CN1775769B - Method for synthesizing gibberellin GA4 - Google Patents

Method for synthesizing gibberellin GA4 Download PDF

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CN1775769B
CN1775769B CN 200510010867 CN200510010867A CN1775769B CN 1775769 B CN1775769 B CN 1775769B CN 200510010867 CN200510010867 CN 200510010867 CN 200510010867 A CN200510010867 A CN 200510010867A CN 1775769 B CN1775769 B CN 1775769B
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ethyl acetate
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CN1775769A (en
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张洪彬
吴松福
刘建平
李良
赵静峰
杨万松
朱洁
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YUNDA SCIENCE & TECHNOLOGY Co Ltd
Yunnan University YNU
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YUNDA SCIENCE & TECHNOLOGY Co Ltd
Yunnan University YNU
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Abstract

The invention surfactant a method for synthesizing gibberellin GA4 (3beta, 10 alpha- dihydroxyl-20-decarbonized Gibberella-16-alkene-7, 19-diacid-19, 10 inner ester), using easy-to-obtain GA3 as initial raw material, dissolving the GA3 in organic solvent, adding in a proper amount of pyridine or organic alkali triethylamine, slowly adding in acetic anhydride to make reaction at room temperature, making catalytic hydrogenation on the products, making halogen inner esterification on the hydrogenated products, using hydroxyl butyl diimine and dicyclohexyl carbondiimine (HOSu/DCC) to react with the products of the inner esterification, successively making sulfoacylation on the obtained activated ester, hydrolyzing the products of the sulfoacylation under the catalysis of hydrogen peroxide, making Birch reduction reaction on the hydrolysate, then making halogen inner esterification on the products of the Birch reaction, finally eliminating the halogens from the products of the halogen inner esterification under the condition of Zn and hydrated nickel chloride (Zn/NiCl2.XH2O) or sodium hydrosulfide so as to obtain the target products GA4. The invention has the advantages of moderate reacting conditions, lower cost, and easy operation.

Description

Plant hormones regulators,gibberellins GA 4Synthetic method
Technical field: the present invention relates to a kind of compound GA with structural formula (I) 4(3 β, 10 alpha-dihydroxy-s-20-lose carbon red mould-16-alkene-7,19-bisgallic acid-19,10 lactone) the preparation method.
Figure DEST_PATH_S05110867620060206D000011
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.
Summary of the invention: the present invention proposes a kind of Plant hormones regulators,gibberellins GA 4Synthetic method, its is with the GA that is easy to get 3Make the synthetic GA that obtains of starting raw material after chemical reaction 4
The present invention is with GA 3Be dissolved in the organic solvent; add a certain amount of pyridine or triethylamine organic bases; slowly add acetic anhydride under the room temperature; to react products therefrom and carry out catalytic hydrogenation; hydrogenated products carries out halo and lactonizes; halo lactonizes product with maloyl imines and dicyclohexylcarbodiimide (HOSu/DCC) reaction, then the Acibenzolar that obtains carry out methylsulfonylization, and the methylsulfonyl product is in hydrogen peroxide catalyzed hydrolysis down.Hydrolysate carries out the Birch reduction reaction, and the product that then Birch is reacted gained carries out halo and lactonizes, and the product that at last halo lactonized is with zinc and hydration nickelous chloride (Zn/NiCl 2XH 2O) or under the sodium borohydride condition behind the dehalogenation recrystallization obtain target product GA 4Reaction conditions gentleness of the present invention, cost is lower, easy handling, reaction formula is as follows:
Figure S05110867620050714D000021
A: the used reagent of acetylize is diacetyl oxide, makes solvent with methylene dichloride, anhydrous acetonitrile and tetrahydrofuran (THF), and consumption is 10～100 a milliliters/gram; Add pyridine or the organic alkali as a catalyst of triethylamine, the organic bases consumption is 0.1%～10% with respect to reaction substrate by weight.
B: the catalytic hydrogenation catalyst system therefor is platinum and palladium, and catalyst levels is 0.1%～10% with respect to reaction substrate by weight; Adopt organic solvent and the organic amine compound mixed solvent that obtains of 10:1～1:10 by volume, consumption be 10～100 milliliters/restrain; Described organic solvent is methyl alcohol, ethanol, ethyl acetate, ether, and organic amine compound is triethylamine or pyridine.
C: the halo halogen that is adopted that lactonizes is a bromine, iodine with and with the mixture of potassium halide or sodium halide, consumption is 1～10:1 with respect to reaction substrate in molar ratio; The solvent that adopts is alcohol, ketone and tetrahydrofuran (THF); The alkali that is adopted is carbonate M 2CO 3Or MHCO 3, wherein M is sodium Na, potassium K, lithium Li, consumption are 2～10:1 with respect to reaction substrate in molar ratio.
The reagent that the esterification of d:7-carboxyl is adopted is nitrogen N-Hydroxysuccinimide and dicyclohexyl imines (HOSu/DCC), and reaction solvent is tetrahydrofuran (THF) (THF) or acetonitrile;
The methylsulfonyl agents useful for same of e:13-hydroxyl is a methane sulfonyl chloride, pyridine or triethylamine catalysis, and reaction solvent can be tetrahydrofuran (THF), methylene dichloride or acetonitrile;
The hydrolysis reaction of f:7-carboxyl adopts saleratus or sodium bicarbonate to make alkali, and acetone or tetrahydrofuran (THF) are made solvent, 30% hydrogen peroxide (H 2O 2) catalysis.
The solvent that the g:Birch reaction is adopted is liquefied ammonia [NH 3(l)] and anhydrous tetrahydro furan (THF), metallic lithium or potassium (Li, or K) are made reductive agent ,-78 ℃ of reactions.
H: the lactonize solvent that adopted of halo is alcohol, ester, ketone, ether and halohydrocarbon; The alkali that is adopted is carbonate M 2CO 3Or MHCO 3, wherein M is sodium Na, potassium K, lithium Li, consumption are 2～10:1 with respect to reaction substrate in molar ratio.The halogen that adopts is a bromine, iodine with and with the mixture of potassium halide or sodium halide, consumption is 1～10:1 with respect to reaction substrate in molar ratio.
I: the reagent of employing 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 reaction substrate in molar ratio; The solvent that is adopted is dehydrated alcohol, methyl alcohol, tetrahydrofuran (THF); Perhaps adopting sodium borohydride is reagent, and consumption is 3～30:1 with respect to reaction substrate in molar ratio, and solvent is anhydrous tetrahydro furan or diglyme.
Final product GA 4With acetone/sherwood oil volume ratio is 1～10:1 or ethyl acetate/petroleum ether volume ratio 2～15:1 solvent recrystallization.
Embodiment: the following example is illustrating rather than limiting it of the inventive method.The multiple condition that it will be apparent to those skilled in the art and other modification and the adaptive change of parameter are included in claims protection domain of the present invention.
