CN102718695B - Method for synthesizing aza-bicyclo octane [3.3.0] derivatives - Google Patents

Method for synthesizing aza-bicyclo octane [3.3.0] derivatives Download PDF

Info

Publication number
CN102718695B
CN102718695B CN201210211875.7A CN201210211875A CN102718695B CN 102718695 B CN102718695 B CN 102718695B CN 201210211875 A CN201210211875 A CN 201210211875A CN 102718695 B CN102718695 B CN 102718695B
Authority
CN
China
Prior art keywords
reaction
compound
formula
och
protecting group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CN201210211875.7A
Other languages
Chinese (zh)
Other versions
CN102718695A (en
Inventor
姜雪峰
谭忠飞
姜卫华
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
East China Normal University
Original Assignee
East China Normal University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by East China Normal University filed Critical East China Normal University
Priority to CN201210211875.7A priority Critical patent/CN102718695B/en
Publication of CN102718695A publication Critical patent/CN102718695A/en
Application granted granted Critical
Publication of CN102718695B publication Critical patent/CN102718695B/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

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

Abstract

The invention discloses a method for synthesizing aza-bicyclo octane [3.3.0] derivatives shown as a formula (I). 1,2,3,6-tetrahydrophthalimide (V) is used as an initial raw material; and the aza-bicyclo octane [3.3.0] derivatives shown as the formula (I) are obtained by protective group addition, reduction reaction, protective group removing reaction, oxidation reaction and cyclization decarboxylation reaction sequentially. The method is mild in reaction conditions, readily available and cheap in raw materials, simple in synthetic route and high in yield; and the aza-bicyclo octane [3.3.0] derivatives serving as important medicinal intermediates are widely applied to industrialized large-scale production.

