CN1082047C - 生产巯基链烷磺酸盐和磷酸盐及其衍生物的方法 - Google Patents
生产巯基链烷磺酸盐和磷酸盐及其衍生物的方法 Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 25
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 title abstract 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 18
- 239000011734 sodium Substances 0.000 claims abstract description 14
- KQYGMURBTJPBPQ-UHFFFAOYSA-L disodium;2-(2-sulfonatoethyldisulfanyl)ethanesulfonate Chemical compound [Na+].[Na+].[O-]S(=O)(=O)CCSSCCS([O-])(=O)=O KQYGMURBTJPBPQ-UHFFFAOYSA-L 0.000 claims abstract description 13
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 9
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 11
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 10
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 claims description 10
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 9
- 239000001301 oxygen Substances 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- 150000002431 hydrogen Chemical class 0.000 claims description 7
- 229910052700 potassium Inorganic materials 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 4
- 150000001336 alkenes Chemical class 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 239000011591 potassium Substances 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 239000003999 initiator Substances 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 2
- NLVXSWCKKBEXTG-UHFFFAOYSA-M ethenesulfonate Chemical compound [O-]S(=O)(=O)C=C NLVXSWCKKBEXTG-UHFFFAOYSA-M 0.000 claims 1
- XOGTZOOQQBDUSI-UHFFFAOYSA-M Mesna Chemical compound [Na+].[O-]S(=O)(=O)CCS XOGTZOOQQBDUSI-UHFFFAOYSA-M 0.000 abstract description 10
- 229960004635 mesna Drugs 0.000 abstract description 10
- -1 thioalkyl ether Chemical compound 0.000 abstract description 10
- 150000001335 aliphatic alkanes Chemical class 0.000 abstract description 6
- 229950009278 dimesna Drugs 0.000 abstract 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 abstract 1
- 150000001350 alkyl halides Chemical class 0.000 abstract 1
- 229910001882 dioxygen Inorganic materials 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 abstract 1
- 238000011065 in-situ storage Methods 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- 239000000047 product Substances 0.000 description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 7
- 239000005864 Sulphur Substances 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 150000003016 phosphoric acids Chemical class 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 229910052697 platinum Inorganic materials 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- NLVXSWCKKBEXTG-UHFFFAOYSA-N vinylsulfonic acid Chemical compound OS(=O)(=O)C=C NLVXSWCKKBEXTG-UHFFFAOYSA-N 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 2
