WO1999061443A1 - Procede de synthese de derives d'halopyridyl-azacyclopentane et d'intermediaires de ceux-ci - Google Patents
Procede de synthese de derives d'halopyridyl-azacyclopentane et d'intermediaires de ceux-ci Download PDFInfo
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- WO1999061443A1 WO1999061443A1 PCT/JP1998/003954 JP9803954W WO9961443A1 WO 1999061443 A1 WO1999061443 A1 WO 1999061443A1 JP 9803954 W JP9803954 W JP 9803954W WO 9961443 A1 WO9961443 A1 WO 9961443A1
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- derivative
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- dicarboxylic acid
- acid ester
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—Bridged systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
Definitions
- the present invention relates to a method for synthesizing halopyridyl-azasic pentane derivatives such as epibatidine, which is an alloidoid having a strong analgesic activity as a pharmacological action, and an intermediate thereof.
- halopyridyl-azasic pentane derivatives such as epibatidine, which is an alloidoid having a strong analgesic activity as a pharmacological action, and an intermediate thereof.
- halopyridyl-azasic pentane derivatives such as epibatidine, which is an alloidoid having a strong analgesic activity as a pharmacological action, and an intermediate thereof.
- Allene compounds have a 1,2-gen structure and are useful for the synthesis of various compounds in organic synthesis due to their specific reactivity.
- a method involving isomerization to an allene compound by a reaction has become common (Alexakis, A. et al., J. Am. Chem. Soc., 1990, 112, 8042-8047).
- Reaction with Grineer reagent From other dithioacetal derivatives Reaction with Grineer reagent (Luh, TY et al., J. Org.
- the present invention provides an optically active allene-1,3-dicarboxylic acid derivative and a 7-azabicyclo [2.2.1] heptane skeleton derivative as intermediates, which shortens the synthesis process, makes the operation simple and convenient.
- An object of the present invention is to provide a method for synthesizing an optically active halopyridyl-azasic pentane derivative and an intermediate thereof, which can provide an optical yield.
- an optically active acetone dicarboxylic acid ester derivative is reacted in the presence of a basic substance and a dehydrating agent to obtain a diastereomer mixture of an allene-1,3-dicarboxylate esterene derivative, and then the asymmetric mixture of the diastereomer mixture is obtained.
- a first step of obtaining an R- or S-form optically active allene-1,3-dicarboxylic acid ester derivative by a conversion reaction, and subjecting the optically active allen-1,3-dicarboxylic acid ester derivative to a Dienophile and Diels-Alder reaction After obtaining the 7-azabisik mouth [2.2.1] heptene derivative, the 7-azabisik mouth [2.2.1] heptene derivative is reduced and the 7-azabisik mouth [2.2.1] heptene derivative is reduced.
- a halopyridino which comprises a second step of obtaining a tan derivative and a third step of obtaining an optically active halopyridyl-azashic-opened pentane derivative from the 7-azabisic mouth [2.2.1] heptane derivative - a method of synthesizing ⁇ The cyclopentane derivatives.
- optically active acetone dicarboxylic acid ester derivative is represented by the following formula (1):
- R 1 and R 2 are groups derived from an optically active alcohol, and R 3 and R 4 are each one selected from the group consisting of a hydrogen atom, an alkyl group or an aryl group, They may be the same or different.
- the optically active allene-1,3-dicarboxylic acid ester derivative is an R-form or an S-form represented by the following formula (2): (2)
- R 1 and R 2 are groups derived from an optically active alcohol, and R 3 and R 4 are each one selected from the group consisting of a hydrogen atom, an alkyl group or an aryl group, They may be the same or different.
- optically active 7-azabicyclo [2.2.1] heptene derivative is represented by the following formula (3) or its enantiomer, formula (4):
- R 1 and R 2 are groups derived from an optically active alcohol, and R 5 is a protecting group for an amino group.
- R '' and R 2 are groups derived from an optically active alcohol, and R 5 is a protecting group for an amino group.
