CN103288698A - Novel method for synthetizing prostaglandin analogue - Google Patents
Novel method for synthetizing prostaglandin analogue Download PDFInfo
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- CN103288698A CN103288698A CN2013101650750A CN201310165075A CN103288698A CN 103288698 A CN103288698 A CN 103288698A CN 2013101650750 A CN2013101650750 A CN 2013101650750A CN 201310165075 A CN201310165075 A CN 201310165075A CN 103288698 A CN103288698 A CN 103288698A
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- 238000000034 method Methods 0.000 title claims abstract description 30
- 150000003180 prostaglandins Chemical class 0.000 title claims abstract description 5
- 230000003407 synthetizing effect Effects 0.000 title abstract 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 17
- 230000032050 esterification Effects 0.000 claims abstract description 13
- 238000005886 esterification reaction Methods 0.000 claims abstract description 13
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000007239 Wittig reaction Methods 0.000 claims abstract description 10
- 230000009435 amidation Effects 0.000 claims abstract description 6
- 238000007112 amidation reaction Methods 0.000 claims abstract description 6
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 34
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- 201000007094 prostatitis Diseases 0.000 claims description 15
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
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- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 10
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- 238000002360 preparation method Methods 0.000 claims description 3
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- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 229940002639 xalatan Drugs 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a novel method for synthetizing prostaglandin analogues, and an important intermediate compound related to the novel method. The method comprises the steps of (a), just protecting 15-site hydroxyl of the compound of a formula 2 by utilizing a hydroxyl protection group under an alkaline condition; (b) restoring a lactone ketone group from DIBAL (diisobutylaluminium hydride) to obtain the intermediate of a formula 4; (c) carrying out Wittig reaction on the intermediate of the formula 4 by utilizing 4-carboxy butyl-triphenylphosphine bromide, carrying out esterification or amidation after connecting an alpha chain; (d) removing 15-site hydroxyl protection group to obtain the prostaglandin analogue of the formula 1. The method is less in side reaction, easy to monitor, and convenient to separate due to the fact that the difference between a crude product and the polarity of a process material is large.
Description
Technical field
The present invention relates to the novel method of the plain analogue in a kind of synthetic prostatitis, and the midbody compound that relates in the novel method.
Background technology
(prostaglandin is that one group of its chemical nature of important active substance that extensively is present in Mammals and human body is the unsaturated fatty acids of 20 carbon atoms of tool PG) to the prostatitis element.The basic framework that constitutes PG is the prostatitis alkanoic acid, a tool ring five alkane cores and two side chains.According to five-ring or whole molecular structure difference, prostaglandin(PG) can be divided into types such as A, B, C, D, E, F, G, H, I.Study more have E, F, A, B, I type (being PGE, PGF, PGA, PGB, PGI).And prostatitis plain class medicine PGF2 α thinks tool potentiality and the most effective local intraocular pressure lowering medicine at present, its reducing iop mainly is that the aqueous humor drainage of the trabecular network approach non-classical by improving uveal tract sclera approach realizes, it has good reducing iop at night simultaneously, can reduce intraocular pressure fluctuation round the clock, alleviate the intraocular pressure fluctuation to the infringement of the visual field and optic nerve.Represent the class medicine comprise latanoprost (Latanoprost, Xalatan), travoprost (Travoprost) and bimatoprost (Bimatoprost).At present this 3 kinds of prostatitis elements synthetic mainly contains following two lines:
Route 1.
R
1And R
2Be hydrogen (EP2143712) or suitable hydroxy-protective group; as THP (WO2005058812); TBS (WO210109476); TMS (WO2003074481) etc. raw material is through the DIBAL reduction; the Wittig reaction, esterification or amidation and corresponding protection and deprotection steps obtain the plain analogue in prostatitis.
Route 2.
Connect the ω chain by the Michael addition, be converted to the plain analogue in prostatitis through 9 carbonyl reductions and corresponding functional group again.
Because there is selective problems in route 29 related carbonyl reductions, so if synthetic methods that adopt routes 1 of a lot of prostatitis element more. when 11,15 hydroxyls are not done protection and caused the Wittig reaction 5, the ratio of 6-trans-isomer(ide) increases.And adopting traditional protecting group when adopting acetal such as THP or ketal class protecting group, deprotection generally uses acidic conditions, might cause the dehydration of 15 hydroxyls, produces a lot of by products, and then causes yield to reduce, and product separates very difficult.Using silicon ethers protecting group is reasonable selection, yet under general silicon ether protecting group, 11 reaction site may partly migrate to 9 under the Wittig reaction conditions, has increased the complexity of reaction, and has produced many by products that are difficult to separate.In addition, the by product diphenyl phosphine oxy pentanoic acid that the Wittig reaction produces makes it very difficult with separating of product owing to its physical properties.
