CN105693684B - A kind of preparation method of isoforskolin - Google Patents
A kind of preparation method of isoforskolin Download PDFInfo
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- CN105693684B CN105693684B CN201610044817.8A CN201610044817A CN105693684B CN 105693684 B CN105693684 B CN 105693684B CN 201610044817 A CN201610044817 A CN 201610044817A CN 105693684 B CN105693684 B CN 105693684B
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- CLOQVZCSBYBUPB-KGGHGJDLSA-N [(3r,4ar,5s,6s,6as,10s,10ar,10bs)-3-ethenyl-5,10,10b-trihydroxy-3,4a,7,7,10a-pentamethyl-1-oxo-5,6,6a,8,9,10-hexahydro-2h-benzo[f]chromen-6-yl] acetate Chemical compound O[C@H]([C@@]12C)CCC(C)(C)[C@@H]1[C@H](OC(=O)C)[C@H](O)[C@]1(C)[C@]2(O)C(=O)C[C@](C)(C=C)O1 CLOQVZCSBYBUPB-KGGHGJDLSA-N 0.000 title claims abstract description 140
- SBMKZIAQTQIEHN-NRADYMPXSA-N Coleonol C Natural products [H][C@@]12[C@H](OC(C)=O)[C@@H](O)[C@@]3(C)O[C@@](C)(CC(=O)[C@]3(O)[C@@]1(C)[C@@H](C)CCC2(C)C)C=C SBMKZIAQTQIEHN-NRADYMPXSA-N 0.000 title claims abstract description 70
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 239000002904 solvent Substances 0.000 claims abstract description 56
- OHCQJHSOBUTRHG-KGGHGJDLSA-N FORSKOLIN Chemical compound O=C([C@@]12O)C[C@](C)(C=C)O[C@]1(C)[C@@H](OC(=O)C)[C@@H](O)[C@@H]1[C@]2(C)[C@@H](O)CCC1(C)C OHCQJHSOBUTRHG-KGGHGJDLSA-N 0.000 claims abstract description 22
- 239000003054 catalyst Substances 0.000 claims abstract description 22
- 238000002425 crystallisation Methods 0.000 claims abstract description 19
- 230000008025 crystallization Effects 0.000 claims abstract description 19
- 239000012043 crude product Substances 0.000 claims abstract description 13
- SUZLHDUTVMZSEV-UHFFFAOYSA-N Deoxycoleonol Natural products C12C(=O)CC(C)(C=C)OC2(C)C(OC(=O)C)C(O)C2C1(C)C(O)CCC2(C)C SUZLHDUTVMZSEV-UHFFFAOYSA-N 0.000 claims abstract description 11
- OHCQJHSOBUTRHG-UHFFFAOYSA-N colforsin Natural products OC12C(=O)CC(C)(C=C)OC1(C)C(OC(=O)C)C(O)C1C2(C)C(O)CCC1(C)C OHCQJHSOBUTRHG-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000002994 raw material Substances 0.000 claims abstract description 11
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims abstract description 8
- 239000000706 filtrate Substances 0.000 claims abstract description 7
- 238000006462 rearrangement reaction Methods 0.000 claims abstract description 7
- 239000007788 liquid Substances 0.000 claims abstract 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- 238000006243 chemical reaction Methods 0.000 claims description 35
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 17
- 238000005406 washing Methods 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 5
- 238000000746 purification Methods 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 claims 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 abstract description 78
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 abstract description 48
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 abstract description 18
- 239000003208 petroleum Substances 0.000 abstract description 6
- 238000000926 separation method Methods 0.000 abstract 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- 238000001953 recrystallisation Methods 0.000 description 9
- 239000012065 filter cake Substances 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- 238000000034 method Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 241000131459 Plectranthus barbatus Species 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 238000004140 cleaning Methods 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 239000011347 resin Substances 0.000 description 5
- 229920005989 resin Polymers 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 238000013019 agitation Methods 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 230000003197 catalytic effect Effects 0.000 description 4
- 239000000470 constituent Substances 0.000 description 4
