Field of the Invention
The present invention relates to a novel process for the preparation of (3R, 5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4- [(4-hydroxy methyl phenyl ammo) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid hemi calcium salt
Background of the Invention
(3R, 5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4- [(4-hydroxy methyl phenyl amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid hemi calcium salt has been claimed as an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, an important coenzyme catalyzing the intracellular synthesis of cholesterol, in PCT Publication No 04/106299, and thus is useful as hypolipidemic and hypocholesterolemic agent
Cardiovascular disease and its associated maladies, dysfunctions and complications are a principal cause of disability and the chief cause of death One specific factor significantly contributing to this pathophysiologic process is atherosclerosis, which has been generally recognized as the leading health care problem both with respect to mortality and health care costs
Atherosclerosis is characterized by the deposition of fatty substances, primarily cholesterol, resulting in plaque formation on the mner surface of the arterial wall and degenerative change to the arteries
It is now well established that cardiovascular disorders including myocardial infarction, coronary heart disease, hypertension and hypotension, cerebrovascular disorders including stroke, cerebral thrombosis and memory loss due to stroke, peripheral vascular disease and intestinal infarction are caused by blockage of arteries and arterioles by atherosclerotic plaque Atherosclerotic plaque formation is multi-factorial in its production Hypercholesterolemia, especially elevated levels of low-density lipoprotein cholesterol (LDL), is an important risk factor for atherosclerosis and arteriosclerosis and associated diseases
The HMG-CoA reductase inhibitors (statins) have been used in reducing blood levels of LDL cholesterol Cholesterol is produced via the mevalonic acid pathway Reducing the formation of mevalonic acid, a precursor to cholesterol, leads to a corresponding decrease in hepatic cholesterol biosynthesis with a reduction in the cellular pool of cholesterol
A synthetic procedure for preparing (3R, 5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4- [(4-hydroxy methyl phenyl amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid hemi calcium salt has been claimed in PCT Publication No WO 04/106299 The aforementioned procedure involves
o a synthetic route having multiple steps involving selective hydrolysis of two chemically similar functionalities e g hydrolysis of methyl ester in the presence of tert -butyl ester
o reduction with sodium borohydnde in the presence of iodine or with borane dimethyl sulphide which are expensive reagents and are air and moisture sensitive, hence difficult to handle
Summary of the Invention
Accordingly, the present invention provides a novel process for preparing (3R, 5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4- [(4-hydroxy methyl phenyl amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid hemi calcium salt by using a novel synthetic procedure incorporating novel intermediates
Further, this invention provides a process, which
o is simple and economical,
o avoids the use of expensive and air and moisture sensitive reagents,
o avoids selective hydrolysis of methyl ester in the presence of tert -butyl ester
In order to achieve the above-mentioned objective and in accordance with the purpose of the invention as embodied and broadly described herein, there is provided a process for the preparation of a compound of Formula I
(Formula Removed)
which process comprises the steps of
(a) reacting an amine of Formula II with methyl isobutyryl acetate of Formula III
(Formula Removed) to form a compound of Formula of IV (wherein R is a hydroxy protecting group, for example, acetyl, benzoyl, tetrahydropyranyl, methoxy methyl, methoxy ethoxymethyl, benzyl),
