Commercially viable synthesis of cantharidin and biologically active cantharidin derivatives

Abstract

To provide methods for synthesizing cantharidin and cantharidin derivatives.SOLUTION: A method includes providing a first compound of formula (1) and subjecting the first compound to a cycloaddition reaction that includes exposing the first compound to furan and Lewis acid such as copper(II) trifluoromethanesulfonate, thereby forming a second compound of formula (2).SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 62 / 093,396, filed December 17, 2014, which is hereby incorporated by reference in its entirety. [Background technology]

[0002] Cantharidin (1,2-dimethyl-3,6-epoxyperhydrophthalic anhydride) is a lipophilic compound traditionally obtained primarily from the hemolymph of blister beetles of the Meloidae family. It is a colorless, odorless, crystalline solid at room temperature. It is an inhibitor of protein phosphatase 2A and has vesicant activity when applied to the skin. Due to its bioactivity, cantharidin has historically been used to treat various skin conditions, including the treatment of common warts and molluscum.

[0003] Chemical name: (3αR,4S,7R,7αS)-3α,7α-dimethylhexahydro-4,7-epoxyisobenzofuran-1,3-dione; 1,2-dimethyl-3,6-epoxyperhydrophthalic anhydride. Common names: cantharidin; cantharone; cantharidine; cantaridin. Structure: [ka] Summary of the Invention [Means for solving the problem]

[0004] The present disclosure provides methods for synthesizing cantharidin and cantharidin derivatives. The methods provided herein can enable the synthesis of cantharidin or cantharidin derivatives in a manner that can enable commercial-scale production and use of cantharidin or cantharidin derivatives, thereby advantageously minimizing or eliminating the use of blister beetles to obtain cantharidin or cantharidin derivatives.

[0005] One aspect of the present disclosure provides a method for producing a cantharidin preparation comprising cantharidin or a cantharidin derivative, the method comprising reacting precursors of the cantharidin or cantharidin derivative to form a cantharidin preparation having an exo-to-endo ratio of cantharidin or cantharidin derivative of at least 6:1.

[0006] In some embodiments of the aspects provided herein, the exo-to-endo ratio is at least 7:1. In some embodiments of the aspects provided herein, the exo-to-endo ratio is at least 8:1. In some embodiments of the aspects provided herein, the exo-to-endo ratio is at least 9:1. In some embodiments of the aspects provided herein, the exo-to-endo ratio is at least 10:1. In some embodiments of the aspects provided herein, the exo-to-endo ratio is at least 20:1. In some embodiments of the aspects provided herein, the exo-to-endo ratio is at least 100:1. In some embodiments of the aspects provided herein, the formulation comprises a cantharidin derivative. In some embodiments of the aspects provided herein, the reaction is carried out at a pressure of less than about 100 atm. In some embodiments of the aspects provided herein, the reaction is carried out at a pressure of less than about 10 atm. In some embodiments of the aspects provided herein, the precursor of cantharidin or a cantharidin derivative is converted to cantharidin or a cantharidin derivative with a yield of at least about 15%.In some embodiments of the aspects provided herein, the reaction is carried out at a temperature of less than about 50°C.In some embodiments of the aspects provided herein, the reaction is carried out in the absence of magnesium ions.In some embodiments of the aspects provided herein, the precursor is a compound of formula (1), (2), or (3): [ka] is selected from.

[0007] One aspect of the present disclosure provides a method for producing a cantharidin preparation containing cantharidin or a cantharidin derivative, the method comprising reacting precursors of cantharidin or a cantharidin derivative (wherein the reaction is carried out (i) in the absence of diethyl ether, (ii) in the absence of lithium or magnesium salts, and (iii) at a pressure of less than about 980 atmospheres (atm)) to form a cantharidin preparation having cantharidin or a cantharidin derivative.

[0008] In some embodiments of the aspects provided herein, the pressure is less than about 900 atm. In some embodiments of the aspects provided herein, the pressure is less than about 800 atm. In some embodiments of the aspects provided herein, the pressure is less than about 700 atm. In some embodiments of the aspects provided herein, the pressure is less than about 600 atm. In some embodiments of the aspects provided herein, the pressure is less than about 500 atm. In some embodiments of the aspects provided herein, the pressure is less than about 100 atm. In some embodiments of the aspects provided herein, the pressure is less than about 10 atm. In some embodiments of the aspects provided herein, the reaction is carried out with the aid of a catalyst. In some embodiments of the aspects provided herein, the catalyst comprises a Lewis acid catalyst. In some embodiments of the aspects provided herein, the catalyst comprises zirconium(IV). In some embodiments of the aspects provided herein, the catalyst comprises bis(cyclopentadienyl)zirconium(IV) bis(trifluoromethanesulfonate)tetrahydrofuran complex. In some embodiments of the aspects provided herein, the catalyst comprises aluminum chloride. In some embodiments of the aspects provided herein, the catalyst comprises boron trifluoride-diethyl ether. In some embodiments of the aspects provided herein, the precursor of cantharidin or a cantharidin derivative is converted to cantharidin or a cantharidin derivative in at least about 75% yield. In some embodiments of the aspects provided herein, the reaction is carried out at a temperature of less than about 50°C. In some embodiments of the aspects provided herein, the reaction is carried out in the absence of magnesium ions.

[0009] One aspect of the present disclosure provides a cantharidin formulation comprising: (i) cantharidin or a cantharidin derivative (wherein the cantharidin or cantharidin derivative is in an exo-to-endo ratio of at least 6:1); (ii) less than 0.1% diethyl ether; and (iii) less than 0.1% lithium salt.

[0010] In some embodiments of the aspects provided herein, the exo-to-endo ratio is at least 7:1. In some embodiments of the aspects provided herein, the exo-to-endo ratio is at least 8:1. In some embodiments of the aspects provided herein, the exo-to-endo ratio is at least 9:1. In some embodiments of the aspects provided herein, the exo-to-endo ratio is at least 10:1. In some embodiments of the aspects provided herein, the exo-to-endo ratio is at least 20:1. In some embodiments of the aspects provided herein, the exo-to-endo ratio is at least 100:1. In some embodiments of the aspects provided herein, the cantharidin formulation comprises diethyl ether. The cantharidin formulation comprises a lithium salt.

[0011] One aspect of the present disclosure provides 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 the one or more Lewis metals are at a concentration of at least about parts per billion (ppb).

[0012] In some embodiments of the aspects provided herein, the cantharidin or cantharidin derivative has an exo-to-endo ratio of at least 6:1. In some embodiments of the aspects provided herein, the Lewis catalyst comprises Zr(IV). In some embodiments of the aspects provided herein, the Lewis catalyst comprises bis(cyclopentadienyl)zirconium(IV)·bis(trifluoromethanesulfonate)tetrahydrofuran complex.

[0013] One aspect of the present disclosure is a process for preparing cantharidin or a derivative thereof, comprising: (a) reacting a first compound of formula (1): [ka] and (b) from the first compound, a second compound having formula (2): [ka] and forming (c) performing a cycloaddition reaction on the second compound to form a third compound having formula (3): [ka] and (d) producing cantharidin or a derivative thereof from the third compound; The present invention provides a process including:

[0014] In some embodiments of the aspects provided herein, the cantharidin or derivative thereof is pharmaceutically acceptable. In some embodiments of the aspects provided herein, (a) is a fourth compound having formula (4): [ka] producing a first compound from In some embodiments of the aspects provided herein, the process includes producing a fifth compound having formula (5): [ka] and producing a fourth compound from the In some embodiments of the aspects provided herein, the process includes producing a sixth compound having formula (6): [ka] and producing a fifth compound from the In some embodiments of the aspects provided herein, the process further comprises obtaining a seventh compound having formula (7): [ka] and producing a sixth compound from the In some embodiments of the aspects provided herein, the process further comprises producing an eighth compound having formula (8): Na2S (8) and producing a sixth compound from the In some embodiments of the aspects provided herein, the process includes producing a ninth compound having formula (9): [ka] and producing a fourth compound from the In some embodiments of the aspects provided herein, (b) comprises subjecting the first compound to a dehydration reaction. In some embodiments of the aspects provided herein, the dehydration reaction comprises exposing the first compound to an acyl halide. In some embodiments of the aspects provided herein, the acyl halide is acetyl chloride. In some embodiments of the aspects provided herein, (c) comprises exposing the second compound to at least one Lewis acid. In some embodiments of the aspects provided herein, the at least one Lewis acid is selected from Table 1. In some embodiments of the aspects provided herein, the at least one Lewis acid contains a Lewis metal 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). In some embodiments of the aspects provided herein, the at least one Lewis acid is selected from magnesium perchlorate, aluminum chloride, lithium trifluoromethanesulfonate, tin(II) trifluoromethanesulfonate, bis(cyclopentadienyl)zirconium(IV) bis(trifluoromethanesulfonate)tetrahydrofuran complex, bis(cyclopentadienyl)titanium(IV) bis(trifluoromethanesulfonate), boron trifluoride diethyl etherate, and gallium(III) chloride. In some embodiments of the aspects provided herein, the at least one Lewis acid is selected from copper(II) tetrafluoroborate hydrate, aluminum bromide, niobium(V) chloride, ytterbium(III) trifluoromethanesulfonate, scandium(III) trifluoromethanesulfonate, magnesium trifluoromethanesulfonate, trimethylsilyl trifluoromethanesulfonate, and copper(II) trifluoromethanesulfonate. In some embodiments of the aspects provided herein, (c) comprises reacting the second compound with furan. In some embodiments of the aspects provided herein, (d) comprises subjecting the third compound to a reduction reaction.In some embodiments of the aspects provided herein, the reduction reaction comprises a hydrogenation and desulfurization reaction carried out using a single reducing agent. In some embodiments of the aspects provided herein, the single reducing agent is Raney nickel. In some embodiments of the aspects provided herein, the reduction reaction comprises a hydrogenation and desulfurization reaction carried out using separate reducing agents. In some embodiments of the aspects provided herein, the hydrogenation reaction is carried out using Pd / C, Pd, PdCl, PtO, or Pt / C. In some embodiments of the aspects provided herein, the desulfurization reaction is carried out using a reducing agent selected from Table 2. In some embodiments of the aspects provided herein, the reducing agent is Raney nickel. In some embodiments of the aspects provided herein, the reduction reaction produces a tenth compound having formula (10): [ka] This includes a hydrogenation reaction to obtain In some embodiments of the aspects provided herein, the hydrogenation reaction is carried out using Pd / C, Pd, PdCl, PtO, or Pt / C. In some embodiments of the aspects provided herein, the process further comprises subjecting the tenth compound to an oxidation reaction. In some embodiments of the aspects provided herein, the oxidation reaction is carried out using at least one oxidizing agent selected from Table 3. In some embodiments of the aspects provided herein, (d) comprises subjecting the third compound to an oxidation reaction. In some embodiments of the aspects provided herein, the oxidation reaction is carried out using at least one oxidizing agent selected from Table 3. In some embodiments of the aspects provided herein, the derivative is selected from the following: [ka] is selected from the group consisting of:

[0015] One aspect of the present disclosure provides a process that includes: (a) a first compound of formula (1): [ka] and (b) preparing a second compound having the formula (2) from the first compound by subjecting the first compound to a hydrolysis reaction carried out using NaOH: [ka] To form.