- FRIOFTKUGOHOEI-UHFFFAOYSA-K P(=O)([O-])([O-])[O-].[Na+].[Na+].[Na+].[Na+].CC Chemical compound P(=O)([O-])([O-])[O-].[Na+].[Na+].[Na+].[Na+].CC FRIOFTKUGOHOEI-UHFFFAOYSA-K 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- VAGSTFRHBOIOKV-UHFFFAOYSA-N [Na].[Na].C(C)S(=O)(=O)O Chemical compound [Na].[Na].C(C)S(=O)(=O)O VAGSTFRHBOIOKV-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229940034982 antineoplastic agent Drugs 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 2
- 229940093495 ethanethiol Drugs 0.000 description 2
- 229960004756 ethanol Drugs 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000000669 high-field nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- HYHCSLBZRBJJCH-UHFFFAOYSA-M sodium hydrosulfide Chemical compound [Na+].[SH-] HYHCSLBZRBJJCH-UHFFFAOYSA-M 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical class OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
- 241001274216 Naso Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010029155 Nephropathy toxic Diseases 0.000 description 1
- WWDPTCAATYOWLH-UHFFFAOYSA-N O1NP=CC=C1.O1NP=CC=C1 Chemical compound O1NP=CC=C1.O1NP=CC=C1 WWDPTCAATYOWLH-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 150000001347 alkyl bromides Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000001351 alkyl iodides Chemical class 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 125000005012 alkyl thioether group Chemical group 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000012431 aqueous reaction media Substances 0.000 description 1
- 238000006701 autoxidation reaction Methods 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- 229910052728 basic metal Inorganic materials 0.000 description 1
- 150000003818 basic metals Chemical class 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- OTDGVEUYQCOUQT-UHFFFAOYSA-N bromoethane phosphoric acid Chemical compound P(O)(O)(O)=O.CCBr OTDGVEUYQCOUQT-UHFFFAOYSA-N 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- WSXCJZORCIZBKO-UHFFFAOYSA-N chloroethane;phosphoric acid Chemical compound CCCl.OP(O)(O)=O WSXCJZORCIZBKO-UHFFFAOYSA-N 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000007872 degassing Methods 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 230000000881 depressing effect Effects 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 239000003344 environmental pollutant Substances 0.000 description 1
- QDPMLKBAQOZXEF-UHFFFAOYSA-N ethanesulfonic acid;sodium Chemical compound [Na].CCS(O)(=O)=O QDPMLKBAQOZXEF-UHFFFAOYSA-N 0.000 description 1
- OMAYPGGVIXHKRO-UHFFFAOYSA-N ethanethiol Chemical compound [CH2]CS OMAYPGGVIXHKRO-UHFFFAOYSA-N 0.000 description 1
- SSVFMICWXDVRQN-UHFFFAOYSA-N ethanol;sodium Chemical compound [Na].CCO SSVFMICWXDVRQN-UHFFFAOYSA-N 0.000 description 1
