CN1305844C - Dialkyl-beta-propiothetin haloid acid salt and carboxylate preparation method - Google Patents
Dialkyl-beta-propiothetin haloid acid salt and carboxylate preparation method Download PDFInfo
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- CN1305844C CN1305844C CNB200510108680XA CN200510108680A CN1305844C CN 1305844 C CN1305844 C CN 1305844C CN B200510108680X A CNB200510108680X A CN B200510108680XA CN 200510108680 A CN200510108680 A CN 200510108680A CN 1305844 C CN1305844 C CN 1305844C
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- 239000002253 acid Substances 0.000 title claims abstract description 22
- 150000003839 salts Chemical class 0.000 title abstract description 11
- 238000002360 preparation method Methods 0.000 title description 4
- 150000007942 carboxylates Chemical class 0.000 title 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims abstract description 33
- 150000003568 thioethers Chemical class 0.000 claims abstract description 27
- 238000000034 method Methods 0.000 claims abstract description 26
- -1 carboxylic acid salt compounds Chemical class 0.000 claims abstract description 23
- 150000002148 esters Chemical class 0.000 claims abstract description 13
- 239000002994 raw material Substances 0.000 claims abstract description 8
- 150000007524 organic acids Chemical class 0.000 claims abstract description 6
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 22
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 claims description 11
- KMTRUDSVKNLOMY-UHFFFAOYSA-N Ethylene carbonate Chemical compound O=C1OCCO1 KMTRUDSVKNLOMY-UHFFFAOYSA-N 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 6
- 239000011707 mineral Substances 0.000 claims description 6
- 239000000463 material Substances 0.000 claims description 5
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 claims description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 4
- 150000001733 carboxylic acid esters Chemical class 0.000 claims description 4
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 claims description 3
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 2
- 230000001186 cumulative effect Effects 0.000 claims description 2
- 235000011187 glycerol Nutrition 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 150000003462 sulfoxides Chemical class 0.000 claims description 2
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 claims 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims 2
- 125000001931 aliphatic group Chemical group 0.000 claims 1
- LJSQFQKUNVCTIA-UHFFFAOYSA-N diethyl sulfide Chemical compound CCSCC LJSQFQKUNVCTIA-UHFFFAOYSA-N 0.000 claims 1
- 125000004494 ethyl ester group Chemical group 0.000 claims 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims 1
- 150000002762 monocarboxylic acid derivatives Chemical class 0.000 claims 1
- 229910052736 halogen Inorganic materials 0.000 abstract description 4
- 150000002367 halogens Chemical class 0.000 abstract description 3
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 abstract 1
- 150000007522 mineralic acids Chemical class 0.000 abstract 1
- 238000005580 one pot reaction Methods 0.000 abstract 1
- DFPOZTRSOAQFIK-UHFFFAOYSA-N S,S-dimethyl-beta-propiothetin Chemical compound C[S+](C)CCC([O-])=O DFPOZTRSOAQFIK-UHFFFAOYSA-N 0.000 description 24
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- 230000000740 bleeding effect Effects 0.000 description 16
- 238000001035 drying Methods 0.000 description 16
- 238000001914 filtration Methods 0.000 description 16
- 238000003756 stirring Methods 0.000 description 15
- 239000007789 gas Substances 0.000 description 13
- 229910052739 hydrogen Inorganic materials 0.000 description 13
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 13
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 12
- 230000003197 catalytic effect Effects 0.000 description 12
- 239000001257 hydrogen Substances 0.000 description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 11
- 241000251468 Actinopterygii Species 0.000 description 10
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 10
- 239000005864 Sulphur Substances 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 241000195493 Cryptophyta Species 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 4
- 230000001737 promoting effect Effects 0.000 description 4
- 230000009182 swimming Effects 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 241000252233 Cyprinus carpio Species 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- FFFHZYDWPBMWHY-VKHMYHEASA-N L-homocysteine Chemical compound OC(=O)[C@@H](N)CCS FFFHZYDWPBMWHY-VKHMYHEASA-N 0.000 description 3
- 241000277331 Salmonidae Species 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000007259 addition reaction Methods 0.000 description 3
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- 238000000605 extraction Methods 0.000 description 3
