Field of the Invention
The present invention relates to a process for the preparation of 3-[(1R)-2-chloro-1-
hydroxyethyl]phenol of Formula II, an intermediate in the preparation of L-phenylephrine
hydrochloride. The present invention further relates to the preparation of L-phenylephrine
hydrochloride using 3-[(1R)-2-chloro-1-hydroxyethyl]phenol of Formula II.
Background of the Invention
L-Phenylephrine hydrochloride, chemically is (-)-m-hydroxy-α-
[(methylamino)methyl]benzyl alcohol hydrochloride, represented by Formula I.
HO NH
CH3
H
OH
.HCl
Formula I
L-Phenylephrine hydrochloride is a sympathomimetic amine that acts predominantly on
α-adrenergic receptors. It is used as a decongestant, to dilate the pupil, to increase blood
pressure, and to relieve hemorrhoids.
Various processes have been disclosed in the literature for the preparation of Lphenylephrine hydrochloride.
Achiwa et al in Tetrahedron Letters 30 (1989), Pages 367-370 discloses a process for
the preparation of L-phenylephrine hydrochloride by asymmetric hydrogenation of 3-
benzyloxy-2-(N-benzyl-N-methyl)-aminoacetophenone hydrochloride as substrate with
hydrogen in the presence of [Rh(COD)Cl]2/(2R,4R)-4-(dicyclohexylphosphino)-2-
(diphenylphosphino-methyl)-N-methyl-aminopyrrolidine as a catalyst.
Achiwa et al in Chem. Pharm. Bull 43(5) (1995) Pages 738-747 further discloses a
process for the preparation of L-phenylephrine hydrochloride using [Rh(COD)Cl]2 as a catalyst
and (2S,4S)-N-(methylcarbamoyl)-4-(dicyclohexylphosphino)-2-[diphenylphosphino)-2-
methyl] pyrrolidine ((2S,4S)-MCCPM) as a ligand for asymmetric hydrogenation of 3-
benzyloxy-2-(N-benzyl-N-methyl)-aminoacetophenone hydrochloride.
3
U.S. Patent No. 6,187,956 discloses an asymmetric reduction of N-benzyl-N-methyl-2-
amino-m-hydroxy-acetophenone hydrochloride using [Rh(COD)Cl]2/(2R,4R)-4-
(dicyclohexylphosphino)-2-(diphenylphosphino-methyl)-N-methyl-aminocarbonylpyrrolidine
as a catalyst in the presence of a base.
U.S. Patent No. 8,617,854 discloses an enantioselective reduction of 3’-hydroxy-2-
chloroacetophenone of Formula III to 3-[(1R)-2-chloro-1-hydroxyethyl]phenol of Formula II
using alcohol dehydrogenase (ADH) enzyme.
However, the processes disclosed in the prior arts are commercially non-viable on
account of number of disadvantages such as long reaction time, use of expensive catalyst,
requirement of removal of protective groups. Moreover, the optical purity achieved by prior
art processes is often inadequate for using the material directly for pharmaceutical purposes
without expensive purification procedures.
Therefore, there is a need in the art to develop an improved process for the preparation
of L-phenylephrine hydrochloride.
Summary of the Invention
The present invention relates to a process for the preparation of 3-[(1R)-2-chloro-1-
hydroxyethyl]phenol of Formula II, an intermediate in the preparation of L-phenylephrine
hydrochloride. The present invention further relates to the preparation of L-phenylephrine
hydrochloride using 3-[(1R)-2-chloro-1-hydroxyethyl]phenol of Formula II.
The present invention provides an improved, economically, and industrially
advantageous process for the preparation of 3-[(1R)-2-chloro-1-hydroxyethyl]phenol having
enantiomeric excess (ee %) greater than 98%.
The present invention involves use of low catalyst to substrate ratio to provide 3-[(1R)-
2-chloro-1-hydroxyethyl]phenol in high enantiomeric excess and excellent yields, thereby
results in a remarkable cost reduction of the active pharmaceutical ingredient (API) along with
a better atom economy of the synthesis.
Detailed Description of the Invention
The term “about,” as used herein, refers to any value which lies within the range defined
by a number up to ±10% of the value.