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethyl mercaptane Natural products CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 1
- 229960001101 ifosfamide Drugs 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- ICIWUVCWSCSTAQ-UHFFFAOYSA-M iodate Chemical compound [O-]I(=O)=O ICIWUVCWSCSTAQ-UHFFFAOYSA-M 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- YWOITFUKFOYODT-UHFFFAOYSA-N methanol;sodium Chemical compound [Na].OC YWOITFUKFOYODT-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000007694 nephrotoxicity Effects 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 150000003057 platinum Chemical class 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000011814 protection agent Substances 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000010129 solution processing Methods 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
Classifications
-
- 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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/02—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of thiols
- C07C319/04—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of thiols by addition of hydrogen sulfide or its salts to unsaturated compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
- C07C319/16—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by addition of hydrogen sulfide or its salts to unsaturated compounds
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
两步单釜方法生产二巯乙磺酸钠(NaSO3-(CH2)2-S-S-(CH2)2-SO3Na)从ω-链烯磺酸盐与硫化物如NaSH反应开始，产生巯乙磺酸钠(HS-(CH2)2-SO3Na)。(其可被分离或通过与烷醇钠和烷基卤化物反应转化为C1-4硫代烷基醚)。在第二步中，用氧气将巯乙磺酸钠就地氧化产生二巯乙磺酸钠。较高链烷的同系物或类似物的磷酸盐可类似地被制备。当制备磷酸盐类似物时，卤代链烷磷酸盐是另一个起始化合物。这些化合物的C1-4-链烯类似物可以被类似地制备。
Description
本发明涉及生产巯基链烷磺酸盐和磷酸盐及其衍生物，特别是2-巯基乙烷磺酸钠(巯乙磺酸钠，HS-CH2CH2SO3Na)和2，2’-(二硫二基)乙烷磺酸二钠(二巯乙磺酸钠，NaSO3CH2CH2-S-S-CH2CH2SO3Na)的方法。
通式(I)化合物：R1-S-(CH2)m-R2，其中R1是氢，C1-4-烷基或R2-(CH2)m-S-和R2是SO3M或PO3M2，其中M或每个M独立地为钠，钾或氢及m是2，3或4，特别被用作化疗保护剂，该保护剂用于减轻给某些类型癌症患者使用的铂复合物抗肿瘤剂的毒性。因此，二巯乙磺酸钠可以与顺铂(顺-二氯二氨合铂)联合给药以保护身体免受肾中毒，并且巯乙磺酸钠和二巯乙磺酸钠可以与卡铂(顺二氨络-1，1-环丁烷二羧酸铂)联合给药以保护身体免受脊髓抑制。巯乙磺酸钠还被用作其它抗肿瘤剂，如异环磷酰胺，氧氮杂膦(oxazaphosphorine)和依托泊甙的保护剂。
巯乙磺酸钠在体内温和碱性条件下和氧存在下，如在血浆中的氧，自动氧化为二巯乙磺酸钠。
合成巯乙磺酸钠和二巯乙磺酸钠(及如硫醇和二硫化物)最主要的方法包括将各种链烷磺酸转化为其各自硫醇衍生物(如巯乙磺酸钠)，然后用含碘试剂如碘酸盐将硫醇氧化为其各自的二硫化物(如二巯乙磺酸钠)。如果需要，这些方法需要从所用试剂中分离和纯化终产物的分离方法。这些方法产生环境污染物，其需要处理并且不能在单一反应容器中进行。
本发明避免了生产二巯乙磺酸钠中的缺点并且提供了更方便制备各种烷硫基，巯基和二硫二链烷磺酸盐和磷酸盐的方法。
本发明提供了制备通式I化合物的方法，所说方法包括
(1)下式化合物
CH2X-CHY-(CH2)n-R2 (II)，
其中
X和Y一起形成烯烃碳-碳双键或其中R2是PO3M2，X可以是卤素及Y是氢；
n是0，1或2；及
R2定义如上，与通式Z-SH的硫化物反应，其中Z是氢，钠或钾，如果R2是PO3M2，X和Y一起代表双键时，该反应在自由基引发剂存在下进行，当X代表卤素及Y是氢时，在加热的帮助下进行；
形成式I的硫醇，其中R1是氢，然后任意地：
(2)(a)加压下将步骤(1)中的产生的硫醇与氧气一起加热产生式I化合物，其中R1是R2-(CH2)m-S-或
(b)将步骤(1)中产生的硫醇首先与碱金属C1-4链烷醇盐在质子溶剂中反应，然后与烷基溴或碘反应产生式I化合物，其中R1是C1-4-烷基。
该方法用下列路线概括：
CH2＝CH-(CH2)n-R2 (IIa)
或
Hal-CH2-CH2-(CH2)nPO3M2 (IIb)
(n＝0，1或2，R2＝PO3M2
或SO3M，M＝Na，K或H)
