US4950770A
Expired / Lapsed
US
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Psoralens aminomethylation
Assignee: Elder Pharmaceuticals Inc
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Filing: 1988-07-14
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Granted: 1990-08-21
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Expires: 2008-07-14
Abstract
Abstract A direct, acid-catalyzed substitution reaction incorporates an N-phthalimidomethyl group on the 4' or 5' carbon of a psoralen in yields of 60-80% via the condensation of an N-hydroxymethylamide or phthalimide (e.g. N-hydroxymethylphthalimide) and an appropriately substituted psoralen. The phthalimide moiety is cleaved from the psoralen ring by treatment with hydrazine to give 60 to 70% yields of the aminomethylpsoralens.
Inventors
- 👤 Ned D. Heindel
- 👤 Mridula D. Choudhuri
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-03 15:09
CPC Classifications
C; C07; C07D; C07D493/00; C07D493/02; C07D493/04
Claims Analysis
Total Claims: 15
Claim 1
Independent Claim
119 words
A process for introducing the aminomethyl moiety (CH 2 NH 2 ) onto the furan ring of a psoralen or furocoumarin ring structure, said psoralen or furocoumarin ring structure being unsubstituted or substituted with a lower alkyl group at the C-4 position, said process consisting of: (1) reacting under anhydrous conditions, a mixture of a psoralen or furocoumarin and an aminomethylating agent selected from the group consisting of N-hydroxymethylphthalimide, N-hydroxymethylbenzamide, N-hydroxymethylacetamide, and N-N'-dimethyl-N-hydroxymethylurea suspended or dissolved in an anhydrous polar solvent with a strong protonic acid, Lewis acid or mixture of such acids, and (2) separating the aminomethylated psoralen or furocoumarin by hydrazine cleavage in hydrazine hydrate and ethanol to produce a 4' or 5' aminomethyl psoralen or furocoumarin.
Claim 2
Dependent Claim
119 words
A process for introducing the aminomethyl moiety (CH 2 NH 2 ) onto the furan ring of a psoralen or furocoumarin ring structure, said psoralen or furocoumarin ring structure being unsubstituted or substituted with a lower alkyl group at the C-4 position, said process consisting of: (1) reacting under anhydrous conditions, a mixture of a psoralen or furocoumarin and an aminomethylating agent selected from the group consisting of N-hydroxymethylphthalimide, N-hydroxymethylbenzamide, N-hydroxymethylacetamide, and N-N'-dimethyl-N-hydroxymethylurea suspended or dissolved in an anhydrous polar solvent with a strong protonic acid, Lewis acid or mixture of such acids, and (2) separating the aminomethylated psoralen or furocoumarin by hydrazine cleavage in hydrazine hydrate and ethanol to produce a 4' or 5' aminomethyl psoralen or furocoumarin.
Claim 3
Dependent Claim
28 words
The process of claim 1 wherein said lower alkyl substituted psoralen is selected from the group consisting of 4,5',8-trimethylpsoralen; 4,4',8-trimethylpsoralen; 4',8-dimethyl-8-ethylpsoralen; 4'-ethyl-4,8-dimethylpsoralen; 5',8-dimethylpsoralen; 4,5'-dimethyl-8-n-propylpsoralen, 4',8-dimethyl-4-m-psopylpsoralen; 4,5'-dimethylpsoralen; and 4-methyl-8-n-propylpsoralen.
Claim 4
Dependent Claim
25 words
The process of claim 1 wherein said anhydrous polar solvent is selected from the group consisting of chloroform, methylene chloride, acetic acid and formic acid.
Claim 5
Dependent Claim
33 words
The process of claim 1 wherein said protonic or Lewis acid is selected from the group consisting of trifluoroacetic acid, methane sulfonic acid, trifluoromethane sulfonic acid, boron trifluoride etherate and fuming sulfuric acid.
Claim 6
Dependent Claim
23 words
The process of claim 1 wherein Step (1) of the reaction sequence is carried out in the temperature range of about 10°-22° C.
Claim 7
Dependent Claim
23 words
The process of claim 1 wherein the relative quantity of said aminomethylating agent is no more than about 20-45% greater than said psoralen.
Claim 8
Dependent Claim
58 words
A process for introducing the aminomethyl moiety (--CH 2 NH 2 ) onto psoralen which consist of: (1) reacting, under anhydrous conditions, a mixture of 4,4',8-trimethylpsoralen and N-hydroxymethylphthalimide suspended in methylene chloride treated to dropwise addition of trifluoromethanesulfonic acid dissolved in trifluoroacetic acid, and (2) cleaving the resulting 5'-N-phthalimidomethyl-4,4',8-trimethylpsoralen in hydrazine hydrate and 95% ethanol to yield 5'-aminomethyl-4,4',8-trimethylpsoralen.
