CN102482200A - Process for preparation of optically active ethyl 1-amino-2-ethenylcyclopropanecarboxylate - Google Patents
Process for preparation of optically active ethyl 1-amino-2-ethenylcyclopropanecarboxylate Download PDFInfo
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- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
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Abstract
A process for the preparation of optically active ethyl 1-amino-2-ethenylcyclopropanecarboxylate represented by formula (3), an enantiomer thereof, or acid addition salts of the same, which comprises a step of reacting a mixture containing the (1R, 2S) and (1S, 2R) isomers of ethyl 1-amino-2 -ethenylcyclopropanecarboxylate represented by formula (1) with an optically active tartranilic acid compound represented by general formula (2) to form a diastereomeric salt mixture, a step of separating one of the diastereomeric salts from the other thereof, and a step of treating each of the separated diastereomeric salts with either an acid or a base to decompose the diastereomeric salt. By this process, ethyl 1-amino-2 -ethenylcyclopropanecarboxylate with a high optical purity can be prepared efficiently.
Description
Technical field
The present invention relates to the method for manufacture of optically active 1-amino-2-vinyl cyclopropanecarboxylic acid ethyl ester or its acid salt and the midbody that is used for this method of manufacture.
Background technology
The method of manufacture of optically active 1-amino-2-vinyl cyclopropanecarboxylic acid ethyl ester is recorded in for example Journal of Organic Chemistry; The 70th volume; The 5869-5879 page or leaf; 2005, the method that known racemic modification with 1-amino-2-vinyl cyclopropanecarboxylic acid ethyl ester carries out the method for optical resolution through two toluoyls base-D-tartrate and carries out optical resolution through enzyme reaction.
But; Utilize in the tartaric optical resolution of two toluoyl base-D-, the optical purity of optically active 1-amino of gained-2-vinyl cyclopropanecarboxylic acid ethyl ester is 50～55%ee, and is not high; In addition; Utilize the optical resolution of enzyme reaction must the amino of 1-amino-2-vinyl cyclopropanecarboxylic acid ethyl ester be protected with tertbutyloxycarbonyl, exist process number to increase such problem, and until making the enzyme reaction completion need 9 day time; But also must in reaction mixture, replenish the such problem of enzyme in existing during this, not a high-efficiency method.
Summary of the invention
The present invention provides the method for manufacture of the optically active 2-vinyl cyclopropanecarboxylic acid ethyl ester that addresses the above problem.
That is, the present invention provides the invention that following (1)～(6) are put down in writing.
(1) the optically active 1-amino-2-vinyl cyclopropanecarboxylic acid ethyl ester shown in the formula (3) or the method for manufacture of its mirror image isomer or their acid salt,
It is characterized in that, comprise following operation:
Make (the 1R of the 1-amino-2-vinyl cyclopropanecarboxylic acid ethyl ester that contains shown in the formula (1); 2S) isomer and (1S; 2R) the reaction of the optically active aniline tartramide acid cpd shown in mixture of isomers and the formula (2) and obtain the operation of the mixture of diastereomeric salt
(in the formula (2); Ar representes to replace or non-substituted phenyl, this substituting group be 1～3 respectively independently carbonatoms be that 1～12 alkyl, carbonatoms are that 3～12 naphthenic base, carbonatoms are that 1～12 alkoxyl group, carbonatoms are 3～12 cycloalkyloxy, halogen atom, nitro, cyanic acid or trifluoromethyl.* represent unsymmetrical carbon.)
With one of them diastereomeric salt isolating operation from another diastereomeric salt,
Through isolated diastereomeric salt is handled the operation of decomposing diastereomeric salt with acid or alkali.
(2) according to (1) described method of manufacture, wherein, Ar is the 2-chloro-phenyl-.
(3) according to (1) or (2) described method of manufacture, wherein, 2 unsymmetrical carbons in above-mentioned optically active aniline tartramide acid cpd are the configuration into S.
(4) the optical resolution method of 1-amino-2-vinyl cyclopropanecarboxylic acid ethyl ester; It is characterized in that; Comprise (the 1R that makes the 1-amino-2-vinyl cyclopropanecarboxylic acid ethyl ester that contains shown in the formula (1); 2S) isomer and (1S, 2R) operation of the optically active aniline tartramide acid cpd reaction shown in mixture of isomers and the formula (2).
