered and washed with hot water to obtain (R)- (-)-desglymidodrine (levo-desglymidodrine) as a solid. The solid was dried under vacuum for 12 to 15 hours at 50 to 60 °C to obtain (R)- (-)- desglymidodrine. [Chiral Purity: 99.85%, HPLC Purity: 99.87%]. While the present invention has been described in terms of a few specific embodiments, modification and equivalents thereof, in light of the teaching and disclosure of the present invention, that are apparent to the skilled artisan, are to be construed as included within the scope of the invention.

Claims

We Claim: 1. An enantiomerically pure desglymidodrine compound.
2. An enantiomerically pure (R)-(-)-desglymidodrine compound, or a pharmaceutically acceptable salt, solvate or a hydrate thereof.
3. The enantiomerically pure (R)-(-)-desglymidodrine according to claim 2 having a chiral purity of 98.5% or more by area percentage of HPLC, or a pharmaceutically acceptable salt, solvate or a hydrate thereof.
4. The enantiomerically pure (R)-(-)-desglymidodrine according to claim 2 having a chemical purity of 98% or more, by area percentage of HPLC, or a pharmaceutically acceptable salt, solvate or a hydrate thereof. 5. (R)-(-)-desglymidodrine having a chiral purity of 98.
5% or more, by area percentage of HPLC, or a pharmaceutically acceptable salt, solvate or a hydrate thereof.
6. (R)-(-)-desglymidodrine having a chemical purity of 98% or more, by area percentage of HPLC, or a pharmaceutically acceptable salt, solvate or a hydrate thereof.
7. An acid addition salt of desglymidodrine with a chiral auxiliary.
8. A composition comprising an enantiomerically pure (R)-(-)-desglymidodrine having a chemical purity 98% or more and a chiral purity of 98.5% or more, by area percentage of HPLC, or a pharmaceutically acceptable salt, solvate or a hydrate thereof.
9. A pharmaceutical composition comprising enantiomerically pure (R)-(-)- desglymidodrine, or a pharmaceutically acceptable salt, solvate or a hydrate thereof, and a pharmaceutically acceptable carrier, excipient or a diluent.
10. A pharmaceutical composition comprising an enantiomerically pure (R)-(-)- desglymidodrine having a chiral purity of about 98.5% or more, or a pharmaceutically acceptable salt, solvate or a hydrate thereof, and a pharmaceutically acceptable carrier, excipient or a diluent.
11. A pharmaceutical composition comprising an enantiomerically pure (R)-(-)- desglymidodrine having a chemical purity of about 98% or more, or a pharmaceutically acceptable salt, solvate or a hydrate thereof, and a pharmaceutically acceptable carrier, excipient or a diluent.
12. A composition comprising (R)-(-)-desglymidodrine having a chemical purity of about 98% or more, by area percentage of HPLC, or a pharmaceutically acceptable salt, solvate or a hydrate thereof, and a pharmaceutically acceptable carrier, excipient or a diluent.
13. The chiral auxiliary according to claim 7 comprises one or more of a resolving acid selected from (+) and (-)-tartaric acid, (+) and (-)-di-p-tolyl-tartaric acid, (+) and (-)-mandelic acid and (+) and (-)-camphor sulphonic acid, or an amino acid selected from D and L-glutamic acid, D and L-aspartic acid, and D and L- pyroglutamic acid.
14. (R)-(-)-mandelic acid salt of (R)-(-)-desglymidodrine.
15. (S)-(+)-mandelic acid salt of (S)-(+)-desglymidodrine.
16. A process for the preparation of a diastereomeric salt of desglymidodrine, the process comprising reacting a racemic desglymidodrine with a chiral resolving acid to obtain a diastereomeric salt of desglymidodrine.
17. The process according to claim 16, wherein the chiral resolving acid is selected from (+) and (-)-tartaric acid, (+) and (-)-di-p-tolyl-tartaric acid, (+) and (-)- mandelic acid and (+) and (-)-camphor sulphonic acid or an amino acid selected from D and L-glutamic acid, D and L-aspartic acid, and D and L-pyroglutamic acid.
18. A process for the preparation of enantiomerically pure (R)-(-)-desglymidodrine, the process comprising: (a) reacting a racemic desglymidodrine with a chiral resolving acid to obtain a diastereomeric salt; and (b) neutralizing the diastereomeric salt to obtain (R)-(-)-desglymidodrine.
19. The process according to claim 18, wherein the chiral resolving acid at step (a) is selected from (+) and (-)-tartaric acid, (+) and (-)-di-p-tolyl-tartaric acid, (+) and (-)-mandelic acid and (+) and (-)-camphor sulphonic acid or an amino acid selected from D and L-glutamic acid, D and L-aspartic acid, and D and L- pyroglutamic acid.
20. The process according to claims 18, wherein the neutralization at step (b) is performed using a base selected from sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, and potassium carbonate.
21. An enantiomerically pure (R)-(-)-desglymidodrine compound, or a pharmaceutically acceptable salt, solvate or a hydrate thereof, substantially free from N-acetyl impurity, by area percentage of HPLC.
22. An enantiomerically pure (R)-(-)-desglymidodrine compound, or a pharmaceutically acceptable salt, solvate or a hydrate thereof, substantially free from 2,5-dimethoxy benzaldehyde impurity, by area percentage of HPLC.
PCT/IB2022/050432 2021-01-20 2022-01-19 Enantiomerically pure desglymidodrine and process for preparation thereof WO2022157633A1 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0654534B1 (en) * 1993-11-18 2000-03-01 Daicel Chemical Industries, Ltd. Processes for producing optically active 2-amino-1-phenylethanol derivatives
EP1267841B1 (en) * 2000-03-31 2004-11-24 Nycomed Austria GmbH Controlled release pharmaceutical composition containing midodrine and/or desglymidodrine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0654534B1 (en) * 1993-11-18 2000-03-01 Daicel Chemical Industries, Ltd. Processes for producing optically active 2-amino-1-phenylethanol derivatives
EP1267841B1 (en) * 2000-03-31 2004-11-24 Nycomed Austria GmbH Controlled release pharmaceutical composition containing midodrine and/or desglymidodrine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KOHARA, T. HASHIMOTO, Y. SAIGO, K.: "Design, Synthesis, and Optical Resolution of a Novel Non-natural Chiral Auxiliary, 1-(2,5-Dimethoxyphenyl)ethylamine. Application to Diastereoselective Alkylation of Aldimines", TETRAHEDRON, ELSEVIER SIENCE PUBLISHERS, AMSTERDAM, NL, vol. 55, no. 21, 21 May 1999 (1999-05-21), AMSTERDAM, NL , pages 6453 - 6464, XP004165614, ISSN: 0040-4020, DOI: 10.1016/S0040-4020(99)00307-5 *

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