Description

The synthetic method of a kind of azabicyclo [3.3.0] Octane derivatives
Technical field
The invention belongs to organic compound process application technical field, be specifically related to the synthetic method of a kind of azabicyclo [3.3.0] Octane derivatives.
Background technology
Azabicyclo [3.3.0] Octane derivatives (aza-bicyclo octane[3.3.0] derivatives) be the very important chemical intermediate of a class, there is very high medical applications and be worth.In some novel drugs of the report of recent years, as treat serine protease dipeptide peptidase (DDP-4) inhibitor (Bioorganic and Medicinal Chemistry Letters for diabetes, 2010,20,3565-3568), be to there is azabicyclo [3.3.0] octane structure.Mainly comprising of the synthetic method of azabicyclo in prior art [3.3.0] Octane derivatives: one of method is as shown in equation (a), by (7S, 8R)-1,4-dioxaspiro[4.4] nonane-7,8-dicarboxylic acid dimethyl ester and secondary amine tube sealing reaction at 190 ℃ obtains (J.Org.Chem.1989 for 16 hours, 54,5115-5122 and WO 2004/087142).The method condition is harsh, in industry, amplifies in large-scale production and is difficult to realize.Another kind method is under metal catalytic, by Pauson-Khand, to be reacted into ring with dimethyl 2-allyl-2-(prop-2-ynyl) malonate, then the ethylene linkage of reducing obtains, (Organic Letters as shown in equation (b), 2002,4,3983-3988, J.Org.Chem.2002,67,1233-246 and US 2004/44029), the method is with hypertoxic metal reagent Co 2(CO) 8for catalyzer, there is potential danger.
Figure BDA00001806468200011
Summary of the invention
The present invention overcomes the above-mentioned defect of prior art, propose a kind of productive rate high, simple to operate, be suitable for the synthetic method of formula (I) compound azabicyclo [3.3.0] Octane derivatives (aza-bicyclo octane[3.3.0] derivatives) of commercial scale production.
The synthetic method of a kind of azabicyclo [3.3.0] Octane derivatives that the present invention proposes, with formula (V) compound 1,2,3,6-tetrahydrochysene phthalimide is raw material, pass through successively protecting group, reduction reaction, deprotection reaction, oxidizing reaction, cyclisation decarboxylic reaction, obtain described azabicyclo [3.3.0] Octane derivatives suc as formula (I);
Its reaction scheme is:
Figure BDA00001806468200022
Wherein,
When A is O, R is C 1～C 8alkyl substituent or aryl;
When A is N, R is hydrogen, C 1～C 8alkyl or aryl;
PG is Ph 3c, the tertiary butyl, MOM, BOM, TMS, menaphthyl,
Figure BDA00001806468200023
wherein, X is H, F, Cl, Br, I, NO 2, CH 3, CH 3cH 2, OCH 3, or OCH 3cH 2.
Wherein, described upper protecting group reaction is that 6-tetrahydric phthalimide is raw material with formula (V) compound 1,2,3, the halo protecting group reaction under alkaline condition, production (IV) compound.
In described upper protecting group reaction, alkali used is K 2cO 3, KHCO 3, KOH, KOMe, KOEt, KO tbu, KOPr, KO ipr, Na 2cO 3, NaHCO 3, NaOH, NaOMe, NaOEt, NaOPr, NaO ipr, NaH, KH, CaH 2, pyridine, triethylamine or diisopropyl ethyl amine.
Wherein, described reduction reaction be in aprotic solvent, take reductive agent will be on the imide of formula (IV) compound carbonyl reduction be methylene radical, production (III) compound.
Described aprotic solvent is tetrahydrofuran (THF), methyltetrahydrofuran, ether, methyl tertiary butyl ether, benzene, toluene or ethylbenzene.
Described reductive agent is LiAlH 4.
Formula (III) compound is through described deprotection reaction production (II) compound, and the high yield of this reaction process is one of determinative of the present invention.