[0016] One aspect of the present disclosure provides a process that includes: (a) a first compound of formula (1): [ka] and (b) preparing a second compound having formula (2) from the first compound by subjecting the first compound to a dehydration reaction comprising exposing the compound of formula (1) to an acyl halide: [ka] To form.

[0017] In some embodiments of the aspects provided herein, the acyl halide is acetyl chloride.

[0018] One aspect of the present disclosure provides a process that includes: (a) a first compound of formula (1): [ka] (Wherein, X is S, O, CH2, CHR 1 , C.R. 1 R 2 , N.H., N.R. 1 , and N.R. 1 R 2 wherein R 1 and R 2are each independently selected from alkyl, aryl, heteroaryl, alkoxy, amine, alcohol, and halogen, or together are carbonyl, alkenyl, imine, or oxime, wherein said R 1 and R 2 are each optionally independently substituted) and providing; (b) From the first compound, the first compound is converted into a compound selected from the group consisting of magnesium perchlorate, aluminum chloride, lithium trifluoromethanesulfonate, tin(II) trifluoromethanesulfonate, bis(cyclopentadienyl)zirconium(IV) bis(trifluoromethanesulfonate)tetrahydrofuran complex, bis(cyclopentadienyl)titanium(IV) bis(trifluoromethanesulfonate), boron trifluoride diethyl etherate, gallium(III) chloride, and copper tetrafluoroborate. and (II) hydrate, aluminum bromide, niobium(V) chloride, ytterbium(III) trifluoromethanesulfonate, scandium(III) trifluoromethanesulfonate, magnesium trifluoromethanesulfonate, trimethylsilyl trifluoromethanesulfonate, and copper(II) trifluoromethanesulfonate to form a second compound having the formula (2): [ka] (Wherein, X is S, O, CH2, CHR 1 , C.R. 1 R 2 , N.H., N.R. 1 , and N.R. 1 R 2 wherein R 1 and R 2 are each independently selected from alkyl, aryl, heteroaryl, alkoxy, amine, alcohol, and halogen, or together are carbonyl, alkenyl, imine, or oxime, where R 1 and R 2are each optionally independently substituted) To form.

[0019] In some embodiments of the aspects provided herein, the at least one Lewis acid contains a Lewis metal 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). In some embodiments of the aspects provided herein, the at least one Lewis acid is selected from magnesium perchlorate, aluminum chloride, lithium trifluoromethanesulfonate, tin(II) trifluoromethanesulfonate, bis(cyclopentadienyl)zirconium(IV) bis(trifluoromethanesulfonate)tetrahydrofuran complex, bis(cyclopentadienyl)titanium(IV) bis(trifluoromethanesulfonate), boron trifluoride diethyl etherate, and gallium(III) chloride. In some embodiments of the aspects provided herein, the at least one Lewis acid is selected from copper(II) tetrafluoroborate hydrate, aluminum bromide, niobium(V) chloride, ytterbium(III) trifluoromethanesulfonate, scandium(III) trifluoromethanesulfonate, magnesium trifluoromethanesulfonate, trimethylsilyl trifluoromethanesulfonate, and copper(II) trifluoromethanesulfonate. In some embodiments of the aspects provided herein, X is S. In some embodiments of the aspects provided herein, the cycloaddition reaction comprises reacting a first compound with a furan.

[0020] One aspect of the present disclosure provides a process for preparing cantharidin, comprising: (a) providing a first compound selected from any one of the following: [ka] (b) Producing cantharidin from the first compound by subjecting the first compound to a reduction reaction comprising hydrogenation and desulfurization reactions carried out using separate reducing agents, wherein the desulfurization reaction is carried out using a reducing agent selected from Table 2 that is not Raney nickel.

[0021] In some embodiments of the aspects provided herein, the hydrogenation reaction is carried out using Pd / C, Pd, PdCl, PtO, or Pt / C. In some embodiments of the aspects provided herein, the first compound is [ka] Includes:

[0022] One aspect of the present disclosure provides a process that includes: (a) a compound of formula (1) or (2): [ka] and (b) from a compound of formula (1) or (2), by subjecting the compound of formula (1) or (2) to an oxidation reaction, [ka] forming a compound having a structure selected from the group consisting of:

[0023] In some embodiments of the aspects provided herein, the oxidation reaction is carried out using at least one oxidizing agent selected from Table 3.

[0024] One aspect of the present disclosure provides a process that includes: (a) or less [ka] providing a compound having a structure selected from the group consisting of: (b) from the compound provided in (a), by subjecting the compound provided in (a) to an oxidation reaction, [ka] forming a compound having a structure selected from the group consisting of:

[0025] In some embodiments of the aspects provided herein, the oxidation reaction is carried out using at least one oxidizing agent selected from Table 3.

[0026] One aspect of the present disclosure is a method for producing a method for manufacturing a semiconductor device comprising: [ka] The present invention provides a composition having a structure selected from the group consisting of:

[0027] One aspect of the present disclosure is a method for producing a method for manufacturing a semiconductor device comprising: [ka] The present invention provides a pharmaceutically acceptable mixture having a composition selected from any of the following:

[0028] One aspect of the present disclosure provides a method of treating a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutically acceptable mixture according to an embodiment provided herein.

[0029] In some embodiments of the aspects provided herein, the therapeutically effective amount is selected from the group consisting of acral fibrokeratoma, acrodermatitis enteropathica, acral keratoelastoid, actinic keratosis (solar keratosis), adenoma sebaceum, angiokeratoma, atopic dermatitis, basal cell carcinoma, benign fibrous histiocytoma, bladder cancer, Bowen's disease, breast cancer, Buschke-Ollendorff syndrome, cervical cancer, cervical dysplasia, senile hemangioma, chronic nodular chondrodermatitis helicalis, common warts, cutaneous endometriosis, leukemia cutis, cutaneous lymphoma, cutaneous meningioma, cutaneous myxoma, Darier's disease, dermal dendrocyte hamartoma, dermatofibroma, dermatofibrosarcoma protuberans, eccrine angiomatous hamartoma, and cutaneous dermatofibroma. hamartoma, ectodermal dysplasia, epidermal inclusion cyst, epidermal nevus, epithelioid cell histiocytoma, familial myxovascular fibromas, dermatomycosis, granular cell tumor, glucagonoma syndrome, genital warts, ichthyosis, idiopathic guttate hypomelanosis, acropustulosis of childhood, childhood fibromatosis, Kaposi's sarcoma, keloid, keratoacanthoma, keratocyst, digital nodule, lentigo, melanoma, venular hemangioma, molluscum contagiosum, Morton's neuroma, multifocal lymphangioendotheliomatosis, multinucleate cell angiohistiocytoma angiohistocytoma), multiple cutaneous leiomyomas, mycosis fungoides, cutaneous neuromas, nerve capsules, fibrillar nevi, superficial lipomatous nevi, pachydermodactyly, palisaded encapsulated neuroma), skin parasitosis, pityriasis pilaris, Piloleiomyomas, plantar warts, Plexiform fibrohistiocytic tumor, Porokeratotic eccrine ostial and dermal duct nevus, Progressive nodularhistiocytoma, psoriasis, porokeratosis, seborrheic dermatitis, seborrheic keratosis, rhinophyma, solitary cutaneous leiomyoma, spider angiomas, targetoid hemosiderotic hemangioma, squamous cell carcinoma, tufted angiomas, venous lakes, pigmented urticaria, xanthelasmoidal mastocytosis, zosteriform metastasis, benign epidermal cysts, birthmarks, calluses, corns, eczema, freckles, lentigines, dyschromatosis, drug-induced hyperpigmentation, hereditary symmetrical dyschromatosis, hereditary generalized dyschromatosis, familial progressive hyperpigmentation, Galli-Galli disease, hemosiderin hyperpigmentation, idiopathic guttate hypomelanosis, iron metallic discoloration discoloration, vitiligo, melasma, Mukamel syndrome, Necklace of Venus, anemic nevus, depigmented nevus, Pallister-Killian syndrome, phylloid achromatopsia pigmentosa, focal albinism, facial and neck reticular pigmentation (Pigmentatio reticularis faciei et colli), hair cyst, pityriasis alba, poikiloderma siva, vascular poikiloderma, post-inflammatory hyperpigmentation, progressive macular achromatopsia pigmentosa, pruritus, flexural reticular dyspigmentation, reticulate acropigmentation of Kitamura, Lille melanosis, Shah-Waardenburg syndrome, Shiitake mushroom dermatitis dermatitis, Tar melanosis, Titanium metallic discoloration, Transient pustular melanosis of the newborn, Vagabond's vitiligo, Vasospastic macule, Wende-Bauckus syndrome, X-linked reticulate pigmentary disorderIt is effective in treating Yemeni hearing and visual impairment hypopigmentation syndrome, scars, skin tags, tattoo removal, or vitiligo.

[0030] Additional aspects and advantages of the present disclosure will become readily apparent to those skilled in the art from the following detailed description, in which merely illustrative embodiments of the present disclosure are shown and described. As will be recognized, the present disclosure is capable of other and different embodiments, and its several details are capable of modification in various obvious respects without departing from the present disclosure. Accordingly, the drawings and description are to be regarded as illustrative in nature, and not as restrictive.

[0031] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

[0032] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings or figures. [Brief explanation of the drawings]

[0033] [Figure 1] 1 shows an exemplary 1H NMR analysis of the reaction product using aluminum chloride. [Figure 2A] 1 shows an exemplary 1H NMR analysis of the reaction product using bis(cyclopentadienyl)zirconium triflate-THF complex in the presence of Me3Al. [Figure 2B] 1 shows an exemplary 1H NMR analysis of the reaction product using bis(cyclopentadienyl)zirconium triflate-THF complex in the absence of Me3Al. DETAILED DESCRIPTION OF THE INVENTION

[0034] While various embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous changes, modifications, and substitutions may occur to those skilled in the art without departing from the invention. It will be understood that various alternatives to the embodiments of the invention described herein may be employed.