(Formula Removed)
b) reacting the compound of Formula IV with benzaldehyde to form a compound of
Formula V,
(Formula Removed)
c) reacting the compound of Formula V with 4-fluorobenzaldehyde to form a
compound of Formula VI,
(Formula Removed)
d) reacting the compound of Formula VI with a compound of Formula VII
(Formula Removed)
to form a compound of Formula VIII,
(Formula Removed)
e) subjecting the compound of Formula VIII simultaneously to acid catalyzed cleavage of ketal and hydroxy protecting group (when R is tetrahydropyranyl) to form a compound of Formula IX, (Formula Removed)
f) subjecting the compound of Formula IX to base catalyzed hydrolysis to form a compound of Formula X,
(Formula Removed)
g) reacting the compound of Formula X with aqueous solution of calcium acetate to form a compound of Formula I
This process may involve one or more of the following features For example,
reaction of an amine of Formula II can be carried out in the presence of one or more organic
bases selected from tnethylamine, pyridine, 1,2-ethylenediamine or mixture thereof, in one or
more aromatic solvents, for example, xylene, toluene or mixture thereof In another feature,
the reaction of a compound of Formula IV can be carried out in the presence of one or more
organic bases selected from pipendine, pyridine, P-alanine or mixture thereof, one or more
organic acids selected from glacial acetic acid or benzoic acid or mixture of organic bases
and organic acids, in one or more solvents selected from hydrocarbon solvents (e g, hexane
or heptane), halogenated solvents (eg, dichloromethane, dichloroethane or chloroform),
aromatic solvents (e g, toluene or xylene) or mixture thereof In another feature, the reaction
of a compound of Formula V can be carried out in the presence of one or more catalysts
selected from sodium cyanide, 3-ethyl-5- (2-hydroxyethyl)-4-methyl thiazohum bromide, 3-
benzyl-5- (2-hydroxyethyl)-4-methyl thiazohum chloride or mixture thereof, one or more
organic bases selected from tnethylamine, pyridine or mixture thereof, in a solvent free
condition or in one or more solvents selected from protic polar solvents (eg, methanol,
ethanol, propanol, isopropanol or water), ethers (e g, dioxan or tetrahydrofuran) or mixture
thereof In another feature, the reaction of a compound of Formula VI can be carried out in
the presence of one or more organic acids selected from pivahc acid, p-toluene sulfonic acid
or mixture thereof, in one or more solvents selected from aromatic solvents (e g xylene or
toluene), hydrocarbon solvents (eg, hexane or heptane), ethers (eg, tetrahydrofuran,
dioxane or diethyl ether) or mixture thereof In another feature, the cleavage of ketal and
hydroxy protecting group of a compound of Formula VIII can be carried out in the presence
of one or more mineral acids selected from hydrochloric acid, hydrobromic acid, hydroiodic
acid or mixture thereof, in one or more solvents selected from protic polar solvents (eg
methanol, ethanol, propanol or water), ethers (eg, tetrahydrofuran or diethyl ether) or
mixture thereof In yet another feature, the hydrolysis of a compound of Formula IX can be
carried out in the presence of one or more bases selected from lithium hydroxide, sodium
hydroxide, potassium hydroxide or mixture thereof, in one or more solvents selected from
protic polar solvents (e g, methanol, ethanol, propanol, isopropanol or water), ethers (e g,
tetrahydrofuran or diethyl ether) or mixture thereof
Detailed description of the invention
(3R, 5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4- [(4-hydroxy methyl phenyl amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid hemi calcium salt described herein may be prepared by following the reaction sequences as depicted in scheme I
(Scheme Removed)
