US3878043A
Expired / Lapsed
US
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Method for preparing L-dopa and novels compounds useful therein
Assignee: Southern Illinois University Carbondale
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Filing: 1973-01-02
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Granted: 1975-04-15
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Expires: 1993-01-02
Abstract
Abstract A method for producing L-dopa at high rates, high yields and relatively low cost. In accordance with the method, a resolution system is prepared comprising a mixture of optical isomers of a precursor compound and a proteolytic enzyme in an aqueous medium. The L-isomer of the precursor compound, which corresponds to the structural formula: WHERE R1 is hydrogen, methyl or ethyl, R2 is hydrogen, alkyl, aryl, furyl, thienyl, styryl, t-butyloxy or benzyloxy, and R3 is methyl, ethyl, n-propyl and isopropyl, is hydrolyzed to produce the L-isomer of a substituted N-acyl alanine intermediate corresponding to the structural formula: WHILE THE D-isomer of the precursor remains substantially unchanged. The N-acyl-L-alanine intermediate is isolated from the D-isomer of the precursor and then hydrolyzed to produce L-dopa.
Inventors
- 👤 Michael S Matta
- 👤 Joe A Kelley
- 👤 Michael F Rohde
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-29 16:25
CPC Classifications
C; C12; C12P; C12P41/00; C12P41/003; C12P41/005; C07; C07D; C07D263/00; C07D263/02; C07D263/30; C07D263/34; C07D263/36; C07D263/42; Y; Y10; Y10S; Y10S435/00; Y10S435/813
Claims Analysis
Total Claims: 22
Claim 1
Independent Claim
46 words
A METHOD OF PREPARING AN INTERMEDIATE WHICH IS READILY CONVERTIBLE TO L-DOPA COMPRISING THE STEPS OF: PREPARING A RESOLUTION SYSTEM COMPRISING A MIXTURE OF OPTICAL ISOMERS OF A PRECURSOR COMPOUND AND A PROTEOLYTIC ENZYME IN AN AQUEOUS MEDIUM, SAID PRECURSOR COMPOUND CORRESPONDING TO THE STRUCTURAL FORMULA:
Claim 2
Independent Claim
46 words
A METHOD OF PREPARING AN INTERMEDIATE WHICH IS READILY CONVERTIBLE TO L-DOPA COMPRISING THE STEPS OF: PREPARING A RESOLUTION SYSTEM COMPRISING A MIXTURE OF OPTICAL ISOMERS OF A PRECURSOR COMPOUND AND A PROTEOLYTIC ENZYME IN AN AQUEOUS MEDIUM, SAID PRECURSOR COMPOUND CORRESPONDING TO THE STRUCTURAL FORMULA:
Claim 3
Dependent Claim
26 words
A method as set forth in claim 1 wherein the pH of the medium is maintained at between about 5.5 and about 9 during the hydrolysis.
Claim 4
Dependent Claim
15 words
A method as set forth in claim 1 wherein said proteolytic enzyme is Alpha -chymotrypsin.
Claim 5
Dependent Claim
22 words
A method as set forth in claim 3 wherein a pH on the order of about 7.8 is maintained during the hydrolysis.
Claim 6
Dependent Claim
32 words
A method as set forth in claim 4 wherein a base selected from the group consisting of alkali metal hydroxides, alkaline earth metal hydroxides and alkali metal alkoxides is present during hydrolysis.
Claim 7
Dependent Claim
18 words
A method as set forth in claim 1 whErein the enzyme is covalently bonded to an insoluble support.
Claim 8
Dependent Claim
21 words
A method as set forth in claim 1 wherein the hydrolysis is conducted in the presence of a water-miscible organic solvent.
Claim 9
Dependent Claim
28 words
A method as set forth in claim 7 wherein said solvent is selected from the group consisting of methanol, ethanol, isopropanol, n-propanol, p-dioxane, dimethyl sulfoxide and dimethyl formamide.
Claim 10
Dependent Claim
22 words
A method as set forth in claim 1 wherein R2 is selected from the group consisting of hydrogen, methyl, ethyl and phenyl.
Claim 11
Dependent Claim
19 words
A method as set forth in claim 9 wherein R1 is methyl, R2 is methyl, and R3 is methyl.
Claim 12
Dependent Claim
79 words
A method as set forth in claim 1 wherein isolation of the substituted N-acyl-L-alanine intermediate from the D-isomer of the precursor comprises the steps of: contacting the aqueous medium with an organic solvent thereby extracting the D-isomer of the precursor from the aqueous medium; acidifying the aqueous layer after extraction; removing the water from the aqueous layer to produce a dry residue containing the L-alanine intermediate; and recrystallizing the substituted L-alanine intermediate from the residue using an organic solvent.
Claim 13
Dependent Claim
26 words
A method as set forth in claim 1 wherein said mixture is initially prepared from a ring-substituted Alpha -acylamido cinnamate ester corresponding to the structural formula:
Claim 14
Dependent Claim
14 words
A method as set forth in claim 12 wherein the hydrogenation catalyst is palladium.
Claim 15
Dependent Claim
17 words
A method as set forth in claim 13 wherein the catalyst is 5 percent palladium on carbon.
Claim 16
Dependent Claim
23 words
A method as set forth in claim 12 wherein a hydrogen pressure of at least about 3 atmospheres is maintained during the hydrogenation.
Claim 17
Dependent Claim
26 words
A method as set forth in claim 12 wherein said ring-substituted Alpha -acyl-amido cinnamate ester is prepared from an azlactone compound corresponding to the structural formula:
Claim 18
Dependent Claim
26 words
A method as set forth in claim 16 wherein preparation of said azlactone compound comprises the reaction of a substituted benzaldehyde corresponding to the structural formula:
Claim 19
Dependent Claim
24 words
A method as set forth in claim 17 wherein the catalyst is selected from the group consisting of alkali metal acetates and tertiary amines.
Claim 20
Dependent Claim
24 words
A method as set forth in claim 17 wherein a dehydrating agent is present during reaction between the substituted benzaldehyde and the N-acyl glycine.
Claim 21
Dependent Claim
17 words
A method as set forth in claim 1 wherein the isolated intermediate is hydrolyzed to produce L-dopa.
Claim 22
Dependent Claim
22 words
A method as set forth in claim 20 wherein said substituted N-acyl-L-alanine intermediate is hydrolyzed in an aqueous solution containing hydrobromic acid.
References Cited (Backward Citations)
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1978-04-14 | 1978-10-14 | 1979-04-15 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1982-04-14 | 1982-10-14 | 1983-04-15 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1986-04-14 | 1986-10-14 | 1987-04-15 | $7700.00 | Window Closed / Lapsed |