CN107118189A - A kind of preparation method of prostaglandin synthetic intermediate - Google Patents
A kind of preparation method of prostaglandin synthetic intermediate Download PDFInfo
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- CN107118189A CN107118189A CN201710395763.4A CN201710395763A CN107118189A CN 107118189 A CN107118189 A CN 107118189A CN 201710395763 A CN201710395763 A CN 201710395763A CN 107118189 A CN107118189 A CN 107118189A
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- furans
- tetrahydrochysene
- cyclopentanos
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- carboxaldehyde radicals
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- 0 *C(C1)O[C@@](C2)[C@]1C=C2C=CC=C Chemical compound *C(C1)O[C@@](C2)[C@]1C=C2C=CC=C 0.000 description 3
- LEPRNSSNTMEFNM-JVIMKECRSA-N CN([C@@H]1[C@H](C2)C=CC1)C2[O]=C Chemical compound CN([C@@H]1[C@H](C2)C=CC1)C2[O]=C LEPRNSSNTMEFNM-JVIMKECRSA-N 0.000 description 1
- ZAGZNWKTMWOQCK-WDSKDSINSA-N O=C(C1)[ClH][C@@H]2[C@H]1C=CC2 Chemical compound O=C(C1)[ClH][C@@H]2[C@H]1C=CC2 ZAGZNWKTMWOQCK-WDSKDSINSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
- C07D307/935—Not further condensed cyclopenta [b] furans or hydrogenated cyclopenta [b] furans
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to the preparation method of the ketone of important intermediate (3aR, 6aS) 3,3a, 6,6a tetrahydrochysene 2H cyclopentanos [b] furans 2 of Lipase absobed in a prostaglandin and Corey, this method is using butanedial as raw material, in catalytic amount（S）Optically pure bicyclic olefine aldehydr is first synthesized to obtain in the presence of proline and dibenzylamine trifluoroacetate, then hydroxyl is protected with methyl, reuses three（Triphenylphosphine）Radium chloride obtains (3aR, 6aS) 2 methoxyl group 3,3a, 6,6a tetrahydrochysene 2H cyclopentanos [b] furans as catalyst decarbonylation.Then hydroxyl is deprotected and aoxidized the ketone of (3aR, 6aS) 3,3a, 6,6a tetrahydrochysene 2H cyclopentanos [b] furans 2.The method reaction condition that the present invention is provided is gentle, and raw material and reagent are cheap and easy to get, simple to operate, and yield is moderate, suitable industrialized production.
Description
Technical field
The present invention relates to field of chemical technology, particularly a kind of preparation method of prostaglandin synthetic intermediate.
Background technology
Prostaglandin is the important endogenous product that a class has a variety of physiologically actives, and carrying out house of correction according to its structure obtains
The derivative arrived much also have important physiologically active, at present have 14 compounds list for treat glaucoma, ulcer,
The diseases such as early pregnancy, constipation and hypertension, synthesize these prostaglandins during, can many times use Corey lactones (1S,
5R, 6R, 7R) -6- methylol -7- hydroxyl -2- oxabicyclos [330] octyl- 3- ketone or (3aR, 6aS) -3,3a, 6,6a- tetra-
Hydrogen -2H- cyclopentanos [b] furans -2- ketone, the latter can also be easily converted to the former, and (Ge Yuanyuan etc., Chinese Medicine industry is miscellaneous
Will, 2013,44 (7), 720-728).Meanwhile, the two compounds can also be used as suppression hepatitis B medication Entecavir
Intermediate (Shen Guobing etc., Chinese Journal of Pharmaceuticals, 2007,38 (10), 749-752).
Corey lactones (1S, 5R, 6R, 7R) -6- methylols -7- hydroxyl -2- oxabicyclos [330] octyl- 3- ketone can be with
It is easily that raw material reacts with paraformaldehyde through Prins with (1S, 5R) -2- oxabicyclos [330] oct-6-ene -3- ketone
Then hydrolyze and be made (Feng Zewang etc., fine chemistry industry, 2008,25 (7), 715-719).
