US5159108A
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Process for preparing an antihypercalcemic agent
Assignee: Merck Sharp & Dohme LLC
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Filing: 1991-08-01
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Granted: 1992-10-27
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Expires: 2011-08-01
Abstract
Abstract Described is a new process for producing 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid (ABP), a new antihypercalcemic agent. The process involves a 3-step sequence starting with 4-phthalimidobutanoyl chloride which can be practiced as a "one-pot" reaction sequence, without employing PCl 3 or H 3 PO 3 .
Inventors
- 👤 Gerard R. Kieczykowski
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-07 18:01
CPC Classifications
C; C07; C07F; C07F9/00; C07F9/02; C07F9/547; C07F9/553; C07F9/5537; C07F9/28; C07F9/38; C07F9/3804; C07F9/3839; C07F9/3873
Claims Analysis
Total Claims: 12
Claim 1
Independent Claim
161 words
A process for producing omega-amino-1-hydroxy-C 2 -C 6 -alkylidene-bisphosphonic acid comprising the steps of: (a) contacting omega-phthalimido-C 2 -C 6 alkanoyl chloride with tri C 1 -C 4 alkyl phosphite in a dry inert organic solvent at a temperature in the range of 0° to 60° C. to form di C 1 -C 4 alkyl omega-phthalimido-C 2 -C 6 -alkanoyl phosphonate; (b) contacting di C 1 -C 4 alkyl omega-phthalimido-C 2 -C 6 -alkanoyl phosphonate from Step (a) with di C 1 -C 4 alkyl phosphite in a dry inert organic solvent in the temperature range of 0° to 60° C. in the presence of a tertiary nitrogen amine, to form tetra C 1 -C 4 alkyl omega-phthalimido-1-hydroxy-C 2 -C 6 -alkylidene-bisphosphonate; (c) contacting tetra C 1 -C 4 alkyl omega-phthalimido-1-hydroxy-C 2 -C 6 -alkylidene-bisphosphonate from Step (b) with aqueous strong acid at a temperature in the range of 90° C. to reflux to form omega-amino-1-hydroxy-C 2 -C 6 -alkylidene-bisphosphonic acid.
Claim 2
Dependent Claim
161 words
A process for producing omega-amino-1-hydroxy-C 2 -C 6 -alkylidene-bisphosphonic acid comprising the steps of: (a) contacting omega-phthalimido-C 2 -C 6 alkanoyl chloride with tri C 1 -C 4 alkyl phosphite in a dry inert organic solvent at a temperature in the range of 0° to 60° C. to form di C 1 -C 4 alkyl omega-phthalimido-C 2 -C 6 -alkanoyl phosphonate; (b) contacting di C 1 -C 4 alkyl omega-phthalimido-C 2 -C 6 -alkanoyl phosphonate from Step (a) with di C 1 -C 4 alkyl phosphite in a dry inert organic solvent in the temperature range of 0° to 60° C. in the presence of a tertiary nitrogen amine, to form tetra C 1 -C 4 alkyl omega-phthalimido-1-hydroxy-C 2 -C 6 -alkylidene-bisphosphonate; (c) contacting tetra C 1 -C 4 alkyl omega-phthalimido-1-hydroxy-C 2 -C 6 -alkylidene-bisphosphonate from Step (b) with aqueous strong acid at a temperature in the range of 90° C. to reflux to form omega-amino-1-hydroxy-C 2 -C 6 -alkylidene-bisphosphonic acid.
Claim 3
Dependent Claim
22 words
The process of claim 1 wherein said alkanoyl chloride is derived from glycine, 3-aminopropanoic acid, 4-aminobutanoic acid, 5-aminopentanoic acid or 6-aminohexanoic acid.
Claim 4
Dependent Claim
21 words
The process of claim 1 wherein the temperature range for Step (a) is in the range of 20° to 25° C.
Claim 5
Dependent Claim
21 words
The process of claim 1 wherein the temperature range for Step (b) is in the range of 20° to 25° C.
Claim 6
Dependent Claim
18 words
The process of claim 1 wherein the temperature for Step (c) is the reflux temperature of the solvent.
Claim 7
Dependent Claim
47 words
The process of claim 1 wherein the solvent for Step (a) is selected from C 6 -C 10 aromatic hydrocarbons, chlorinated C 6 -C 10 aromatic hydrocarbons, chlorinated C 1 -C 4 alkyl hydrocarbons, C 2 -C 3 alkylnitriles, C 4 -C 6 linear or cyclic ethers.
Claim 8
Dependent Claim
18 words
The process of claim 1 wherein the solvent for Step (b) is the same as for Step (a).
Claim 9
Dependent Claim
16 words
The process of claim 1 wherein the strong acid in Step (c) is aqueous hydrochloric acid.
Claim 10
Dependent Claim
20 words
The process of claim 1 wherein the product phosphonate from Step (a) is not isolated prior to conducting Step (b).
Claim 11
Dependent Claim
94 words
A process for producing 4-amino-1-hydroxybutylidene-bisphosphonic acid comprising the steps of: (a) contacting 4-phthalimidobutanoyl chloride with trimethyl phosphite in a dry inert organic solvent at a temperature in the range of 0° to 60° C. to form dimethyl 4-phthalimidobutanoyl phosphonate; (b) contacting dimethyl 4-phthalimidobutanoyl phosphonate from Step (a) with dimethylphosphite in a dry inert organic solvent in the temperature range of 0° to 60° C. to form tetramethyl phthalimido-1-hydroxybutylidene-bisphosphonate; (c) contacting tetramethyl phthalimido-1-hydroxybutylidene-bisphosphonate from Step (b) with aqueous hydrochloric acid at a temperature in the range of 80° C. to reflux to form 4-amino-1-hydroxybutylidene-bisphosphonic acid.
Claim 12
Dependent Claim
94 words
A process for producing 4-amino-1-hydroxybutylidene-bisphosphonic acid comprising the steps of: (a) contacting 4-phthalimidobutanoyl chloride with trimethyl phosphite in a dry inert organic solvent at a temperature in the range of 0° to 60° C. to form dimethyl 4-phthalimidobutanoyl phosphonate; (b) contacting dimethyl 4-phthalimidobutanoyl phosphonate from Step (a) with dimethylphosphite in a dry inert organic solvent in the temperature range of 0° to 60° C. to form tetramethyl phthalimido-1-hydroxybutylidene-bisphosphonate; (c) contacting tetramethyl phthalimido-1-hydroxybutylidene-bisphosphonate from Step (b) with aqueous hydrochloric acid at a temperature in the range of 80° C. to reflux to form 4-amino-1-hydroxybutylidene-bisphosphonic acid.
References Cited (Backward Citations)
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| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
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| 3.5 Years (Year 4) | 1995-10-27 | 1996-04-27 | 1996-10-27 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1999-10-27 | 2000-04-27 | 2000-10-27 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2003-10-27 | 2004-04-27 | 2004-10-27 | $7700.00 | Window Closed / Lapsed |