- Optically active 7-azabisic [2.2.1] heptane derivative is a ketoester derivative represented by the following formula (5) or its enantiomer formula (6):
- R 2 is a group derived from an optically active alcohol
- R 5 is a protecting group for an amino group.
- R 2 is a group derived from an optically active alcohol, and R 5 is a protecting group for an amino group.
- R 5 is a protecting group for an amino group.
- R 5 is a protecting group for an amino group.
- the halopyridyl-azacyclopentane derivative is a method for synthesizing a halopyridyl-azacyclopentane derivative represented by the following formula (8).
- X is a halogen atom selected from C1, F, Br, I or their radioisotopes.
- the second embodiment of the present invention is a method for synthesizing an optically active allene-1,3-dicarboxylic acid ester derivative which is an intermediate for the synthesis of a halopyridyl-azabicyclo mouth derivative. That is, an acetone dicarboxylic acid and an optically active alcohol are used.
- the optically active acetone dicarboxylic acid ester derivative is subjected to an allene diester derivative in the presence of a basic substance and a dehydrating agent to form an allene-1,3-dicarboxylic acid ester derivative.
- Diastereomer a mixture is obtained, then cooled in the presence of a basic substance, and crystallization-induced asymmetric transformation by crystallization Optically active allene-1,3-dicarboxylate derivatives characterized by obtaining R-allene-1,3-dicarboxylate derivatives or S-allene-1,3-dicarboxylate derivatives Is a synthesis method.
- Another embodiment of the present invention relates to a method for synthesizing a ketoester or ketone of an optically active 7-azabisic mouth [2.2.1] heptane derivative useful as a precursor of a halopyridyl-azacyclo derivative represented by the formula (8).
- the formula (3) or a formula (4) which is an enantiomer thereof is obtained.
- the optically active 7-azabicyclo [2.2.1] heptene derivative represented by the formula (5) is obtained, and the isolated olefin is selectively reduced, followed by ozonolysis to obtain formula (5) or the enantiomer of formula (6).
- the ketoester derivative of the optically active 7-azabicyclo [2.2.1] heptane derivative shown by) can be synthesized.
- X is a halogen atom selected from Cl, F, Br, I or a radioisotope thereof.
- RR 2 is a group derived from an optically active alcohol, and R 5 is a protecting group for an amino group.
- R 1 and R 2 are groups derived from an optically active alcohol, and R 5 is a protecting group for an amino group.
- R 2 is a group derived from an optically active alcohol, and R 5 is a protecting group for an amino group.
- R 2 is a group derived from an optically active alcohol
- R 5 is a protecting group for an amino group.
- an optically active 7-azabicyclo [2.2.1] represented by the formula (5) or (6)
- an optically active 7-azabisic port [2.2.1] heptan-2-one represented by formula (7).
- R 5 is a protecting group for an amino group.
- the optically active alcohol is a menthol such as (-)-menthol, (+) _ menthol, (+)-isomenthol, or (R)-(+)-1,2-bi (2,2 ' -Naphthol), (R)-(+)-1, ⁇ -Bi (2,2'-naphthol) monomethyl ether, (S)-(-) -1, ⁇ -Bi (2,2, -naphthol), Derivatives of pinaphthol such as (S)-(-)-1, ⁇ ⁇ ⁇ -bi (2,2'-naphthol) monomethyl ether, and dehydrating agents are 2-buta-1,3-dimethylimidazolium chloride or 2-chloro
- the basic substance such as 1,3-dimethylimidazoliniumhexafluorophosphate is one selected from tertiary amines such as triethylamine and dimethylaminopyr
- acetone dicarboxylic acid or its lower alkyl ester as a starting material, synthesis of optical acetone dicarboxylic acid ester and efficiency of diastereomer mixture of optically active allene-1,3-dicarboxylic acid derivative by allenation reaction
- the optical synthesis and the asymmetric crystallization of the diastereomer mixture made it possible to obtain optically active allen-1,3-dicarboxylic acid derivatives with high optical purity without complicated optical resolution operations.
- 7-azabizic is a precursor of halopyridyl-azasic pentane derivative.
