CN1775770B - Method for preparing gibberellin GA4 - Google Patents
Method for preparing gibberellin GA4 Download PDFInfo
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- CN1775770B CN1775770B CN 200510010868 CN200510010868A CN1775770B CN 1775770 B CN1775770 B CN 1775770B CN 200510010868 CN200510010868 CN 200510010868 CN 200510010868 A CN200510010868 A CN 200510010868A CN 1775770 B CN1775770 B CN 1775770B
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- 229930191978 Gibberellin Natural products 0.000 title claims abstract description 10
- 239000003448 gibberellin Substances 0.000 title claims abstract description 10
- 238000000034 method Methods 0.000 title abstract description 6
- IXORZMNAPKEEDV-UHFFFAOYSA-N gibberellic acid GA3 Natural products OC(=O)C1C2(C3)CC(=C)C3(O)CCC2C2(C=CC3O)C1C3(C)C(=O)O2 IXORZMNAPKEEDV-UHFFFAOYSA-N 0.000 title abstract 3
- IXORZMNAPKEEDV-OBDJNFEBSA-N gibberellin A3 Chemical compound C([C@@]1(O)C(=C)C[C@@]2(C1)[C@H]1C(O)=O)C[C@H]2[C@]2(C=C[C@@H]3O)[C@H]1[C@]3(C)C(=O)O2 IXORZMNAPKEEDV-OBDJNFEBSA-N 0.000 claims abstract description 14
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 5
- 150000002367 halogens Chemical class 0.000 claims abstract description 4
- 239000002994 raw material Substances 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 96
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 52
- 239000000203 mixture Substances 0.000 claims description 45
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 26
- 238000006243 chemical reaction Methods 0.000 claims description 26
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 26
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 17
- 238000006317 isomerization reaction Methods 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 239000003375 plant hormone Substances 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 9
- 239000002841 Lewis acid Substances 0.000 claims description 9
- 238000001953 recrystallisation Methods 0.000 claims description 9
- 239000012046 mixed solvent Substances 0.000 claims description 8
- 239000000758 substrate Substances 0.000 claims description 8
- 239000010948 rhodium Substances 0.000 claims description 7
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 6
- 239000011630 iodine Substances 0.000 claims description 6
- 229910052740 iodine Inorganic materials 0.000 claims description 6
- 239000003208 petroleum Substances 0.000 claims description 6
- -1 potassium halide Chemical class 0.000 claims description 6
- 239000011734 sodium Substances 0.000 claims description 6
- 238000000855 fermentation Methods 0.000 claims description 5
- 230000004151 fermentation Effects 0.000 claims description 5
- 150000007517 lewis acids Chemical class 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 5
- 239000003054 catalyst Substances 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 229910052700 potassium Inorganic materials 0.000 claims description 4
- 239000011591 potassium Substances 0.000 claims description 4
- 229910052703 rhodium Inorganic materials 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 4
- 239000012279 sodium borohydride Substances 0.000 claims description 4
- ASZCVNVMQXNJGH-ZYRRHWMLSA-N (1S,2R,9S,12S)-4,12-dimethyl-13-oxotetracyclo[10.2.1.01,9.03,8]pentadeca-3,5,7-triene-2-carboxylic acid Chemical compound Cc1cccc2[C@H]3CC[C@@]4(C)C[C@@]3(CC4=O)[C@@H](C(O)=O)c12 ASZCVNVMQXNJGH-ZYRRHWMLSA-N 0.000 claims description 3
- ASZCVNVMQXNJGH-UHFFFAOYSA-N Gibberic acid Natural products C12CCC(C3)(C)C(=O)CC23C(C(O)=O)C2=C1C=CC=C2C ASZCVNVMQXNJGH-UHFFFAOYSA-N 0.000 claims description 3
- 229960004756 ethanol Drugs 0.000 claims description 3
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- 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 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims description 2
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 claims description 2
- 239000012467 final product Substances 0.000 claims description 2
