Sapphyrins, derivatives and syntheses

• US 5,302,714 A
• Filed: 10/26/1992
• Issued: 04/12/1994
• Est. Priority Date: 12/21/1989
• Status: Expired due to Fees

• Current Assignee: Board of Regents of the University of Texas System (University of Texas System)
• Original Assignee: Board of Regents of the University of Texas System (University of Texas System)
• Inventors: Cyr, Michael J., Sessler, Jonathan L.
• Primary Examiner(s): Shah, Mukund J.
• Assistant Examiner(s): GUPTA, YOGENDRA N
• Application Number:
  US07/966,317
• Time in Patent Office: 533 Days
• Field of Search: 540/469, 540/472, 534/560, 548/518
• US Class Current: 540/472
• CPC Class Codes: A61K 41/0076 PDT with expanded (metallo)porphyrins, i.e. having more than 20 ring atoms, e.g. texaphyrins, sapphyrins, hexaphyrins, pentaphyrins, porphocyanines
• CPC Class Codes: A61K 47/54 the modifying agent being an organic compound
• CPC Class Codes: A61K 47/546 Porphyrines; Porphyrine with an expanded ring system, e.g. texaphyrine
• CPC Class Codes: A61K 47/558 the modifying agent being a chemiluminescent acceptor
• CPC Class Codes: C07D 487/22 in which the condensed system contains four or more hetero rings
• CPC Class Codes: C07H 15/26 Acyclic or carbocyclic radicals, substituted by hetero rings
• CPC Class Codes: C07H 21/00 Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
• CPC Class Codes: C12N 15/101 by chromatography, e.g. electrophoresis, ion-exchange, reverse phase

Abstract

The present invention involves, in addition to many unique substituted sapphyrins, a novel method for synthesizing sapphyrins with good efficiency and high yield. An improved 9-step synthesis of substituted sapphyrins, e.g., the two C₂ symmetric sapphyrins, compounds 2 and 4 of FIG. 1C, is described herein. This synthesis involves as an important step the condensation between a tripyrrane diacid and a diformyl bipyrrole. The key tripyrrane component is prepared in three high-yield steps from readily available pyrrolic precursors and the bipyrrole portion is prepared in four steps from ethyl 3-methyl-4-methylpyrrole-2-carboxylate in roughly 33% yield overall.

Claims

1. A method for synthesizing sapphyrins comprising the steps of:

(A) reacting an alkyl derivative_a aldehyde and an n-nitromethylenealkyl derivative_b to produce beta-hydroxynitroalkyl derivative_c ;

(B) reacting the beta-hydroxynitroalkyl derivative_c with acetic anhydride to form beta-acetoxynitroalkyl derivative_c ;

(C) reacting the beta-acetoxynitroalkyl derivative_c with ethyl isocyanoacetate in the presence of a nonnucleophilic base to form ethyl 3-alkyl derivative_a -4-alkyl derivative_b pyrrole-2-carboxylate;

(D) reacting ethyl 3-alkyl derivative_a -4-alkyl derivative_b pyrrole-2-carboxylate with iodine and iodide to form ethyl 3-alkyl derivative_a -4-alkyl derivative_b -5-iodopyrrole-2-carboxylate;

(E) coupling two molecular equivalents of ethyl 3-alkyl derivative_a -4-alkyl derivative_b -5-iodo-pyrrole-2-carboxylate in the presence of copper bronze and heat to produce diethyl 4,4'"'"'-dialkyl derivative_a -3,3'"'"'-dialkyl derivative_b -2,2'"'"'-bipyrrole-5,5'"'"'-dicarboxylate;

(F) converting diethyl 4,4'"'"'-dialkyl derivative_a -3,3'"'"'-dialkyl derivative_b -2,2'"'"'-bipyrrole-5,5'"'"'-dicarboxylate to 4,4'"'"'-dialkyl derivative_a -3,3'"'"'-dialkyl derivative_b -2,2'"'"'-bipyrrole by saponification and decarboxylation;