Summary of the invention
At the above problem that prior art exists, the plain analogue in the synthetic prostatitis of the route below the present invention has used:
| ? | ? | 13,14 | X | Z | W |
| a | Bimatoprost | Two keys | -CH2- | -H | -NHEt |
| b | Latanoprost | Singly-bound | -CH2- | -H | -O-i-Pr |
| c | Travoprost | Two keys | -O- | -CF 3 | -O-i-Pr |
On the one hand, the invention provides the preparation method for the preparation of the plain analogue in formula 1 prostatitis, described method comprises:
(a) under alkaline condition, use hydroxyl protecting group, only 15 hydroxyls of formula 2 compounds are protected;
(b) DIBAL reduction lactone ketone group, acquisition formula 4 intermediates,
(c) use 4-carboxylic butyl-triphenylphosphine bromide and formula 4 intermediates to carry out the Wittig reaction, behind the connection α chain, esterification or amidation;
(d) slough 15-position hydroxyl protecting group, obtain the plain analogue in prostatitis of formula 1.
Formula 2 starting compounds be 2-oxa--3-oxo-6-suitable-(1-alkyl or alkoxyl group replace-3 ' Alpha-hydroxy-1 '-trans-butenyl)-7-is trans-phenoxy group-suitable-dicyclo also ［ 3.3.0 ］ octane be that known compound (is pressed Bioorg﹠amp; Med Chem12 (2004) 3451-3469 method is synthetic).
Preferably, be hydroxyl protecting group with tert-butyl diphenyl silicon ether (TBDPS), only 15 hydroxyls are protected, behind the connection α chain, do esterification or amidation earlier, slough silicon ether protecting group by tetrabutyl ammonium fluoride at last, obtain the prostatitis element.
Method of the present invention had both guaranteed the solvability of hemiacetal 4, again can be in nearly neutral environment the deprotection base, thereby avoided the side reaction of 15 hydroxyls.Introduce the uv-absorbing that tert-butyl diphenyl silicon ether has strengthened each intermediate in addition, be convenient to middle controlling/monitoring. and this silicon ether protecting group strengthened the hydrophobic nature of each intermediate, reduced the extraction times of last handling process.The crude product of Wittig reaction directly carries out the esterification of back, and the esterification products polarity of esterification products and diphenyl phosphine oxy pentanoic acid differs bigger, the convenient separation.
Can select alkane and various ethers, alkane, reagent such as aromatics for use with 15 hydroxyls of tert-butyl diphenyl silicon ether protection; such as methylene dichloride, THF, MCPE; DMF; toluene equal solvent, alkali can select for use various alkali such as imidazoles, triethylamine; pyridine; DMAP, DEA etc. temperature of reaction-10～60 degree, the reaction times was at 1～20 hour.
DIBAL reduction solvent can be selected ethers, THF, toluene, haloalkane etc. for use. and temperature of reaction-80～-10 degree, the reaction times was at 1～20 hour.
The Wittig reaction can be used systems such as DMSO/NaH, t-BuOK/THF, NaHMDS/THF.Temperature of reaction-50～50 degree. 1～20 hour reaction times.
Esterification can be used diazomethane, or methyl-sulfate, methylating reagent and DBU such as methyl iodide, and pyridine, triethylamine, DME etc. are rich, and use is united in sour agent.The i-PrI/DBU system is generally used in the isopropyl esterification. temperature of reaction-50～50 degree. and 1～20 hour reaction times.
Use pure ethamine or its water/alcoholic solution as the aminolysis step 1.Temperature of reaction-20～50 degree, 4 hours～4 days reaction times.
Deprotection steps is generally used tetrabutyl fluoride amine or hydrofluoric acid or other silicon ethers deprotecting regent.Solvent can be selected ethers for use, THF, ester class, haloalkane and aromatics etc. and temperature of reaction-10～70 degree, the reaction times was at 1～20 hour.
On the other hand, the present invention relates to the midbody compound that novel method is used, these intermediates comprise the compound of above-mentioned formula 3, formula 4 and formula 5, and the structure of these midbody compounds is significant to reducing the by product that generates in the target product process.