- 239000013505 freshwater Substances 0.000 description 3
- 210000000867 larynx Anatomy 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 230000003204 osmotic effect Effects 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000013535 sea water Substances 0.000 description 3
- HHVIBTZHLRERCL-UHFFFAOYSA-N sulfonyldimethane Chemical compound CS(C)(=O)=O HHVIBTZHLRERCL-UHFFFAOYSA-N 0.000 description 3
- 239000001763 2-hydroxyethyl(trimethyl)azanium Substances 0.000 description 2
- 241000143060 Americamysis bahia Species 0.000 description 2
- 235000019743 Choline chloride Nutrition 0.000 description 2
- 241000238557 Decapoda Species 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- MYGVPKMVGSXPCQ-JEDNCBNOSA-N Methylmethionine sulfonium salt Chemical compound [Cl-].C[S+](C)CC[C@H](N)C(O)=O MYGVPKMVGSXPCQ-JEDNCBNOSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 125000001118 alkylidene group Chemical group 0.000 description 2
- 230000002180 anti-stress Effects 0.000 description 2
- 230000006399 behavior Effects 0.000 description 2
- 229960003403 betaine hydrochloride Drugs 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- HOPSCVCBEOCPJZ-UHFFFAOYSA-N carboxymethyl(trimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)(C)CC(O)=O HOPSCVCBEOCPJZ-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- SGMZJAMFUVOLNK-UHFFFAOYSA-M choline chloride Chemical compound [Cl-].C[N+](C)(C)CCO SGMZJAMFUVOLNK-UHFFFAOYSA-M 0.000 description 2
- 229960003178 choline chloride Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000004634 feeding behavior Effects 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 229910000039 hydrogen halide Inorganic materials 0.000 description 2
- 239000012433 hydrogen halide Substances 0.000 description 2
- MLFHJEHSLIIPHL-UHFFFAOYSA-N isoamyl acetate Chemical compound CC(C)CCOC(C)=O MLFHJEHSLIIPHL-UHFFFAOYSA-N 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- PSBDWGZCVUAZQS-UHFFFAOYSA-N (dimethylsulfonio)acetate Chemical compound C[S+](C)CC([O-])=O PSBDWGZCVUAZQS-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 108010088623 Betaine-Homocysteine S-Methyltransferase Proteins 0.000 description 1
- 102100025991 Betaine-homocysteine S-methyltransferase 1 Human genes 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical class S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- 101100001672 Emericella variicolor andG gene Proteins 0.000 description 1
- 101000933413 Homo sapiens Betaine-homocysteine S-methyltransferase 1 Proteins 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- YEJCDKJIEMIWRQ-UHFFFAOYSA-N Linopirdine Chemical compound O=C1N(C=2C=CC=CC=2)C2=CC=CC=C2C1(CC=1C=CN=CC=1)CC1=CC=NC=C1 YEJCDKJIEMIWRQ-UHFFFAOYSA-N 0.000 description 1
- DMULVCHRPCFFGV-UHFFFAOYSA-N N,N-dimethyltryptamine Chemical compound C1=CC=C2C(CCN(C)C)=CNC2=C1 DMULVCHRPCFFGV-UHFFFAOYSA-N 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 229930003779 Vitamin B12 Natural products 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 235000019728 animal nutrition Nutrition 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
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- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid group Chemical class C(CC(O)(C(=O)O)CC(=O)O)(=O)O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 1
- AGVAZMGAQJOSFJ-WZHZPDAFSA-M cobalt(2+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2 Chemical compound [Co+2].N#[C-].[N-]([C@@H]1[C@H](CC(N)=O)[C@@]2(C)CCC(=O)NC[C@@H](C)OP(O)(=O)O[C@H]3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)\C2=C(C)/C([C@H](C\2(C)C)CCC(N)=O)=N/C/2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O AGVAZMGAQJOSFJ-WZHZPDAFSA-M 0.000 description 1
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- SEACYXSIPDVVMV-UHFFFAOYSA-L eosin Y Chemical compound [Na+].[Na+].[O-]C(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C([O-])=C(Br)C=C21 SEACYXSIPDVVMV-UHFFFAOYSA-L 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 1
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- 150000002500 ions Chemical class 0.000 description 1
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- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a method for economically and effectively preparing dialkyl-beta-propanoic acid thetine halogen acid salts and carboxylic acid salt compounds The present invention comprises the steps that acrylic acid or the ester thereof, thioether, organic acid or inorganic acid is used as a raw material, and a product with intensive nose-stimulation stinky odour is obtained in organic solvent under the condition of 0-150 DEG C temperature through a one-step reaction for 1-24 hours.
Description
Technical field
The present invention relates to the preparation method of dialkyl-beta-propiothetin haloid acid salt and carboxylate salt, belong to the field of fine chemistry goods and medicine, fodder additives.