The synthetic method of (3aR, 6aS) -3,3a, 6,6a- tetrahydrochysene -2H- cyclopentanos [b] furans -2- ketone is existing so far a variety of
Report, be mainly raw material with cyclopentene two, can by the amyl- 2- alkene-Isosorbide-5-Nitrae-glycol of symmetrical ring (M.Nara et al,
Tetrahedron, 1980,36,3161-3170), or route (R.F.Newton et are aoxidized by Baeyer-Villiger
Al, J.Chem.Soc.Perkin Trans.I, 1983,683-685), and vitamin B12 catalytic reaction (S.Busato,
Tetrahedron,1990,46(9),3155-3166).This several routes are directed to optical resolution, thus have 50% raw material most
Become useless compound afterwards.
Due to the importance of this intermediate, finding more easily preparation method will be easy to get to its follow-up pharmaceutical synthesis offer
Raw material, and finally reduce medicine cost.
The content of the invention
It is a primary object of the present invention to provide a kind of preparation method of prostaglandin synthetic intermediate.
Technical scheme is as follows：
A kind of preparation method of prostaglandin synthetic intermediate, the prostaglandin synthetic intermediate is (3aR, 6aS) -3,
3a, 6,6a- tetrahydrochysene -2H- cyclopentanos [b] furans -2- ketone, its chemical structural formula is：
Its synthesis path is as follows：
Comprise the following steps：
1) butanedial carries out aldol reaction under (S)-Proline-Catalyzed and closed loop obtains (3aR, 6aS) -5- formaldehyde
Base -3,3a, 6,6a- tetrahydrochysene -2H- cyclopentanos [b] furans -2- alcohol；
2) (3aR, 6aS) -5- carboxaldehyde radicals -3,3a, 6,6a- tetrahydrochysene -2H- cyclopentanos [b] furans -2- alcohol protect (3aR,
6aS) -2- methoxyl groups -5- carboxaldehyde radicals -3,3a, 6,6a- tetrahydrochysene -2H- cyclopentano [b] furans；
3) (3aR, 6aS) -2- methoxyl groups -5- carboxaldehyde radicals -3,3a, 6,6a- tetrahydrochysene -2H- cyclopentanos [b] furans decarbonylation base is obtained
To (3aR, 6aS) -2- methoxyl groups -3,3a, 6,6a- tetrahydrochysene -2H- cyclopentanos [b] furans；
4) (3aR, 6aS) -2- methoxyl groups -3,3a, 6,6a- tetrahydrochysene -2H- cyclopentanos [b] furans removes first in watery hydrochloric acid
Base protection group obtains (3aR, 6aS) -3,3a, 6,6a- tetrahydrochysene -2H- cyclopentanos [b] furans -2- alcohol；
5) (3aR, 6aS) -3,3a, 6,6a- tetrahydrochysene -2H- cyclopentanos [b] furans -2- alcohol oxidation obtains (3aR, 6aS) -3,
The preparation of 3a, 6,6a- tetrahydrochysene -2H- cyclopentanos [b] furans -2- ketone
Complete the preparation of prostaglandin synthetic intermediate.
Preferably, the step 1) aldol reaction of (S)-Proline-Catalyzed carries out in tetrahydrofuran, butanedial
Concentration range 0.1-1.0M, preferred concentration 0.3-0.5M, (S)-proline consumption are the 1.0%-2.5% of butanedial quality, excellent
From amount 1.5-2.0%.
It is further preferred that the step 1) specific method is：After butanedial stirs in tetrahydrofuran, (S)-dried meat
Propylhomoserin is disposably added, and 36-48h is stirred at 10-40 DEG C, then adds dibenzylamine trifluoroacetate；Continuation is stirred at 10-40 DEG C
Mix 18-24h；Methyl tert butyl ether is added after reaction solution concentration, is filtered, (3aR, 6aS) -5- carboxaldehyde radicals -3 are obtained after filtrate concentration,
3a, 6,6a- tetrahydrochysene -2H- cyclopentanos [b] furans -2- alcohol crude products are directly used in next step reaction.