THP: tetrahydropyrans-2-base
TBS: tertiary butyl dimethyl is silica-based
DIBAL: diisobutylaluminium hydride
THF: tetrahydrofuran (THF)
MCPE: methylcyclopentyl ether
DMF: dimethyl formamide
The DMAP:4-Dimethylamino pyridine
DEA: diethylamine
MTBE: methyl tertiary butyl ether
DBU:1,8-diazabicylo [5.4.0] 11 carbon-7-alkene
TBAF: tetrabutyl ammonium fluoride
Embodiment
Embodiment 1
(3aR, 4R, 5R, 6aS)-((S, E)-3-(tert-butyl diphenyl silica)-5-benzene penta-1-alkene-1-yl)-2-oxo six hydrogen-2H-pentamethylene is [b] furans-5-yl benzoic acid ester (3a) also for 4-
Add 10 in the 1L there-necked flask and digest compound 2a, 90 milliliters of methylene dichloride, 5 gram imidazoles; 0.25 gram DMAP is cooled to the 0-10 degree under the nitrogen protection, drip the mixed solution of 10.1 gram TBDPSCl and 30 milliliters of methylene dichloride; added in about 10 minutes; the adularescent insolubles generates about the .20 degree and stirred 10 hours, TLC(Rf=0.9, and toluene: EtOAc3:2) detection reaction is complete; with salt washing 2 times; anhydrous sodium sulfate drying filters the solution that obtains compound 3a, is directly used in later reaction.
Get concentrate in a small amount the back silica gel column chromatography (eluent is methylene dichloride: normal hexane 1:1) obtain pure product.
1H-NMR(CDCl
3,300MHz)δ(ppm)1.04(s,9H),1.81(m,2H),2.12(dd,1H),1.83-2.61(m,6H),2.74(m,1H),4.22(q,1H),4.92(m,1H),5.08(t,1H),5.26(dd,1H),5.56(dd,1H),6.98(d,2H),7.11-7.22(m,3H),7.31-7.43(m,8H),7.53(m,1H),7.63(m,4H),7.96(m,2H).
Embodiment 2
(3aR, 4R, 5R, 6aS)-((S, E)-3-(tert-butyl diphenyl silica)-5-benzene penta-1-alkene-1-yl) six hydrogen-2H-pentamethylene is [b] furans-2 also, 5-glycol (4a) for 4-
In the solution of embodiment 1, add 140 milliliters of methylene dichloride again; be cooled to-60 degree under the nitrogen protection; 130 milliliters of the DIBAL toluene solutions of dropping 25%; added in about 60 minutes. keep-60 degree and stirred 1.5 hours; slowly add 70 ml waters and destroy unnecessary DIBAL; remove by filter aluminium hydroxide, concentrated filtrate. residue is obtained compound 4a, 15.4g with silica gel column chromatography (methylene dichloride/methyl tertiary butyl ether 1:1).
1H-NMR(CDCl
3,300MHz)δ(ppm)1.05(s,9H),1.64-2.05(m,6H),2.10-2.29(m,2H),2.58(m,2H),3.60(m,1H),4.19(m,1H),4.46-4.55(m,1H),5.02(m,1H),5.46-5.62(m,2H),7.09(m,2H),7.16(m,1H),7.22-7.25(m,2H),7.34-7.45(m,6H),7.66(m,4H).
Embodiment 3
(Z)-7-((1R, 2R, 3R, 5S)-2-((S, E)-3-(tert-butyl diphenyl silica-5-benzene penta-1-alkene-1-yl)-3,5-dihydroxyl cyclopentyl) heptan-5-olefin(e) acid (5a)
Add 50 in 500 milliliters of there-necked flasks and digest compound 7(4-carboxylic butyl-triphenylphosphine bromide); 150 milliliters of anhydrous THF; add 25.5 gram potassium tert.-butoxides under the nitrogen protection in batches; stir after 30 minutes; be cooled to 0 to 10 degree; drip the solution of 14.5 gram 4a and 25 milliliters of THF; added in about 20 minutes; keeping 0 to 10 degree stirred 1 hour. rose to the room temperature restir naturally 10 to 20 hours. and most of solvent is removed in decompression; the 300 ml water solution dissolving that residuum is joined with 0.6 gram salt of wormwood, water layer is transferred PH=4-5 with 1N hydrochloric acid, adds 200 milliliters of MTBE; filter; with MTBE drip washing filter cake 2 times. the filtrate phase-splitting, merge organic phase, concentrate; obtain about 26 grams of 5a crude product, be directly used in next step.
Get concentrate in a small amount the back silica gel column chromatography (eluent is chloroform: methyl alcohol 40:1) obtain pure product.
1H-NMR(CDCl
3,300MHz)δ(ppm):1.06(s,9H),1.34(m,1H),1.62-2.27(m,11H),2.31(t,2H),2.61(t,2H),3.70(s,1H),4.09(s,1H),4.18(q,1H),5.07(dd,1H),5.32(m,2H),5.53(dd,1H),7.06(m,2H),7.14(m,1H),7.22(m,2H),7.33-7.43(m,6H),7.68(m,4H).
