US4072677A
Expired / Lapsed
US
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Penicillin synthesis
Assignee: Beecham Group PLC
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Filing: 1976-11-30
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Granted: 1978-02-07
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Expires: 1996-11-30
Abstract
Abstract Process of preparing phthalidyl ampicillin or other orally absorbable penicillin ester by esterification of the parent penicillin in a two-phase system using a phase transfer catalyst which increases the solubility of a salt form of the penicillin in the water-immiscible solvent used in the process. The phase transfer catalysts are quaternary ammonium salts or tertiary amines of non-low molecular weight, or crown ethers.
Inventors
- 👤 Sidney E. Callander
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-07 14:46
CPC Classifications
C; C07; C07D; C07D499/00; A; A61; A61P; A61P31/00; A61P31/04
Claims Analysis
Total Claims: 12
Claim 1
Independent Claim
180 words
A process for the preparation of a compound of formula (I): ##STR9## wherein R 1 is a group ##STR10## wherein R 3 is phenyl, p-hydroxyphenyl, cyclohexadienyl, or 2-or 3-thienyl, R 4 is an amino or conventional penicillin protected amino group, R 5 and R 6 are both methyl or, together with the carbon atom to which they are joined, represent a cycloheptyl ring; and R 2 is a group of formula (II) or (IIA): ##STR11## wherein R 7 and R 8 are the same or different and are hydrogen, methyl or methoxy, R 9 is acetoxy, pivaloyloxy or ethoxycarbonyloxy, and R is hydrogen or methyl; which process comprises reacting an aqueous solution of a compound of formula (III): ##STR12## wherein R 1 has the above meaning and A is a salt-forming ion, with a solution in a water-immiscible organic solvent of a compound R 2 OH or a reactive esterifying derivative thereof, in the presence of a phase transfer catalyst which is a compound which increases the solubility of the salt form of the parent penicillin in the water-immiscible solvent.
Claim 2
Dependent Claim
180 words
A process for the preparation of a compound of formula (I): ##STR9## wherein R 1 is a group ##STR10## wherein R 3 is phenyl, p-hydroxyphenyl, cyclohexadienyl, or 2-or 3-thienyl, R 4 is an amino or conventional penicillin protected amino group, R 5 and R 6 are both methyl or, together with the carbon atom to which they are joined, represent a cycloheptyl ring; and R 2 is a group of formula (II) or (IIA): ##STR11## wherein R 7 and R 8 are the same or different and are hydrogen, methyl or methoxy, R 9 is acetoxy, pivaloyloxy or ethoxycarbonyloxy, and R is hydrogen or methyl; which process comprises reacting an aqueous solution of a compound of formula (III): ##STR12## wherein R 1 has the above meaning and A is a salt-forming ion, with a solution in a water-immiscible organic solvent of a compound R 2 OH or a reactive esterifying derivative thereof, in the presence of a phase transfer catalyst which is a compound which increases the solubility of the salt form of the parent penicillin in the water-immiscible solvent.
Claim 3
Dependent Claim
12 words
A process as claimed in claim 1 wherein R 3 is phenyl.
Claim 4
Dependent Claim
25 words
A process as claimed in claim 1 wherein R 2 is a group of formula (II) wherein R 7 and R 8 are both hydrogen.
Claim 5
Dependent Claim
24 words
A process as claimed in claim 1 wherein the phase transfer catalyst is a quaternary ammonium salt, a tertiary amine or a crown ether.
Claim 6
Dependent Claim
95 words
A process as claimed in claim 4 wherein the phase transfer catalyst is a compound of formula (V): ##STR13## wherein Y - is an anion, R 10 and R 11 are C 1 -C 18 organic groups, R 12 is a C 1 -C 10 alkyl group, R 13 is a C 1-6 alkyl group, or R 11 , R 12 and R 13 and the nitrogen to which they are attached may form a pyridine ring, the moiety R 10 R 11 R 12 R 13 N + containing at least nine carbon atoms.
Claim 7
Dependent Claim
22 words
A process as claimed in claim 5 wherein R 10 and R 11 are C 1 -C 10 straight chain alkyl groups.
Claim 8
Dependent Claim
26 words
A process as claimed in claim 6 wherein the phase transfer catalyst is a compound in which the cation is selected from: tetrabutylammonium; tetrapropylammonium; tributylethylammonium; trioctylmethylammonium.
Claim 9
Dependent Claim
43 words
A process for the preparation of the phthalidyl ester of [D-N-(1-methoxycarbonylpropen-2-yl)-α-aminophenylacetamido]penicillanic acid, which process comprises reacting an aqueous solution of a salt of [D-N-(1-methoxycarbonylpropen-2-yl)-α-aminophenylacetamido]penicillanic acid with a solution of bromophthalide in a water-immiscible organic solvent, in the presence of a phase transfer catalyst.
Claim 10
Dependent Claim
43 words
A process for the preparation of the phthalidyl ester of [D-N-(1-methoxycarbonylpropen-2-yl)-α-aminophenylacetamido]penicillanic acid, which process comprises reacting an aqueous solution of a salt of [D-N-(1-methoxycarbonylpropen-2-yl)-α-aminophenylacetamido]penicillanic acid with a solution of bromophthalide in a water-immiscible organic solvent, in the presence of a phase transfer catalyst.
Claim 11
Dependent Claim
29 words
A process as claimed in claim 8 which further comprises hydrolysis of the resulting phthalidyl ester of [D-N-(1-methoxycarbonylpropen-2-yl)-α-aminophenylacetamido]penicillanic acid to give phthalidyl ampicillin or an acid addition salt thereof.
Claim 12
Dependent Claim
123 words
A process for the preparation of a penicillin ester by esterification of the parent penicillin having an unesterified carboxyl group in the 3-position in a two-phase system using a phase transfer catalyst which process comprises reacting an aqueous solution of the parent penicillin in which the carboxyl group in the 3-position is in salt form with the hydrogen atom of the carboxyl group replaced by a salt forming ion with a compound R 2 OH dissolved in a water-immiscible solvent in the presence of a phase transfer catalyst which is a compound which increases the solubility of the salt form of the parent penicillin in the water-immiscible solvent, R 2 in the compound R 2 OH having the meaning defined in claim 1.
References Cited (Backward Citations)
US3860579A
Cited
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1981-02-06 | 1981-08-08 | 1982-02-07 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1985-02-06 | 1985-08-08 | 1986-02-07 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1989-02-06 | 1989-08-08 | 1990-02-07 | $7700.00 | Window Closed / Lapsed |