Back to results
US 2003/0195353 A1Published application
Novel 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
AssigneeWarner-Lambert Company
InventorsDonald Eugene Butler, Randall Lee Dejong, Jade Douglas Nelson, Michael Gerard Pamment, Timothy Lee Stuk
Life of this patent
Estimating the term…
Abstract
An improved process for the preparation 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 by a novel synthesis is described where methyl cyanoacetate is converted in eight operations or fewer to the desired product, as well as other valuable intermediates used in the process.
Claims91
A process for the preparation of a compound of Formula (13)
- 68
- which comprises:
- Step (a) reacting a compound of Formula (1)
- 69
- 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
- 70
- 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)
- 71
- 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)
- 72
- 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)
- 73
- wherein R and R1 are as defined above;
- Step (d) reacting a compound of Formula (6) with Compound (7)
- 74
- in a solvent with removal of water to afford a compound of Formula (8)
- 75
- wherein R1 is as defined above;
- Step (e) reacting a compound of Formula (8) with a compound of Formula (9)
- 76
- 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)
- 77
- 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)
- 78
- wherein R1 is as defined above or a compound of Formula (11a)
- 79
- Step (g) reacting a compound of Formula (11b)
- 80
- wherein R1a is OH, XR wherein
- X is O,
- S, or
- Se, or R1a is
- 81
- 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)
- 82
- 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).
81 more elements
The process according to Step 38 wherein the acid is sulfuric acid.
A process for the preparation of a compound of Formula (8)
- 87
- wherein R1 is —XR wherein
- X is O,
- S, or
- Se, or R1 is
- 88
- 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 which comprises:
- reacting a compound of Formula (4)
- 89
- wherein Y is Cl, Br, TsO, MsO, or HSO4, and R1 is as defined above with a compound of Formula (20)
- R—CO2⊖⊕M (20)
- wherein R is as defined above and M is sodium, lithium, potassium, zinc, magnesium, copper, calcium, or aluminum with Compound (7)
- 90
- in a solvent with removal of water to afford a compound of Formula (8).
26 more elements
A process for the preparation of compound (13)
- 91
- which comprises:
- Step (a) reacting a compound of Formula (11)
- 92
- wherein R1 is —XR wherein
- X is O,
- S, or
- Se, or R1 is
- 93
- 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 with an acetal of Formula (15)
- 94
- 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)
- 95
- wherein R1 and R are as defined above:
- Step (b) reacting a compound of Formula (14) in a 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 (11a) in a
- 96
- solvent in the presence of an acid to afford a compound of Formula (13).
31 more elements
A process for the preparation of a compound of Formula (11b)
- 97
- wherein R1a is OH, —XR wherein
- X is O,
- S,
- Se, or R1a is
- 98
- 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 which comprises:
- Step (a) reacting a compound of Formula (10)
- 99
- wherein R1 is XR or R1 is
- 100
- wherein X, R, R2, and R3 are 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)
- 101
- wherein R1 is 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 (11b).
28 more elements
A compound of Formula (6)
- 102
- wherein R is alkyl, aryl, arylalkyl, or heteroaryl, and
- wherein R1 is —XR wherein
- X is O,
- S, or
- Se, or R1 is
- 103
- 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.
19 more elements
A compound of Formula (8)
- 106
- wherein R1 is —XR wherein
- X is O,
- S, or
- Se, or R1 is
- 107
- 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.
19 more elements
A compound of Formula (10) or a pharmaceutically acceptable salt thereof
- 109
- wherein R1 —XR wherein
- X is O,
- S, or
- Se, or R1 is
- 110
- 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.
19 more elements
A compound of Formula (12)
- 112
A compound of Formula (18) or a pharmaceutically acceptable salt thereof
- 113
- wherein R1 is —XR wherein
- X is O,
- S, or
- Se, or R1 is
- 114
- 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.
19 more elements
A compound of Formula (18a) or a pharmaceutically acceptable salt thereof
- 116
- wherein R1 is —XR wherein
- X is O,
- S, or
- Se, or R1 is
- 117
- 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.
19 more elements
Dependencies are inferred from the claim text.