CN105693684A - Isoforskolin preparing method - Google Patents
Isoforskolin preparing method Download PDFInfo
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- CN105693684A CN105693684A CN201610044817.8A CN201610044817A CN105693684A CN 105693684 A CN105693684 A CN 105693684A CN 201610044817 A CN201610044817 A CN 201610044817A CN 105693684 A CN105693684 A CN 105693684A
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- isoforskolin
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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 154
- 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 77
- 238000000034 method Methods 0.000 title abstract description 10
- 239000002904 solvent Substances 0.000 claims abstract description 56
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 54
- 238000006243 chemical reaction Methods 0.000 claims abstract description 34
- 239000003054 catalyst Substances 0.000 claims abstract description 23
- 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
- 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
- 238000001914 filtration Methods 0.000 claims abstract description 7
- 238000006462 rearrangement reaction Methods 0.000 claims abstract description 7
- 239000007788 liquid Substances 0.000 claims abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- 238000002360 preparation method Methods 0.000 claims description 23
- 238000001953 recrystallisation Methods 0.000 claims description 11
- 238000000746 purification Methods 0.000 claims description 9
- 239000003513 alkali Substances 0.000 claims description 7
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 7
- 238000005406 washing Methods 0.000 claims description 7
- 239000002585 base Substances 0.000 claims description 6
- 238000004821 distillation Methods 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 6
- 239000002245 particle Substances 0.000 claims description 6
- 239000011347 resin Substances 0.000 claims description 6
- 229920005989 resin Polymers 0.000 claims description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000000741 silica gel Substances 0.000 claims description 2
- 229910002027 silica gel Inorganic materials 0.000 claims description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 abstract description 78
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 abstract description 18
- 239000003208 petroleum Substances 0.000 abstract description 9
- 239000007787 solid Substances 0.000 abstract description 5
- 238000002425 crystallisation Methods 0.000 description 22
- 230000008025 crystallization Effects 0.000 description 22
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- 238000010992 reflux Methods 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 238000001816 cooling Methods 0.000 description 8
- 239000012065 filter cake Substances 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- 239000012567 medical material Substances 0.000 description 6
- 238000004140 cleaning Methods 0.000 description 5
- 239000000470 constituent Substances 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 238000002791 soaking Methods 0.000 description 5
- 235000005320 Coleus barbatus Nutrition 0.000 description 4
- 241000131459 Plectranthus barbatus Species 0.000 description 4
- 238000013019 agitation Methods 0.000 description 4
- 230000003197 catalytic effect Effects 0.000 description 4
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 4
- 239000010413 mother solution Substances 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- 241000628997 Flos Species 0.000 description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 3
- 229910001873 dinitrogen Inorganic materials 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 238000004519 manufacturing process Methods 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
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 230000008901 benefit Effects 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
- 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
- 238000009825 accumulation Methods 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 238000005815 base catalysis Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- QGBSISYHAICWAH-UHFFFAOYSA-N dicyandiamide Chemical compound NC(N)=NC#N QGBSISYHAICWAH-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000694 effects Effects 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
- 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
- 239000000243 solution Substances 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
Abstract
The invention relates to an isoforskolin preparing method. The method comprises the steps of utilizing forskolin as a raw material, utilizing a basic catalyst and a dichloromethane (DCM) solvent to carry out ethanoyl rearrangement reaction in an appropriate condition, filtering after reaction, separating liquid from solid, combining filter liquid, distilling the filter liquid to obtain a crude product and crystallizing and purifying the certain proportion and the certain amount of ethyl acetate (EA) and petroleum ether (PE) to prepare the high-purity isoforskolin with the purity larger than or equal to 99 percent.