- 150000005826 halohydrocarbons Chemical class 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- 229910052744 lithium Inorganic materials 0.000 claims description 2
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 229910052723 transition metal Inorganic materials 0.000 claims description 2
- 150000003624 transition metals Chemical class 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 3
- 238000005984 hydrogenation reaction Methods 0.000 abstract description 11
- 238000004519 manufacturing process Methods 0.000 abstract description 7
- 238000005695 dehalogenation reaction Methods 0.000 abstract description 3
- 230000002829 reductive effect Effects 0.000 abstract description 3
- 239000005980 Gibberellic acid Substances 0.000 abstract 1
- 239000002253 acid Substances 0.000 abstract 1
- 230000032050 esterification Effects 0.000 abstract 1
- 238000005886 esterification reaction Methods 0.000 abstract 1
- 150000002148 esters Chemical class 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 26
- 238000004809 thin layer chromatography Methods 0.000 description 22
- 239000007787 solid Substances 0.000 description 18
- 239000000047 product Substances 0.000 description 17
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 13
- 238000001514 detection method Methods 0.000 description 13
- 238000001035 drying Methods 0.000 description 13
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 235000013399 edible fruits Nutrition 0.000 description 10
- 238000005406 washing Methods 0.000 description 10
- 239000003643 water by type Substances 0.000 description 9
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 235000011167 hydrochloric acid Nutrition 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 125000005843 halogen group Chemical group 0.000 description 5
- 241000196324 Embryophyta Species 0.000 description 4
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 4
- 235000007715 potassium iodide Nutrition 0.000 description 4
- 229960004839 potassium iodide Drugs 0.000 description 4
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 125000001246 bromo group Chemical class Br* 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000005648 plant growth regulator Substances 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N Alumina Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 238000003810 ethyl acetate extraction Methods 0.000 description 2
- 238000007245 halolactonization reaction Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 2
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 230000008635 plant growth Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000003750 conditioning effect Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 229930004069 diterpene Natural products 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000012262 fermentative production Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 229940059936 lithium bromide Drugs 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- LAIZPRYFQUWUBN-UHFFFAOYSA-L nickel chloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].[Cl-].[Ni+2] LAIZPRYFQUWUBN-UHFFFAOYSA-L 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 230000007226 seed germination Effects 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a method for preparing gibberellin GA4 (3beta, 10 alpha- dihydroxyl-20-decarbonized Gibberella-16-alkene-7, 19-diacid-19, 10 inner ester), using gibberellic acid GA4+7 obtained by fermenting as initial raw material, processing GA7 in the GA4+7 by Ease acid and so on to obtain open-loop products, making hydrogenation, halogen inner esterification and reductive dehalogenation on the open-loop products, then recrysatllizing the coarse products to obtain the target products GA4. The invention has the advantages of moderate reacting conditions, high yield, easy operation and applicability to industrialized production.
Description
Technical field
The present invention is the Plant hormones regulators,gibberellins GA of a kind of preparation following formula (I) expression
4Method.