Embodiment 4
(Z)-7-((1R, 2R, 3R, 5S)-2-((S, E)-3-(tert-butyl diphenyl siloxy-5-benzene penta-1-alkene-1-yl)-3,5-dihydroxyl cyclopentyl)-N-ethyl heptan-5-alkene acid amides (6a)
25 gram 5a are dissolved in 300 milliliters of acetone, 0 degree drips 45 gram DBU, there is heat release .20 degree to stir after 1 hour slightly, be cooled to 0 degree again, drip 32 gram MeI, added in about 5 minutes, there are a large amount of white insolubless to separate out. stirring at room 15 hours. be concentrated into driedly, add as 300 mL of saline, extract waters with 600 milliliters of ethyl acetate gradation. merge organic phase, wash 2 times with 500 milliliters of 1N aqueous hydrochloric acids, 5% NaHCO3 washes 2 times, concentrates last silica gel, obtain about 10.2 gram (Z)-7-((1R with n-hexane/ethyl acetate (1:1) drip washing, 2R, 3R, 5S)-2-((S, E)-and 3-(tert-butyl diphenyl silica-5-benzene penta-1-alkene-1-yl)-3,5-dihydroxyl cyclopentyl) heptan-the yellow thick liquid of 5-olefin(e) acid methyl esters.
1H-NMR(CDCl
3,300MHz)δ(ppm):1.05(s,9H),1.34(m,1H),1.62-2.25(m,11H),2.29(t,2H),2.61(t,2H),3.63(s,3H),3.66(m,1H),4.09(m,1H),4.19(q,1H),5.04(dd,1H),5.34(m,2H),5.52(dd,1H),7.07(m,2H),7.14(m,1H),7.24(m,2H),7.33-7.44(m,6H),7.68(m,4H).
Ethylamine solution dissolving with 300 milliliter 70%, stirring at room 72 hours, TLC(product Rf=0.4, EtOAc/Hexane1:1) demonstration reacts completely. the most of solvent of pressure reducing and steaming, and residuum is transferred PH=5 with the NaHSO4 aqueous solution of 2N, with ethyl acetate extraction 4 times, merge organic phase, the NaHCO3 with 5% washes 2 times, concentrates to obtain semi-solid 6a, about 10 grams are directly used in next step.
1H-NMR(CDCl
3,300MHz)δ(ppm):1.07(s,9H),1.10(t,3H),1.35(m,1H),1.62-2.35(m,13H),2.60(t,2H),3.22(m,2H),3.75(s,1H),4.09(m,1H),4.20(q,1H),5.10(dd,1H),5.34(m,2H),5.55(dd,1H),5.88(s,1H),7.08(m,2H),7.15(m,1H),7.23(m,2H),7.35-7.45(m,6H),7.69(m,4H).
Embodiment 5
Bimatoprost (1a)
10 digest compound 6a dissolves with 100 milliliters of THF, adds 10 gram TBAF, and 50 degree stirred 4 hours, TLC (product Rf=0.2 EtOAc) detects no raw material. is poured onto in 250 milliliters of 1N aqueous hydrochloric acids, with 500 milliliters of ethyl acetate extraction, merge organic phase, wash salt washing, anhydrous sodium sulfate drying with 5% sodium bicarbonate aqueous solution, concentrate, obtain yellow semisolid, the white powder 4.5 that obtains 1a with ethyl acetate/normal hexane recrystallization restrains, six step total recoverys 60.8%.
1H-NMR(CDCl
3,300MHz)δ(ppm)1.09(t,3H),136(m,1H),1.57-2.39(m,13H),2.60(m,2H),3.21(m,2H),3.92(t,1H),4.05-4.17(m,2H),5.31-5.64(m,4H),5.95(t,1H),7.18-7.30(m,5H)
Embodiment 6
(3aR, 4R, 5R, 6aS)-((R)-3-(tert-butyl diphenyl siloxy-5-benzene amyl group)-2-oxo six hydrogen-2H-pentamethylene is [b] furans-5-yl benzoic acid ester (3b) also for 4-
Add 10 in the 1L there-necked flask and digest compound 2b, 100 milliliters of methylene dichloride, 5 gram imidazoles; 0.25 gram DMAP is cooled to 0 degree under the nitrogen protection, drip the mixed solution of 10.1 gram TBDPSCl and 30 milliliters of methylene dichloride; added in about 10 minutes; the adularescent insolubles generates the .20 degree and stirred 16 hours, TLC(Rf=0.9, and toluene: EtOAc3:2) detection reaction is complete; with salt washing 2 times; anhydrous sodium sulfate drying filters the solution that obtains compound 3b, is directly used in later reaction.
