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US 6,605,707 B1Granted
Process for the preparation of 6-O-propargyl erythromycin derivatives
AssigneeAbbott Laboratories
InventorsFrancis A. J. Kerdesky, Ramiya Premchandran, Gregory S. Wayne, Sou-Jen Chang, Jonathan P. Pease, Lakshmi Bhagavatula, John E. Lallaman, Howard E. Morton, Steven A. King
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Abstract
Disclosed herein is a process for the preparation of erythromycin derivatives, or pharmaceutically acceptable salts thereof, which contain an optionally substituted propargyl group at the 6-O-position.
Claims36
A process for preparing a compound of formula (IV)
- wherein
- R1 is hydrogen or optionally substituted furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, or triazinyl,
- and
- R4 and R5 are independently hydrogen or a hydroxyl protecting group;
- the process comprising:
- (a) simultaneously reacting a compound of formula (I)
- wherein
- L1 is selected from the group consisting of halo, trifluoromethanesulfonyl, and optionally substituted phenylsulfonyl;
- and
- R1 is hydrogen or optionally substituted furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, or triazinyl,
- a compound of formula (II)
- wherein
- R2 and R3 are taken together and are selected from the group consisting of ═N—O—R6, ═N—O—C(O)—R6, ═N—O—C(R7a)(R7b)—OR8, ═N—O—Si(R9)3, ═N—N(R10a)(R10b), and ═N—N═C(R11a)(R11b);
- R4 and R5 are independently hydrogen or a hydroxyl protecting group;
- R6 is selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, phenyl, and phenylalkyl;
- R7a and R7b are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl, and phenylalkyl;
- R8 is selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, phenyl, and phenylalkyl;
- or
- R7a and R7b together or R7a and R8 together are alkylene;
- each R9 is independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, phenyl, and phenylalkyl;
- R10a and R10b are independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, phenyl, phenylalkyl, and a nitrogen-protecting group;
- or
- R10a and R10b together are alkylene;
- and
- R11a and R11b are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl, and phenylalkyl;
- or
- R11a and R11b together are alkylene,
- and an alkoxide base to provide a compound of formula (III)
- and
- (b) reacting the product of step (a) with a first acid and sodium nitrite at a pressure of about 30 psi to about 70 psi.
27 more elements
A process for preparing a compound of formula (IV-a)
- wherein
- R4 and R5 are hydroxyl protecting groups;
- the process comprising:
- (a) simultaneously reacting 3-bromo-1-propyne, a compound of formula (II)
- wherein
- R2 and R3 together are ═N—O—C(R7a)(R7b)—OR8;
- R4 and R5 are hydroxyl protecting groups;
- R7a and R7b are together and are pentylene;
- and
- R8 is isopropyl,
- and potassium tert-butoxide over about 2.5 to about 4 hours to provide a compound of formula (III-b)
- wherein
- R4 and R5 are hydroxyl protecting groups;
- and
- (b) reacting the product of step (a) with about 5 to about 10 molar equivalents of hydrochloric acid per molar equivalent of the compound of formula (III-b) and about 5 to about 8 molar equivalents of sodium nitrite per molar equivalent of the compound of formula (III-b) at a pressure of about 15 psi to about 70 psi.
12 more elements
A process for preparing a compound of formula (IV-a)
- wherein
- R4 and R5 are hydroxyl protecting groups;
- the process comprising:
- (a) simultaneously reacting 3-bromo-1-propyne, a compound of formula (II)
- wherein
- R2 and R3 together are ═N—O—C(R7a)(R7b)—OR8;
- R4 and R5 are hydroxyl protecting groups;
- R7a and R7b together are pentylene;
- and
- R8 is isopropyl,
- and potassium tert-butoxide, in a mixture of tetrahydrofuran and dimethylsulfoxide, at a temperature between about 0° C. to about 5° C., to provide a compound of formula (II-b)
- wherein
- R4 and R5 are hydroxyl protecting groups;
- and
- (b) reacting the product of step (a) with about 7 to about 10 molar equivalents of hydrochloric acid and about 5 to about 8 molar equivalents of sodium nitrite per equivalent of the compound of formula (III-b), in a mixture of water and ethanol, at a temperature of about 20° C. to about 40° C., and at a pressure of about 15 psi to about 70 psi.
12 more elements
A process for preparing compounds of formula (V-b)
- and compounds of formula (VII-b)
- wherein, for compounds of formulas (V-b) and (VII-b),
- R1a is optionally substituted furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, or triazinyl, and
- R4 and R5 are independently hydrogen or a hydroxyl protecting group,
- the process comprising:
- (a) reacting a compound of formula (V-a)
- or a compound of formula (VII-a)
- with a compound of formula L1, —R1a wherein
- L1 is selected from the group consisting of halo, trifluoromethanesulfonyl, and optionally substituted phenylsulfonyl,
- a palladium catalyst, an additive and a first base;
- and
- (b) optionally deprotecting the product of step (a).
9 more elements
A process for preparing compounds of formula (V-c)
- or compounds of formula (Vd-d)
- wherein, for compounds of formulas (V-c) and (VII-d),
- R4 and R5 are independently hydrogen or a hydroxyl protecting group,
- the process comprising:
- (a) reacting a compound of formula (V-a)
- or a compound of formula (VII-a)
- with 2-(5-bromo-2-thienyl)pyridine, palladium acetate, triphenylphosphine and triethylamine;
- and
- (b) optionally deprotecting the product of step (a).
6 more elements
A process for preparing compounds of formula (V-c)
- or compounds of formula (VII-d)
- wherein, for compounds of formulas (V-c) and (VII-d),
- R4 and R5 are independently hydrogen or a hydroxyl protecting group,
- the process comprising:
- (a) reacting a compound of formula (V-a)
- or a compound of formula (VII-a)
- with 2-(5-bromo-2-thienyl)pyridine, palladium acetate, triphenylphosphine and triethylamine in acetonitrile at a temperature of about 60° C. to about 80° C.;
- and
- (b) optionally deprotecting the product of step (a).
6 more elements
Dependencies are inferred from the claim text.