One, GA 3The acetylization reaction of 3-hydroxyl:
Figure S05110867620050714D000031
Embodiment 1: Plant hormones regulators,gibberellins GA 37.0 gram is dissolved in 10 milliliters of cooling bath refrigerative anhydrous tetrahydro furans and the 5 milliliters of pyridines, slowly adds 3 ml acetic anhydride under the induction stirring.Drip to finish under the room temperature of back and continue reaction tens of hours, after thin-layer chromatography TLC detection reaction finishes, slowly add 2 ml waters under ice-water bath cooling and the vigorous stirring, add 100 milliliters of ethyl acetate then.Hcl acidifying is to PH=1.0, and water is with ethyl acetate extraction (100 milliliters * 3).Combined ethyl acetate phase, saturated brine washing be to neutral, anhydrous sodium sulfate drying, and underpressure distillation removes and desolvates, and resistates obtains white solid acetic ester (1) 6.6 gram (yield 95%) with recrystallization from ethyl acetate/petroleum ether, fusing point mp:219～220 ℃.
1H-NMR(300MHz，CD3COCD3)：δ：6.58(1H，d，J＝9.2Hz)，5.86(1H，dd，J＝3.7，9.2Hz)，5.27(1H，d，J＝3.7Hz)，4.89(1H，brs)，3.25(1H，d，J＝10.8Hz)，2.73(1H，d，J＝10.8Hz)，2.42～2.22(2H，m)，2.10(3H，s，CH3)，2.10～1.98(2H，m)，1.95～1.68(5H，m)，1.13(3H，s，CH3)。
13C-NMR(75.5MHz，CD3COCD3)：δ：177.61，173.12，170.45，158.80，135.77，129.49，106.92，90.96，78.14，70.85，54.03，52.83，51.68，51.47，50.61，45.32，43.67，39.73，20.71，17.58，14.70。
MS(m/z，％)：388(M +，4％)，370(11)，342(4)，328(34)，310(20)，284(100)，269(25)，266(29)，255(40)，239(77)，223(52)，209(82)，195(53)，181(36)，165(40)，155(56)，141(37)，136(84)，128(39)，121(51)，105(36)，91(42)。
HRMS：C21H24O7Na?Calculated411.1419，Found：411.1411。
Embodiment 2: Plant hormones regulators,gibberellins GA 37.0 gram is dissolved in 10 milliliters of cooling bath refrigerative methylene dichloride and the 5 milliliters of pyridines, slowly adds 3 ml acetic anhydride under the induction stirring.Drip to finish under the room temperature of back and continue reaction tens of hours, after thin-layer chromatography TLC detection reaction finishes, slowly add 2 ml waters under ice-water bath cooling and the vigorous stirring, add 100 milliliters of ethyl acetate then.Hcl acidifying is to PH=1.0, and water is with ethyl acetate extraction (100 milliliters * 3).The combined ethyl acetate phase, the saturated brine washing is extremely neutral, anhydrous sodium sulfate drying, underpressure distillation removes and desolvates, and resistates obtains white solid acetic ester (1) 6.4 gram (yield 92%) with recrystallization from ethyl acetate/petroleum ether.
Embodiment 3: Plant hormones regulators,gibberellins GA 37.0 gram is dissolved in 10 milliliters of cooling bath refrigerative anhydrous tetrahydro furans and the 5 milliliters of pyridines, slowly adds 3 ml acetic anhydride under the induction stirring.Drip to finish under the room temperature of back and continue reaction tens of hours, after thin-layer chromatography TLC detection reaction finishes, slowly add 2 ml waters under ice-water bath cooling and the vigorous stirring, add 100 milliliters of ethyl acetate then.Hcl acidifying is to PH=1.0, and water is with ethyl acetate extraction (100 milliliters * 3).The combined ethyl acetate phase, the saturated brine washing is extremely neutral, anhydrous sodium sulfate drying, underpressure distillation removes and desolvates, and resistates obtains white solid acetic ester (1) 6.2 gram (yield 88%) with recrystallization from ethyl acetate/petroleum ether.
Embodiment 4: Plant hormones regulators,gibberellins GA 37.0 gram is dissolved in 10 milliliters of cooling bath refrigerative methylene dichloride and 5 milliliters of triethylamines, slowly adds 3 ml acetic anhydride under the induction stirring.Drip to finish under the room temperature of back and continue reaction tens of hours, after thin-layer chromatography TLC detection reaction finishes, slowly add 2 ml waters under ice-water bath cooling and the vigorous stirring, add 100 milliliters of ethyl acetate then.Hcl acidifying is to PH=1.0, and water is with ethyl acetate extraction (100 milliliters * 3).The combined ethyl acetate phase, the saturated brine washing is extremely neutral, anhydrous sodium sulfate drying, underpressure distillation removes and desolvates, and resistates obtains white solid acetic ester (1) 6.4 gram (yield 91%) with recrystallization from ethyl acetate/petroleum ether.
Embodiment 5: Plant hormones regulators,gibberellins GA 37.0 gram is dissolved in 10 milliliters of cooling bath refrigerative tetrahydrofuran (THF)s and 5 milliliters of triethylamines, slowly adds 3 ml acetic anhydride under the induction stirring.Drip to finish under the room temperature of back and continue reaction tens of hours, after thin-layer chromatography TLC detection reaction finishes, slowly add 2 ml waters under ice-water bath cooling and the vigorous stirring, add 100 milliliters of ethyl acetate then.Hcl acidifying is to PH=1.0, and water is with ethyl acetate extraction (100 milliliters * 3).The combined ethyl acetate phase, the saturated brine washing is extremely neutral, anhydrous sodium sulfate drying, underpressure distillation removes and desolvates, and resistates obtains white solid acetic ester (1) 6.5 gram (yield 93%) with recrystallization from ethyl acetate/petroleum ether.
Two, compound GA 3The catalytic hydrogenolysis of-acetic ester (1):
Figure S05110867620050714D000051
Embodiment 6: compound GA 3-acetic ester (1) 11.7 gram is dissolved in 100 milliliter of 95% ethanol and the 20 milliliters of pyridines, add 0.1 gram, 10% palladium carbon (Pd-C), logical hydrogen (H2) stoichiometric number is hour to tens of hours under the stirring at room, silica gel thin-layer chromatography (TLC) detects, after reacting completely, filtering palladium carbon (Pd-C), permitted to wash filter residue with few 95% ethanol, merging filtrate, decompression and solvent recovery, resistates adds 100 milliliters of ethyl acetate, and hydrochloric acid transfers to PH=1.0, and is extremely neutral with the saturated brine washing then, anhydrous sodium sulfate drying, vacuum concentration is to doing, and resistates obtains white solid hydroformylation product solution (2) 9.4 grams (yield 80%) with recrystallization from ethyl acetate/petroleum ether, fusing point mp:201～203 ℃.