Get concentrate in a small amount the back silica gel column chromatography (eluent is methylene dichloride: normal hexane 1:1) obtain pure product.
1H-NMR(CDCl
3,300MHz)δ(ppm)1.06(s,9H),1.21(m,1H),1.34(m,1H),1.55(m,2H),1.72-1.88(m,3H),2.23-2.38(m,4H),2.60(m,2H),2.73(m,1H),3.84(s,1H),4.92(m,1H),5.08(m,1H),7.03(d,2H),7.15(m,1H),7.22(t,2H),7.34-7.42(m,8H),7.54(t,1H),7.65(m,4H),7.97(d,2H).
Embodiment 7
(3aR, 4R, 5R, 6aS)-((R)-3-(tert-butyl diphenyl siloxy-5-benzene amyl group) six hydrogen-2H-pentamethylene is [b] furans-2 also, 5-glycol (4b) for 4-
In the solution of embodiment 6, add 340 milliliters of methylene dichloride again; be cooled to-70 degree under the nitrogen protection; 150 milliliters of the DIBAL toluene solutions of dropping 25%; added in about 20 minutes. keep-70 degree and stirred 1.5 hours; slowly add 90 ml waters and destroy unnecessary DIBAL, remove by filter aluminium hydroxide, concentrated filtrate. with silica gel on the residue; column chromatography (methylene dichloride/methyl tertiary butyl ether 1:1) obtains compound 4b, 14.6g.
1H-NMR(CDCl
3,300MHz)δ(ppm)1.03(s,9H),1.12-1.33(m,2H),1.51(m,2H),1.74-2.25(m,8H),2.59(m,2H),3.71(m,1H),3.80(m,1H),4.55(m,1H),5.44(m,1H),6.99(m,2H),7.13(m,1H),7.22(m,2H),7.34-7.45(m,6H),7.67(m,4H).
Embodiment 8
(Z)-7-((1R, 2R, 3R, 5S)-2-((R)-3-(tert-butyl diphenyl siloxy-5-benzene amyl group)-3,5-dihydroxyl cyclopentyl) heptan-5-olefin(e) acid (5b)
Add 60 in 500 milliliters of there-necked flasks and digest compound 7; 150 milliliters of anhydrous THF; add 30.5 gram potassium tert.-butoxides under the nitrogen protection in batches; stir after 30 minutes; 0 degree drips the solution of 14.5 gram 4b and 50 milliliters of THF, adds in about 10 minutes, keeps 0 degree and stirs 3 hours. and be poured onto 1.0 and restrain in the 400 ml water solution that salt of wormwood join; extract 2 times with 200 milliliters of MTBE; water layer is transferred PH=4, adds 300 milliliters of MTBE, filters; the filtrate phase-splitting; water extracts 2 times with 200 milliliters of MTBE again, merges organic phase, concentrates; obtain about 12.4 grams of 5b crude product, be directly used in next step.
Get concentrate in a small amount the back silica gel column chromatography (eluent is chloroform: methyl alcohol 40:1) obtain pure product.
1H-NMR(CDCl
3,300MHz)δ(ppm):1.05(s,9H),1.22-1.36(m,3H),1.49-1.83(m.9H),2.05-2.34(m,6H),2.55(m,2H),3.72-3.83(m,2H),4.09(s,1H),5.36(m,2H),7.01(d,2H),7.12(m,1H),7.20(m,2H),7.32-7.42(m,6H),7.67(m,4H).
Embodiment 9
(Z)-7-((1R, 2R, 3R, 5S)-2-((R)-3-(tert-butyl diphenyl siloxy-5-benzene amyl group)-3,5-dihydroxyl cyclopentyl) heptan-5-isopropyl gadoleate (6b)
12.4 gram 5b is dissolved in 190 milliliters of acetone, 0 degree drips 21 gram DBU, there is heat release .20 degree to stir after 1 hour slightly, be cooled to 0 degree again, drip 16.7 gram i-PrI, added in about 5 minutes, there are a large amount of white insolubless to separate out. stirring at room 15 hours. be concentrated into dried, add 300 mL of saline, extract water with 600 milliliters of ethyl acetate gradation. merge organic phase, wash 2 times with the 1N aqueous hydrochloric acid, 5% NaHCO3 washes 2 times, concentrate, last silica gel obtains about 7.1 grams of colourless viscous liquid 6b with n-hexane/ethyl acetate (1:1) drip washing. be directly used in next step.