[0035] The term " pharmaceutically acceptable salts " as used herein generally refers to salts derived from various organic and inorganic counterions well known in the art, and includes, by way of example only, base addition salts and acid addition salts.Base addition salts can be formed when a compound contains an acidic moiety.Acid addition salts can be formed when a compound contains a basic moiety.Examples of base addition salts include alkali metal salts, such as sodium, potassium, and lithium salts; alkaline earth metal salts, such as calcium and magnesium salts; ammonium salts, such as ammonium and tetraalkylammonium salts; salts with organic bases such as triethylamine, morpholine, piperidine, and dicyclohexylamine; and salts with basic amino acids such as arginine and lysine. Examples of acid addition salts may include salts of organic or inorganic acids, such as hydrochloride, hydrobromide, sulfate, nitrate, formate, acetate, benzoate, maleate, fumarate, succinate, tartrate, citrate, oxalate, methanesulfonate, toluenesulfonate, aspartate, glutamate, etc. In compounds with two or more basic moieties, the two or more basic moieties may be converted into salt forms, including, but not limited to, bis- or tris-salts. Alternatively, compounds with two or more basic moieties may form a salt with only one of these basic moieties. Pharmaceutically acceptable salts may also include salts of the parent compound with one or more amino acids. Any of the amino acids listed above, including the naturally occurring amino acids that can be found as protein components, may be suitable, but amino acids generally have side chains with, optionally, basic or acidic groups (e.g., lysine, arginine, or glutamic acid) or neutral groups (such as glycine, serine, threonine, alanine, isoleucine, or leucine).

[0036] The term "Lewis acid," as used herein, generally refers to a chemical species capable of accepting electrons or reacting with a Lewis base to form a Lewis adduct. Non-limiting examples of Lewis acids include protons, acidic compounds, metal cations, metal complexes, trigonal planar species, species with empty or partially filled atomic or molecular orbitals, and electron-deficient π-systems. Lewis acids can include Lewis metals.

[0037] The term "aryl" (Ar), as used herein, generally refers to a polyvalent unsaturated aromatic hydrocarbon substituent, which may be a single ring or multiple rings that may be fused together or covalently linked, and which may be optionally substituted. Non-limiting examples of aryl groups include phenyl, naphthyl, and biphenyl.

[0038] The term "heteroaryl," as used herein, generally refers to a polyunsaturated aromatic ring having at least one heteroatom (nitrogen, oxygen, or sulfur) within its cyclic chain. Heteroaryl groups can be single rings or multiple rings that may be fused together or covalently linked, and can be optionally substituted. Non-limiting examples of heteroaryl groups include pyrrole, pyrazole, imidazole, pyridine, pyrazine, pyrimidine, furan, thiphene, oxazole, isoxazole, purine, benzimidazole, quinoline, isoquinoline, indole, benzothiophene, and the like. When a heteroaryl group, as defined herein, is substituted, a substituent may be attached to a ring carbon atom or to a ring heteroatom (i.e., nitrogen, oxygen, or sulfur) of the heteroaryl group having a valence that allows for substitution.

[0039] The term "alkyl," as used herein, by itself or as part of another substituent, generally refers to a straight-chain, branched-chain, or cyclic hydrocarbon that may be saturated, monounsaturated, or polyunsaturated and may be optionally substituted. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, pentyl, hexyl, and the like. When an alkyl group, as defined herein, is substituted, the substituent may be bonded to a carbon atom of the alkyl group. Non-limiting examples of substituted alkyl groups include haloalkanes, primary amines, secondary amines, tertiary amines, quaternary ammonium cations, cyclic amines, ethers, alcohols, carbonyls, imines, and oximes.

[0040] The term "alkoxy," as used herein by itself or as part of another substituent, generally refers to the group O-alkyl, O-aryl, or O-heteroaryl, where alkyl includes straight-chain, branched, or cyclic alkyl groups, as defined above.

[0041] The term "halogen," as used herein, generally refers to fluorine, chlorine, bromine, and iodine.

[0042] The term "halide," as used herein, generally refers to fluoride, chloride, bromide, and iodide.

[0043] The chemical synthesis of cantharidin can be challenging. Early reported syntheses can be time-consuming, low-productivity processes, involve potentially dangerous working conditions, or be commercially impractical. Some recent cantharidin syntheses have fewer steps and improved yields, but can require extreme reaction conditions or the use of dangerous reagents.

[0044] In 1928, German chemist Von Bruchhausen attempted to synthesize cantharidin. See von Bruchhausen, F.; Bersch, II. W. Arch. Pharm. Ber. Disch. Phurm. Ges. 1928, 266, 697-702, which is incorporated herein by reference in its entirety. His synthetic approach was based on the following retrosynthetic analysis: [ka]

[0045] Unfortunately, the Diels-Alder reaction between the two reactants leads to an unfavorable equilibrium for the product. As demonstrated in the following experiment, when natural cantharidin is dehydrogenated, it spontaneously undergoes a retro-Diels-Alder reaction. [ka]

[0046] Studies have shown that the instability of the Diels-Alder product is due to repulsion between the methyl groups on C1 and C2, as well as between the methyl groups on C4 and C5 and the endo hydrogens.

[0047] Stork published the synthesis of cantharidin in 1951. See Stork, G.; et al. J. Am. Chem. Soc. 1951, 73, 4501, which is incorporated herein by reference in its entirety, and Stork, G.; van Tamelen, EE; Friedman, LI; Burgstahler, AWJ Am. Chem. Soc. 1953, 75, 384, which is incorporated herein by reference in its entirety. This synthesis would not be economically feasible. It is a time-consuming, linear, multi-step, and low-yield process. On a large scale, this process may require the use of hazardous reagents that are expensive and may result in worker injury, as well as have unacceptable environmental disposal issues.

[0048] In 1953, Schenck published a Diels-Alder-based approach to cantharidin. See Schenck, G.; Wirtz, R. Naturwissenshaften 1953, 40, 531, incorporated herein by reference in its entirety. However, this still suffers from many of the problems noted above, including a lengthy, low-yielding, linear, multi-step synthesis. Its use on a manufacturing scale would require the large-scale use of toxic bromine and the disposal of environmentally harmful waste streams of brominated by-products.

[0049] In 1976, Dauben began exploring extremely high-pressure conditions for synthesizing cantharidin. See Dauben, WG; Kessel, CR; Takemura, KHJ Am. Chem. Soc. 1980, 102, 6893-6894, which are incorporated herein by reference in their entirety, and Dauben, WG; Krabbenhoft, II. OJ Am. Chem. Soc. 1976, 98, 1992-1993, which are incorporated herein by reference in their entirety. While this synthesis requires fewer steps to prepare cantharidin in excellent yield, the extremely high pressures of 4 to 15 kilobars (kbar) required to successfully complete the Diels-Alder reaction would be dangerous for commercial-scale production. This process would be economically unattractive if performed in multiple small batches. This step may also require a significant capital investment in exotic hydraulic high-pressure production equipment and protective containment housing to ensure worker and party safety. [ka]

[0050] In 1990, Grieco demonstrated that the addition of 5 molar (M) lithium perchlorate (diethyl ether solution) could accelerate the Diels-Alder reaction reported by Dauben at ambient temperature and pressure, rather than the extremely high pressures described above. See Grieco, PA et al. J. Am. Chem. Soc. 1990, 112, 4595-4596, incorporated herein by reference in its entirety. Grieco noted that this process could be useful for the synthesis of cantharidin. The relatively high yield and relatively high exo-to-endo Diels-Alder product ratio from this reaction make this an attractive synthetic route for the large-scale production of cantharidin. Unfortunately, lithium perchlorate is a high-energy oxidizing agent that can form explosion-sensitive or highly explosive mixtures when combined with organic materials. Furthermore, diethyl ether is a highly volatile and flammable solvent. This reaction mixture of high-energy oxidizing agents and easily ignitable solvents can be dangerous even under controlled, small-scale conditions. Furthermore, perchlorate ions can be considered a serious environmental pollutant, especially when released into groundwater. Perchlorate can have adverse effects on human health, particularly targeting iodine metabolism in the thyroid gland. This combination of serious safety and environmental impact issues related to this synthesis makes its use unviable as a process for the commercial production of cantharidin. However, the principles of this process remain attractive for a commercial process using this short-term synthetic strategy. [ka]

[0051] Subsequent work by Handy in 1995 demonstrated that solutions of lithium trifluoromethanesulfonimide in diethyl ether or acetone also gave excellent yields of the Diels-Alder adduct. See Handy, ST; Grieco, PA; Mineur, C.; Ghosez, L.; Synlett 1995, 565-567, incorporated herein by reference in its entirety. Unfortunately, this modification to the Grieco synthesis exhibits a significant reduction in the exo-endo Diels-Alder product ratio. The exo-endo product can be difficult to separate, resulting in significant loss of the desired product required for subsequent conversion to cantharidin. Such losses at such a late stage in the synthesis can be detrimental to production costs and the ultimate profitability of the drug. Additionally, controlling the increased amount of endo by-products in the product stream can increase production regulation and quality control burdens, as well as waste disposal costs.

[0052] Despite these advances in cantharidin synthesis, there is a lack of safe, simple, scalable and efficient synthesis of cantharidin on a manufacturing scale.The present inventors have devised a complete synthetic process that can be used to produce cantharidin and cantharidin analogues and derivatives that may be bioactive on a commercial scale, starting from available reagents, and provides cantharidin under mild conditions.

[0053] The present disclosure provides methods for synthesizing cantharidin and cantharidin derivatives. The methods provided herein can enable the synthesis of cantharidin or cantharidin derivatives in a manner that can enable commercial-scale production and use of cantharidin or cantharidin derivatives.

[0054] The method of the present disclosure can provide a synthesis of cantharidin or cantharidin derivatives without using diethyl ether or compounds containing diethyl ether (e.g., elastic collodion). Diethyl ether can be a highly volatile and flammable solvent, and its use in manufacturing sites can lead to potentially unsafe and even explosive reaction conditions.

[0055] The method of the present disclosure can provide for the synthesis of cantharidin or cantharidin derivatives without using a lithium salt catalyst. Lithium salts, such as lithium perchlorate or lithium trifluoromethanesulfonimide, which can be high-energy oxidizing agents, can form explosion-sensitive or highly explosive mixtures when combined with organic materials.

[0056] The disclosed methods can provide for the synthesis of cantharidin or cantharidin derivatives with low or no magnesium content, for example, cantharidin or cantharidin derivatives with less than about 30%, 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1%, 0.1%, 0.01%, 0.001%, or 0% magnesium ions.