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000012452 mother liquor Substances 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 235000005320 Coleus barbatus Nutrition 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 238000007654 immersion Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000004575 stone Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 235000021508 Coleus Nutrition 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000012797 qualification Methods 0.000 description 2
- 230000036632 reaction speed Effects 0.000 description 2
- 238000002791 soaking Methods 0.000 description 2
- YOEWQQVKRJEPAE-UHFFFAOYSA-L succinylcholine chloride (anhydrous) Chemical compound [Cl-].[Cl-].C[N+](C)(C)CCOC(=O)CCC(=O)OCC[N+](C)(C)C YOEWQQVKRJEPAE-UHFFFAOYSA-L 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 238000005815 base catalysis Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000469 ethanolic extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 229930002697 labdane diterpene Natural products 0.000 description 1
- 210000000867 larynx Anatomy 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/78—Ring systems having three or more relevant rings
- C07D311/92—Naphthopyrans; Hydrogenated naphthopyrans
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to the preparation methods of isoforskolin (Isoforskolin) a kind of, using Forskolin as raw material, using basic catalyst, dichloromethane (DCM) solvent, carry out acetyl group rearrangement reaction under optimum conditions；It filters, is separated by solid-liquid separation after the completion of reacting, filtrate is distilled after merging obtains crude product；With certain with the EA (ethyl acetate) when measured and PE (petroleum ether) crystallization purifying, the high-purity isoforskolin (Isoforskolin) of purity >=99% is prepared.
Description
Technical field
The present invention relates to the preparation method of isoforskolin (Isoforskolin), more particularly to a kind of different Buddhist department of high-purity
The preparation method of Kelin (Isoforskolin).
Background technology
Studies have shown that labiate Coleus forskohlii (Coleus forskohlii (Wild.) Briq) is derived from, production
In Huize, yunnan, Dongchuan of the country such as India, Nepal and China and other places, with isoforskolin (Isoforskolin) for generation
The labdane diterpenes compound of table, to relevant diseases such as treatment bronchial asthma, congestive heart failure, kinds of tumors
With apparent effect, demand dramatically increases.It is domestic active ingredient purification, expand planting scale, improve effectively at
Point content etc. is done a lot of work.The Chinese patent literature of Patent No. 201110458818.4 discloses a kind of extraction hair
The method that larynx sheath stamen spends active ingredient isoforskolin (Isoforskolin), after Coleus forskohlii herb or root are crushed, with
Hydrous ethanol extracts, and the methods of macroporous resin column chromatography, octadecyl silane column chromatography, recrystallization are purified, and are made
Purity is more than 90% isoforskolin (Isoforskolin).Researcher Hubei Province Tongcheng County manually standardize base plant
Coleus forskohlin medicinal material.Medicinal material is planted compared with Yunnan Wild medicinal material in Tongcheng County, the equal nothing of the indexs such as pharmacognosy, chemical composition and pharmacology
Significant difference, but the content of active ingredient isoforskolin is relatively low.The Chinese patent literature of Patent No. 201310636981.4
A kind of method improving isoforskolin (Isoforskolin) content in coleus forskohlin medicinal material has been disclosed, ultraviolet induction is utilized
Coleus forskohlin medicinal material promotes the method that isoforskolin (Isoforskolin) is synthesized and accumulated.
Due to being limited by suitable cultivation condition, principle active component isoforskolin (Isoforskolin) cannot be satisfied increasingly
The demand (isoforskolin (ISOF) content is only 0.5-1.15 ‰ in dry medicinal material) of growth, different Buddhist department is prepared using chemical synthesis
(Isoforskolin) is imperative for Kelin.