(in the formula (2); Ar representes to replace or non-substituted phenyl, this substituting group be 1～3 respectively independently carbonatoms be that 1～12 alkyl, carbonatoms are that 3～12 naphthenic base, carbonatoms are that 1～12 alkoxyl group, carbonatoms are 3～12 cycloalkyloxy, halogen atom, nitro, cyanic acid or trifluoromethyl.* represent unsymmetrical carbon.)
(5) (1R, 2S)-salt of the optically active aniline tartramide acid cpd shown in 1-amino-2-vinyl cyclopropanecarboxylic acid ethyl ester and the formula (2).
(in the formula (2); Ar representes to replace or non-substituted phenyl, this substituting group be 1～3 respectively independently carbonatoms be that 1～12 alkyl, carbonatoms are that 3～12 naphthenic base, carbonatoms are that 1～12 alkoxyl group, carbonatoms are 3～12 cycloalkyloxy, halogen atom, nitro, cyanic acid or trifluoromethyl.* represent unsymmetrical carbon.)
(6) (1R, 2S)-1-amino-2-vinyl cyclopropanecarboxylic acid ethyl ester with (2S, 3S)-2 '-salt of chloroaniline tartaroyl amino acid.
Embodiment
Below, the present invention is elaborated.
As (the 1R that contains the 1-amino shown in the formula (1)-2-vinyl cyclopropanecarboxylic acid ethyl ester; 2S) isomer and (1S; 2R) mixture of isomers is used as (1R, 2S) isomer and (1S usually; 2R) the racemic modification of isomer equal amount of mixture comprises wherein any mixture of isomers but also can use morely.Below, will contain the 1-amino shown in the formula (1)-2-vinyl Trimetylene-1-ethyl formate (1R, 2S) isomer with (1S, 2R) mixture of isomers is abbreviated as isomer mixture (1).
Isomeric compound (1) can be made according to the method for any known.For example; Can adopt Journal of Organic Chemistry; The 70th volume, 5869-5879 page or leaf, the method for being put down in writing in 2005; Will be in the presence of alkali, make N-phenylmethylene glycine ethyl ester and 1,1-(the N-phenylmethylene is amino)-2-vinyl cyclopropanecarboxylic acid ethyl ester of 4-two bromo-2-butylene reaction gained carry out s.t. to wait and make.Isomer mixture (1) with remove any acid the optically active aniline tartramide acid cpd shown in the formula (2) (below be abbreviated as optical activity aniline tartramide acid cpd (2)) when forming salt, preferably before itself and optical activity aniline tartramide acid cpd (2) are reacted, this salt is carried out alkaline purification.
In optical activity aniline tartramide acid cpd (2); Among the replacement that Ar is represented or the substituting group of non-substituted phenyl; As carbonatoms is 1～12 alkyl, for example can enumerate methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, hexyl, heptyl, octyl group, nonyl, decyl, undecyl, dodecyl; As carbonatoms is 3～12 naphthenic base, for example can enumerate cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group; As carbonatoms is 1～12 alkoxyl group, for example can enumerate methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, tert.-butoxy, pentyloxy, hexyloxy, heptan oxygen base, octyloxy, ninth of the ten Heavenly Stems oxygen base, last of the ten Heavenly stems oxygen base, undecane oxygen base, dodecyloxy; As carbonatoms is 3～12 cycloalkyloxy, for example can enumerate ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy, ring oxygen in heptan base, ring octyloxy; As halogen atom, can enumerate fluorine atom, chlorine atom, bromine atoms, iodine atom.Ar is preferably phenyl or chloro-phenyl-, and more preferably chloro-phenyl-further is preferably the 2-chloro-phenyl-.
In optical activity aniline tartramide acid cpd (2), 2 represented unsymmetrical carbons of * preferably are the S configuration or are the R configuration, more preferably are the S configuration.
The optical purity of optical activity aniline tartramide acid cpd (2) is preferably more than 90%ee (below, ee representes the enantiomorph excess rate), more preferably more than 95%ee, further preferably more than 98%ee, more than 99%ee.