Wherein, when PG is Ph 3when C, the tertiary butyl, dimethyl cellosolve base (MOM), methyl benzyl ether base (BOM), trimethyl silicon based (TMS) or menaphthyl; described deprotection reaction is formula (III) compound first to be sloughed to protecting group under acidity or alkaline condition become secondary amine; again under alkaline condition with haloformate or halo formamide, the compound of production (II).
In formula (III) compound; five-ring N atom connects a common blocking group (PG); under acid or alkaline condition, slough protecting group, then on N atom, connect the protecting group containing ester group or amide group, thereby can not destroy this five-ring when building another one five-ring.
In described deprotection reaction, alkali used is NaOH, KOH, Na 2cO 3, K 2cO 3, NaHCO 3or KHCO 3.
The acid used of described deprotection reaction is HCl, HBr, H 2sO 4, H 3pO 4, AcOH, CF 3cOOH or TsOH.
Wherein, when PG is
Figure BDA00001806468200031
described deprotection agent reaction is that formula (III) compound is first reacted with phosgene or triphosgene under the catalysis of catalyzer alkali, then reacts production (II) compound with corresponding alcohol or amine; Wherein, X is H, F, Cl, Br, I, NO 2, CH 3, CH 3cH 2, OCH 3, or OCH 3cH 2.
When PG is
Figure BDA00001806468200032
time, the structure of formula (III) compound is suc as formula shown in (III').In formula (III'), X is H, F, Cl, Br, I, NO 2, CH 3, CH 3cH 2, OCH 3, or OCH 3cH 2.Formula (III') compound reacts with phosgene or triphosgene under the catalysis of catalyzer alkali, and generating structure is suc as formula (chloride compounds shown in III "), then react with corresponding alcohol or amine obtains formula (II) compound.This reaction is that one kettle way is synthetic, does not need isolation of intermediate products, and the loss that can avoid like this operation to bring, raises the efficiency and productive rate, saves cost.
Described catalyzer alkali is triethylamine, Trimethylamine 99, diisopropyl ethyl amine, diethylamine, dipropyl amine, dibutylamine, any one of pyridine or DMAP.
Wherein, described oxidizing reaction is that formula (II) compound is oxidized to dicarboxylic acid structure through oxygenant; Preferably, described oxygenant is strong oxidizer.Preferably, described oxygenant is H 2o 2, O 3, KMnO 4or K 2cr 2o 7.
Wherein, described cyclisation decarboxylic reaction is to carry out after described oxidizing reaction, is cyclisation decarboxylation production (I) compound in acid solvent; Wherein, described acid solvent is acetic acid, diacetyl oxide or propionic acid.
Reaction scheme of the present invention, as follows:
Figure BDA00001806468200041
The mild condition of synthetic method of the present invention, raw material is easy to get inexpensive, and synthetic route is simple, and productive rate is higher, and product formula (I) compound, as an important class medicine intermediate, is widely used in commercial scale production.Synthetic method of the present invention is protected by upper protecting group, improves the yield of whole route committed step (reduction reaction, cost is the highest), removes impurity simple, saves cost.And with regard to the productive rate of final product, do not follow loss, improve on the contrary.
Embodiment
In conjunction with following specific embodiment, the present invention is described in further detail, and protection content of the present invention is not limited to following examples.Do not deviating under the spirit and scope of inventive concept, variation and advantage that those skilled in the art can expect are all included in the present invention, and take appending claims as protection domain.Implement process of the present invention, condition, reagent, experimental technique etc., except the content of mentioning specially below, be universal knowledege and the common practise of this area, the present invention is not particularly limited content.The given data of following examples comprise concrete operations and reaction conditions and product.Product purity is identified by nuclear-magnetism.
