WO2001047836A1 - Nouveaux agents de desacetlylation selective - Google Patents
Nouveaux agents de desacetlylation selective Download PDFInfo
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- WO2001047836A1 WO2001047836A1 PCT/JP2000/009126 JP0009126W WO0147836A1 WO 2001047836 A1 WO2001047836 A1 WO 2001047836A1 JP 0009126 W JP0009126 W JP 0009126W WO 0147836 A1 WO0147836 A1 WO 0147836A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
- C07C211/02—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C211/09—Diamines
- C07C211/10—Diaminoethanes
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
- C07C211/02—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C211/09—Diamines
- C07C211/11—Diaminopropanes
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/20—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
- C07C67/29—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by introduction of oxygen-containing functional groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
- C07C67/297—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/317—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
Definitions
- the present invention relates to novel compounds having a selective deacetylation action, and a method for selective deacetylation using such compounds. More specifically, the present invention relates to a novel hydroxylamine compound or an amine compound having a selective deacetylation action, a method for selective deacetylation using the same, and particularly to a method for selectively producing a compound useful as a raw material for pharmaceuticals. The present invention relates to a method for deacetylation. Background art
- the compounds used as the selective deacetylating agent of the present invention are as shown below.
- N— A— y (Wherein, R 1 and R 2 each represent a lower alkyl group, or bond to each other to form a lower alkylene group, is a hydrogen or hydroxy group, R 4 is a hydrogen or acyl group, and A is Lower alkylene group)
- novel compounds include the following compounds.
- R 1 and R 2 each represent a lower alkyl group, or bond to each other to form a lower alkylene group
- R 4 represents an acyl group
- A represents a lower alkylene group.
- R 1 and R 2 are each a lower alkyl group
- R 4 is an acyl group other than a lower alkyl group
- Suitable salts of the target compound (I) include salts with acids, ie, inorganic acid addition salts (eg, hydrochloride, hydrobromide, sulfate, phosphate, etc.), organic acid addition salts (eg, formic acid Salt, acetate, trifluoroacetate, maleate, tartrate, fumarate, methanesulfonate, benzenesulfonate, etc.);
- acids ie, inorganic acid addition salts (eg, hydrochloride, hydrobromide, sulfate, phosphate, etc.), organic acid addition salts (eg, formic acid Salt, acetate, trifluoroacetate, maleate, tartrate, fumarate, methanesulfonate, benzenesulfonate, etc.);
- salts with acidic amino acids eg, arginine, aspartic acid, glutamic acid, etc.
- “Lower” means 1 to 6 carbon atoms, preferably 1 to 4 unless otherwise specified.
- Suitable "lower alkyl groups” include straight-chain or branched ones such as methyl, ethyl, propynole, isopropynole, butyl, tertiary butyl, pentinole, hexyl and the like.
- Preferred examples of R— and / or R include a methyl group and an ethyl group.
- Suitable "lower alkylene groups” include straight-chain or branched ones, for example, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexmethylene, methylmethylene, methylethylene, propylene and the like.
- Preferred examples of A include an ethylene group and a trimethylene group, and the like, and examples of a group formed by R and R 2 include a pentamethylene group and the like.
- acyl group examples include carbamoyl; aliphatic acyl; and an acyl ring having an aromatic ring, which is called an aromatic acyl, or a heterocyclic ring, which is called a heterocyclic acyl.
- acyl group examples include the following.
- Aliphatic acyls for example, lower alkanols (eg, formyl, acetyl, pronoyl, butanol, 2-methylpropanol, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, etc.);
- lower alkanols eg, formyl, acetyl, pronoyl, butanol, 2-methylpropanol, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, etc.
- Lower alkoxycarbonyl eg, methoxycarbonyl, ethoxycarbonyl, tertiary butoxycarbonyl, tertiary pentyloxycarbonyl, hexyloxycarbonyl, etc.
- Lower alkylsulfonyl eg, methylsulfonyl, ethylsulfonyl, etc.