Optical activity aniline tartramide acid cpd (2) can use commercially available article, also can use the compound that adopts method that JP2001-89431A put down in writing etc. to process.
The consumption of optical activity aniline tartramide acid cpd (2) is unrestricted; But when using racemic modification as isomer mixture (1); With respect to isomer mixture (1), be generally more than 0.5 mole times, consider from the viewpoint of yield and economy; Be preferably 0.5 mole times～2 moles doubly, more preferably 0.9 mole times～1.5 moles times.
Isomer mixture (1) preferably carries out in solvent with the reaction of optical activity aniline tartramide acid cpd (2).As said solvent, for example can enumerate aliphatic hydrocarbon solvents such as pentane, hexane, isohexane, heptane, isoheptane, octane, octane-iso, nonane, isononane, decane, isodecane, undecane, dodecyl, pentamethylene, hexanaphthene, methylcyclohexane, tertiary butyl hexanaphthene, sherwood oil; Benzene, toluene, ethylbenzene, isopropyl benzene, tert.-butylbenzene, YLENE, sym-trimethylbenzene, monochloro benzene, single fluorobenzene, α, α, α-trifluoromethylbenzene, 1,2-dichlorobenzene, 1,3-dichlorobenzene, 1,1,2, aromatic solvents such as 4-trichlorobenzene; THF, methyltetrahydrofuran, 1; 4-dioxane, Anaesthetie Ether, dipropyl ether, Di Iso Propyl Ether, dibutyl ether, diamyl ether, hexyl ether, diheptyl ether, dicaprylyl ether, t-butyl methyl ether, cyclopentyl-methyl ether, 1, ether solvents such as 2-glycol dimethyl ether, diethylene glycol dimethyl ether, methyl-phenoxide, diphenyl ether; Methyl alcohol; Ethanol; The 1-propyl alcohol; The 2-propyl alcohol; The 1-butanols; Isopropylcarbinol; The trimethyl carbinol; The 1-amylalcohol; The 2-amylalcohol; Primary isoamyl alcohol; The 1-hexanol; The 2-hexanol; Isohexyl alcohol; The 1-enanthol; The 2-enanthol; The 3-enanthol; Iso-heptanol; Ethylene glycol monomethyl ether; Ethylene glycol monoethyl ether; Ethylene glycol ether; The glycol monomethyl isopropyl ether; Ethylene glycol monobutyl ether; The glycol monomethyl isobutyl ether; The glycol monomethyl tertbutyl ether; Diethylene glycol monomethyl ether; Diethylene glycol monoethyl ether; Diethylene glycol monopropyl ether; The Diethylene Glycol monoisopropyl ether; Diethylene glycol monobutyl ether; Diethylene Glycol list isobutyl ether; Alcoholic solvents such as Diethylene Glycol list tertbutyl ether; Nitrile solvents such as acetonitrile, propionitrile, cyanobenzene; Methylene dichloride, trichloromethane, 1, chlorinated aliphatic hydrocarbon solvents such as 2-ethylene dichloride; Ester solvents such as methyl acetate, ETHYLE ACETATE, propyl acetate, isopropyl acetate, butylacetate, isobutyl acetate, tert.-butyl acetate, pentyl acetate, Isoamyl Acetate FCC, NSC 7323, methyl propionate, ethyl propionate, propyl propionate, isopropyl propionate; Ketone solvents such as acetone, methyl ethyl ketone, methyl propyl ketone, MIPK, methyl butyl ketone, MIBK, metacetone, ketopentamethylene, pimelinketone; DMSO 99.8MIN., tetramethylene sulfone, N, dinethylformamide, DMAC N,N, N; N-dimethyl propylene acid amides, N-Methyl pyrrolidone, gamma-butyrolactone, methylcarbonate, diethyl carbonate, ethylene carbonate, Texacar PC, 1; 3-dimethyl--2-imidazolone, 1,3-dimethyl--3,4; 5,6-tetrahydrochysene-2 (1H)-aprotic polar solvents such as pyridone; Water; Their mixture.Solvent is preferably aromatic solvent and the mixed solvent that is selected from least a solvent in ketone solvent, ester solvent, alcoholic solvent and the ether solvents; Be more preferably the mixed solvent of aromatic solvent and ketone solvent or alcoholic solvent; The mixed solvent of mixed solvent, toluene and the methyl ethyl ketone of mixed solvent, toluene and the acetone of further preferred toluene and ethanol mixed solvent, toluene and 2-propyl alcohol is preferably the mixed solvent of toluene and 2-propyl alcohol especially.
