Field of the Invention:
The present invention relates to novel process for obtaining ulipristal (I).
Background of the Invention:
Ulipristal is, chemically known as 17-α-hydroxy-11-β-[4-(dimethylamino) phenyl]-19
norpregna-4,9-diene-3,20-dione, represented by formula I. It’s acetyl derivative known as
ulipristal acetate (II), it possesses anti-progestational and anti-glucocoticoid activity
which is useful in therapeutic and contraceptive gynaecological indications.
The synthesis of ulipristal is disclosed in patent US 4,954,490 which involves oxidation of
17-vinyl compound to obtain diol compound by using osmium tetroxide as shown below.
The use of osmium tetroxide makes the process costly and hence industrially non feasible.
The patent US 5,929,262 involves the epoxidation of bis-ketal compound, as shown in the
reaction below. Later patent application US 2006111577 states that, the epoxidation of the
bis-ketal compounds remains incomplete and involves extensive chromatographic
separation in order to purify the epoxy product.
Further, the ulipristal acetate obtained in example 7 of US 5,929,262 is in the form of
yellow crystals. The Indian patent application IN 1987/CHENP/2005 states that the yellow
color of ulipristal acetate is due to the presence of impurities, mainly phenol compounds
which requires further purification and causes decrease in yields.
Rao et al, Steroids 63, 1998, pages 53-57 describes preparation of ulipristal via 17-beta
nitroxy derivate as an intermediate wherein yield of nitroxy derivative is only 29% and
requires purification by column chromatography.
In view of the disadvantages of prior methods, a need exists for a more efficient process
for the preparation of ulipristal (I).
Summary of the Invention:
The present invention relates to a novel process for preparation of ulipristal (I), which
comprises: (i) reaction of 3-keto compound (III) with phenyl sulphenyl chloride (IVa) or
p-nitro phenyl sulphenyl chloride (IVb) in the presence of organic base and solvent to give
sulfoxide (Va) or (Vb) respectively, (ii) reaction of sulfoxide (Va) or (Vb) with alkali
metal alkoxide in alcoholic solvent to give 20-alkoxy-compound (VI) and (iii) reaction of
20-alkoxy-compound (VI) with aqueous acid.
Detailed description of the invention:
The present invention is related to a novel process for the preparation of ulipristal (I), that
comprises the following steps:
(i) reaction of 3-keto compound (III) with phenyl sulphenyl chloride (IVa) or pnitro
phenyl sulphenyl chloride (IVb) in the presence of organic base and
solvent to give sulfoxide (Va) or (Vb) respectively,
(ii) reaction of sulfoxide (Va) or (Vb) with alkali metal alkoxide in alcoholic
solvent to give 20-alkoxy-compound (VI) and
(iii) reaction of 20-alkoxy-compound (VI) with aqueous acid to give ulipristal (I).
The compound 17-α-ethynyl-17-β-hydroxy-11-β-(4-N,N-dimethylamino phenyl)-19-
norpregna-4,9-diene-3-one (III) was prepared by acidic hydrolysis of 19-norpregn-9-en-
20-yn-3-one, 11-β-(4-N,N-dimethylamino phenyl)-5α, 17β-dihydroxy-cyclic 1,2-
ethanediyl ketal which in turn can be prepared by the methods disclosed in prior art
documents Mais dale et al, Journal of Labelled Compounds & Radiopharmaceuticals
(1995), 36(12), 1199-1203; Weignin et al, Steroids (2006), 71(11-12), 949-954; US
7678781 and US 7671045.
The synthetic scheme of the process for the preparation of ulipristal (I) of present
invention is shown in scheme I
The process of step (i) involves reaction of 3-keto compound (III) with phenyl sulphenyl
chloride (IVa) or p-nitro phenyl sulphenyl chloride (IVb) in the presence of organic base
and solvent to give sulfoxide Va or Vb respectively.
An organic base that can be used in step (i) includes pyridine, N-methyl morpholine, Nmethyl
pyrrolidine, tertiary alkyl amine such as triethyl amine, tertiary butyl amine etc, the
most preferred base is triethyl amine.
The sulphenyl chloride compounds IVa /IVb are used in the range of 1-10 mole
equivalent, preferably 2-4 mole equivalent.
The process of step (i) of the present invention can be carried out in organic solvent that
include aromatic hydrocarbons like benzene, toluene and xylene; esters like ethyl acetate
and isopropyl acetate; ethers such as ethyl ether, methyl t-butyl ether, di-isopropyl ether
and tetrahydrofuran; amides such as formamide, dimethylforamide and N-methylpyrrolidone;
nitriles such as acetonitrile and propionitrile; chlorinated hydrocarbons such
as dichloromethane, ethylene dichloride and chloroform, alcohols such as methanol,
ethanol, isopropanol, ketones such as actone, methyl ethyl ketone and mixtures thereof.