- R ′ is a lower alkyl group or a phenyl group, and R is a group derived from an optically active alcohol.
- the esterification of acetonedicarboxylic acid (1) -a with an optically active alcohol or the transesterification of an alkyl or phenyl acetondicarboxylate (I) -b with an optically active alcohol leads to an optically active compound.
- acetone dicarboxylic acid (I) -a for example, (-)-menthol can be used as a photoalcohol to give 2,3-dimethylimidazo.
- Dialkyl esters of acetone dicarboxylic acid are more preferable because they are easily available, have high transesterification yields, and are easy to process after the reaction. It is.
- This diastereomer mixture is a mixture of the R-form [(III) -R] and the S-form [(III) -S] of the allene-1,3-dimenthyl ester, and the R-form and the S-form in the presence of triethylamine. Therefore, this diastereomer mixture (III) is cooled to about -20 to -80 ° C in a pentane solution in the presence of a catalytic amount of triethylamine to crystallize the R-form.
- asymmetric crystallization crystallization-induced asymmetric transformation reaction
- a diastereomer mixture (III) of allene-1,3-dimenthyl ester can be obtained by carrying out a two-stage reaction of esterification and dehydration reaction (allenation).
- esterification and dehydration reaction allenation
- methyl acetone dicarboxylate is chlorinated with phosphorus pentachloride, demethylated with hydrochloric acid, then esterified with optically active alcohol, and then dehydrochlorinated.
- the method was equally complicated requiring four equal reaction steps (Kanematsu, K. et al., Tetrahedron Lett., 1992, 33, 5787-5790).
- the present method also used an approximately 1: 1 mixture of diastereomers. While maintaining the equilibrium state due to the presence of the tertiary amine, asymmetric crystallization is performed by setting the conditions for the precipitation of one of them, and a specific mixture can be obtained from the diastereomer mixture without complicated optical resolution. 'It is a very easy and efficient way to selectively obtain one.
- a dehydrating agent used for esterification of acetone dicarboxylic acid or allene of 1,3-acetone dicarboxylic acid menthyl ester 2-chloro-1,3-dimethylimidazolyl chloride or 2-chloromethane is used.
- Imidazolinium salts such as 1,3-dimethylimidazolidiniumhexafluorophosphate are preferably used.
- Tertiary amines having high basicity are preferred as the basic substance.
- Triethylamine dimethylaminopyridine, ⁇ , ⁇ -diisopropylmethylamine, ⁇ , ⁇ -diisopropylethylamine, pyrrolidine, (S) -2-methoxymethylpyrrolidine, spartin, etc.
- the use of the above imidazolinium salt as a dehydrating agent and the use of amines as a basic substance allow the esterification and allenation reactions to proceed in one step, respectively, and are useful for shortening the reaction step and improving the yield.
- the allene-1,3-dicarboxylates obtained in Examples 1 and 2 are both racemic and optically active. It is preferable to obtain an optically active alene compound as an ester of active alcohol and acetone dicarboxylic acid.
- the following compounds are exemplified as the optically active alcohol used in the synthesis of the acetone dicarboxylic acid derivative used in this step.
- the organic solvent to be used is not particularly limited, and may be any organic solvent used in ordinary organic synthesis. Pentane, hexane, methylene chloride, tetrahydrofuran, etc. are used. Esterification and arelenization are performed at room temperature. The transesterification is carried out under reflux. The asymmetric crystallization may be carried out at any temperature at which crystallization occurs below room temperature, and can be selected appropriately according to the system.
- the second step of the present invention is a step of obtaining an optically active butane derivative by a Diels-Alder reaction between an optically active allene-1,3-dicarboxylic acid ester derivative and genofinole [2.2.1].
- pyrrole is preferably used, and the amino group of pyrrole is a lower aliphatic acyl group, an aromatic acyl group, a formyl group, a vinyl group, a lower alkoxycarbonyl group, an aralkylcarboxyl group, or an aryloxycarbonyl group.
