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US4066658A
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Resolution of d,l-dehydroproline
Assignee: Hoffmann La Roche Inc
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Filing: 1975-08-11
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Granted: 1978-01-03
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Expires: 1995-08-11
Abstract
Abstract D,L-3,4-dehydroproline is resolved in high optical yield by conversion to its N-protected derivative, treatment with R(+)alpha-methyl-p-nitrobenzylamine to form the diastereomeric salts, fractional crystallization, decomposition of the L-R salt and regeneration of the secondary amine group. The product L-3,4-dehydroproline obtained in extremely high optical purity is useful as an inhibitor of collagen synthesis.
Inventors
- 👤 Arthur Martin Felix
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-26 04:29
CPC Classifications
C; C07; C07D; C07D207/00; C07D207/02; C07D207/18; C07D207/22
Claims Analysis
Total Claims: 8
Claim 1
Independent Claim
90 words
A method for the preparation of L-3,4-dehydroproline comprising in combination the steps of: A. treating N-protected D,L-3,4-dehydroproline with R(+)-alpha-methyl-p-nitrobenzylamine so as to form the corresponding diastereomeric salt, the said N-protecting group being selected from conventional N-protecting groups which can be deblocked without racemization of the resolved compound; B. selectively crystallizing the N-protected L-3,4-dehydroproline (R)-alpha-methyl-p-nitrophenethyl ammonium salt from solution; C. decomposing the aforesaid diastereomeric salt with cold aqueous weak acid so as to produce N-protected-L-3,4-dehydroproline; and D. removing the N-protecting group under conditions which do not cause racemization thereby yielding L-3,4-dehydroproline.
Claim 2
Independent Claim
90 words
A method for the preparation of L-3,4-dehydroproline comprising in combination the steps of: A. treating N-protected D,L-3,4-dehydroproline with R(+)-alpha-methyl-p-nitrobenzylamine so as to form the corresponding diastereomeric salt, the said N-protecting group being selected from conventional N-protecting groups which can be deblocked without racemization of the resolved compound; B. selectively crystallizing the N-protected L-3,4-dehydroproline (R)-alpha-methyl-p-nitrophenethyl ammonium salt from solution; C. decomposing the aforesaid diastereomeric salt with cold aqueous weak acid so as to produce N-protected-L-3,4-dehydroproline; and D. removing the N-protecting group under conditions which do not cause racemization thereby yielding L-3,4-dehydroproline.
Claim 3
Dependent Claim
17 words
The process of claim 1 wherein said N-protecting group is selected from t-butyloxycarbonyl, formyl, trifluoroacetyl and phthaloyl.
Claim 4
Dependent Claim
27 words
The process of claim 2 wherein said N-protecting group is t-butyloxycarbonyl and the deblocking is accomplished by treatment of the resolved protected compound with aqueous formic acid.
Claim 5
Dependent Claim
26 words
The process of claim 1 wherein the formation of the diastereomeric salt in step (A) is carried out in lower alkanol or lower alkyl ketone solvent.
Claim 6
Dependent Claim
10 words
The process of claim 4 wherein said solvent is isopropanol.
Claim 7
Independent Claim
143 words
A method for the preparation of L-3,4-dehydroproline and D-3,4-dehydroproline comprising in combination the steps of: A. treating N-protected D,L-3,4-dehydroproline with R(+)-alpha-methyl-p-nitrobenzylamine so as to form the corresponding diastereomeric salt, the said N-protecting group being selected from conventional N-protecting groups which can be deblocked without racemization of the resolved compound; B. selectively crystallizing the N-protected L-3,4-dehydroproline-(R)-alpha-methyl-p-nitrophenethyl-ammonium salt from solution; C. decomposing the aforesaid diastereomeric salt with cold weak aqueous organic acid so as to produce N-protected L-3,4-dehydroproline; D. removing the N-protecting group under conditions which do not cause racemization thereby yielding L-3,4-dehydroproline; E. treating the mother liquors from step (B) with S-(-)-alpha-methyl-p-nitrobenzylamine so as to produce N-protected D-3,4-dehydroproline-(S)-alpha-methyl-p-nitrophenethyl-ammonium salt; F. decomposing the diastereomeric salt of step (E) with cold weak aqueous acid so as to produce N-protected D-3,4-dehydroproline; and G. removing the N-protecting group under conditions which do not cause racemization thereby yielding D-3,4-dehydroproline.
Claim 8
Independent Claim
143 words
A method for the preparation of L-3,4-dehydroproline and D-3,4-dehydroproline comprising in combination the steps of: A. treating N-protected D,L-3,4-dehydroproline with R(+)-alpha-methyl-p-nitrobenzylamine so as to form the corresponding diastereomeric salt, the said N-protecting group being selected from conventional N-protecting groups which can be deblocked without racemization of the resolved compound; B. selectively crystallizing the N-protected L-3,4-dehydroproline-(R)-alpha-methyl-p-nitrophenethyl-ammonium salt from solution; C. decomposing the aforesaid diastereomeric salt with cold weak aqueous organic acid so as to produce N-protected L-3,4-dehydroproline; D. removing the N-protecting group under conditions which do not cause racemization thereby yielding L-3,4-dehydroproline; E. treating the mother liquors from step (B) with S-(-)-alpha-methyl-p-nitrobenzylamine so as to produce N-protected D-3,4-dehydroproline-(S)-alpha-methyl-p-nitrophenethyl-ammonium salt; F. decomposing the diastereomeric salt of step (E) with cold weak aqueous acid so as to produce N-protected D-3,4-dehydroproline; and G. removing the N-protecting group under conditions which do not cause racemization thereby yielding D-3,4-dehydroproline.
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) | 1981-01-02 | 1981-07-04 | 1982-01-03 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1985-01-02 | 1985-07-04 | 1986-01-03 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1989-01-02 | 1989-07-04 | 1990-01-03 | $7700.00 | Window Closed / Lapsed |