Background technology
The salt of dialkyl group-β-DMPT is existing a large amount of applied researcies report in fields such as atmospheric environment, medicine and feed, and wherein studying more is the salt of DMPT (being dimethyl-β-DMPT).
DMPT is a kind of sulfonium salt compound that occurring in nature exists, it is an element sulphur round-robin important step in the atmospheric marine environment, algae in the marine organisms absorbs with the conversion inorganic sulfur with planktonic organism becomes different organic molecule (be mainly tervalent dimethyl sulfonium salt, representational is DMPT).These sulfonium salts are considered to the important source of element sulphur round-robin in the environment, mode by enzyme and physics is degraded to dimethyl thioether (DMS), DMS is water insoluble, volatile, solubleness is lower in seawater, then DMS discharge into the atmosphere from the ocean (DMS account for from all biogenic element sulphur circulatioies of ocean 90%).Nonpolar DMS in the atmosphere becomes dimethyl sulfoxide (DMSO) (DMSO), dimethyl sulfone (MSM) and sulfuric acid isopolarity compound through the catalysed oxidn of solar ultraviolet, because the water absorbability of these materials, form the back and assemble steam formation cloud, and return ground with rainwater, for all land life entities provide the sulphur that needs, thereby finish the working cycle of sulphur at large nature.
DMPT is under neutrality, the elementary charge condition at pH value, has very high solubleness in water, is the main osmotic pressure regulatory factor of algae.Though the mineral ion of high density also can be regulated osmotic pressure, they will enter proteinic peripheral water layer, can cause proteinic tortuous structure to be unfolded, and have influenced proteinic character, to the toxic effect of algae; And DMPT belongs to the good solute of mutual capacitive owing to the zwitter-ion structure in its molecule, and it is ostracised outside the protein water layer, thereby has stablized crumpled proteinic structure, can not cause reacting to each other between macromole and the solvent.Up-to-date studies show that (Sunda W, 2002, S.F.Riseman andG.R.2004), DMPT may be a kind of antioxidant also except the function as the osmotic pressure regulatory factor, be marine alga or planktonic organism to anti-ultraviolet a kind of stress measure.
Aspect medical, DMPT also has some applied researcies, as NakajimaK. (1991), the research of people (1990) such as Ishida Y. report DMPT aspect treatment stomach ulcer, duVigneaud et al. (1948), Dubnoff and Borsook (1948), J.D.Mulligan, (1998), Eric I.Park and Timothy A.Garrow (1999), Timothy A.Garrow, (1996) also reported DMPT conduct methyl donor efficiently, through intravital BHMT enzyme of higher animal (Betaine-homocysteinemethyltransferase) and B12-MS enzyme (vitamin B12-dependent Metsynthase), make homocysteine homocysteine be converted into methionine(Met), thereby reduce homocysteine content in the blood, reach prevention and treatment arteriosclerosis, the purpose of vascular disease such as thrombosis.
Particularly, DMPT is widely used in field of fodder, it be behind amino acid, trimethyl-glycine, glutamine, develop the 4th generation aquatic animal phagostimulant.DMPT to the trophism of aquatic animal is:
1. to the promoter action of fish feeding behavior.Contain (CH with 20 kinds
3)
2The low molecule organic matter of S-group is stung the food behavioral experiment to the sea water and fresh water fish, find the promoter action of the stinging food behavior the strongest (Nakajima of DMPT to three kinds of fishes such as goldfish, carp and black crucian of fresh water, Nippon Suisan Gakaishi 1989,55 (4); 689～695), to the feeding behavior of the porgy in the seawater also have significant promoter action (Nakajima, Nippon SuisanGakaishi 1990,56 (7); 1151～1154).
2. to the growth promoting function of aquatic animal.
(1). to the growth promoting function of fish.DMPT is to the growth promoting function of porgy the most obvious (Nakajima, Nippon Suisan Gakaishi 1989,55 (7); 1291), to two kinds of fresh-water fishes goldfish and the growth promoting function that splits the larynx trout also clearly (Nakajima, NipponSuisan Gakaishi 1991,57 (8); 1603).Contain (CH with containing Vitamin U and DMPT at interior three kinds
3)
2The low molecular compound of S-group adds breeding goldfish in the daily ration, carp and porgy to, as a result the promotes growth effect of DMPT best (Nakajima, Nippon SuisanGakaishi 1991,57 (4); 673～679).