1H-NMR(CDCl
3,300MHz)δ(ppm):1.07(s,9H),1.22(d,6H),1.22-1.38(m,3H),1.48-1.85(m.9H),2.05-2.32(m,6H),2.57(m,2H),3.75(s,1H),3.80(t,1H),4.11(s,1H),5.01(m,1H),5.37(m,2H),7.04(d,2H),7.14(m,1H),7.22(m,2H),7.34-7.44(m,6H),7.67(m,4H).
Embodiment 10
Latanoprost (1b)
Dissolve with 120 milliliters of THF 7.1 digest compound 6b, add 10 gram TBAF, 50 degree stirred 4 hours, TLC(product Rf=0.3, EtOAc) detect no raw material. be poured onto in 600 milliliters of 1N aqueous hydrochloric acids, with 500 milliliters of ethyl acetate extraction, merge organic phase, wash with 5% sodium bicarbonate aqueous solution, the salt washing, anhydrous sodium sulfate drying concentrates, last silica gel obtains about 4.2 grams, the five steps total recovery 39.6% of colourless viscous liquid 1b with n-hexane/ethyl acetate drip washing.
1H-NMR(CDCl
3,300MHz)δ(ppm)1.23(d,6H),1.34(m,1H),1.40(m,1H),1.52(m,1H,),1.62(m,2H),1.65-173(m,3H),1.75-1.82(m,2H,),1.87(m,2H),2.13(m,2H),2.22(m,1H),2.28(t,2H),2.32(m,1H),2.68(m,1H),2.80(m,1H,),3.67(m,1H)3.95(m,1H,),4.18(m,1H),5.00(q,1H),5.40(dd,1H),5.46(dd,1H),7.18(m,1H,),7.21(m,2H,),7.29(m,2H,)
Embodiment 11
(3aR, 4R, 5R, 6aS)-4-((R, E)-3-(tert-butyl diphenyl siloxy-4-(3-4-trifluoromethylphenopendant) but-1-ene-1-yl)-2 oxo six hydrogen-2H-pentamethylene [b] furans-5-yl benzoic acid ester (3c) also
Add 10 in the 1L there-necked flask and digest compound 2c, 100 milliliters of methylene dichloride, 4.3 gram imidazoles, 0.25 gram DMAP is cooled to 0 degree under the nitrogen protection, drip the mixed solution of 8.6 gram TBDPSCl and 30 milliliters of methylene dichloride, adds in about 10 minutes.20 degree stirred 16 hours, and the TLC detection reaction is complete, and with salt washing 2 times, anhydrous sodium sulfate drying filters the solution that obtains compound 3c, is directly used in later reaction.
Get concentrate in a small amount the back silica gel column chromatography (eluent is methylene dichloride: normal hexane 1:1) obtain pure product.
1H-NMR(CDCl
3,300MHz)δ(ppm)1.04(s,9H),2.13(s,1H),2.36-2.80(m,5H),3.81(m,1H),3.93(s,1H),4.52(q,1H),4.95(t,1H),5.11(q,1H),5.44(dd,1H),5.67(dd,1H),6.83(d,1H),6.92(s,1H),7.15(d,1H),7.29-7.42(m,9H),7.54(t,1H),7.66(m,4H),7.97(d,2H).
Embodiment 12
(3aR, 4R, 5R, 6aS)-4-((R, E)-3-(tert-butyl diphenyl siloxy-4-(3-4-trifluoromethylphenopendant) but-1-ene-1-yl) six hydrogen-2H-pentamethylene [b] furans-2 also, 5-glycol (4c)
In the solution of embodiment 11, add 340 milliliters of methylene dichloride again; be cooled to-70 degree under the nitrogen protection; 200 milliliters of the DIBAL toluene solutions of dropping 25%; added in about 20 minutes. keep-70 degree and stirred 2 hours; slowly add 110 ml waters and destroy unnecessary DIBAL, remove by filter aluminium hydroxide, concentrated filtrate. with silica gel on the residue; column chromatography (methylene dichloride/methyl tertiary butyl ether 1:1) obtains compound 4c, 14.1g.
1H-NMR(CDCl
3,300MHz)δ(ppm)1.06(s,9H),1.39-2.35(m,6H),3.69(m,1H),3.88(m,1H),4.00(m,1H),4.51-4.58(m,2H),5.30(dd,1H),5.55-5.62(m,2H),6.89(m,1H),6.98(s,1H),7.16(d,1H),7.30-7.46(m,7H),7.69(d,4H).