The consumption of solvent also is to decide according to the structure of employed solvent and optical activity aniline tartramide acid cpd (2), with respect to the isomer mixture (1) of 1kg, is preferably the ratio of 1～50L, more preferably the ratio of 3～30L.
The reaction of isomer mixture (1) and optical activity aniline tartramide acid cpd (2) also can also be carried out through solvent is mixed, in the mixture of gained, adds isomer mixture (1) with optical activity aniline tartramide acid cpd (2) through for example solvent being mixed with isomer mixture (1), in the mixture of gained, adds optical activity aniline tartramide acid cpd (2) and carry out.
Isomer mixture (1) is unrestricted with the temperature of reaction of optical activity aniline tartramide acid cpd (2), is preferably the boiling point of 0 ℃～solvent.
Can preferentially from the mixture of the diastereomeric salt that generates, separate out through in solvent, making side's diastereomeric salt, thereby it is separated from another diastereomeric salt.
Do not observe when separating out in the mixture of the diastereomeric salt of diastereomeric salt from solvent; Can add as crystal seed through side's diastereomeric salt preparation in advance; Cool off the solution of diastereomeric salt mixture then, thereby side's diastereomeric salt is preferentially separated out.
When confirming to separate out diastereomeric salt; Can solution directly be cooled off; But, cool off after preferably making the precipitate dissolving, thereby side's diastereomeric salt is preferentially separated out through heated soln for the optical purity that makes the diastereomeric salt of separating out improves; In the separating out of said diastereomeric salt, also can the side's diastereomeric salt that prepare in advance be used as crystal seed.The optical purity of crystal seed is high more good more, preferably more than 90%ee, more preferably more than 95%ee, further preferably more than 98%ee, more than 99%ee.
When the solution of diastereomeric salt mixture is heated, preferably be heated to the boiling point of 30 ℃～solvent.As processing under cooling, preferably be cooled to 0～25 ℃, for the optical purity that makes the diastereomeric salt of separating out improves, preferably cool off lentamente.
After side's diastereomeric salt is preferentially separated out, can handle like solid-liquid separation such as filtration, decants through embodiment and take out side's diastereomeric salt.After solid-liquid separation is handled, improve this point from the optical purity that makes diastereomeric salt and consider, preferably implement carrying out washing treatment.For said carrying out washing treatment, can use and the above-mentioned solvent phase of in the reaction of isomer mixture (1) and optical activity aniline tartramide acid cpd (2), mentioning solvent together.After the carrying out washing treatment, preferably carry out drying treatment.Drying treatment can be under normal pressure or reduced pressure, preferably carry out 20～80 ℃ scope.
The liquid that has carried out above-mentioned solid-liquid separation to handle and got contains another diastereomeric salt, can adopt ordinary method from liquid phase, another diastereomeric salt to be taken out.
Also can its optical purity further be improved through diastereomeric salt being carried out refinement treatment.
