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US3925354A
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Process for the production of an 1-n-(s)-alpha- substituted-w-aminoacyl) derivative of neamine, 3', 4'-dideoxyneamine, ribostamycin or 3',4'-dideoxyribostamycin
Assignee: Microbial Chemistry Research Foundation
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Filing: 1973-10-01
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Granted: 1975-12-09
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Expires: 1993-10-01
Abstract
Abstract A new process of synthetizing an 1-N-((S)- Alpha -substitutedomega -aminoacyl) derivatives of aminoglycosidic antibiotic, including known compounds such as butirosin B as well as new compounds such as the derivatives of neamines and deoxyribostamycins, is provided according to this invention, in which process the initial aminoglycosidic antibiotic is poly-Nalkloxy- or -aralkyloxy- or aryloxy-carbonylated, the resulting poly-N-alkyloxy- or aralkyloxy- or aryloxy-carbonylated product is treated with a strong base such as sodium hydroxide or an alkali metal hydride to form the cyclic carbamate derivative according to new reactions and in which the cyclic carbamate derivative is treated with a weak base such as barium hydroxide to convert the 1-amino group of the antibiotic selectively into the free state while the other amino groups still remain in the protected condition. The 1-amino group of the antibiotic having the other amino groups protected is then acylated by reacting with the (S)- Alpha -substituted-107 -amino acid, and the acylation product is treated so as to remove the amino-protecting groups, giving the desired compound.
Inventors
- 👤 Hamao Umezawa
- 👤 Sumio Umezawa
- 👤 Osamu Tsuchiya
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-04 15:17
CPC Classifications
C; C07; C07H; C07H15/00; C07H15/20; C07H15/22; C07H15/222; C07H15/224; A; A61; A61P; A61P31/00; A61P31/04; C07H15/226; C07H15/228; C07H15/23; C07H15/234
Claims Analysis
Total Claims: 19
Claim 1
Independent Claim
12 words
A PROCESS FOR PREPARING AN AMINOGLYCOSIDIC ANITIBIOTIC AMINOL DERIVATIVE OF THE FORMULA
Claim 2
Dependent Claim
12 words
A PROCESS FOR PREPARING AN AMINOGLYCOSIDIC ANITIBIOTIC AMINOL DERIVATIVE OF THE FORMULA
Claim 3
Dependent Claim
18 words
A process according to claim 1, wherein R'''', X'', Y'', Z and Z'' are each cyclohexylidene or methoxycyclohexyl.
Claim 4
Dependent Claim
10 words
A process according to claim 1, wherein R'' is benzyl.
Claim 5
Dependent Claim
22 words
A process according to claim 1 wherein tetra-N-benzyloxycarbonylated neamine, 3'',4''-dideoxyneamine, ribostamycin or 3'',4''-dideoxyribostamycin is used as the starting compound of formula (II).
Claim 6
Dependent Claim
20 words
A process according to claim 1 wherein the alkali metal compound in step (a) is sodium hydroxide or sodium hydride.
Claim 7
Dependent Claim
34 words
A process according to claim 1 wherein one molar proportion of the starting compound of formula (II) is reacted with 1-3 molar proportions of sodium hydride to form the cyclic carbamate of formula (III).
Claim 8
Dependent Claim
16 words
A process according to claim 1 wherein the weak base in step (b) is barium hydroxide.
Claim 9
Dependent Claim
44 words
A process according to claim 1 wherein R'' is benzyl; R'''', X'', Y'', Z and Z'' are each cyclohexylidene or methoxycyclohexyl; the alkali metal compound in step (a) is sodium hydroxide or sodium hydride; and the weak base in step (b) is barium hydroxide.
Claim 10
Dependent Claim
22 words
A process according to claim 1, further comprising reacting said cyclic carbonate with an (S)- Alpha -substituted amino acid of the formula
Claim 11
Dependent Claim
10 words
A process according to claim 9, wherein R1 is hydroxyl.
Claim 12
Dependent Claim
10 words
A process according to claim 9, wherein n is 2.
Claim 13
Dependent Claim
13 words
A process according to claim 9, wherein R3 and R4 together form phthaloyl.
Claim 14
Dependent Claim
17 words
A process according to claim 9 wherein said amino acid is (S)- Alpha -hydroxy- gamma -aminobutyric acid.
Claim 15
Dependent Claim
21 words
A process according to claim 9 wherein said amino acid is the N-hydroxysuccinimide ester of (S)- Alpha -hydroxy- gamma -phthalimidobutyric acid.