(G) reacting 4,4'"'"'-dialkyl derivative_a -3,3'"'"'-dialkyl derivative_b -2,2'"'"'-bipyrrole with dimethylformamide and phosphorus oxychloride to form 4,4'"'"'-dialkyl derivative_a -5,5'"'"'-diformyl-3,3'"'"'-dialkyl derivative_b -2,2'"'"'-bipyrrole;

(H) treating benzyl 4-alkyl derivative_d -3,5-dimethylpyrrole-2-carboxylate with an oxidizing agent to produce benzyl 5-(X-methyl)-4-alkyl derivative_d -3-methylpyrrole-2-carboxylate;

(I) condensing two molecular equivalents of benzyl 5-(X-methyl)-4-alkyl derivative_d -3-methylpyrrole-2-carboxylate with 3-alkyl derivative_e -4-alkyl derivative_f pyrrole under acidic conditions to produce 2,5-bis(5-benzyloxycarbonyl-3-alkyl derivative_d -4-methylpyrrol-2-ylmethyl)-3-alkyl derivative_e -4-alkyl derivative_f pyrrole;

(J) hydrogenating 2,5-bis(5-benzyloxycarbonyl-3-alkyl derivative_d -4-methylpyrrol-2-ylmethyl)-3-alkyl derivative_e -4-alkyl derivative_f pyrrole to produce 2,5-bis(5-carboxy-3-alkyl derivative_d -4-methylpyrrol-2-ylmethyl)-3-alkyl derivative_e -4-alkyl derivative_f pyrrole; and

(K) condensing 4,4'"'"'-dialkyl derivative_a -5,5'"'"'-diformyl-3,3'"'"'-dialkyl derivative_b -2,2'"'"'-bipyrrole with 2,5-bis(5-carboxy-3-alkyl derivative_d -4-methylpyrrol-2-ylmethyl)-3-alkyl derivative_e -4-alkyl derivative_f pyrrole under acidic oxidizing conditions to produce a 2,23-dialkyl derivative_b -3,22-dialkyl derivative_a -7,18-dimethyl-8,17-dialkyl derivative_d -12-alkyl derivative_e -13-alkyl derivative_f sapphyrin;

wherein alkyl derivative_a, alkyl derivative_b, alkyl derivative_c, alkyl derivative_d, alkyl derivative_e and alkyl derivative_f are independently alkane, functionalized alkane, derivatized alkane or derivatized functional alkane and x is a substituent capable of leaving as an anionically stable moiety.

2. The method of claim 1 wherein the functionalized alkane is an alkane with one or more chemically reactive amino, hydroxyl, carboxyl, carbonyl, cyanate, isocyanate, thiocyanate, sulfhydryl, nitrile, diazo, iodide, disulfide or sulfonic substituents;

and when the chemically reactive substituent is isocyanate, thiocyanate, or diazo, said substituent is formed from a carboxyl substituent after step K.

3. The method of claim 1 wherein the derivatized alkane is an alkane with an alkenyl, alkynyl, cycloalkyl or halide (other than iodide) substituent.

4. The method of claim 1 wherein the derivatized functional alkane is an amide, ester, ether or disulfide.

5. A method for producing an alkyl substituted sapphyrin, the method comprising:

(A) reacting propionaldehyde and nitroethane to produce 4-nitro-3-pentanol;

(B) reacting 4-nitro-3-pentanol with acetic anhydride to form 3-acetoxy-2-nitropentane;

(C) reacting 3-acetoxy-2-nitropentane with ethyl isocyanoacetate in the presence of a nonnucleophilic base to form ethyl 3-ethyl-4-methylpyrrole-2-carboxylate;

(D) reacting ethyl 3-ethyl-4-methylpyrrole-2-carboxylate with iodine and iodide to form ethyl 3-ethyl-5-iodo-4-methylpyrrole-2-carboxylate;

(E) coupling two molecular equivalents of ethyl 3-ethyl-5-iodo-4-methylpyrrole-2-carboxylate in the presence of copper-bronze and heat to produce diethyl 4,4'"'"'-diethyl-3,3'"'"'-dimethyl-2,2'"'"'-bipyrrole-5,5'"'"'-dicarboxylate;

(F) converting diethyl 4,4'"'"'-diethyl-3,3'"'"'-dimethyl-2,2'"'"'-bipyrrole-5,5'"'"'-dicarboxylate to 4,4'"'"'-diethyl-3,3'"'"'-dimethyl-2,2'"'"'-bipyrrole by saponification and decarboxylation;