- Preferred are compounds protected with an alkenyl group, an aryloxycarbonyl group, an aralkyl group, a tri-lower alkylsilyl group, etc.
- the lower aliphatic acetyl group is an acetyl group, a propionyl group, a ptyryl group, an isoptyryl group, a valeryl group, an isovaleryl group, A group having 1 to 6 carbon atoms, such as a bivaloyl group, is used.
- An aromatic acetyl group is a benzoyl group, a toluoyl group, a xylyl group, a phenylacetyl group, and the like.
- a lower alkoxycarbyl group is a methoxycarbonyl group.
- the benzyl group is a phenyloxycarbonyl group, a nitrophenoxycarbonyl group
- the aralkyl group is a benzyl group, a methoxybenzinole group, a nitrobenzyl group, a chlorobenzyl group, etc.
- the tri-lowerarylsilyl group is a trimethylsilanol group. Examples include a triethylsilyl group and a triphenylsilyl group.
- Heptene derivative (IV) has two types of olefins, and the isolated olefins can be selectively reduced. This is reduced almost quantitatively with hydrogen using Pt, Pd, Wilkinson complex, etc., which are commonly used. This reduction is performed almost quantitatively, and the optically active 7-azabicyclo [2.2.1] heptane is used. The derivative (V) is obtained.
- ketoester optically active 7-azabic-hept [2.2.1] heptane-2-one-3-carboxylate VI
- Ozonolysis uses methylene chloride as a solvent. Ozone gas is passed at about -70 to -80 ° C, and the generated ozone is reduced with dimethyl sulfide or triphenylphosphine. It is difficult to perform ketoesterification by direct ozone using methanol as a solvent. Yes, it is necessary to reduce the ester once to make it an alcohol and then ozonolysis, which requires one less reaction.
- the optically active 7-azabisic port obtained in the second step [2.2.1] heptane-2-one-3-carboxylic acid ester (VI) is used as a precursor for the halopyridyl-azapic port.
- pen This is a step of synthesizing a tan derivative, for example, (-)-epibatidine.
- 7-azabicyclo [2.2.1] heptane-2-one-3-carboxylate can be used for the synthesis of epipibidine using known methods (Fletcher et al. J. Org. Chem. , 1994, 59, 1771-1778). That is, 7-azabicyclo [2.2.1] heptane-2-one-3-capronic acid ester (VI) is simultaneously hydrolyzed and decarboxylated with an acid. To give 7-azabicyclo [2.2.1] heptan-2-one (VII), and then added 2-chloro-5-chloropyridin at -70 ° C in the presence of n-BuLi.
- the halopyridyl-azacyclopentane derivative is represented by the formula (8) as described above.
- Exo-2- (6, -chloro-3'-pyridyl) -7-azabisic [2.2.1] heptane Exo-2- (6-, bromo-3, -pyridyl) -7-azabicyclo [2.2.1] heptane, exo-2- (6-fur Oro-3'-pyridyl) _7-azabicyclo [2.2.1] heptane, exo-2_ (6'-chloro-2'-pyridyl) -7-azabicyclo [2.2.1] heptane, exo-2- (6 7-azabicyclo [2.2.1] heptane, exo-2- (5'-chloro-3'-pyridyl) -7_azabicyclo [2.2.1] heptane, exo- 2- (4, -Bromo-3'-pyridyl) -7-azabic
- Mass spectrum JEOL JMX-SX102AQQ mass spectrometer, JEOL JMS-Gcraate mass spectrometer for measurement.
- the ether solvent and aromatic solvent used in the reaction were prepared with benzophenone and Na at the time of use and made anhydrous; methylene chloride was treated with water to remove methanol, a stabilizer. After washing 10 times, CaH., Prepared at the time of use and made anhydrous, was used. The other anhydrous solvents used were anhydrous according to the usual method. The NaH used in the reaction was washed three times with ether to remove the oil component.
- (-)-Menthol was used to synthesize optically active menthyl ester of acetone dicarboxylic acid.