Preferably, the step 2) specific method is：(3aR, 6aS) -5- carboxaldehyde radicals -3,3a, 6,6a- tetrahydrochysene -2H- rings penta
And [b] furans -2- alcohol crude products are dissolved in dichloromethane, methanol, ion exchange resin 15 and magnesium sulfate, 10- are added at 10-40 DEG C
Stir and concentrated after 18-24h, reacting liquid filtering at 40 DEG C, column chromatography obtains (3aR, 6aS) -2- methoxyl group -5- carboxaldehyde radicals -3,3a, 6,
6a- tetrahydrochysene -2H- cyclopentanos [b] furans.
Preferably, the step 3) reaction in catalyst be three (triphenylphosphine) radium chlorides, reactant and three (triphenyls
Phosphine) radium chloride mol ratio be 1:0.5~1.0.
It is further preferred that the step 3) specific method is：By (3aR, 6aS) -2- methoxyl group -5- carboxaldehyde radicals -3,3a,
6,6a- tetrahydrochysene -2H- cyclopentanos [b] furans and three (triphenylphosphine) radium chlorides are added separately in benzonitrile, are heated to 110-
150 DEG C, 1-2 hours are incubated, ether is added after ice bath cooling, filters, solid is washed with ether, merge extract solution, it is dense after drying
Contracting, (3aR, 6aS) -2- methoxyl groups -3,3a, 6,6a- tetrahydrochysene -2H- cyclopentanos [b] furans are obtained after column chromatography purification.
Preferably, the step 4) reaction temperature be 10-40 DEG C, preferable temperature be 20-30 DEG C.
It is further preferred that the step 4) specific method is：By (3aR, 6aS) -2- methoxyl group -3,3a, 6,6a- tetra-
It is 3 that hydrogen -2H- cyclopentanos [b] furans, which is dissolved in 1.5% hydrochloric acid with tetrahydrofuran volume ratio,：In 1.5-2.5 solution, at 10-40 DEG C
18-24h is stirred, is extracted after concentration with dichloromethane, is concentrated after drying, obtains (3aR, 6aS) -3,3a, 6,6a- tetrahydrochysene -2H- rings
Penta simultaneously [b] furans -2- alcohol crude products.
Preferably, the step 5) oxidising agent that uses of oxidation is CrO3- pyridine complex (Collins reagents).
It is further preferred that the step 5) specific method is：(3aR, 6aS) -3,3a, 6,6a- tetrahydrochysene -2H- cyclopentanos
After [b] furans -2- alcohol crude product is aoxidized with Collins oxidising agents, with extracted by ether, then column chromatography for separation purify (3aR,
6aS) -3,3a, 6,6a- tetrahydrochysene -2H- cyclopentanos [b] furans -2- ketone.
The present invention has the beneficial effect that：
1st, (3aR, 6aS) -3,3a, 6,6a- tetrahydrochysene -2H- cyclopentanos [b] furans -2- ketone is always received according to obtained by the present invention
Rate 20% or so.Method of the present invention is simple to operate, is micromolecule catalyst, gained with cheap (S)-proline
The optical purity of product meets the requirements, and can realize prepared by the other scale of feather weight.
2nd, low in raw material price, butanedial can be obtained simply from the hydrolysis of 2,5- dimethyl-tetrahydrofurans, while we
The concentration reacted in tetrahydrofuran is reduced into below 1.0M to carry out, temperature is room temperature (10-40 DEG C).Fourth two in the prior art
The reaction density of aldehyde is 2M, can produce substantial amounts of polymer accessory substance, and the yield of bicyclic olefine aldehydr is only 15% or so, but we will
Concentration of the reactant butanedial in tetrahydrofuran is reduced to 0.1~0.5M progress, and temperature is 10~40 DEG C (room temperature), selection
(S)-proline is catalyst, extends the reaction time compared with prior art to 36~48h, it is found that polymer accessory substance substantially subtracts
It is few, and product increase so that yield reaches more than 35%.