Claim 16
Dependent Claim
35 words
A process according to claim 9, further comprising reducing said -COOR'', R-, X'' and Y'' to hydrogen to form an 1-N-(S)- Alpha -substituted- gamma -aminoacyl derivative of neamine, 3'',4''-dideoxyneamine, ribostamycin or 3'',4''-dideoxyribostamycin of the formula:
Claim 17
Dependent Claim
131 words
A process according to claim 15 in which 1-N-((S)- Alpha -hydroxy- gamma -aminobutyryl)ribostamycin is produced, comprising: a. reacting sodium hydride with tetra-N-benzyloxycarbonyl-3'',4''; 2'''',3''''-di-0-cyclohexylidene-5''''-0-(1-methoxycyclohexyl) ribostamycin in a non-aqueous reaction medium to produce tri-N-benzyloxycarbonyl-3'',4''; 2'''',3''''-di-0-cyclohexylidene-5''''-0-(1-methoxycyclohexyl) ribostamycin-1,6-carbamate; b. partially hydrolyzing the resultant carbamate with barium hydroxide in an aqueous organic solvent to produce 3,2'',6''-tri-N-benzyloxycarbonyl-3'',4''; 2'''',3''''-di-0-cyclohexylidene-5''''-0-(1-methoxycyclohexyl) ribostamycin; c. reacting the resultant partially hYdrolyzed product with (S)-Alpha -hydroxy- gamma -phthalimidobutyric acid or its N-hydroxy-succinimide ester to produce the 1-N-((S)- Alpha -hydroxy- Alpha -phthalimidobutyryl) derivative thereof; and d. reacting the resultant derivative successively with hydrazine in an aqueous organic solvent to remove the phthaloyl group thereof, with palladium-carbon and hydrogen to remove the benzyloxycarbonyl groups thereof and then with a dilute mineral acid to remove the cyclohexylidene groups thereof to form 1-N-((S)- Alpha -hydroxy- gamma -amino-butyryl) ribostamycin.
Claim 18
Dependent Claim
112 words
A process according to claim 15 in which 1-N-((S)- Alpha -hydroxy- gamma -aminobutyryl)-3'',4''-dideoxyneamine is produced, comprising: a. reacting sodium hydride with tetra-N-benzyloxycarbonyl-3'',4''-dideoxyneamine in a non-aqueous reaction medium to produce 3, 2'',6''-tri-N-benzyloxycarbonyl-3'',4''-dideoxyneamine-1,6-carbamate; b. partially hydrolyzing the resultant carbamate with barium hydroxide in an aqueous reaction medium to produce 3,2'',6''-tri-N-benzyloxycarbonyl-3'',4''-dideoxyneamine; c. reacting the resultant partially hydrolyzed product with (S)-Alpha -hydroxy- gamma -phthalimido-butyric acid or its N-hydroxysuccinimide ester to produce 3,2'',6''-tri-N-benzyloxycarbonyl-3'',4''-dideoxy-1-N-((S)- Alpha -hydroxy- gamma -phthalimido-butyryl) neamine; and d. treating the resultant product successively with hydrazine in an aqueous organic solvent to remove the phthaloyl group thereof and then with palladium-carbon and hydrogen to remove the benzyloxycarbonyl groups thereof to form 3'',4''-dideoxy-1-N-((S)- Alpha -hydroxy- gamma -aminobutyryl)neamine.
Claim 19
Dependent Claim
112 words
A process according to claim 15 in which 1-N-((S)- Alpha -hydroxy- gamma -aminobutyryl)neamine is produced, comprising: a. reacting sodium hydride with tetra-N-benzyloxycarbonyl-3'',4''-0-cyclohexylidene-neamine in a non-aqueous reaction medium to produce 3,2''-6''-tri-N-benzyloxycarbonyl-3'',4''-0-cyclohexylidene-neamine-1,6 -carbamate; b. partially hydrolyzing the resultant carbamate with barium hydroxide in an aqueous reaction medium to produce 3,2'',6''tri-N-benzyloxycarbonyl-3'',4''-0-cyclohexylidene-neamine; c. reacting the resultant partially hydrolyzed product with (S)-Alpha -hydroxy- gamma -benzyloxycarbonylamino-butyric acid or its N-hydroxy-succinimide ester to produce 3,2'',6''-tri-N-benzyloxycarbonyl-3'',4''-0-cyclohexylidene-1-N((S)- Alpha -hydroxy- gamma -benzyloxycarbonylamino-butyryl) neamine; and d. treating the resultant product successively with hydrazine in an aqueous organic solvent to remove the phthaloyl group thereof and then with palladium-carbon and hydrogen to remove the benzyloxycarbonyl groups thereof to form 1-N-((S)- Alpha -hydroxy- gamma -aminobutyryl)neamine.
References Cited (Backward Citations)
US3753973A
Cited
US3781268A
Cited
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1978-12-08 | 1979-06-09 | 1979-12-09 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1982-12-08 | 1983-06-09 | 1983-12-09 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1986-12-08 | 1987-06-09 | 1987-12-09 | $7700.00 | Window Closed / Lapsed |