1H-NMR(300MHz，CD3COCD3)：δ：5.30(1H，d，J＝3.9Hz)，5.27(1H，t，J＝3.0Hz)，5.08(1H，brs)，4.92(1H，brs)，3.26(1H，d，J＝5.1Hz)，3.13(1H，brs)，2.87(1H，m)，2.72(2H，m)，2.54(1H，brs)，2.28(1H，m)，2.12(1H，m)，2.04(3H，s，CH3)，1.95(1H，d，J＝10.2Hz)，1.68～1.61(3H，m)，1.45～1.42(3H，m)，1.25(3H，s，CH3)。
13C-NMR(75.5MHz，CD3COCD3)：δ：177.60，175.32，170.92，156.62，142.40，111.59，106.35，79.78，73.13，50.85，50.19，50.05，47.86，47.63，47.59，40.40，39.12，31.31，22.55，21.53，19.74。
MS(m/z，％)：390(M +，4％)，372(4)，330(20)，312(48)，297(16)，284(100)，269(52)，251(15)，239(89)，221(47)，209(24)，193(30)，181(23)，169(19)，155(35)，128(25)，115(21)，105(25)，91(26)。
HRMS：C21H26O7Na?Calculated413.1576，Found：413.1582。
Embodiment 7:5.0 restrains GA 3-acetic ester (1) is dissolved in 50 ml methanol, adds 10 milliliters of triethylamines and 0.5 gram, 5% palladium carbon (Pd-C), logical hydrogen (H under the stirring at room 2) stoichiometric number hour was to tens of hours, silica gel thin-layer chromatography (TLC) detects, after reacting completely, filtering palladium carbon (Pd-C), with a little methanol wash filter residue, merge methyl alcohol, reclaim under reduced pressure methyl alcohol, resistates is dissolved in 100 milliliters of ethyl acetate, hcl acidifying is to PH=1.0, and washs this filtrate, anhydrous sodium sulfate drying with saturated brine, vacuum concentration obtains shallow white solid (2) 4.6 grams (yield 92%) to doing.
Embodiment 8:5.0 restrains GA 3-acetic ester (1) is dissolved in 50 milliliters of ethyl acetate, adds 10 milliliters of triethylamines and 0.5 gram, 5% palladium carbon (Pd-C), logical hydrogen (H under the stirring at room 2) stoichiometric number hour was to tens of hours, silica gel thin-layer chromatography (TLC) detects, after reacting completely, filtering palladium carbon (Pd-C) is with a little ethyl acetate washing filter residue, combined ethyl acetate, decompression and solvent recovery, resistates is dissolved in 100 milliliters of ethyl acetate, and hcl acidifying is to PH=1.0, and washs this filtrate with saturated brine, anhydrous sodium sulfate drying, vacuum concentration with acetone/sherwood oil crystallization, obtains shallow white solid (2) 4.5 grams (yield 90%) to doing.
Embodiment 9:8.0 restrains GA 3-acetic ester (1) is dissolved in 50 milliliters of ethyl acetate, adds 10 milliliters of pyridines and 0.9 gram, 5% palladium carbon (Pd-C), logical hydrogen (H under the stirring at room 2) stoichiometric number hour was to tens of hours, silica gel thin-layer chromatography (TLC) detects, after reacting completely, filtering palladium carbon (Pd-C) is with a little ethyl acetate washing filter residue, combined ethyl acetate, decompression and solvent recovery, resistates is dissolved in 100 milliliters of ethyl acetate, and hcl acidifying is to PH=1.0, and washs this filtrate with saturated brine, anhydrous sodium sulfate drying, vacuum concentration with acetone/sherwood oil recrystallization, obtains shallow white solid (2) 7.5 grams (yield 94%) to doing.
Embodiment 10:10.0 restrains GA 3-acetic ester (1) is dissolved in 10 milliliters of ether, adds 100 milliliters of triethylamines and 1.5 grams, 5% palladium carbon (Pd-C), logical hydrogen (H under the stirring at room 2) stoichiometric number hour was to tens of hours, silica gel thin-layer chromatography (TLC) detects, after reacting completely, filtering palladium carbon (Pd-C), with a little ether washing filter residue, merge the back decompression and solvent recovery, resistates is dissolved in 100 milliliters of ethyl acetate, hcl acidifying is to PH=1.0, and wash this filtrate with saturated brine, and anhydrous sodium sulfate drying, vacuum concentration is to doing, with the ethyl acetate/petroleum ether solvent recrystallization, obtain shallow white solid (2) 8.8 grams (yield 88%).
Embodiment 11:10.0GA 3In 100 milliliters of ethanol of-acetic ester (1) dissolving, add 10 milliliters of triethylamines and 1.5 grams, 5% palladium carbon (Pd-C), logical hydrogen (H under the stirring at room 2) stoichiometric number hour was to tens of hours, silica gel thin-layer chromatography (TLC) detects, after reacting completely, filtering palladium carbon (Pd-C), with a little ether washing filter residue, merge the back decompression and solvent recovery, resistates is dissolved in 100 milliliters of ethyl acetate, hcl acidifying is to PH=1.0, and wash this filtrate with saturated brine, and anhydrous sodium sulfate drying, vacuum concentration is to doing, with the ethyl acetate/petroleum ether solvent recrystallization, obtain shallow white solid (2) 8.5 grams (yield 85%)
Embodiment 12:10.0 restrains GA 3-acetic ester (1) is dissolved in 50 milliliters of ethanol, adds 5 milliliters of pyridines and 0.5 gram, 5% palladium carbon (Pd-C), logical hydrogen (H under the stirring at room 2) stoichiometric number hour was to tens of hours, silica gel thin-layer chromatography (TLC) detects, after reacting completely, filtering palladium carbon (Pd-C), with a little ether washing filter residue, merge the back decompression and solvent recovery, resistates is dissolved in 100 milliliters of ethyl acetate, hcl acidifying is to PH=1.0, and wash this filtrate with saturated brine, and anhydrous sodium sulfate drying, vacuum concentration is to doing, with the ethyl acetate/petroleum ether solvent recrystallization, obtain shallow white solid (2) 9.2 grams (yield 92%)
Embodiment 13:10.0 restrains GA 3-acetic ester (1) is dissolved in 50 milliliters of ethanol, adds 5 milliliters of pyridines and 0.5 gram, 5% platinum carbon (Pt-C), logical hydrogen (H under the stirring at room 2) stoichiometric number hour was to tens of hours, silica gel thin-layer chromatography (TLC) detects, after reacting completely, filtering platinum carbon (Pt-C), with a little ether washing filter residue, merge the back decompression and solvent recovery, resistates is dissolved in 100 milliliters of ethyl acetate, hcl acidifying is to PH=1.0, and wash this filtrate with saturated brine, and anhydrous sodium sulfate drying, vacuum concentration is to doing, with the ethyl acetate/petroleum ether solvent recrystallization, obtain shallow white solid (2) 8.5 grams (yield 85%)
Embodiment 14:10.0 restrains GA 3-acetic ester (1) is dissolved in 100 milliliters of ethanol, adds 10 milliliters of triethylamines and 1.5 grams, 5% platinum carbon (Pt-C), logical hydrogen (H under the stirring at room 2) stoichiometric number hour was to tens of hours, silica gel thin-layer chromatography (TLC) detects, after reacting completely, filtering platinum carbon (Pt-C), with a little ether washing filter residue, merge the back decompression and solvent recovery, resistates is dissolved in 100 milliliters of ethyl acetate, hcl acidifying is to PH=1.0, and wash this filtrate with saturated brine, and anhydrous sodium sulfate drying, vacuum concentration is to doing, with the ethyl acetate/petroleum ether solvent recrystallization, obtain shallow white solid (2) 8.0 grams (yield 80%)
Embodiment 15:8.0 restrains GA 3-acetic ester (1) is dissolved in 50 milliliters of ethyl acetate, adds 10 milliliters of pyridines and 0.9 gram, 5% platinum carbon (Pt-C), logical hydrogen (H under the stirring at room 2) stoichiometric number hour was to tens of hours, silica gel thin-layer chromatography (TLC) detects, after reacting completely, filtering platinum carbon (Pt-C) is with a little ethyl acetate washing filter residue, combined ethyl acetate, decompression and solvent recovery, resistates is dissolved in 100 milliliters of ethyl acetate, and hcl acidifying is to PH=1.0, and washs this filtrate with saturated brine, anhydrous sodium sulfate drying, vacuum concentration with acetone/sherwood oil recrystallization, obtains shallow white solid (2) 6.7 grams (yield 84%) to doing.
