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US 2005/0239869 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-1eta-pyrrole-3-carboxylic acid phenylamide
AssigneeWarner-Lambert Company
InventorsDonald Butler, Randall DeJong, Jade Nelson, Michael Pamment, Timothy Stuk
Life of this patent
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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)
- 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{circle over (+)} {circle over (−)} OCH2-Aryl (16)
- or M{circle over (+)} {circle over (−)} 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).
65 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)
- 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 alkyl, aryl, arylalkyl, or heteroaryl which comprises:
- reacting a compound of Formula (4)
- wherein Y is Cl, Br, TsO, MsO, or HSO4, and R1 is as defined above with a compound of Formula (20)
- R—CO2 {circle over (−)} {circle over (+)} M (20)
- wherein R is as defined above and M is sodium, lithium, potassium, zinc, magnesium, copper, calcium, or aluminum with Compound (7)
- in a solvent with removal of water to afford a compound of Formula (8).
22 more elements
A process for the preparation of compound (13)
- which compris es:
- Step (a) reacting a compound of Formula (11)
- 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 alkyl, aryl, arylalkyl, or heteroaryl with an acetal of Formula (15)
- 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 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
- solvent in the presence of an acid to afford a compound of Formula (13).
25 more elements
A process for the preparation of a compound of Formula (11b)
- wherein R1a is OH, —XR wherein
- X is O,
- S,
- 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 which comprises:
- Step (a) reacting a compound of Formula (10)
- wherein R1 is XR or R1 is
- 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)
- 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).
23 more elements
A compound of Formula (6)
- wherein R is alkyl, aryl, arylalkyl, or heteroaryl, and
- 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.
18 more elements
A compound of Formula (8)
- 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 alkyl, aryl, arylalkyl, or heteroaryl.
17 more elements
A compound of Formula (10) or a pharmaceutically acceptable salt thereof
- wherein R1—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 alkyl, aryl, arylalkyl, or heteroaryl.
17 more elements
A compound of Formula (12)
A compound of Formula (18) or a pharmaceutically acceptable salt thereof
- 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 alkyl, aryl, arylalkyl, or heteroaryl.
17 more elements
A compound of Formula (18a) or a pharmaceutically acceptable salt thereof
- 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 alkyl, aryl, arylalkyl, or heteroaryl.
17 more elements
Dependencies are inferred from the claim text.