Title of Invention

DERIVATIVES OF COMPOUND 3-AMINO-1-MORPHOLINE-4-YL-PROPAN-1-ONE

Abstract Derivatives of compound 3-amino-l-morpholine-4-yl-propan-l-one represented by Formula (6) : Wherein R is alkyl, aryl, arylalkyl, or heteroaryl, and S, or Se, or R1 is wherein R4 is alkyl of from one to four carbon atoms, A is O, S, or N, and R is as defined above.
Full Text FORM 2
THE PATENTS ACT 1970
[39 OF 1970]
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
[See Section 10; rule 13]
"DERIVATIVES OF COMPOUND 3-AMINO-1-MORPHOLINE-4-YL-
PROPAN-1-ONE"
WARNER-LAMBERT COMPANY LLC, a corporation organized and existing under and by virtue of the laws of the State of Delaware and having an office and place of business at 201 Tabor Road, Morris Plains, New Jersey 07950, United States of America
The following specification particularly describes the invention and the manner in which it is to be performed:


The present invention relates to derivatives of compound 3-amino-l-morpholine-4-yl-propan-1-one.
An improved synthesis for the preparation of 5-(4-fIuorophenyl)-l-[2-((2R,4R)^-hydroxy-6HDXo4etrahydro-py^^ ljy-pyrrole-3-carboxyllc acid phenylarnide is described where methyl ' cyanoacetate is converted in eight operations or fewer to the desired product, as well as other valuable intermediates usedM'the process.
BACKGROUND OF THE INVENTION
5-(4-Fluorophenyl)-1 -[2"((2R,4R)-4-hydroxy-6~oxo-tetrahydro-pyran--2-yl)-ethyl]-2-isopropyI-4-phenyl-li?-pyrrole-3-carboxylic acid phenylarnide is a valuable intermediate in the synthesis of Iipitor® (atorvastatra. calcium) known by the chemical name [R-(R*,R*)]-2-(4T-fJuorophenyI)-|335-dihydroxy-:5-(l-memylemyI)-3-phenyi-4-f(phenylammo)carb6nyI]-lH-pyrrole-l"heptanoicacid calcium salt (2:1) trihydrate. The aforementioned compound is useful as an inhibitor of the enzyme 3-hydroxy-3-memylglutary]-coenzyme A reductase (HMG-CoA reductase) and is thus •useful as a hypolipidemic and/or hypocholesterqlemic agent.
United States Patent No. 4,681,893, which, is herein incorporated by reference, discloses certain trans-6~[2-(3- or4-carboxainido-substitated-pyirol-l-yl)alkylJ-4-hydroxy-pyran-2-ones including trans (±)~5-(4~fLuorophenyl)-2-(l -methyIethyl)-N, 4-diphenyl-1 -] (2-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2^yl)ethyl]-lH-pyrrole-3-carboxamide.
United States'Patent No. 5,273,995, which is herein incorporated by reference, discloses the enantiomer having the (R,R) form of the ring-opened acid oftrans-5-(4-fluorophenyl)-2-(l-memyJethyl)-N, 4-diphenyl-l-[(2-fetrahydro^-

hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-lH-pyrrole-3-carboxaniide, i.e.,
[R-(R*3R*)]-2-(4-fluorophenyl)-p,6-dihydroxy-5-(l-methylethyl)-3-phenyl-4-
[(phenyIamino)carbonyl]-lif-pyrrole-l-heptanoic acid.
United States Patent Nos. 5,003,080; 5,097,045; 5,103,024; 5,124,482;
5,149,837; 5,155,251; 5,216,174; 5,245,047; 5,248,793; 5,280,126; 5,397,792;
5,342,952; 5,298,627; 5,446,054; 5,470,981; 5,489,690; 5,489,691; 5,510,488;
5,998,633; and 6,087,511, which are herein incorporated by reference, disclose
various processes and key intermediates for preparing atorvastatin.
Crystalline forms of atorvastatin calcium are disclosed in United States
Patent Nos. 5,969,156 and 6,121,461 which are herein incorporated by reference. A synthetic procedure for the preparation of 5-(4-fluorophenyl)-l-[2-
((2R,4R)^-hyd^oxy-6xo-tetrahydro-pyran-2-yl)-ethyl]-2-isopropyl-4-phenyl-
lif-pyrrole-3-carboxyIic acid phenylamide is disclosed in United States Patent No. 5,273,995.
The asymmetric reduction of p-ketoesters, as well as P-diketones, is a well-established transformation in organic synthesis. However, the complexity of these reactions increases in the case of 1,3,5-tricarbonyl systems and poor yields and poor stereoselectivities often result In fact, investigations by Saburi (Tetrahedron, 1997,1993;49) and Carpentier (Eur. J. Org. Chem. 1999;3421) have independently demonstrated low to moderate diastereo- and/or enantio-selectivities for diketoester asymmetric hydrogenarions. Furthermore, the fact that the processes in the prior art require high pressure hydrogenation and extended reaction times makes these procedures impractical and not amenable to large-scale manufacturing processes.
However, we have surprisingly and unexpectedly found that the diol esters of the present invention, (R)-7-[2-(4-fluorophenyI)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid esters, can be obtained directly from the corresponding 1,3,5-tricarbonyl precursors in a highly stereoselective manner via a mild and efficient ruthenium-catalyzed asymmetric hydrogenation reaction utilizing chiral non-racemic diphosphine ligands in the presence of secondary activating agents such as protic acids.

The object of the present invention is a short and efficient process for the preparation of 5-(4-fiuorophenyl)-l -[2-((2R,4R)-4-hydroxy-6-oxo-tetrahydro-.pyran-2-yJ)-ethyIJ-2-isopropyl-4-phenyl-lif-pyrrole-3-carboxylic acid phenylamide. The present process avoids the use of a costly chiral raw material ((R)-4-cyano-3-hydroxy-butyric acid ethyl ester), and a low temperature diastereoselective borane reduction. Furthermore, a key Paal-Knorr condensation step, common to the present and prior art processes, has been improved through a significant decrease in reaction time.
Thus, the present process has significant advantages over the prior art processes and is amenable to large-scale synthesis.
SUMMARY OF THE INVENTION

which comprises:
Step (a) reacting a compound of Formula (1)

Accordingly, the first aspect of the present invention is an improved process for the preparation of a compound of Formula (13)
wherein R is alkyl, aryl, arylalkyl, or heteroaryl in a solvent with a compound of Formula (2)




Step (b) reacting a compound of Formula (3) with hydrogen in the presence of a catalyst and a strong acid in a solvmt to afford a compound of
Formula (4)

wherein Y is CI, Br, TsO, MsO, or HSO4, and R* is as defined above;
Step (c) reacting a compound of Formula (4) with a base in a solvent followed by the addition of a compound of Formula.(5)

wherein R is as defined above in a solvent to afford a compound of Formula (6)

wherein R and R* are as defined above;
Step (d) reacting a compound of Formula (6) with Compound (7)

in a solvent with removal of water to afford a compound of Formula (8)


wherein Rl is as defined above;
Step (e) reacting a compound of Formula (8) with a compound of Formula (9)

wherein M is sodium, lithium, potassium, zinc, magnesium, copper,
calcium, or aluminum and R* is as defined above, in a solvent in the presence of a strong base to afford a compound of Formula (10)

wherein Rl is as defined above;
Step (f) reacting a compound of Formula (10) with hydrogen in the presence of a catalyst in a solvent in the presence of an acid to afford a compound of Formula (11)


wherein RT is alkyl of from one to four carbon atoms, A is O, S, or N, and R is as defined above in a solvent in the presence of an acid, followed by reaction with a base, an acylating agent, and an acylation catalyst in a solvent to afford a compound of Formula (12)


Step (h) reacting a compound of Formula (12) with HO-M in an alcohol of Formula (17) or (17b)
HOCH2-Aryl (17) or HOAllyl (17b)
wherein M is sodium, lithium, potassium, zissc, magaesium, copper, calcium, or aluminum; or with a compound of Formula (16) or (16b)
M © 0 0CH2-Aryl (16) or M ® ® O-Allyl (16b) wherein M is as defined above in an alcohol of Formula (17) or (17b)
wherein aryl or allyl in a compound of Formula (16) or (16b) and (17) or (17b) is
the same, in a solvent followed by the addition of hydrogen in the presence of a
catalyst and an acid to afford the compound of Formula (13).
A second aspect of the present invention is an improved process for the

wherein R1 is as defined above which comprises: reacting a compound of Formula (4)
preparation of a compound of Formula (8).


wherein R and M are as defined above with Compound (7)

wherein Y is CI, Br, TsO, MsO, or HS.O4, and R1 is as defined above with a compound of Formula (20)

in a solvent with removal of water to afford a compound of Formula (8). A third aspect of the present invention is an improved process for the preparation of compound (13)

which comprises:
Step (a) reacting a compound of Formula (11) with an acetal of Formula (IS)


wherein R5 and R5a are independently the same or different and are,
methyl, ethyl, or -(CH2)n- wherein n is an integer of 2 to 4, and R is as defined above in a solvent in the presence of an acid followed by the addition of an aldehyde corresponding to the previous acetal in the presence of a base to afford a compound of Formula (14)

wherein R* and R are as defined above;
Step (b) reacting a compound of Formula (14) in a nucleophilic solvent in the presence of an acid or optionally reaction with hydrogen in the presence of a catalyst and an acid in a solvent to afford the compound of Formula (13); and
Step (c) alternatively, reacting a compound of Formula (11) or (1 la) in a non-nucleophilic solvent in the presence of an acid to afford a compound of Formula (13).
A fourth aspect of the present invention is a process for the preparation of a compound of Formula (lib)




wherein R4 is alkyl of from one to four carbon atoms, A is 0, S, or N, and R is alkyl, aryl, arylalkyl, or heteroaryl which comprises:
Step (a) reacting a compound of Formula (10)

wherein Rl is as defined above with one mole of hydrogen in the presence of a catalyst in a solvent in the presence of an acid to afford compounds of Formula (18) and/or Formula (18a)


wherein RMS as defined above; and
Step (b) reacting either a compound of Formula (18) or (18a) with hydrogen in the presence of a catalyst in a solvent in the presence of an acid to afford a compound of Formula (1 lb).
A fifth aspect of the present invention is a compound of Formula (6)


