US4397786A
Expired / Lapsed
US
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Method of preparing statine and derivatives
Assignee: Merck and Co Inc
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Filing: 1981-11-23
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Granted: 1983-08-09
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Expires: 2001-11-23
Abstract
Abstract Statine (Sta), a naturally-occurring amino acid and closely related derivatives, are prepared by a novel method involving an oxidative route to the requisite chiral alpha -aminoaldehyde intermediate, L-leucinal; the novel method may be illustrated by the following reaction scheme: <IMAGE> <IMAGE> +TR <IMAGE> .
Inventors
- 👤 Ben E. Evans
- 👤 Kenneth E. Rittle
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-26 17:08
CPC Classifications
C; C07; C07C; C07C271/00; C07C271/06; C07C271/08; C07C271/10; C07C271/22; Y; Y10; Y10S; Y10S530/00; Y10S530/86
Claims Analysis
Total Claims: 8
Claim 1
Independent Claim
159 words
A method of preparing compounds of the formula: ##STR9## wherein A is hydrogen; or a blocking group B conventionally employed in peptide synthesis; R 1 is C 3-6 alkyl; C 3-7 cycloalkyl; phenyl; or phenyl monosubstituted with a member selected from the group consisting of methyl, trifluoromethyl, hydroxy, methoxy, fluoro, chloro, bromo, and iodo; and R 2 is hydrogen; or C 1-4 alkyl; comprising the following steps: (a) reducing a compound of the formula: ##STR10## to form the corresponding carbinol of the formula: ##STR11## (b) oxidizing the carbinol of Formula III with chromium trioxide and pyridine in methylene chloride to form the corresponding aldehyde of the formula: ##STR12## and; (c) treating the aldehyde of Formula IV with an organometallic derivative of acetic acid or its C 1-4 alkyl ester, followed by enantiomer separation, to form a compound of Formula I of the desired chirality where A=B; and, optionally, N-deprotecting to form the Formula I compound where A is hydrogen.
Claim 2
Independent Claim
159 words
A method of preparing compounds of the formula: ##STR9## wherein A is hydrogen; or a blocking group B conventionally employed in peptide synthesis; R 1 is C 3-6 alkyl; C 3-7 cycloalkyl; phenyl; or phenyl monosubstituted with a member selected from the group consisting of methyl, trifluoromethyl, hydroxy, methoxy, fluoro, chloro, bromo, and iodo; and R 2 is hydrogen; or C 1-4 alkyl; comprising the following steps: (a) reducing a compound of the formula: ##STR10## to form the corresponding carbinol of the formula: ##STR11## (b) oxidizing the carbinol of Formula III with chromium trioxide and pyridine in methylene chloride to form the corresponding aldehyde of the formula: ##STR12## and; (c) treating the aldehyde of Formula IV with an organometallic derivative of acetic acid or its C 1-4 alkyl ester, followed by enantiomer separation, to form a compound of Formula I of the desired chirality where A=B; and, optionally, N-deprotecting to form the Formula I compound where A is hydrogen.
Claim 3
Dependent Claim
20 words
A method according to claim 1 wherein B is tert-butyloxycarbonyl (BOC), R 1 is isopropyl, and R 2 is hydrogen.
Claim 4
Dependent Claim
14 words
A method according to claim 1 wherein the compound prepared is 3S,4S-BOC-4-amino-3-hydroxy-6-methylheptanoic acid (BOC-statine).
Claim 5
Dependent Claim
19 words
A method according to claim 1 wherein the reduction in Step (a) is carried out using borane in tetrahydrofuran.
Claim 6
Dependent Claim
43 words
A method according to claim 1 wherein in Step (c) the metallic portion of the organometallic derivative of acetic acid or its C 1-4 alkyl ester is selected from the group consisting of lithium, magnesium bromide, magnesium chloride, zinc bromide, and zinc chloride.
Claim 7
Dependent Claim
22 words
A method according to claim 5 wherein in Step (c) α-lithio ethyl acetate is used to treat the aldehyde of Formula IV.
Claim 8
Dependent Claim
17 words
A method according to claim 1 wherein in Step (c) the enantiomers are separated by flash chromatography.
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) | 1986-08-08 | 1987-02-07 | 1987-08-09 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1990-08-08 | 1991-02-07 | 1991-08-09 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1994-08-08 | 1995-02-07 | 1995-08-09 | $7700.00 | Window Closed / Lapsed |