Background technology: Plant hormones regulators,gibberellins class material (Gibberellins, GA) being the tetracyclic diterpene compounds, is that a class extensively is present in the endogenous plant growth regulating substance in the plant, has separated from plant so far and has identified 129 kinds of such materials, Plant hormones regulators,gibberellins class material has the promotion plant cell division, make cell elongation, blade enlarges, and stem prolongs, collateral generation, bolting promotes teleianthous male flower to form, and promotes effects such as seed germination and fruit growth.Gibberic acid GA wherein
3(Chinese commodity by name 920) in the existing nearly 30 years use history of China, it is the strongest to the promoter action activity of fruit cell elongation.In the plantation of multiple kinds of crops, obtain widespread use, remarkable in economical benefits.So far be still the plant-growth regulator that China hybridisation rice plantation institute must use.For fruit plantation and produce and play crucial effects, especially important effect is arranged for the flower and fruit protecting of plant (in the cold spell in later spring as no Plant hormones regulators,gibberellins spray application and will cause the underproduction significantly), the increase of fruit and the control of quality.Worldwide, Plant hormones regulators,gibberellins class endogenous plant growth regulator has been widely used in agriculture production, and microbial fermentation is the important production method of commercial Plant hormones regulators,gibberellins, and at present, the Plant hormones regulators,gibberellins class plant-growth regulator product of China's fermentative Production mainly contains GA
3(promptly 920) and GA
4+ GA
7Mixture.Because zymotechnique is limit, and still can not produce pure product GA so far
4For the production of large cash crop fruit, GA
4Be the most effective, one of Plant hormones regulators,gibberellins class plant-growth regulation and control substance that has no side effect, and the GA in the mixture
7Then can cause bad influence to 1 year bloom.Thereby produce pure product GA
4For the conditioning agent industry with and applied fruit production field all have great importance and economic worth.In recent years, GA
4+7Application aspect cash crop receives publicity, but the GA that fermentation obtains
4+7GA in the mixture
7Have comparatively significant side effects, mainly show the influence that next year is bloomed.To from this mixture, remove GA
7It is the thing of a difficulty.GA
4+ GA
7Be widely used in the production of fruit, flower and fruit protecting for example improves the quality of fruit, but GA
7Can have influence on blooming of next year, be the composition that remove.Be limited to zymotechnique and method and can only obtain GA at present
4+ GA
7(GA wherein
7Account for 30%) mixture, and GA
4And GA
7Textural difference is less, is difficult to separate pure system.CN1111286A, application number 95102240.7 is that a kind of acid-hydrolysis method that utilizes obtains Plant hormones regulators,gibberellins GA in the fermentation aftertreatment
4Method, but account for the GA of fermenting mixture three/the last one
7All destroyed.
Summary of the invention
The present invention proposes a kind of Plant hormones regulators,gibberellins GA
4The preparation method, the gibberic acid GA that it obtains with fermentation
4+7Be starting raw material, with GA
4+7In GA
7The open-loop products that obtains through processing such as Lewis acids, through hydrogenation, halo lactonize, reductive dehalogenation, then with the crude product recrystallization that obtains and obtain target product GA
4
Reaction conditions gentleness of the present invention, yield is higher, and easy handling is suitable for suitability for industrialized production, and reaction formula is as follows:
In the following formula, handle through Lewis acid, hydrochloric acid, Hydrogen bromide isomerization open loop, GA wherein
7Transform, the organic solvent of employing is the mixed solvent of ethyl acetate and ether, and Lewis acid adopts FeCl
3, ZnCl
2, ZnBr
2
The catalyzer that catalytic hydrogenation adopted is the transition metal rhodium; Catalyst levels is by weight with respect to reaction substrate GA
4+7Be 0.1%～10%, the solvent of employing is ethanol or tetrahydrofuran (THF).
The halo halogen that is adopted that lactonizes is the mixture of bromine, iodine and potassium halide or sodium halide, and consumption is halogen: GA in molar ratio
4+7=1～10:1, the solvent of employing be alcohol, ketone and halohydrocarbon and with the mixed solvent of water; The alkali that is adopted is carbonate M
2CO
3Or MHCO
3, wherein M=sodium, potassium, lithium, consumption is M with respect to the halo substrate in molar ratio
2CO
3Or MHCO
3: GA
4+7=3～10:1.
The reagent that the dehalogenation reduction reaction adopted is that zinc powder and moisture nickelous chloride are Zn:NiCl in molar ratio
2XH
2O=1～30:1, consumption are 5～20:1 with respect to the halo substrate in molar ratio; The solvent that is adopted is dehydrated alcohol, tetrahydrofuran (THF), 1,4-dioxane, acetonitrile; The reagent that adopts is sodium borohydride, and consumption is 3～30:1 with respect to the halo substrate in molar ratio; The solvent that is adopted can be anhydrous tetrahydro furan, DMSO, diglyme.
Final product GA4 is 1～10:1 or ethyl acetate/petroleum ether volume ratio 2～15:1 solvent recrystallization with acetone/sherwood oil volume ratio.