-CH(R4)-CH2-A-CH2-CH(R4)-
wherein R4 is alkyl of from one to four carbon atoms, A is 0, S, or N and R is as defined above.
More particularly preferred, is a compound of Formula (6) wherein R is

A sixth aspect of the present invention is a compound of Formula (8)

Particularly preferred, is a compound of Formula (6) wherein R is PI1CH2-

wherein Rl is as defined above. Particularly preferred is a compound of Formula (8) wherein R1 is

A seventh aspect of the present invention is a compound of Formula (10) or a pharmaceutically acceptable salt thereof


wherein R^ is as defined above. Particularly preferred is a compound of Formula (10) wherein R* is

An eighth aspect of the present invention is the compound of Formula (12)

A ninth aspect of the present invention is a compound of Formula (18) or a pharmaceutically acceptable salt thereof


wherein R1 is as defined above.
Particularly preferred is a compound of Formula (18) wherein R1
A tenth aspect of the present invention is a compound of Formula (18a) or a pharmaceutically acceptable salt thereof

wherein Rl is as defined above.
Particularly preferred is a compound of Formula (18a) wherein R1 is


DETAILED DESCRIPTION OF THE INVENTION
The term "alkyl" means a straight or branched hydrocarbon radical having from 1 to 8 carbon atoms and includes, for example, methyl, ethyl, ^-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 7J-pentyl, w-hexyl, w-heptyl, /j-octyl, and the like.
"Alkoxy" and "thioalkoxy" are O-alkyl or S-alkyl of from 1 to 6 carbon atoms as defined above for "alkyl".
The term "cycloalkyl" means a saturated hydrocarbon ring having 3 to 8 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
The term "aryl" means an aromatic radical which is a phenyl group, a phenylalkyl group, a phenyl group substituted by 1 to 4 substituents selected from alkyl as defined above, alkoxy as defined above, thioalkoxy as defined above, halogen, trifluoromethyl, dialkylamino as defined above for alkyl, nitro, cyano,

The term "allyl" means a hydrocarbon radical of 3 to 8 carbon atoms, containing a double bond between carbons 2 and 3, unsubstituted or substituted by 1 to 3 substituents on the carbons containing the double bond selected from alkyl or aryl as defined above, and includes, for example, propenyl, 2-butenyl, cinnamyl, and the like.
The term "arylalkyl" means an aromatic radical attached to an alkyl radical wherein aryl and alkyl are as defined above for example, benzyl, phenylethyl, 3-phenylpropyl, (4-chIorophenyI)methyl, and the like.
"Alkali metal" is a metal in Group IA of the periodic table and includes, for example, lithium, sodium, potassium, and the like.

"Alkaline-earth metal" is a metal in Group IIA of the periodic table and includes, for example; calcium, barium, strontium, magnesium, and the like.
The term "heteroaryl" means a 5- and 6-membered heteroaromatic radical which may optionally be fused to a benzene ring containing 1 to 3 heteroatoms selected from N, O, and S and includes, for example, a heteroaromatic radical which is 2- or 3-thienyl, 2- or 3-furanyl, 2- or 3-pyrrolyl, 2-, 3-, or 4-pyridinyl, 2-pyrazinyl, 2-, 4-, or 5-pyrimidinyl, 3- or 4-pyridazinyl, lH-indol-6-yl, lH-indol-5-yl, lH-benzimidazoI-6-yl, lH-benzimidazol-S-yl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-, 4-, or 5-imidazolyl, 3-, 4-, or 5-pyrazolyl, or 2- or 5-thiadiazolyl and the like optionally substituted by a substituent selected from alkyl as defined above, alkoxy as defined above, thioalkoxy as defined above, halogen, trifluoromethyl, dialkylamino as defined above for alkyl, nitro, cyano,

defined above for alkyl and
Pharmaceutically acceptable acid addition salts of the compounds of the present invention include salts derived from inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, hydrofluoric, phosphorous, and the like, as well as the salts derived from nontoxic organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic • sulfonic acids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, . trifiuoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like.

Also contemplated are salts of amino acids such as arginate and the like and gluconate, galacturonate (see, for example, Berge S.M. et al., "Pharmaceutical Salts,"! ofPharma. Set, 1977;66:1).
The acid addition salts of said basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner. The free base form may be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner. The free base forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free base for purposes of the present invention.
Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N,N'^ben^lemylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediarxiine, N-memylglucamine, and procaine (see, for example, Berge S.M. et al., "Pharmaceutical Salts," J. ofPharma Set, 1977;66:1).
The base addition salts of said acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner. The free acid form may be regenerated by contacting the salt form with an acid and isolating the free acid in the conventional manner. The free acid forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free acid for purposes of the present invention.
Additionally, the compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms, are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. The following list contains abbreviations and acronyms used within the schemes and text:

H2SO4 Sulfuric acid
NaOMe Sodium methoxide
MeOH Methanol
MtBE Methyl tert-butyl ether
GC Gas chromatography
Pt/C Platinum on carbon
Pd/C Palladium on carbon
H2 Hydrogen
HC1 Hydrochloric acid
Hg Mercury
psi Pounds per square inch
iPrOH (EPA) Isopropyl alcohoi"
HPLC High pressure liquid chromatography
NaOH Sodium hydroxide
CH2CI2 Dichloromethane (methylene chloride)
DMSO-d6 Deuterated dimethylsulfoxide
THF Tetrahydrofuran
Na2SO4 Sodium sulfate
nBuLi n-Butyllithium
NaCl Sodium chloride
KOtBu Potassium tert-butoxide
NaHCO3 Sodium bicarbonate
BnOH Benzyl alcohol
Pd(OH)2/C Palladium hydroxide on carbon
H2O Water
PivOH Pivalic acid
PhCHO Benzaldehyde
PhCH3 Toluene
CDCI3 Deuterated chloroform
BnONa Sodium ben2ylate
NH4OH Ammonium hydroxide

PhCH(0Me)2 Benzaldehyde dimethyl acetal
MsOH Methanesuifonic acid
pTsOH para Toluenesulfonic acid
CSA Camphorsulfonic acid
Ph Phenyl
NaH Sodium hydride
KH Potassium hydride
EtOAc Ethyl acetate
tBuOH(HOtBu) tert-Butanol
PhCH2C02H Phenylacetic acid
NaNH2 Sodium amide
KHMDS Potassium hexamethyldisilazide
LAH Lithium aluminum hydride
Pd/Al203 Palladium on alumina
APCI Atmospheric pressure chemical ionization
ESI Electrospray ionization
DO Direct chemical ionization
1H NMR Proton nuclear magnetic resonance spectroscopy
13C NMR 13Carbon nuclear magnetic resonance spectroscopy
BINAP (R)-(+)-2,2'-Bis(diphenylphosphino)-l, 1 '-binaphthyl
pTol-BINAP (R)-(+)-Bis(di-p-tolyl-phosphino)-l,l,-binaphthyl
Cl-MeO-BIPHEP [(R)-(+)-5,5,-Dichloro-6,6/-dimethoxy[l,l/-biphenyl]-
2,2/-diyI]-bis-diphenyIphosphine
C2-TunaPhos [(12aR)-6,7-dihydrodibenzo[e,g][l,4]dioxocin-l,12-
diylj-bis-diphenylphosphine
C4-TunaPhos [(14aR>6,7,8,9-tetfahydrodibenzo|>,d](;i,6]dioxecm-
1,14-diyl] -bis-diphenylphosphine
MeO-BMffiP [(1 S)-(->6,6'-Dimethoxy[l, 1 '-biphenyl]-2,2'-diyl]-bis-
diphenylphosphine
p-cymene 4-isopropyltoluene
ee Enantiomeric excess

HRMS High resolution mass spectrometry
m/z Mass to charge ratio
tR Retention time
The process of the present invention in its first aspect is a new, improved, economical, and commercially feasible method for the preparation of the compound of Formula (13)

The process of the present invention in its first aspect is outlined in Scheme 1. Thus, a compound of Formula (1) wherein R is alkyl, aryl, arylalkyl, or
heteroaryl is reacted with a compound of Formula (2) wherein R1 is -XR wherein



wherein R4 is alkyl of from one to four carbon atoms, A is O, S, or N and R is as defined above in a solvent such as, for example, methyl tertiary butyl ether, and the like, to afford a compound of
Formula (3) whereas R1 is as defined above. Preferably, the reaction is carried out with a compound of Formula (2) wherein
Rl-H is morpholine in methyl tertiary butyl ether. A compound of Formula (3) is reacted with hydrogen in the presence of a catalyst such as, for example, Pt/C, PdVC in the presence of an acid such as,, for example, a strong acid, for example, hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid, methanesulfonic acid, sulfuric acid, and the like (optionally the reduction is carried out with Sponge N1/NH4OH, metal hydrides,
and the like, to afford the free base of a compound of Formula (4)) in a solvent such as, for example, methanol, ethanol, and the like to afford a compound of
Formula (4) wherein Y is CI, Br, TsO, MsO, or HSO4 and R* is as defined above.
Preferably, the reaction is carried out in the presence of Pt/C, hydrochloric acid and hydrogen in methanol.
A compound of Formula (4) is reacted with a base such as, for example, sodium methoxide and the like in a solvent such as, for example, tetrahydrofuran, toluene, methyl tertiary butyl ether, and the like, and in an alcohol such as, for example, isopropanol, ethanol, methanol, and the like, to afford the free base