embodiment 1
Figure BDA00001806468200051
Take 1,2,3,6-tetrahydric phthalimide V (4540.0mg, 30.0mmol), K 2cO 3(12440.0mg, 90.0mmol), TBAB (970.0mg, 3.0mmol), in 250mL round-bottomed flask, adds 50.0mL DMF to dissolve.Take Benzyl Chloride (4940.0mg, 39.0mmol), under stirring, be added drop-wise in reaction flask slowly.After 5h, react complete, add the 50.0mL shrend reaction of going out.Then add the extraction of 100.0mL ethyl acetate, after separatory, saturated common salt water washing (40.0mL * 5) for organic phase, spends the night with anhydrous sodium sulfate drying.Remove by filter sodium sulfate, rotary evaporation is removed ethyl acetate, obtains the thick product of white solid.With ethyl acetate/normal hexane recrystallization, obtain 5740.0mg target compound, yield 79.3%.Mass spectroscopy MS (ESI, m/s): 241.
1H-NMR(CDCl 3/TMS,400MHz):δ(ppm)7.30~7.27(m,5H),5.88~5.87(t,2H),4.62(s,2H),3.10~3.08(t,2H),2.63~2.58(m,2H),2.25~2.19(m,2H)。
embodiment 2
Figure BDA00001806468200052
Operation is with example 1.Productive rate: 81.3%, white solid.Mass spectroscopy MS (ESI, m/s): 393.
1H-NMR(CDCl 3/TMS,400MHz):δ(ppm)7.29~7.04(m,15H),5.84~5.83(t,2H),2.96~2.94(m,2H),2.50~2.46(m,2H),2.11~2.06(m,2H)。
embodiment 3
Figure BDA00001806468200061
Take content 60%NaH (96.0mg) in 50mL round-bottomed flask, add the THF of new steaming.Taking 1,2,3,6-tetrahydric phthalimide V (302.3mg) is dissolved in 5.0mL THF slowly in reaction flask, until there is no Bubble formation.MOMCl (193.0mg) is added drop-wise to behind above-mentioned reaction solution the inside slowly, adds KI (32.2mg), stirring reaction 3h is complete.Add the shrend reaction of going out.Then add ethyl acetate extraction, after separatory, organic phase saturated common salt water washing, uses anhydrous sodium sulfate drying.Obtain the thick product of colourless liquid, column chromatography obtains 321.3mg target compound, yield 82.3%.Mass spectroscopy MS (ESI, m/s) 196 (M+H).
1H-NMR(CDCl 3/TMS,400MHz):δ(ppm)5.92~5.90(t,2H),4.84(s,2H),3.29(s,2H),3.14~3.13(t,2H),2.66~2.61(m,2H),2.27~2.21(m,2H)。
embodiment 4
Figure BDA00001806468200062
Take LiAlH 4(380.0mg) in 100mL, in the bottle with two necks with reflux condensing tube, find time to change nitrogen, add 20.0mLTHF.Take compound IV (a) and (1206.5mg) with 15.0mL THF, dissolve, be slowly added drop-wise in bottle with two necks.After dropwising, reflux, TLC detects raw material and substantially disappears.Cool to room temperature, water cancellation reaction, and then add THF dilution, use anhydrous sodium sulfate drying.Obtain the thick product of colorless oil.Product is enough pure, without purifying, directly drops into the next step.Mass spectroscopy MS (ESI, m/s): 214 (M+H).
1H-NMR(CDCl 3/TMS,400MHz):δ(ppm)7.31~7.19(m,5H),5.81~5.80(t,2H),3.60(s,2H),2.93~2.89(m,2H),2.38~2.37(m,2H),2.20~2.11(m,4H),1.87~1.83(d,2H)。
embodiment 5
Figure BDA00001806468200071
Operation is with example 4.Productive rate: 72.3%, white solid.Mass spectroscopy MS (ESI, m/s): 365.
1H-NMR(CDCl 3/TMS,400MHz):δ(ppm)7.37~7.10(m,15H),5.52~5.46(t,2H),3.46~2.45(m,2H),2.79~2.70(m,2H),2.23~2.10(m,4H),2.05~1.97(m,2H),1.86~1.79(m,2H)。
embodiment 6
Figure BDA00001806468200072
Operation is with example 4.Productive rate: 83.2%, colorless oil.Mass spectroscopy MS (ESI, m/s): 138 (M+H).
1H-NMR(CDCl 3/TMS,400MHz):δ(ppm)5.81~5.79(t,2H),2.87~2.83(m,2H),2.41~2.37(m,2H),2.31(s,2H),2.16~2.10(m,4H),1.86~1.81(m,2H)。
embodiment 7
Figure BDA00001806468200073
Take triphosgene (98.0mg) and DMAP (6.1mg) in reaction flask, add 3.0mL methylene dichloride, place cryosel and bathe.Then the dichloromethane solution that adds 4.0mL compound III ' (a), after dropwising, reacts 2h at temperature therewith.TLC monitoring raw material disappears.Rapid column chromatography obtains 99.6mg target product.Productive rate: 54.6%, colourless oil liquid.Mass spectroscopy MS (ESI, m/s): 185.