Invention content
The present invention, using Forskolin as raw material, selects suitable solvent in view of the shortcomings of the prior art, using chemical synthesis
System resets chemical synthesis process using base catalysis acetyl group, isolates and purifies, prepare the isoforskolin of purity >=99%
(Isoforskolin), meets the needs of isoforskolin is growing, industrialized production is significant.
Technical scheme is as follows:
A kind of preparation method of isoforskolin, using Forskolin as raw material, using basic catalyst, in methylene chloride
Isoforskolin is obtained by acetyl group rearrangement reaction.
Preferably, the preparation method of above-mentioned isoforskolin, the basic catalyst is alkalescent catalyst, selected from alkalinity
One or more of aluminium oxide, basic resin, alkaline silica gel or alkaline diatomite.The grain size of further preferred alkali alumina
For 200-400 mesh, pH value 9.0-10.0 (100g/L, 25 DEG C).
Basic resin can be weakly base resin, such as 717 type ion exchange resin, D301 macroreticular resins.
The preparation method of above-mentioned isoforskolin, preferably Forskolin：Alkali alumina：Dichloromethane=1g:(10-
30)g:(10-100)ml.More preferable Forskolin：Alkali alumina：Dichloromethane=1g:20g:25ml.
The preparation method of above-mentioned isoforskolin, preferable reaction temperature are 15 DEG C -40 DEG C, reaction time 48h-72h.
The preparation method of above-mentioned isoforskolin can further include the separating step to isoforskolin.It can be with
By the reaction solution filtering containing isoforskolin, then soaked in solvent washing catalyst, is distilled after merging with filtrate and obtain different Buddhist
Scoline crude product is, it is preferable to use methanol washing by soaking catalyst, further preferred catalyst：Cleaning solvent=1kg:1.5L.
The preparation method of isoforskolin of the present invention can also further comprise the purifying to isoforskolin
Step.It is preferred that being recrystallized to isoforskolin crude product.
One preferred purification schemes is：It is purified using secondary crystallization, first time crystallization purifying, solvent burden ratio (volume ratio)
For ethyl acetate (EA):Petroleum ether (PE)=1:2, solvent dosage is crude product (kg):Recrystallisation solvent (L)=1:9, it is heated to back
Stream, maintains the reflux for 2h, is naturally cooling to 25 DEG C, and filtering is crystallized (I) filter cake EA:PE=1:The solvent of 3 (about 200ml)
It washs (3-5 times)；Second of crystallization purifying, solvent burden ratio (volume ratio) are ethyl acetate (EA):Petroleum ether (PE)=1:2, it is molten
Agent dosage is crystallization (I) (kg):Recrystallisation solvent (L)=1:9, it is heated to flowing back, maintains the reflux for 2h, be naturally cooling to 25 DEG C, mistake
Filter, is prepared the high-purity isoforskolin (Isoforskolin) of purity >=99%, filter cake EA:PE=1:3 (about
Solvent washing (3-5 times) 200ml)；Solvent recovery cycle in mother liquor uses, spare after solid constituent analysis.
Beneficial effects of the present invention are：
(1) single step reaction is used, target product selectivity is good, and reaction system is cleaner, and by-product is less, and the reaction used time is very
It is short；
(2) select solvent toxicity smaller；
(3) crystallization yield is higher, the recyclable application of solvent, can reach 99% or more purity after crystallizing twice.
In conclusion the present invention requires catalyst, solvent, reaction condition etc. low, it is a kind of suitable industrialized production
Isoforskolin new technology paths, have the used time it is short, high income is of low cost, easy to operate, it is safe the advantages that.
Description of the drawings
Fig. 1 is the HPLC figures for the isoforskolin that the method for the invention is prepared.
Fig. 2 is the LCMS figures for the isoforskolin that the method for the invention is prepared.
Fig. 3 is the NMR figures for the isoforskolin that the method for the invention is prepared.
Specific implementation mode
Below by the drawings and specific embodiments, the invention will be further described, but is not meant to protect the present invention
Protect the limitation of range.