followed by reaction with a compound of Formula (5) wherein R is as defined above in a solvent such as, for example, isopropanol, tetrahydrofuran, and the like to afford a compound of Formula (6) wherein R is as defined above. Optionally, the free base of a compound of Formula (4) may be reacted with a compound of Formula (5) to afford a compound of Formula (6). Preferably, the reaction is carried out with sodium methoxide in methyl tertiary butyl ether and methanol to afford the free base followed by reaction with phenylacetic in tetrahydrofuran.
A compound of Formula (6) is reacted with the compound of Formula (7) in a solvent such as, for example, a profic, an aprotic, a polar or a non-polar solvent, for example, tetrahydrofuran and the like with removal of water with the aid of a chemical drying agent such as, for example, molecular sieves and the like or with the aid of a Dean-Stark water trap or using azeotropic distillation with a suitable solvent such as, for example toluene and the like to afford a compound of
Formula (8) wherein R1 is as defined above. Preferably, the reaction is carried out with activated 3A molecular sieves in tetrahydrofuran.
A compound of Formula (8) is reacted with a compound of Formula (9) wherein M is sodium, lithium, potassium, zinc, magnesium, copper, calcium, or aluminum and R1 is as defined above in a solvent such as, for example, a nonreactive aprotic solvent, for example, tetrahydrofuran, toluene, and the like in the presence of a strong base such as, for example, n-butyllithium, lithium or potassium hexamethyldisilazide, lithium diisopropylamide, and the like to afford a
compound of Formula (10) wherein R1 is as defined above. Preferably, the reaction is carried out with a compound of Formula (9) wherein M is sodium, the base is Ai-butyllithium and the solvent is tetrahydrofuran.
The carbonyls of a compound of Formula (10) in Scheme 1 are shown in the keto form. However, a compound of Formula (10) can undergo "keto-enol" tautomerism and thus can exist in several tautomeric forms which are encompassed within the present invention.
A compound of Formula (10) is treated with hydrogen in the presence of a catalyst such as, for example, a chiral non-racemic ruthenium (IThdiphosphine complex. For example, a ruthenium catalyst precursor such as [dichloro-(l,5-cyclooctadiene)] ruthenium (II) oligomer and chiral diphosphine ligand such as

[(R)-(+)-2,2'-bis(diphenyl-phosphino)-l,r-binaphthyI]. However, any chiral no racemic ruthenium (H)/diphosphine combination may be employed in this reduction reaction. For example, ruthenium (II) catalyst precursors include [dibromo-(l,5-cyclooctadiene)j ruthenium (II) dimer, [bis-(2-methaIlyl)cycIooc 1,5-diene] ruthenium (II) complex and [dichloro(D-cymene)] ruthenium (II) dim and the like. Examples of effective chiral diphosphine ligands include 2,2'-bis(di-j?-tolyl-phosphino)-l, I '-binaphthyl, 2-diphenyl-phosphinomethyl-4-diphenylphosphino-l-/er/-butoxy-carbonylpvrrolidhie, tricyclo[8.2.2.24,7]hexadeca-4J6,10,12J13,15-hexaene-5,ll-diyl-bis(diphenylphosphine) derivatives, 4,4/-bidibenzofuran-3,3/-diylbis(diphenylphosphine), 6,6'-dimethoxy[l, 1 '-biphenylj^^'-diy^bis-diphenylphosphine, [5,5'-dicMoro-6,6' A compound of Formula (1 lb) wherein R^a is wherein R^a is OH, -XR wherein
X is O,
S, or
Se, or Rla is


wherein R2 or R3 is independently

alkyl, cycloalkyl,


wherein R.4 is alkyl of from one to four carbon atoms, A is O, S, or N, and R is alkyl, aryl, arylalkyl, or heteroaryl is reacted with an acid such as, for example, jp-toluenesulfonic acid, camphor-sulfonic acid, sulmric acid, hydrogen chloride, and the like in a non-nucleophilic solvent such as, for example, toluene, acetonitrile, dichloromethane, methyl tertiary butyl ether, and the like, followed by reaction with a base, such as, for example, triethylamine, pyridine, diisopropylethylamine, and the like, and with an acylating agent, such as, for example, acetic anhydride, benzoyl chloride, benzyl chloroformate, and the like, in the presence of 4-dimethylaminopyridine to afford the compound of Formula (12). Preferably, the reaction is carried out in toluene in the presence of P-toluenesulfonic acid, followed by treatment with triethylamine, acetic anhydride, and 4-dimethylaminopyridine in toluene.
A compound of Formula (12) is reacted with HO-M in an alcohol of Formula (17) or (17b) wherein M is sodium, lithium, potassium, zinc, magnesium, copper, calcium, or aluminum, or with a compound of Formula (16) or (16b) wherein M is as defined above in an alcohol of Formula (17) or (17b) wherein aryl or allyl in a compound of Formula (16) or (16b) and (17) or (17b) is the same, in an optional cosolvent, such as, for example, a nonnucleophilic solvent, for

example, acetone, tetrahydrofuran, 1,2-dimethoxyethane, and the like, followed b the addition of hydrogen in the presence of a catalyst, such as, for example, Pd(OH)2/C, Pd/C, Pd/Al2O3, and the like, in the presence of an acid, such as, fo example, hydrochloric acid, hydrobromic acid, sulfuric acid, and the like, to affoi the compound of Formula (13). Preferably, the reaction is carried out with sodiun hydroxide in benzyl alcohol followed by hydrogenation in the presence of Pd(OH)2/C and sulfuric acid.
The process of the present invention in its second aspect is outlined in Scheme 2. Thus, a compound of Formula (4), prepared as described in Scheme 1, is reacted with a compound of Formula (20) wherein R and M are as defined above and a compound of Formula (7) with removal of water with the aid of a chemical drying agent such as, for example; molecular sieves and the like or with the aid of a Dean-Stark water trap or using azeotropic distillation with a suitable solvent such as, for example tetrahydrofuran, toluene, and the like, to afford a
compound of Formula (8) wherein R1 is as defined above. Preferably, the reaction is carried out with a compound of Formula (20) wherein R is PhCH2 and M is
sodium in the presence of activated 3 A molecular selves in tetrahydrofuran. The process of the present invention in its third aspect is outlined in Scheme 3. Thus, a compound of Formula (11) is reacted with an acetal of Formula (15) wherein R-> and R^a are independently the same or different and are, methyl, ethyL or -(CH2)n- wherein n is an integer of 2 to 4, and R is as defined above in the presence of an acid such as, for example, hydrochloric acid, pyridinium />-toluenesulfonate, jp-toluenesulfonic acid and the like in a solvent such as, for example, toluene, dichloromethane, methyl tertiary butyl ether, and the like, followed by the addition of an aldehyde corresponding to the previous acetal of Formula (15) in the presence of a strong base such as, for example, a non-nucleophilic base, for example, potassium tertiary butoxide, potassium bis(trimethylsilyl) amide, l,8-diazabicyclo[5.4.0] undec-7-ene and the like, to afford a compound of Formula (14) wherein R1 and R are as defined above. Preferably, the reaction is carried out with benzaldehyde dimethyl acetal in toluene in the presence ofp-toluenesulfonic acid followed by the addition of benzaldehyde and potassium tertiary butoxide in teti^ydrofuran.

A compound of Formula (14) is reacted with hydrogen in the presence of a catalyst such as, for example, palladium on carbon or platinum on carbon and the like in the presence of an acid such as, for example, hydrochloric acid and the like in a solvent such as, for example, toluene, tetrahydrofuran, methyl tertiary butyl ether, ethyl acetate, and the like, and an alcohol, such as, for example, methanol, ethanol, and the like, to afford a compound of Formula (13). Preferably, the reaction is carried out in toluene in the presence of platinum on carbon in the presence of methanol in the presence of hydrochloric acid.
Optionally, a compound of Formula (14) is reacted with an acid such as, for example, hydrochloric acid, pyridinium/7-toIuenesulfonate,/>-toluenesulfonic acid, and the like, in a solvent such as, for example, toluene, dichloromethane, methyl tertiary butyl ether, and the like to afford the compound of Formula (13). Preferably, the reaction is carried out in methylene chloride in the presence of p-toluenesulfonic acid.
Alternatively, a compound of Formula (11) is reacted with an acid, such as, for example, hydrochloric acid, hydrobromic acid,/?-toluenesulfonic acid, and the like, in a non-nucleophilic solvent, such as, for example, toluene, acetonitrile, methyl tertiary butyl ether, tetrahydroiuran, and the like, to afford a compound of . Formula (13). Preferably, the reaction is carried out in toluene in the presence of p-toluenesulfonic acid.
The process of the present invention in its fourth aspect is outlined in
Scheme 4. Thus, a compound of Formula (10) wherein R* is as defined above is reacted with one molar equivalent of hydrogen in the presence of a catalyst using the methodology described above for the conversion of a compound of Formula (10) to a compound of Formula (11) to afford either a compound of Formula (18)
or Formula (18a) wherein R* is as defined above or a mixture thereof. A mixture of compounds of Formula (18) and (18a) may be separated using conventional methodology, such as, for example, chromatography and the like. Preferably, a mixture of compounds of Formula (IS) and (18a) is separated using HPLC.
A compound of Formula (18) or (18a) or a mixture thereof is reacted with hydrogen in the presence of a catalyst as described above for preparing a compound of Formula (11) to afford a compound of Formula (1 lb) wherein R*a



EXAMPLE 1 5-(4-fluorophenyl)-l-{2-((2R,4R)-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-l-isopropyW-phenyl-Uy-pyrrole-S-carboxylicacidphenylamide
Step 1: 3-Morpholin-4-vl~3-oxo-propioiiitTile



A nitrogen inerted reactor equipped with reflux condenser, nitrogen inlet and mechanical stirring is charged with morpholine (1.2 mol), methyl cyanoacetate (1.0 mol) and MtBE (52 mL). The homogeneous solution is heated to ca. 55°C and stirred at that temperature for 12 to 18 hours. MtBE (33 mL) is added over ca. 15 minutes, and the solution is slowly cooled below 50°C where nucleation becomes evident. Additional MtBE (66 mL) is added over a 1-hour period. During this time, the reaction is allowed to cool to near ambient temperature. After complete MtBE addition, the reaction is cooled with stirring to ca, 0°C. The resulting precipitate is collected via filtration and the cake is washed with additional MtBE (ca. 40 mL). The solid is dried under vacuum at ca. 45°C to provide 3-morpholin-4-yl-3-oxo-propionitrile (139 g). This material is used in subsequent steps without further purification. m/z (APCIOH+1)) 154.9;calcd for C7H10N2O2 154.07.
Step 2: 3-Amino-l-morphoIin-4-vl-Dropan-l-one: hvdrochloride