1H-NMR(CDCl 3/TMS,400MHz):δ(ppm)5.67~5.61(t,2H),3.67~3.53(m,2H),3.37~3.28(m,2H),2.43~2.23(m,4H),1.93~1.86(m,2H)。
embodiment 8
Figure BDA00001806468200081
Take compound III and " (18.6mg) be dissolved in 1.0mL methylene dichloride and join in the test-tube reaction pipe of finishing changing nitrogen; the methanol solution of 1.0mLNaOMe (concentration is 0.12mol/L) is slowly added drop-wise in reaction tubes, have immediately colourless solid to generate.After 5h, TLC monitoring raw material disappears, and adds the shrend reaction of going out.With dichloromethane extraction 3 times, merge organic layer, use anhydrous sodium sulfate drying.Obtain the thick product of colorless oil, column chromatography obtains 17.5mg target compound.Productive rate: 96.6%, colourless oil liquid.
Compound I I ' preparation (a) also can be prepared compound III by compound III ' (a) " time reaction while finishing, not separated, directly add the methanol solution reaction of sodium methylate to obtain.Mass spectroscopy MS (ESI, m/s): 181.
1H-NMR(CDCl 3/TMS,400MHz):δ(ppm)5.66~5.61(t,2H),3.68(s,3H),3.49~2.39(m,2H),3.23~3.10(m,2H),2.31~2.19(m,4H),1.92~1.88(m,2H)。
embodiment 9
Figure BDA00001806468200082
Operation is with example 8.Productive rate: 83.2%, colorless oil.Mass spectroscopy MS (ESI, m/s): 195.
1H-NMR(CDCl 3/TMS,400MHz):δ(ppm)5.63~5.58(t,2H),4.10~4.07(m,2H),3.45~3.37(m,2H),3.19~3.07(m,2H),2.32~2.16(m,4H),1.89~1.84(m,2H),1.24~1.20(t,3H)。
embodiment 10
Figure BDA00001806468200083
Operation is with example 8.NaOBn is prepared in THF solution by BnOH and NaH.Productive rate: 82.3%, colorless oil.Mass spectroscopy MS (ESI, m/s): 257.
1H-NMR(CDCl 3/TMS,400MHz):δ(ppm)7.37~7.29(m,5H),5.64(s,2H),5.16~5.09(m,2H),3.50~3.47(m,2H),3.26~3.16(m,2H),2.32~2.20(m,4H),1.93~1.88(m,2H)。
embodiment 11
Figure BDA00001806468200091
Take compound III and " (18.6mg) be dissolved in 1.0mL methylene dichloride and join in the test-tube reaction pipe of finishing changing nitrogen, the aqueous solution of the dimethylamine of 0.5mL 33% is slowly added drop-wise in reaction tubes.After 5h, TLC monitoring raw material disappears, and adds the shrend of the 2.0mL reaction of going out.With dichloromethane extraction 3 times, merge organic layer, with anhydrous sodium sulfate drying, obtain the thick product of colorless oil.Column chromatography obtains 14.6mg target compound II (d).Productive rate: 75.4%, colourless oil liquid.
The preparation of Compound I I (d) also can be prepared compound III by compound III ' (a) " time reaction while finishing, not separated, directly add the methanol solution reaction of sodium methylate to obtain.Mass spectroscopy MS (ESI, m/s): 194.
1H-NMR(CDCl 3/TMS,400MHz):δ(ppm)5.64~5.58(t,2H),3.42~3.38(m,2H),3.16~3.12(m,2H),2.79(s,6H),2.25~2.16(m,4H),1.90~1.86(m,2H)。
embodiment 12
Figure BDA00001806468200092
Operation is with example 11.Productive rate: 80.3%, colorless oil.Mass spectroscopy MS (ESI, m/s): 223 (M+H).
1H-NMR(CDCl 3/TMS,400MHz):δ(ppm)5.67~5.60(t,2H),3.43~3.39(m,2H),3.21~3.11(m,6H),2.29~2.18(m,4H),1.91~1.87(m,2H),1.12~1.09(t,6H)。
embodiment 13
Operation is with example 11.Productive rate: 79.4%, colorless oil.Mass spectroscopy MS (ESI, m/s): 278.
1H-NMR(CDCl 3/TMS,400MHz):δ(ppm)5.66~5.59(t,2H),3.41~3.37(m,2H),3.15~3.09(m,6H),2.28~2.17(m,4H),1.90~1.86(m,2H),1.50~1.44(m,4H),1.29~1.24(m,4H),0.91~0.87(t,6H)。
embodiment 14
Operation is with example 11.Productive rate: 65.3%, colorless oil.Mass spectroscopy MS (ESI, m/s): 255 (M-H).
1H-NMR(CDCl 3/TMS,400MHz):δ(ppm)7.33~7.27(m,5H),5.67~5.61(t,2H),4.44(s,2H),3.42~3.41(m,2H),3.18~3.17(m,2H),2.37~2.21(m,4H),1.94~1.89(m,2H)。
embodiment 15
Figure BDA00001806468200102