(3R, 5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4- [(4-hydroxy methyl phenyl amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid hemi calcium salt of Formula I can be prepared according to Scheme I Thus, amine of Formula I can be reacted with methyl isobutyryl acetate of Formula III to form a compound of Formula of IV (wherein R is the same as defined earlier) The compound of Formula IV can be reacted with benzaldehyde to form a compound of Formula V The compound of Formula V can be reacted with 4-fluorobenzaldehyde to form a compound of Formula VI The compound of Formula VI can be reacted with a compound of Formula VII to form a compound of Formula VIII The compound of Formula VIII can be simultaneously subject to acid catalyzed cleavage of ketal and hydroxy protecting group (when R is tetrahydropyranyl) to form a compound of Formula IX The compound of Formula IX can be subject to alkali base catalyzed hydrolysis to form a compound of Formula X The compound of Formula X can be further converted to hemi calcium salt of Formula I by following the procedure well known in the art
The reaction of an amine of Formula II can be carried out in one or more aromatic solvents, for example, xylene, toluene or mixture thereof The reaction can also be carried out in the presence of one or more organic bases, for example, tnethylamine, pyridine, 1,2-ethylenediamine or mixture thereof
The reaction of a compound of Formula IV can be carried out in one or more solvents, for example, hydrocarbon solvents (e g, hexane or heptane), or halogenated solvents (e g, dichloromethane, dichloroethane or chloroform), aromatic solvents (e g, toluene or xylene) or mixture thereof The reaction can also be carried out in the presence of one or more organic bases, for example, pipendine, pyridine or P-alanme, one or more organic acids, for example, glacial acetic acid or benzoic acid or mixture of organic bases and organic acids
The reaction of a compound of Formula V can be carried out in the presence of one or more catalysts, for example, sodium cyanide, 3-ethyl-5- (2-hydroxyethyi)-4-methyl thiazohum bromide, 3-benzyl-5- (2-hydroxyethyl)-4-methyl thiazohum chloride or mixture thereof The reaction can also be carried out in the presence of one or more organic bases, for example, tnethylamine, pyridine or mixture thereof, in a solvent free condition or in one or
more solvents, for example, protic polar solvents (eg methanol, ethanol, propanol, isopropanol or water), ethers (e g, dioxan or tetrahydrofuran) or mixture thereof
The reaction of a compound of Formula VI can be carried out in one or more solvents, for example, aromatic solvents (e g, xylene or toluene), hydrocarbon solvents (e g, hexane or heptane), ethers (e g tetrahydrofuran, dioxane or diethyl ether) or mixture thereof The reaction can also be carried out in the presence of one or more organic acids, for example, pivahc acid, p-toluene sulfonic acid or mixture thereof
The cleavage of ketal and hydroxy protecting group of a compound of Formula VIII can be carried out in the presence of one or more mineral acids, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid or mixture thereof The reaction can also be carried out in one or more solvents, for example, protic polar solvents (eg, methanol, ethanol, propanol or water), ethers (eg, tetrahydrofuran or diethyl ether) or mixture thereof The cleavage of ketal and hydroxy protecting group can also be carried out by any other cleavage method known in prior art
The hydrolysis of a compound of Formula IX can be carried out in the presence of one or more bases, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide or mixture thereof The reaction can also be carried out in one or more solvents, for example, protic polar solvents (e g methanol, ethanol, propanol, isopropanol or water), ethers (e g, tetrahydrofuran or diethyl ether) or mixture thereof
The compound of Formula X can be converted into its corresponding hemi calcium salt of Formula I by following procedure known in the art