A nitrogen inerted reactor is charged with 5% Pt-C (43 g; 58% water-wet) followed by 3-morpholin-4-yl-3-oxo-propionitrile (2.8 mol). A solution of MeOH (3.4 L) and 12N HC1 (3.08 mol) is added at such a rate as to maintain an internal temperature of ca. 25°C. The vessel and its contents are degassed via three N2 pressure purges (50 psi). The atmosphere is switched to hydrogen via three H2 pressure purges (50 psi), and the reaction is stirred vigorously at ca. 25°C under a

sustained pressure of hydrogen (50 psi) for ca. 24 hours. The H2 pressure is released and replaced with N2- The reaction is passed through filter agent, which
is subsequently washed with MeOH (500 mL). The reaction is concentrated in
vacuo to a volume of ca. 1.4 L, and IPA (2.2 L) is added. The reaction mixture is
cooled to 0°C and filtered. The filter cake is washed with MtBE (500 mL) and
dried under vacuum at ca. 30°C to provide 3-amino-l-morphoIin-4-yl-propan-l-
one, hydrochloride as a white solid (439 g). This material is used in subsequent
steps without further purification.
1HNMR (400 MHz, DMSO) 5 2.72 (t, 2H, J = 6.78), 2.96 (t, 2H, J= 6.77), 3.83-
3.44 (m, 2H), 3.52-3.58 (m, 2 H), 8.08 (bs, 3H).
13C NMR (100 MHz, DMSO) 5 168.4, 65.9,45.1,41.45,35.1, 29.6.
Free base: mfz (APCI(m+l)) 159.2; calcd for C7H14N202 158.11.
Step 3: 3-Amino-l-morphoIin-4-vI-propan-l-one; compound with phenvlacetic acid

A reactor is charged with 3-amino-l-morpholm-4-yl-propan-l-one; hydrochloride (765 mmol). MeOH (380 mL) is added, and the mixture is stirred vigorously at room temperature for ca. 10 minutes. MtBE (380 mL) is added and the resulting slurry is cooled to -10°C, where a 25% (w/w) MeOH solution of NaOMe (765 mmol) is added slowly via addition funnel at such a rate as to maintain an internal temperature of ca. -10°C. The resulting suspension is stirred vigorously under a N2 atmosphere as it is allowed to warm to 0°C. Solids are
removed via filtration, rinsing with additional MtBE (50 mL). Solvent is removed in vacuo to provide the free base as a crude oil that is taken up in MtBE (600 mL). The mixture is cooled with vigorous agitation to ca. 0°C, where phenylacetic acid (765 mmol) is added slowly as a solution in MtBE (300 mL). The reaction mixture is stirred an additional 10 minutes after complete addition, during which time the product precipitates out of solution. The solids are collected via filtration,

washed with additional MtBE (100 mL) and dried under vacuum at provide 3-amino-l-morpholui-4-yl-propan-l-one; compound with phenylacetic
acid (191 g). This material is carried on to subsequent steps without further
purification, or optionally, it can be re-precipitated from MtBE.
2H NMR (400 MHz, DMSO) 5 2.55 (t, 2H, J= 6.78), 2.86 (t, 2H, /= 6.78) 3.62
(t, 2H), 3.42 (t, 2 H), 6.22 (bs, 3H), 7.25-7.12 (m, 5H).
13c NMR (100 MHz, DMSO) 5 174.2, 169.0, 138.2, 129.2,127.8, 125.5, 66.0,
45.2,44.4,41.4,35.7,31.6.
Step 4: 5-f4-FluorophenvO-2-isopropyl-l -f3-morpholin-4-yl-3-oxo-propyl)-4-phenyl-l/f-pyrrole-3-carboxylic acid phenvlamide

A nitrogen inerted reactor, equipped with a suitable reflux condenser and soxhlet extractor containing freshly activated 3 A molecular sieves (4-8 mesh; 97.2 g), is charged with 3-arnmo-l~morpholin-4-yl-propan-l-one, compound with phenylacetic acid (765 mmol) and 2-[2-(4-fluorophenyl)-2-oxo-l-phenyl-ethyl]-4-methyl-3-oxo-pentanoic acid phenylamide (450 mmol). THF (360 mL) is added, and the resulting solution is stirred vigorously as the reaction is heated at reflux temperature for ca. 24 hours, during which time the product begins to precipitate. Half-saturated aqueous NaHCC>3 (100 mL) is added, and the reaction mixture is
cooled with continued stirring to ca. 0°C. MtBE (100 mL) is added, and the solids are collected via filtration. The solid is washed with distilled water (100 mL) and MtBE (2 x 100 mL), collected, and dried under vacuum at fluorophenyl)-2-isopropyl-l-(3-morpholin-4-yl-3-oxo-propyl)-4-phenyl-l//:-pyrrole-3-carboxylic acid phenylamide as a white solid (194 g). This material is carried on to subsequent steps without further purification.


A nitrogen inerted reactor, equipped with a suitable reflux condenser and soxhlet extractor containing freshly activated 3 A molecular sieves (4-8 mesh; 36 g), is charged with 3-amino-l-morpholin-4-yl-propan-l-one hydrochloride (170 mmol), phenylacetic acid sodium salt (170 mmol) and 2-[2-(4-fluorophenyl)-2-oxo-l-phenyl-erhyl]-4-methyl-3-oxo-pentanoic acid phenylamide (100 mmol). THF (150 mL) is added, and the resulting solution is stirred vigorously as the reaction is heated at reflux temperature for CCL 24 hours, during which time the product begins to precipitate. Aqueous NaHCO3 (100 mL) is added slowly, and
the reaction mixture is cooled with continued stirring to ca, 0°C. MtBE (100 mL) is added, and the solids are collected via filtration. The yellow-colored solid is washed with distilled water (15 mL) and MtBE (2 x 15 mL), collected, and dried under vacuum at ^50°C to afford 5-(4-fluorophenyl)-2-isopropyl-l-(3-morpholin-4-yl-3-oxo-propyl)-4-phenyl-lH-pyrroie-3-carboxylic acid phenylamide as a white solid (42.1 g). This material is carried on to subsequent steps without further purification. m/z (APCI(w-l)) 538.2; (APCI(/H+1) 540.2; calcd for C33H34FN3O3 539.26.


A nitrogen inerted reactor equipped with reflux condenser, nitrogen inlet and mechanical stirring is charged with morpholine (1.2 mol), methyl cyanoacetate (1.0 mol), and MtBE (52 mL). The homogeneous solution is heated to ca. 55°C and stirred at that temperature for 12 to 18 hours. MtBE (33 mL) is added over ca. 15 minutes, and the solution is slowly cooled below 50°C until
nucleation becomes evident. Additional M*BE (66 mL) is added over a 1-hour period. During this time, the reaction is allowed to cool to near ambient temperature. After complete MtBE addition, the reaction is cooled with stirring to ca. 0°C. The resulting precipitate is collected via filtration and the cake is washed with additional MtBE (40 mL). The crude 3-morpholin-4-yl-3-oxo-propionitrile is taken up in MeOH (2 L) and transferred to a nitrogen inerted pressure reactor that has been charged with 5% Pt-C (55 g; 58% water-wet). HC1 (12 N; 1.1 mol) is added at such a rate as to maintain an internal temperature of ca. 25°C. The vessel and its contents are degassed via three N2 pressure purges (50 psi). The atmosphere is switched to hydrogen via three H2 pressure purges (50 psi), and the reaction is stirred vigorously at ca. 25 °C under a sustained pressure of hydrogen (50 psi) for ca. 24 hours. The H2 pressure is released and replaced with N2. The
reaction is passed through filter agent, which is subsequently washed with MeOH (500 mL). The reaction is concentrated to a MeOH-wet solid, which is reslurried in EPA (100 mL). The slurry is cooled to 0°C and filtered. The filter cake is washed with cold (0°C) IPA (75 mL) and reslurried in MeOH (500 mL) and MtBE (500 mL). The slurry is cooled with agitation to -10°C where a 25% (w/w)

solution of NaOMe in MeOH (I mol) is added, drop wise at such a rate as to maintain an internal reaction temperature of Step 5: 7-r2-(4-Fluorophenyl)-5-isopropvI-3-Dhenvl-4-phenvlcarbamovl-pvrrol-l-yl7-3.5-dioxo-heptanoic acid, ethyl ester

A dry, nitrogen inerted reactor is charged with sodium hydride (300 mmol). Anhydrous THF (150 mL) is added and the resulting mixture is cooled under nitrogen to ca. -20°C. Ethyl acetoacetate (307 mmol) is added at

such a rate as to maintain an internal reaction temperature of le-3-carboxylic acid phenylamide (74 mmol), and the resulting slurry is stirred at ca. -23 °C for 20 hours. The reaction is quenched into a mixture of 18% aqueous HC1 (898 mmol) and MtBE (20 mL) at such a rate as to maintain an internal reaction temperature of HRMS m/z (ESI(m-l)) 581.2463; calcd for C35H35FN2O5 582.2530.
In a process analogous to Step 5 METHOD A, by substituting the appropriate ester or amide of acetoacetic acid for ethyl acetoacetate, one obtains the following compounds:

7-[2-(4-Fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-l-yl]-3,5-dioxo-heptanoic acid, tert-butyl ester, HRMS m/z (ESI(w-l)) 609.2772; APCI(«+1) 611.3; calcd for C37H39FN2O5
610.2843.
7-[2-(4-Fluorophenyl)-5-isopropyl-3-phenyl-4»phenyicarbamoyl-pyrrol-l-yl]-3,5-dioxo-heptanoic acid, isopropyl ester. m/z (DCI(/w+l)) 597; calcd for C36H37FN2O5 596.27.
7-f2-(4-FJuorophenyJ)-5-isopropyl-3-phenyl-4-phenyIcarbamoyl-pyrrol-l-ylJ-3,5-dioxo-heptanoic acid, methyl ester. m/z (DCI(w+l)) 569; calcd for C34H33FN2O5 568.24.
7-[2-(4-Fluorophenyl)-5-isopropyI-3-phenyI-4-phenylcarbamoyl-pyrroI-l-yl]-3,5-dioxo-heptanoic acid, raorpholind amide. HRMS m/z (ESI(/w-l)) 622.2715; calcd for C37H38FN3O5 623.2795.
7'[2-(4-Fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-l-yl]-3,5-dioxo-heptanoic acid, ^TV-dimethyl amide. m/z (DCI(w+l)) 582; calcd for C35H36FN3O4 581.27.
METHODS
7-[2-f4"FluorophenylV5-isopropvl-3-phenvl-4-phenvlcarbamovl-Pvrrol-l-vl")-3.5-dioxo-heptanoic acid. /er/-butvl ester

A nitrogen inerted reactor is charged with the sodium salt of ferf-butyl acetoacetate (100 mmol). Anhydrous toluene (71.5 mL) and THF (8.2 mL, 101 mmol) are added, and the resulting solution is cooled under a positive pressure of nitrogen to ca.-10°C. A 10 M hexanes solution of w-BuLi (104 mmol) is added at such a rate as to maintain an internal reaction temperature of
addition as the temperature is allowed to cool to ca. -6°C. Meanwhile, 5-(4-fluorophenyl)-2-isopropyl-1 -(3 -moiphoIin-4-yI-3 -oxo-propyI)-4-phehyl- IH-pyrrole-3-carboxylic acid phenylamide (25 mmol) is charged to a second nitrogei inerted reactor. Anhydrous THF (50 mL) is added at room temperature, and the resulting slurry is cooled to ca. -10°C and stirred for 15 to 90 minutes. The solution of dienolate is added to the slurry of morpholine amide at such a rate as t maintain an internal reaction temperature ca. -5°C. Following this addition, the slurry is stirred at ca. -5°C for >2 hours. Water (35 mL) is added with vigorous agitation at such a rate as to maintain ah internal reaction temperature of £0°C. Concentrated 37% hydrochloric acid (19.0 mL, 229 mmol) is added at such a rate as to maintain an internal reaction temperature of ^0°C. The two-layered reaction mixture is vacuum distilled, removing >50%'of the organic solvents. The distillation is stopped and the lower aqueous layer is discarded. Water (55 mL) is added and the vacuum distillation is continued until a majority of the organic solvents are removed. [Note: It is preferable to drain and replace the aqueous layei before initiating the vacuum distillation.] EPA (100 mL) is added followed by water (100 mL). The mixture is stirred for >6 hours, allowing for solidification of the product. The solid is collected via filtration, and the cake is washed with pre-mixed 1:1 IPA:H20. The resulting solid is dried in vacuo at 35°C to provide 7-[2-
(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-l-yl]-3,5-dioxo-heptanoic acid, tert-butyl ester (14.1 g) as a white solid. This material is carried on to subsequent steps without further purification, or optionally, it can be re-precipitated from toluene. HRMS m/z (ESI(TH-I)) 609.2772; APCI(m+l) 611.3; calcd for C37H39FN2O5
610.2843.
In a process analogous to Step 5 METHOD B, by substituting the sodium salt of the appropriate ester or amide of acetoacetic acid for the sodium salt oi tert-butyl acetoacetate, one obtains the following compounds:
7-[2-(4-Fluorophenyl)-5-isopropyl-3 -phenyl-4-phenylcarbamoyl-pyrrol-1 -yl]-3,5-dioxo-heptanoic acid, ethyl ester. HRMS m/z (ESI(m-l)) 581.2463; calcd for C35H35FN2O5 582.2530.

7-[2-(4-Fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyirol-l-yl]-3,5-dioxo-heptanoic acid, isopropyl ester. m/z (DCI(m+l)) 597; calcd for C36H37FN2O5 596.27.
7-[2-(4-Fluorophenyl)-5-isopropyl-3-phenyl-4-phenyIcarbamoyl-pyrroI-l-yl]-3,5-dioxo-heptanoic acid, methyl ester. m/z (DCI(m+l)) 569; calcd for C34H33FN2O5 568.24.
7-[2-(4-Fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-l-yl]-3,5-dioxo-heptanoic acid, morpholino amide. HRMS m/z (ESI(m-l)) 622.2715; calcd for C37H38FN3O5 623.2795.
7-[2-(4-Fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-l-yl]-3,5-dioxo-heptanoic acid, N,N-dimethyl amide. m/z (DCI(m+l)) 582; calcd for C35H36FN3O4 581.27.
Step 6: (5RV7-[2-(4-FluorophenYl)-5-isopropvl-3-phenvl-4-phenvlcarbamovl-pvrrol-l-vn-3.5-dihvdroxv-heptanoic acid, methyl ester
METHOD A

A nitrogen inerted pressure reactor is charged with 7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-l-yl]-3,5-dioxo-heptanoicacid, ethyl ester (100.0 mmol) and MeOH (250 mL). The resulting slurry is heated with stirring to ca. 55°C to afford a homogeneous solution. The vessel and its contents are degassed via three 50 psi pressure purges with argon. Under a steady flow of argon, 1 M methanolic HBr (7.0 mmol) and the RuCl2(DMF)n[(R)-Cl-MeO-BIPHEP)] catalyst (0.5 mmol) are added, and the reactor is given an additional 50 psi pressure purge with argon. The atmosphere is switched to hydrogen via three 50 psi pressure purges. The reaction is stirred vigorously at 65°C under a

sustained pressure of hydrogen (50 psi) until hydrogen uptake ceases. The reaction is allowed to cool to ambient temperature, and the hydrogen pressure is released and replaced with nitrogen. The crude MeOH solution of (5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3 -phenyl-4-phenylcarbamoyl-pyrrol-1 -yl] -3,5-dihydroxy-heptanoic acid, methyl ester is carried on to subsequent steps without purification, or optionally, it can be isolated via flash column chromatography on silica gel, eluting with ethyl acetate-heptane mixtures. HPLC analysis (YMC ODS AQ S5; 1 mL/min; 30°C; 254 nm: CH3CN/H2O, 60:40 (0-22 min) to 100:0 (27-37 min) to 60:40) indicated a syn:anti ratio of 1:1.5. Chiral HPLC analysis (Chiralcel OD-H column; 5% EtOH:Hexanes; tR(3R,5R) = 23.1 min./tR(3R,5S) - 18.0 mm./tR(3S,5S) = 24.8 minJtR(3S,5R) = 19.9 min.) indicated an enantiomeric excess at C-5 of >98%, favoring the (R) configuration. m/z (DC«>+1)) 573; calcd for C34H37FN2O5 572.27.
In a process analogous to Step 6 METHOD A, using the appropriate alcoholic solvent in place of MeOH, one obtains the following compounds, for example:
(5R)-7-[2-(4-Fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid, ethyl ester. m/z (DCI(m+l)) 587; calcd for C35H39FN2O5 586.28.
Chiral HPLC analysis (Chiralcel OD-H column; 5% EtOH:Hexanes; tR(3R,5R) = 17.6 min./tR(3R,5S) = 14.7 min./tR(3S,5S)« 20.9 min./tR(3S,5R) =
15.9 min.) indicated an enantiomeric excess at C-5 of >98%, favoring the (R) configuration.
(5R)-7-[2-(4-Fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid, isopropyl ester.. m/z (DCI(m+l)) 601; calcd for C36H41FN2O5 600.30.
In a process analogous to Step 6 METHOD A, using the appropriate ester or amide from Step 5 in a non-nucleophilic/non-coordinating solvent (e.g., toluene) in place of MeOH, and acetic acid in place of HBT, one can avoid transesterification and obtain the following compounds, for example:

(5R)-7-[2-(4-Fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-l-yl]-3,5-dih.ydroxy-heptanoic acid, ter/-butyl ester. m/z (APCI(m+l)) 615.3; calcd for C37H43FN2O5 614.32.
(5R)-7-[2-(4-Fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid, moipholino amide. m/z (APCI(m-H-HC02H)) 672.3; calcd for C37H42FN3O5 627.31.
(5R)-7-[2-(4-Fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid, N,N-dimethyl amide. m/z (APCI(m+l)) 586; calcd for C35H40FN3O4 585.30.
In a process analogous to Step 6 METHOD A, using alternative Ru(II)-chiral diphosphine complexes in place of RnCl2(DMF)n[(R)-Cl-MeO-BIPHEP)]
as the hydrogenation catalyst, one can obtain the identical products with varying enantiomeric excess at C-5. For example, in the reduction of 7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-l-yl)-3,5-dioxo-heptanoic acid, ethyl ester to (5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid, methyl ester proceeded as follows:
RuCl2(DMF)n[(R)-(+)-BINAP] complex provided product with 90% ee
(favoring the (R) configuration) at C-5 as determined by chiral HPLC analysis.
RuCl2(DMF)n[(R)-(+)-/?Tol-BINAP] complex provided.product with 91%
ee (favoring the (R) configuration) at C-5 as determined by chiral HPLC analysis. RuCl2(PMF)n[(R)-(+)-C4-TunaPhos] complex provided product with
93% ee (favoring the (R) configuration) at C-5 as determined by chiral HPLC analysis.
RuCl2(DMF)n[(R>(+)-C2-TunaPhos] complex provided product with
98% ee (favoring the (R) configuration) at C-5 as determined by chiral HPLC analysis.
RuCl2(DMF)n[(S)-(-)-MeO-BIPHEP] complex provided product with
95% ee (favoring the (S) configuration) at C-5 as determined by chiral HPLC analysis.