(G) reacting 4,4'"'"'-diethyl-3,3'"'"'-dimethyl-2,2'"'"'-bipyrrole with dimethylformamide and phosphorus oxychloride to form 4,4'"'"'-diethyl-5,5'"'"'-diformyl-3,3'"'"'-dimethyl-2,2'"'"'-bipyrrole;

(H) condensing 3,4-diethylpyrrole with two molecular equivalents of benzyl 5-(acetoxymethyl)-4-ethyl-3-methylpyrrole-2-carboxylate to produce 2,5-bis(5-benzyloxycarbonyl-3-ethyl-4-methylpyrrol-2-ylmethyl)-3,4-diethylpyrrole;

(I) hydrogenating 2,5-bis(5-benzyloxycarbonyl-3-ethyl-4-methylpyrrol-2-ylmethyl)-3,4-diethylpyrrole to produce 2,5-bis(5-carboxy-3-ethyl-4-methylpyrrol-2-ylmethyl)-3,4-diethylpyrrole; and

(J) condensing 4,4'"'"'-diethyl-5,5'"'"'-diformyl-3,3'"'"'-dimethyl-2,2'"'"'-bipyrrole and 2,5-bis(5-carboxy-3-ethyl-4-methylpyrrol-2-ylmethyl)-3,4-diethyl-pyrrole under acidic oxidizing conditions to produce 3,8,12,13,17,22-hexaethyl-2,7,18,23-tetramethylsapphyrin.

6. A method for producing a carboxy substituted sapphyrin, the method comprising:

(A) reacting propionaldehyde and nitroethane to produce 4-nitro-3-pentanol;

(B) reacting 4-nitro-3-pentanol with acetic anhydride to form 3-acetoxy-2-nitropentane;

(C) reacting 3-acetoxy-2-nitropentane with ethyl isocyanoacetate in the presence of a nonnucleophilic base to form ethyl 3-ethyl-4-methylpyrrole-2-carboxylate;

(D) reacting ethyl 3-ethyl-4-methylpyrrole-2-carboxylate with iodine and iodide to form ethyl 3-ethyl-5-iodo-4-methylpyrrole-2-carboxylate;

(E) coupling two molecular equivalents of ethyl 3-ethyl-5-iodo-4-methylpyrrole-2-carboxylate in the presence of copper bronze and heat to produce diethyl 4,4'"'"'-diethyl-3,3'"'"'-dimethyl-2,2'"'"'-bipyrrole-5,5'"'"'-dicarboxylate;

(F) converting diethyl 4,4'"'"'-diethyl-3,3'"'"'-dimethyl-2,2'"'"'-bipyrrole-5,5'"'"'-dicarboxylate to 4,4'"'"'-diethyl-3,3'"'"'-dimethyl-2,2'"'"'-bipyrrole by saponification and decarboxylation;

(G) reacting 4,4'"'"'-diethyl-3,3'"'"'-dimethyl-2,2'"'"'-bipyrrole with dimethylformamide and phosphorus oxychloride to form 4,4'"'"'-diethyl-5,5'"'"'-diformyl-3,3'"'"'-dimethyl-2,2'"'"'-bipyrrole;

(H) reacting benzyl 4-ethoxycarboxylmethyl-3,5-dimethylpyrrole-2-carboxylate with lead tetraacetate to produce benzyl 5-(acetoxymethyl)-4-ethoxycarbonylmethyl-3-methylpyrrole-2-carboxylate;

(I) condensing 3,4-diethylpyrrole with two molecular equivalents of benzyl 5-(acetoxymethyl)-3-ethoxycarbonylmethyl-4-methylpyrrole-2-carboxylate under acidic conditions to produce 2,5-bis(5-benzyloxycarbonyl-3-ethoxycarbonylmethyl-4-methylpyrrol-2-ylmethyl)-3,4-diethylpyrrole;