3rd, selection (S)-proline is catalyst, and (S)-proline is as the catalyst of asymmetric syntheses, and valency is low to be easy to get.
4th, it can be split without optically pure resolution reagent, the three wastes are reduced, synthetic route is economical and practical.
5th, the method that the present invention is provided is using butanedial as initiation material, and step is few, and reaction condition is gentle, raw material and reagent valency
Honest and clean to be easy to get, simple to operate, yield is moderate, suitable industrialized production.
Embodiment
The present invention is further illustrated with reference to embodiment, but the scope of protection of present invention is not limited to implement
The scope of example statement.
The preparation of embodiment 1 (3aR, 6aS) -5- carboxaldehyde radicals -3,3a, 6,6a- tetrahydrochysene -2H- cyclopentanos [b] furans -2- alcohol
Butanedial (5.75 grams, 66.8 mMs) 25 DEG C of stirrings, (S)-proline (150 in tetrahydrofuran (130 milliliters)
Milligram, 1.3 mMs) it is disposable add, stirring reaction 48h at 25 DEG C, then add dibenzylamine trifluoroacetate (416 milligrams,
1.34 mMs), continue to stir 24h.Reaction solution is concentrated into 30 milliliters of methyl tert butyl ethers of addition after 20 milliliters, filtering, filtrate
(3aR, 6aS) -5- carboxaldehyde radicals -3,3a, 6,6a- tetrahydrochysene -2H- cyclopentanos [b] furans -2- alcohol crude products are obtained after concentration to be directly used in down
Single step reaction.
Embodiment 2 (3aR, 6aS) -2- methoxyl group -5- carboxaldehyde radicals -3,3a, 6,6a- tetrahydrochysene -2H- cyclopentanos [b] furans
Prepare
Crude product obtained above is dissolved in 12 milliliters of dichloromethane, methanol (340 milligrams), ion exchange are added at 25 DEG C
Resin 15 (76 milligrams) and magnesium sulfate (1.6 grams), stir and are concentrated after 24h, reacting liquid filtering, column chromatography obtains (3aR, 6aS) -2- first
2.10 grams of epoxide -5- carboxaldehyde radicals -3,3a, 6,6a- tetrahydrochysene -2H- cyclopentanos [b] furans.Two step total recoverys 35%, hydrogen nuclear magnetic spectrum
It is consistent with document.
The preparation of embodiment 3 (3aR, 6aS) -2- methoxyl groups -3,3a, 6,6a- tetrahydrochysene -2H- cyclopentanos [b] furans
By 180 milligrams of (3aR, 6aS) -2- methoxyl group -5- carboxaldehyde radicals -3,3a, 6,6a- tetrahydrochysene -2H- cyclopentanos [b] furans
(1.0 mMs) are added separately in benzonitrile (5 milliliters) with three (triphenylphosphine) radium chlorides (0.8 gram, 0.8 mM), plus
Heat is incubated 1.5 hours to 130 DEG C, adds ether after ice bath cooling, filters, solid is washed with ether, merge extract solution, dries
After concentrate, after column chromatography purification (3aR, 6aS) -2- methoxyl groups -3,3a, the milli of 6,6a- tetrahydrochysene -2H- cyclopentanos [b] furans 129
Gram, yield 85%,1H NMR(DMSO-d6)δ:1.95(brs,2H),2.41(m,2H),2.58(m,1H),3.24(m,1H),
3.27(s,3H),5.10(m,1H)。
The preparation of embodiment 4 (3aR, 6aS) -3,3a, 6,6a- tetrahydrochysene -2H- cyclopentanos [b] furans -2- ketone
By 152 milligrams of (3aR, 6aS) -2- methoxyl groups -3,3a, 6,6a- tetrahydrochysene -2H- cyclopentanos [b] furans (1.0 mmoles
You) it is dissolved in 1.5% hydrochloric acid/tetrahydrofuran (3:2) in, 24h is stirred at 25 DEG C, is extracted after concentration with dichloromethane, it is dense after drying
Contracting.After crude product is aoxidized with Collins oxidising agents, with extracted by ether, then column chromatography for separation purification, obtains (3aR, 6aS) -3,
3a, 6,6a- 105 milligrams of tetrahydrochysene -2H- cyclopentanos [b] furans -2- ketone, yield 83%, nuclear magnetic spectrum is consistent with standard diagram.