Embodiment
One, GA
4+7Lewis acid isomerization ring-opening reaction.GA is only arranged in an embodiment
7Isomerization reaction, the GA in the mixture can take place
4Obtain keeping.
Embodiment 1
With 2.0 gram GA
4+7Join in 200 milliliters of ether, stirring makes it to dissolve fully, adds 23.3 gram ZnBr then
2, treat that it dissolves the back fully and adds 0.1 ml water, uncovered stirring at room tens of hours.The TLC detection reaction fully after, adds 100 milliliters of ethyl acetate, transfer PH=1.0 with dilute hydrochloric acid, the saturated common salt water washing, anhydrous sodium sulfate drying, vacuum concentration be to doing, and obtains yellow solid (1 and GA4 mixture) 1.9 and restrain (yield 97%).The nuclear magnetic resonance spectrum of mixture
1H-NMR (300MHz, Acetone): δ: 6.44 (1H, d, J=9.7Hz), 5.92 (1H, d, J=9.7Hz), 4.97 (1H, s), 4.93 (1H, s), 4.89 (2H, brs), 4.26 (1H, m), 3.73 (1H, m), 3.23 (1H, d, J=10.8Hz), 3.10～1.35 (26H, m), 1.33～1.15 (6H, 2xs).
Embodiment 2
3.5 gram GA
4+7Be dissolved in the mixed solvent of 75 milliliters of ether and 25ml ethyl acetate, add 19.5 gram ZnCl
2After the dissolving, add 0.5 ml water, uncovered stirring at room tens of hours fully.TLC detects GA
7After reacting completely, add 100 milliliters of ethyl acetate, transfer PH=1.0 with 1N hydrochloric acid, the saturated common salt water washing, anhydrous sodium sulfate drying, vacuum concentration be to doing, and obtains yellow solid (1 and GA4 mixture) 3.1 grams (yield 90%).
Embodiment 3
3.5 gram GA
4+7Be dissolved in the mixed solvent of 75 milliliters of ether and 25ml ethyl acetate, add 19.5 gram FeCl
3, after the dissolving, add 0.5 ml water, uncovered stirring at room tens of hours fully.TLC detects GA
7After reacting completely, add 100 milliliters of ethyl acetate, transfer PH=1.0 with 1N hydrochloric acid, the saturated common salt water washing, anhydrous sodium sulfate drying, vacuum concentration be to doing, and obtains yellow solid (1 and GA4 mixture) 3.0 grams (yield 85%).
Embodiment 4
In the mixed solvent of 75 milliliters of ether of ice bath refrigerative, 5 ml waters and 25ml ethyl acetate, drip 5 milliliters of concentrated hydrochloric acids, drip off the back and stirred 30 minutes, add 3.5 gram GA
4+7, uncovered stirring at room tens of hours.TLC detects GA
7After reacting completely, add the washing of 100 milliliters of saturated sodium bicarbonate solutions, organic phase is transferred PH=1.0 with 1N hydrochloric acid, the saturated common salt water washing, and anhydrous sodium sulfate drying, vacuum concentration be to doing, and obtains yellow solid (1 and GA
4Mixture) 3.2 the gram (yield 91%).
Embodiment 5
3.5 gram GA
4+7Be dissolved in the mixed solvent of 75 milliliters of ether and 25ml ethyl acetate 20 milliliters of the glacial acetic acid solutions of dropping hydrogen bromide, uncovered stirring at room tens of hours.TLC detects GA
7After reacting completely, add the washing of 100 milliliters of saturated sodium bicarbonate solutions, organic phase is transferred PH=1.0 with 1N hydrochloric acid, the saturated common salt water washing, and anhydrous sodium sulfate drying, vacuum concentration be to doing, and obtains yellow solid (1 and GA
4Mixture) 2.8 the gram (yield 80%).
Two, GA
4+7Lewis acid isomerization open-loop products (1 and GA
4Mixture) hydrogenation.Under the embodiment condition, only have 1 hydro-reduction reaction, the GA in the mixture can take place
4Obtain keeping.