As refinement treatment, preferred recrystallization method.For example, can adopt following method to carry out refinement treatment: diastereomeric salt to be dissolved in the solvent, to cool off the method that the diastereomeric salt that refines is separated out; After making diastereomeric salt be dissolved in the solvent, drip the method that poor solvent is separated out the diastereomeric salt that refines; After making diastereomeric salt be dissolved in the solvent, distillation removes the method desolvate the diastereomeric salt that refines is separated out; Perhaps their combination.When refinement treatment, also can side's diastereomeric salt of preparation in advance be added as crystal seed.As the solvent that is used for refinement treatment, for example can enumerate alcoholic solvents such as methyl alcohol, ethanol, 1-propyl alcohol, 2-propyl alcohol, 1-butanols, isopropylcarbinol, the trimethyl carbinol, 1-amylalcohol, 2-amylalcohol, primary isoamyl alcohol, 1-hexanol, 2-hexanol, isohexyl alcohol, 1-enanthol, 2-enanthol, 3-enanthol, iso-heptanol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol ether, glycol monomethyl isopropyl ether, ethylene glycol monobutyl ether, glycol monomethyl isobutyl ether, glycol monomethyl tertbutyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, Diethylene glycol monopropyl ether, Diethylene Glycol monoisopropyl ether, diethylene glycol monobutyl ether, Diethylene Glycol list isobutyl ether, Diethylene Glycol list tertbutyl ether; THF, methyltetrahydrofuran, 1, the isothrausmatic ether solvents of 4-dioxane; Water, alcohols solvent or cyclic ether solvents, more preferably ethanol, 2-propyl alcohol or THF.The consumption of solvent can suitably be regulated according to employed solvent, with respect to the diastereomeric salt of 1kg, is preferably the ratio of 1～10L.Make diastereomeric salt dissolved temperature be preferably 0～80 ℃.As poor solvent, for example can enumerate aliphatic hydrocarbon solvents such as pentane, hexane, isohexane, heptane, isoheptane, octane, octane-iso, nonane, isononane, decane, isodecane, undecane, dodecyl, pentamethylene, hexanaphthene, methylcyclohexane, tertiary butyl hexanaphthene, sherwood oil; Benzene, toluene, ethylbenzene, isopropyl benzene, tert.-butylbenzene, YLENE, sym-trimethylbenzene, monochloro benzene, single fluorobenzene, α, α, α-trifluoromethylbenzene, 1; 2-dichlorobenzene, 1,3-dichlorobenzene, 1,2; The 3-trichlorobenzene, 1,2; Aromatic solvents such as 4-trichlorobenzene, aliphatic hydrocarbon solvent, more preferably heptane.The consumption of poor solvent can suitably be regulated according to the degree of separating out of refining diastereomeric salt.When through processing under cooling refining diastereomeric salt being separated out, preferably be cooled to 0～25 ℃, per 1 hour cooling temperature is preferably 3～10 ℃.
The diastereomeric salt of gained is a novel cpd thus; Be preferably (1R, 2S)-1-amino-2-vinyl cyclopropanecarboxylic acid ethyl ester with have (2S, 3S) salt of the optical activity aniline tartramide acid cpd (2) of absolute configuration, perhaps (1S; 2R)-1-amino-2-vinyl cyclopropanecarboxylic acid ethyl ester with have (a 2R; 3R) the salt of the optical activity aniline tartramide acid cpd (2) of absolute configuration, more preferably (1R, 2S)-1-amino-2-vinyl cyclopropanecarboxylic acid ethyl ester with have (a 2S; 3S) the salt of the optical activity aniline tartramide acid cpd (2) of absolute configuration; Further be preferably (1R, 2S)-1-amino-2-vinyl cyclopropanecarboxylic acid ethyl ester with (2S, 3S)-2 '-salt of chloroaniline tartaroyl amino acid.
Can be through the diastereomeric salt of gained be handled optically active 1-amino-2-vinyl cyclopropanecarboxylic acid ethyl ester or its mirror image isomer or their acid salt shown in the acquisition formula (3) with acid or alkali.Below, the optically active 1-amino-2-vinyl cyclopropanecarboxylic acid ethyl ester shown in the formula (3) or its mirror image isomer or their acid salt are write a Chinese character in simplified form into optical activity aminocompound (3).
The acidity of the acid of processing diastereomeric salt as said acid, for example can be enumerated mineral acids such as hydrochloric acid, phosphoric acid, sulfuric acid generally than optical activity aniline tartramide acid cpd (2) height; Organic acids such as tosic acid, Phenylsulfonic acid, camphorsulfonic acid.Acid is hydrochloric acid or sulfuric acid preferably.These acid can be used separately, also can with after the solvent stated use.
With respect to diastereomeric salt, the consumption of acid is generally more than 1 mole times.