- Mono (or di or tri) halo (lower) alkylsulfonyl for example, fluoromethinoles zolephoninole, dichloromethinoles / levoninore, trifnoroleolomethinolesnorefonynorre, chloromethinolesnorlehoninole, dichloromethine Noresnoreffoninole, trichloromethinolesulfonyl, 1 or 2-fluoroethyls / lefonyl, 1 or 2-chloroethylsulfonyl, etc.).
- Aroyl eg, benzyl, toluoyl, naphthoinole, etc.
- Al (lower) alkanoyl for example phenyl (lower) alkanoyl (for example, pheninoleasetinole, feninoleprono, noinole, feninolebutanoinole, feninoleiso butanoinole, feninolepentanoinole, feninolehexenoinole, etc.]
- Naphtinol (lower) alkanols for example, naphthyl acetyl, naphthylpropanoyl, naal (lower) alkenoyl [for example, phenyl (lower) alkenoyl (for example, feninolepropeninole, feninolef) Phenylhexen
- Al (lower) alkoxycarbonyl for example, phenyl (lower) alkoxycarbonyl (for example, benzyloxycarbonyl) etc.];
- Aryloxycarbonyl for example, phenoxycarbonyl, naphthyloxynorolebonyl, etc.
- Aryloxy (lower) alkanols eg phenoxyacetyl, phenoxypropionyl, etc.
- Arylglyoxyloyl eg, phenyldalioxyloyl, naphthyldaroxyloyl, etc.
- Arylsulfonyl for example, phenylsulfonyl, p-torinolesulfonyl, etc.; and the like.
- Heterocyclic ring for example
- Heterocyclic (lower) alkanols eg, heterocyclic acetyl, heterocyclic propanoyl, heterocyclic butanol, heterocyclic pentanoyl, heterocyclic hexanoyl, etc.
- heterocyclic alkanols eg, heterocyclic acetyl, heterocyclic propanoyl, heterocyclic butanol, heterocyclic pentanoyl, heterocyclic hexanoyl, etc.
- Heterocycle (lower) alkenoyl for example, heterocycle pronoyl, heterocycle butenoyl, heterocycle pentenoyl, heterocycle hexenoyl, etc.
- Heterocyclic dalioxyloyl and the like.
- heterocyclic moiety of the above “heterocyclic carbonyl”, “heterocyclic (lower) alkyl”, “heterocyclic (lower) alkenoyl” and “heterocyclic dalioxyloyl” More specifically refers to a saturated or unsaturated, monocyclic or polycyclic heterocyclic group having at least one heteroatom such as an oxygen atom, a sulfur atom and a nitrogen atom ( particularly preferred heterocyclic ring As a basis,
- a 3- to 8-membered (more preferably 5- or 6-membered) unsaturated heteromonocyclic group having 1 to 4 nitrogen atoms such as pyrrolyl, pyrrolinyl, imidazolyl, virazolinole, pyridyl, dihydropyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, Triazolinole (for example, 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolinole (for example, 1H-tetrazolyl, 2H —Tetrazolyl) etc .;
- a 3- to 8-membered (more preferably 5- or 6-membered) saturated heteromonocyclic group having 1 to 4 nitrogen atoms such as pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl and the like;
- a 7- to 12-membered (more preferably 9- or 10-membered) unsaturated condensed heterocyclic group having 1 to 4 nitrogen atoms for example, indolyl, isoindolyl, indolininole, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl Benzotriazolyl, etc .;
- a 3- to 8-membered (more preferably 5- or 6-membered) unsaturated heteromonocyclic group having 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms for example, oxazolyl, isoxazolyl, oxaziazolyl (for example, 1, 2, or 4-oxadiazolyl, 1,3,4-oxadazolyl, 1,2,5-oxadazolyl, etc.);
- 3- to 8-membered (more preferably 5- or 6-membered) unsaturated heteromonocyclic group having 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms for example, thiazolyl, isothiazole Azolyl, thiadiazolyl (for example, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.), dihydrothiazinyl and the like;
- a 7- to 12-membered (more preferably 9- or 10-membered) unsaturated condensed heterocyclic group having 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms for example, benzothia 3- to 8-membered having one oxygen atom (More preferably 5 or 6 membered) unsaturated heteromonocyclic group, such as furyl;
- the acyl moiety may be one or more (preferably 1 to 3) of the same or different suitable substituents, for example, lower alkyl as described above; lower alkoxy as described below; lower as lower alkyl moiety as defined above.
