CN101863892B - Preparation mothod of epibatidine and analogues thereof - Google Patents
Preparation mothod of epibatidine and analogues thereof Download PDFInfo
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Abstract
The invention relates to a preparation method of epibatidine or analogues thereof, mainly comprising the following step of: sequentially carrying out Henry reaction, elimination reaction, intramolecularly asymmetrical Michael addition reaction, asymmetrical reduction reaction, hydroxyl-easy-leaving group transformation reaction, nitryl reduction reaction, intramolecularly amino ring closing reaction and isomerization on a pyridine derivative and 5-nitryl pentanone-2 as initial raw materials to obtain a target object. Compared with the prior art, the invention has the advantages of concise synthesis route, mild reaction condition of each step, higher overall yield and the like without adopting noble metal as a catalyst.
Description
Technical field
This paper invention relates to the preparation method of a kind of vegeto-alkali or its analogue, specifically, relates to the preparation method of a kind of epibatin (Epibatidine) or its analogue.
Background technology
Epibatin (Epibatidine) is the stimulant of a kind of efficient non-opium type analgesic agent and Nicotine acetylcholine receptor; It is present in the epidermis that America Ecuador produces malicious frog Epipedobates tricolor, at occurring in nature content extremely low (only can be separated the epibatin that obtains 1 milligram of less than by 750 malicious frogs).Outstanding biological activity and scarcity make the chemosynthesis epibatin enjoy chemists' concern.
Nilantha S.Sirisoma etc. has reported a kind of preparation method of epibatin, and its synthesis strategy is: be starting raw material with the 1; Go through the raceme that 13 steps can obtain epibatin, total recovery is 13% (Tetrahedron Letters, 1998; 39,2059-2062).
Bary M.Trost etc. has disclosed a kind of preparation method (Tetrahedron Letters of optical purity epibatin; 1996; 37; 7485-7487), used precious metal palladium (Pd) to be catalyzer in the comparatively crucial therein step (suitable-3, the linked reaction of 6-dibenzoic acid base-tetrahydrobenzene-2 and pyridine stannane).So, not only increased preparation cost, and maybe be because the residual contamination product of metal.
Aggarwal etc. have reported with the method for aryl salt as the pure epibatin of aromatic yl reagent-ing synthesizing optical; Its synthesis strategy is: with silicon ether protection hydroxy-cyclohexanone is set out; Carry out the asymmetric pyridinium salt arylation of symmetrization of going with chiral base reagent and obtain the female ring of pyridine (Angew.Chem.Intern.Ed.2005; 44,5516-5519), its chiral base reagent need prepare through polystep reaction.So increased the reaction difficulty, route is wordy.
In sum, this area presses for the preparation method of the epibatin that a kind of synthetic route is succinct, preparation cost is cheap and total recovery is higher
Summary of the invention
The objective of the invention is to, a kind of synthetic route is succinct, preparation cost is cheap and total recovery the is higher optical purity epibatin or the preparation method of its analogue are provided.
The present invention the structure of the epibatin that will prepare or its analogue suc as formula shown in 1:
In the formula 1, R
1Be halogen (F, Cl, Br or I), R
2, R
3And R
4Independently be selected from respectively: hydrogen (H), C
1～C
6Alkyl, C
1～C
6Perfluoroalkyl, C
1～C
6Alkoxyl group, amino (NH
2), nitro (NO
2) or aromatic ring yl in a kind of.
The said method for preparing optical purity epibatin or its analogue of the present invention; Its key step is: with pyridine derivate (its structure is suc as formula shown in 2) and 5-nitro pentanone-2 (compound shown in the formula 3) is starting raw material, changes into through Henry reaction, elimination reaction, the asymmetric Michael addition reaction of intramolecularly, asymmetric reduction reaction, hydroxyl successively to be prone to get target compound (epibatin or its analogue) after leavings group reaction, nitro-reduction reaction, the amino ring closure reaction of intramolecularly and the isomerizing (configuration conversion).