The most preferred solvent for step (i) is dichloromethane.
The reaction of step (i) is carried at a temperature ranging from -80 to 10°C, more
preferably, at -60 to -10°C, most preferably -60 to -40°C.
The process of step (ii) involves of reaction of sulfoxide (Va or Vb) with alkali metal
alkoxide as base in alcoholic solvent to give 20-alkoxy compound (VI, R=C1-C5 alkyl).
Sodium alkoxide is used in the range of 1-10 mole equivalent, preferably 2-4 mole
equivalent.
The alkali metal alkoxide used in step (ii) is selected from a group comprising of sodium
methoxide, sodium ethoxide, potassium tertiary butoxide and the like. The most preferred
base is sodium methoxide.
The step (ii) can be carried out in C1-C5 alcohol such as methanol, ethanol, isopropanol, nbutanol,
iso-butanol, t-butanol, pentanol etc, preferably methanol.
The reaction of step (ii) is carried at a temperature ranging from 10 to 100°C, preferrably
range is 50-80°C.
The process of step (iii) involves of reaction of 20-alkoxy-compound (VI) with acid in
water to give ulipristal (I).
The acid used in step (iii) is selected from group of hydrochloric acid, sulphuric acid,
phosphoric acid, methane sulphonic acid, para-toluene sulfonic acid, propionic acid, acetic
acid, the most preferred acid is acetic acid.
The reaction of step (iii) is carried at a temperature ranging from 5 to 100°C. The most
preferred range is 20-50°C.
Another aspect of the invention involves the conversion of ulipristal (I) to ulipristal acetate
(II) using acetic anhydride and perchloric acid. Acetylation of ulipristal (I) to ulipristal
acetate (II) can also be carried out by methods known in literature such as US 4,954,490,
which discloses acetylation using phosphoric acid and acetic anhydride.
The preferred embodiments of the present invention have been described in the foregoing
examples.
Examples
Example 1: 17-α-ethynyl-17-β-hydroxy-11-β-(4-N,N-dimethylamino phenyl)-19-
norpregna-4,9-diene-3-one (III)
19-Norpregn-9-en-20-yn-3-one, 11-β-(4-N,N-dimethylamino phenyl)-5α, 17β-dihydroxycyclic
1,2-ethanediyl ketal (30 gm) was dissolved in water (150 ml) followed by addition
of 1:1 aqueous hydrochloric acid (30 ml). The reaction mixture was stirred at 25oC.
Dichloromethane (150 ml) was added to the reaction mass followed by addition of 20%
sodium hydroxide solution. The reaction mass was stirred at 25oC for 20 minutes. Organic
layer was separated and concentrated. The solid was dried under reduced pressure. Yield=
22 gm (83%).
Example 2: Preparation of sulfoxide compound (Va)
3-keto compound (III, 20 gm) was dissolved in dichloromethane (1000 ml). Triethyl
amine (19.5 gm) was added to the reaction mass at 25°C. The reaction was cooled to -
60°C. Solution of phenyl sulfynyl chloride (IVa, 28 gm) in dichloromethane (200 ml) was
added to the reaction mass. The reaction mixture was stirred. After completion of reaction
1:1 mixture of water-methanol (200 ml) was added. The organic layer was separated,
concentrated and residue was chromatographed over silica gel, sulphoxide compound (Va)
was eluted with 1:1 ethyl acetate-hexane mixture. The fractions were collected and solvent
was distilled out. To the sticky residue hexane was added and distilled. The solid was
dried under reduced pressure. Yield: 18 gm (71%).
Example 3: Preparation of sulfoxide compound (Vb)
The 3-keto compound (III, 1 gm) was dissolved in dichloromethane (10 ml). Triethyl
amine (2 ml) and 4-nitro-phenyl sulfynyl chloride solution (IVb, 1.5 gm) was added to the
reaction mass. The reaction mixture was stirred at 25-30°C for 30 minutes. To the reaction
1:1 mixture of water-methanol (200 ml) was added. The organic layer was separated and
concentrated. Residue was chromatographed over silica gel. The sulfoxide compound (Vb)
was eluted with 1:1 ethyl acetate-hexane mixture. The fractions were collected and
distilled. To the sticky residue hexane was added and distilled. The solid was dried under
reduced pressure. Yield: 0.70 gm (51%).