Claim 9
Dependent Claim
58 words
A process for introducing the aminomethyl moiety (--CH 2 NH 2 ) onto psoralen which consist of: (1) reacting, under anhydrous conditions, a mixture of 4,4',8-trimethylpsoralen and N-hydroxymethylphthalimide suspended in methylene chloride treated to dropwise addition of trifluoromethanesulfonic acid dissolved in trifluoroacetic acid, and (2) cleaving the resulting 5'-N-phthalimidomethyl-4,4',8-trimethylpsoralen in hydrazine hydrate and 95% ethanol to yield 5'-aminomethyl-4,4',8-trimethylpsoralen.
Claim 10
Dependent Claim
58 words
A process for introducing the aminomethyl moiety (--CH 2 NH 2 ) onto psoralen which consist of: (1) reacting, under anhydrous conditions, a mixture of 4,5',8-trimethylpsoralen and N-hydroxymethylphthalimide suspended in methylene chloride treated to dropwise addition of trifluoromethane sulfonic acid and trifluoroacetic acid, and (2) cleaving the resulting 4'-N-phthalimidomethyl-4,5',8-trimethylpsoralen in hydrazine hydrate and 95% ethanol to yield 4'-aminomethyl-4,5',8-trimethylpsoralen.
Claim 11
Dependent Claim
58 words
A process for introducing the aminomethyl moiety (--CH 2 NH 2 ) onto psoralen which consist of: (1) reacting, under anhydrous conditions, a mixture of 4,5',8-trimethylpsoralen and N-hydroxymethylphthalimide suspended in methylene chloride treated to dropwise addition of trifluoromethane sulfonic acid and trifluoroacetic acid, and (2) cleaving the resulting 4'-N-phthalimidomethyl-4,5',8-trimethylpsoralen in hydrazine hydrate and 95% ethanol to yield 4'-aminomethyl-4,5',8-trimethylpsoralen.
Claim 12
Dependent Claim
57 words
A process for introducing the aminomethyl moiety (--CH 2 NH 2 ) onto psoralen which consist of: (1) reacting, under anhydrous conditions, a mixture of 4,4'-dimethylpsoralen and N-hydroxymethylphthalimide suspended in methylene chloride treated to dropwise addition of trifluoromethanesulfonic acid and trifluoroacetic acid, and (2) cleaving the resulting 5'-N-phthalimidomethyl-4,4'-dimethylpsoralen in hydrazine hydrate and 95% ethanol to yield 5'-aminomethyl-4,4'-dimethylpsoralen.
Claim 13
Dependent Claim
57 words
A process for introducing the aminomethyl moiety (--CH 2 NH 2 ) onto psoralen which consist of: (1) reacting, under anhydrous conditions, a mixture of 4,4'-dimethylpsoralen and N-hydroxymethylphthalimide suspended in methylene chloride treated to dropwise addition of trifluoromethanesulfonic acid and trifluoroacetic acid, and (2) cleaving the resulting 5'-N-phthalimidomethyl-4,4'-dimethylpsoralen in hydrazine hydrate and 95% ethanol to yield 5'-aminomethyl-4,4'-dimethylpsoralen.
Claim 14
Dependent Claim
57 words
A process for introducing the aminomethyl moiety (--CH 2 NH 2 ) onto psoralen which consist of: (1) reacting, under anhydrous conditions, a mixture of 4'-methylpsoralen and N-hydroxymethylphthalimide suspended in methylene chloride treated to dropwise addition of trifluoromethanesulfonic acid and trifluoroacetic acid, and (2) cleaving the resulting 5'-N-phthalimidomethyl-4'-methylpsoralen in hydrazine hydrate and 95% ethanol to yield 5'-aminomethyl-4'-methylpsoralen.
Claim 15
Dependent Claim
57 words
A process for introducing the aminomethyl moiety (--CH 2 NH 2 ) onto psoralen which consist of: (1) reacting, under anhydrous conditions, a mixture of 4'-methylpsoralen and N-hydroxymethylphthalimide suspended in methylene chloride treated to dropwise addition of trifluoromethanesulfonic acid and trifluoroacetic acid, and (2) cleaving the resulting 5'-N-phthalimidomethyl-4'-methylpsoralen in hydrazine hydrate and 95% ethanol to yield 5'-aminomethyl-4'-methylpsoralen.
References Cited (Backward Citations)
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| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
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