(2) shell and the growth of promotion shrimps.Add daily ration with DMT, DMPT, Vitamin U, betaine hydrochloride and choline chloride 60 respectively, raise the long-armed shrimp of striped, no matter the result is from upgrowth situation or surviving rate, the effect of DMPT is best, the poorest (the Nakajima of the effect of betaine hydrochloride and choline chloride 60, Nippon Suisan Gakaishi 1991,57 (9); 1717～1722).Both hold methyl donor the most frequently used in fowl and the fish feed back.This results suggest: can effectively utilize (CH in the shrimps nutritional-physiological process
3)
2Methyl on the S-group utilizes (CH
3)
3The efficient of the methyl on the N-group is extremely low.Must be allowed a choice when reminding us in shrimp feed, to add the methyl donor material.
3. improve swimming ability and the anti-stress ability of fish.The power of fish swimming ability has embodied the state of health of muscle.Nakajima (1991) has measured the influence of DMPT counterincision larynx trout, goldfish, carp and porgy swimming ability with the study of behaviour method, the amplitude of the swimming energy force rate other drug group raising of DMPT group is many greatly as a result, especially to the experiment of porgy, effect is (Nakajima especially obviously, Nippon Suisan Gakaishi 1991,57 (8); 1603 and 1991,57 (4); 673～679).Recover normal required time as the quantitative criterion of fish stress reaction with in conjunction with the influence of short period of time caloric test DMPT with the dried up fish afterwards of record to above-mentioned several fish anti-stress abilities.As a result, goldfish and split larynx trout DMPT group to the resistivity of alternating temperature than separately control group improve 21% and 31% respectively (Nakajima, Nippon SuisanGakaishi 1992,58 (8); 1453～1458).
4. as methyl donor.(CH on the DMPT molecule
3)
2The S-group is the source of the required methyl of Animal nutrition metabolism, and two kinds of methyltransgerases (E.C.2.1.1.3 and E.C.2.1.1.5) are animal use (CH in the animal livers
3)
2The key point of methyl on the S-group.Making material with the porgy liver, with numerous (CH that contain
3)
2Find that DMPT is the most effective substrate in the active research of transmethylase of the compound of S-group as E.C.2.1.1.3 and E.C.2.1.1.5 in the substrate test liver.
What the application report of dialkyl group-β-DMPT salt compounds was more is halogen acid salt, and seldom relates to its vitriol, as dimethyl-β-DMPT vitriol.
About the preparation of dialkyl group-β-DMPT salt compounds two kinds of natural extract and chemical synthesiss are arranged.
Natural extract method such as the Japan clear 63-222670 of special permission communique are with the algae raw material, obtain with the water-containing organic solvent extraction.Because the DMPT content in the phycophyta is lower, the extraction cost height; And contain a large amount of impurity, be difficult to obtain highly purified product; Also will make the involved enzyme inactivation to improve the extraction yield in addition in extraction, technology is more numerous and diverse.
The following several pieces of reports of chemical synthesis: the Japan flat 2-56461 of special permission communique is with halogenated carboxylic acid and thioether reactant, and the sulfonium compound ingot that reaction end back forms is pulverized in mortar, uses organic solvent washing, obtains product with pure recrystallization.Very loaded down with trivial details in this method operation, very the labor intensive and the energy make it be difficult to carry out in suitability for industrialized production.
Mentioned among the CN1482117 with halogenated carboxylic acid and thioether in carboxylicesters,, stirred, made product be cooled to the room temperature suction filtration, obtained product with the low-carbon alcohol recrystallization through heating.This method is compared with preceding method and has been added carboxylicesters and make solvent, has improved the flowability of reaction system, and product is the powder that is easy to move, prevented from caking, and the product purity height, but too high with halogenated carboxylic acid as raw materials cost, and overall yield is very low.
It is that raw material has synthesized dimethyl-β-DMPT vitriol with vinylformic acid or acrylate and dimethyl sulphide, the vitriol oil that the Japanese Patent spy opens 2004-307402.This method is compared with vinylformic acid with preceding two kinds of methods and has been substituted halogenated carboxylic acid, though reduced raw materials cost, owing to used the vitriol oil, has increased the danger of operation, and it feeds intake and need proceed step by step, makes complex operation.Preparing halogen acid salt according to the processing condition of this patent disclosure is actually and carries out in two steps: the first step is that the addition reaction of vinylformic acid and hydrogen halide generates β-halopropanoic acid, second step was the substitution reaction of thioether and β-halopropanoic acid.The addition reaction of the first step vinylformic acid and hydrogen halide has many pieces of reports (US438639, US2759018, CN1138569, US5731469, CN1569799), wherein CN1569799 has summed up the technology of former pieces of documents, following two kinds of schemes have been proposed: the one, be halide reagent with hydrochloric acid, reaction pressure is a normal pressure, but temperature higher (70 ℃), the reaction times is grown (7 hours); The 2nd, be halide reagent with the hydrogen chloride gas, reaction pressure is a high pressure (0.3～0.8MPa).Doing this step addition reaction according to the technology of Japanese Patent takes any method reaction conditions all complicated.Mentioned above the reaction of second step halopropanoic acid and the thioether, the yield when being raw material with the bromo acid among the CN1482117 is 64.7%, and owing to the specific activity bromine of chlorine is also low, productive rate can be lower.In sum, according to Japanese Patent two-step approach synthesization of dimethyl-β-propionic acid halogen acid salt technology is loaded down with trivial details, reaction conditions is complicated, cost is higher.Therefore, need development technology is more simple, cost is lower, yield the is higher synthetic dialkyl-beta-propiothetin haloid acid salt and the method for carboxylate salt.