Concrete synthesis strategy is following:
Wherein: R
5For Br or-OSO
2CH
3
That is: compound shown in compound shown in the formula 2 and the formula 3 is reacted through Henry, get compound shown in the formula 4; Compound shown in the formula 4 need not purifying and directly eliminates reaction, gets compound shown in the formula 5; Having under amino acid and phenylformic acid, substituted benzoic acid or the Glacial acetic acid min. 99.5 existence condition, compound shown in the formula 5 gets compound shown in the formula 6 through the asymmetric Michael addition reaction of intramolecularly; Compound is through NaBH shown in the formula 6
4Or NaBH
4/ TarB-H asymmetric reduction gets compound shown in the formula 7; With hydroxyl in the compound shown in the formula 7 change into easy leavings group (as Br or-OSO
2CH
3Deng), get compound shown in the formula 8; Compound shown in the formula 8 gets compound shown in the formula 9 through (nitro) reduction reaction; Compound shown in the formula 9 gets compound shown in the formula 10 through the amino ring closure reaction of intramolecularly; Under alkaline condition, compound shown in the formula 10 gets target compound (compound shown in the formula 1) after isomerizing.
In optimal technical scheme of the present invention, R
1Be Cl or Br; R
2, R
3And R
4Independently be selected from respectively: H, C
1～C
3Alkyl, C
1～C
3Perfluoroalkyl or C
1～C
3A kind of in the alkoxyl group.
Preferred R
2, R
3And R
4Independently be selected from respectively: H, C
1～C
3Alkyl or C
1～C
3A kind of in the alkoxyl group.
Best R
2, R
3And R
4Be H.
In another optimal technical scheme of the present invention, used alkali is in described Henry reaction: KF, KF/Al
2O
3Or organic bases such as triethylamine.
In another optimal technical scheme of the present invention, used elimination reagent is aceticanhydride (Ac in described elimination reaction (compound 4 to compound 5)
2O), triethylamine (Et
3N) or N, N-lutidine (DMAP), compound 4 is 1 with the mol ratio of eliminating reagent: (1～1.3).
In another optimal technical scheme of the present invention; In the asymmetric Michael addition reaction of described intramolecularly; Compound shown in the formula 5 and amino acid whose mol ratio are 1: (0.1～0.2), the mol ratio 1 of compound and phenylformic acid, substituted benzoic acid or Glacial acetic acid min. 99.5 shown in the formula 5: (0.1～1);
Said amino acid is proline(Pro) or tryptophane; Said substituted benzoic acid is: anisic acid, o-methoxybenzoic acid, m-methoxybenzoic acid, 2,4-dimethoxybenzoic acid, 2,5-dimethoxybenzoic acid, 3; 4-dimethoxybenzoic acid, 2,4,6-trimethoxybenzoic acid, 3; 4,5-trimethoxybenzoic acid, 2,4; 6-trimethoxybenzoic acid, PHB, p-Nitrobenzenecarboxylic acid, p-methylbenzoic acid, o-toluic acid, m-methyl benzoic acid, 2; 6-dimethoxybenzoic acid, 3,5-dimethoxybenzoic acid or 2,3-dimethoxybenzoic acid.
Principal feature of the present invention is: synthetic route succinctly, respectively goes on foot the reaction conditions gentleness, avoids adopting precious metal is that catalyzer (so, not only reduced preparation cost, and avoided product by metal " pollution ") and total recovery are not less than 20%.
Embodiment
Below by embodiment the present invention is further elaborated, its purpose only is better to understand content of the present invention.The restriction of the example that protection scope of the present invention does not receive to be lifted.
Said room temperature is 20 ℃～25 ℃ in the following example.
Embodiment 1
(1) compound 5a (compound shown in the formula 5, wherein R
1Be Cl; R
2, R
3And R
4Be H, down with) preparation:
Get 1.41g, (10mmol) compound 2a (R
1Be Cl; R
2, R
3And R
4Be H) be dissolved in 20ml Virahol and THF (v/v=3/1) mixing solutions, adding compound 3 (1.31g, 10mmol), Potassium monofluoride (0.23g, 5mmol), stirring at room at least 24 hours.Add a spot of water to this reaction solution, dried organic solvent is revolved in decompression.The ethyl acetate extraction water, separatory, organic phase is washed with saturated sodium-chloride respectively, and anhydrous sodium sulfate drying filters the back removal of solvent under reduced pressure, gets yellow oily liquid 2.72g compound 4a, and yield is near 100%.