RuCl2[(R)-(+)-Cl-MeO-BIPHEP3 (NEt3)n complex provided product with >98% ee (favoring the (R) configuration) at C-5 as determined by chiral HPLC analysis.
RuCl2[(R)-(+)-BINAP] (NEt3)n complex provided product with 91% ee
(favoring the (R) configuration) at C-5 as determined by chiral HPLC analysis.
RuCl2[(RM+)-.pTol-BINAP] (NEt3)n complex provided product with 91% ee (favoring the (R) configuration) at C-5 as determined by chiral HPLC analysis.
[Ru(TFA)2((R)-(+)-Cl-MeO-BIPHEP)]n complex provided product with
S98% ee (favoring the (R) configuration) at C-5 as determined by chiral HPLC analysis.
[Ru(TFA)2((R)-(+)-BIN AP)]n complex provided product with 90% ee
(favoring the (R) configuration) at C-5 as determined by chiral HPLC analysis.
METHOD B
A nitrogen inerted pressure reactor is charged with benzene ruthenium (H) chloride dimer (11 mg) and (R)-(+)-C2-TunaPhos (26 mg). The reactor is given a pressure purge with N2 and N2-sparged MeOH (1.0 rnL) is added via syringe. The
resulting mixture is thoroughly purged with N2 and stirred at 25°C for 30 minutes.
A solution of 7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-l-ylJ-3,5-dioxo-heptanbic acid, /er/-butyl ester (0.5 g) inN2-sparged
MeOH (4.5 mL) is added to the reactor via syringe, and the resulting mixture is allowed to stir under N2 at 60°C for 30 minutes. The solution is stirred at 60°C under a sustained H2 pressure of 60 psi for 22 hours. The reaction is cooled to ambient temperature where it is repeatedly purged with N2. The crude MeOH
solution of (5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-l-yI]-3,5-dihydroxy-heptanoic acid, methyl ester is carried on to subsequent steps without purification, or optionally, it can be isolated via flash column chromatography on silica gel, eluting with ethyl acetate-heptane mixtures.

HPLC analysis (YMC ODS AQ S5; 1 mL/min; 30°C; 254 nm: CH3CN/H2O,
60:40 (0-22 min.) to 100:0 (27-37 rain.) to 60:40) indicated a synianti ratio of
1:1.4.
Chiral HPLC analysis (Chiralcel OD-H column; 5% EtOH:Hexanes; tR(3R,5R) =
23.1 min./tR(3R,5S) = 18.0 min./tR(3S,5S) = 24.8 min./tR(3S,5R) = 19.9 min.) indicated an enantiomeric excess at C-5 of £97%, favoring the (R) configuration. m/z (DCI(m+l)) 573; calcd for C34H37FN2O5 572.27.
Step 7: 5-f4-Fluorophenvl)-2-isopropyl-l -r2-(fSV6-oxo-3.6-dihvdro-2#-pyran-2-vlVethvn-4-phenvl-l/T-pyiTole-3-carboxvlic acid phenvlamide

A suitable nitrogen inerted reactor is charged with KOH (110.0 mmol) and water (300 mL). To this rapidly stirring solution is added the crude Step 6 solution of(5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid, methyl ester (ca. 100 mmol/>98% ee) in MeOH (250 mL). The mixture is heated under a nitrogen atmosphere to an internal temperature ofca. 85°C. During this time, MeOH is removed via distillation. The resulting reaction mixture is allowed to cool to 45 °C, where it is washed with MtBE (2x150 mL). The MtBE phases are separated and discarded. To the 45°C aqueous phase is added toluene (125 mL), followed by a slow addition of 6N HC1 (20 mL). The two-phase mixture is stirred for 10 minutes, and the layers are separated. The aqueous phase is extracted with a second portion of toluene (125 mL) and discarded. The combined organics are heated to reflux under a nitrogen atmosphere. During this time, 130 mL of distillate is collected and discarded. The resulting solution is cooled to ca. 60°C, where NEt3 (140 mmol),

DMAP (2.0 mmol) and Ac2O (70.0 mmol) are added successively at such a rate as to maintain an internal reaction temperature of 55°C to 65°C. This solution is stirred for ca. 1.5 hrs at 60°C. The mixture is cooled to 50°C, where IN HC1 (100 mL) is added slowly. The two-phase mixture is stirred for 10 minutes, the phases are separated, and the aqueous phase discarded. The organic phase is washed with second portions of IN HC1 (100 mL) and water (100 mL) while mamtaining a temperature of 45°C to 55°C. The toluene solution is diluted with BU2O (200 mL) and the resulting solution is slowly cooled to 0°C with continuous
agitation. The resulting solid is collected on a filter funnel and dried under vacuum to provide 5-(4-fluorophenyl)-2-isopropyl-l-[2-((S)-6-oxo-3,6-dihydro-2//-pyran-2-yl)-ethyl]-4-phenyl-lJr/-pyrTole-3-carboxylic acid phenylamide as a white to off-white solid (34.4 g). This material is carried on to subsequent steps without further purification, or optionally, it can be re-precipitated from IPA/H2O.
m/z (DCI(w+l)) 523; calcd for C33H31FN2O3 522.23. Chiral HPLC analysis (Chiralpak AD column; 1 mL/min; 30°C; 254 nm; 10% IPA:Hexanes; 1R(R) =18 min7tR(S) =16 min.) indicated an enantiomeric excess of >98%, favoring the (R) configuration.
Step 8: 5-(4-Fluorophenvn-1 -r2-((2K,4R)-4-hvdroxy-6-oxo»tetrahvdro-pvran-2-vl)-ethyll-2-isoDropyl-4-phenvl-1 H-pvrrole-3-carboxvlic acid phenylamide


An argon-purged reactor is charged with 5-(4-fluorophenyl)-2-isopropyl-l-[2-((S)-6-oxo-3,6-dihydro-2H-pyran-2-yl)-ethyl]-4-phenyl-lH-pyrrole-3-carboxylic acid phenylamide (0.020 mol/>99% ee) and benzyl alcohol (52 mL). The reaction mixture is cooled to -10°C and NaOH (0.040 mol) is added. After stirring for 19 hours at -10°C the reaction is quenched with 37% HC1 (0.042 mol) and diluted with water (25 mL) and toluene (25 mL). After the mixture is warmed to ambient temperature, the lower aqueous layer is discarded. The upper organic layer is combined with 20% Pd(OH)2/C (1.0 g) and H2SO4 (0.01 moles) and
hydrogenated under 50 psi hydrogen at 50°C for 16 hours. The reaction mixture is heated to 80°C and filtered through diatomaceous earth. The reactor and catalyst cake is rinsed with hot toluene (10 mL). The lower aqueous layer is discarded. The upper organic layer is washed with a warm solution of aqueous HC1 (0.16 g 37% HC1 in 25 mL hot water) and heated to reflux for 2.5 hours under argon, removing water azeotropically. The reaction mixture is cooled to 65°C and seeded with 5-(4-fluorophenyl)- 1 -[2-((2R,4RH-hy&oxy-6-oxo-tetrahydro-pyran-2-yI)-

ethyl]-2-isopropyl-4-phenyl-li7-pyirole-3-carboxylic acid phenylamide. After 2 hours the reaction mixture is allowed to slowly cool to ambient temperature. The resulting slurry is cooled to about 0°C. The product is collected and washed with cold toluene (25 mL). The resulting solid is dissolved in hot toluene (95 mL) and cooled to 65°C and held for 2 hours. The reaction mixture is slowly cooled to ambient temperature and further cooled to 0°C. The product is collected, washed with cold toluene (25 mL) and dried in vacuo at 70°C overnight to afford 5-(4-
fluorophenyl)-l-[2-((2R,4R)4-hydroxy-6^xo-tetrahyd^o-pyran-2-yl)-ethyl]-2-
isopropyl-4-phenyl-l#-pyrrole-3-carboxyIic acid phenylamide (8.4 g) as a white
solid.
HPLC analysis (YMC ODS AQ S5; 1 mL/min; 30°C; 254 nm: CH3CN/H2O,
60:40 (0-22 min.) to 100:0 (27-37 nun/) to"60:40) indicated an antvsyn ratio of
>99:L
Chiral HPLC analysis (Chiralcel OF; 1 mL/min; 60°C; 254 nm; 20%
IPA:Hexanes; tR(3R,5R) = 26 min./tR(3R,5S) = 59 min./tR(3S,5S) = 33 min./
tR(3S,5R) = 37 min.) indicated an enantiomeric excess at C-5 of >99%, favoring
the (R) configuration.
m/z(DCI(m+l)) 541; calcd for C33H33FN2O4 540.24.
In a process analogous to Step 8 METHOD A, substituted benzylic alcohol derivatives (e.g.,P-methoxy-benzyl alcohol) may be used in place of benzyl alcohol to afford the corresponding compounds.