The s.t. of diastereomeric salt is carried out in solvent usually.As said solvent, for example can enumerate aliphatic hydrocarbon solvents such as pentane, hexane, isohexane, heptane, isoheptane, octane, octane-iso, nonane, isononane, decane, isodecane, undecane, dodecyl, pentamethylene, hexanaphthene, methylcyclohexane, tertiary butyl hexanaphthene, sherwood oil; Benzene, toluene, ethylbenzene, isopropyl benzene, tert.-butylbenzene, YLENE, sym-trimethylbenzene, monochloro benzene, single fluorobenzene, α, α, α-trifluoromethylbenzene, 1,2-dichlorobenzene, 1,3-dichlorobenzene, 1,1,2, aromatic solvents such as 4-trichlorobenzene; THF, methyltetrahydrofuran, 1; 4-dioxane, Anaesthetie Ether, dipropyl ether, Di Iso Propyl Ether, dibutyl ether, diamyl ether, hexyl ether, diheptyl ether, dicaprylyl ether, t-butyl methyl ether, cyclopentyl-methyl ether, 1, ether solvents such as 2-glycol dimethyl ether, diethylene glycol dimethyl ether, methyl-phenoxide, diphenyl ether; Methyl alcohol; Ethanol; The 1-propyl alcohol; The 2-propyl alcohol; The 1-butanols; Isopropylcarbinol; The trimethyl carbinol; The 1-amylalcohol; The 2-amylalcohol; Primary isoamyl alcohol; The 1-hexanol; The 2-hexanol; Isohexyl alcohol; The 1-enanthol; The 2-enanthol; The 3-enanthol; Iso-heptanol; Ethylene glycol monomethyl ether; Ethylene glycol monoethyl ether; Ethylene glycol ether; The glycol monomethyl isopropyl ether; Ethylene glycol monobutyl ether; The glycol monomethyl isobutyl ether; The glycol monomethyl tertbutyl ether; Diethylene glycol monomethyl ether; Diethylene glycol monoethyl ether; Diethylene glycol monopropyl ether; The Diethylene Glycol monoisopropyl ether; Diethylene glycol monobutyl ether; Diethylene Glycol list isobutyl ether; Alcoholic solvents such as Diethylene Glycol list tertbutyl ether; Nitrile solvents such as acetonitrile, propionitrile, cyanobenzene; Ester solvents such as ETHYLE ACETATE, propyl acetate, isopropyl acetate, butylacetate, isobutyl acetate, tert.-butyl acetate, pentyl acetate, Isoamyl Acetate FCC; Ketone solvents such as acetone, methyl ethyl ketone, MIPK, MIBK, ketopentamethylene, pimelinketone; Methylene dichloride, trichloromethane, 1, chlorinated aliphatic hydrocarbon solvents such as 2-ethylene dichloride; Carboxylic acid solvents such as formic acid, acetate, propionic acid; Water; Their mixture.Solvent is preferably the mixed solvent of aromatic solvent and ketone solvent or alcoholic solvent, more preferably the mixed solvent of aromatic solvent and alcoholic solvent.With respect to the diastereomeric salt of 1kg, the consumption of solvent is preferably the ratio of 1～50L, more preferably the ratio of 3～30L.
The s.t. of diastereomeric salt can be through for example carrying out diastereomeric salt and solvent to wherein adding acid.Treatment temp is preferably 0～40 ℃, more preferably 0～30 ℃.Treatment time is unrestricted, is preferably 1 minute～24 hours.
In the mixture that diastereomeric salt gets through s.t., optical activity aminocompound (3) is when separating out as acid salt, can handle and takes out this acid salt through this acid salt being applied for example solid-liquid separation such as filtration, decant.Acid salt separate out when insufficient, when acid salt is not separated out; Can apply concentration for example through mixture, acid salt separated out, and can handle and take out this acid salt through the acid salt of separating out being applied for example solid-liquid separation such as filtration, decant with the combination treatment or the processing under cooling of the solvent that is difficult to dissolve this salt to gained.The acid salt that takes out also can be made with extra care through for example recrystallization etc., also can with after the alkaline purification of the diastereomeric salt stated likewise optical activity aminocompound (3) is taken out as free alkali.
As the object lesson of acid salt, can enumerate the additive salt of hydrochloric acid, phosphoric acid, sulfuric acid, tosic acid, Phenylsulfonic acid and camphorsulfonic acid.
Handle the filtrating that gets through above-mentioned solid-liquid separation and contain optical activity aniline tartramide acid cpd (2), can adopt ordinary method from this filtrating, to take out optical activity aniline tartramide acid cpd (2), be used further to the present invention.