Summary of the invention
Therefore, the purpose of this invention is to provide a kind of method that can prepare dialkyl-beta-propiothetin haloid acid salt and carboxylate salt by simple steps low-cost, with high yield.
To achieve these goals, the inventor has carried out intensive research, found that, with obtain easily, vinylformic acid that price is comparatively cheap or its ester, thioether and organic acid or mineral acid be raw material, in organic solvent, under 0～150 ℃ temperature condition,, can high yield for example can obtain product up to 94% through single step reaction 1～24 hour.
Reaction formula of the present invention is as follows:
Wherein solvent represents that solvent, cat. represent catalyzer.
Wherein: R
1=H, CH
3, CH
2CH
3
During n=1, R
2=Cl, Br or RCOO, wherein R is H, C
1-6Aliphatic alkyl (straight or branched);
N=2,3 o'clock, R
2=R ' is n (COO), and wherein R ' is C
1-6Aliphatics alkylidene group or alkylidene (straight or branched);
R
3, R
4Be C
1-3Alkyl.
The mol ratio of described vinylformic acid or its ester and thioether is 1: 0.5～4, preferably is controlled at 1: 0.8～3.0.
Described vinylformic acid or its ester are 1: 0.8～2 with the mol ratio of acid, preferably are controlled at 1: 1～1.5.
Described solvent is carboxylicesters, ketone, ether, aliphatic hydrocarbon, aromatic hydrocarbon, acid amides, sulfoxide etc., ethyl formate for example, ethyl acetate, isopropyl acetate, Isoamyl Acetate FCC, acetone, butanone, tetrahydrofuran (THF), 1-4 dioxane, isopropyl ether, benzene, toluene, normal hexane, dimethyl sulfoxide (DMSO), dimethyl formamide etc.Consumption is 50～300% of vinylformic acid or its ester and a thioether gross weight, preferably is controlled at 80～220%.
Described temperature of reaction is 0～150 ℃, preferably is controlled at 20～100 ℃.Preferred room temperature is not because separate easily solvent and product at ambient temperature can reduce productive rate.
According to a preferred embodiment of the invention a, adopt the catalyzer that for example is easy to get, can reuses in the reaction process, catalyzer is a specific inductivity at 20～90 material, a kind of or its mixture in methyl alcohol, ethanol, glycerine, ethylene glycol, water, Nitromethane 99Min., Y-butyrolactone, the NSC 11801 for example, described catalyst consumption is below 5% of cumulative volume.
State in the use under the condition of catalyzer, the described reaction times is 1～24 hour, because of used acid difference difference.Use the mineral acid time to be controlled at 2～8 hours, use the organic acid time to be controlled at 10～18 hours.
Required condition is simple because the present invention reacts, and the reaction times is short, the reaction yield height, thus reduced total cost.Reaction finishes the good fluidity of back system, and is simple to operate, is easy to industrialization.
Embodiment
The comparative example 1
Add 15 milliliters of vinylformic acid in 100 milliliters of autoclaves, 30 milliliters of ethyl acetate feed hydrogen chloride gas, keeping the still internal pressure is 0.5Mpa, reaction is 2 hours under the room temperature, removes pressure, adds 16 milliliters of dimethyl sulphides, 70 degrees centigrade were reacted 24 hours, cool to room temperature, the filtration of bleeding, drying, obtaining the white solid that 10.4 grams contain strong pungent fishy odor is dimethyl-β-DMPT hydrochloride, and yield only is 28.3%.M.p.128～129 ℃; [analysis]
1HNMR:2.86 (6H, unimodal, for connecting on the sulphur atom hydrogen on two methyl), 2.92 (2H is to connect the hydrogen on the methylene radical on the carboxyl, triplet), 3.46 (2H, triplet are to connect the hydrogen on the methylene radical on the sulphur atom).