[0057] The methods of the present disclosure can provide for the synthesis of cantharidin formulations containing residual amounts of catalysts, such as Lewis acid catalysts or other catalysts discussed herein, including, but not limited to, 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). Such catalytic materials may be present in cantharidin formulations at levels of at least about 1 part per trillion (ppt), 2 ppt, 3 ppt, 4 ppt, 5 ppt, 6 ppt, 7 ppt, 8 ppt, 9 ppt, 10 ppt, 20 ppt, 30 ppt, 40 ppt, 50 ppt, 60 ppt, 70 ppt, 80 ppt, 90 ppt, 100 ppt, 200 ppt, 300 ppt, 400 ppt t, 500ppt, 600ppt, 700ppt, 800ppt, 900ppt, parts per billion (ppb), 2ppb, 3ppb, 4ppb, 5ppb, 6ppb, 7ppb, 8ppb, 9ppb, 10ppb, 20ppb, 30ppb, 40ppb, 50ppb, 60ppb, 70ppb, 80ppb, 90ppb, 100ppb, 200ppb, 3 00ppb, 400ppb, 500ppb, 600ppb, 700ppb, 800ppb, 900ppb, parts per million (ppm), 2ppm, 3ppm, 4ppm, 5ppm, 6ppm, 7ppm, 8ppm, 9ppm, 10ppm, 20ppm, 30ppm, 40ppm, 50ppm, 60ppm, 70ppm, 80ppm, 90ppm, 100 It may be present at concentrations of ppm, 200 ppm, 300 ppm, 400 ppm, 500 ppm, 600 ppm, 700 ppm, 800 ppm, 900 ppm, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or more.These catalytic materials may be present in cantharidin formulations at concentrations up to approximately 1 part per trillion (ppt), 2 ppt, 3 ppt, 4 ppt, 5 ppt, 6 ppt, 7 ppt, 8 ppt, 9 ppt, 10 ppt, 20 ppt, 30 ppt, 40 ppt, 50 ppt, 60 ppt, 70 ppt, 80 ppt, 90 ppt, 100 ppt, 200 ppt, 300 ppt, 400 ppt t, 500ppt, 600ppt, 700ppt, 800ppt, 900ppt, parts per billion (ppb), 2ppb, 3ppb, 4ppb, 5ppb, 6ppb, 7ppb , 8ppb, 9ppb, 10ppb, 20ppb, 30ppb, 40ppb, 50ppb, 60ppb, 70ppb, 80ppb, 90ppb, 100ppb, 200ppb , 300ppb, 400ppb, 500ppb, 600ppb, 700ppb, 800ppb, 900ppb, parts per million (ppm), 2ppm, 3ppm, 4ppm, 5ppm, 6ppm, 7ppm, 8ppm, 9ppm, 10ppm, 20ppm, 30ppm, 40ppm, 50ppm, 60ppm, 70ppm, 80ppm, 90ppm , 100 ppm, 200 ppm, 300 ppm, 400 ppm, 500 ppm, 600 ppm, 700 ppm, 800 ppm, 900 ppm, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% concentration.

[0058] The disclosed method can provide for the synthesis of cantharidin or cantharidin derivatives without the use of high pressures. High pressures can be energy intensive to generate and maintain, can necessitate the use of more expensive equipment capable of withstanding such pressures, and can be potentially explosive or otherwise hazardous. The disclosed method can be used to synthesize cantharidin or cantharidin derivatives at pressures of about 1000 atmospheres (atm), 980 atm, 975 atm, 950 atm, 925 atm, 900 atm, 875 atm, 850 atm, 825 atm, 800 atm, 775 atm, 750 atm, 725 atm, 700 atm, 675 atm, 650 atm, 625 atm, 600 atm, 575 atm, 550 atm, 525 atm, 500 atm, 475 atm, 450 atm, 425 atm, 400 atm, 375 atm, 350 atm, 32 The synthesis of cantharidin or cantharidin derivatives can be provided at pressures of 5 atm, 300 atm, 275 atm, 250 atm, 225 atm, 200 atm, 175 atm, 150 atm, 125 atm, 100 atm, 75 atm, 50 atm, 45 atm, 40 atm, 35 atm, 30 atm, 25 atm, 20 atm, 15 atm, 10 atm, 9 atm, 8 atm, 7 atm, 6 atm, 5 atm, 4 atm, 3 atm, 2 atm, or 1 atm or less.

[0059] The disclosed method can provide for the synthesis of cantharidin or cantharidin derivatives without the use of high temperatures. High pressures can be energy intensive to produce and maintain, may require the use of more expensive equipment capable of withstanding such temperatures, and may be potentially dangerous. The disclosed method can provide for the synthesis of cantharidin or cantharidin derivatives at temperatures of about 500°C, 490°C, 480°C, 470°C, 460°C, 450°C, 440°C, 430°C, 420°C, 410°C, 400°C, 390°C, 380°C, 370°C, 360°C, 350°C, 340°C, 330°C, 320°C, 310°C, 300°C, 290°C, 280°C, 270°C, 260°C, 250°C, 240°C, 230°C, 220°C, 210°C, 200°C, 190°C, 18 ...40°C, 250°C, 260°C, 270°C, 280°C, 290°C, 280°C, 290°C, 280°C, 290°C, 280°C, 290°C, 290°C, 290°C, 280°C, 290°C The present invention can provide for the synthesis of cantharidin or cantharidin derivatives at temperatures below 100°C, 170°C, 160°C, 150°C, 140°C, 130°C, 120°C, 110°C, 100°C, 90°C, 80°C, 70°C, 60°C, 50°C, 40°C, 30°C, 20°C, 10°C, 0°C, -10°C, -20°C, -30°C, -40°C, -50°C, -60°C, -70°C, -80°C, -90°C, or -100°C. The disclosed method can be used to heat the refrigerated batteries at temperatures of about 500°C, 490°C, 480°C, 470°C, 460°C, 450°C, 440°C, 430°C, 420°C, 410°C, 400°C, 390°C, 380°C, 370°C, 360°C, 350°C, 340°C, 330°C, 320°C, 310°C, 300°C, 290°C, 280°C, 270°C, 260°C, 250°C, 240°C, 230°C, 220°C, 210°C, 200°C, 190°C, 180°C, 190°C, 200°C, 210°C, 220°C, 230°C, 240°C, 250°C, 260°C, 270°C, 280°C, 290°C, 280°C, 290°C, 280°C, 290°C, 260°C, 250°C, 240°C, 230°C, 220°C, 210°C, 200°C, 230°C, 240°C, 250°C, 260°C, 270°C, 280°C, 29 ... The present invention can provide for the synthesis of cantharidin or cantharidin derivatives at temperatures above 170°C, 160°C, 150°C, 140°C, 130°C, 120°C, 110°C, 100°C, 90°C, 80°C, 70°C, 60°C, 50°C, 40°C, 30°C, 20°C, 10°C, 0°C, -10°C, -20°C, -30°C, -40°C, -50°C, -60°C, -70°C, -80°C, -90°C, or -100°C or higher.The disclosed method can be used to heat the refrigerated product at temperatures of about 500°C, 490°C, 480°C, 470°C, 460°C, 450°C, 440°C, 430°C, 420°C, 410°C, 400°C, 390°C, 380°C, 370°C, 360°C, 350°C, 340°C, 330°C, 320°C, 310°C, 300°C, 290°C, 280°C, 270°C, 260°C, 250°C, 240°C, 230°C, 220°C, 210°C, 200°C, 190°C, 180°C, 190°C, 200°C, 210°C, 220°C, 230°C, 240°C, 250°C, 260°C, 270°C, 280°C, 290°C, 280°C, 290°C, 290°C, 260°C, 250°C, 240°C, 230°C, 220°C, 210°C, 200°C, 230°C, 240°C, 250°C, 260°C, 270°C, 280°C, 29 ... Synthesis of cantharidin or cantharidin derivatives at temperatures of 0°C, 170°C, 160°C, 150°C, 140°C, 130°C, 120°C, 110°C, 100°C, 90°C, 80°C, 70°C, 60°C, 50°C, 40°C, 30°C, 20°C, 10°C, 0°C, -10°C, -20°C, -30°C, -40°C, -50°C, -60°C, -70°C, -80°C, -90°C, or -100°C may be provided.

[0060] Methods for synthesizing cantharidin The process for preparing cantharidin or a derivative thereof includes providing compound (1) and producing compound (2) from compound (1). [ka]

[0061] Compound (2) can then be subjected to a cycloaddition reaction to obtain compound (3), from which cantharidin or a derivative thereof can be produced. [ka]

[0062] Cantharidin or its derivatives can be pharmaceutically acceptable.In some examples, cantharidin or its derivatives can be prescribed and / or administered to subject for example, for treating skin disorder, skin disease, dermatitis, contact dermatitis, skin cancer, precancerous lesion, skin infection, molluscum lesion or wart.Cantharidin or its derivatives are useful in treating a variety of skin conditions, including, but not limited to, acral fibrokeratoma, acrodermatitis enteropathica, acral keratoelastoid disease, actinic keratosis (solar keratosis), sebaceous adenoma, angiokeratoma, atopic dermatitis, basal cell carcinoma, benign fibrous histiocytoma, bladder cancer, Bowen's disease, breast cancer, Buschke-Ollendorff syndrome, cervical cancer, cervical dysplasia, senile hemangioma, chronic nodular chondrodermatitis helicarii, common warts, cutaneous endometriosis, leukemia cutis, cutaneous lymphoma, cutaneous meningioma, cutaneous myxoma, Darier's disease, dermal dendritic cell carcinoma, and dermal dendritic cells. Alveolar hamartoma, dermatofibroma, dermatofibrosarcoma protuberans, eccrine angiomatoid hamartoma, ectodermal dysplasia, epidermal inclusion cyst, epidermal nevi (including but not limited to sebaceous nevus, comedonal nevus, Proteus syndrome, Becker's nevus), epithelioid histiocytoma, familial myxoangiofibroma, dermatomycoses (including lobomycosis), granular cell tumor, glucagonoma syndrome, genital warts, ichthyosis (including but not limited to ichthyosis vulgaris, ichthyosis lamellar, X-linked ichthyosis, epidermolytic keratosis, acquired ichthyosis, and palmoplantar keratosis) plantaris), idiopathic guttate hypomelanosis, acropustulosis of childhood, childhood fibromatosis, Kaposi's sarcoma, keloid, keratoacanthoma, keratocyst, digital nodule, lentigo, melanoma, venular hemangioma, molluscum contagiosum, Morton's neuroma, multifocal lymphangioendotheliomatosis, multinucleated hemangiohistiocytoma, multiple cutaneous leiomyomas, mycosis fungoides, cutaneous neuroma, nerve cyst, nevus flametus, superficial lipomatous nevus, sclerodermactyly, encapsulated palisade neuroma, skin parasitosis (including but not limited to scabies, pediculosis, sand flea infection, hookworm-associated cutaneous larva migrans), pityriasis rubra pilaris, It can be used to treat a subject for conditions including arrector piloleiomyoma, plantar warts, fibrous fascicular histiocytoma, porokeratosis eccrine gland and duct nevus, progressive nodular histiocytoma, psoriasis (including but not limited to erythrodermic psoriasis, palmoplantar psoriasis, palmoplantar pustulosis, generalized pustular psoriasis of the Zumbusch type, geographic tongue), porokeratosis (including Mibelli porokeratosis), seborrheic dermatitis, seborrheic keratosis, rhinophyma, solitary cutaneous leiomyoma, spider angiomas, target hematoid angiomas, squamous cell carcinoma, tufted angiomas, venous lakes, urticaria pigmentosa, xanthomatous mastocytosis, or zosteriform metastases.Benign epidermal cysts, birthmarks, calluses, corns, eczema, freckles, lentigines, pigmentation disorders (drug-induced hyperpigmentation, hereditary symmetrical dyschromatosis, hereditary generalized dyschromatosis, familial progressive hyperpigmentation, Galli-Galli disease, hemosiderin hyperpigmentation, idiopathic guttate hypomelanosis, iron metallic discoloration, vitiligo, melasma, Mukamel syndrome, Venus necklace) Venus), anemic nevus, depigmented nevus, Pallister-Killian syndrome, phylloid achromatopsia pigmentosa, focal albinism, facial and neck reticular pigmentation, hair cyst, pityriasis alba, poikiloderma sibatta, vascular poikiloderma, post-inflammatory hyperpigmentation, progressive macular achromatopsia pigmentosa, pruritus, flexural reticular dyschromatosis, acropigmentation reticularis, Lille melanosis, Shah-Waalde Other conditions, including vitiligo (including, but not limited to, non-segmental vitiligo, segmental vitiligo, hairy vitiligo, quadrichrome vitiligo, and punctate vitiligo), can also be treated. Cantharidin or its derivatives can be prescribed and / or administered to a subject in a non-lethal dose. Cantharidin or its derivatives can be a pharmaceutically acceptable salt or cocrystal.