An argon-purged reactor is charged with 5-(4-fluorophenyl)-2-isopropyl-l-[2-((S)-6-oxoO,6-dihydro-2Jff-pyran-2-yl)-ethyl]-4-phenyl-lif-pyrrole-3-carboxylic acid phenylamide (19.1 mmol/>99% ee) and allyl alcohol (50 mL). The reaction mixture is cooled to -5°C and LiOH (38.2 mmol) is added. After stirring for 1 hour at -5°C the reaction is quenched with 37% HC1 (42 mmol) and toluene (125 mL). After the mixture is wanned to ambient temperature, the reaction is concentrated to a volume of ca. 15 mL. Additional toluene (50 mL) is added and the reaction is concentrated via distillation to a crude oil that solidifies upon standing. The crude residue is taken up in DME (340 mL). To this solution is added deionized water (20 mL), p-toluenesulfonic acid (2.25 g) and 5% Pd/C (11 g; 50% water-wet). The resulting mixture is heated to 45°C under a N2 atmosphere for 1.5 hours and at ambient temperature for an additional 16 hours. The solution is passed through filter aid to remove catalyst, and solvent is removed in vacuo. The residue is taken up in toluene (50 mL). Water (75 mL) and KOH (950 mg) are added, and the reaction mixture is heated to 65°C where the layers are separated. The aqueous phase is washed with toluene (25 mL) at 65°C

and the combined toluene layers are discarded. To the aqueous phase is added toluene (50 mL), followed by 6N HC1 (3.8 mL). The mixture is stirred vigorously at 65°C for 5 minutes and the phases are separated. The toluene phase is heated to reflux for 2.5 hours under argon, removing water azeotropically. The reaction mixture is cooled to 65°C and seeded with 5-(4-fluorophenyl)-l-f2-((2R,4R)-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-2-isopropyl-4-phenyl-l/f-pyrrole-3-carboxylic acid phenylamide. After 2 hours the reaction mixture is allowed to slowly cool to ambient temperature. The resulting slurry is cooled to about 0°C. The product is collected and washed with cold toluene (25 mL). The resulting solid is dissolved in hot toluene (95 mL) and cooled to 65°C and held for 2 hours. The reaction mixture is slowly cooled to ambient temperature and further cooled to 0°C. The product is collected, washed with cold toluene (25 mL) and dried in vacuo at 70°C overnight to afford 5-(4-fluorophenyl)-l-[2-((2R,4R)-4-hydroxy-6-oxo4etrahydro-pyran-2-yi)-ethyl]-2-isopropyl-4-phenyl-l//-pyrrole-3-carboxylic acid phenylamide as a white solid. HPLC analysis (YMC ODS AQ S5; 1 mL/min; 30°C; 254 nm: CH3CN/H2Q,
60:40 (0-22 min) to 100:0 (27-37 min) to 60:40) indicated an antusyn ratio of
>99:1.
Chiral HPLC analysis (ChiralCel OF; 1 mL/min; 60°C; 254 nm; 20%
IPA:Hexanes; 1R(3R,5R) = 26 min./tR(3R,5S) = 59min. tR(3S,5S) = 33 min./
tR(3S?5R) = 37 min.) indicated an enantiomeric excess at C-5 of >99%, favoring
the (R) configuration.
m/z (DCI(m+l)) 541; calcd for C33H33FN2O4 540.24.
In a process analogous to Step 8 METHOD B, allylic alcohol derivatives (e.g., crotyl alcohol) may be used in place of allyl alcohol to afford the corresponding compounds.


OPERATION A
A nitrogen inerted reactor is charged with (5R)-7-t2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-l-ylJ-3,5-dihydroxy-heptanoic acid, ter/-butyl ester (10.0 mmol), benzaldehyde dimethyl acetal (44.0 mmol), toluene (40 mL) andp-toluenesulfonic acid monohydrate (1.0 mmol). The reaction is stirred vigorously under vacuum for ca. 20 hours, or until complete reaction as determined by analysis of an aliquot by HPLC. The solution is cooled under a nitrogen atmosphere to ca. -5°C where a 1M THF solution of KOtBu (9.0 mmol) is added in three equal portions, separated by 30 to 45 minutes. The resulting solution is allowed to stir an additional 12 to 14 hours at 0°C. The reaction is quenched by the slow addition of IN HC1 (10 mL). The resulting two-phase mixture is allowed to warm to ca, 15°C and is transferred to a separatory funnel where the aqueous phase is removed and discarded. The organic phase is washed with saturated aqueous NaCl (100 mL), dried over anhydrous MgS04 (25 g), filtered and concentrated in vacuo to a crude oil. This material is carried on to subsequent steps without purification, or optionally, it can be re-precipitated from ether/hexanes. m/z (APCI(m+l)) 703.4; calcd for C44H47FN2O5 702.35.
In a process analogous to Step 8 METHOD C OPERATION A using the appropriate ester from Step 6 in place of (5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl~4-phenylcarbamoyl-pyrrol-l -yl]-3,5-dihydroxy-heptanoic acid, tert-buryl ester, one obtains the following compounds, for example:

((4R,6R)-6-{2-[2-(4-fluorophenyI)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1 -ylj-ethyl}~2-phenyl-[l,3]dioxan-4-yl)-acetic acid
methyl ester.
((4R,6R)-6-{2-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-l-yl]-ethyl}-2-phenyl-[l,3]dioxan-4-yl)-acetic acid ethyl ester.
((4R,6R)-6-{2-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol~l -yl]-ethyl}-2-phenyl-[l ,3]dioxan-4-yl)-acetic acid isopropyl ester.
OPERATION B
A nitrogen inerted pressure reactor is charged with ((4R,6R)-6-{2-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-l-yl]-ethyl}-2-phenyl-[l,3]dioxan-4-yI)-acetic acid ter/-butyl ester from OPERATION A (5.0 g), 5% Pd/C (0.45 g; 50% J^O-wet), 2N HC1 in MeOH (1.9 mL), toluene (11 mL),
and MeOH (3.1 mL). The vessel and its contents are degassed via two cycles of partial evacuation and nitrogen pressurization (25 mm Hg and 50 psi, respectively). The atmosphere is switched to hydrogen via three cycles of partial evacuation and hydrogen pressurization (25 mm Hg and 50 psi, respectively). The reaction is stirred vigorously at 40°C under a positive pressure of H2 (pa. 50 psi)
for ca. 2.5 hours. The reaction is allowed to cool to ambient temperature, and the hydrogen pressure is released and replaced with nitrogen. The reaction is passed through filtering agent to remove the catalyst, rinsing thoroughly with MeOH (2 x 5 mL). To this solution is added KOH (0.6 g) in water (25 mL). The reaction is stirred vigorously under a nitrogen atmosphere and heated to an internal reaction temperature of ca. 90°C, removing MeOH via distillation. The two-phase mixture is allowed to cool to 70°C and the upper toluene phase is separated and discarded. The aqueous phase is washed with a second portion of toluene (10 mL) at 70°C. This organic wash is also separated and discarded. To the aqueous phase is added toluene (10 mL), followed by a slow addition of 2N HC1 (5 mL). The two-phase mixture is stirred for 10 minutes and the layers are separated. The aqueous phase is extracted with a second portion of toluene (10 mL) and is discarded. The

combined organics are heated to reflux under a Dean-Stark water trap for 2.5 hours under argon. The reaction mixture is cooled to 65°C and seeded with 5-(4-fluorophenyl)-l-[2-((2R,4R)^-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-2-isopropyl-4-phenyl-l#-pyrrole-3-carboxyIic acid phenylamide. After 2 hours the reaction mixture is allowed to slowly cool to ambient temperature. The resulting slurry is cooled to ca. 0°C. The product is collected and washed with cold toluene (5 mL). The resulting solid is dissolved in hot toluene (20 mL) and cooled to 65°C and held for 2 hours. The reaction mixture is slowly cooled to ambient temperature and then to 0°C. The product is collected, washed with cold toluene (5 mL) and dried in vacuo at 70°C overnight to afford 5-(4-fluorophenyl)-l-[2-((2R,4R)-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-2-isopropyl-4-phenyl-1 #-pyrrole-3-carboxylic acid phehyiarnide as a white solid. mfz (DCI(/w+l)) 541; calcd for C33H33FN2O4 540.24.

A nitrogen inerted pressure reactor is charged with 7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-l-yl]-3,5-dioxo-heptanoicacid, ethyl ester (100.0 mmol) and EtOH (250 mL). The resulting slurry is heated with stirring to ca. 55°C to afford a homogeneous solution. The vessel and its contents are degassed via three 50 psi pressure purges with argon. Under a steady flow of argon, 1 M ethanolic HBr (7.0 mmol) and the RuCl2([(R)-BINAP] NEt3 catalyst
(0.5 mmol) are added, and the reactor is given an additional 50 psi pressure purge with argon. The atmosphere is switched to hydrogen via three 50 psi pressure purges. The reaction is stirred vigorously at 6S°C under a sustained pressure of hydrogen (50 psi) until H2 uptake ceases. The reaction is allowed to cool to ca. 50°C, where the hydrogen pressure is released and replaced with nitrogen. The

crude EtOH solution of (5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-l-ylJ-3,5-dihydroxy-heptanoic acid, methyl ester is diluted with toluene (250 mL). To this solution is added benzaldehyde (150 mmol) and;?-TsOH monohydrate (5 mmol). The resulting reaction mixture is heated to a pot temperature of 110°C, removing EtOH and water via their toluene azeotropes. The solution is cooled under a nitrogen atmosphere to ca. -5°C where a 1 M THF solution of KOtBu (90 mmol) is added in three equal portions, separated by 30 to 45 minutes. The resulting solution is allowed to stir an additional 12 to 14 hours at 0°C. The reaction is quenched by the slow addition of IN HC1 (100 mL). The resulting two-phase mixture is allowed to warm to ca. 15°C and is transferred to a separatory funnel where the aqueous phase is removed and discarded. The organic phase is washed with saturated aqueous NaCl (25 mL), dried over anhydrous MgSC>4 (5 g), filtered and concentrated in vacuo to a crude
oil that is taken up in MeOH (200 mL). This solution is transferred to a nitrogen inerted pressure reactor containing 5% Pd/C (5 g; 50% water-wet). Concentrated HC1 (2 mL) is added and the reaction is stirred under a sustained pressure of H2
(50 psi) for ca. 3 hours at 50°C. The reaction mixture is cooled to ambient temperature, the H2 is replaced by N2, and the catalyst is removed via filtration. This solution of (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pynt>l-l-yl]-3,5-dihydroxy-heptanoic acid, methyl ester is transferred to a nitrogen inerted reactor charged with KOH (110.0 mmol) and water (300 mL). The mixture is heated under a nitrogen atmosphere to an internal temperature of ca. 85°C. During this time, MeOH is removed via distillation. The resulting reaction mixture is allowed to cool to 45°C, where it is washed with
MteE (2 x 150 mL). The MteE phases are separated and discarded. To the 45°C aqueous phase is added toluene (125 mL), followed by a slow addition of 6N HC1 (20 mL). The two-phase mixture is stirred for 10 minutes and the layers are separated. The aqueous phase is extracted with a second portion of toluene (125 mL) and is discarded. The combined organics are heated to reflux under a Dean-Stark water trap for 2.5 hours under argon. The reaction mixture is cooled to 65°C and seeded with 5-(4-fluorophenyl)-l-[2-((2R,4RM-Mroxy-6-oxo-

tetrahydro-pyran-2-yl)-ethyl]-2-isopropyl~4-phenyl-lif'-pyrrole-3-carboxylicacid phenylamide. After 2 hours the reaction mixture is allowed to slowly cool to ambient temperature. The resulting slurry is cooled to ca. 0°C. The product is collected and washed with cold toluene (100 mL). The resulting solid is dissolved in hot toluene (350 mL) and cooled to 65°C where it is held for 2 hours. The reaction mixture is slowly cooled to ambient temperature and then to 0°C. The product is collected, washed with cold toluene (100 mL) and dried in vacuo at 70°C to afford 5-(4-fluorophenyl)-l-[2-((2R,4R)-4-hydroxy-6-oxo-tetrahydro~ pyran-2-yl)-ethylJ-2-isopropyl-4-phenyl-lif-pyrrole~3-carboxylicacid phenylamide as a white solid. m/z (DCI(w+I)) 541; calcd for C33H33FN2O4 540.24.
Step 9: (R.R)-7-F2-f4-FluorophenvlV5-isopropyl-3-phenvl>4-phenvlcarbamoyl-PYrrol-l-vl1-3,5-dihvdroxv-heptanoic acid, calcium salt.