Three, the halo of hydroformylation product solution (2) lactonizes:
Figure S05110867620050714D000071
Embodiment 16: hydroformylation product solution (2) 7.8 grams are dissolved in 50 milliliters of acetone and 10 ml waters, add sodium bicarbonate 6.5 grams, iodine 10.0 grams and potassiumiodide 3.5 grams.Stirring at room stoichiometric number ten minutes, after silica gel thin-layer chromatography (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, and water is with ethyl acetate extraction (50 milliliters * 3).The combined ethyl acetate phase, the saturated brine washing, anhydrous sodium sulfate drying, vacuum concentration is to doing.The resistates recrystallization from ethyl acetate/petroleum ether obtains shallow white solid iodide (3) 9.2 grams (yield 90%), fusing point mp:216～218 ℃.
1H-NMR(300MHz，CDC13)：δ：5.26(1H，brs)，4.96(1H，brs)，4.90(1H，brs)，4.38(1H，d，J＝5.1Hz)，3.79(1H，d，J＝10.3Hz)，2.61(1H，d，J＝10.3Hz)，2.55～2.49(3H，m)，2.25(2H，m)，2.04(3H，s，CH3)，1.95(1H，d，J＝11.4Hz)，1.81～1.71(4H，m)，1.51(1H，m)，1.08(3H，s，CH3)。
13C-NMR(75.5MHz，CDCl3)：δ：176.82，174.61，170.88，156.13，108.69，95.45，78.69，71.42，53.77，51.30，51.20，49.61，49.38，44.58，42.53，38.53，35.66，21.68，20.11，17.31，14.87。
MS(m/z，％)：516(M +，5％)，498(6)，471(8)，389(74)，371(7)，329(57)，311(47)，283(72)，265(236)，255(100)，239(94)，209(46)，195(51)，181(30)，169(32)，155(49)，143(34)，135(74)，121(33)，105(62)，91(50)。
HRMS：C21H25O7I?Na?Calculated539.0542Found：539.0537。
Embodiment 17: hydroformylation product solution (2) 6.5 grams are dissolved in 100 milliliters of methylene dichloride and 20 ml waters, add yellow soda ash 4.8 grams, iodine 6.9 grams and potassiumiodide 3.0 grams.Stirring at room stoichiometric number hour.After thin-layer chromatography (TLC) detection reaction finishes, slowly add saturated sodium thiosulfate solution to reaction soln color under stirring and disappear, add 100 milliliters of methylene dichloride then, water dichloromethane extraction (30 milliliters * 3).Combined dichloromethane phase, hcl acidifying are to PH=1.0, and with saturated brine washing, anhydrous sodium sulfate drying, vacuum concentration obtains faint yellow solid iodide (3) 8.2 grams (yield 95%) to doing.
Embodiment 18: hydroformylation product solution (2) 3.1 grams are dissolved in 30 milliliters of acetone and 5 ml waters, add yellow soda ash 2.8 gram iodine, 6.8 grams and potassiumiodide 1.7 grams.Stirring at room stoichiometric number ten minutes, thin-layer chromatography TLC detection reaction finishes slowly to add saturated sodium thiosulfate solution to reaction soln color under the stirring of back and disappears, add 50 milliliters of ethyl acetate then, hcl acidifying is to PH=1.0, ethyl acetate is extremely neutral with the saturated brine washing, anhydrous sodium sulfate drying, vacuum concentration is to doing, and resistates obtains white solid iodide (3) 3.0 grams (yield 94%) with recrystallization from ethyl acetate/petroleum ether.
Embodiment 19: hydroformylation product solution (2) 5.6 restrains in the ethanol that is dissolved in 50 milliliter 95%, adds in 100 ml waters and sodium bicarbonate 5.0 grams, and Sodium Bromide 5.0 grams 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 further obtains white crystals iodide (3) 4.6 grams (yield 82%) to dried faint yellow solid 5.1 grams (yield 92%) that obtain after the recrystallization from ethyl acetate/petroleum ether
Embodiment 20: hydroformylation product solution (2) 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 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 further obtains white crystals iodide (3) 3.5 grams (yield 76%) to dried faint yellow solid 5.3 grams (yield 86%) that obtain after the recrystallization from ethyl acetate/petroleum ether.
Embodiment 21: hydroformylation product solution (2) 4.6 grams are dissolved in 50 ml methanol, add in 100 ml waters and sodium bicarbonate 5.0 grams, lithiumbromide 5.0 grams 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 further obtains white crystals iodide (3) 4.6 grams (yield 75%) to dried faint yellow solid 5.3 grams (yield 86%) that obtain after the recrystallization from ethyl acetate/petroleum ether
Embodiment 22: hydroformylation product solution (2) 3.1 grams are dissolved in 30 milliliters of acetone and 5 ml waters, add salt of wormwood 2.8 gram iodine, 6.8 grams and potassiumiodide 1.7 grams.Stirring at room stoichiometric number ten minutes, thin-layer chromatography TLC detection reaction finishes slowly to add saturated sodium thiosulfate solution to reaction soln color under the stirring of back and disappears, add 50 milliliters of ethyl acetate then, hcl acidifying is to PH=1.0, ethyl acetate is extremely neutral with the saturated brine washing, anhydrous sodium sulfate drying, vacuum concentration is to doing, and resistates obtains white solid iodide (3) 2.9 grams (yield 94%) with recrystallization from ethyl acetate/petroleum ether.