In the above schemes, where specific reducing agents, solvents, bases, catalysts, acids etc, are mentioned, it is to be understood that other reducing agents, solvents, bases, catalysts, acids etc , known to those skilled in the art may be used Similarly, the reaction temperature and duration may be adjusted
While the present invention has been described in terms of its specific 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
Examples
Example 1 Preparation of 4-methyl-3-oxo-pentanoic acid [4-(tetrahydropyran-2-yloxymethyl) phenyl! amide
A mixture of 4-(tetrahydropyran-2-yloxymethyl) phenyl amine (70g, 0 34mol, lequiv) (prepared following the procedure mentioned in J Med Chem 41, 26, 1998 5297-5309, Tetrahedron Lett 43,30,2002, 5353), methyl isobutyryl acetate (49g, 0 34mol, lequiv ), toluene (600mL) and 1,2-ethylenediamine (2 Og, 0 034mol, 0 lequiv) was placed in a 2-necked round bottom flask and the reaction mixture was refluxed under Dean-Stark set up After completion of the reaction, the solvent was removed under vacuum The crude product was taken as such for next step Yield 116gms (crude) MS (+ion mode) m /z 320 16 (M+ 1)
1H NMR(CDC13, 300HZ) δ 1 27(d, J=6Hz, 6H), 1 33(s, 2H), 1 54-1 72(m, 7H), 2 74(sep, J=6Hz, 1H), 3 52-3 56(m, 1H), 3 61(s, 2H), 3 87-3 95(m, 1H), 4 47(d, J=12Hz, 1H), 4 68(m, 1H), 4 74(d, J=12Hz, 1H), 7 32(d, J=9Hz, 2H), 7 53(d, J=6Hz, 2H), 9 22(brs, 1H)
Example 2 Preparation of 2-benzylidine-4-methyl-3-oxo-pentanoic acid [4-(tetrahydro-pyran-2-yloxy methyl) phenyl] amide
A mixture of crude 4-methyl-3-oxo-pentanoic acid [4-(tetrahydropyran-2-yloxy methyl) phenyl] amide (lOOg, 0 31 mol, 1 equiv), B-alanine (5 6g, 0 063mol, 0 2 equiv), benzaldehyde (30 5mL, 0 31 mol, 1 equiv ), glacial acetic acid (10 6mL, 0 19 mol, 0 6equiv ) and hexane (500mL) was placed in a 2 necked-flask equipped with a Dean-Stark setup The reaction mixture was refluxed with azeotropic removal of water At the end of the reaction (TLC monitoring) the solvent was evaporated under reduced pressure to give solid, which was washed with hot hexane, and the solid was collected on a Buchner funnel The crude compound was purified on column (silica gel, 100-200 mesh, 15% ethyl acetate/hexane) to afford the pure product Yield 66 81 gms (52 36%)
MS (+ion mode) m /z 408 12 (M+ 1)
1H NMR(CDCl3, 300Hz) δ 1 22(d, J=6 0Hz, 6H), 1 52-1 85(m, 8H), 3 35(sep, J=6Hz, 1H), 3 52-3 56(m, 1H), 3 87-3 91(m, 1H), 4 47(d, J=12Hz, 1H), 4 68-4 7(m, 1H), 4 75(d, J=12Hz, 1H), 7 32-7 64(m, 11H)
Example 3 Preparation of 2-[2-(4-fluorophenyl)-2-oxo-l-phenylethyl]-4-methyl-3-oxo-pentanoic acid [4-(tetrahydropyran-2-yloxy methyl phenyl] amide
A mixture of 2-benzyhdine-4-methyl-3-oxo-pentanoic acid [4-(tetrahydropyran-2-yloxy methyl) phenyl] amide (5 Og, 0 012mol, 1 equiv), 4-fluorobenzaldehyde (1 5mL, 0 0013mol, 1 lequiv), 3-ethyl-5- (2-hydroxyethyl)-4-methyl thiazohum bromide (0 77g 0 0003mol, 0 25equiv), triethyl amine (dry,10mL, 0 0072mol, 5 8equiv) were placed in round bottom flask, purged with nitrogen gas The reaction mixture was refluxed at 90° C for about 6 hrs After the reaction was over, the reaction mixture was extracted with ethyl acetate and washed with water, dried over anhydrous sodium sulphate Organic layer was concentrated and the crude mixture was purified on column (silica gel, 100-200 mesh, 17% ethyl acetate/hexane) to afford the pure product Yield 2 52g (38 6%) MS (-Hon mode) m /z 532 17 (M + 1)
1H NMR(CDC13, 300Hz) δ 1 15(d,J=6 0Hz,3H),l 23(d,J=6 0Hz,3H), 1 45-1 851(m, 6 H), 2 85-3 05(m, 1H), 3 20-3 55(m, 1H), 3 70-3 95(m, 1H), 4 40-4 53(m, 2H), 4 67-4 72(m, 2H), 5 34(d,J=9 0Hz, 1H), 7 01-7 28(m, 12H), 7 95-8 00(m, 2H)
Example 4 Preparation of [(4R.6R)-6-(2-{2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(tetrahydropyran-2-vloxv methyl) phenyl amino)carbnoyl]pyrrol-l-yl}ethyl)-2,2-dimethyl-[1.31dioxan-4-yl]-acetic acid tert-butyl ester