The above embodiments are only the preferred technical solution of the present invention, and are not construed as the limitation for the present invention, this Shen
Please in embodiment and feature in embodiment in the case where not conflicting, can mutually be combined.The protection model of the present invention
Enclose the equivalent substitution side of technical characteristic in the technical scheme that should be recorded with claim, including the technical scheme of claim record
Case is protection domain.Equivalent substitution i.e. within this range is improved, also within protection scope of the present invention.
Claims (10)
1. a kind of preparation method of prostaglandin synthetic intermediate, it is characterised in that the prostaglandin synthetic intermediate is
(3aR, 6aS) -3,3a, 6,6a- tetrahydrochysene -2H- cyclopentanos [b] furans -2- ketone, its chemical structural formula is：
Its synthesis path is as follows：
Comprise the following steps：
1) butanedial carries out aldol reaction under (S)-Proline-Catalyzed and closed loop obtains (3aR, 6aS) -5- carboxaldehyde radicals -3,
3a, 6,6a- tetrahydrochysene -2H- cyclopentanos [b] furans -2- alcohol；
2) (3aR, 6aS) -5- carboxaldehyde radicals -3,3a, 6,6a- tetrahydrochysene -2H- cyclopentanos [b] furans -2- alcohol protect (3aR, 6aS) -
2- methoxyl group -5- carboxaldehyde radicals -3,3a, 6,6a- tetrahydrochysene -2H- cyclopentanos [b] furans；
3) (3aR, 6aS) -2- methoxyl groups -5- carboxaldehyde radicals -3,3a, 6,6a- tetrahydrochysene -2H- cyclopentanos [b] furans decarbonylation base is obtained
(3aR, 6aS) -2- methoxyl groups -3,3a, 6,6a- tetrahydrochysene -2H- cyclopentanos [b] furans；
4) (3aR, 6aS) -2- methoxyl groups -3,3a, 6,6a- tetrahydrochysene -2H- cyclopentanos [b] furans removes methyl guarantor in watery hydrochloric acid
Shield base obtains (3aR, 6aS) -3,3a, 6,6a- tetrahydrochysene -2H- cyclopentanos [b] furans -2- alcohol；
5) (3aR, 6aS) -3,3a, 6,6a- tetrahydrochysene -2H- cyclopentanos [b] furans -2- alcohol, which is aoxidized, obtains (3aR, 6aS) -3,3a, and 6,
The preparation of 6a- tetrahydrochysene -2H- cyclopentanos [b] furans -2- ketone
Complete the preparation of prostaglandin synthetic intermediate.
2. method according to claim 1, it is characterised in that：The step 1) aldol reaction of (S)-Proline-Catalyzed exists
Carried out in tetrahydrofuran, butanedial concentration range 0.1-1.0M, preferred concentration 0.3-0.5M, (S)-proline consumption is butanedial
The 1.0%-2.5% of quality, preferable amount 1.5-2.0%.
3. method according to claim 2, it is characterised in that：The step 1) specific method is：Butanedial is in tetrahydrofuran
After stirring, (S)-proline is disposably added, and 36-48h is stirred at 10-40 DEG C, then adds dibenzylamine trifluoroacetate；
Continuation stirs 18-24h at 10-40 DEG C；Methyl tert butyl ether is added after reaction solution concentration, is filtered, after filtrate concentration (3aR,
6aS) -5- carboxaldehyde radicals -3,3a, 6,6a- tetrahydrochysene -2H- cyclopentanos [b] furans -2- alcohol crude products are directly used in next step reaction.