Embodiment 6
GA
4+7Lewis acid isomerization open-loop products (1 and GA
4Mixture) 3.4 grams are dissolved in 80 milliliters of tetrahydrofuran (THF)s, add 5% rhodium catalyst (Rh/Al2O3) 0.5 gram that is deposited on aluminium sesquioxide, logical hydrogen (H under the stirring at room
2) reacted tens of hours, after silica gel thin-layer chromatography (TLC) detection reaction is complete, filtering Rh/Al
2O
3, and with a little tetrahydrofuran (THF) washing filter residue, reclaim under reduced pressure tetrahydrofuran (THF), vacuum concentration are handled and are obtained faint yellow solid 3.4 grams (2 and GA
4Mixture) (yield 99%).The nuclear magnetic resonance spectrum of mixture
1H-NMR (300MHz, Acetone): δ: 4.97 (1H, s), 4.93 (1H, s), 4.89 (2H, brs), 4.06 (1H, m), 3.73 (1H, m), 3.23 (1H, d, J=10.8Hz), 3.10～1.35 (mH, m), 1.33～1.15 (6H, 2xs).
Embodiment 7
GA
4+7Lewis acid isomerization open-loop products (1 and GA
4Mixture) 3.4 grams are dissolved in 80 milliliters of ethanol, add the 5% rhodium catalyst (Rh/Al that is deposited on aluminium sesquioxide
2O
3) 1.5 grams, logical hydrogen H under the stirring at room
2Reacted tens of hours, after silica gel thin-layer chromatography (TLC) detection reaction is complete, filtering Rh/Al
2O
3, and with a little washing with alcohol filter residue, decompression and solvent recovery, vacuum concentration are handled and are obtained faint yellow solid 3.4 grams (2 and GA
4Mixture) (yield 99%).The nuclear magnetic resonance spectrum of mixture
1H-NMR (300MHz, Acetone): δ: 4.97 (1H, s), 4.93 (1H, s), 4.89 (2H, brs), 4.06 (1H, m), 3.73 (1H, m), 3.23 (1H, d, J=10.8Hz), 3.10～1.35 (mH, m), 1.33～1.15 (6H, 2xs).
Three, GA
4+7The product of isomerization and hydrogenation (2 and GA
4Mixture) the halo lactonization reaction.Under the embodiment condition, only have 2 halo lactonization reaction, the GA in the mixture can take place
4Obtain keeping.
Embodiment 8
With GA
4+7The product of isomerization and hydrogenation (2 and GA
4Mixture) 3.4 grams are dissolved in 50 milliliters of acetone and 10 ml waters, add salt of wormwood 2.8 grams, iodine 2.4 grams and potassiumiodide 1.5 grams.Stirring at room stoichiometric number hour is after the TLC detection reaction finishes.Slowly adding saturated sodium thiosulfate solution to reaction soln color under stirring disappears, add 100 milliliters of ethyl acetate then, hcl acidifying is to PH=1.0, ethyl acetate is washed with saturated brine, anhydrous sodium sulfate drying, vacuum concentration is to doing, and obtains faint yellow solid (3 and GA4 mixture) 3.5 grams (yield about 86%).The nuclear magnetic resonance spectrum of mixture
1H-NMR (300MHz, Acetone): δ: 5.03 (1H, brs), 4.97 (1H, s), 4.93 (1H, s), 4.89 (1H, brs), 4.06 (1H, m), 3.73 (1H, m), 3.23 (1H, d, J=10.8Hz), 3.10～1.35 (mH, m), 1.33～1.15 (6H, 2xs).