[0063] In some examples, compound (1) is produced from compound (4). [ka] This reaction can be carried out using tetrahydrofuran, water, or any mixture thereof as a solvent. This reaction can be carried out in the presence of sodium hydroxide, NaOH. The reaction time can be 30 seconds, 1 minute, 5 minutes, 10 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, or 5 hours or more. This reaction can occur at temperatures of 0°C, 10°C, 20°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, or 100°C or higher. This reaction can occur at room temperature or higher.

[0064] Compound (4) can be produced from compound (5). [ka] This reaction can be carried out in the presence of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU). This reaction can be carried out in the presence of dimethyl acetylenedicarboxylate, compound (6). [ka] The reaction time can be 30 seconds, 1 minute, 5 minutes, 10 minutes, or 30 minutes or more. The reaction temperature can be 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, 100°C, 110°C, 120°C, 130°C, 140°C, or 150°C or more.

[0065] Compound (5) can be produced from compound (7). [ka] This reaction can be carried out using dichloromethane (DCM) as a solvent. This reaction can be carried out in the presence of a peracid. The peracid can be metachloroperbenzoic acid (mCPBA). The reaction time can be 30 seconds, 1 minute, 5 minutes, 10 minutes, 30 minutes, or 1 hour or more. The reaction temperature can be 0°C, -10°C, -20°C, -30°C, -40°C, -50°C, -60°C, -70°C, -78°C, or -80°C or lower.

[0066] Compound (7) can be produced from compound (8). [ka] This reaction can be carried out using water as a solvent, and in the presence of sodium sulfide, i.e., compound (9), or its hydrate. Na2S (9) The reaction time can be 30 seconds, 1 minute, 5 minutes, 10 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, or 5 hours or more. The reaction can be refluxed.

[0067] Compound (7) can be produced from sodium sulfide, i.e., compound (9), or its hydrate. This reaction can be carried out using water as a solvent. This reaction can be carried out in the presence of compound (8). The reaction time can be 30 seconds, 1 minute, 5 minutes, 10 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, or 5 hours or more. The reaction can be refluxed.

[0068] Compound (4) can be produced from compound (6) and compound (5). This reaction can be carried out in the presence of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU). This reaction can be carried out in the presence of compound (5). The reaction time can be 30 seconds, 1 minute, 5 minutes, 10 minutes, or 30 minutes or more. The reaction temperature can be 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, 100°C, 110°C, 120°C, 130°C, 140°C, or 150°C or more.

[0069] In this process, compound (1) can undergo a dehydration reaction to form compound (2). The dehydration reaction can include exposing compound (1) to an acyl halide. The acyl halide can be an acyl chloride, acyl bromide, or acyl iodide. The acyl halide can be acetyl chloride. The acyl bromide can be acetyl bromide. The acyl iodide can be acetyl iodide. The reaction time can be 30 seconds, 1 minute, 5 minutes, 10 minutes, 30 minutes, or 1 hour or more. The reaction can be refluxed.

[0070] In this process, compound (2) and furan can be exposed to at least one Lewis acid to form compound (3). The at least one Lewis acid can contain a Lewis metal 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). The at least one Lewis acid can be selected from Table 1. The at least one Lewis acid may be selected from magnesium perchlorate, aluminum chloride, lithium trifluoromethanesulfonate, tin(II) trifluoromethanesulfonate, bis(cyclopentadienyl)zirconium(IV) bis(trifluoromethanesulfonate)tetrahydrofuran complex, bis(cyclopentadienyl)titanium(IV) bis(trifluoromethanesulfonate), boron trifluoride diethyl etherate, and gallium(III) chloride. The at least one Lewis acid may be selected from copper(II) tetrafluoroborate hydrate, aluminum bromide, niobium(V) chloride, ytterbium(III) trifluoromethanesulfonate, scandium(III) trifluoromethanesulfonate, magnesium trifluoromethanesulfonate, trimethylsilyl trifluoromethanesulfonate, and copper(II) trifluoromethanesulfonate. The concentration of the Lewis acid can be 0.01 molar (moles per liter, M), 0.02 M, 0.03 M, 0.04 M, 0.05 M, 0.06 M, 0.07 M, 0.08 M, 0.09 M, 0.1 M, 0.2 M, 0.3 M, 0.4 M, 0.5 M, 0.6 M, 0.7 M, 0.8 M, 0.9 M, 1 M, 2 M, 3 M, 4 M, 5 M, 6 M, 7 M, 8 M, 9 M, 10 M, 11 M, 12 M, 13 M, 14 M, 15 M, 16 M, 17 M, 18 M, 19 M, or 20 M or more. The reaction can be carried out in the presence of furan (e.g., in furan).The reaction can be carried out using acetone, toluene, benzene, xylene, chlorobenzene, methylene chloride, ethylene dichloride, dioxane, tetrahydrofuran (THF), tert-butyl methyl ether, diisopropyl ether, 1,2-dimethoxyethane (glyme), acetonitrile, ethyl acetate, isopropyl acetate, water, or mixtures thereof as a solvent. The reaction time can be 30 seconds, 1 minute, 5 minutes, 10 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 10 hours, 20 hours, 30 hours, 40 hours, 50 hours, 60 hours, 70 hours, 80 hours, 90 hours, or 100 hours or more. The reaction temperature can be -20°C, -10°C, 0°C, 10°C, 20°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, 100°C, 110°C, 120°C, 130°C, 140°C, or 150°C or higher. The reaction can occur at room temperature or above.

[0071] In this process, compound (2) can be reacted with furan to form compound (3). This reaction can be carried out in the presence of at least one Lewis acid. The at least one Lewis acid can contain a Lewis metal 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). The at least one Lewis acid can be selected from Table 1. The at least one Lewis acid may be selected from magnesium perchlorate, aluminum chloride, lithium trifluoromethanesulfonate, tin(II) trifluoromethanesulfonate, bis(cyclopentadienyl)zirconium(IV) bis(trifluoromethanesulfonate)tetrahydrofuran complex, bis(cyclopentadienyl)titanium(IV) bis(trifluoromethanesulfonate), boron trifluoride diethyl etherate, and gallium(III) chloride. The at least one Lewis acid may be selected from copper(II) tetrafluoroborate hydrate, aluminum bromide, niobium(V) chloride, ytterbium(III) trifluoromethanesulfonate, scandium(III) trifluoromethanesulfonate, magnesium trifluoromethanesulfonate, trimethylsilyl trifluoromethanesulfonate, and copper(II) trifluoromethanesulfonate. The concentration of the Lewis acid can be 0.01 molar (M), 0.02M, 0.03M, 0.04M, 0.05M, 0.06M, 0.07M, 0.08M, 0.09M, 0.1M, 0.2M, 0.3M, 0.4M, 0.5M, 0.6M, 0.7M, 0.8M, 0.9M, 1M, 2M, 3M, 4M, 5M, 6M, 7M, 8M, 9M, 10M, 11M, 12M, 13M, 14M, 15M, 16M, 17M, 18M, 19M, or 20M or greater.The reaction can be carried out using solvents such as acetone, toluene, benzene, xylene, chlorobenzene, methylene chloride, ethylene dichloride, dioxane, tetrahydrofuran (THF), tert-butyl methyl ether, diisopropyl ether, 1,2-dimethoxyethane (glyme), ethyl acetate, isopropyl acetate, acetonitrile, methanol, water, or mixtures thereof. The reaction time can be 30 seconds, 1 minute, 5 minutes, 10 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 10 hours, 20 hours, 30 hours, 40 hours, 50 hours, 60 hours, 70 hours, 80 hours, 90 hours, or 100 hours or more. The reaction temperature can be -20°C, -10°C, 0°C, 10°C, 20°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, 100°C, 110°C, 120°C, 130°C, 140°C, or 150°C or higher. The reaction can occur at room temperature or above.

[0072] Compound (3) can be subjected to a reduction reaction. The reaction can be carried out using a solvent such as ethyl acetate, isopropyl acetate, tetrahydrofuran, dioxane, diisopropyl ether, tert-butyl methyl ether, methylene chloride, ethylene dichloride, toluene, 1,2-dimethoxyethane, hexane, cyclohexane, acetone, acetonitrile, methanol, or water. The reaction time can be 30 seconds, 1 minute, 5 minutes, 10 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, more than 5 hours, 10 hours, more than 10 hours, 15 hours, or 20 hours or more. The reaction can be carried out using at least one reducing agent selected from Table 2. The reaction can be carried out in the presence of Raney nickel, Ni(II) / NaBH4, Co(II) / NaBH4, Li / EtNH2, LAH / TiCl3, LAH / CuCl2, Ni(II) / Zn, Ni(II) / Al, LAH / Cp2Ni, Pd / C, Pd, PdCl2, PtO2, or Pt / C. The reaction can be carried out in the presence of H2. The reaction can be refluxed. In some cases, the reduction reaction can include hydrogenation and desulfurization reactions carried out using a single reducing agent. The single reducing agent can be Raney nickel. In other cases, the reduction reaction can include hydrogenation and desulfurization reactions carried out using separate reducing agents. The hydrogenation reaction can be carried out using Pd / C, Pd, PdCl2, PtO2, or Pt / C. The hydrogenation reaction can be carried out in the presence of H2. The desulfurization reaction can be carried out using at least one reducing agent selected from Table 2. The reducing agent can be Raney nickel. In still other cases, the reduction reaction can include a hydrogenation reaction to give compound (10). [ka] The hydrogenation reaction can be carried out using Pd / C, Pd, PdCl, PtO, or Pt / C. The reaction can be carried out in the presence of H.