Description
Technical field
The preparation method that the present invention relates to isoforskolin (Isoforskolin), particularly to the preparation method of a kind of high-purity isoforskolin (Isoforskolin)。
Background technology
Research shows, derive from labiate Coleus forskohlii Briq. (Coleusforskohlii (Wild.) Briq), originate in the ground such as the country such as India, Nepal and the Huize, yunnan of China, Dongchuan, the labdane diterpenes compound being representative with isoforskolin (Isoforskolin), the relevant diseases such as treatment bronchial asthma, congestive heart failure, kinds of tumors are had obvious effect, and demand dramatically increases。Domestic effective ingredient purification, expand planting scale, improve active constituent content etc. in do a lot of work。The patent No. be 201110458818.4 Chinese patent literature disclose a kind of method extracting Coleus forskohlii Briq. effective ingredient isoforskolin (Isoforskolin), after Coleus forskohlii Briq. herb or root are pulverized, extract with aquiferous ethanol, the methods such as macroporous resin column chromatography, octadecyl silane column chromatography, recrystallization are purified, and prepare the purity isoforskolin (Isoforskolin) more than 90%。Researcher manually standardize in Tongcheng County, Hubei Province base plantation Flos Colei esquirolii medical material。Tongcheng County plantation medical material is compared with Yunnan Wild medical material, and the index such as the pharmacognosy, chemical composition and pharmacology is all without significant difference, but the content of effective ingredient isoforskolin is on the low side。The patent No. be 201310636981.4 Chinese patent literature openly know clearly and a kind of improve the method for isoforskolin (Isoforskolin) content in Flos Colei esquirolii medical material, utilize the method that ultraviolet induction Flos Colei esquirolii medical material promotes isoforskolin (Isoforskolin) synthesis and accumulation。
Owing to being limited by suitable cultivation condition, principle active component isoforskolin (Isoforskolin) cannot meet growing demand (in dry medical material, isoforskolin (ISOF) content is only 0.5-1.15 ‰), adopts chemosynthesis to prepare isoforskolin (Isoforskolin) imperative。
Summary of the invention
The present invention is directed to prior art deficiency; adopt chemical synthesis; with Forskolin for raw material; select suitable dicyandiamide solution; adopt base catalysis acetyl group to reset chemical synthesis process, separate purification, prepare the isoforskolin (Isoforskolin) of purity >=99%; meeting the demand that isoforskolin is growing, industrialized production is significant。
Technical scheme is as follows:
The preparation method of a kind of isoforskolin, with Forskolin for raw material, adopts base catalyst, obtains isoforskolin through acetyl group rearrangement reaction in dichloromethane。
Preferably, the preparation method of above-mentioned isoforskolin, described base catalyst is alkalescence catalyst, one or more in alkali alumina, basic resin, alkaline silica gel or alkalescence kieselguhr。It is preferred that the particle diameter of alkali alumina is 200-400 order, pH value 9.0-10.0 (100g/L, 25 DEG C)。
Basic resin can be weakly base resin, for instance 717 type ion exchange resin, D301 macroporous resin。
The preparation method of above-mentioned isoforskolin, it is preferable that Forskolin: alkali alumina: dichloromethane=1g:(10-30) g:(10-100) ml。More preferably Forskolin: alkali alumina: dichloromethane=1g:20g:25ml。
The preparation method of above-mentioned isoforskolin, it is preferable that reaction temperature is 15 DEG C-40 DEG C, the response time is 48h-72h。
The preparation method of above-mentioned isoforskolin, it is also possible to farther include the separating step to isoforskolin。Can by the reacting liquid filtering containing isoforskolin, then soaked in solvent washing catalyst, after merging with filtrate, distillation obtains isoforskolin crude product, it is preferred to use methanol washing by soaking catalyst, it is preferred that catalyst: cleaning solvent=1kg:1.5L。
The preparation method of isoforskolin of the present invention, it is also possible to farther including the purification step to isoforskolin。Preferably isoforskolin crude product is carried out recrystallization。
One preferred purification schemes is: adopt secondary crystallization purification, first time crystallization purifying, solvent burden ratio (volume ratio) is ethyl acetate (EA): petroleum ether (PE)=1:2, solvent load is crude product (kg): recrystallisation solvent (L)=1:9, heating is to refluxing, maintain the reflux for 2h, it is naturally cooling to 25 DEG C, filter, obtain the solvent wash (3-5 time) of crystallization (I) filter cake EA:PE=1:3 (about 200ml)；Second time crystallization purifying, solvent burden ratio (volume ratio) is ethyl acetate (EA): petroleum ether (PE)=1:2, solvent load is crystallization (I) (kg): recrystallisation solvent (L)=1:9, heating is to refluxing, maintain the reflux for 2h, it is naturally cooling to 25 DEG C, filter, prepare the high-purity isoforskolin (Isoforskolin) of purity >=99%, the filter cake solvent wash (3-5 time) of EA:PE=1:3 (about 200ml)；Solvent recovery cycle in mother solution uses, and solid constituent is standby after analyzing。
The invention have the benefit that