Embodiment 23: hydroformylation product solution (2) 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 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 further obtains white crystals iodide (3) 4.6 grams (yield 76%) to dried faint yellow solid 5.3 grams (yield 86%) that obtain after the recrystallization from ethyl acetate/petroleum ether
Four, the 7-carboxyl esterification of iodo compound (3) reaction:
Embodiment 24: compound (3) 10.5 grams and maloyl imines (HOSu) 2.5 grams are dissolved in 20 milliliters of tetrahydrofuran (THF)s, add dicyclohexylcarbodiimide (DCC) under the ice-water bath cooling induction stirring, naturally rise to room temperature reaction a few hours to tens of hours, after thin-layer chromatography (TLC) detection reaction finishes, the filtering precipitation, filter residue is with a little tetrahydrofuran (THF) washing, merging filtrate, decompression and solvent recovery, resistates adds 100 milliliters of ethyl acetate, successively with saturated sodium bicarbonate solution and saturated brine washing, anhydrous sodium sulfate drying, vacuum concentration is to doing the resistates recrystallization from ethyl acetate/petroleum ether, obtain shallow white solid (4) 11.7 grams (yield 95%), fusing point mp:149～152 ℃.
1H-NMR(300MHz，CDCl3)：δ：5.23(1H，brs)，4.98(1H，brs)，4.90(1H，brs)，4.39(1H，d，J＝5.0Hz)，3.84(1H，d，J＝10.3Hz)，2.90(1H，d，J＝10.3Hz)，2.80(4H，s)，2.66(1H，brs)，2.61～2.55(4H，m)，2.25(1H，m)，2.10(3H，s，CH3)，2.00～1.97(1H，m)，1.82～1.40(4H，m)，1.15(3H，s，CH3)。
13C-NMR(75.5MHz，CDC13)：δ：175.95，170.49，169.36，168.07，156.50，108.44，94.99，78.29，71.33，53.67，51.63，50.79，49.87，48.92，45.06，42.36，38.18，35.60，35.26，26.00，21.51，19.98，17.34，14.71。
MS(m/z，％)：613(M +，5％)，499(5)，486(9)，367(6)，311(20)，283(19)，255(24)，239(100)，221(27)，211(23)，197(21)，169(17)，155(24)，135(34)，129(17)，105(24)，91(18)。
HRMS：C25H28NO9I?Na?Calculated636.0706Found：636.0712。
Embodiment 25: compound (3) 10.5 grams and maloyl imines (HOSu) 2.5 grams are dissolved in 20 milliliters of acetonitriles, add dicyclohexylcarbodiimide (DCC) under the ice-water bath cooling induction stirring, naturally rise to room temperature reaction a few hours to tens of hours, after thin-layer chromatography (TLC) detection reaction finishes, the filtering precipitation, filter residue is with a little tetrahydrofuran (THF) washing, merging filtrate, decompression and solvent recovery, resistates adds 100 milliliters of ethyl acetate, successively with saturated sodium bicarbonate solution and saturated brine washing, anhydrous sodium sulfate drying, vacuum concentration is to doing, and the resistates recrystallization from ethyl acetate/petroleum ether obtains shallow white solid (4) 9.7 grams (yield 92%).
Five, the 13-hydroxyl methylsulfonyl reaction of compound (4):
Embodiment 26: compound (4) 12.3 gram is dissolved in 20 milliliters of acetonitriles and the 10 milliliters of pyridines, the ice bath cooling, slowly be added dropwise to 5 milliliters of methane sulfonyl chlorides under the induction stirring, finish, remove ice bath, room temperature continues stoichiometric number hour, and after thin-layer chromatography (TLC) detection reaction finished, cryosel was bathed cooling down, slowly drip 2 ml waters, add 100 milliliters of ethyl acetate then, use dilute sodium bicarbonate solution successively, dilute hydrochloric acid and saturated brine washing, anhydrous sodium sulfate drying, vacuum concentration obtains faint yellow solid (7) 13.7 grams (yield 99%) to doing, fusing point mp:139～142 ℃.
1H-NMR(300MHz，CDCl3)：δ：5.35(1H，brs)，5.17(1H，brs)，4.91(1H，brs)，4.39(1H，d，J＝5.2Hz)，3.87(1H，d，J＝10.2Hz)，2.98(3H，s，CH3)，2.97(1H，d，J＝10.2Hz)，2.81(4H，s)，2.76～2.46(6H，m)，2.30～2.20(1H，m)，2.11(3H，s，CH3)，1.98～1.37(4H，m)，1.16(3H，s，CH3)。
13C-NMR(75.5MHz，CDCl3)：δ：175.60，170.44，169.19，167.75，151.26，111.50，94.61，91.33，71.20，53.65，51.12，50.80，50.60，48.56，41.51，41.45，41.16，37.56，35.51，25.99，21.52，19.84，17.34，14.70。
MS(m/z，％)：691(M +，4％)，595(5)，480(7)，364(14)，317(7)，284(12)，251(20)，239(15)，221(100)，207(18)，193(23)，179(21)，165(15)，155(26)，141(18)，128(30)，115(24)，91(24)。
HRMS：C26H30NO11S?I?Na?Calculated714.0482Found：714.0494。
Embodiment 27: compound (4) 12.4 gram is dissolved in 100 milliliters of methylene dichloride and the 10 milliliters of triethylamines, the ice bath cooling, slowly be added dropwise to 5 milliliters of methane sulfonyl chlorides under the induction stirring, adding the recession deicing bathes, continue stoichiometric number hour under the room temperature, after thin-layer chromatography (TLC) detection reaction finishes, cryosel is bathed cooling, slowly drip 2 ml waters, add 100 milliliters of methylene dichloride then, use dilute sodium bicarbonate solution successively, dilute hydrochloric acid and saturated brine washing, anhydrous sodium sulfate drying, vacuum concentration obtain light brown solid (5) 13.7 grams (yield 98%) to doing.