本发明制备其中R1是R2-(CH2)m-S-的式I化合物的优选方法涉及两步单釜法，其导致链烯基磺酸盐或酸(ω-链烯磺酸盐或磺酸)转化为所需式I化合物，特别是二巯乙磺酸钠，因此其可以高纯度形式大规模生产。
步骤1涉及在反马氏加成(anti-Markovnikov fashion)中通过产生SP3中心将巯基加到不饱和末端双键上。双键的加成通过起始链烯基磺酸盐与硫氢化物的盐或与硫化氢反应进行，优选在弱碱性溶液(pH8-9.5)中进行。硫化物优选以至少化学计量比例，通常以至少摩尔过量2∶1，优选3∶1至5∶1的比例存在。该步骤形成巯基(或者称为硫氢基)链烷磺酸盐，其可被直接重结晶产生其中R2是氢的式I化合物，特别是巯乙磺酸钠。
该方法步骤2，上述称为步骤2(a)涉及巯基链烷磺酸盐至二硫化物的氧化，并且该步骤在水介质和如步骤1的相同反应容器中进行，而不需要对步骤1的产物的分离和纯化。步骤2包括氧气的引入，优选通过向反应容器中鼓气，同时增加上述环境的压力和温度，优选在弱碱性pH下。优选pH值是8-9.5。其最大优点是可以不调节步骤1的pH值。优选温度至少是40℃，最优选至少60℃。预期用于多数目的的温度范围为40-100℃。优选计量压力(过压)至少是20psi(138kPa)，最优选至少30psi(207kPa)，最希望至少50psi(345kPa)。预期用于多数目的的压力范围为20-60psi(138-414kPa)。基本上可以定量产率形成二巯乙磺酸钠或其同系物或其类似物。所需终产物可以容易从其水性反应介质中结晶。
如果所需终产物是其中R1是C1-4烷基的式I的烷基硫醚，方法步骤1如上述进行，然后将硫醇产物溶解在质子溶剂，优选C1-4烷醇中，该醇含有所需的C1-4-链烷醇盐，优选甲醇钠。该溶液优选被温热至约60℃，接着加入C1-4烷基碘或溴以进行烷基化。该醇盐的烷基部分优选与烷基碘或溴的烷基部分相同，甚至优选质子溶剂含有相应的烷醇。因此，该硫醚一般以定量产率形成。
当需要式I的磷酸盐时，起始化合物可以是卤代链烷磷酸盐，优选溴代链烷或氯代链烷磷酸盐。优选n是0或1，这时起始原料是卤代乙烷或卤代丙烷磷酸盐。该两步单釜方法涉及首先用硫氢化钠或硫化氢在升高温度时，特别是在40-120℃处理该起始化合物。如上所述，优选以摩尔过量使用硫化物。或者，步骤1可以通过加入硫源及如上所述条件和试剂，在自由基引发剂的存在下将烯烃磷酸转化为硫醇来实现。步骤2中对二硫化物的氧化如上所述。
下列非限定性实施例说明本发明。
实施例1
2，2’-(二硫二)乙烷磺酸二钠
将100mL 25％乙烯基磺酸(VSA)钠盐(Aldrich ChemicalCompany)的水储存液(25克VSA，0.192摩尔)放在帕尔氏容器中，并且鼓入氩气1小时以除去水溶液中的氧。向该溶液中加入33.5克硫氢化钠单水合物(Aldrich Chemical Company)(0.598摩尔，计算如NaSH)和10mL氢氧化钠。溶液的pH约为9.0。将反应混合物在帕尔氏容器中搅拌2小时，这期间每隔30分钟用NMR监测。
将该步骤中获得的产物不经分离用于下步，加热至60℃，向容器中鼓入氧气30分钟。然后将容器加压至50psi(345kPa)并在60℃搅拌超过6小时。
然后通过在80℃用工业真空浓缩水溶液处理反应完全的反应混合物，接着从水中扩散(diffused)重结晶。加入1N HCl调节pH至7.2并用0.2微米孔膜过滤器过滤后，冷冻结晶产物。NMR和元素分析确认纯(99％)2，2’-(二硫二基)乙烷磺酸钠存在。
实施例2
2，2’-(二硫二基)乙烷磷酸四钠
将2-氯乙烷磷酸(1克，6.9摩尔)溶解在无水乙醇(10ml)中并用连续的氩气流脱气至少30分钟。然后将其加到硫氢化钠水合物(1.4克，25毫摩尔，计算如NaSH)的乙醇沸腾溶液中得到最终反应混合物的pH约为9。然后将所得反应混合物回流10小时。将反应混合物冷却并用1N HCl调节pH为8。除去溶剂并用分散结晶纯化产物。然后将白色固体放在帕尔氏瓶中并加入50ml水。向水溶液中鼓入氧气流至少1小时。将用50psi(345kPa)的氧气将该瓶加压并在60℃振荡4小时。通过在80℃和工业真空浓缩水溶液的一半分离产物，接着结晶。将所得产物用高场NMR和元素分析鉴定并与真实样品比较。
实施例3
2，2’-(二硫二基)乙烷磷酸四钠
重复实施例2，只是用相同摩尔量的2-溴乙烷磷酸作为起始原料及用水代替乙醇溶剂。然后将所得产物用高场NMR和元素分析鉴定并与真实样品比较。
实施例4
2-(甲硫基)乙烷磺酸一钠
将甲醇钠(1.5克)溶解在无水甲醇(20ml)中并加入巯基乙烷磺酸钠(巯乙磺酸钠)(1克)。然后将反应混合物回流6小时。向上述溶液中加入甲基碘(2ml)并将溶液搅拌2小时。然后浓缩反应混合物并将产物从水中结晶。以定量产率得到标题化合物，其NMR为：1H NMR(300 MHz， D2O)：1.99δ(3H，s)；2.67-2.72δ(2H，m)；2.99-3.04δ(2H，m)13C NMR：δ13.89，27.28，29.92，50.31
实施例5
2-(乙硫基)乙烷磺酸一钠
重复实施例4，用相同重量和体积的乙醇钠，乙醇和乙基碘代替甲醇钠，甲醇和甲基碘。以定量产率得到标题化合物，其NMR为：1H NMR(300 MHz，D2O)：1.07δ(3H，t，J＝7.5Hz)；2.45δ(2H，q，J＝7.5Hz)；2.69-2.75δ(2H，m)；2.96-3.02δ(2H，m)13C NMR：δ12.65，23.84，24.05，28.96，49.98
Claims (8)
1.一种生产以下通式化合物的方法：
R2-(CH2)m-S-S-(CH2)m-R2 (I)
其中
R2是SO3M或PO3M2，其中M为钠，钾或氢，及m是2，3或4，
所述方法包括
在压力至少20psi和温度至少60℃下将式化合物R2-(CH2)m-SH，
其中m如上定义，
与氧气加热。
2.根据权利要求1的方法，其中压力至少为30psi。
3.根据权利要求1或2的方法，其中R2为SO3M且m为2。
4.根据权利要求3的方法，其中M是钠，产物是二巯乙磺酸钠。
5.权利要求1的方法，其中R2-(CH2)m-SH硫醇是如下制备的：
将下式化合物
CH2X-CHY-(CH2)n-R2 (II)，
其中
X和Y一起形成烯烃碳-碳双键，或其中R2是PO3M2，X是卤素及Y是氢；
n是0，1或2；及
R2如权利要求1中定义，与通式Z-SH的硫化物反应，其中Z是氢，钠或钾；条件是，如果R2是PO3M2，X和Y一起代表双键时，该反应在自由基引发剂存在下进行，当X代表卤素及Y是氢时，在加热的帮助下进行；形成R2-(CH2)m-SH硫醇。