- Ashiru group a lower Arukanoiru group, a lower alkoxycarbonyl group, c s - c 1 0 Aroiru group, etc.
- Asechiru group a propionyl group
- An isopropoxycarbonyl group a tertiary butoxycarbonyl group, a benzoyl group, and the like.
- acyl group other than the “lower alkanoyl group” include those obtained by removing the “lower alkanoyl group” from the above-mentioned alkyl groups, and preferably include a lower alkoxycarbonyl group, c 6 — ⁇ Eh. And particularly preferably an isopropoxycarbonyl group, a tertiary butoxycarbonyl group, a benzoyl group, and the like.
- Suitable "lower alkoxy groups” include straight or branched ones such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tertiary butoxy, pentyloxy, hexyloxy and the like.
- cyclo (lower) alkyl cycloalkyl (c.-C 6) alkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, and the like cyclohexyl out.
- cyclo (lower) alkenyl can be exemplified (c 3 c s) Aruke two Honoré, e.g. Shikuropuro Bae Ninore, Shikurobuteninore, cyclopent two Honoré, and cyclohexenyl.
- Suitable “protected amino group” includes a conventional protected amino group protected with the above-mentioned acryl group and the like.
- Suitable “protected hydroxy groups” include substituted or unsubstituted arylmethyloxy groups (eg, benzyl, lower alkoxybenzyl, etc.), acyloxy groups, substituted silyloxy groups (eg, tertiary butyldiphenylsilyl, etc.), and the like.
- 6 1 u arylmethyloxy, lower alkoxycarbonyloxy, C —.
- the most preferred examples include a benzyloxy group, an isopropoxycarbonyloxy group, a tertiary butoxycarbonyloxy group, a benzoyloxy group, and the like.
- Suitable “lower alkanoyl groups” include formyl, acetyl, propanol, butanol, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanol, and hexanoyl. More preferred examples include And C 4 -C 4 alkanoyl group, and the like, and most preferred are an acetyl group and a propionyl group.
- esterified carboxy group examples include the following.
- esterified carboxy ester moieties include, for example, lower alkyl esters optionally having at least one suitable substituent (e.g., methyl ester, ethenole ester, propionyl).
- suitable substituent e.g., methyl ester, ethenole ester, propionyl
- lower alkanoyloxy (lower) Alkyl esters for example, acetomethyl ester, propionyloxymethyl ester, butylinoleoxymethyl ester, phenolinoleoxymethyl ester, bivaloyloxymethyl ester, hexanoinoleoxymethyl ester, Or 2—
- Asetokishetilesute 1— (or
- Lower alkoxycarbonyloxy (lower) alkyl esters [eg methoxycarbonyloxymethylester, ethoxycarbonyloxymethylester, propoxycanoleboninoleoxymethinoleestenole, tert-butoxycanoleponinoleoxymethyl ester, 1 — (Or 2—) methoxycarboninoleoxyethyl ester, 1- (or 2—) ethoxycarbonyloxyxetyl ester, 1— (or 2—1) isopropoxycarbonyloxyxethyl ester, etc.], phthalidylidene
- (Lower) alkyl esters or (5-lower alkyl 1-2-oxo-1,3-dioxol-14-yl) (lower) alkyl esters [for example, (5-methyl-1-oxo-1, 3-dioxole-1) 4-methyl) methyl ester, (5-ethyl-1, 2-oxo-1,3-dioxol-4-yl) methyl ester, (5-propyl-1 -2-oxo-1,3, dioxo-1-) Lower alkenyl esters (eg, vinyl esters, aryl esters, etc.); lower anoleskininoleestenoles (eg, ethininoleestenoles, propyninoleestenoles, etc.); at least one suitable substitution Al (lower) alkyl estenole which may have a group (for example, benzinole estenole, 4-methoxybenzinole estenole, 4- Benzyl
- lower alkyl ester group preferred examples include a lower alkyl ester group, and particularly preferred examples include an ethyl ester group.