Embodiment 1
In 100 milliliters of there-necked flasks, add 16 milliliters of dimethyl sulfides, 15 milliliters of vinylformic acid, 30 milliliters of ethyl acetate are warmed up to 50 degrees centigrade, stir to feed 4.83 liters of hydrogen chloride gas down, led in 4 hours, cool to room temperature, the filtration of bleeding, drying, obtain 17.5 gram dimethyl-β-DMPT hydrochlorides, yield 47.6%.M.p.128～129 ℃; [analysis]
1HNMR:2.86 (6H, unimodal, for connecting on the sulphur atom hydrogen on two methyl), 2.92 (2H is to connect the hydrogen on the methylene radical on the carboxyl, triplet), 3.46 (2H, triplet are to connect the hydrogen on the methylene radical on the sulphur atom).
Embodiment 2
In 100 milliliters of there-necked flasks, add 16 milliliters of dimethyl sulfides, 15 milliliters of vinylformic acid, 30 milliliters of ethyl acetate, the NSC 11801 of adding catalytic amount is warmed up to 50 degrees centigrade, stirs to feed 4.83 liters of hydrogen chloride gas down, has led in 4 hours.Cool to room temperature, the filtration of bleeding, drying obtains 31.4 gram dimethyl-β-DMPT hydrochlorides, yield 85.3%.
Embodiment 3
In 100 milliliters of there-necked flasks, add 16 milliliters of dimethyl sulfides, 15 milliliters of vinylformic acid, 30 milliliters of acetone, 13 milliliters of acetic acid, the Nitromethane 99Min. that adds catalytic amount, be warmed up to 60 degrees centigrade, stirring reaction 12 hours, cool to room temperature, the filtration of bleeding, drying, obtaining the pale solid that 26.2 grams contain strong pungent fishy odor is dimethyl-β-DMPT acetate, yield 61.7%.
Embodiment 4
In 100 milliliters of there-necked flasks, add 16 milliliters of thioethers, 15 milliliters of vinylformic acid, 30 milliliters of acetone, 11.8 gram oxalic acid, the Nitromethane 99Min. that adds catalytic amount, be warmed up to 60 degrees centigrade, stirring reaction 12 hours, cool to room temperature, the filtration of bleeding, drying, obtaining the white solid that 32.2 grams contain strong pungent fishy odor is dimethyl-β-DMPT oxalate, yield 65.8%.[analysis]
1HNMR:2.87 (6H, unimodal, for connecting on the sulphur atom hydrogen on two methyl), 2.93 (2H is to connect the hydrogen on the methylene radical on the carboxyl, triplet), 3.49 (2H, triplet are to connect the hydrogen on the methylene radical on the sulphur atom).
Embodiment 5
In 100 milliliters of there-necked flasks, add 16 milliliters of thioethers, 15 milliliters of vinylformic acid, 30 milliliters of acetone, 14.6 gram citric acids, the Nitromethane 99Min. that adds catalytic amount, be warmed up to 60 degrees centigrade, stirring reaction 12 hours, cool to room temperature, the filtration of bleeding, drying, obtaining the white solid that 46.1 grams contain strong pungent fishy odor is dimethyl-β-DMPT Citrate trianion, yield 64.7%.
Embodiment 6
In 100 milliliters of there-necked flasks, add 16 milliliters of thioethers, 15 milliliters of vinylformic acid, 30 milliliters of tetrahydrofuran (THF)s, the NSC 11801 of adding catalytic amount is warmed up to 50 degrees centigrade, stirs to feed 4.83 liters of hydrogen chloride gas down, has led in 4 hours.Cool to room temperature, the filtration of bleeding, drying obtains 31.4 gram dimethyl-β-DMPT hydrochlorides, yield 85.2%.
Embodiment 7
In 100 milliliters of there-necked flasks, add 16 milliliters of thioethers, 15 milliliters of vinylformic acid, 30 milliliters of 1-4 dioxane are warmed up to 55 degrees centigrade, stir down and feed 4.83 liters of hydrogen chloride gas, have led in 4 hours.Cool to room temperature, the filtration of bleeding, drying obtains 21.2 gram dimethyl-β-DMPT hydrochlorides, yield 57.7%.
