Commercially viable synthesis of cantharidin and bioactive cantharidin derivatives

Abstract

The present disclosure provides methods for synthesizing cantharidin and cantharidin derivatives.

1 . A method for generating a cantharidin formulation comprising cantharidin or a cantharidin derivative, the method comprising reacting a precursor of said cantharidin or cantharidin derivative to form said cantharidin formulation having said cantharidin or cantharidin derivative at an exo-to-endo ratio of at least 6:1. 
     
     
         2 - 8 . (canceled) 
     
     
         9 . The method of  claim 1 , wherein said reacting is conducted at a pressure less than about 100 atm. 
     
     
         10 - 12 . (canceled) 
     
     
         13 . The method of  claim 1 , wherein said precursor is selected from compound of formula (1), (2) or (3): 
       
         
           
           
               
               
           
         
       
     
     
         14 . A method for generating a cantharidin formulation comprising cantharidin or a cantharidin derivative, the method comprising reacting a precursor of said cantharidin or cantharidin derivative to form said cantharidin formulation having said cantharidin or cantharidin derivative, wherein said reacting is conducted (i) in the absence of diethyl ether, (ii) in the absence of a lithium or magnesium salt, and (iii) at a pressure less than about 980 atmospheres (atm). 
     
     
         15 - 21 . (canceled) 
     
     
         22 . The method of  claim 14 , wherein said reacting is conducted with the aid of a catalyst. 
     
     
         23 - 24 . (canceled) 
     
     
         25 . The method of  claim 22 , wherein said catalyst comprises bis(cyclopentadienyl)zirconium(IV) bis(trifluoromethanesulfonate)tetrahydrofuran complex. 
     
     
         26 . The method of  claim 22 , wherein said catalyst comprises aluminum chloride. 
     
     
         27 - 29 . (canceled) 
     
     
         30 . A cantharidin formulation comprising (i) cantharidin or a cantharidin derivative, (ii) less than 0.1% diethyl ether and (iii) less than 0.1% lithium salt, wherein said cantharidin or cantharidin derivative is at an exo-to-endo ratio of at least 6:1. 
     
     
         31 - 36 . (canceled) 
     
     
         37 . A cantharidin formulation comprising (i) cantharidin or a cantharidin derivative and (ii) a Lewis catalyst comprising one or more Lewis metals selected from the group consisting of Li (I), Mg (II), B (III), Al (III), Ti (IV), Zr (IV), Zn (II), Cu(I), Cu (II), Sn (II), Sn(IV), Si (IV), La (III), Sc (III), Yb (III), Eu (III), Ga (III), Sb (V), Nb (V), Fe (III), and Co (III), wherein said one or more Lewis metals are at concentration of at least about 1 part per billion (ppb). 
     
     
         38 - 40 . (canceled) 
     
     
         41 . A process for preparing cantharidin or a derivative thereof, comprising:
 a) providing a first compound of formula (1):   
       
         
           
           
               
               
           
         
         b) forming a second compound having formula (2) from said first compound: 
       
       
         
           
           
               
               
           
         
         c) performing a cycloaddition reaction on said second compound to yield a third compound having formula (3): 
       
       
         
           
           
               
               
           
         
       
       and
 d) generating said cantharidin or derivative thereof from said third compound. 
 
     
     
         42 - 71 . (canceled) 
     
     
         72 . The process of  claim 41  further comprising:
 a) providing a first compound of formula (1): 
 
       
         
           
           
               
               
           
         
         b) forming a second compound having formula (2): 
       
       
         
           
           
               
               
           
         
         from said first compound by subjecting said first compound to a hydrolysis reaction that is performed using NaOH. 
       
     
     
         73 . The process of  claim 41 , comprising:
 a) providing a first compound of formula (1):   
       
         
           
           
               
               
           
         
       
       and
 b) forming a second compound having formula (2): 
 
       
         
           
           
               
               
           
         
         from said first compound by subjecting said first compound to a dehydration reaction that includes exposing said compound of formula (1) to an acyl halide. 
       
     
     
         74 - 80 . (canceled) 
     
     
         81 . A process for preparing cantharidin, comprising:
 a) providing a first compound that is selected from any one of:   
       
         
           
           
               
               
           
         
       
       and
 b) generating said cantharidin from said first compound by subjecting said first compound to a reduction reaction that includes hydrogenation and desulfurization reactions performed using separate reducing agents, wherein said desulfurization reaction is performed using a reducing agent selected from Table 2 that is not Raney Nickel. 
 
     
     
         82 - 83 . (canceled) 
     
     
         84 . A process, comprising:
 a) providing a compound of formula (1) or (2):   
       
         
           
           
               
               
           
         
       
       and
 b) forming a compound having a structure selected from the group consisting of 
 
       
         
           
           
               
               
           
         
         from said compound of formula (1) or (2) by subjecting said compound of formula (1) or (2) to an oxidation reaction. 
       