4a is dissolved in the 90ml methylene dichloride with 2.72g bullion compound, adds N, and the N-lutidine (0.24g, 2mmol), acetic anhydride (1.12g, 11mmol), room temperature reaction at least 18 hours.Use the methylene dichloride dilute reaction solution, organic phase is washed with saturated sodium carbonate successively, the saturated common salt washing; Pass through anhydrous sodium sulfate drying then; Filter the back decompression and revolve dried organic solvent, enriched material gets compound 5a (yellow solid) 1.90g, yield: 76% through 300-400 order silica gel chromatography column purification.
1H?NMR(400MHz，CDCl
3)δ8.46(d，J＝2.0Hz，1H)，8.01(s，1H)，7.82(dd，J1＝2.4Hz，J2＝8.0Hz，1H)，7.47(d，J＝8.8Hz，1H)，3.08(t，J＝6.8Hz，2H)，2.84(t，J＝8.0Hz，2H)，2.21(s，3H).
13C?NRM(400MHz，CDCl
3)δ205.8，152.9，152.4，150.4，138.8，129.6，127.0，124.7，40.6，29.8，21.4.
(2) compound 6a (R
1=Cl, R
2=H, R
3=H, R
4=H) preparation:
With compound 5a (1.27g 5mmol) is dissolved in the 150ml methyl-sulphoxide, add again Glacial acetic acid min. 99.5 (120mg, 2mmol), proline(Pro) (230mg, 2mmol), room temperature reaction at least 12 hours.Remove most of methyl-sulphoxide under reduced pressure, residuum dilute with water, ethyl acetate extraction water; Separatory, organic phase is washed with saturated sodium-chloride respectively, anhydrous sodium sulfate drying; Filter decompression and remove organic solvent, enriched material gets compound 6a (white solid) 1.01g, yield: 79% through silica gel column chromatography.[α]D＝26.0(c＝0.38，CHCl
3).
1H?NMR(400MHz，CDCl
3)δ8.32(d，J＝2.4Hz，1H)，7.57(dd，J
1＝2.4Hz，J
2＝8.4Hz，1H)，7.35(d，J＝8.4Hz，1H)，5.15-5.04(m，1H)，3.77-3.70(m，1H)，2.73-2.46(m，6H).
13C?NMR(400MHz，CDCl
3)δ204.0，151.5，148.6，137.3，132.6，124.8，87.4，45.0，43.8，37.9，29.6.
(3) compound 7a (R
1=Cl, R
2=H, R
3=H, R
4=H) preparation:
Under 0 ℃ of condition, (150mg 0.6mmol), is dissolved in the 2ml THF, adds 2mlTarB-H (0.5M), stirs to add Peng Qinghuana after 30 minutes again (44mg 1.2mmol) reacted 2 hours at least with compound 6a.Drip Hydrogen chloride cancellation reaction, add 330mg sodium hydroxide and stirred dichloromethane extraction 1 hour; Separatory; Organic phase respectively with the saturated common salt washing, can be crossed anhydrous sodium sulfate drying more then, filters decompression and removes organic solvent; The enriched material column chromatography purification gets compound 7a (white solid) 149mg, productive rate: 96%.[α]D＝18.5(c＝0.6，CHCl
3).
1H?NMR(400MHz，CDCl
3)δ8.27(s，2H)，7.54(d，J＝8.0Hz，1H)，7.31(d，J＝8.4Hz，1H)，4.64-4.58(m，1H)，3.95-3.89(m，1H)，3.35-3.29(m，1H)，2.48-2.44(m，1H)，2.27-2.20(m，4H)，1.67-1.54(m，2H).
13C?NMR(100MHz，CDCl
3)δ150.9，148.7，137.4，134.0，124.6，89.2，68.3，42.9，40.6，32.8，29.8.