(J) hydrogenating 2,5-bis(5-benzyloxycarbonyl-3-ethoxycarbonylmethyl-4-methylpyrrol-2-ylmethyl)-3,4-diethylpyrrole to produce 2,5-bis(5-carboxy-3-ethoxycarbonylmethyl-4-methylpyrrol-2-ylmethyl)-3,4-diethylpyrrole;

(K)

(a) condensing 4,4'"'"'-diethyl-5,5'"'"'-diformyl-3,3'"'"'-dimethyl-2,2'"'"'-bipyrrole and 2,5-bis(5-carboxy-3-ethoxycarbonylmethyl-4-methylpyrrol-2-ylmethyl)-3,4-diethylpyrrole under acidic oxidizing conditions to produce 3,12,13,22-tetraethyl-8,17-di(ethoxycarbonylmethyl)-2,7,19,23-tetramethylsapphyrin; and

(b) producing 3,12,13,22-tetraethyl-8,17-di(ethoxycarbonylmethyl)-2,7,18,23-tetramethylsapphyrin as described in step (K) (a) and saponifying it to produce 3,12,13,22-tetraethyl-8,17-di(carboxymethyl)-2,7,18,23-tetramethylsapphyrin;

or

(c) producing 3,12,13,22-tetraethyl-8,17-di(ethoxycarbonylmethyl)-2,7,18,23-tetramethylsapphyrin as described in step (K) (a) and partially saponifying it to produce 3,12,13,22-tetraethyl-8-(ethoxy-carbonylmethyl)-17-(carboxymethyl)-2,17,18,23-tetramethylsapphyrin.

7. A method for synthesizing dioxosapphyrins comprising the steps of:

(A) reacting benzyl 4-alkyl derivative_d -3,5-dimethylpyrrole-2-carboxylate with an oxidizing agent to produce benzyl 5-(X-methyl)-4-alkyl derivative_d -3-methylpyrrole-2-carboxylate;

(B) condensing two molecular equivalents of benzyl 5-(X-methyl)-4-alkyl derivative_d -3-methylpyrrole-2-carboxylates with 3-alkyl derivative_e -4-alkyl derivative_f pyrrole under acidic conditions to produce 2,5 -bis(5-benzyloxycarbonyl-3-alkyl derivative_d -4-methylpyrrol-2-ylmethyl)-3-alkyl derivative_e -4-alkyl derivative_f pyrrole;

(C) hydrogenating 2,5-bis(5-benzyloxycarbonyl-3-alkyl derivative_d -4-methylpyrrol-2-ylmethyl)-3-alkyl derivative_e -4-alkyl derivative_f pyrrole to produce 2,5-bis(5-carboxy-3-alkyl derivative_d -4-methylpyrrol-2-ylmethyl)-3-alkyl derivative_e -4-alkyl derivative_f pyrrole; and

(D) reacting furfuraldehyde and palladium acetate to produce 5,5'"'"'-diformyl-2,2'"'"'-bifuran;

(E) condensing 5,5'"'"'-diformyl-2,2'"'"'-bifuran and 2,5-bis(5-carboxy-3-alkyl derivative_d -4-methylpyrrol-2-ylmethyl)-3-alkyl derivative_e -4-alkyl derivative_f pyrrole under acidic oxidizing conditions to produce 8,17-dialkyl derivative_d -12-alkyl derivative_e -13-alkyl derivative_f -7,18-dimethyldioxosapphyrin;

wherein alkyl derivative_d, alkyl derivative_e and alkyl derivative_f are independently alkane, functionalized alkane, derivatized alkane or derivatized functional alkane and X represents a substituent which may leave as an anionically stable moiety.

8. The method of claim 7 wherein the functionalized alkane is an alkane with one or more chemically reactive amino, hydroxyl, carboxyl, carbonyl, cyanate, isocyanate, thiocyanate, sulfhydryl, nitrile, diazo, iodide, disulfide or sulfonic substituents;

and when the chemically reactive substituent is isocyanate, thiocyanate, or diazo, said substituent is formed from a carboxyl substituent after step E.

9. The method of claim 7 wherein the derivatized alkane is an alkane with one or more alkenyl, alkynyl, cycloalkyl or halide (other than iodide) substituents.

10. The method of claim 7 wherein the derivatized functional alkane is one or more of an amide, ester, ether or disulfide substituent.