Embodiment 28: compound (4) 12.4 gram is dissolved in 100 milliliters of methylene dichloride and the 10 milliliters of pyridines, the ice bath cooling, slowly be added dropwise to 5 milliliters of methane sulfonyl chlorides under the induction stirring, adding the recession deicing bathes, continue stoichiometric number hour under the room temperature, after thin-layer chromatography (TLC) detection reaction finishes, cryosel is bathed cooling, slowly drip 2 ml waters, add 100 milliliters of methylene dichloride then, use dilute sodium bicarbonate solution successively, dilute hydrochloric acid and saturated brine washing, anhydrous sodium sulfate drying, vacuum concentration obtain light brown solid (5) 13.2 grams (yield 97%) to doing.
Six, the ester hydrolysis of methanesulfonates compound (5):
Figure S05110867620050714D000101
Embodiment 29: compound (5) 7.0 gram is dissolved in 50 milliliters of acetone and 10 ml waters, adds the hydrogen peroxide (H of 4.2 gram sodium bicarbonates and 5 milliliter 30% 2O 2) solution, stirring at room stoichiometric number hour, thin-layer chromatography (TLC) detection reaction adds 100 milliliters of ethyl acetate after finishing, and hcl acidifying is to PH=1.0, and ethyl acetate is with the saturated brine washing, anhydrous sodium sulfate drying, vacuum concentration is to dried.The resistates recrystallization from ethyl acetate/petroleum ether obtains white solid (6) 5.3 gram (yield 90%), fusing point mp:118～121 ℃.
1H-NMR(300MHz，CDCl3)：δ：5.39(1H，brs)，5.20(1H，brs)，4.95(1H，brs)，4.41(1H，d，J＝4.8Hz)，3.86(1H，d，J＝10.2Hz)，3.30(3H，s，CH3)，2.75(1H，d，J＝10.2Hz)，2.70～2.50(5H，m)，2.24～2.25(3H，m)，2.19(3H，s，CH3)，2.00～1.50(3H，m)，1.16(3H，s，CH3)。
13C-NMR(75.5MHz，CDCl3)：δ：176.28，176.08，170.71，151.56，111.49，94.85，91.67，71.38，53.69，50.84，50.77，50.33，49.75，41.72，41.57，41.27，37.64，65.60，21.69，19.90，17.31，14.96。
MS(m/z，％)：594(M +，7％)，498(8)，407(9)，389(26)，361(10)，317(72)，311(22)，283(9)，267(66)，249(22)，239(26)，221(100)，209(28)，193(43)，181(37)，169(23)，155(40)，129(34)，105(41)，91(45)。
HRMS：C22H27O9S?I?Na?Calculated617.0318Found：617.0307。
Embodiment 30: compound (5) 7.0 gram is dissolved in 50 milliliters of acetone and 10 ml waters, adds the hydrogen peroxide (H of 4.2 gram saleratus and 5 milliliter 30% 2O 2) solution, stirring at room stoichiometric number hour, thin-layer chromatography (TLC) detection reaction adds 100 milliliters of ethyl acetate after finishing, and hcl acidifying is to PH=1.0, and ethyl acetate is with the saturated brine washing, anhydrous sodium sulfate drying, vacuum concentration is to dried.The resistates recrystallization from ethyl acetate/petroleum ether obtains white solid (6) 5.8 grams (yield 92%).
Embodiment 31: compound (5) 7.5 gram is dissolved in 50 milliliters of tetrahydrofuran (THF)s and 10 ml waters, adds the hydrogen peroxide (H of 4.2 gram saleratus and 5 milliliter 30% 2O 2) solution, stirring at room stoichiometric number hour, thin-layer chromatography (TLC) detection reaction adds 100 milliliters of ethyl acetate after finishing, and hcl acidifying is to PH=1.0, and ethyl acetate is with the saturated brine washing, anhydrous sodium sulfate drying, vacuum concentration is to dried.The resistates recrystallization from ethyl acetate/petroleum ether obtains white solid (6) 6.1 grams (yield 90%).
Seven, the Birch reduction reaction of compound (6):
Figure S05110867620050714D000111
Embodiment 32: compound (6) 6.0 gram is dissolved in 20 milliliters of anhydrous tetrahydro furans and the 2 milliliters of trimethyl carbinols, slowly add in the about 150 milliliters of liquefied ammonia of prior refrigerative, subcooling (78 ℃), add metallic lithium to reaction solution under the induction stirring to be mazarine and about 0.5 hour colour-fast in batches, add a little ammonium chloride then, the reaction solution avy blue disappears, continue to stir and spend the night, after liquefied ammonia is evaporated completely naturally, add 100 milliliters of ethyl acetate, hydrochloric acid transfers to PH=1.0, the saturated brine washing, anhydrous sodium sulfate drying, vacuum concentration is to doing.The resistates recrystallization from ethyl acetate/petroleum ether obtains white solid (7) 3.0 gram (yield 90%), fusing point mp:137～140 ℃.
1H-NMR(300MHz，CD3COCD3)：δ：5.20(1H，brs)，4.89(2H，brs)，4.04(1H，m)，3.15(1H，brs)，2.85～2.65(1H，m)，2.60～2.45(3H，m)，2.30～2.00(2H，m)，1.96(1H，s)，1.80～1.50(5H，m)，1.50～1.40(1H，m)，1.33(3H，s，CH3)。
13C-NMR(75.5MHz，CD3COCD3)：δ：117.87，176.45，155.27，142.64，110.93，106.21，70.70，52.61，50.22，49.04，48.24，46.81，42.89，42.82，41.59，33.33，31.91，22.09，17.90。
MS(m/z，％)：322(M +，3％)，314(12)，296(21)，286(82)，268(79)，253(17)，241(15)，223(100)，195(25)，181(36)，169(17)，155(32)，143(24)，129(23)，115(21)，91(30)。
HRMS：C19H24O5Na?Calculated355.1521Found：355.1514。
Embodiment 33: compound (6) 6.0 gram is dissolved in 20 milliliters of anhydrous tetrahydro furans and the 2 milliliters of trimethyl carbinols, slowly add in the about 180 milliliters of liquefied ammonia of prior refrigerative, subcooling (78 ℃), add potassium metal to reaction solution under the induction stirring to be mazarine and about 0.5 hour colour-fast in batches, adding a little ammonium chloride to reaction solution avy blue then disappears, continue to stir and spend the night, after liquefied ammonia is evaporated completely naturally, add 100 milliliters of ethyl acetate, hydrochloric acid transfers to PH=1.0, the saturated brine washing, anhydrous sodium sulfate drying, vacuum concentration is to doing.The resistates recrystallization from ethyl acetate/petroleum ether obtains white solid (7) 2.5 gram (yield 75%), fusing point mp:138～140 ℃. 1H-NMR(300MHz，CD3COCD3)：δ：5.20(1H，brs)，4.89(2H，brs)，4.04(1H，m)，3.15(1H，brs)，2.85～2.65(1H，m)，2.60～2.45(3H，m)，2.30～2.00(2H，m)，1.96(1H，s)，1.80～1.50(5H，m)，1.50～1.40(1H，m)，1.33(3H，s，CH3)。
Eight, the halo of diacid compounds (7) lactonizes:
Figure S05110867620050714D000121
Embodiment 34: diacid compounds (7) 3.4 grams are dissolved in 40 milliliters of acetone and 10 ml waters, add sodium bicarbonate 4.2 grams, iodine 5.0 grams and potassiumiodide 1.8 grams.Stirring at room stoichiometric number ten minutes, after thin-layer chromatography (TLC) detection reaction finishes, slowly add saturated sodium thiosulfate solution to reaction soln color under stirring and disappear, add 100 milliliters of ethyl acetate, hcl acidifying is to PH=1.0, ethyl acetate is washed with saturated brine, anhydrous sodium sulfate drying, vacuum concentration obtain faint yellow solid 5.3 grams to doing, obtain white crystals (8) 3.9 gram (yield 91%) after the recrystallization from ethyl acetate/petroleum ether, fusing point mp:165～168 ℃.