As handling the employed alkali of diastereomeric salt, for example can enumerate alkali metal hydroxides such as Pottasium Hydroxide, sodium hydroxide; Alkaline carbonate such as yellow soda ash, salt of wormwood; Alkali metal alcoholates such as sodium methylate, sodium ethylate, potassium methylate, potassium ethylate; Amine compound such as triethylamine, diethylamine.Alkali preferred alkali metal hydroxide, more preferably sodium hydroxide.Alkali can use separately, also can with after the solvent stated use.
With respect to diastereomeric salt, the consumption of alkali is generally more than 1 mole times.
The alkaline purification of diastereomeric salt is preferably carried out in solvent.As said solvent, for example can enumerate alcoholic solvents such as methyl alcohol, ethanol, 2-propyl alcohol, 1-propyl alcohol, 1-butanols; Anaesthetie Ether, t-butyl methyl ether, methyl-isobutyl ether, Di Iso Propyl Ether, methylcyclopentyl ether, 1, ether solvents such as 2-Methylal(dimethoxymethane); Aromatic solvents such as toluene, YLENE, chlorobenzene; Aliphatic hydrocarbon solvent such as hexane, hexanaphthene; Ketone solvent such as methyl ethyl ketone, MIBK; Ester solvent such as ETHYLE ACETATE, tert.-butyl acetate; Halogenation aliphatic hydrocarbon solvents such as methylene dichloride; Water; Their mixture.Solvent is preferably aromatic solvent, alcoholic solvent or water or their mixed solvent, more preferably toluene or water or their mixed solvent.When using mineral alkalis such as alkali metal hydroxide, alkaline carbonate, more preferably make water or organic solvent (for example above-mentioned ether solvents, aromatic solvent, aliphatic hydrocarbon solvent, ketone solvent, ester solvent, halon solvent) that will be low mix use with water separately with the water dissolubility as alkali.
With respect to the diastereomeric salt of 1kg, the consumption of solvent is preferably the ratio of 1～50L, more preferably the ratio of 3～30L.
The alkaline purification of diastereomeric salt can be through for example with diastereomeric salt and solvent, carry out to wherein adding alkali.Treatment temp is preferably 0～60 ℃, more preferably 10～30 ℃.Treatment time is unrestricted, is preferably 1 minute～24 hours.
The alkaline purification of diastereomeric salt particularly can adopt for example following method to carry out.
In the mixture of water and diastereomeric salt, add alkali; Make the water layer of mixture be alkalescence (preferably more than pH8.5); In the mixture of gained, add and the low organic solvent of water dissolubility, carry out separatory and handle, can obtain to contain the organic layer of optical activity aminocompound (3) thus.After as required organic layer being washed processing, concentrate and can optical activity aminocompound (3) emanated out as free alkali.Adopt alkali metal alcoholates as alkali, when adopting alcoholic solvent as solvent; An alkali metal salt of optical activity aniline tartramide acid cpd (2) is separated out; Filter this precipitate; Solution to gained carries out concentration, can optical activity aminocompound (3) emanated out as free alkali thus.The optical activity aminocompound (3) of gained can be made with extra care through implementing refinement treatment such as rectifying, column chromatography.Optical activity aminocompound (3) also can be used as the acid salt taking-up with acid arbitrarily.
Handle the water layer that gets through above-mentioned separatory and contain optical activity aniline tartramide acid cpd (2), can adopt ordinary method from this water layer, to take out optical activity aniline tartramide acid cpd (2), be used further to the present invention.In addition, also can adopt ordinary method from an alkali metal salt of the above-mentioned optical activity aniline tartramide acid cpd (2) that leaches, to take out optical activity aniline tartramide acid cpd (2), be used further to the present invention.
The optical purity of the optical activity aminocompound (3) that obtains thus also depends on the optical purity of employed optical activity aniline tartramide acid cpd (2); It is preferably more than 80%ee; More preferably more than 95%ee; Further preferably more than 98%ee, more than 99%ee.
Embodiment
Below, through embodiment the present invention is described in further detail, but the present invention is not limited to these embodiment.