Take compound V (302.3mg) and in the bottle with two necks with reflux condensing tube, find time to change nitrogen in 50mL, add the triethylamine of 8.0mL.With syringe, drip slowly TMSCl (434.6mg), have immediately a large amount of solids to generate.Be heated to 90 ℃, react after 4 hours, add normal hexane, fast filtering.Filtrate rotary evaporation is removed, obtained 450.0mg crude product.
Take LiAlH 4(152.0mg), in the mouth bottle of 50.0mL, adds the new THF steaming of 10.0mL, and the 450.0mg crude product of upper step is added drop-wise in reaction flask with 3.0mL THF dilution, dropwises heating and makes its back flow reaction 5 hours.Cool to room temperature, adds 10.0mL THF/H 2o (10:1) mixed solution cancellation reaction, adds anhydrous sodium sulfate drying.Toward filtrate the inside, add K 2cO 3(276.4mg), slowly drip CbzCl (375.0mg), stirring reaction 2 hours, reaction finishes substantially.Reaction solution is drained in rotation, adds 20.0mL water, is extracted with ethyl acetate 4 times, merges organic layer, and with anhydrous sodium sulfate drying, column chromatography obtains 255.0mg target compound II (c).Productive rate: 49.6%.
embodiment 16
Figure BDA00001806468200103
Take Compound I I (a) (158.7mg) and TBAB (28.0mg) in the single port bottle of 50mL, add 10.0mL methylene dichloride to dissolve, slowly drip 10.0mL KMnO 4(415.2mg, 2.63mmol) aqueous solution.Under room temperature, stirring reaction is 2 hours, and TLC monitoring raw material disappears.Add 1200.0mg S-WAT and 1.0mL concentrated hydrochloric acid, by obtaining after methylene dichloride rotary evaporation in reaction solution, be extracted with ethyl acetate 4 times.Combined ethyl acetate, with anhydrous sodium sulfate drying, obtains 199.2mg white foam shape solids crude product.Directly drop into the next step.
Take sodium-acetate (107.8mg) in above-mentioned thick product, add 4.0mL acetic anhydride, and then be heated to 120 ℃ of reactions reaction end in 2 hours.Cool to room temperature, adds 10.0mL water, adds several times solid sodium carbonate.With dichloromethane extraction, merge organic layer, with anhydrous sodium sulfate drying, column chromatography obtains 108.5mg target product.Productive rate: 67.7%, colourless oil liquid.Mass spectroscopy MS (ESI, m/s): 183.
1H-NMR(CDCl 3/TMS,400MHz):δ(ppm)3.63~3.58(m,5H),3.25~3.14(m,2H),2.89~2.85(m,2H),2.46~2.39(m,2H),2.20~2.06(m,2H)。
embodiment 17
Figure BDA00001806468200111
Operation is with example 16.Productive rate 72.7%, colourless oil liquid.Mass spectroscopy MS (ESI, m/s): 198 (M+H).
1H-NMR(CDCl 3/TMS,400MHz):δ(ppm)4.14~4.08(q,2H),3.72~3.64(m,2H),3.30~3.18(m,2H),2.93~2.92(m,2H),2.51~2.44(m,2H),2.17~2.11(m,2H),1.26～1.22(t,3H)。
embodiment 18
Figure BDA00001806468200112
Operation is with embodiment 16.Productive rate 70.0%, light Bu look solid.Mass spectroscopy MS (ESI, m/s): 259.
1H-NMR(CDCl 3/TMS,400MHz):δ(ppm)7.37~7.30(m,5H),5.13(s,2H),3.77~3.71(m,2H),3.35~3.25(m,2H),2.96.~2.94(m,2H),2.53~2.47(m,2H),2.19~2.13(m,2H)。
embodiment 19
Figure BDA00001806468200113
Operation is with embodiment 16.Productive rate 56.3%, colourless liquid.Mass spectroscopy MS (ESI, m/s): 196.
1H-NMR(CDCl 3/TMS,400MHz):δ(ppm)3.71~3.66(m,2H),3.28~3.23(m,2H),3.06~2.88(m,4H),2.83(s,6H),2.51~2.44(m,2H),2.19~2.13(m,2H)。
embodiment 20
Figure BDA00001806468200121
Operation is with embodiment 16.Productive rate 59.0%, colourless liquid.Mass spectroscopy MS (ESI, m/s): 225 (M+H).
1H-NMR(CDCl 3/TMS,400MHz):δ(ppm)3.68~3.64(d,2H),3.23~3.15(m,6H),2.94~2.85(m,2H),2.50~2.44(m,2H),2.17~2.11(m,2H),1.12~1.09(t,6H)。
embodiment 21
Operation is with embodiment 16.Productive rate 61.6%, colourless liquid.Mass spectroscopy MS (ESI, m/s): 281 (M+H).
1H-NMR(CDCl 3/TMS,400MHz):δ(ppm)3.67~3.63(d,2H),3.23~3.20(m,2H),3.14~3.10(t,4H),2.94~2.85(m,2H),2.51~2.44(m,2H),2.17~2.11(m,2H),1.52~1.45(m,4H),1.32~1.22(m,4H),0.92~0.88(t,6H)。