The investigation of 1 reaction condition of embodiment
Using Forskolin as raw material, using grain size：200-400 mesh, pH value (100g/L, 25 DEG C):9.0-10.0 alkalinity oxygen
Change Al catalysts, select dichloromethane, tetrahydrofuran, methanol, ethyl alcohol, benzene for reaction dissolvent respectively, investigates under room temperature to different Buddhist
Influence prepared by scoline；Reaction vessel is closed using nitrogen；Using mechanical agitation mode, acetyl group rearrangement reaction is carried out.It is complete
At being filtered after reaction, with catalytic amount (kg)：Cleaning solvent (L)=1:1.5 methanol (MeOH) washing by soaking catalyst, filtrate are closed
And distillation obtains crude product afterwards；
| Reaction dissolvent | Response situation | Reaction time | Yield |
| Dichloromethane | Reaction is very fast | There is no product generations, reaction to complete after 48-72h | 53% |
| Tetrahydrofuran | Reaction is very slow | Reaction only has a small amount of target product to 72h and generates. | / |
| Methanol | Reaction is very slow | Reaction only has a small amount of target product to 72h and generates. | / |
| Ethyl alcohol | Reaction is very slow | Reaction only has a small amount of target product to 72h and generates. | / |
| Benzene | Reaction is slower | There is no product generations, reaction to complete after 120h. | 55% |
By the comparison to different solvents, it is found that reaction dissolvent has a significant impact to preparation method of the present invention, select tetrahydrochysene
As reaction dissolvent, reaction speed is very slow for furans, methanol and ethyl alcohol, and reaction to 72h only has a small amount of target product and generates.Such as
Fruit heats reaction system, then by-product increases much in reaction system.Select benzene and dichloromethane as solvent, the two yield
Quite, but benzene is as reaction dissolvent, and reaction speed is slower, and needing 120h ability, the reaction was complete, and selects dichloromethane, reacts
There are many speed, and 48h can reach that the reaction was complete.Since benzene has prodigious toxicity, and the long time is not suitable for
Industrialized production, therefore the reaction dissolvent for selecting dichloromethane to be prepared as isoforskolin.
Embodiment 2
A kind of preparation method of isoforskolin (Isoforskolin), specifically includes following steps described in the present embodiment：
(1) using Forskolin as raw material, using grain size：200-400 mesh, pH value (100g/L, 25 DEG C):9.0-10.0 alkaline
Aluminium oxide catalyst, dichloromethane (DCM) solvent；
(2) in suitable condition：1. raw material dosage：Catalyst amount：Solvent dosage=1g:20g:25ml；2. 15 DEG C of temperature；
3. time 48h；4. reaction vessel is closed using nitrogen；5. using mechanical agitation mode, acetyl group rearrangement reaction is carried out；
(3) it completes to filter after 1. reacting, with catalytic amount (kg)：Cleaning solvent (L)=1:1.5 methanol (MeOH) immersion is washed
Catalyst is washed, filtrate is distilled after merging obtains crude product；
(4) secondary crystallization is used to purify, first time crystallization purifying, solvent burden ratio (volume ratio) is ethyl acetate (EA):Stone
Oily ether (PE)=1:2, solvent dosage is crude product (kg):Recrystallisation solvent (L)=1:9, it is heated to flowing back, maintains the reflux for 2h, it is natural
25 DEG C are cooled to, filtering is crystallized (I) filter cake EA:PE=1:The solvent washing (3-5 times) of 3 (about 200ml)；Second
Crystallization purifying, solvent burden ratio (volume ratio) are ethyl acetate (EA):Petroleum ether (PE)=1:2, solvent dosage is crystallization (I)
(kg)：Recrystallisation solvent (L)=1：9, it is heated to flowing back, maintains the reflux for 2h, be naturally cooling to 25 DEG C, purity is prepared in filtering
>=99% high-purity isoforskolin (Isoforskolin), filter cake EA:PE=1:The solvent of 3 (about 200ml) washs (3-
5 times)；Solvent recovery cycle in mother liquor uses, spare after solid constituent analysis.Yield 53%.