1H-NMR(300MHz，D-Pyridine)：δ：4.99(1H，brs)，4.89(1H，brs)，4.77(1H，d，J＝5.4Hz)，4.63(1H，d，J＝10.5Hz)，4.28(1H，brs)，3.18(1H，d，J＝10.5Hz)，2.95(1H，m)，2.85～2.50(5H，m)，2.05～1.70(6H，m)，1.64(3H，s，CH3)。
13C-NMR(75.5MHz，D-Pyridine)：δ：178.57，174.87，157.35，107.67，96.12，69.70，55.76，52.59，52.17，51.35，49.00，44.35，39.31，39.03，37.29，31.68，22.45，16.28，15.51。
MS(m/z，％)：458(M +，3％)，331(3)，313(26)，295(10)，285(100)，267(77)，254(7)，239(25)，223(75)，195(22)，181(29)，169(16)，155(24)，128(23)，115(17)，105(24)，91(37)。
HRMS：C19H23O5?INa?Calculated?481.0487?Found：418.0484。
Embodiment 35: diacid compounds (7) 6.8 grams are dissolved in 120 milliliters of methylene dichloride and 20 ml waters, add yellow soda ash 4.8 grams, iodine 6.9 grams and potassiumiodide 3.0 grams.Stirring at room stoichiometric number hour.After thin-layer chromatography (TLC) detection reaction finishes, slowly add saturated sodium thiosulfate solution to reaction soln color under stirring and disappear, add 100 milliliters of methylene dichloride then, water dichloromethane extraction (30 milliliters * 3).Combined dichloromethane phase, hcl acidifying are to PH=1.0, and with saturated brine washing, anhydrous sodium sulfate drying, vacuum concentration obtains faint yellow solid iodide (8) 7.9 grams (yield 92%) to doing.
Embodiment 36: diacid compounds (7) 5.6 is restrained in the ethanol that is dissolved in 50 milliliter 95%, add in 100 ml waters and sodium bicarbonate 5.0 grams, Sodium Bromide 5.0 grams 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 further obtains white crystals bromide (8) 4.4 grams (yield 79%) to dried faint yellow solid 4.4 grams (yield 86%) that obtain after the recrystallization from ethyl acetate/petroleum ether
Embodiment 37: diacid compounds (7) 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 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 further obtains white crystals bromide (8) 3.5 grams (yield 76%) to dried faint yellow solid 5.3 grams (yield 86%) that obtain after the recrystallization from ethyl acetate/petroleum ether.
Embodiment 38: diacid compounds (7) 4.6 grams are dissolved in 50 ml methanol, add in 100 ml waters and sodium bicarbonate 5.0 grams, lithiumbromide 5.0 grams 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 further obtains white crystals bromide (2) 4.6 grams (yield 75%) to dried faint yellow solid 5.3 grams (yield 86%) that obtain after the recrystallization from ethyl acetate/petroleum ether
Embodiment 39: diacid compounds (7) 3.1 grams are dissolved in 30 milliliters of acetone and 5 ml waters, add salt of wormwood 2.8 gram iodine, 6.8 grams and potassiumiodide 1.7 grams.Stirring at room stoichiometric number ten minutes, thin-layer chromatography TLC detection reaction finishes slowly to add saturated sodium thiosulfate solution to reaction soln color under the stirring of back and disappears, add 50 milliliters of ethyl acetate then, hcl acidifying is to PH=1.0, ethyl acetate is extremely neutral with the saturated brine washing, anhydrous sodium sulfate drying, vacuum concentration is to doing, and resistates obtains white solid iodide (8) 3.0 grams (yield 74%) with recrystallization from ethyl acetate/petroleum ether.
Embodiment 40: diacid compounds (7) 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 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 further obtains white crystals bromide (8) 4.6 grams (yield 75%) to dried faint yellow solid 5.3 grams (yield 86%) that obtain after the recrystallization from ethyl acetate/petroleum ether.
Nine, the dehalogenation reaction of iodo compound (8):
Figure S05110867620050714D000141
Embodiment 41: compound (8) 2.3 gram is dissolved among 20 milliliters of DMSO, stirs among 30 milliliters of DMSO that slow adding down is dissolved with 2.0 gram sodium borohydrides in advance, finishes, and is warming up to 80 ℃ of stoichiometric numbers hour.After thin-layer chromatography (TLC) detection reaction finishes.Add a little sodium hydroxide frozen water solution, stirring reaction a few hours.Hydrochloric acid transfers to PH=1.0, ethyl acetate extraction (50ml * 3).The combined ethyl acetate phase, the saturated brine washing, anhydrous sodium sulfate drying, vacuum concentration is to doing.The resistates recrystallization from ethyl acetate/petroleum ether obtains white solid GA41.2 gram (yield 70%), fusing point 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 42: take by weighing Zn powder 5.2 gram and NiCl 26H 2The O1.9 gram mixes with 100 milliliters of tetrahydrofuran (THF)s, adds 5 ml waters, and stirring at room 30 minutes adds halogenated compound (8) 2.3 grams then.Stirring at room stoichiometric number hour, thin-layer chromatography (TLC) detection reaction fully after, the filtering precipitation, 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 is to doing, and pale yellow colored solid body and function recrystallization from ethyl acetate/petroleum ether obtains white crystal 1.4 gram GA 4(yield 82%).Fusing point 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。
Embodiment 43: sodium borohydride 2.6 gram is dissolved in 100 milliliters of diglymes, under the stirring at room slowly adding be dissolved in halogenated compound (8) 2.3 grams of 50 milliliters of diglymes in advance, add the back in 40～50 ℃ of stoichiometric numbers hour to tens of hours.After thin-layer chromatography (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, resistates acetone the sherwood oil recrystallization, obtain white crystal GA 41.3 gram (yield 76%).