Embodiment 13
(Z)-7-((1R, 2R, 3R, 5S)-2-((R, E)-3-(tert-butyl diphenyl siloxy-4-(3-4-trifluoromethylphenopendant) but-1-ene-1-yl)-3,5-dihydroxyl cyclopentyl) heptan-5-olefin(e) acid (5c)
Add 50 in 500 milliliters of there-necked flasks and digest compound 7; 150 milliliters of anhydrous THF; add 25.5 gram potassium tert.-butoxides under the nitrogen protection in batches; stir after 10-40 minute; 0 degree drips the solution of 14.1 gram 4c and 40 milliliters of THF; added in about 20 minutes; keeping the 0-10 degree stirred 3 hours. and be poured onto in the 400 ml water solution that 1.0 gram salt of wormwood join, extract 2 times with 200 milliliters of MTBE, water layer is with 1N hydrochloric acid accent PH=4-5; add 300 milliliters of MTBE; filter, the filtrate phase-splitting, organic phase concentrates; obtain about 11.2 grams of 5c crude product, be directly used in next step.
Get concentrate in a small amount the back silica gel column chromatography (eluent is chloroform: methyl alcohol 40:1) obtain pure product.
1H-NMR(CDCl
3,300MHz)δ(ppm)1.06(s,9H),1.38(m,1H),1.63-1.77(m,3H),1.95-2.33(m,8H),3.76(m,1H),3.86(m,1H),3.98(m,1H),4.10(m,1H),4.53(m,1H),5.33(m,3H),5.60(dd,1H),6.89(m,1H),6.95(s,1H),7.15(d,1H),7.30-7.43(m,7H),7.7(d,4H).
Embodiment 14
(Z)-7-((1R, 2R, 3R, 5S)-2-((R, E)-3-(tert-butyl diphenyl siloxy-4-(3-4-trifluoromethylphenopendant) but-1-ene-1-yl)-3,5-dihydroxyl cyclopentyl) heptan-5-isopropyl gadoleate (6c)
11.2 gram 5c is dissolved in 160 milliliters of acetone, 0 degree drips 19 gram DBU, there is heat release .20 degree to stir after 1 hour slightly, be cooled to 0 degree again, drip 15.6 gram i-PrI, added in about 5 minutes, there are a large amount of white insolubless to separate out. stirring at room 15 hours. be concentrated into dried, add as 300 mL of saline, extract water with 600 milliliters of ethyl acetate gradation. merge organic phase, wash 2 times with 500 milliliters of 1N aqueous hydrochloric acids, 5% NaHCO3 washes 2 times, concentrate, last silica gel obtains about 7.4 grams of colourless viscous liquid 6c with n-hexane/ethyl acetate drip washing. be directly used in next step.
1H-NMR(CDCl
3,300MHz)δ(ppm)1.06(s,9H),1.20(d,6H),1.38(m,1H),1.63-1.76(m,3H),1.95-2.26(m,8H),3.75(m,1H),3.86(m,1H),3.99(m,1H),4.13(m,1H),4.53(m,1H),4.99(m,1H),5.34(m,3H),5.59(dd,1H),6.87(m,1H),6.96(s,1H),7.15(d,1H),7.31-7.45(m,7H),7.7(m,4H).
Embodiment 15
Travoprost (1c)
Dissolve with 120 milliliters of THF 7.4 digest compound 6c, add 10 gram TBAF, 50 degree stirred 4 hours, TLC(product Rf=0.4, EtOAc) detect no raw material. be poured onto in 600 milliliters of 1N aqueous hydrochloric acids, with 500 milliliters of ethyl acetate extraction, merge organic phase, wash with 5% sodium bicarbonate aqueous solution, the salt washing, anhydrous sodium sulfate drying concentrates, last silica gel obtains about 4.5 grams, the five steps total recovery 42.8% of colourless viscous liquid 1c with n-hexane/ethyl acetate drip washing.
1H-NMR(CDCl
3,300MHz)δ(ppm)δ1.22(d,6H),1.40(m,1H),1.66(t,2H),1.81(dd,1H),2.08(m,4H),2.26(m,4H),2.53(bs,1H),3.13(bs,2H),3.99(m,3H),4.19(t,1H),4.55(m,1H),5.00(m,1H),5.39(m,2H),5.71(m,2H),7.15-7.25(m,3H),7.39(t,1H).
Claims (16)
1. the preparation method who prepares the plain analogue in following formula 1 prostatitis,
Wherein
A:X=-CH
2-, Z=-H is two keys between 13,14;
B:X=-CH
2-, Z=-H is singly-bound between 13,14;
C:X=-O-, Z=-CF
3, be two keys between 13,14;
Described method comprises:
(a) under alkaline condition, use hydroxyl protecting group, only 15 hydroxyls of formula 2 compounds are protected;
(b) DIBAL reduction lactone ketone group, acquisition formula 4 intermediates,
(c) use 4-carboxylic butyl-triphenylphosphine bromide and formula 4 intermediates to carry out the Wittig reaction, behind the connection α chain, esterification or amidation;
(d) slough 15-position hydroxyl protecting group, obtain the plain analogue in prostatitis of formula 1.