Embodiment 9
With GA
4+7The product of isomerization and hydrogenation (2 and GA
4Mixture) 9.7 grams are dissolved in 100 milliliters of acetone and 20 ml waters, add saleratus 7.6 grams, iodine 6.9 grams and potassiumiodide 4.5 grams, stirring at room stoichiometric number ten minutes.After the TLC detection reaction finishes, slowly add saturated sodium thiosulfate solution to reaction soln color under stirring and disappear, add 100 milliliters of ethyl acetate then, hcl acidifying is to PH=1.0, ethyl acetate is washed with saturated brine, anhydrous sodium sulfate drying, and vacuum concentration is to doing.Obtain faint yellow solid (3 and GA
4Mixture) 9.5 the gram (yield 86%).
Embodiment 10
With GA
4+7The product 2 of isomerization and hydrogenation and the mixture of GA4 9.5 grams are dissolved in 100 milliliters of methylene dichloride and 20 ml waters, add yellow soda ash 4.8 grams, iodine 4.6 grams and potassiumiodide 3.0 grams.Stirring at room stoichiometric number hour.After the TLC detection reaction finishes, slowly adding saturated sodium thiosulfate solution to reaction soln color under stirring disappears, add 100 milliliters of ethyl acetate then, hcl acidifying is to PH=1.0, ethyl acetate is washed with saturated brine, anhydrous sodium sulfate drying, vacuum concentration be to doing, and obtains faint yellow solid (3 and GA
4Mixture) 9.4 the gram (yield 85%).
Embodiment 11
With GA
4+7The product of isomerization and hydrogenation (2 and GA
4Mixture) 3.4 grams are dissolved in 50 milliliters of acetone and 10 ml waters, add salt of wormwood 2.8 grams, iodine 2.4 grams and potassiumiodide 1.5 grams.Stirring at room stoichiometric number hour is after the TLC detection reaction finishes.Slowly add saturated sodium thiosulfate solution to reaction soln color under stirring and disappear, add 100 milliliters of ethyl acetate then, hcl acidifying is to PH=1.0, ethyl acetate is washed with saturated brine, anhydrous sodium sulfate drying, vacuum concentration be to doing, and obtains faint yellow solid (3 and GA
4Mixture) 3.5 the gram (yield about 86%).
Embodiment 12
With GA
4+7The product of isomerization and hydrogenation (2 and GA
4Mixture) 4.6 grams are dissolved in 50 milliliters of tetrahydrofuran (THF)s, add in 100 ml waters and saleratus 5.0 grams, Sodium Bromide 5.0 grams are cooled to-20 ℃, slowly drip 3 milliliters of liquid bromines.Stirring at room stoichiometric number ten minutes, after thin-layer chromatography TLC detection reaction finishes, slowly adding saturated sodium thiosulfate solution to reaction soln color under stirring disappears, add 100 milliliters of ethyl acetate then, hcl acidifying is to PH=1.0, and ethyl acetate is washed with saturated brine, anhydrous sodium sulfate drying, vacuum concentration is to dried faint yellow solid 5.3 gram (yield 86%) that obtains, and further obtains faint yellow solid (3 and GA after the recrystallization from ethyl acetate/petroleum ether
4Mixture) 3.0 the gram (yield 65%).
Embodiment 13
The product of GA4+7 isomerization and hydrogenation (2 and GA4 mixture) 4.6 grams are dissolved in 50 ml methanol, add in 100 ml waters and sodium bicarbonate 5.0 grams, lithiumbromide 5.0 grams are cooled to-20 ℃, slowly drip 3 milliliters of liquid bromines.Stirring at room stoichiometric number ten minutes, after thin-layer chromatography TLC detection reaction finishes, slowly adding saturated sodium thiosulfate solution to reaction soln color under stirring disappears, add 100 milliliters of ethyl acetate then, hcl acidifying is to PH=1.0, and ethyl acetate is washed with saturated brine, anhydrous sodium sulfate drying, vacuum concentration is to dried faint yellow solid 5.3 gram (yield 86%) that obtains, and further obtains faint yellow solid (3 and GA after the recrystallization from ethyl acetate/petroleum ether
4Mixture) 4.6 the gram (yield 75%),
Embodiment 14
With GA
4+7The product of isomerization and hydrogenation (2 and GA
4Mixture) 4.6 grams are dissolved in 50 milliliters of tetrahydrofuran (THF)s, add in 100 ml waters and Quilonum Retard 5.0 grams, Sodium Bromide 5.0 grams are cooled to-20 ℃, slowly drip 3 milliliters of liquid bromines.Stirring at room stoichiometric number ten minutes, after thin-layer chromatography TLC detection reaction finishes, slowly adding saturated sodium thiosulfate solution to reaction soln color under stirring disappears, add 100 milliliters of ethyl acetate then, hcl acidifying is to PH=1.0, and ethyl acetate is washed with saturated brine, anhydrous sodium sulfate drying, vacuum concentration is to dried faint yellow solid 5.3 gram (yield 86%) that obtains, and further obtains faint yellow solid (3 and GA after the recrystallization from ethyl acetate/petroleum ether
4Mixture) 4.6 the gram (yield 75%).