A mixture of 2-[2-(4-fluorophenyl)-2-oxo-l-phenylethyl]-4-methyl-3-oxo-pentanoic acid [4-(tetrahydropyran-2-yloxy methyl)phenyl] amide (2 0g, 0 004mol, 1 equiv ), an amine of Formula IX (1 5g, 0 006mol, 1 5eqmv ), pivahc acid (0 45mL, 0 004mol, 1 03equiv ), and heptane toluene tetrahydrofuran (4 11, 24ml) was placed in a round bottom flask equipped with a Dean-Stark setup The reaction mixture was refluxed at with azeotropic removal of water After the completion of reaction (TLC monitoring), the solvents were removed on rotary evaporator The residue was diluted with ethyl acetate and a saturated solution of sodium bicarbonate was added to this solution The aqueous layer was extracted with ethyl acetate and the organic layer was washed with water, brine, dried over anhydrous sodium sulphate and concentrated The crude mixture was purified on column (silica gel, 100-200 mesh, 15% ethyl acetate/hexane) to obtain the pure product Yield 1 0 g (34 6%) MS (+ion mode) m /z 769 45 (M+ 1)
1H NMR (CDCI3, 300Hz) δ 0 9-1 l(m, 2H), 1 30(s, 1H), 1 36(s, 3H), 1 43(s, 9H), 1 50-1 77(m,14 6H), 2 20-2 40(m, 2H), 3 52-3 70(m, 3H), 3 85-3 89(m, 2H), 4 05-4 25(m, 2H), 4 40(d, J=12 Hz,lH),4 64-4 70(m, 2H), 6 86-7 25(m, 14H)
Example 5 Preparation of (3R.5R)-7-[2-(4-fluorophenyl)-4-(4-hydroxymethyl-phenylamino) carbnoyl)-5-isopropyl-3-phenylpyrrol-l-yl]-3.5-dihydroxy heptanoic acid tert-butyl ester
A mixture of [(4R, 6R)-6-(2-{2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4- [4-(tetrahydro-pyran-2-yloxy methyl) phenyl amino) carbnoyl]-pyrrol-l-yl}ethyl)-2,2-dimethyl-[1,3] dioxan-4-yl]-acetic acid tert-butyl ester (0 8g, 0 0015mol, lequiv), lequiv) and a mixture of IN hydrochloric acid methanol tetrahydrofuran in the ratio 2 5 5 (24 mL) was placed in a single neck flask The reaction mixture was stirred at room temperature Reaction mixture was concentrated by evaporating solvent under reduced pressure The crude compound was extracted with ethyl acetate and the ethyl acetate layer was washed with brine, dried over anhydrous sodium sulphate and concentrated The crude mixture was purified on column (silica gel, 100-200 mesh, 60% ethyl acetate/hexane) to obtain the pure product Yield 446mg(66 56%)
MS (+ion mode) m /z 645 32 (M+ 1)
1H NMR(CDC13, 300Hz) δ 1 15-1 30(m, 2H), 1 45(s, 9H), 1 47-1 62(m, 8H),2 32(d,J=6 0Hz,2H), 3 53-3 60(m, 2H), 3 69-3 92(m, 1H), 4 08-4 13(m, 2H), 4 58(s, 2H), 6 87(s, 1H), 6 97-7 25(m, 13H)
Example 6 Preparation of (3R.5R)-7-r2-(4-fluorophenyl)-4-(4-hvdroxy methyl- pheny lamino) carbnoyl)-5-isopropyl-3-phenyl-pyrrol-l-yl}-3.5-dihydroxy-heptanoic acid hemi calcium salt
Step 1 (3R, 5R)-7-[2-(4-fluorophenyl)-4-(4-hydroxy methyl phenyl amino) carbnoyl)-5-isopropyl-3-phenylpyrrol-l-yl]-3,5-dihydroxyheptanoic acid tert-butyl ester in a mixture of methanol-tetrahydrofuran (1 1) was cooled to 0°C and sodium hydroxide pellets were added The reaction mixture was then stirred at an ambient temperature At the end of ester hydrolysis, solvents were removed and the residue was dissolved in water, aqueous layer was washed with ether
Step 2 To an aqueous solution of sodium salt of (3R,5R)-7-[2-(4-fiuorophenyl)-4-(4-hydroxy methyl- pheny lamino) carbnoyl)-5-isopropyl-3-phenyl-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid was added drop wise an aqueous solution (1M) of calcium acetate (0 55 equiv) White precipitate was obtained, which was filtered off, washed with copious amount of water, and dried in vacuo Yield = 63 4% MS (positive ion mode) m/z 589 (Acid+1) mp =189-204°C
1HNMR (DMSO-d6) δ 1 22-1 62 (m, 11H), 1 98 (dd, J=15 & 8 1Hz, 1H), 2 06-2 16 (m, 1H), 3 25-3 37 (m, 2H), 3 57 (brs, 2H), 3 80 (brs, 1H), 4 43 (s, 2H), 7 03-7 28 (m, 12H), 7 50 (d, J=6H, 2H), 9 80 (s, 1H)

WE CLAIM:
1. A novel process for the preparation of (3R, 5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4- [(4-hydroxy methyl phenyl amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid hemi calcium salt of Formula I,
(Formula Removed)
