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US4391982A Expired / Lapsed US ⏱️ 0.0 years remaining

Intermediates for the production of picropodophyllin and related compounds and processes for the preparation and use thereof

Assignee: University of Rochester
•
Filing: 1981-03-25
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Granted: 1983-07-05
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Expires: 2001-03-25
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Abstract

Abstract The present invention provides compounds having the structure: ##STR1## wherein R 1 represents alkoxy or aralkoxy, R 2 represents hydrogen, alkoxy, aralkoxy, alkyl, aralkyl, or R 1 and R 2 taken together represent the group --O--CH 2 --O--, R 3 represents hydrogen, alkyl, aralkyl, acyl or a protecting group, Y represents Cl, Br, I or a leaving group; and X represents Cl, Br or I. The present invention also provides a process for preparation of compounds VI in a single step wherein X and Y are the same and represent Cl, Br, ,or I, and R 3 is as previously defined except that in this instance, it does not represent a protecting group. According to another aspect of the present invention there are provided compounds VII-a and VII-b having the structure: ##STR2## wherein R 1 , R 2 and R 3 are as previously defined, j is an integer having a value of 0 or 1, Z 1 represents a non-reacting electron withdrawing group, and Z 2 represents a non-reacting electron withdrawing group or hydrogen, R 8 and R 9 are the same or different and represent hydrogen, alkyl, aralkyl, alkoxy, or aralkoxy, and R 7 represents hydrogen, alkyl, aralkyl or acyl. Compounds VII-a may be prepared from compounds VI through the use of the process of "insertion-cyclization" which is provided by another aspect of the present invention. According to a further aspect of the present invention, compounds VII-a are converted into tetralone III-a shown below: ##STR3## wherein R 1 , R 2 , R 3 , Z 1 , Z 2 , R 7 , R 8 and R 9 are as previously defined. Certain of these compounds can, in turn, be readily converted into picropodophyllin and picrosikkimotoxin. The latter can be converted into known antineoplastic agents by known procedures.

Inventors

  • 👤 Andrew S. Kende
  • 👤 Dennis P. Curran
  • 👤 Margaret L. King
  • 👤 Neil A. Feldstein

Bibliographic Details

Application Number —
Jurisdiction US
Data Source google_patents
Last Synchronized 2026-10-29 20:47
CPC Classifications
C; C07; C07D; C07D493/00; C07D493/02; C07D493/04; C07D317/00; C07D317/08; C07D317/44; C07D317/46; C07D317/48; C07D317/50; C07D317/62; C07D317/70; Y; Y02; Y02P; Y02P20/00; Y02P20/50; Y02P20/55

Claims Analysis

Total Claims: 13
Claim 1
Independent Claim 203 words
A process for the preparation of a compound of the formula: ##STR23## wherein; R 1 represents alkoxy or aralkoxy, R 2 represents hydrogen, alkoxy, aralkoxy, alkyl, or aralkyl, or R 1 and R 2 taken together represent the group --O--CH 2 --O--, j is an integer having a value of 0 or 1, R 3 represents hydrogen, alkyl, aralkyl, acyl or a protecting group, Z 1 represents a non-reacting electron withdrawing group which can be readily converted to a carboxyl group, Z 2 represents a non-reacting electron withdrawing group which can be readily converted to a carboxyl group or hydrogen, and R 10 represents hydrogen, alkyl, aryl, substituted aryl, or aralkyl; which comprises treating a compound of the formula: ##STR24## wherein: R 1 , R 2 , R 3 and j are as previously defined, Y represents Cl, Br, I or a leaving group, and X represents Cl, Br or I; (A) initially with an alkyl lithium at a temperature of less than -40° C., and (B) thereafter with a compound of the formula: ##STR25## wherein: Z 1 , Z 2 and R 10 are as previously defined, followed by warming to a temperature of between about 0° C. and about 120° C.
Claim 2
Dependent Claim 203 words
A process for the preparation of a compound of the formula: ##STR23## wherein; R 1 represents alkoxy or aralkoxy, R 2 represents hydrogen, alkoxy, aralkoxy, alkyl, or aralkyl, or R 1 and R 2 taken together represent the group --O--CH 2 --O--, j is an integer having a value of 0 or 1, R 3 represents hydrogen, alkyl, aralkyl, acyl or a protecting group, Z 1 represents a non-reacting electron withdrawing group which can be readily converted to a carboxyl group, Z 2 represents a non-reacting electron withdrawing group which can be readily converted to a carboxyl group or hydrogen, and R 10 represents hydrogen, alkyl, aryl, substituted aryl, or aralkyl; which comprises treating a compound of the formula: ##STR24## wherein: R 1 , R 2 , R 3 and j are as previously defined, Y represents Cl, Br, I or a leaving group, and X represents Cl, Br or I; (A) initially with an alkyl lithium at a temperature of less than -40° C., and (B) thereafter with a compound of the formula: ##STR25## wherein: Z 1 , Z 2 and R 10 are as previously defined, followed by warming to a temperature of between about 0° C. and about 120° C.
Claim 3
Dependent Claim 12 words
The process of claim 1, wherein j has a value of 1.
Claim 4
Dependent Claim 13 words
The process of claim 2, wherein said alkyl lithium is a tertiary-alkyl lithium.
Claim 5
Dependent Claim 33 words
The process of claim 3, wherein Z 1 represents COOR 5 and Z 2 represents COOR 6 wherein R 5 and R 6 are the same or different and represent alkyl or aralkyl.
Claim 6
Dependent Claim 44 words
The process of claim 4, wherein R 10 represents a radical of the formula: ##STR26## wherein; R 7 represents hydrogen, alkyl, aralkyl or acyl, and R 8 and R 9 are the same or different and represent hydrogen, alkyl, aralkyl, alkoxy, aralkoxy, or acyl.
Claim 7
Dependent Claim 23 words
The process of claim 5, wherein R 3 , R 5 and R 6 are the same or different and represent lower alkyl.
Claim 8
Dependent Claim 14 words
The process of claim 6, wherein R 1 and R 2 each represent methoxy.
Claim 9
Dependent Claim 19 words
The process of claim 6, wherein R 1 and R 2 taken together represent the group --O--CH 2 --O--.
Claim 10
Dependent Claim 19 words
The process of claim 8, wherein R 7 represents methyl and R 8 and R 9 each represent methoxy.
Claim 11
Dependent Claim 19 words
The process of claim 9, wherein R 3 represents methyl and R 5 and R 6 each represent ethyl.
Claim 12
Dependent Claim 36 words
The process of claim 10 wherein said reaction is initiated at a temperature of less than -78° C. and the reaction mixture is thereafter slowly warmed to a temperature between about 40° C. and 90° C.
Claim 13
Dependent Claim 17 words
The process of claim 10 wherein said reaction is initiated at a temperature of about -100° C.

References Cited (Backward Citations)

US2507473A Cited
US2658910A Cited

USPTO Annuity & Maintenance Windows

Annuity Stage Window Opens Payment Deadline Surcharge Period Until Estimated Fee Status
3.5 Years (Year 4) 1986-07-04 1987-01-03 1987-07-05 $2000.00 Window Closed / Lapsed
7.5 Years (Year 8) 1990-07-04 1991-01-03 1991-07-05 $3760.00 Window Closed / Lapsed
11.5 Years (Year 12) 1994-07-04 1995-01-03 1995-07-05 $7700.00 Window Closed / Lapsed

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