[0073] Compound (10) can be subjected to an oxidation reaction. The oxidation reaction can be carried out using at least one oxidizing agent selected from Table 3. The oxidation reaction can be carried out in the presence of HO, RCOH, NaBO, KHSO, NRSO, NaOCl, or RuO.

[0074] Compound (3) can be subjected to an oxidation reaction. The oxidation reaction can be carried out using at least one oxidizing agent selected from Table 3. The oxidation reaction can be carried out in the presence of H2O2, RCO3H, NaBO3, KHSO5, NR4S3O8, NaOCl, or RuO4.

[0075] The derivative is selected from the group consisting of: [ka] The sulfoxides can be the α or β isomers.

[0076] A process for preparing compound (1) can include providing compound (4) and subjecting compound (4) to a hydrolysis reaction carried out using NaOH. The reaction can be carried out using tetrahydrofuran, water, or any mixture thereof as a solvent. The reaction time can be 30 seconds, 1 minute, 5 minutes, 10 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, or 5 hours or more. The reaction temperature can be 0°C, 10°C, 20°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, or 100°C or more. The reaction can occur at room temperature or above.

[0077] The process for preparing compound (2) can include providing compound (1) and subjecting compound (1) to a dehydration reaction comprising exposing compound (1) to an acyl halide. The acyl halide can be acyl chloride, acyl bromide, or acyl iodide. The acyl halide can be acetyl chloride. The acyl bromide can be acetyl bromide. The acyl iodide can be acetyl iodide. The reaction time can be 30 seconds, 1 minute, 5 minutes, 10 minutes, 30 minutes, or 1 hour or more. The reaction can be refluxed.

[0078] One process involves preparing a compound of formula (17): [ka] (Wherein, X is S, O, CH2, CHR 1 , C.R. 1 R 2 , N.H., N.R. 1 , and N.R. 1 R 2 wherein R 1 and R 2 are each independently selected from alkyl, aryl, heteroaryl, alkoxy, amine, alcohol, and halogen, or together are carbonyl, alkenyl, imine, or oxime, wherein said R 1 and R 2 are each optionally independently substituted), and subjecting compound (17) to a cycloaddition reaction comprising exposing compound (17) to at least one Lewis acid selected from Table 1 to produce a compound having formula (18): [ka] (Wherein, X is S, O, CH2, CHR 1 , C.R. 1 R 2 , N.H., N.R. 1 , and N.R. 1 R 2 wherein R 1 and R2 are each independently selected from alkyl, aryl, heteroaryl, alkoxy, amine, alcohol, and halogen, or together are carbonyl, alkenyl, imine, or oxime, wherein said R 1 and R 2and forming a Lewis metal (each optionally independently substituted). The at least one Lewis acid can contain a Lewis metal 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). The at least one Lewis acid can be selected from Table 1. The at least one Lewis acid may be selected from magnesium perchlorate, aluminum chloride, lithium trifluoromethanesulfonate, tin(II) trifluoromethanesulfonate, bis(cyclopentadienyl)zirconium(IV) bis(trifluoromethanesulfonate)tetrahydrofuran complex, bis(cyclopentadienyl)titanium(IV) bis(trifluoromethanesulfonate), boron trifluoride diethyl etherate, and gallium(III) chloride. The at least one Lewis acid may be selected from copper(II) tetrafluoroborate hydrate, aluminum bromide, niobium(V) chloride, ytterbium(III) trifluoromethanesulfonate, scandium(III) trifluoromethanesulfonate, magnesium trifluoromethanesulfonate, trimethylsilyl trifluoromethanesulfonate, and copper(II) trifluoromethanesulfonate. The concentration of the Lewis acid can be 0.01 molar (M), 0.02M, 0.03M, 0.04M, 0.05M, 0.06M, 0.07M, 0.08M, 0.09M, 0.1M, 0.2M, 0.3M, 0.4M, 0.5M, 0.6M, 0.7M, 0.8M, 0.9M, 1M, 2M, 3M, 4M, 5M, 6M, 7M, 8M, 9M, 10M, 11M, 12M, 13M, 14M, 15M, 16M, 17M, 18M, 19M, or 20M or greater.The reaction can be carried out using solvents such as acetone, toluene, benzene, xylene, chlorobenzene, methylene chloride, ethylene dichloride, dioxane, tetrahydrofuran (THF), tert-butyl methyl ether, diisopropyl ether, 1,2-dimethoxyethane (glyme), ethyl acetate, isopropyl acetate, acetonitrile, methanol, water, or mixtures thereof. The reaction time can be 30 seconds, 1 minute, 5 minutes, 10 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 10 hours, 20 hours, 30 hours, 40 hours, 50 hours, 60 hours, 70 hours, 80 hours, 90 hours, or 100 hours or more. The reaction temperature can be -20°C, -10°C, 0°C, 10°C, 20°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, 100°C, 110°C, 120°C, 130°C, 140°C, or 150°C or higher. The reaction can occur at room temperature or higher. X can be S. X can be O. X can be CH. The cycloaddition reaction can include reacting compound (17) with furan.

[0079] A process for preparing cantharidin can include providing compound (3) and subjecting compound (3) to a reduction reaction, including hydrogenation and desulfurization reactions carried out using separate reducing agents, wherein the desulfurization reaction is carried out using a reducing agent selected from Table 2. The hydrogenation reaction can be carried out using Pd / C, Pd, PdCl, PtO, or Pt / C. The hydrogenation reaction can be carried out in the presence of H. The reaction can be carried out using ethyl acetate as a solvent. The reaction time can be 30 seconds, 1 minute, 5 minutes, 10 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, more than 5 hours, 10 hours, more than 10 hours, 15 hours, or 20 hours or more. The reaction can be carried out in the presence of Raney nickel, Ni(II) / NaBH, Co(II) / NaBH, Li / EtNH, LAH / TiCl, LAH / CuCl, Ni(II) / Zn, Ni(II) / Al, LAH / CpNi, Pd / C, Pd, PdCl, PtO, or Pt / C. The reaction can be refluxed.

[0080] A process can include providing compound (3) or (10) and forming a compound having a structure selected from the group consisting of compounds (11), (12), (13), (14), (15), and (16) from compound (3) or (10) by subjecting compound (3) or (10) to an oxidation reaction. The oxidation reaction can be carried out using at least one oxidizing agent selected from Table 3. The oxidation reaction can be carried out in the presence of HO, RCOH, NaBO, KHSO, NRSO, NaOCl, or RuO. The sulfoxide can be the α or β isomer.

[0081] A process can include providing a compound having a structure selected from the group consisting of compounds (11), (12), (14), and (15), and forming a compound having a structure selected from the group consisting of compounds (13) and (16) from the provided compound by subjecting the provided compound to an oxidation reaction. The oxidation reaction can be carried out using at least one oxidizing agent selected from Table 3. The oxidation reaction can be carried out in the presence of HO, RCOH, NaBO, KHSO, NRSO, NaOCl, or RuO. The sulfoxide can be the α or β isomer.

[0082] The composition comprises: [ka] The sulfoxide may have a structure selected from the group consisting of: The sulfoxide may be an α or β isomer.

[0083] The pharmaceutically acceptable mixture may be [ka] The sulfoxide may be an α or β isomer.

[0084] The synthesis of cantharidin can be carried out in three steps.

[0085] Stage 1 - This stage involves the production of compound (2) from available starting materials. Compound (2) can be synthesized from compound (1). Compound (2) can be synthesized from compound (4). Compound (2) can be synthesized from compound (5). Compound (2) can be synthesized from compound (6). Compound (2) can be synthesized from compound (7). Compound (2) can be synthesized from compound (8). Compound (2) can be synthesized from compound (9). [ka]

[0086] Step 2 - This step involves the stereospecific Diels-Alder cycloaddition of compound (2) with furan to produce compound (3). [ka]

[0087] Step 3 - This step involves the reduction of compound (3) to produce cantharidin. [ka]

[0088] Phase 1 Compound (2) is prepared in improved yield and purity to provide a high quality product and improved yield that facilitates synthetic scale-up.

[0089] Phase 2 This process involves the Diels-Alder reaction of compound (2) with furan. It is unexpected that this reaction can be promoted by many Lewis acids other than lithium perchlorate or lithium trifluoromethanesulfonimide. Grieco's work suggests the uniqueness of using lithium perchlorate as a catalyst for this particular cycloaddition reaction. We identify several Lewis acids (see Table 1) that can catalyze this reaction to give high yields of the cycloadduct (3) with low levels of the undesired endo-isomer, offering significant improvements over the lithium trifluoromethanesulfonimide process. These alternative Lewis acids do not suffer from the disadvantages of the diethyl ether / lithium perchlorate system described by Grieco. The Lewis acids can contain a Lewis metal 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). The Lewis acids can be selected from Table 1. These Lewis acids can be selected from magnesium perchlorate, aluminum chloride, lithium trifluoromethanesulfonate, tin(II) trifluoromethanesulfonate, bis(cyclopentadienyl)zirconium(IV) bis(trifluoromethanesulfonate)tetrahydrofuran complex, bis(cyclopentadienyl)titanium(IV) bis(trifluoromethanesulfonate), boron trifluoride diethyl etherate, and gallium(III) chloride. These Lewis acids can be selected from copper(II) tetrafluoroborate hydrate, aluminum bromide, niobium(V) chloride, ytterbium(III) trifluoromethanesulfonate, scandium(III) trifluoromethanesulfonate, magnesium trifluoromethanesulfonate, trimethylsilyl trifluoromethanesulfonate, and copper(II) trifluoromethanesulfonate.

[0090] These Lewis acids can be used in a wide range of commercially viable preparative solvents, including acetone, ethyl acetate, isopropyl acetate, benzene, xylene, toluene, chlorobenzene, methylene chloride, ethylene dichloride, dioxane, THF, tert-butyl methyl ether, diisopropyl ether, 1,2-dimethoxyethane (glyme), acetonitrile, methanol, and water. The temperature range for various Lewis acid-catalyzed Diels-Alder reactions between furan and (2) varies from -20 °C to 150 °C, depending on the properties of the solvent and Lewis acid. The reaction can be enhanced using microwave heating or sonication, depending on the properties of the Lewis acid and solvent. Improvements in yield and exo-endo ratio in certain cases can be achieved by adding trace amounts of alkali perchlorates, silver perchlorate, amines, desiccant-like trialkylaluminum reagents, and zeolites, as well as by adding various standard free radical scavengers to the reaction.

[0091] The exo to endo product ratio produced by the synthetic methods disclosed herein can be at least about 85:15, 86:14, 87:13, 88:12, 89:11, 90:10, 91:9, 92:8, 93:7, 94:6, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0. The proportion of exo product per total production can be at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, 99.999%, or 100%.