- Suitable "lower alkylidene groups" include straight or branched ones such as methylidene, ethylidene, propylidene, isopropylidene, butylidene, pentylidene, hexylidene, methylmethylidene, ethylethylidene, propylidene and the like.
- the preferred “aroyl” is C II.
- Aroyl such as benzoyl, toluoyl, and naphthoyl.
- These reactions are carried out by reacting the starting compound with an appropriate amount of the compound (I) in an appropriate temperature range from room temperature to elevated temperature in a solvent that does not adversely affect the reaction, for example, methanol, tetrahydrofuran, or the like. , It can be carried out.
- the compounds (A) and (B) are known, for example, from JP-A-61-10590, and are known to have antitumor activity.
- the publication also describes a solvolysis reaction from compound (A) to compound (B) using sodium bicarbonate, but the yield is about 55%. Hard to say.
- Compound (A) has one or more asymmetric centers and may exist as an enantiomer or diastereomer, but in any case, it is used as a starting compound for a selective deacetylation reaction. It goes without saying that you can do it.
- Specific examples of the compound which can be used as the selective deacetylating agent of the present invention are listed below, but are not necessarily limited thereto.
- R 1, R ′ R 3 and R 4 have the same meanings as described above, and R 6 represents a hydroxy protecting group
- Compound (Ia) can be obtained by subjecting compound (H) to an elimination reaction of a hydroxy protecting group.
- This reaction can be usually performed by a conventional method such as solvolysis / hydrolysis or reduction.
- Solvolysis / hydrolysis is preferably carried out in the presence of a base or an acid.
- Preferred bases include alkali metal hydroxides (eg, sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxides (eg, magnesium hydroxide, calcium hydroxide, etc.), alkali metal hydrides (eg, sodium hydride).
- Alkali metal hydrides such as calcium hydride
- alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.
- alkali metal carbonates Eg, sodium carbonate, potassium carbonate, etc.
- alkaline earth metal carbonates eg, magnesium carbonate, calcium carbonate, etc.
- alkali metal bicarbonates eg, sodium bicarbonate, potassium bicarbonate, etc.
- Preferred acids include organic acids (eg, formic acid, acetic acid, propionic acid, trifluorophenolic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.) and inorganic acids (eg, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.) Can be mentioned. Acidic hydrolysis with trifluoroacetic acid is usually accelerated by the addition of a cation scavenger (eg, phenol, anisol, etc.).
- a cation scavenger eg, phenol, anisol, etc.
- This reaction is usually carried out in the presence of a conventional solvent that does not adversely influence the reaction, for example, alcohol (eg, methanol, ethanol, etc.) or water, but may contain dichloromethane, tetrahydrofuran, dioxane, acetone, or These mixtures may be further used as a solvent.
- a conventional solvent for example, alcohol (eg, methanol, ethanol, etc.) or water, but may contain dichloromethane, tetrahydrofuran, dioxane, acetone, or These mixtures may be further used as a solvent.
- Liquid bases or acids can also be used as solvents.
- the reaction temperature is not particularly limited, and the reaction is performed under cooling or heating.