4. method according to claim 1, it is characterised in that：The step 2) specific method is：(3aR, 6aS) -5- carboxaldehyde radicals -
3,3a, 6,6a- tetrahydrochysene -2H- cyclopentanos [b] furans -2- alcohol crude products are dissolved in dichloromethane, and methanol, ion are added at 10-40 DEG C
Exchanger resin 15 and magnesium sulfate, stir at 10-40 DEG C and are concentrated after 18-24h, reacting liquid filtering, column chromatography obtains (3aR, 6aS) -2-
Methoxyl group -5- carboxaldehyde radicals -3,3a, 6,6a- tetrahydrochysene -2H- cyclopentanos [b] furans.
5. method according to claim 1, it is characterised in that：The step 3) reaction in catalyst be three (triphenylphosphine) chlorine
Change rhodium.
6. method according to claim 5, it is characterised in that：The step 3) specific method is：By (3aR, 6aS) -2- methoxies
Base -5- carboxaldehyde radicals -3,3a, 6,6a- tetrahydrochysene -2H- cyclopentanos [b] furans and three (triphenylphosphine) radium chlorides are added separately to benzene first
In nitrile, 110-150 DEG C is heated to, 1-2 hours are incubated, ether is added after ice bath cooling, filters, solid is washed with ether, merge
Extract solution, is concentrated after drying, and (3aR, 6aS) -2- methoxyl groups -3,3a, 6,6a- tetrahydrochysene -2H- cyclopentanos are obtained after column chromatography purification
[b] furans.
7. method according to claim 1, it is characterised in that：The step 4) reaction temperature be 10-40 DEG C, preferable temperature is
20-30℃。
8. method according to claim 7, it is characterised in that：The step 4) specific method is：By (3aR, 6aS) -2- methoxies
It is 3 that base -3,3a, 6,6a- tetrahydrochysene -2H- cyclopentanos [b] furans, which is dissolved in 1.5% hydrochloric acid with tetrahydrofuran volume ratio,：1.5-2.5
In solution, 18-24h is stirred at 10-40 DEG C, is extracted after concentration with dichloromethane, concentrated after drying, obtain (3aR, 6aS) -3,
3a, 6,6a- tetrahydrochysene -2H- cyclopentanos [b] furans -2- alcohol crude products.
9. method according to claim 1, it is characterised in that：The step 5) oxidising agent that uses of oxidation is CrO3- pyridines
Compound (Collins reagents).
10. method according to claim 9, it is characterised in that：The step 5) specific method is：(3aR,6aS)-3,3a,6,
After 6a- tetrahydrochysene -2H- cyclopentanos [b] furans -2- alcohol crude products are aoxidized with Collins oxidising agents, with extracted by ether, then post layer
Analysis separating-purifying obtains (3aR, 6aS) -3,3a, 6,6a- tetrahydrochysene -2H- cyclopentanos [b] furans -2- ketone.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109761942A (en) * | 2017-11-09 | 2019-05-17 | 上海茂晟康慧科技有限公司 | A kind of synthetic method of Ke Linei esterdiol |
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2017
- 2017-05-31 CN CN201710395763.4A patent/CN107118189A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4020173A (en) * | 1976-04-14 | 1977-04-26 | The Upjohn Company | 4α,6-Dihydroxy-2β-carboxaldehyde-3α-tetrahydropyranacetic acid γ-lactone, 6-alkyl ethers |
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| Title |
|---|
| GRAEME COULTHARD ET AL.,: "Stereocontrolled organocatalytic synthesis of prostaglandin PGF2α in seven steps", 《NATURE》 * |
| TSUTOMU SUGAHARA ET AL.,: "An Expedient Route to (-)-cis-2-Oxabicyclo[3.3.0]oct-6-en-3-one via a meso-Asymmetrization", 《SYNLETT》 * |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109761942A (en) * | 2017-11-09 | 2019-05-17 | 上海茂晟康慧科技有限公司 | A kind of synthetic method of Ke Linei esterdiol |
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