[0092] The synthetic methods disclosed herein provide product yields of at least about 5%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 110%, 111%, 112%, 113%, 114%, 115%, 116%, 117%, 118%, 119%, 120%, 121%, 122%, 123%, 124%, 125%, 126%, It can be 37%, 38%, 39%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, 99.999%, or 100%.

[0093] [Table 1]

[0094] where: bisoxa= [ka] and fod= [ka] and , NTf2 = [(CF3SO2)2N] - and -OTf=CF3SO3 - and Tf = CF3SO2.

[0095] For example, a 0.01 M to 20 M solution (in diethyl ether) of at least one Lewis acid can be added to a stirred mixture of furan and compound (2) at room temperature under an argon atmosphere. The at least one Lewis acid can contain a Lewis metal 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). The at least one Lewis acid can be selected from Table 1. The at least one Lewis acid can be selected from magnesium perchlorate, aluminum chloride, lithium trifluoromethanesulfonate, tin(II) trifluoromethanesulfonate, bis(cyclopentadienyl)zirconium(IV) bis(trifluoromethanesulfonate) tetrahydrofuran complex, bis(cyclopentadienyl)titanium(IV) bis(trifluoromethanesulfonate), boron trifluoride diethyl etherate, and gallium(III) chloride. The at least one Lewis acid can be selected from copper(II) tetrafluoroborate hydrate, aluminum bromide, niobium(V) chloride, ytterbium(III) trifluoromethanesulfonate, scandium(III) trifluoromethanesulfonate, magnesium trifluoromethanesulfonate, trimethylsilyl trifluoromethanesulfonate, and copper(II) trifluoromethanesulfonate. The resulting mixture can be stirred for 1 to 100 hours or more, and water can be added. The mixture can be extracted with MTBE. This crude material can be dissolved in a small amount of dichloromethane and passed through a pad of silica, washing with dichloromethane. The combined filtrates can be evaporated to give a white solid; this mixture of product and starting material can be used in the next step without further purification or purified and stored.

[0096] Phase 3 The final step in the synthesis of cantharidin from (3) involves reduction of the carbon-carbon double bond and desulfurization. The original Dauben procedure for the direct conversion of (3) to cantharidin, which uses a single-step reduction of the olefin and desulfurization with Raney nickel, suffers from inherent difficulties, including the stable generation of the Raney nickel catalyst, which affords high and consistent yields of cantharidin at production scale. One major issue with this step may be the production of the unstable olefin (19), which can readily undergo a retro-Diels-Alder reaction, resulting in significant product losses later in the synthesis. We identify a specific commercially available Raney nickel catalyst that minimizes losses due to a delay in olefin hydrogenation before desulfurization. [ka]

[0097] Alternatively, compound (3) can be efficiently hydrogenated using standard palladium or platinum catalysts and low-pressure hydrogen to give product (10) in high yield. Subsequent desulfurization of (10) with at least one reducing agent listed in Table 2 affords cantharidin in excellent yield. This scalable two-step process greatly increases the quality and yield of the product cantharidin, and can minimize or avoid the use of Raney nickel or other similar sponge metal catalysts, as well as potential health and environmental hazards. This process is a significant process improvement over the one-step reduction process using Raney nickel. [ka]

[0098] [Table 2]

[0099] Typical solvents for the desulfurization reaction can be alcohols, ethers, ester-based solvents, and water, or various mixtures of these solvents. The reaction temperature can range from -20°C to 100°C, depending on the specific solvent. These reactions can be accelerated with the aid of sonication or microwave heating.

[0100] For example, a slurry (in water) of at least one desulfurizing agent listed in Table 2 can be added to a solution of compound (3) in ethyl acetate. The mixture can be refluxed for 1 to 10 hours, filtered hot through a pad of Celite, and washed with hot acetone. The filtrate can be evaporated to dryness, and the crude material can be triturated with ethyl acetate. The resulting solid can be filtered to obtain cantharidin as a white solid.

[0101] Synthesis of cantharidin derivatives These described procedures can also be used to generate cantharidin derivatives and analogs that may be biologically active. These molecules include, but are not limited to, sulfides (3) and (10); their respective sulfoxide derivatives (11), (12), (14), and (15); and their respective sulfone derivatives (13) and (16). Oxidation of (3) or (10), or a mixture thereof, with at least one of the reagents listed in Table 3, can yield at least one of sulfoxides (α or β isomers) (11), (12), (14), and (15), or sulfones (13) and (16), or a mixture thereof. Oxidation of at least one of (11), (12), (14), and (15), or a mixture thereof, with at least one of the reagents listed in Table 3, can yield at least one of sulfones (13) and (16). These sulfide, sulfoxide, and sulfone derivatives can be biologically active. These sulfide, sulfoxide, and sulfone derivatives may be pharmaceutically acceptable. These sulfide, sulfoxide, and sulfone derivatives may be pharmaceutically acceptable salts.

[0102] [Table 3]

[0103] where R is independently selected from alkyl, aryl, heteroaryl, alkoxy, amine, alcohol, and halogen, and is optionally substituted.

[0104] Reaction solvents include water, alcohols, methylene chloride and other halogenated hydrocarbons, ethers, water, toluene, benzene, xylene, acetone, and similar ketone solvents, organic acids, ethyl acetate, isopropyl acetate, acetonitrile, or various mixtures of these solvents. These reactions can be facilitated using sonication, microwave irradiation, and / or the addition of phase transfer salts.

[0105] For example, a solution of compound (3) in ethyl acetate can be hydrogenated in the presence of Pd / C in a hydrogen atmosphere for 1 to 72 hours. The mixture can be passed through a pad of Celite and washed with ethyl acetate. The resulting solid can be dissolved in a small amount of dichloromethane and purified by silica gel chromatography to obtain compound (10), a white crystalline solid. Compound (3) or compound (10), or a mixture thereof, can then be oxidized with at least one oxidizing agent listed in Table 3 to produce a sulfoxide or sulfone product, or a mixture thereof.

[0106] Some reactions can be adapted from Chem. Pharm. Bull. 1987, 35(5), 1734-1740; Heteroatom Chemistry 2006, Volume 17, Number 7, 648-652; J. Am. Chem. Soc. 1990, 112, 4595-4596; J. Org. Chem. 1985, 50, 2576-2578; and J. Am. Chem. Soc. 1980, 102, 6893-6894.

[0107] The scheme follows, with information about each step provided at the end. [ka] [Example]

[0108] Example 1: Bis(trimethylsilylmethyl) sulfide, Compound (2) Experimental method for Step 1: Chloromethyltrimethylsilane (50.0 g, 407.5 millimoles (mmol)) and tetrabutylammonium iodide (7.52 g, 20.3 mmol) are added to a solution of sodium sulfide hydrate (23.1 g, 203.5 mmol) in 100 mL of water. The mixture is stirred at reflux for 5 hours and then cooled to room temperature. The organic layer is separated, and the aqueous layer is extracted with MTBE (2 × 50 mL). The combined solution is dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product (7), obtained as a pale yellow oil, is used directly in the next step without further purification (40 g, 95%).

[0109] Example 2: Compound (3) Experimental procedure for Step 2: Compound 7 (30 g, 145.2 mmol) in DCM (15 vol) is cooled to −78°C. m-CPBA (predried over 4A molecular sieves) in DCM (5 vol) is slowly added. The mixture is stirred at −78°C for 1 h. The disappearance of the starting material is confirmed by TLC analysis, and the mixture is warmed to 0°C. The mixture is added to an ice-cold solution of saturated NaHCO3 and the layers are separated. The organic layer is dried over MgSO4, filtered, and concentrated under reduced pressure at a bath temperature of 5-10°C to quantitatively obtain the sulfoxide product 5. This crude product is used directly in the next step without further purification.

[0110] Example 3: Dimethyl 2,5-dihydrothiophene-3,4-dicarboxylate, Compound (4) Experimental method for Step 3: A mixture of compound (5) (32.0 g, 145.6 mmol) and dimethyl acetylenedicarboxylate (10.34 g, 72.8 mmol) in DMPU (1 vol) is added to a preheated solution of DMPU at 100° C. The resulting mixture is stirred at 100° C. for 30 minutes and then poured into ice water (250 g). The mixture is extracted with dichloromethane (500 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material is purified by column chromatography to give ester (4) (8.5 g, 60.0%) as a pale yellow oil.

[0111] Example 4: Compound (1) Experimental procedure for Step 4: Compound (4) (8.5 g, 42 mmol) is dissolved in a 1:1 mixture of THF and water (85 mL, 10 vol). NaOH (6.73 g, 168.3 mmol) is added at room temperature, and the resulting mixture is stirred at room temperature for 4 hours. After confirming the disappearance of the starting material by TLC, the mixture is washed twice with MTBE to remove unreacted materials and impurities. The pH of the aqueous solution is adjusted to ∼4 with 1N HCl solution and extracted with ethyl acetate (2 × 100 mL). The combined organic layers are dried over MgSO4, filtered, and concentrated under reduced pressure to give product (1) (6.05 g, 83%) as an off-white solid.

[0112] Example 5: 2,2,4,4-tetrahydrothiophene-3,4-dicarboxylic anhydride, Compound (2) Experimental procedure for Step 5: A solution of compound (1) (6.05 g, 34.7 mmol) in acetyl chloride (30 mL, 5 vol) is refluxed for 1 hour. The reaction mixture is concentrated under reduced pressure, dissolved in a small amount of dichloromethane, and triturated with heptane. The resulting solid is filtered and dried under high vacuum overnight to give product (2) (4.47 g, 84%) as an off-white solid.

[0113] Example 6: Compound (3) Experimental method for Step 6: A 5.0 M solution of LiClO in diethyl ether (25.15 g, 235.6 mmol) is added to a stirred mixture of furan (5.45 g, 80.1 mmol) and compound (2) (2.5 g, 16.0 mmol) at room temperature under an argon atmosphere. The resulting mixture is stirred for 10 hours, and water (80 ml) is added. The mixture is extracted with MTBE (3 × 50 mL). The crude material is dissolved in a small amount of DCM and passed through a pad of silica, washing with dichloromethane. The combined filtrate is evaporated to give a white solid; a 75:25 mixture of this product and starting material is used in the next step without further purification.

[0114] Example 7: Cantharidin Experimental method for Step 7: To a solution of compound (3) (0.25 g, 1.11 mmol) in ethyl acetate (10 mL) is added a slurry of Raney Nickel 2800 (Aldrich, 2.5 g in 4 mL of water) in water. The mixture is refluxed for 4 hours and filtered hot through a pad of Celite, washing with hot acetone (40 mL). The filtrate is evaporated to dryness, and the crude product is triturated with ethyl acetate. The resulting solid is filtered to give cantharidin as a white solid (50 mg, 23%).

