Process for the synthesis of 5-(4-fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid phenylamide

A process for the preparation of a compound of Formula (13)

• which comprises:
• Step (a) reacting a compound of Formula (1)
• wherein R is alkyl, aryl, arylalkyl, or heteroaryl in a solvent with a compound of Formula (2)
• R1—H (2)
• wherein R1 is —XR wherein
• X is O,
• S, or
• Se, or R1 is
• wherein R2 or R3 is independently
• alkyl,
• cycloalkyl,
• arylalkyl, or
• aryl, or
• R2 and R3 together are
• —(CH2)4—,
• —(CH2)5—,
• —(CH(R4)—CH2)3—,
• —(CH(R4)—CH2)4—,
• —(CH(R4)—(CH2)2—CH(R4))—,
• —(CH(R4)—(CH2)3—CH(R4))—,
• —CH2—CH2—A—CH2—CH2—,
• —CH(R4)—CH2—A—CH2CH2—,
• —CH(R4)—CH2—A—CH2—CH(R4)—
• wherein R4 is alkyl of from one to four carbon atoms, A is O, S, or N, and R is as defined above to afford a compound of Formula (3)
• wherein R1 is as defined above;
• Step (b) reacting a compound of Formula (3) with hydrogen in the presence of a catalyst and a strong acid in a solvent to afford a compound of Formula (4)
• wherein Y is Cl, Br, TsO, MsO, or HSO4, and R1 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)
• R—CO2H (5)
• wherein R is as defined above in a solvent to afford a compound of Formula (6)
• wherein R and R1 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 R1 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 R1 is as defined above in a solvent in the presence of a strong base to afford a compound of Formula (10)
• wherein R1 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 R1 is as defined above or a compound of Formula (11a)
• Step (g) reacting a compound of Formula (11b)
• wherein R1a is OH, XR wherein
• X is O,
• S, or
• Se, or R1a is
• wherein R2 or R3 is independently
• alkyl,
• cycloalkyl,
• arylalkyl, or
• aryl, or
• R2 and R3 together are
• —(CH2)4—,
• —(CH2)5—,
• —(CH(R4)—CH2)3—,
• —(CH(R4)—CH2)4—,
• —(CH(R4)—(CH2)2—CH(R4))—,
• —(CH(R4)—(CH2)3—CH(R4))—,
• —CH2—CH2—A—CH2—CH2—,
• —CH(R4)—CH2—A—CH2CH2—,
• —CH(R4)—CH2—A—CH2—CH(R4)—
• wherein R4 is alkyl of from one to four carbon atoms, A is O, S, or N and R is alkyl, aryl, arylalkyl, or heteroaryl 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
• HO-Allyl (17b)
• wherein M is sodium, lithium, potassium, zinc, magnesium, copper, calcium, or aluminum, or with a compound of Formula (16) or (16b)
• M⊕⊖OCH2-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).