An argon-purged reactor is charged with 5-(4-fluorophenyl)-l-[2-((2R,4R)-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-2-isopropyI-4-phenyl-lH-pyrrole-3-carboxylic acid phenylamide (14.8 mmol), MtBE (45 mL) and MeOH (20 mL). A solution of NaOH (15.2 mmol) in water (103 mL) is added and the reaction mixture heated to 52°C. After heating for ca. 1 hour, the reaction mixture is cooled to 34°C and the layers are allowed to separate. The upper organic layer is discarded. The lower aqueous layer is washed with MtBE (33 mL) at ca. 33°C. The lower aqueous layer is diluted with MtBE (2 mL) and heated to 52°C under argon. A warm solution of Ca(OAc)2-H20 (7.5 mmol) in water (44 mL) is added over ca. 1 hours. About 5 minutes aftet the start of the Ca(OAc)2 addition, the reaction mixture is seeded with a slurry of (R,R)-7-[2-(4-
fluorophenyl)'5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-l-yl]-3,5-

dihydroxy-heptanoic acid, calcium salt (0.08 mmol) in water (1.2 mL) and methanol (0.4 mL). After the Ca(OAc>2 addition is complete, the reaction mixture is held for ca. 15 minutes at 52°C and cooled to 20°C. The product is collected, washed sequentially with a 2:1 solution of aqueous methanol (48 mL) and water (49 mL). After drying in vacuo at 70°G, (R,R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1 -yl]-3,5-dihydroxy-heptanoic acid, calcium salt (8.7 g) is obtained as a white solid. The analytical specifications of this material are in agreement with the values reported in the prior art.
PREPARATION OF CATALYSTS
EXAMPLEA RuC^roMFyfRVf+yCl-MeO-BIPHEPI complex
A suitable reaction flask is charged with DMF (17.5 mL). The vessel and its contents are degassed via two cycles of partial evacuation and nitrogen pressurization (25 mm Hg and 10 psi, respectively). The excess nitrogen pressure is released, and benzene ruthenium(II) chloride dimer (0.50 mmol) and (R)-(+)-Cl-MeO-BIPHEP (1.10 mmol) are added in rapid succession. The vessel and its contents are again degassed via two cycles of partial evacuation and nitrogen pressurization (25 mm Hg and 10 psi, respectively). The excess nitrogen pressure is released, and the reactor is heated to ca. 100°C for 10 minutes. The resulting solution is allowed to cool to complex is used directly in subsequent reactions without purification or unambiguous characterization, or optionally, can be stored under an inert atmosphere for future use.
In a process analogous to EXAMPLE A using the appropriate chiral diphosphine ligand in place of (R)-(+)-Cl-MeO-BIPHEP, the following complexes can be obtained, for example:
RuCl2(DMF)ni(R)-(+)-BINAP]n complex.
RuCl2(DMF)n[(R)-(+)-JpTol-BINAP]n complex.

RuCl2(DMF)n[(R)-(+)-C4-TunaPhos]n complex. RuCl2(DMF)n[(R)-(+)-C2-TunaPhos]n complex. RuCl2(DMF)n[(S)-(-)-MeO-BIPHEP]n complex..
EXAMPLE B RuChrfRVf+VBINAPl fNEt3 \ complex
A nitrogen incited pressure reactor is charged with dichloro-(l,5-cyclooctadiene)-ruthenium (II) dimer (0.15 mmol) and (R)-(+)-BINAP (0.32 mmol). Toluene (8.0 mL) is added, followed by triethylamine (4.5 mmol). The vessel and its contents are degassed via two cycles of partial evacuation and nitrogen pressurization (25 mm Hg and 10 psi, respectively). The excess nitrogen pressure is released, and the reactor is sealed and heated to ca. 140°C where it is maintained for ca. 4 hours. The resulting clear red solution is allowed to cool to subsequent reactions without purification or unambiguous characterization, or optionally, can be stored under an inert atmosphere for future use.
In a process analogous to EXAMPLE B using the appropriate chiral diphosphine ligand in place of (R)-(+)-BINAP, the following complexes can be obtained, for example:
RuCl2[(R)-(+)-Cl-MeO-BIPHEP] (NEt3)n complex.
RuCl2[(R)-(+)-BINAP] (NEt3)n complex. RuCl2t(R)-(+)-/?Tol-BINAP] (NEt3)n complex.
EXAMPLE C fRuflTA)2(mW)-Cl-MeO-BIPHEP)1n complex
A suitable reaction flask is charged with acetone (50 mL). The vessel and its contents are degassed via two cycles of partial evacuation and argon pressurization (25 mm Hg and 10 psi, respectively). The excess argon pressure is released, and (0.50 mmol) and (R)-(+>Cl-MeO-BIPHEP (0.51 mmol) are added in rapid succession. The vessel and its contents are again degassed via two cycles

of partial evacuation and argon pressurization (25 nun Hg and 10 psi, respectively). The excess argon pressure is released, and the reactor is stirred vigorously at ca. 30°C. Trifluoroacetic acid (1.2 mmol) is added via syringe and the reaction mixture is stirred for an additional 1-hour period. Solvent is removed in vacuo, with careful omission of O2, to afford [Ru(TjFA)2((R)-(+)-Cl-MeO-BIPHEP)]n complex as a solid. The crude complex is used directly in subsequent
reactions without purification or unambiguous characterization, or optionally, can be stored under an inert atmosphere for future use.
In a process analogous to EXAMPLE C using the appropriate chiral diphosphine ligand in place of (R)-(+)-Cl-MeO-BIPHEP, the following complexes can be obtained, for example:
[RufTFA)2((RM+)-MeO-BIPHEP)]n complex.
[Ru(TFA)2((R)-(+)-BINAP)]n.complex. [Ru(TFA)2((R)-(+)-pTol-BINAP)]n complex.

WE CLAIM:
1. Derivatives of compound 3-amino-l-morpholine-4-yl-propan-l-one represented by Formula (6) :



Wherein R is alkyl, aryl, arylalkyl, or heteroaryl, and S, or Se, or R1 is





wherein R4 is alkyl of from one to four carbon atoms, A is O, S, or N, and R is as defined above.
2. Derivatives of compound 3-amino-l-morpholine-4-yl-propan-l-one
as claimed in claim 1, wherein R is PhCKb-or (CH3)3-C-
And R1 is N
3. Derivatives of compound 3-aroino-l-rnorpholine-4-yl-propan-l-one
represented by Formula (6), substantially as hereinbefore described with
reference to foregoing examples.


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Patent Number 206034
Indian Patent Application Number 396/MUMNP/2004
PG Journal Number 28/2007
Publication Date 13-Jul-2007
Grant Date 16-Apr-2007
Date of Filing 19-Jul-2004
Name of Patentee WARNER-LAMBERT COMPANY LLC
Applicant Address 201 TABOR ROAD, MORRIS PLAINS, NEW JERSEY 07950, UNITED STATES OF AMERICA.
Inventors:
# Inventor's Name Inventor's Address
1 RANDALL LEE DEJONG PFIZER GLOBAL RESEARCH AND DEVELOPMENT, ANN ARBOR LABORATORIES, 2800 PLYMOUTH ROAD, ANN ARBOR, MICHIGAN 48105, UNITED STATES OF AMERICA.
2 JADE DOUGLAS NELSON PFIZER GLOBAL RESEARCH AND DEVELOPMENT, ANN ARBOR LABORATORIES, 2800 PLYMOUTH ROAD, ANN ARBOR, MICHIGAN 48105, UNITED STATES OF AMERICA.
3 MICHAEL GERARD PAMMENT PFIZER GLOBAL RESEARCH AND DEVELOPMENT, ANN ARBOR LABORATORIES, 2800 PLYMOUTH ROAD, ANN ARBOR, MICHIGAN 48105, UNITED STATES OF AMERICA.
4 TIMOTHY LEE STUK PFIZER GLOBAL RESEARCH AND DEVELOPMENT, ANN ARBOR LABORATORIES, 2800 PLYMOUTH ROAD, ANN ARBOR, MICHIGAN 48105, UNITED STATES OF AMERICA.
5 DONALD EUGENE BUTLER PFIZER GLOBAL RESEARCH AND DEVELOPMENT, ANN ARBOR LABORATORIES, 2800 PLYMOUTH ROAD, ANN ARBOR, MICHIGAN 48105, UNITED STATES OF AMERICA.
PCT International Classification Number C07D 405/06
PCT International Application Number PCT/IB01/02729
PCT International Filing date 2001-12-27
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60 / 260,505 2001-01-09 U.S.A.