(4) compound 8a (R
1=Cl, R
2=H, R
3=H, R
4=H) preparation:
Under condition of ice bath, (256mg 1mmol) is dissolved in the 15mg anhydrous methylene chloride, and (121mg, 1.2mmol), (137mg 1.2mmol), reacted 45 minutes at least methylsulfonyl chloride to add triethylamine more successively with compound 7a.Add saturated ammonium chloride solution cancellation reaction, separatory, water is used dichloromethane extraction; Merge organic phase; Organic phase, is filtered decompression and is removed organic solvent then through anhydrous sodium sulfate drying more respectively with the saturated common salt washing; The enriched material column chromatography purification gets compound 8a (white blister solid) 315mg, productive rate: 94%.[α]D＝11.5(c＝1，CHCl
3).
1H?NMR(400MHz，CDCl
3)δ8.27(d，J＝2.4Hz，1H)，7.53(dd，J
1＝2.4Hz，J
2＝8.4Hz，1H)，7.31(d，J＝8.0Hz，1H)，4.87-4.80(m，1H)，4.68-4.62(m，1H)，3.41-3.34(m，1H)，3.05(s，3H)，2.54-2.42(m，3H)，2.16-2.13(m，1H)，1.96-1.80(m，2H).
13C?NMR(100MHz，CDCl
3)δ151.3，148.7，137.4，132.9，124.7，88.0，76.4，42.7，38.7，37.8，30.3，29.3.
(5) compound 10a (R
1=Cl, R
2=H, R
3=H, R
4=H) preparation:
With compound 8a (262mg 0.78mmol) is dissolved in the 5ml Glacial acetic acid min. 99.5, add zinc powder (1.9g, 29mmol), room temperature reaction 1 hour.Reaction solution is used diatomite filtration, and filter cake is washed with ETHYLE ACETATE, and filtrating is washed with saturated common salt, separatory, and organic phase is used the dry potassium carbonate bath, and the filtration decompression is removed organic solvent and is got compound 9a (yellow oily liquid) 238mg, yield: 100%.
(138mg 0.45mmol) is dissolved in the 30ml anhydrous chloroform bullion compound 9a, heating reflux reaction 65 hours.Organic phase is washed with saturated sodium carbonate solution, separatory, and water is used chloroform extraction, and separatory merges organic phase.Organic phase is washed with saturated sodium-chloride again, and is dry through Anhydrous potassium carbonate, filters decompression and removes organic solvent, and enriched material gets compound 10a (yellow oily liquid) 74mg, productive rate: 78% through purification by silica gel column chromatography.[α]D＝-7.7(c＝0.6，CH
2Cl
2).
1H?NMR(400MHz，CDCl
3)δ8.25(d，J＝1.6Hz，1H)，7.47(dd，J
1＝2.0Hz，J
2＝8.0Hz，1H)，7.27(d，J＝6.4Hz，1H)，3.61-3.77(m，2H)，3.35-3.29(m，1H)，2.16-2.09(m，1H)，1.67-1.65(m，1H)，1.51(dd，J
1＝5.6Hz，J
2＝12.8Hz，1H)，1.44-1.37(m，3H).
13C?NMR(100MHz，CDCl
3)δ149.5，149.3，138.4，135.1，123.8，61.2，57.7，44.1，34.3，30.4，23.6.
(6) compound 1a (R
1=Cl, R
2=H, R
3=H, R
4=H) preparation:
With 130mg compound 10a (130mg 0.62mmol) is dissolved in the 20ml anhydrous tertiary butanol, add under the room temperature potassium tert.-butoxide (210mg, 1.86mmol), back flow reaction 3 hours, cooling, (210mg 1.86mmol), continued back flow reaction 2 days to add potassium tert.-butoxide.Add entry to reaction solution, organic solvent is removed in decompression, and residuum is with chloroform extraction (25ml * 3), and separatory merges organic phase.Organic phase is divided and is added with the saturated common salt washing, anhydrous sodium sulfate drying, and organic solvent is removed in decompression, and enriched material gets compound 1a (yellow oily liquid) 65mg, productive rate: 50% through purification by silica gel column chromatography.[α]D＝-6.0(c＝0.6，CHCl
3).