4
The term “room temperature,” as used herein, refers to a temperature in the range of
about 25°C to about 35°C.
The term “reaction mixture,” as used herein, refers to suspension, solution, emulsion,
or precipitate.
The term “lot-wise,” as used herein, refers to addition of distinct portions of a reagent
to a reaction mixture.
A first aspect of the present invention relates to a process for the preparation of a
compound of Formula II comprising
OH
Cl
HO
Formula II
enantioselective reduction of a compound of Formula III using catalyst RuCl-(S,S)-TsDENEB.
OH
O
Cl
Formula III
A second aspect of the present invention relates to a process for the preparation of Lphenylephrine hydrochloride of Formula I comprising
HO NH
CH3
H OH
.HCl
Formula I
a) enantioselective reduction of a compound of Formula III using catalyst RuCl-(S,S)-TsDENEB
5
OH
O
Cl
Formula III
to obtain a compound of Formula II; and
OH
Cl
HO
Formula II
b) converting the compound of Formula II to L-phenylephrine hydrochloride of Formula
I.
A third aspect of the present invention related to a process for the preparation of Lphenylephrine hydrochloride of Formula I comprising
HO NH
CH3
H OH
.HCl
Formula I
a) halogenation a compound of Formula IV with a halogenating agent
OH
CH3
O
Formula IV
to obtain a compound of Formula III;
6
OH
O
Cl
Formula III
b) enantioselective reduction of the compound of Formula III using catalyst RuCl-(S,S)-
Ts-DENEB to obtain a compound of Formula II; and
OH
Cl
HO
Formula II
b) converting the compound of Formula II to L-phenylephrine hydrochloride of Formula
I.
Catalyst RuCl-(S,S)-Ts-DENEB®, is chemically designated as ruthenium, chloro[4-
methyl-N-[(1S,2S)-2-[(R)-[2-[[(1,2,3,4,5,6-η)-4-methylphenyl]methoxy]ethyl]amino-κN]-1,2-
diphenylethyl]benzenesulfonamidato-κN]- [as per Scifinder, cas no. 1384974-37-1]
The compound of Formula IV used for the preparation of the compound of Formula
III may be prepared by any method provided in the art, for example, the method as disclosed
in U.S. Patent No. 8,617,854.
The halogenation of the compound of Formula IV to obtain the compound of Formula
III is carried out in the presence of halogenating agent in a solvent.
The halogenating agent used for the halogenation of compound of Formula IV can be
selected from sulfuryl chloride and phosphoryl chloride.
The solvent used for the halogenation of the compound of Formula IV is selected from
alcohols, chlorinated hydrocarbons, aromatic hydrocarbons, ethers, water, and mixtures thereof.
Examples of alcohols include methanol, ethanol, n-propanol, isopropanol, n-butanol, tertbutanol, and mixtures thereof. Examples of chlorinated hydrocarbons include dichloromethane,
7
dichloroethane, carbon tetrachloride, chloroethane, and mixture thereof. Examples of aromatic
hydrocarbons include toluene and xylene. Example of ethers include tetrahydrofuran, ethyl
methyl ether, diethyl ether, and di-isopropyl ether.
The halogenation of the compound of Formula IV is carried out at room temperature.
The halogenation of the compound of Formula IV is carried out for about 2 hours to
about 24 hours. In an embodiment, the halogenation of the compound of Formula IV is carried
out for about 5 hours to about 20 hours. In another embodiment, the halogenation of the
compound of Formula IV is carried out for about 8 hours to about 16 hours. In yet another
embodiment, the halogenation of the compound of formula IV is carried out for about 10 hours
to about 14 hours.
The compound of Formula III may be isolated by filtration, decantation, extraction,
distillation, evaporation, chromatography, precipitation, concentration, crystallization,
centrifugation, and recrystallization. The compound of Formula III may be dried using
conventional techniques, for example, drying, drying under vacuum, spray drying, suck drying,
air drying, or agitated thin film drying.
The enantioselective reduction of the compound of Formula III to obtain the compound
of Formula II is carried out in a solvent using RuCl-(S,S)-Ts-DENEB as a catalyst.