2. the method for claim 1 is hydroxyl protecting group with tert-butyl diphenyl silicon ether (TBDPS) wherein, only 15 hydroxyls is protected; after connecting the α chain; do esterification or amidation earlier, slough silicon ether protecting group by tetrabutyl ammonium fluoride at last, obtain prostaglandin(PG).
3. method as claimed in claim 2 can be selected alkane and various ethers, alkane, aromatics equal solvent for use during wherein with 15 hydroxyls of tert-butyl diphenyl silicon ether protection.
4. method as claimed in claim 3 wherein can be selected methylene dichloride for use, THF, and MCPE, DMF, toluene are as the solvent of step (a), and alkali can be selected imidazoles, triethylamine, pyridine, DMAP, DEA for use.
5. as the arbitrary described method of claim 1-3, wherein temperature of reaction control is at-10～60 degree, and the reaction times was at 1～20 hour.
6. the method for claim 1, wherein DIBAL reduction solvent can be selected ethers, THF, toluene, haloalkane for use. and temperature of reaction-80～-10 degree, the reaction times was at 1～20 hour.
7. method as claimed in claim 1 or 2, wherein the Wittig reaction can be used systems such as DMSO/NaH, t-BuOK/THF, NaHMDS/THF.
8. the method for claim 1, wherein the control of the temperature of reaction of step (c) is at-50～50 degree. 1～20 hour reaction times.
9. as claim 1 or 9 described methods, wherein esterification can be used diazomethane, or methyl-sulfate, methylating reagent and DBU such as methyl iodide, and pyridine, triethylamine, DME etc. are rich, and use is united in sour agent; The i-PrI/DBU system is generally used in the isopropyl esterification.
10. use pure ethamine or its water/alcoholic solution as the method as claimed in claim 1 or 2, aminolysis step 1, temperature of reaction-20～50 degree, 4 hours～4 days reaction times.
11. method as claimed in claim 1 or 2, deprotection steps are generally used tetrabutyl fluoride amine or hydrofluoric acid or other silicon ethers deprotecting regent; Solvent can be selected ethers for use, THF, ester class, haloalkane and aromatic solvents.
12. method as claimed in claim 11, the temperature of reaction of deprotection are-10～70 degree, the reaction times was at 1～20 hour.
13. formula 3 compounds:
Wherein
A:X=-CH
2-, Z=-H is two keys between carbon 13 and the carbon 14
B:X=-CH
2-, Z=-H is singly-bound between carbon 13 and the carbon 14
C:X=-O-, Z=-CF
3, be two keys between carbon 13 and the carbon 14.
14. separate the intermediate that obtains in the method for claim 1, formula 4 compounds:
Wherein
A:X=-CH
2-, Z=-H is two keys between carbon 13 and the carbon 14
B:X=-CH
2-, Z=-H is singly-bound between carbon 13 and the carbon 14
C:X=-O-, Z=-CF
3, be two keys between carbon 13 and the carbon 14.
15. separate the intermediate that obtains in the method for claim 1, formula 5 compounds:
Wherein
A:X=-CH
2-, Z=-H is two keys between carbon 13 and the carbon 14
B:X=-CH
2-, Z=-H is singly-bound between carbon 13 and the carbon 14
C:X=-O-, Z=-CF
3, be two keys between carbon 13 and the carbon 14.
16. separate the intermediate that obtains in the method for claim 1, formula 6 compounds:
Wherein
A:X=-CH
2-, Z=-H is two keys between carbon 13 and the carbon 14, W=-CH3, or-NHEt
B:X=-CH
2-, Z=-H is singly-bound between carbon 13 and the carbon 14, W=-i-Pr
C:X=-O-, Z=-CF
3, be two keys between carbon 13 and the carbon 14, W=-i-Pr.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108084074A (en) * | 2017-12-25 | 2018-05-29 | 厦门欧瑞捷生物科技有限公司 | A kind of method of simple and effective synthesis dinoprost |
| CN111757868A (en) * | 2018-02-21 | 2020-10-09 | 尼科斯股份有限公司 | The preparation method of the prostaglandin analog that supplies nitric oxide |
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| CN111757868A (en) * | 2018-02-21 | 2020-10-09 | 尼科斯股份有限公司 | The preparation method of the prostaglandin analog that supplies nitric oxide |
| CN111757868B (en) * | 2018-02-21 | 2023-03-14 | 尼科斯股份有限公司 | Preparation method of prostaglandin analogs donating nitric oxide |
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