1H?NMR(400MHz，CDCl
3)δ8.26(d，J＝2.4Hz，1H)，7.77(dd，J
1＝2.0Hz，J
2＝8.0Hz，1H)，7.27(d，J＝7.2Hz，1H)，3.61-3.77(m，1H)，3.56(s，1H)，2.79(dd，J1＝6.0Hz，J2＝8.4Hz，1H)，1.97-1.94(m，1H)，1.65-1.56(m，5H).
13C?NMR(100MHz，CDCl
3)δ148.8，148.5，141.1，137.8，123.8，62.8，56.7，44.1，40.1，31.4，30.3。
Embodiment 2
(1) compound 5b (compound shown in the formula 5, wherein R
1Be Br; R
2, R
3And R
4Be H, down with) preparation:
Get 1.41g (10mmol) compound 2b (R
1Be Br; R
2, R
3And R
4Be H) be dissolved in 20ml Virahol and THF (v/v=1/1) mixing solutions, adding compound 3 (1.31g, 10mmol), triethylamine (1.01g, 10mmol), stirring at room at least 20 hours.In reaction solution, add a spot of water, dried organic solvent is revolved in decompression.The ethyl acetate extraction water, separatory, organic phase is washed with saturated sodium-chloride respectively, and anhydrous sodium sulfate drying filters the back removal of solvent under reduced pressure, gets yellow oily liquid 2.72g compound 4b, and yield is near 100%.
4b is dissolved in the 90ml methylene dichloride with 2.72g bullion compound, adds N, and the N-lutidine (0.48g, 4mmol), acetic anhydride (1.12g, 11mmol), room temperature reaction at least 20 hours.Use the methylene dichloride dilute reaction solution, organic phase is washed with saturated sodium carbonate successively, the saturated common salt washing; Pass through anhydrous sodium sulfate drying then; Filter the back decompression and revolve dried organic solvent, enriched material gets compound 5b (yellow solid) 2.25g, yield: 90% through 300-400 order silica gel chromatography column purification.
1H?NMR(400MHz，CDCl
3)δ8.45(d，J＝2.0Hz，1H)，8.02(s，1H)，7.82(dd，J
1＝2.4Hz，J
2＝8.0Hz，1H)，7.46(d，J＝8.8Hz，1H)，3.08(t，J＝6.8Hz，2H)，2.86(t，J＝8.0Hz，2H)，2.23(s，3H).
13C?NRM(400MHz，CDCl
3)δ205.8，152.8，152.5，150.4，138.8，129.6，127.1，124.7，40.6，29.8，21.5.
(2) compound 6b (R
1=Br, R
2=H, R
3=H, R
4=H) preparation:
With compound 5b (1.49g 5mmol) is dissolved in the 150ml methyl-sulphoxide, add again phenylformic acid (224mg, 2mmol), proline(Pro) (115mg, 1mmol), room temperature reaction at least 10 hours.Remove most of methyl-sulphoxide under reduced pressure, residuum dilute with water, ethyl acetate extraction water; Separatory, organic phase is washed with saturated sodium-chloride respectively, anhydrous sodium sulfate drying; Filter decompression and remove organic solvent, enriched material gets compound 6b (white solid) 1.27g, yield: 85% through silica gel column chromatography.[α]D＝36.5(c＝0.6，CHCl
3).
1H?NMR(400MHz，CDCl
3)δ8.34(d，J＝2.8Hz，1H)，7.60(dd，J
1＝2.4Hz，J
2＝8.4Hz，1H)，7.36(d，J＝8.0Hz，1H)，5.15-5.07(m，1H)，3.77-3.70(m，1H)，2.73-2.46(m，6H).