The solvent used for the enantioselective reduction of the compound of Formula III is
selected from ester, chlorinated hydrocarbons, hydrocarbons, ethers, polar aprotic solvents,
water and mixtures thereof. Examples of esters include methyl acetate, ethyl acetate, tert-butyl
acetate, butyl acetate, isopropylacetate, isoamylacetate, isobutyl acetate, and mixtures thereof.
Examples of chlorinated hydrocarbons include dichloromethane, dichloroethane, carbon
tetrachloride, chloroethane, and mixture thereof. Examples of hydrocarbons include
cyclohexane, toluene, xylene, hexane, and chlorobenzene. Example of ethers include
tetrahydrofuran, ethyl methyl ether, diethyl ether, and di-isopropyl ether. Examples of polar
aprotic solvents include N, N-dimethylformamide, N, N-dimethylacetamide,
dimethylsulphoxide, acetonitrile, and N-methylpyrrolidone.
8
The catalyst RuCl-(S,S)-Ts-DENEB used for the asymmetric hydrogenation may be
added in a lot-wise manner or in a single lot. In an embodiment, the catalyst is added in a lotwise manner. In yet another embodiment, the catalyst is added in three or more lots.
The catalyst to substrate (Formula III) ratio is between about 0.01 to about 0.1. In an
embodiment, the catalyst to substrate (Formula III) ratio is between about 0.001 to about 0.1.
In another embodiment, the catalyst to substrate (Formula III) ratio is between about 0.0001 to
about 0.1.
The compound of Formula III may be added in a lot-wise manner or in a single lot.
The hydrogen gas used for the asymmetric hydrogenation may be taken from blanketing
gas, or may be produced in situ in solution from suitable hydrogen sources. The hydrogen
sources include, for example, formic acid, hydrazine, in the presence of metal salts such as
potassium formate, ammonium formate or in the presence of organic bases for example,
triethylamine, pyridine, di-isopropylamine, 1-methyl-piperidine, 1-methyl-pyrrolidine, 1,4-
diazabicyclo[2.2.2]octane (DABCO), and 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU).
The asymmetric hydrogenation of the compound of Formula III is carried out at a
temperature of about 40°C to about 65°C. In an embodiment, the asymmetric hydrogenation
of the compound of Formula III is carried out at a temperature of about 45°C to about 60°C. In
another embodiment, the asymmetric hydrogenation of the compound of Formula III is carried
out at a temperature of about 50°C to about 58°C. In yet another embodiment, the asymmetric
hydrogenation of the compound of Formula III is carried out at a temperature of about 52°C to
about 55°C.
The asymmetric hydrogenation of the compound of Formula III is carried out for about
8 hours to about 48 hours. In an embodiment, the asymmetric hydrogenation of the compound
of Formula III is carried for about 16 hours to about 40 hours. In another embodiment, the
asymmetric hydrogenation of the compound of Formula III is carried for about 20 hours to
about 36 hours.
The compound of Formula II may be isolated by filtration, decantation, extraction,
distillation, evaporation, chromatography, precipitation, concentration, crystallization,
centrifugation, and recrystallization. The compound of Formula II may be dried using
9
conventional techniques, for example, drying, drying under vacuum, spray drying, suck drying,
air drying, or agitated thin film drying.
The compound of Formula II is converted to L-phenylephrine hydrochloride of Formula
I by the process known in the art, for example, U.S. Patent No. 8,617,854.
While the present invention has been described in terms of specific aspects and
embodiments, certain modifications and equivalents will be apparent to those skilled in the art,
and are intended to be included within the scope of the present invention.
Method
Enantiomeric excess was determined using an Agilent 1269 Infinity (HPLC-01). The
column used was Phenomenex LUX Amylose (250 x 4.6 mm).
The following examples are for illustrative purposes only and should not be construed
as limiting the scope of the invention in any way.
EXAMPLES
Example 1: Preparation of 3’-hydroxy-2-chloroacetophenone (Formula III)
3-Hydroxyacetophenone of Formula IV (20 g) was added to a mixture of
dichloromethane (105 mL) and methanol (20 mL) at room temperature to obtain a reaction
mixture. Sulfuryl chloride (17.4 mL) was slowly added to the reaction mixture over a period
of two hours. The reaction mixture was stirred at room temperature till the completion of the
reaction. Demineralized water (DM; 400 mL) was added to the reaction mixture and the layers
were separated. The organic layer was washed twice with aqueous solution of sodium
bicarbonate followed by washing with brine solution. The solvent was distilled off under
vacuum at 40°C to obtain a solid. The solid so obtained was stirred with hexane (20 mL), then
filtered and dried under vacuum at room temperature to obtain title compound.