     
     
         85 . (canceled) 
     
     
         86 . A process, comprising:
 a) providing a compound having a structure selected from the group consisting of   
       
         
           
           
               
               
           
         
       
       and
 b) forming a compound having a structure selected from the group consisting of 
 
       
         
           
           
               
               
           
         
         from said compound provided in (a) by subjecting said compound provided in (a) to an oxidation reaction. 
       
     
     
         87 . (canceled) 
     
     
         88 . A composition having a structure selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         89 . A pharmaceutically acceptable mixture having a composition that is selected from any one of: 
       
         
           
           
               
               
           
         
       
     
     
         90 . A method of treating a subject, comprising administering to said subject a therapeutically effective amount of said pharmaceutically acceptable mixture according to  claim 88 . 
     
     
         91 . The method of  claim 90 , wherein said therapeutically effective amount is effective to treat Acral fibrokeratoma, Acrodermatitus enterpathica, Acrokeratoelastoidosis, Actinic keratosis (solar keratoses), Adenoma sebaceum, Angiokeratoma, Atopic Dermatitis, Basal cell carcinoma, Benign fibrous histiocytomas, Bladder cancer, Bowen's disease, Breast cancer, Buschke-Ollendorff syndrome, Cervical cancer, Cervical dysplasia, Cherry angiomas, Chondrodermatitis nodularis chronica helicis, Common warts, Cutaneous endometriosis, Cutaneous Leukemia, Cutaneous Lymphoma, Cutaneous meningioma, Cutaneous myxoma, Darier's disease, Dermal dendrocyte hamartoma, dermatofibroma, Dermatofibrosarcoma protuberans, Eccrine angiomatous hamartoma, Ectodermal dysplasia, Epidermal inclusion cysts, Epidermal Naevi, Epithelioid cell histiocytoma, Familial myxovascular fibromas, Fungal skin disease, Granular cell tumor, Glucaonoma syndrome, Genital warts, Ichthyosis, Idiopathic guttate hypomelanosis, Infantile acropustulosis, Infantile fibromatosis, Kaposi's sarcoma, Keloid, Keratoacanthoma, Keratocyst, Knuckle pads, Lentigo, Melanoma, Microvenular hemangioma, Molluscum contagiousum, Morton's neuroma, Multifocal lymphangioendotheliomatosis, Multinucleate cell angiohistocytoma, Multiple cutaneous leiomyomas, Mycosis fungoides, Neuroma cutis, Neurothekeoma, Nevus flammeus, Nevus lipomatosus superficialis, Pachydermodactyly, Palisaded encapsulated neuroma, Parasitic skin diseases, Pityriasis ruba pilaris, Piloleiomyomas, Plantar warts, Plexiform fibrohistiocytic tumor, Porokeratotic eccrine ostial and Dermal duct nevus, Progressive nodular histiocytoma Psoriasis, Porokeratosis, Seborrhoeic dermatitis, Seborrhoeic keratosis, Rhinophyma, Solitary cutaneous leiomyoma, Spider angioma, Targetoid hemosiderotic hemangioma, Squamous cell carcinoma, Tufted angioma, Venous lake, Urticaria pigmentosa, Xanthelasmoidal mastocytosis, Zosteriform metastasis, Benign epidermal cysts, Birthmarks, Calluses, Corns, Eczema, Freckles, Moles, Pigmentation disorders, Drug induced hyperpigmentation, Dyschromatosis symmetrica hereditaria, Dyschromatosis universalis hereditaria, Familial progressive hyperpigmentation, Galli-Galli disease, Hemosiderin hyperpigmentation, Idiopathic guttate hypomelanosis, Iron metallic discoloration, leukoderma, Melasma, Mukamel syndrome, Necklace of Venus, Nevus anemicus, Nevus depigmentosus, Pallister-Killian syndrome, Phylloid hypomelanosis, Piebaldism, Pigmentatio reticularis faciei et colli, Pilar Cysts, Pityriasis alba, Poikiloderma of Civatte, Poikiloderma vasculare atrophicans, Postinflammatory hyperpigmentation, Progressive macular hypomelanosis, Pruritus, Reticular pigmented anomaly of the flexures, Reticulate acropigmentation of Kitamura, Riehl melanosis, Shah-Waardenburg syndrome, Shiitake mushroom dermatitis, Tar melanosis, Titanium metallic discoloration, Transient neonatal pustular melanosis, Vagabond's leukomelanoderma, Vasospastic macules, Wende-Bauckus syndrome, X-linked reticulate pigmentary disorder, Yemenite deaf-blind hypopigmentation syndrome, Scars, Skin tags, Tattoo removal or Vitiligo.