The results are shown in Figure 1 by the HPLC of the present embodiment.HPLC conditions are as follows：
Column：sun fire(150mm×4.6mm)；
Mobile phase：A：H2O+0.1%THA, B:ACN+0.1%THA；
| Min | A (%) | B (%) |
| 0 | 95 | 5 |
| 2 | 95 | 5 |
| 5 | 70 | 30 |
| 20 | 25 | 75 |
| 30 | 5 | 95 |
Isoforskolin retention time is 15.304min, purity 99.3%.
H1NMR(DMSO-d6):
δ=7.69 (s, 1H), 6.22 (d, 1H), 6.10 (dd, 1H), 5.54 (dd, 1H), 5.10 (d, 1H), 4.84 (dd,
1H),4.74(d,1H),4.42(d,1H),4.02(t,1H),3.05(d,1H),2.45(d,1H),2.17(d,1H),2.04(m,
4H),1.69(m,1H),1.45(s,3H),1.29,1.30(m,7H),1.01(m,4H),0.89(s,3H).
LCMS, NMR of the present embodiment are as shown in Figure 2,3.
Embodiment 3
A kind of preparation method of isoforskolin (Isoforskolin), specifically includes following steps described in the present embodiment：
(1) using Forskolin as raw material, using grain size：200-400 mesh, pH value (100g/L, 25 DEG C):9.0-10.0 alkaline
Aluminium oxide catalyst, dichloromethane (DCM) solvent；
(2) in suitable condition：1. raw material dosage：Catalyst amount：Solvent dosage=1g:20g:25ml；2. 25 DEG C of temperature；
3. time 60h；4. reaction vessel is closed using argon gas；5. using mechanical agitation mode, acetyl group rearrangement reaction is carried out；
(3) it completes to filter after 1. reacting, with catalytic amount (kg)：Cleaning solvent (L)=1:1.5 methanol (MeOH) immersion is washed
Catalyst is washed, filtrate is distilled after merging obtains crude product；
(4) secondary crystallization is used to purify, first time crystallization purifying, solvent burden ratio (volume ratio) is ethyl acetate (EA):Stone
Oily ether (PE)=1:2, solvent dosage is crude product (kg):Recrystallisation solvent (L)=1:9, it is heated to flowing back, maintains the reflux for 2h, it is natural
25 DEG C are cooled to, filtering is crystallized (I) filter cake EA:PE=1:The solvent washing (3-5 times) of 3 (about 200ml)；Second
Crystallization purifying, solvent burden ratio (volume ratio) are ethyl acetate (EA):Petroleum ether (PE)=1:2, solvent dosage is crystallization (I)
(kg)：Recrystallisation solvent (L)=1:9, it is heated to flowing back, maintains the reflux for 2h, be naturally cooling to 25 DEG C, purity is prepared in filtering
>=99% high-purity isoforskolin (Isoforskolin), filter cake EA:PE=1:The solvent of 3 (about 200ml) washs (3-
5 times)；Solvent recovery cycle in mother liquor uses, spare after solid constituent analysis.Yield 53%.
H1NMR(DMSO-d6):
δ=7.69 (s, 1H), 6.22 (d, 1H), 6.10 (dd, 1H), 5.54 (dd, 1H), 5.10 (d, 1H), 4.84 (dd,
1H),4.74(d,1H),4.42(d,1H),4.02(t,1H),3.05(d,1H),2.45(d,1H),2.17(d,1H),2.04(m,
4H),1.69(m,1H),1.45(s,3H),1.29,1.30(m,7H),1.01(m,4H),0.89(s,3H).
HPLC, LCMS, NMR qualification result of the present embodiment are same as Example 2.