Example 4: Preparation of 20-methoxy-compound (VI, R=CH3) from sulfoxide
compound (Va)
The sulfoxide compound (Va, 10 gm) was added to methanol (300 ml) followed by
addition of sodium methoxide (2 gm). The reaction mass was heated to 64°C. Second lot
of sodium methoxide (1 gm) was added to the reaction mass. The reaction was stirred for 6
hours at 65°C. The reaction mass was cooled, silica gel (30 gm) was added to the reaction
mass and solvent was distilled out. Residue left was chromatographed over silica gel using
10% ethyl acetate-hexane mixture. The fractions were collected and concentrated under
vacuum to give a gummy mass. Yield: 5.6 gm (65%).
Example 5: Preparation of 20-methoxy-compound (VI, R=CH3) from sulfoxide
compound (Vb)
The sulphoxide compound (Vb) was converted to 20-methoxy-compound (VI, R=CH3) by
similar process as above.
Example 6: Preparation of ulipristal (I)
1:1 Mixture of acetic acid-water (35 ml) was added to 20-methoxy-compound (VI,
R=CH3) (3.5 gm). The reaction mass was stirred for one hour at 25°C. Dichloromethane
(35 ml) was added to the reaction mixture followed by addition of water (35 ml). The
reaction mass was stirred at 25°C for one hour. The dichloromethane layer was separated
and washed with 5% sodium bicarbonate solution. The organic layer was separated and
concentrated. To the residue cyclohexane was added and distilled. The solid separated was
dried under reduced pressure.Yield: 0.71 gm (74%).
Example 7: Preparation of ulipristal acetate (II)
Acetic anhydride (2 gm) was added to perchloric acid (0.5 gm) and the mixture was
cooled to -20°C. To the reaction mass ulipristal (1 gm) was added and the mixture was
stirred for 30 minutes at 0-5°C. To the reaction mass 5% sodium bicarbonate solution was
added and warmed to 25°C. The reaction was stirred for thirty minutes and the layers were
separated. Organic layer was concentrated and cyclohexane (25 ml) was added. The
solvent was distilled and the reaction mass was stirred. The solid was washed with
cyclohexane and dried under reduced pressure.

WE CLAIM :
1) A process for the preparation of ulipristal (I)
comprising

with phenyl sulphenyl chloride (IVa) or p-nitro phenyl sulphenyl chloride
(IVb)
in the presence of organic base and solvent to give sulfoxide (Va) or
(Vb) respectively,
(ii) reaction of sulfoxide (Va) or (Vb) with alkali metal alkoxide in
alcoholic solvent to give 20-alkoxy-compound (VI)
and
(iii)reaction of 20-alkoxy-compound (VI) with aqueous acid.
2) A process of claim 1 wherein organic base used in step (i) is selected from a
group comprising of pyridine, N-methyl morpholine, N-methyl pyrrolidine,
tertiary alkyl amine such as triethyl amine, tertiary butyl amine.
3) A process of claim 2 wherein the most preferred base is triethyl amine.
4) A process of claim 1 wherein the solvents used in step (i) is selected from group
comprising of aromatic hydrocarbons like benzene, toluene and xylene; esters
like ethyl acetate and isopropyl acetate; ethers such as ethyl ether, methyl tbutyl
ether, di-isopropyl ether and tetrahydrofuran; amides such as formamide,
dimethylforamide and N-methyl-pyrrolidone; nitriles such as acetonitrile and
propionitrile; chlorinated hydrocarbons such as dichloromethane, ethylene
dichloride and chloroform, alcohols such as methanol, ethanol, isopropanol,
ketones such as actone, methyl ethyl ketone and mixtures thereof
5) A process according to claim 4, wherein preferred solvent is dichloromethane.
6) A process of claim 1 wherein alkali metal alkoxide used in step (ii) is selected
from sodium methoxide, sodium ethoxide, potassium tertiary butoxide.
7) A process of claim 6 wherein the most preferred alkali metal alkoxide is sodium
methoxide.
8) A process of claim 1 wherein alcoholic solvent used in step (ii) is selected from a
group comprising of methanol, ethanol, isopropanol, t-butanol, n-butanol,
isobutanol, pentanol.
9) A process of claim 8 wherein preferred solvent is methanol.
10) A process of claim 1, wherein acid used in step (iii) is selected from group of
hydrochloric acid, sulphuric acid, phosphoric acid, para-toluene sulfonic acid,
methane sulfonic acid, propionic acid and acetic acid.
11) A process of claim 10 wherein the most preferred acid is acetic acid.
12) The process of claim 1 further comprising conversion of ulipristal (I) to ulipristal
acetate (II).
(i) reaction of 3-keto compound (III)