Claims (1)

1. the synthetic method of an azabicyclo [3.3.0] Octane derivatives, it is characterized in that, with formula (V) compound 1,2,3,6-tetrahydric phthalimide is raw material, passes through successively protecting group, reduction reaction, deprotection reaction, oxidizing reaction, cyclisation decarboxylic reaction, azabicyclo [3.3.0] Octane derivatives as shown in the formula (I) described in obtaining;
Figure FDA0000398353760000011
Its reaction scheme is:
Figure FDA0000398353760000012
Wherein,
When A is O, R is C 1～C 8alkyl substituent or aryl;
When A is N, R is hydrogen, C 1～C 8alkyl or aryl;
PG is
Figure FDA0000398353760000013
wherein, X is H, F, Cl, Br, I, NO 2, CH 3, CH 3cH 2, OCH 3, or OCH 3cH 2;
Wherein, described upper protecting group reaction is that described formula V compound is through reacting with halo protecting group under alkaline condition, production (IV) compound; In described upper protecting group reaction, alkali used is K 2cO 3, KHCO 3, KOH, KOMe, KOEt, KO tb u, KOPr, KO ipr, Na 2cO 3, NaHCO 3, NaOH, NaOMe, NaOEt, NaOPr, NaO ipr, NaH, KH, CaH 2, pyridine, triethylamine or diisopropyl ethyl amine;
Wherein, described reduction reaction is that in aprotic solvent, to take reductive agent be methylene radical by the carbonyl reduction on the imide of formula (IV) compound, production (III) compound; Described aprotic solvent is tetrahydrofuran (THF), methyltetrahydrofuran, ether, methyl tertiary butyl ether, benzene, toluene or ethylbenzene; Described reductive agent is LiAlH 4;
Wherein, described deprotection reaction is that formula (III) compound is first reacted with phosgene or triphosgene under the catalysis of alkali, then reacts with corresponding alcohol or amine, obtains general structure for the compound of (II); Wherein, X is H, F, Cl, Br, I, NO 2, CH 3, CH 3cH 2, OCH 3, or OCH 3cH 2; Wherein, described catalyzer alkali is triethylamine, Trimethylamine 99, diisopropyl ethyl amine, diethylamine, dipropyl amine, dibutylamine, any one of pyridine or DMAP;
Wherein, described oxidizing reaction is that formula (II) compound is oxidized to dicarboxylic acid through oxygenant; Wherein, described oxygenant is H 2o 2, O 3, KMnO 4or K 2cr 2o 7;
Wherein, described cyclisation decarboxylic reaction is cyclisation decarboxylation production (I) compound in acid solvent; Wherein, described acid solvent is acetic acid, diacetyl oxide or propionic acid.
CN201210211875.7A 2012-06-25 2012-06-25 Method for synthesizing aza-bicyclo octane [3.3.0] derivatives Expired - Fee Related CN102718695B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201210211875.7A CN102718695B (en) 2012-06-25 2012-06-25 Method for synthesizing aza-bicyclo octane [3.3.0] derivatives