Three, Iod R is taken off in the lactonize reduction of product 3 of halo.Under the embodiment condition, only have 3 can take place to reduce to take off Iod R, the GA in the mixture
4Obtain keeping.
Embodiment 15
Take by weighing Zn powder 5.2 gram and Nickel dichloride hexahydrate (NiCl
26H
2O) 1.9g mixes with 100 milliliters of tetrahydrofuran (THF)s, adds 5 ml waters, and stirring at room 30 minutes adds (3 and GA then
4Mixture) 9.5 the gram.Stoichiometric number hour under the stirring at room, TLC detection reaction be back filtering precipitation fully, and filter residue washs with a little tetrahydrofuran (THF), merging filtrate, decompression and solvent recovery.Residue adds 100 milliliters of ethyl acetate, uses dilute hydrochloric acid water successively, the saturated common salt water washing.Anhydrous sodium sulfate drying, vacuum concentration obtain 8.0 gram faint yellow solids to doing, and recrystallization from ethyl acetate/petroleum ether obtains almost white crystal 7.3 gram GA
4(three step total recoverys 73%).Pure compound GA
4Spectrogram mp:214～215 ℃
1H-NMR (300MHz, Acetone): δ: 4.97 (1H, brs), 4.85 (1H, brs), 4.46 (1H, brs), 3.72 (1H, m), 3.21 (1H, d, J=10.8Hz), 2.64 (1H, m), 2.60 (1H, d, J=10.8Hz), 2.20～2.03 (3H, m), 2.00～1.47 (9H, m), 1.44～1.30 (1H, m), 1.12 (3H, s, Me).
13C-NMR (300MHz, Acetone): δ: 178.65,173.84,158.27,107.45,94.27,70.34,55.38,54.34,52.54,51.90,51.81,45.10,39.84,37.62,32.28,29.19,28.17,16.79,15.26.MS m/z:332 (M
+, 1%), 314 (11), 296 (5), 286 (16), 271 (24), 270 (100), 268 (18), 255 (15), 241 (19), 227 (19), 225 (36), 224 (33), 213 (7), 197 (13), 183 (14), 169 (14), 157 (17), 155 (16), 143 (15), 141 (13), 129 (18), 128 (13), 115 (12), 105 (19), 91 (36) .HRMS (ESI
+) m/z Found:355.1519[M+Na]
+, C
19H
24O
5Na requires355.1521.
Embodiment 16
Sodium borohydride 2.3 gram is dissolved in 100 milliliters of dimethyl sulfoxide (DMSO), under the stirring at room slowly adding be dissolved in (3 and GA of 20 milliliters of tetrahydrofuran (THF)s in advance
4Mixture) 5.3 grams, add the back in 50 ℃ of stoichiometric numbers hour to tens of hours.TLC detection reaction back fully adds a little sodium hydroxide frozen water solution, and stirred for several ten minutes is transferred PH=1.0 with dilute hydrochloric acid then, ethyl acetate extraction (100 milliliters * 3).The combined ethyl acetate phase, conventional aftertreatment, vacuum concentration is to doing, and resistates acetone/sherwood oil recrystallization obtains white crystal GA
42.6 gram.
