Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C327/00—Thiocarboxylic acids
  • C07C327/20—Esters of monothiocarboxylic acids
  • C07C327/22—Esters of monothiocarboxylic acids having carbon atoms of esterified thiocarboxyl groups bound to hydrogen atoms or to acyclic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
  • C07C319/22—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of hydropolysulfides or polysulfides
  • C07C319/24—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of hydropolysulfides or polysulfides by reactions involving the formation of sulfur-to-sulfur bonds
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/28—Phosphorus compounds with one or more P—C bonds
  • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
  • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
  • C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl

Definitions

• This invention relates to a process for synthesizing disulfide salts, and will have application to a process for synthesizing pharmaceutically active disulfides.
• Disodium 2 , 2 ' -dithiobis ethane sulfonate (Dimesna), and other salts and derivatives thereof, are known chemotherapeutic protective agents used to mitigate the toxicity of platinum complex antitumor drugs which are given to patients with certain types of cancer. Disclosure of Dimesna and like compounds as platinum protecting agents are found in U.S. Patents 5,789,000; 5,866,169; 5866,615; 5,866,617; and elsewhere in the literature.
• Dimesna is a physiological auto-oxidation product of sodium 2-mercaptoethane sulfonate (Mesna) , which is also a protective agent for chemotherapeutic drugs.
• the structures of the preferred sodium salts (disodium in the case of the dianionic Dimesna molecule) of Mesna and Dimesna are seen below as formula I and formula II, respectively.
• Both Mesna and Dimesna have been used with varying degrees of success as protective agents for administration with platinum complex anti-tumor drugs.
• Dimesna has been shown to be effective in providing protection against cisplatin (cis-diammine dichloro platinum) induced nephrotoxicity
• both Mesna and Dimesna have been shown to be effective against carboplatin (cis-diammine-1 , 1 cyclobutane dicarboxylato platinum) induced myelosuppression
• Mesna has also been used as a protective agent with other antitumor drugs, and is approved for such use in the United States and a number of foreign j risdictions.
• Mesna is auto-oxidized in the body to Dimesna under mildly basic conditions and in the presence of oxygen, such as those present in plasma.
• Dimesna Prior synthetic methods of making Dimesna involved the oxidation of Mesna to form its dimer (Dimesna) in substantially quantitative yield. This synthesis was accomplished by reacting the dissolved Mesna with an oxidizing agent, which contained a source of elemental iodine as the oxidant , or in iodate form in an aqueous medium.
• an oxidizing agent which contained a source of elemental iodine as the oxidant , or in iodate form in an aqueous medium.
• the prior art processes for synthesizing Mesna and Dimesna include the conversion of various alkyl sulfonic acids into their respective mercaptane derivatives and the subsequent oxidation into their respective disulfides by use of iodine-containing reagents as an oxidizing reagent. These processes, while efficient, required isolation procedures to be performed to isolate and purify the end products from the reagents used. Further, environmental pollutants were generated by the prior art processes which required disposal . Finally, the prior art processes could not be carried out in a single-pot process .
• the process of this invention includes a two step, single pot method of synthesizing Dimesna and derivatives thereof from commonly available starting materials.
• the first step of the process involves the synthesis of a key intermediate, an S-acetyl derivative of the desired disulfide. Addition of a strong base and a source of oxygen converts the key intermediate to the desired disulfide.
• the compounds synthesized by the process are useful as pharmaceuticals, particularly those uses referred to above, as well as other pharmaceutical uses.
• Another object of this invention is to provide for a process of synthesizing disulfides which is efficient and economical .
• Other objects of this invention will become apparent upon a reading of the following description.
• the process of this invention comprises two steps and functions to synthesize the desired disulfide end product from commercially available starting materials.
• the disulfides to be synthesized have the following formula I :
• R x is sulfonate or phosphonate and lower alkyl denotes a straight or branched chain hydrocarbon with one to six total carbon atoms.
• Scheme 1 illustrates a synthesis of the formula I compounds according to this invention.
• X is a leaving group, preferably a halogen atom, and lower alkyl and R ⁇ are as defined above.
• All processes may be carried out in aqueous solution.
• the starting material is converted to the key intermediate, an S-acetyl derivative of the starting material, through a substitution reaction wherein the leaving group is replaced by the S-acetyl moiety shown.
• a preferred reactant to facilitate this conversion is an alkali metal salt of thioacetic acid.
• Step two of the process is preferably carried out in the same reactant vessel (pot) , and involves the addition of a strong base and a source of oxygen gas to convert the thioacetate intermediate to its sulfhydryl form and thence to its oxidized disulfide.
• the formula I compounds will preferably be symmetrical disulfides.
• Scheme 2 illustrates an alternative starting material for the process of this invention.
• the process is the same as in Scheme I, but the starting material is an alkenyl alkylene salt, which is converted to the key thioacetate intermediate by addition of an alkali metal salt of thioacetic acid.
• the resulting thioacetate intermediate is converted to a formula I disulfide by addition of a strong base and a source of oxygen.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
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• Molecular Biology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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• 2002
  • 2002-04-30 US US10/135,756 patent/US6504049B1/en not_active Expired - Lifetime
• 2003
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  • 2003-04-29 ES ES03724301.1T patent/ES2523653T3/es not_active Expired - Lifetime
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