which process comprises the steps of: (a) reacting an amine of Formula II with methyl isobutyryl acetate of Formula III
(Formula Removed)
to form a compound of Formula of IV (wherein R is a hydroxy protecting group selected from acetyl, benzoyl, tetrahydropyranyl, methoxy methyl, methoxy ethoxymethyl or benzyl),
(Formula Removed)
b) reacting the compound of Formula IV with benzaldehyde to form a compound
of Formula V,
(Formula Removed)
c) reacting the compound of Formula V with 4-fluorobenzaldehyde to form a
compound of Formula VI,
(Formula Removed)
d) reacting the compound of Formula VI with a compound of Formula VII
(Formula Removed)
to form a compound of Formula VIII,
(Formula Removed)
e) subjecting the compound of Formula VIII simultaneously to acid catalyzed
cleavage of ketal and hydroxy protecting group (when R is tetrahydropyranyl) to
form a compound of Formula IX,
(Formula Removed)
f) subjecting the compound of Formula IX to base catalyzed hydrolysis to form a
compound of Formula X,
(Formula Removed)
g) reacting the compound of Formula X with aqueous solution of calcium acetate
to form a compound of Formula I.
2. The process of claim 1, wherein the reaction of an amine of Formula II is carried out
i) in the presence of one or more organic bases selected from triethylamine,
pyridine, 1,2-ethylenediamine or mixture thereof;
ii) in one or more aromatic solvents, for example, xylene, toluene or mixture thereof.
3. The process of claim 1, wherein the reaction of a compound of Formula IV is carried
out
i) in the presence of one or more organic bases selected from piperidine,
pyridine or P-alanine; one or more organic acids selected from glacial acetic acid or benzoic acid or mixture of organic bases or organic acids;
ii) in one or more solvents selected from hydrocarbon solvents (selected from hexane or heptane), halogenated solvents (selected from dichloromethane, dichloroethane or chloroform), aromatic solvents (selected from toluene or xylene) or mixture thereof.
4. The process of claim I, wherein the reaction of a compound of Formula V is carried
out
i) in the presence of one or more catalysts selected from sodium cyanide, 3-
ethyl-5- (2-hydroxyethyl)-4-methyl thiazolium bromide, 3-benzyl-5- (2-hydroxyethyl)-4-methyl thiazolium chloride or mixture thereof;
ii) one or more organic bases selected from triethylamine, pyridine or mixture thereof;
iii) in a solvent free condition or in one or more solvents selected from protic polar solvents (selected from methanol, ethanol, propanol, isopropanol or water), ethers (selected from dioxan or tetrahydrofuran) or mixture thereof.
5. The process of claim 1, wherein the reaction of a compound of Formula VI is carried
out
i) in the presence of one or more organic acids selected from pivalic acid, p-toluene sulfonic acid or mixture thereof;
ii) in one or more solvents selected from aromatic solvents (selected from xylene or toluene), hydrocarbon solvents (selected from hexane or heptane), ethers (selected from tetrahydrofuran, dioxane or diethyl ether) or mixture thereof.
6. The process of claim 1, wherein the cleavage of ketal and hydroxy protecting group of
a compound of Formula VIII is carried out
i) in the presence of one or more mineral acids selected from hydrochloric acid,
hydrobromic acid, hydroiodic acid or mixture thereof;
ii) in one or more solvents selected from protic polar solvents (selected from
methanol, ethanol, propanol or water), ethers (selected from tetrahydrofuran or diethyl ether) or mixture thereof.
7. The process of claim 1, wherein the hydrolysis of a compound of Formula IX is carried out
i) in the presence of one or more bases selected from lithium hydroxide, sodium
hydroxide, potassium hydroxide or mixture thereof;
ii) in one or more solvents selected from protic polar solvents (selected from methanol, ethanol, propanol, isopropanol or water), ethers (selected from tetrahydrofuran or diethyl ether) or mixture thereof.