Embodiment 8
In 100 milliliters of there-necked flasks, add 16 milliliters of thioethers, 15 milliliters of vinylformic acid, 30 milliliters of 1-4 dioxane, the NSC 11801 of adding catalytic amount is warmed up to 55 degrees centigrade, stirs to feed 4.83 liters of hydrogen chloride gas down, has led in 4 hours.Cool to room temperature, the filtration of bleeding, drying obtains 30.8 gram dimethyl-β-DMPT hydrochlorides, yield 83.7%.
Embodiment 9
In 100 milliliters of there-necked flasks, add 16 milliliters of thioethers, 15 milliliters of vinylformic acid, 30 milliliters of butanone, the water of adding catalytic amount is warmed up to 50 degrees centigrade, stirs to feed 4.83 liters of hydrogen chloride gas down, has led in 4 hours.Cool to room temperature, the filtration of bleeding, drying obtains 31.2 gram dimethyl-β-DMPT hydrochlorides, yield 84.9%.
Embodiment 10
In 100 milliliters of there-necked flasks, add 16 milliliters of thioethers, 15 milliliters of vinylformic acid, 30 milliliters of dimethyl formamides, the NSC 11801 of adding catalytic amount is warmed up to 55 degrees centigrade, stirs to feed 4.83 liters of hydrogen chloride gas down, has led in 4 hours.Cool to room temperature, the filtration of bleeding, drying obtains 34 gram dimethyl-β-DMPT hydrochlorides, yield 92.6%.
Embodiment 11
In 100 milliliters of there-necked flasks, add 16 milliliters of thioethers, 15 milliliters of vinylformic acid, 30 milliliters of isopropyl ethers, the NSC 11801 of adding catalytic amount is warmed up to 50 degrees centigrade, stirs to feed 4.83 liters of hydrogen chloride gas down, has led in 4 hours.Cool to room temperature, the filtration of bleeding, drying obtains 27.4 gram dimethyl-β-DMPT hydrochlorides, yield 74.5%.
Embodiment 12
In 100 milliliters of there-necked flasks, add 16 milliliters of thioethers, 15 milliliters of vinylformic acid, 30 milliliters of dimethyl sulfoxide (DMSO), the NSC 11801 of adding catalytic amount is warmed up to 55 degrees centigrade, stirs to feed 4.83 liters of hydrogen chloride gas down, has led in 4 hours.Cool to room temperature, the filtration of bleeding, drying obtains 34.6 gram dimethyl-β-DMPT hydrochlorides, yield 94.3%.
Embodiment 13
In 100 milliliters of there-necked flasks, add 16 milliliters of thioethers, 15 milliliters of vinylformic acid, 30 ml n-hexanes, the NSC 11801 of adding catalytic amount is warmed up to 45 degrees centigrade, stirs to feed 4.83 liters of hydrogen chloride gas down, has led in 4 hours.Cool to room temperature, the filtration of bleeding, drying obtains 23.9 gram dimethyl-β-DMPT hydrochlorides, yield 64.9%.
Embodiment 14
In 100 milliliters of there-necked flasks, add 19 milliliters of thioethers, 15 milliliters of vinylformic acid, 30 milliliters of butanone, 25.9 gram hydrochloric acid is warmed up to 50 degrees centigrade, stirring reaction 4 hours, be cooled to room temperature, system is divided into two-layer, discards the upper strata, lower floor's sealing and standing 8 hours, the filtration of bleeding, drying, obtaining the white-yellowish solid that 29.7 grams contain strong pungent fishy odor is dimethyl-β-DMPT hydrochloride, yield 81%.M.p.129 ℃; [analysis]
1HNMR:2.86 (6H, unimodal, for connecting on the sulphur atom hydrogen on two methyl), 2.92 (2H is to connect the hydrogen on the methylene radical on the carboxyl, triplet), 3.46 (2H, triplet are to connect the hydrogen on the methylene radical on the sulphur atom).
Embodiment 15
In 100 milliliters of there-necked flasks, add 22 milliliters of thioethers, 19.5 milliliters of methyl acrylates, 30 milliliters of dimethyl sulfoxide (DMSO), the NSC 11801 of adding catalytic amount is warmed up to 55 degrees centigrade, stirs to feed 4.83 liters of hydrogen chloride gas down, has led in 4 hours.Cool to room temperature left standstill 8 hours, the filtration of bleeding, and drying, obtaining the white-yellowish solid that 36.8 grams contain strong pungent fishy odor is dimethyl-β-methyl propionate thetin hydrochloride, yield 92.7%.
Claims (14)
1. method for preparing uncle's sulfonium salt compounds, it is characterized in that with vinylformic acid or its ester, thioether, organic acid or mineral acid be raw material, in organic solvent, under 20～100 ℃ temperature condition, through single step reaction 1～24 hour, obtain described uncle's sulfonium salt compounds.