Embodiment 17
Sodium borohydride 2.6 gram is dissolved in 100 milliliters of diglymes, under the stirring at room slowly adding be dissolved in (3 and GA of 50 milliliters of diglymes in advance
4Mixture) 10.8 grams, add the back in 40～50 ℃ of stoichiometric numbers hour to tens of hours.After the TLC detection reaction is complete, add a little sodium hydroxide frozen water solution, stirred for several ten minutes is transferred PH=1.0 with dilute hydrochloric acid then, ethyl acetate extraction (100 milliliters * 3).The combined ethyl acetate phase, conventional aftertreatment, vacuum concentration is to doing, and resistates acetone/sherwood oil recrystallization obtains white crystal GA
45.2 gram.
Claims (2)
1. Plant hormones regulators,gibberellins GA as structural formula (I) expression
4The preparation method
It is characterized in that:
1), the gibberic acid GA that obtains with fermentation
4+7Be starting raw material, handle through Lewis acid, hydrochloric acid, Hydrogen bromide isomerization open loop, GA wherein
7Transform, the organic solvent of employing is the mixed solvent of ethyl acetate and ether;
2), adopt the transition metal rhodium to carry out catalytic hydrogenation as catalyzer, catalyst levels is by weight with respect to reaction substrate GA
4+7Be 0.1%～10%, the solvent of employing is ethanol or tetrahydrofuran (THF);
3), adopt the mixture of bromine, iodine and potassium halide or sodium halide to carry out halo to lactonize, consumption is halogen: GA in molar ratio
4+7=1～10: 1; Used solvent be alcohol, ketone and halohydrocarbon and with the mixed solvent of water, alkali is carbonate M
2CO
3Or MHCO
3, wherein M=sodium, potassium, lithium, consumption is M with respect to reaction substrate in molar ratio
2CO
3Or MHCO
3: GA
4+7=3～10: 1;
4), remove halogen reaction, the reagent of employing is that zinc powder and moisture nickelous chloride are 1～30: 1 in molar ratio, consumption is 5～20: 1 with respect to the halo substrate in molar ratio; The solvent that is adopted is dehydrated alcohol, tetrahydrofuran (THF), 1,4-dioxane, acetonitrile; Perhaps, the reagent of employing is sodium borohydride, and consumption is 3～30: 1 with respect to the halo substrate in molar ratio; The solvent that is adopted is anhydrous tetrahydro furan, DMSO, diglyme;
5), final product GA
4With acetone/sherwood oil volume ratio be 1～10: 1 or the ethyl acetate/petroleum ether volume ratio be that 2～15: 1 solvent recrystallization obtains compound (I).
2. preparation method as claimed in claim 1 is characterized in that: the Lewis acid in the step 1) is FeCl
3, ZnCl
2, ZnBr
2
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| CN114958626B (en) * | 2022-07-06 | 2023-04-07 | 江西新瑞丰生化股份有限公司 | GA4 strain for producing gibberellin and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB964987A (en) * | 1961-06-22 | 1964-07-29 | Ici Ltd | Reduction of gibberellic acid and derivatives thereof |
| CN1111286A (en) * | 1995-03-16 | 1995-11-08 | 北京农业大学 | Method for stage extraction gibberellin A4 and A7 from gibberellin mixture |
| US5562831A (en) * | 1991-06-14 | 1996-10-08 | Abbott Laboratories | Method for separation of gibberellin mixtures |
-
2005
- 2005-06-22 CN CN 200510010868 patent/CN1775770B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB964987A (en) * | 1961-06-22 | 1964-07-29 | Ici Ltd | Reduction of gibberellic acid and derivatives thereof |
| US5562831A (en) * | 1991-06-14 | 1996-10-08 | Abbott Laboratories | Method for separation of gibberellin mixtures |
| CN1111286A (en) * | 1995-03-16 | 1995-11-08 | 北京农业大学 | Method for stage extraction gibberellin A4 and A7 from gibberellin mixture |
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