(1) adopting single step reaction, target product selectivity is good, and reaction system is relatively clean, and by-product is less, and the reaction used time is very short；
(2) select solvent toxicity less；
(3) crystallization yield is higher, the recyclable application of solvent, can reach purity more than 99% after twice crystallization。
The advantages such as in sum, catalyst, solvent, reaction condition etc. are required low by the present invention, are the Isoforskolin new technology paths of a kind of applicable industrialized production, have the used time short, and yield is high, with low cost, easy and simple to handle, safety。
Accompanying drawing explanation
Fig. 1 is the HPLC figure of the isoforskolin that the method for the invention prepares。
Fig. 2 is the LCMS figure of the isoforskolin that the method for the invention prepares。
Fig. 3 is the NMR figure of the isoforskolin that the method for the invention prepares。
Detailed description of the invention
Below by the drawings and specific embodiments, the invention will be further described, but is not meant to limiting the scope of the invention。
The investigation of embodiment 1 reaction condition
With Forskolin for raw material, adopt particle diameter: 200-400 order, pH value (100g/L, 25 DEG C): the alkaline oxygenated Al catalysts of 9.0-10.0, selecting dichloromethane, oxolane, methanol, ethanol, benzene respectively is reaction dissolvent, investigates the impact under room temperature prepared by isoforskolin；Reaction vessel adopts using nitrogen gas to seal off；Adopt mechanical agitation mode, carry out acetyl group rearrangement reaction。Filtering after completing reaction, with catalytic amount (kg): cleaning solvent (L)=1:1.5 methanol (MeOH) washing by soaking catalyst, after filtrate merges, distillation obtains crude product；
| Reaction dissolvent | Response situation | Response time | Yield |
| Dichloromethane | Reaction is very fast | No longer having product to generate after 48-72h, reaction completes | 53% |
| Oxolane | Reaction is slowly | Reaction only has a small amount of target product to 72h and generates。 | / |
| Methanol | Reaction is slowly | Reaction only has a small amount of target product to 72h and generates。 | / |
| Ethanol | Reaction is slowly | Reaction only has a small amount of target product to 72h and generates。 | / |
| Benzene | React slower | No longer having product to generate after 120h, reaction completes。 | 55% |
By the comparison to different solvents, it has been found that preparation method of the present invention is had a significant impact by reaction dissolvent, selecting oxolane, methanol and ethanol as reaction dissolvent, slowly, reaction only has a small amount of target product to 72h and generates response speed。If reaction system is heated, then in reaction system, by-product increases a lot。Selecting benzene and dichloromethane as solvent, the two yield is suitable, but benzene is as reaction dissolvent, and response speed is slower, it is necessary to 120h just can react completely, and selects dichloromethane, and response speed is substantially fast a lot, and 48h can reach to react completely。Owing to benzene has very big toxicity, and the long time is not suitable for industrialized production, therefore selects the reaction dissolvent that dichloromethane is prepared as isoforskolin。
Embodiment 2
The preparation method of a kind of isoforskolin (Isoforskolin) described in the present embodiment, specifically includes following steps:
(1) with Forskolin for raw material, particle diameter is adopted: 200-400 order, pH value (100g/L, 25 DEG C): the alkaline oxygenated Al catalysts of 9.0-10.0, dichloromethane (DCM) solvent；
(2) at suitable condition: 1. raw material dosage: catalyst amount: solvent load=1g:20g:25ml；2. temperature 15 DEG C；3. time 48h；4. reaction vessel adopts using nitrogen gas to seal off；5. adopt mechanical agitation mode, carry out acetyl group rearrangement reaction；
(3) filtering after completing 1. reaction, with catalytic amount (kg): cleaning solvent (L)=1:1.5 methanol (MeOH) washing by soaking catalyst, after filtrate merges, distillation obtains crude product；
(4) secondary crystallization purification is adopted, first time crystallization purifying, solvent burden ratio (volume ratio) is ethyl acetate (EA): petroleum ether (PE)=1:2, solvent load is crude product (kg): recrystallisation solvent (L)=1:9, heating, to backflow, maintains the reflux for 2h, is naturally cooling to 25 DEG C, filter, obtain the solvent wash (3-5 time) of crystallization (I) filter cake EA:PE=1:3 (about 200ml)；Second time crystallization purifying, solvent burden ratio (volume ratio) is ethyl acetate (EA): petroleum ether (PE)=1:2, solvent load is crystallization (I) (kg): recrystallisation solvent (L)=1:9, heating is to refluxing, maintain the reflux for 2h, it is naturally cooling to 25 DEG C, filter, prepare the high-purity isoforskolin (Isoforskolin) of purity >=99%, the filter cake solvent wash (3-5 time) of EA:PE=1:3 (about 200ml)；Solvent recovery cycle in mother solution uses, and solid constituent is standby after analyzing。Yield 53%。
The HPLC result of the present embodiment is as shown in Figure 1。HPLC condition is as follows:
Post: sunfire (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%。
H 1 NMR(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 2
The preparation method of a kind of isoforskolin (Isoforskolin) described in the present embodiment, specifically includes following steps:
(1) with Forskolin for raw material, particle diameter is adopted: 200-400 order, pH value (100g/L, 25 DEG C): the alkaline oxygenated Al catalysts of 9.0-10.0, dichloromethane (DCM) solvent；
(2) at suitable condition: 1. raw material dosage: catalyst amount: solvent load=1g:20g:25ml；2. temperature 25 DEG C；3. time 60h；4. reaction vessel adopts argon airtight；5. adopt mechanical agitation mode, carry out acetyl group rearrangement reaction；
(3) filtering after completing 1. reaction, with catalytic amount (kg): cleaning solvent (L)=1:1.5 methanol (MeOH) washing by soaking catalyst, after filtrate merges, distillation obtains crude product；
(4) secondary crystallization purification is adopted, first time crystallization purifying, solvent burden ratio (volume ratio) is ethyl acetate (EA): petroleum ether (PE)=1:2, solvent load is crude product (kg): recrystallisation solvent (L)=1:9, heating, to backflow, maintains the reflux for 2h, is naturally cooling to 25 DEG C, filter, obtain the solvent wash (3-5 time) of crystallization (I) filter cake EA:PE=1:3 (about 200ml)；Second time crystallization purifying, solvent burden ratio (volume ratio) is ethyl acetate (EA): petroleum ether (PE)=1:2, solvent load is crystallization (I) (kg): recrystallisation solvent (L)=1:9, heating is to refluxing, maintain the reflux for 2h, it is naturally cooling to 25 DEG C, filter, prepare the high-purity isoforskolin (Isoforskolin) of purity >=99%, the filter cake solvent wash (3-5 time) of EA:PE=1:3 (about 200ml)；Solvent recovery cycle in mother solution uses, and solid constituent is standby after analyzing。Yield 53%。
H 1 NMR(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 is identical with embodiment 1。
Embodiment 3
The preparation method of a kind of isoforskolin (Isoforskolin) described in the present embodiment, specifically includes following steps:
(1) with Forskolin for raw material, particle diameter is adopted: 200-400 order, pH value (100g/L, 25 DEG C): the alkaline oxygenated Al catalysts of 9.0-10.0, dichloromethane (DCM) solvent；
(2) at suitable condition: 1. raw material dosage: catalyst amount: solvent load=1g:20g:25ml；2. temperature 40 DEG C；3. time 72h；4. reaction vessel adopts using nitrogen gas to seal off；5. adopt mechanical agitation mode, carry out acetyl group rearrangement reaction；
(3) filtering after completing 1. reaction, with catalytic amount (kg): cleaning solvent (L)=1:1.5 methanol (MeOH) washing by soaking catalyst, after filtrate merges, distillation obtains crude product；
(4) secondary crystallization purification is adopted, first time crystallization purifying, solvent burden ratio (volume ratio) is ethyl acetate (EA): petroleum ether (PE)=1:2, solvent load is crude product (kg): recrystallisation solvent (L)=1:9, heating, to backflow, maintains the reflux for 2h, is naturally cooling to 25 DEG C, filter, obtain the solvent wash (3-5 time) of crystallization (I) filter cake EA:PE=1:3 (about 200ml)；Second time crystallization purifying, solvent burden ratio (volume ratio) is ethyl acetate (EA): petroleum ether (PE)=1:2, solvent load is crystallization (I) (kg): recrystallisation solvent (L)=1:9, heating is to refluxing, maintain the reflux for 2h, it is naturally cooling to 25 DEG C, filter, prepare the high-purity isoforskolin (Isoforskolin) of purity >=99%, the filter cake solvent wash (3-5 time) of EA:PE=1:3 (about 200ml)；Solvent recovery cycle in mother solution uses, and solid constituent is standby after analyzing。Yield 53%。
H 1 NMR(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 is identical with embodiment 1。
Claims (10)
1. the preparation method of an isoforskolin, it is characterised in that with Forskolin for raw material, adopts base catalyst, obtains isoforskolin through acetyl group rearrangement reaction in dichloromethane。
2. the preparation method of isoforskolin as claimed in claim 1, it is characterised in that described base catalyst is alkalescence catalyst, one or more in alkali alumina, basic resin, alkaline silica gel or alkalescence kieselguhr。
3. the preparation method of isoforskolin as claimed in claim 2, it is characterised in that the particle diameter of described alkali alumina is 200-400 order, pH value 9.0-10.0。
4. the preparation method of isoforskolin as claimed in claim 3, it is characterised in that Forskolin: alkali alumina: dichloromethane=1g:(10-30) g:(10-100) ml。
5. the preparation method of isoforskolin as claimed in claim 1, it is characterised in that reaction temperature is 15 DEG C-40 DEG C, and the response time is 48h-72h。
6. the preparation method of the isoforskolin as described in one of claim 1-5 item, it is characterised in that also include the separating step to isoforskolin。
7. the preparation method of isoforskolin as claimed in claim 6, it is characterised in that by the reacting liquid filtering containing isoforskolin, then soaked in solvent washing catalyst, after merging with filtrate, distillation obtains isoforskolin crude product。
8. the preparation method of isoforskolin as claimed in claim 6, it is characterised in that described solvent is methanol。
9. the preparation method of isoforskolin as claimed in claim 6, it is characterised in that still further comprise the purification step to isoforskolin。
10. the preparation method of isoforskolin as claimed in claim 9, it is characterised in that isoforskolin crude product is carried out recrystallization。
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