2. the method for preparing uncle's sulfonium salt compounds according to claim 1 is characterized in that: described vinylformic acid or its ester are vinylformic acid, methyl acrylate and/or ethyl ester; Described thioether is be selected from dimethyl sulfide, ethyl-sulfide and first and second thioethers at least a; Described organic acid is C
1-6The monocarboxylic acid of aliphatic straight or branched or polycarboxylic acid; Described mineral acid is hydrochloric acid and/or Hydrogen bromide.
3. the method for preparing uncle's sulfonium salt compounds according to claim 1 is characterized in that: the mol ratio of described vinylformic acid or its ester and thioether is 1: 0.5～4.
4. the method for preparing uncle's sulfonium salt compounds according to claim 3 is characterized in that: the mol ratio of described vinylformic acid or its ester and thioether is 1: 0.8～3.0.
5. the method for preparing uncle's sulfonium salt compounds according to claim 1 is characterized in that: described vinylformic acid or its ester are 1: 0.8～2 with the mol ratio of acid.
6. the method for preparing uncle's sulfonium salt compounds according to claim 5 is characterized in that: described vinylformic acid or its ester are 1: 1～1.5 with the mol ratio of acid.
7. the method for preparing uncle's sulfonium salt compounds according to claim 1 is characterized in that: described solvent is be selected from carboxylicesters, ketone, ether, aliphatic hydrocarbon, aromatic hydrocarbon, acid amides and sulfoxide at least a.
8. the method for preparing uncle's sulfonium salt compounds according to claim 1 is characterized in that: the consumption of described solvent is 50～300% of vinylformic acid or its ester and a thioether gross weight.
9. the method for preparing uncle's sulfonium salt compounds according to claim 8 is characterized in that: the consumption of described solvent is 80～220% of vinylformic acid or its ester and a thioether gross weight.
10. the method for preparing uncle's sulfonium salt compounds according to claim 1 is characterized in that: described temperature of reaction is 20～60 ℃.
11. the method for preparing uncle's sulfonium salt compounds according to claim 10 is characterized in that: described temperature of reaction is 45～60 ℃.
12. the method for preparing uncle's sulfonium salt compounds according to claim 1 is characterized in that: described single step reaction carries out under the condition that catalyzer exists, and described catalyzer is a specific inductivity at 20～90 material.
13. the method for preparing uncle's sulfonium salt compounds according to claim 12, it is characterized in that: described catalyzer is a kind of or its mixture in methyl alcohol, ethanol, glycerine, ethylene glycol, water, Nitromethane 99Min., gamma-butyrolactone, the NSC 11801, and consumption is below 5% of cumulative volume.
14. according to claim 12 or the 13 described methods that prepare uncle's sulfonium salt compounds, it is characterized in that: when using organic acid, the reaction times of described single step reaction is 10～18 hours; When using mineral acid, the reaction times of described single step reaction is 2～8 hours.
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| CN104262220B (en) * | 2014-08-18 | 2016-03-30 | 杭州海尔希畜牧科技有限公司 | A kind of preparation method of dimethyl-β-DMPT |
| CN105533267A (en) * | 2015-12-17 | 2016-05-04 | 宁波大学 | Special phagostimulant for sepia pharaonis and application of special phagostimulant |
| CN107382802A (en) * | 2017-06-21 | 2017-11-24 | 宜兴市天石饲料有限公司 | The preparation method of dimethyl beta DMPT |
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| CN1482117A (en) * | 2002-09-13 | 2004-03-17 | 北京桑普生物化学技术有限公司 | Method for preparing dimethyl sulfonium compound |
| JP2004307402A (en) * | 2003-04-08 | 2004-11-04 | Res Inst For Prod Dev | Method for producing 2-carboxyethyl dimethylsulfonium sulfate |
| CN1569799A (en) * | 2004-04-23 | 2005-01-26 | 上海华谊丙烯酸有限公司 | Process for preparing high-purity 3-chloropropionic acid |
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| JP2004307402A (en) * | 2003-04-08 | 2004-11-04 | Res Inst For Prod Dev | Method for producing 2-carboxyethyl dimethylsulfonium sulfate |
| CN1569799A (en) * | 2004-04-23 | 2005-01-26 | 上海华谊丙烯酸有限公司 | Process for preparing high-purity 3-chloropropionic acid |
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| CN102895506B (en) * | 2012-09-25 | 2013-12-18 | 王善 | Traditional Chinese medicine granular capsule for treating chronic cardiac failure |
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