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201210211875.7A CN102718695B (en) 2012-06-25 2012-06-25 Method for synthesizing aza-bicyclo octane [3.3.0] derivatives

Publications (2)

Publication Number Publication Date
CN102718695A CN102718695A (en) 2012-10-10
CN102718695B true CN102718695B (en) 2014-04-02

Family

ID=46944600

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201210211875.7A Expired - Fee Related CN102718695B (en) 2012-06-25 2012-06-25 Method for synthesizing aza-bicyclo octane [3.3.0] derivatives

Country Status (1)

Country Link
CN (1) CN102718695B (en)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1489592A (en) * 2001-02-02 2004-04-14 3,7-diazabicyclo[3,3,o] otanes and their use in treatment of cardiac arrhythmias
WO2007093515A1 (en) * 2006-02-15 2007-08-23 F. Hoffmann La-Roche Ag Heterocyclic antiviral compounds
CN101384596A (en) * 2006-02-15 2009-03-11 弗·哈夫曼-拉罗切有限公司 Heterocylic antiviral compounds
CN101622240A (en) * 2007-01-05 2010-01-06 第一三共株式会社 Fused substituted aminopyrrolidine derivative

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7381738B2 (en) * 2004-02-19 2008-06-03 Bristol-Myers Squibb Company Substituted bicycloalkylamine derivatives as modulators of chemokine receptor activity
WO2007049224A1 (en) * 2005-10-25 2007-05-03 Actelion Pharmaceuticals Ltd Novel hexahydro- or octahydro-cyclopenta[c]pyrrole derivatives
CN101463001A (en) * 2007-12-21 2009-06-24 上海药明康德新药开发有限公司 Octahydro cyclopenteno [c] pyrroletetrazole derivative and preparation thereof
TW200944523A (en) * 2008-02-08 2009-11-01 Organon Nv (Dihydro)pyrrolo[2,1-a]isoquinolines
CN102417475A (en) * 2010-09-28 2012-04-18 江苏恒瑞医药股份有限公司 Azabicyclooctane derivative, preparation method and application thereof to medicine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1489592A (en) * 2001-02-02 2004-04-14 3,7-diazabicyclo[3,3,o] otanes and their use in treatment of cardiac arrhythmias
WO2007093515A1 (en) * 2006-02-15 2007-08-23 F. Hoffmann La-Roche Ag Heterocyclic antiviral compounds
CN101384596A (en) * 2006-02-15 2009-03-11 弗·哈夫曼-拉罗切有限公司 Heterocylic antiviral compounds
CN101622240A (en) * 2007-01-05 2010-01-06 第一三共株式会社 Fused substituted aminopyrrolidine derivative

Also Published As

Publication number Publication date
CN102718695A (en) 2012-10-10

Similar Documents

Publication Publication Date Title
CN102627573B (en) Synthesis method for 5-aminolevulinic acid hydrochloride
CN102070575B (en) New synthesis method of caronic anhydride
CN108129288B (en) Synthesis method of trans-3-hydroxycyclobutylformic acid
CN102827064B (en) Synthetic method for aza-bicyclo octane[3.3.0] derivatives
CN114539048B (en) Carlong anhydride intermediate and preparation method of Carlong anhydride
CN102827063B (en) Synthetic method for aza-bicyclo octane[3.3.0] derivatives
CN104177331B (en) The preparation method of bilastine
CN103694237A (en) Preparation method and key intermediate of anticoagulant apixaban
CN108456238A (en) The preparation method of shellfish chlolic acid derivatives difficult to understand and shellfish cholic acid difficult to understand
CN108623455B (en) Intermediate of anti-heart failure medicine
CN113416150A (en) Novel synthesis method of lobaplatin intermediate
CN105968040B (en) A kind of preparation method of Lei Dipawei intermediate
CN109651367B (en) Method for preparing 1, 4-dihydroquinoline and pyrrolo [1,2-a ] quinoline compounds
CN102718695B (en) Method for synthesizing aza-bicyclo octane [3.3.0] derivatives
CN111533689B (en) 2,2' -biquinoline compound and one-pot preparation method thereof
CN107629064B (en) A kind of synthetic method of Azacyclooctane and Furanones compound
CN107674016B (en) Preparation method of telaprevir intermediate and intermediate thereof
CN112194548B (en) Alpha-amino-gamma-butyrolactone compound and preparation method thereof
CN104774183B (en) A kind of auspicious relax of formoxyl cuts down the preparation method of spit of fland calcium intermediate
CN109134351B (en) Synthesis method of S-3- (4-aminophenyl) piperidine
US8173832B2 (en) Process for producing 2-isopropenyl-5-methyl-4-hexene-1-yl-3-methyl-2-butenoate
CN102838609B (en) Azabicyclo [3.3.0] octane derivative, as well as preparation method and application thereof
CN114573512B (en) Method for synthesizing C2-difluoro alkyl benzimidazole derivative
CN116082155A (en) Method for preparing pinoxaden intermediate by using symmetrical epoxy compound
CN100556906C (en) A kind of preparation method of proteinase inhibitor important intermediate

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20140402

Termination date: 20210625

CF01 Termination of patent right due to non-payment of annual fee