13C?NMR(400MHz，CDCl
3)δ204.1，151.6，148.4，137.6，132.5，124.8，87.6，45.1，43.6，37.8，29.5。
(3) compound 7b (R
1=Br, R
2=H, R
3=H, R
4=H) preparation:
Under 0 ℃ of condition, (150mg 0.5mmol), is dissolved in the 2ml THF, adds 2mlTarB-H (0.5M), stirs to add Peng Qinghuana after 30 minutes again (38mg 1.0mmol) reacted 2 hours at least with compound 6b.Drip Hydrogen chloride cancellation reaction, add 330mg sodium hydroxide and stirred dichloromethane extraction 1 hour; Separatory; Organic phase respectively with the saturated common salt washing, can be crossed anhydrous sodium sulfate drying more then, filters decompression and removes organic solvent; The enriched material column chromatography purification gets compound 7b (white solid) 135mg, productive rate: 90%.
1H?NMR(400MHz，CDCl
3)8.26(d，J＝1.6Hz，1H)，7.48-7.41(m，2H)，4.64-4.58(m，1H)，3.96-3.90(m，1H)，3.34-3.27(m，1H)，2.50-2.45(m，1H)，2.29-2.23(m，2H)，2.17-2.06(m，1H)，1.71-1.52(m，2H).
13C?NMR(100MHz，CDCl
3)δ151.0，148.8，137.6，134.1，124.7，89.4，68.1，42.7，40.7，32.9，29.7.
(4) compound 8b (R
1=Br, R
2=H, R
3=H, R
4=H) preparation:
Under condition of ice bath, (90mg 0.3mmol) is dissolved in the 5mg anhydrous methylene chloride, and (50mg, 0.36mmol), (41mg 0.36mmol), reacted 45 minutes at least methylsulfonyl chloride to add triethylamine more successively with compound 7b.Add saturated ammonium chloride solution cancellation reaction, separatory, water is used dichloromethane extraction; Merge organic phase; Organic phase, is filtered decompression and is removed organic solvent then through anhydrous sodium sulfate drying more respectively with the saturated common salt washing; The enriched material column chromatography purification gets compound 8b (white blister solid) 80mg, productive rate: 71%.
1H?NMR(400MHz，CDCl
3)δ8.28(s，1H)，7.49(d，J＝8.0Hz，1H)，7.44-7.42(m，1H)，4.88-4.82(m，1H)，4.67-4.60(m，1H)，3.41-3.34(m，1H)，3.07(s，3H)，2.58-2.47(m，3H)，2.22-2.11(m，1H)，1.96-1.82(m，2H).
13C?NMR(100MHz，CDCl
3)δ151.1，148.7，137.5，132.8，124.6，88.1，76.5，42.8，38.6，37.9，30.2，29.4.
(5) compound 10b (R
1=Br, R
2=H, R
3=H, R
4=H) preparation:
With compound 8b (76mg 0.2mmol) is dissolved in the 5ml Glacial acetic acid min. 99.5, add zinc powder (390g, 6mmol), room temperature reaction 1 hour.Reaction solution is used diatomite filtration, and filter cake is washed with ETHYLE ACETATE, and filtrating is washed with saturated common salt, separatory, and organic phase is used the dry potassium carbonate bath, and the filtration decompression is removed organic solvent and is got compound 9b (yellow oily liquid) 70mg, yield: 100%.
(70mg 0.2mmol) is dissolved in the 15ml anhydrous chloroform bullion compound 9b, heating reflux reaction 65 hours.Organic phase is washed with saturated sodium carbonate solution, separatory, and water is used chloroform extraction, and separatory merges organic phase.Organic phase is washed with saturated sodium-chloride again, and is dry through Anhydrous potassium carbonate, filters decompression and removes organic solvent, and enriched material gets compound 10b (yellow oily liquid) 38mg, productive rate: 76% through purification by silica gel column chromatography.[α]D＝-14.8(c＝0.12，CH
2Cl
2).
1H?NMR(400MHz，CDCl
3)δ8.25(d，J＝2.4Hz，1H)，7.46(d，J＝8.4Hz，1H)，7.39(dd，J
1＝2.4Hz，J
2＝8.0Hz，1H)，3.92-3.88(m，2H)，3.44-3.42(m，1H)，2.28-2.20(m，1H)，1.81-1.74(m，1H)，1.60-1.42(m，4H).
13C?NMR(100MHz，CDCl
3)δ150.0，140.0，138.2，135.1，127.7，61.2，57.9，43.9，34.0，30.2，23.4.