- DMC 7.13 mraol
- 5.00 g (34.2 mmol) of setondicarboxylic acid and 10.7 g of (-)-menthol (68.4 10.8 g (137 mraol) of pyridine was added dropwise in a water bath, and the mixture was stirred at room temperature for 7.5 hours. After completion of the reaction, the solid product precipitated was filtered through celite to obtain a crude product.
- Example 5 Asymmetric reaction of a mixture of diastereomers; synthesis of [3R (1R, 2S, 5R)]-bis [5-methyl-2--methyltyl) cyclohexyl] -2,3-pentadiene diate
- the diastereomer mixture was subjected to crystallization-induced asymmetric conversion reaction (asymmetric crystallization).
- the R-form obtained in Example 4: S-form 4: 5
- the mixture was placed in a freezer and kept at ⁇ 20 ° C. and allowed to stand for 1 day. After large crystals were precipitated, the mixture was further allowed to stand at ⁇ 78 ° C. for 1 day. After the crystals are precipitated, suck the crystals at -78 ° C and take care not to remove them.
- the solvent remaining in the crystals was distilled off. The same operation was repeated twice with the removed mother liquor to obtain 1.8 g of crystals.
- the obtained crystals were only R-forms, and the yield was 90%.
- a Diels-Alder reaction with a pyrrole derivative was performed under various conditions using allene-1,3-dicarboxylic acid methyl ester as the allene compound.
- Method 1 Under a nitrogen flow, Aren - 1, 3 - dry methylene chloride solution of methyl dicarboxylic acid ester 620mg (l.53 Yuzuru ol) (25ml) - 78 ° C with A1C1 3 to 224m g (1.68 mmol) was added, 30 minutes ⁇ N- butoxycarbonyl two Rubiroru -.
- Method 2 In a nitrogen stream, 1.10 g (6.40 mL) of N-butoxycarbonyl bilole was added dropwise to 10 mL of a dry methylene chloride solution of 100 mg (0.64 mL) of allene-1,3-dicarboxylic acid methyl ester, and the solution was added at 90 ° The mixture was stirred for 24 hours while heating at C.
- Optically active compound obtained in Example 7, [IS, 2R (1R, 2S, 5R), 3Z (1R, 2S, 5R), 4R] -5-methyl- 2- ⁇ -Methylethynole) cyclohexyl 3- [2-[[5-Methyl-2- (1-methylethyl) cyclohexyl] oxy] -2-oxoethylidene] -7- (t-butoxycarbonyl) -7-azabicyclo [2.2 ⁇ 1] hept-5-ene-2-carboxylate 578 mg (1.01 liter) of ethyl acetate solution 15 ml of 10% Pd-C 10 mg, and 10 atm under hydrogen stream After completion of the reaction, the metal Pd was removed by celite filtration, and the filtrate was distilled off.
- Example 11 Optically active compound obtained in 1 [IS, 2R (1R, 2S, 5R), 3Z (1R, 2S, 5R), 4R] -5-Methyl-2- 2-methyl-ethyl) cyclohexyl 7- (t-Butoxycarbonyl) -3-oxo-7-azabisic mouth [2.2.1] Heptane-2-carboxylate 100 mg (0.250 mmol) was added with 3 ml of 10% HC1 aqueous solution, and the mixture was heated at 100 ° C. The mixture was heated and refluxed for 3.5 hours. After the reaction was completed, the solvent was removed, and the remaining water was distilled off azeotropically with ethanol.
- the obtained crude product was dissolved in 10 ml of dry methylene chloride, and 61 :; , 7601111) and (80 (:) 2 0 11111 ⁇ (0.5111111101) pressurized tut, extracted with black port Holm poured. after completion of the reaction which was stirred at room temperature for 12 hours, the reaction solution, a saturated sodium chloride ⁇ 3 ⁇ 4, Na 2 S0 4 with dry silica gel chromatography of the crude product obtained filtered and then evaporated to remove the solvent -.