Embodiment 44: zinc (Zn) powder 4.8 gram and Nickel dichloride hexahydrate (NiCl 26H 2O) 0.5 gram mixes with 100 milliliters of ethanol, adds little water, and stirring at room 30 minutes adds halogenide (8) 2.4 grams then.Stirring at room stoichiometric number hour, after thin-layer chromatography TLC detection reaction finishes, filtering precipitation, a little washing with alcohol of filter residue, merging filtrate, decompression and solvent recovery.Residue adds 50 milliliters of ethyl acetate, and hydrochloric acid is transferred PH=1.0, and saturated common salt is washed to neutrality, anhydrous sodium sulfate drying, and vacuum concentration is to doing, and the resistates recrystallization from ethyl acetate/petroleum ether obtains white solid GA 41.0 gram (yield 60%).
Embodiment 45: zinc (Zn) powder 10 gram and Nickel dichloride hexahydrate (NiCl 26H 2O) 7.0 grams mix with 100 milliliters of tetrahydrofuran (THF)s, stirring at room adds 3.5 gram halogenide (8) after 15 minutes, stirring at room stoichiometric number hour, silica gel thin-layer chromatography (TLC) detection reaction finishes back filtering solid, with a little tetrahydrofuran (THF) washing filter residue, merge tetrahydrofuran (THF), decompression and solvent recovery, resistates adds 100 milliliters of acetic acid ethyl dissolutions, and hcl acidifying is to PH=1.0, and the saturated common salt water washing is closely neutral, anhydrous sodium sulfate drying, vacuum concentration is to doing, and the resistates recrystallization from ethyl acetate/petroleum ether obtains shallow white solid GA 43.1 gram (yield 90%).
Embodiment 46: zinc (Zn) powder 10 gram and Nickel dichloride hexahydrate (NiCl 26H 2O) 7.0 grams mix with 50 milliliters of ethanol, stirring at room adds 3.5 gram halogenide (8) after 15 minutes, stirring at room stoichiometric number hour, silica gel thin-layer chromatography (TLC) detection reaction finishes back filtering solid, with a little tetrahydrofuran (THF) washing filter residue, merge ethanol, decompression and solvent recovery, resistates adds 50 milliliters of acetic acid ethyl dissolutions, and hcl acidifying is to PH=1.0, and the saturated common salt water washing is closely neutral, anhydrous sodium sulfate drying, vacuum concentration is to doing, resistates acetone the sherwood oil recrystallization, obtain shallow white solid GA 43.0 gram (yield 85%).
Embodiment 47: zinc (Zn) powder 10 gram and Nickel dichloride hexahydrate (NiCl 26H 2O) 7.0 grams mix with 60 ml methanol, stirring at room adds 5.5 gram halogenide (8) after 15 minutes, stirring at room stoichiometric number hour, silica gel thin-layer chromatography (TLC) detection reaction finishes back filtering solid, with a little tetrahydrofuran (THF) washing filter residue, merge ethanol, decompression and solvent recovery, resistates adds 50 milliliters of acetic acid ethyl dissolutions, and hcl acidifying is to PH=1.0, and the saturated common salt water washing is closely neutral, anhydrous sodium sulfate drying, vacuum concentration is to doing, and the resistates recrystallization from ethyl acetate/petroleum ether obtains shallow white solid GA 44.8 gram (yield 88%).

Claims (2)

1. compound Plant hormones regulators,gibberellins GA with following structural formula (I) 4Synthetic method:
It is characterized in that the gibberic acid GA that obtains with fermentation 3Be starting raw material; obtain compound 1 through the step a) acetylize; the step b) catalytic hydrogenation obtains compound 2; the step c) halo lactonizes and obtains compound 3; step d) 7-carboxyl esterification obtains compound 4; step e) 13-hydroxyl methylsulfonylization obtains compound 5; hydrolysis through step f) 7-carboxyl obtains compound 6; reaction obtains compound 7 to compound 6 through step g); passing through step h again) halo lactonizes and obtains compound 8; step I) remove halogen reaction back recrystallization and obtain compound (I), reaction formula is as follows:
Figure FSB00000116776200012
In step a), used reagent is diacetyl oxide, makes solvent with methylene dichloride, anhydrous acetonitrile and tetrahydrofuran (THF), and consumption is 10～100 a milliliters/gram; Adding pyridine or the organic alkali as a catalyst of triethylamine, is 0.1%～10% by weight the organic bases consumption with respect to reaction substrate;
In step b), the catalyzer that is adopted is platinum and palladium, catalyst levels is by weight being 0.1%～10% with respect to reaction substrate, and the mixed solvent that adopts organic solvent and organic amine compound to obtain in 10: 1 by volume～1: 10, consumption are 10～100 milliliters/gram; Described organic solvent is methyl alcohol, ethanol, ethyl acetate, ether, and organic amine compound is triethylamine or pyridine;
At step c) and h) in, the halo halogen that is adopted that lactonizes is a bromine, iodine with and with the mixture of potassium halide or sodium halide, consumption is 1～10: 1 with respect to reaction substrate in molar ratio, the solvent that is adopted is alcohol, ketone and tetrahydrofuran (THF); The alkali that is adopted is carbonate M 2CO 3Or MHCO 3, wherein M is sodium Na, potassium K, lithium Li, consumption are 2～10: 1 with respect to reaction substrate in molar ratio;
In step d), the reagent that the esterification of 7-carboxyl is adopted is nitrogen N-Hydroxysuccinimide and dicyclohexyl imines, and reaction solvent is tetrahydrofuran (THF) or acetonitrile;
In step e), the methylsulfonyl agents useful for same of 13-hydroxyl is a methane sulfonyl chloride, pyridine or triethylamine catalysis, and reaction solvent is tetrahydrofuran (THF), methylene dichloride or acetonitrile;
In step f), the hydrolysis reaction of 7-carboxyl adopts saleratus or sodium bicarbonate to make alkali, and acetone or tetrahydrofuran (THF) are made solvent, 30% hydrogen peroxide catalysis;
In step g), the solvent that is adopted is liquefied ammonia and anhydrous tetrahydro furan, and metallic lithium or potassium are made reductive agent ,-78 ℃ of reactions;
In step I) in reagent that the dehalogenation reaction adopted be that zinc powder and moisture nickelous chloride are 1～30: 1 in molar ratio, consumption is 5～20: 1 with respect to reaction substrate in molar ratio; The solvent that is adopted is dehydrated alcohol, methyl alcohol, tetrahydrofuran (THF); Also can adopt sodium borohydride is reagent, and consumption is 3～30: 1 with respect to reaction substrate in molar ratio, and solvent is anhydrous tetrahydro furan or diglyme.
2. synthetic method as claimed in claim 1 is characterized in that final product GA 4With acetone/sherwood oil volume ratio is 1～10: 1 or ethyl acetate/petroleum ether volume ratio 2～15: 1 solvent recrystallization.
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