(6) compound 1b (R
1=Br, R
2=H, R
3=H, R
4=H) preparation:
With compound 10b (38mg 0.15mmol) is dissolved in the 10ml anhydrous tertiary butanol, add under the room temperature potassium tert.-butoxide (110mg, 0.93mmol), back flow reaction 3 hours, cooling, (110mg 0.93mmol), continued back flow reaction 2 days to add potassium tert.-butoxide.Add entry to reaction solution, organic solvent is removed in decompression, and residuum is with chloroform extraction (15ml * 3), and separatory merges organic phase.Organic phase is divided and is added with the saturated common salt washing, anhydrous sodium sulfate drying, and organic solvent is removed in decompression, and enriched material gets compound 1b (yellow oily liquid) 18mg, productive rate: 48% through purification by silica gel column chromatography.[α]D＝-8.0(c＝0.6，CHCl
3).
1H?NMR(400MHz，CDCl
3)δ8.27(d，J＝2.4Hz，1H)，7.77(dd，J
1＝2.0Hz，J
2＝8.0Hz，1H)，7.26(d，J＝7.2Hz，1H)，3.62-3.76(m，1H)，3.54(s，1H)，2.78(dd，J
1＝6.0Hz，J
2＝8.4Hz，1H)，1.98-1.94(m，1H)，1.66-1.58(m，5H).
13C?NMR(100MHz，CDCl
3)δ149.0，148.6，141.3，137.9，123.7，62.9，56.8，44.3，40.0，31.4，30.2。
Claims (5)
1. method for preparing the optical purity epibatin; It is characterized in that; The key step of said method is: with compound shown in compound shown in the formula 2 and the formula 3 is starting raw material, and compound shown in compound shown in the formula 2 and the formula 3 is reacted through Henry, gets compound shown in the formula 4; Compound shown in the formula 4 need not purifying and directly eliminates reaction, gets compound shown in the formula 5; Having under amino acid and phenylformic acid or the Glacial acetic acid min. 99.5 existence condition, compound shown in the formula 5 gets compound shown in the formula 6 through the asymmetric Michael addition reaction of intramolecularly; Compound is through NaBH shown in the formula 6
4Or NaBH
4/ TarB-H asymmetric reduction gets compound shown in the formula 7; Change hydroxyl in the compound shown in the formula 7 into easy leavings group, get compound shown in the formula 8; Compound shown in the formula 8 gets compound shown in the formula 9 through nitro-reduction reaction; Compound shown in the formula 9 gets compound shown in the formula 10 through the amino ring closure reaction of intramolecularly; Under alkaline condition, compound shown in the formula 10 gets target compound after isomerizing:
Wherein: R
1Be Cl or Br, R
2, R
3And R
4Be H, R
5For-OSO
2CH
3
2. the method for claim 1 is characterized in that, used alkali is in the Henry reaction: Potassium monofluoride or triethylamine.
3. the method for claim 1; It is characterized in that; In the reaction of the elimination of compound shown in compound to the formula 5 shown in the formula 4: compound shown in the formula 4 is 1: 1～1.3 with the mol ratio of eliminating reagent, and said elimination reagent is aceticanhydride, triethylamine or N, the N-lutidine.
4. the method for claim 1 is characterized in that, in the asymmetric Michael addition reaction of intramolecularly: compound shown in the formula 5 and amino acid whose mol ratio are 1: 0.1～0.2, the mol ratio 1: 0.1～1 of compound and phenylformic acid or Glacial acetic acid min. 99.5 shown in the formula 5.
5. method as claimed in claim 4 is characterized in that, wherein said amino acid is proline(Pro).
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| HUT69381A (en) * | 1993-12-09 | 1995-09-28 | Egyt Gyogyszervegyeszeti Gyar | Process for producing (2-chloro pyridyl)-7-azabicyclo [2.2.1.]heptane |
| BE1008622A3 (en) * | 1993-12-09 | 1996-06-04 | Egyt Gyogyszervegyeszeti Gyar | DERIVATIVES The EPI-Epibatidine. |
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