- the reduction methods applicable to this elimination reaction include, for example, a metal (eg, zinc, zinc amalgam, etc.) or a salt of a chromium compound (eg, chromic chloride, acetic acid, etc.) and an organic or inorganic acid (eg, acetic acid, Reduction using a combination with propionic acid, hydrochloric acid, sulfuric acid, etc .; conventional metal catalysts such as palladium catalysts (eg palladium sponge, palladium black, palladium oxide, palladium charcoal, colloid palladium, palladium monosulfate, palladium monosulfate) Barium carbonate, palladium hydroxide charcoal, etc.), nickel catalyst (eg, reduced nickel, nickel oxide, Raney nickel, etc.), platinum catalyst (eg, platinum plate, platinum sponge, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.); hydrogen Sodium borohydride; hydrogen hydride And conventional catalytic reduction performed in the presence of luminous lithium.
- a metal
- the reaction is usually carried out in a conventional solvent that does not adversely affect the reaction, such as alcohol (eg, methanol, ethanol, propanol), water, dioxane, tetrahydrofuran, acetic acid, buffers (eg, phosphate buffer, acetate buffer). Etc.) or in a mixture thereof.
- a conventional solvent that does not adversely affect the reaction, such as alcohol (eg, methanol, ethanol, propanol), water, dioxane, tetrahydrofuran, acetic acid, buffers (eg, phosphate buffer, acetate buffer). Etc.) or in a mixture thereof.
- the reaction temperature is not particularly limited, and the reaction is usually performed under cooling or heating.
- the present invention will be described in more detail by way of examples, but is by no means limited to these.
- Toluene (60 ml) and hexane (60 ml) are added to the concentrated oil, and the mixture is stirred under ice-cooling for 2 hours to crystallize a reagent decomposition product.
- the crystals are filtered and washed with toluene (20 ml) and hexane (20 ml). Extract the target substance twice with 2N hydrochloric acid (80 ml and 20 ml), and wash the aqueous layer with diisopropyl ether (20 ml).
- Dichloromethane (100 ml) is added to the aqueous layer, and the pH is adjusted to 11 or more with aqueous sodium hydroxide solution.
- the crystals are dissolved in water (40 ml) and dichloromethane (80 ml), and the pH is adjusted to 10 or more with a sodium hydroxide aqueous solution. After liquid separation, the aqueous layer is further extracted with 20 ml of dichloromethane, and the combined organic layers are washed with saturated saline (20 ml).
- Example 11 A crude oil (31.2 g) of N- (2-piberidinoethyl) -N, 0-bis (tert-butoxycarbonyl) hydroxylamine is dissolved in a 4N solution of ethyl acetate monohydrochloride (170 ml) and stirred at room temperature. . The product separates during the course of the reaction and then crystallizes. After stirring at room temperature for 3 hours, the precipitated crystals are filtered. The obtained crystals are dried under reduced pressure to obtain N- (2-piberidinoethyl) hydroxylamine 'dihydrochloride as pale yellow crystals.
- isopropyl alcohol and toluene are added to the residue, and water is removed by repeating concentration under reduced pressure to obtain brown hygroscopic crystals.
- N- (2-piberidinoethyl) hydroxylamine dihydrochloride (18.5 g) as hygroscopic brown crystals.
- reaction mixture is extracted with THF (60 ml) and extracted again with THF (20 ml).
- the combined THF layer was washed with saturated saline (30 ml) and concentrated under reduced pressure to obtain N- (2-piberidinoethyl) -1-N, 0-dibenzoylhydroxylamine (23.9 g) as brown crystals.
- This is dissolved in methanol (60 ml) and stirred at room temperature for 4 hours.
- the reaction mixture is concentrated under reduced pressure, and toluene is added thereto for reconcentration, whereby crude crystals of N- (2-piberidinoethyl) -1-N-benzoylhydroxylamine (hereinafter referred to as compound (la)) are obtained.
- Toluene ( 30 ml ) is added to the suspension, followed by suspension crystallization, followed by filtration and drying to obtain compound (la) (14.6 g) as pale brown crystals.
- the separated saline layer was re-extracted with ethyl acetate (35 ml), and the organic layers were combined and washed with saturated saline (140 ml).