[0115] Example 8: Compound (10) Experimental method for Step 8: A solution of compound (3) (0.4 g, 1.78 mmol) in ethyl acetate (10 mL) is hydrogenated in the presence of 10% Pd / C (40 mg) under a hydrogen atmosphere for 4 hours. TLC shows only partial conversion. An additional 10% catalyst (40 mg) is added, and the mixture is stirred overnight for complete conversion. The mixture is filtered through a pad of Celite and washed with ethyl acetate. The resulting solid is dissolved in a small amount of dichloromethane and purified by silica gel chromatography to give compound (10) (0.2 g, 50%) as a white crystalline solid.

[0116] Example 9: Diels-Alder catalyst Experiments were conducted to determine a two or three step synthesis for cantharidin that did not use lithium perchlorate, resulting in the following final reduction / desulfurization reaction: [ka]

[0117] The original Diels-Alder (DA) chemistry using lithium perchlorate (LiClO4) is as follows: [ka]

[0118] The original DA chemistry between intermediate 2 and furan was carried out in ether in the presence of a large excess of lithium perchlorate (15.6 equivalents). This process may have several drawbacks, including the use of a large excess of lithium perchlorate, the explosive properties of lithium perchlorate, the need to dry the lithium perchlorate (e.g., at 140°C for 48 hours) (which can be difficult and dangerous upon scale-up), the high volatility and flammability of the solvent ether, and the production of a binary mixture of isomer 3 and 3a, which is not the only desired isomer 3.

[0119] The DA reaction was studied using 41 Lewis acid catalysts. Table 4 lists the catalyst names and results from the DA chemistry. A total of 41 Lewis acid catalysts were tested for the Diels-Alder reaction between intermediate 2 and furan, as shown in Table 4 below. Two equivalents of catalyst were used for 25 mg scale reactions in screw-cap vials. 0.3 mL of the desiccant trimethylaluminum was used in each reaction. The reactions were carried out in toluene at room temperature and analyzed by thin-layer chromatography (TLC) at 5 and 20 hours after completion.

[0120] [Table 4-1]

[0121] [Table 4-2]

[0122] Of these 41 reactions shown above, several positive reactions were observed. Significant product peaks were observed for tin triflate, bis(cyclopentadienyl)zirconium triflate-THF complex, bis(cyclopentadienyl)titanium triflate, gallium chloride, and boron trifluoride-diethyl ether complex. Traces of product were observed for copper tetrafluoroborate hydrate, aluminum bromide, niobium chloride, ytterbium triflate, scandium triflate, magnesium perchlorate, magnesium triflate, copper triflate, lithium triflate, and trimethylsilyl triflate. For magnesium perchlorate, 5 equivalents provided superior results than the previously used lithium perchlorate-based method.

[0123] The DA reaction was repeated using several catalysts: aluminum chloride, lithium triflate, tin triflate, bis(cyclopentadienyl)zirconium triflate-THF complex, bis(cyclopentadienyl)titanium triflate, and boron trifluoride-diethyl ether complex. Magnesium perchlorate was excluded because it may have many of the same drawbacks as lithium perchlorate. Two sets of reactions were performed to compare the effect of drying agents; the first set was performed in the presence of trimethylaluminum, and the second set was performed in the absence of trimethylaluminum. These reactions were performed on a 25 mg scale of compound 2 in the presence of excess furan and two equivalents of Lewis acid (LA).

[0124] Reaction with aluminum chloride showed a product spot in the absence of the drying agent trimethylaluminum (Me3Al). In the presence of Me3Al, no product was observed. 1H nuclear magnetic resonance (NMR) shows a ∼3:1 mixture of the desired exo (∼5.2 ppm) and undesired endo (∼5 ppm) with some starting material (SM) present (∼4 ppm) (see, for example, Figure 1). Figure 1 shows the peaks at 7.261 ppm, 7.255 ppm, 7.187 ppm, 4.238 ppm, 2.356 ppm, 1.314 ppm, 1.225 ppm, −0.000 ppm, and −0.002 ppm. 1 H NMR peaks are shown. Similar results were observed for tin triflate. Both bis(cyclopentadienyl)zirconium triflate-THF complex and bis(cyclopentadienyl)titanium triflate show cleaner TLC analysis in the presence of MeAl compared to its absence. 1 H NMR shows only the desired product. Figures 2A and 2B show the NMR spectra of the bis(cyclopentadienyl)zirconium triflate-THF complex with and without MeAl, respectively. 1 The results of H NMR are shown in Figure 2A. 1 Figure 2B shows the H NMR peaks at 7.255 ppm, 7.186 ppm, 2.355 ppm, and -0.002 ppm. 1 H NMR peaks are shown. Little, if any, of the undesired endo isomer is formed.

[0125] The boron trifluoride-diethyl ether complex showed some product in the presence of Me3Al. 1 1 H NMR shows the product along with the undesired endo-isomer and the starting material.

[0126] TMS triflate showed some product in the presence of Me3Al.

[0127] Bis(cyclopentadienyl)zirconium triflate-THF complex without trimethylaluminum resulted in a mixture of two isomers, as shown by NMR, as opposed to a single isomer when trimethylaluminum was used. This indicates the importance of the presence of trimethylaluminum in some reactions with respect to the desired stereoselectivity. Apparently, all reactions without trimethylaluminum resulted in a mixture of isomers. The presence of trimethylaluminum resulted in a mixture of isomers for some LAs. For Zr-, Ti-, and TMS-triflates, a single isomer was formed.

[0128] Bis(cyclopentadienyl)zirconium triflate-THF complex is desirable for its stereoselectivity towards the desired exo-isomer. Aluminum chloride and boron trifluoride-diethyl ether complexes may be desirable because they may be available at low cost.

[0129] Example 10: Two-step process for desulfurization and hydrogenation Previous studies have shown low yields of cantharidin (e.g., 10–12%) during Raney-nickel-mediated hydrogenation and desulfurization in one pot. Some yield can be lost in reverse-DA chemistry once sulfur disappears before double bond reduction. A two-step process of double bond reduction using Pd-C and hydrogen followed by desulfurization with Raney nickel was studied. [ka]

[0130] Pd-C (10%) hydrogenation of compound 3 (5 g) afforded the double bond-reduced material (compound 10) with intact sulfur. 4.1 g of pure product was isolated (82% yield).

[0131] The double bond reduced compound underwent Raney nickel chemistry in ethyl acetate at 50° C. under 30 psi of hydrogen for 4 hours on a 1 g scale. [ka]

[0132] Partial conversion was observed by NMR. The reaction was extended at 50° C. and 50 psi of hydrogen for 16 hours. The reaction mixture was filtered hot through a pad of Celite and washed with hot ethyl acetate (100 mL). The filtrate was concentrated, and the solid product was triturated with a small amount of ethyl acetate to give 150 mg of product (17%). NMR analysis appeared consistent. The filtrate was concentrated to give 350 mg of a semi-solid. NMR analysis indicated some product present. A second reaction was carried out at 50° C. and 30 psi of hydrogen; 0.3 g of product (34%) was isolated after filtration, concentration, and titration.

[0133] This double bond hydrogenation gave better yields than the single step process.

[0134] While preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous changes, modifications, and substitutions will readily occur to those skilled in the art without departing from the invention. It will be understood that various alternatives to the embodiments of the invention described herein can be employed in practicing the invention. It is intended that the following claims define the scope of the invention, and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

1. (a) a first compound of the following formula: 【Chemistry 1】 providing; and (b) converting said first compound into a second compound of the formula: by subjecting said first compound to a cycloaddition reaction comprising exposing said first compound to furan and a Lewis acid selected from the group consisting of tin(II) trifluoromethanesulfonate, bis(cyclopentadienyl)zirconium(IV) bis(trifluoromethanesulfonate)tetrahydrofuran complex, bis(cyclopentadienyl)titanium(IV) bis(trifluoromethanesulfonate), boron trifluoride diethyl etherate, and gallium(III) chloride; 【Chemistry 2】 forming A method comprising:

2. 2. The method of claim 1, wherein the Lewis acid is selected from the group consisting of bis(cyclopentadienyl)zirconium(IV) bis(trifluoromethanesulfonate)tetrahydrofuran complex and bis(cyclopentadienyl)titanium(IV) bis(trifluoromethanesulfonate).

3. 2. The method of claim 1, wherein the Lewis acid is bis(cyclopentadienyl)zirconium(IV) bis(trifluoromethanesulfonate)tetrahydrofuran complex.

4. 2. The method of claim 1, wherein the Lewis acid is bis(cyclopentadienyl)titanium(IV) bis(trifluoromethanesulfonate).

5. The method of claim 1, wherein the Lewis acid is tin(II) trifluoromethanesulfonate.

6. The method of claim 1, wherein the Lewis acid is boron trifluoride diethyl etherate.

7. The method of claim 1, wherein the Lewis acid is gallium(III) chloride.

8. The cycloaddition reaction is carried out by Me ３ The process according to any one of claims 1 to 7, carried out in the presence of Al.

9. The method of claim 1, wherein the second compound is produced in an exo-to-endo ratio of at least 85:

15.

10. The method of claim 1, wherein the second compound is produced in an exo-to-endo ratio of at least 95:

5.

11. The method of any one of claims 1 to 10, wherein the second compound is produced in an exo to endo ratio of at least 99:

1.

12. The method according to any one of claims 1 to 11, wherein the cycloaddition reaction is carried out in a solvent.

13. 13. The method of claim 12, wherein the solvent is selected from the group consisting of acetone, ethyl acetate, isopropyl acetate, benzene, xylene, toluene, chlorobenzene, methylene chloride, ethylene dichloride, dioxane, THF, tert-butyl methyl ether, diisopropyl ether, 1,2-dimethoxyethane (glyme), acetonitrile, methanol, water, and mixtures thereof.

14. The process of any one of claims 1 to 13, wherein the cycloaddition reaction is carried out at a temperature range of -20°C to 150°C.

15. The process of any one of claims 1 to 14, wherein the cycloaddition reaction is carried out at a temperature range of -20°C to 50°C.

16. 16. The method of any one of claims 1 to 15, wherein the cycloaddition reaction is carried out at about room temperature.

17. The second compound is hydrogenated to produce compound (10): 【Transformation 3】 The method of any one of claims 1 to 16, further comprising forming:

18. 20. The process of claim 17, wherein the hydrogenating step is carried out in the presence of Pd / C and hydrogen.

19. Compound (10) is desulfurized to give cantharidin: 【Chemistry 4】 19. The method of claim 17 or 18, further comprising forming:

20. The desulfurization step may include the use of Raney nickel, Ni(II) / NaBH ４ , Co(II) / NaBH ４ , Li / EtNH ２ , LAH / TiCl ３ , LAH / CuCl ２ , Ni(II) / Zn, Ni(II) / Al or LAH / Cp ２ 20. The method of claim 19 carried out in the presence of Ni.

21. 21. The method of claim 19 or 20, wherein the desulfurizing step is carried out in the presence of Raney nickel.

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