Yield: 19 g
Example 2: Preparation of 3-[(1R)-2-chloro-1-hydroxyethyl]phenol (Formula II)
3’-Hydroxy-2-chloroacetophenone of Formula III (15 g; obtained from Example 1) was
dissolved in a mixture of ethyl acetate (75 mL) and water (120 mL) under nitrogen atmosphere
to obtain a reaction mixture. The nitrogen gas was purged into reaction mixture over a period
of 15 minutes and potassium formate (15 g) followed by formic acid (45 mL) were added
10
dropwise over a period of 30 minutes. Catalyst RuCl-(S,S)-Ts-DENEB (10 mg) was added to
the reaction mixture and stirred for 5 hours at 60°C. The nitrogen gas was again purged into
reaction mixture and catalyst RuCl-(S,S)-Ts-DENEB (20 mg) was added. The reaction mixture
was then stirred for 16 hours at 60°C. The reaction mixture was further purged with nitrogen
gas followed by addition of catalyst RuCl-(S,S)-Ts-DENEB (10 mg). The reaction mixture was
then stirred for 16 hours at 60°C. The layers were separated and the organic layer was distilled
off to obtain an oily mass. Di-isopropylether (20 mL) was added to the oily layer and stirred
for 15 minutes to obtain a solid. The solid was filtered and dried to obtain title compound.
Yield: 12.2 g
Enantiomeric excess: 96.88%

Claims

1. A process for the preparation of a compound of Formula II comprising
OH
Cl
HO
Formula II
enantioselective reduction of a compound of Formula III using catalyst RuCl-(S,S)-TsDENEB.
OH
O
Cl
Formula III
2. A process for the preparation of L-phenylephrine hydrochloride of Formula I
comprising
HO NH
CH3
H OH
.HCl
Formula I
enantioselective reduction of a compound of Formula III using catalyst RuCl-(S,S)-TsDENEB
OH
O
Cl
Formula III
to obtain a compound of Formula II; and
12
OH
Cl
HO
Formula II
converting the compound of Formula II to L-phenylephrine hydrochloride of Formula I.
3. A process for the preparation of L-phenylephrine hydrochloride of Formula I
comprising
HO NH
CH3
H OH
.HCl
Formula I
b) halogenation a compound of Formula IV with a halogenating agent
OH
CH3
O
Formula IV
to obtain a compound of Formula III;
OH
O
Cl
Formula III
c) enantioselective reduction of the compound of Formula III using catalyst RuCl-(S,S)-
Ts-DENEB to obtain a compound of Formula II; and
13
OH
Cl
HO
Formula II
c) converting the compound of Formula II to L-phenylephrine hydrochloride of Formula
I.
4. The process according to claim 3, wherein the halogenating agent is selected from
sulfuryl chloride and phosphoryl chloride.
5. The process according to claim 3, wherein the solvent used for halogenation is selected
from alcohols, chlorinated hydrocarbons, aromatic hydrocarbons, ethers, water, and
mixtures thereof.
6. The process according to claims 1, 2 or 3, wherein the solvent used for the
enantioselective reduction is selected from ester, chlorinated hydrocarbons,
hydrocarbons, ethers, polar aprotic solvents, water and mixtures thereof.
7. The process according to claims 1, 2 or 3, wherein the catalyst to substrate (Formula III)
ratio is between about 0.01 to about 0.1.
8. The process according to claims 1, 2 or 3, wherein the catalyst may be added in a lotwise manner or in a single lot.
9. The process according to claims 1, 2 or 3, wherein the asymmetric hydrogenation of the
compound of Formula III is carried out at a temperature of about 40°C to about 65°C.
10. The process according to claims 1, 2 or 3, wherein the asymmetric hydrogenation of
the compound of Formula III is carried out for about 8 hours to about 48 hours.