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Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
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JP54337599A JP4364313B2 (ja) | 1998-05-26 | 1998-09-03 | ハロピリジル−アザシクロペンタン誘導体及びその中間体の合成方法 |
US09/462,379 US6384228B2 (en) | 1998-05-26 | 1998-09-03 | Method for synthesis of halopyridyl-azacyclopentane derivative and intermediate thereof |
CA002297124A CA2297124C (en) | 1998-05-26 | 1998-09-03 | Method for synthesis of halopyridyl-azacyclopentane derivative and intermediate thereof |
KR10-2000-7000568A KR100519905B1 (ko) | 1998-05-26 | 1998-09-03 | 할로피리딜-아자시클로펜탄 유도체 및 그 중간체의 합성 방법 |
Applications Claiming Priority (2)
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JP14363998 | 1998-05-26 | ||
JP10/143639 | 1998-05-26 |
Publications (1)
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WO1999061443A1 true WO1999061443A1 (fr) | 1999-12-02 |
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PCT/JP1998/003954 WO1999061443A1 (fr) | 1998-05-26 | 1998-09-03 | Procede de synthese de derives d'halopyridyl-azacyclopentane et d'intermediaires de ceux-ci |
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US (1) | US6384228B2 (ja) |
JP (1) | JP4364313B2 (ja) |
KR (1) | KR100519905B1 (ja) |
CA (1) | CA2297124C (ja) |
WO (1) | WO1999061443A1 (ja) |
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US6143845A (en) * | 1992-05-28 | 2000-11-07 | Idemitsu Petrochemical Co., Ltd. | Process for producing polyolefin |
EP0591756B1 (en) * | 1992-09-22 | 1998-11-25 | Idemitsu Kosan Company Limited | Polymerization catalysts and process for producing polymers |
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1998
- 1998-09-03 JP JP54337599A patent/JP4364313B2/ja not_active Expired - Lifetime
- 1998-09-03 US US09/462,379 patent/US6384228B2/en not_active Expired - Fee Related
- 1998-09-03 CA CA002297124A patent/CA2297124C/en not_active Expired - Fee Related
- 1998-09-03 WO PCT/JP1998/003954 patent/WO1999061443A1/ja not_active Application Discontinuation
- 1998-09-03 KR KR10-2000-7000568A patent/KR100519905B1/ko not_active IP Right Cessation
Non-Patent Citations (5)
Title |
---|
ASO MARIKO et al., "Preparation of Optically Active (R)-and (S)-Allene-1,3-Dicarboxylates and their Asymmetric Cycloaddition Reactions with Cyclopentadiene", TETRAHEDRON LETTERS, 1992, Vol. 33, No. 39, pp. 5787-5790. * |
FLETCHER STEPHAN R. et al., "Total Synthesis and Determination of the Absolute Configuration of Epibatidine", J. ORG. CHEM., 1994, Vol. 59, pp. 1771-1778. * |
IKEDA IZUMI et al., "Structure and Asymmetric Diels-Alder Reactions of Optically Active Allene-1,3-Dicarboxylates", J. ORG. CHEM., 1996, Vol. 61, No. 6, pp. 2031-2037. * |
PAVRI NEVILLE P. et al., "A New (4+2)Cycloaddition Atrategy for the Synthesis of N-Acyl-7-Azabicyclo(2.2.1)Heptan-2-Ones: A Formal Synthesis of (+-)-Epibatidine", TETRAHEDRON LETTERS, 1997, Vol. 38, No. 46, pp. 7993-7996. * |
ZHANG CHUNMING et al., "A Short and Efficient Total Synthesis of (+-)-Epibatidine", J. ORG. CHEM., 1996, Vol. 61, No. 20, pp. 7189-7191. * |
Also Published As
Publication number | Publication date |
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JP4364313B2 (ja) | 2009-11-18 |
US20020010339A1 (en) | 2002-01-24 |
KR20010022001A (ko) | 2001-03-15 |
CA2297124C (en) | 2007-10-16 |
US6384228B2 (en) | 2002-05-07 |
KR100519905B1 (ko) | 2005-10-10 |
CA2297124A1 (en) | 1999-12-02 |
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