6.根据权利要求5的方法，其中R2为SO3M，m为2。
7.根据权利要求6的方法，其中起始化合物是其中X和Y一起形成双键，n是O及R2是SO3M的式II的乙烯基磺酸盐，R2-(CH2)m-SH硫醇不分离，随后在相同反应容器中制备式I化合物。
8.根据权利要求6或7的方法，其中M为钠，产物为二巯乙磺酸钠。
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| US6031006A (en) * | 1999-10-21 | 2000-02-29 | Bionumerik Pharmaceuticals, Inc. | Method of treating diabetic nephropathy |
| FR2811987A1 (fr) * | 2000-07-18 | 2002-01-25 | Expansia Sa | Procede de preparation du 2,2'-dithiobis(ethanesulfonate) de disodium |
| EP1322323A4 (en) | 2000-09-11 | 2004-07-28 | Therapro Technologies Inc | THIONIN AS AN ANTINEOPLASTIC AND IMMUNO-STIMULATING AGENT |
| US7034054B2 (en) * | 2000-12-15 | 2006-04-25 | Galileo Pharmaceuticals, Inc. | Methods for the prevention and treatment of cerebral ischemia using non-alpha tocopherols |
| US6504049B1 (en) * | 2002-04-30 | 2003-01-07 | Bionumerik Pharmaceuticals, Inc. | Process for synthesizing pharmaceutically active disulfide salts |
| US6765148B2 (en) | 2002-04-30 | 2004-07-20 | Illinois Tool Works Inc. | C-shaped grommet |
| US8710095B2 (en) | 2002-04-30 | 2014-04-29 | Bionumerik Pharmaceuticals, Inc. | Drugs for prophylaxis or mitigation of taxane-induced neurotoxicity |
| MXPA06006709A (es) * | 2003-12-17 | 2006-08-31 | Bionumerik Pharmaceuticals Inc | Proceso para sintetizar disulfuros. |
| US20050256055A1 (en) * | 2004-05-12 | 2005-11-17 | Hausheer Frederick H | Compounds and methods for reducing undesired toxicity of chemotherapeutic agents |
| US20060063742A1 (en) * | 2004-09-21 | 2006-03-23 | Hausheer Frederick H | Method of treatment for or protection against lymphedema |
| US7282602B2 (en) * | 2004-09-21 | 2007-10-16 | Bionumerik Pharmaceuticals, Inc. | Medicinal disulfide salts |
| JP5109081B2 (ja) * | 2006-04-26 | 2012-12-26 | 東洋紡株式会社 | アルケンスルホン酸塩を用いたチオカルボアルキルアルカンスルホン酸塩、メルカプトアルカンスルホン酸塩およびジチオビス（アルカンスルホン酸）塩の製造方法 |
| WO2009019119A1 (en) | 2007-08-03 | 2009-02-12 | Ucb Pharma S.A. | Sulfanyl derivatives and their use as synthesis intermediates |
| WO2009113989A1 (en) | 2008-03-14 | 2009-09-17 | Bionumerik Pharmaceuticals, Inc. | Compositions and methods of use of compounds to increase cancer patient survival time |
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| DE69707911T2 (de) | 2002-04-04 |
| WO1998014426A1 (en) | 1998-04-09 |
| EP0934261A1 (en) | 1999-08-11 |
| DE69707911D1 (de) | 2001-12-06 |
| CN1231658A (zh) | 1999-10-13 |
| US5922902A (en) | 1999-07-13 |
| ES2163197T3 (es) | 2002-01-16 |
| PT934261E (pt) | 2002-04-29 |
| JP2001501219A (ja) | 2001-01-30 |
| CA2263204C (en) | 2005-06-07 |
| AU4390297A (en) | 1998-04-24 |
| EP0934261B1 (en) | 2001-10-31 |
| CA2263204A1 (en) | 1998-04-09 |
| ATE207892T1 (de) | 2001-11-15 |
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