Embodiment 4
A kind of preparation method of isoforskolin (Isoforskolin), specifically includes following steps described in the present embodiment：
(1) using Forskolin as raw material, using grain size：200-400 mesh, pH value (100g/L, 25 DEG C):9.0-10.0 alkaline
Aluminium oxide catalyst, dichloromethane (DCM) solvent；
(2) in suitable condition：1. raw material dosage：Catalyst amount：Solvent dosage=1g:20g:25ml；2. 40 DEG C of temperature；
3. time 72h；4. reaction vessel is closed using nitrogen；5. using mechanical agitation mode, acetyl group rearrangement reaction is carried out；
(3) it completes to filter after 1. reacting, with catalytic amount (kg)：Cleaning solvent (L)=1:1.5 methanol (MeOH) immersion is washed
Catalyst is washed, filtrate is distilled after merging obtains crude product；
(4) secondary crystallization is used to purify, first time crystallization purifying, solvent burden ratio (volume ratio) is ethyl acetate (EA):Stone
Oily ether (PE)=1:2, solvent dosage is crude product (kg):Recrystallisation solvent (L)=1:9, it is heated to flowing back, maintains the reflux for 2h, it is natural
25 DEG C are cooled to, filtering is crystallized (I) filter cake EA:PE=1:The solvent washing (3-5 times) of 3 (about 200ml)；Second
Crystallization purifying, solvent burden ratio (volume ratio) are ethyl acetate (EA):Petroleum ether (PE)=1:2, solvent dosage is crystallization (I)
(kg)：Recrystallisation solvent (L)=1:9, it is heated to flowing back, maintains the reflux for 2h, be naturally cooling to 25 DEG C, purity is prepared in filtering
>=99% high-purity isoforskolin (Isoforskolin), filter cake EA:PE=1:The solvent of 3 (about 200ml) washs (3-
5 times)；Solvent recovery cycle in mother liquor uses, spare after solid constituent analysis.Yield 53%.
H1NMR(DMSO-d6):
δ=7.69 (s, 1H), 6.22 (d, 1H), 6.10 (dd, 1H), 5.54 (dd, 1H), 5.10 (d, 1H), 4.84 (dd,
1H),4.74(d,1H),4.42(d,1H),4.02(t,1H),3.05(d,1H),2.45(d,1H),2.17(d,1H),2.04(m,
4H),1.69(m,1H),1.45(s,3H),1.29,1.30(m,7H),1.01(m,4H),0.89(s,3H).
HPLC, LCMS, NMR qualification result of the present embodiment are same as Example 2.
Claims (8)
1. a kind of preparation method of isoforskolin, it is characterised in that using Forskolin as raw material, using basic catalyst, two
Isoforskolin is obtained by acetyl group rearrangement reaction in chloromethanes, the basic catalyst is that grain size is 200-400 mesh, pH value
The alkali alumina of 9.0-10.0.
2. the preparation method of isoforskolin as described in claim 1, it is characterised in that Forskolin：Alkali alumina：Two
Chloromethanes=1g:（10-30）g:（10-100）ml.
3. the preparation method of the isoforskolin as described in claim 1, it is characterised in that reaction temperature is 15 DEG C -40 DEG C,
Reaction time is 48h-72h.
4. the preparation method of isoforskolin as described in any one of claims 1-3, it is characterised in that further include to different Buddhist department
The separating step of Kelin.
5. the preparation method of isoforskolin as claimed in claim 4, it is characterised in that by the reaction containing isoforskolin
Liquid filters, then soaked in solvent washing catalyst, is distilled after merging with filtrate and obtains isoforskolin crude product.
6. the preparation method of isoforskolin as claimed in claim 5, it is characterised in that the solvent is methanol.
7. the preparation method of isoforskolin as claimed in claim 4, it is characterised in that still further comprising can to different Buddhist department
The purification step of woods.
8. the preparation method of isoforskolin as claimed in claim 7, it is characterised in that carry out weight to isoforskolin crude product
Crystallization.
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