- the organic layer is concentrated (crystal precipitation), and methylene chloride (70 ml) is added for crystallization.
- Ethyl acetate (70 ml) and 10% saline (140 ml) are added to the reaction mixture for extraction, and the separated aqueous layer is re-extracted with ethyl acetate (35 ml). After combining the organic layers, wash with 10% saline (70ml). The separated saline layer was re-extracted with ethyl acetate (35 ml). After combining the organic layers, the mixture is washed with a saturated saline solution (140 ml).
- the reaction solution is concentrated under reduced pressure and crystallized from water.
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Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP00987704A EP1245550A1 (en) | 1999-12-27 | 2000-12-21 | Novel selective deacetylating agents |
JP2001549312A JP4945875B2 (ja) | 1999-12-27 | 2000-12-21 | 新規選択的脱アセチル化剤 |
AU24007/01A AU2400701A (en) | 1999-12-27 | 2000-12-21 | Novel selective deacetylating agents |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP37104099 | 1999-12-27 | ||
JP11/371040 | 1999-12-27 |
Publications (1)
Publication Number | Publication Date |
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WO2001047836A1 true WO2001047836A1 (fr) | 2001-07-05 |
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Application Number | Title | Priority Date | Filing Date |
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PCT/JP2000/009126 WO2001047836A1 (fr) | 1999-12-27 | 2000-12-21 | Nouveaux agents de desacetlylation selective |
Country Status (5)
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US (1) | US20030009030A1 (ja) |
EP (1) | EP1245550A1 (ja) |
JP (1) | JP4945875B2 (ja) |
AU (1) | AU2400701A (ja) |
WO (1) | WO2001047836A1 (ja) |
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FR2190430A1 (en) * | 1972-06-29 | 1974-02-01 | Ferlux | N-aminomethylhydroxamic acids - with antiinflammatory activity pre-pared by Mannich reaction |
JPS61173246A (ja) * | 1985-01-28 | 1986-08-04 | Fuji Photo Film Co Ltd | ハロゲン化銀写真感光材料の処理方法 |
JP2649855B2 (ja) * | 1990-04-12 | 1997-09-03 | 富士写真フイルム株式会社 | 拡散転写型ハロゲン化銀カラー感光材料 |
JPH08114884A (ja) * | 1994-08-25 | 1996-05-07 | Fuji Photo Film Co Ltd | ハロゲン化銀写真感光材料 |
JPH09304898A (ja) * | 1996-05-15 | 1997-11-28 | Fuji Photo Film Co Ltd | ハロゲン化銀カラー写真感光材料 |
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2000
- 2000-12-21 JP JP2001549312A patent/JP4945875B2/ja not_active Expired - Fee Related
- 2000-12-21 US US10/149,747 patent/US20030009030A1/en not_active Abandoned
- 2000-12-21 EP EP00987704A patent/EP1245550A1/en not_active Withdrawn
- 2000-12-21 WO PCT/JP2000/009126 patent/WO2001047836A1/ja not_active Application Discontinuation
- 2000-12-21 AU AU24007/01A patent/AU2400701A/en not_active Abandoned
Non-Patent Citations (2)
Title |
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GREHN L. ET AL.: "Selective cleavage of Boc-acylamides. A novel approach to deacylation of carboxamides", ACTA CHEM. SCAND., SER. B, vol. B41, no. 1, 1987, pages 18 - 23, XP002937355 * |
PAYARD M. ET AL.: "N-aminomethyl derivatives of some hydroxamic acids as antiinflammatory agents", EUR. J. MED. CHEM. - CHIM. THER., vol. 10, no. 2, 1975, pages 125 - 128, XP002937356 * |
Also Published As
Publication number | Publication date |
---|---|
JP4945875B2 (ja) | 2012-06-06 |
EP1245550A1 (en) | 2002-10-02 |
AU2400701A (en) | 2001-07-09 |
US20030009030A1 (en) | 2003-01-09 |
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