Reference example 1
(E)-manufacturing of N-phenylmethylene glycine ethyl ester
41.4g (297mmol) glycine ethyl ester hydrochloride is mixed with 129g toluene, at room temperature add the N-Methyl pyrrolidone of 19.5g.In the mixture of gained, drip 30.0g (283mmol) phenyl aldehyde, then, drip 31.5g (297mmol) trimethyl orthoformate.After being added dropwise to complete, the mixture of gained is adjusted to 15 ℃, wherein drips the mixing solutions of 31.5g (311mmol) triethylamine and 15.9g toluene with 40 fens clockwise.After being added dropwise to complete, stirred 4 hours in 15 ℃.Reaction mixture is cooled to 8 ℃, drips the water of 84g.After being added dropwise to complete, stir after 20 minutes, carry out separatory, wash the organic layer of gained with 20% salt solution 57g.Behind the dried over mgso organic layer, underpressure distillation removes desolvates, thus obtained (E)-N-phenylmethylene glycine ethyl ester of 127g toluene solution (the pure article 51.1g of (E)-N-phenylmethylene glycine ethyl ester, 267mmol).Yield is 95%.
Reference example 2
The manufacturing of 1-amino-2-vinyl cyclopropanecarboxylic acid ethyl ester racemic modification
To 1 of 50.0g (234mmol), (purity 97%, the t-butyl methyl ether of adding 294g is cooled to 10 ℃ while stirring in the mixture of the lithiumbromide of trimethyl carbinol lithium 538mmol), 0.041g (0.47mmol) for 4-two bromo-2-butylene, 44.4g.(the pure article 49.1g of (E)-N-phenylmethylene glycine ethyl ester 257mmol), makes its reaction 14 hours in 10 ℃ with the toluene solution that in the mixture of gained, dripped (E)-N-phenylmethylene glycine ethyl ester of the 123g of gained in the reference example 1 in 4 hours.After the reaction, at 10 ℃ of 10% aqueous ammonium chloride solutions that in mixture, drip 100g.After being added dropwise to complete, stir after 20 minutes, carry out separatory, wash the organic layer of gained with 10% aqueous ammonium chloride solution of 100g.In room temperature flowed into the water of 67.5g in organic layer after, 35% aqueous hydrochloric acid with dripping 24.4g in 1 hour after 3 hours, carried out separatory in stirring at room, obtains water layer.On the other hand, in organic layer, add 0.5% aqueous hydrochloric acid of 42.6g, extract again.Merge the water layer of gained, thus obtained containing 1-amino-2-vinyl cyclopropanecarboxylic acid ethyl ester racemic modification aqueous solution 196g (the 1-amino-pure article 27.3g of 2-vinyl cyclopropanecarboxylic acid ethyl ester, 194mmol).By 1,4-two bromo-2-butylene and yield be 83%.
(the pure article 18.2g of 1-amino-2-vinyl cyclopropanecarboxylic acid ethyl ester 129mmol), adds the toluene of 73.3g in minute aqueous solution of taking-up from the 196g aqueous solution of gained, to divide taking-up 131g.After this mixture limit of stirring, limit is cooled to 15 ℃, drip 48% aqueous sodium hydroxide solution 13.6g (sodium hydroxide 164mmol).After being added dropwise to complete, stirred 30 minutes, carry out separatory, behind minute taking-up organic layer, the toluene that in the water layer of gained, flows into 73.3g extracts again.Merge the organic layer of gained, carry out drying with sal epsom, thus obtained containing 1-amino-2-vinyl cyclopropanecarboxylic acid ethyl ester racemic modification toluene solution 187g (the pure article 19.9g of 1-amino-2-vinyl cyclopropanecarboxylic acid ethyl ester, 128mmol).By 1,4-two bromo-2-butylene and yield be 82%.
Embodiment 1
(1R, 2S)-1-amino-2-vinyl cyclopropanecarboxylic acid ethyl ester (2S, 3S)-2 '-manufacturing of chloroaniline tartramide hydrochlorate
(the pure article 19.9g of 1-amino-2-vinyl cyclopropanecarboxylic acid ethyl ester flows into the 2-propyl alcohol of 8.0g in 128mmol), stirs in the toluene solution of room temperature 187g of gained in reference example 2.In the gained mixture, add (2S in room temperature; 3S)-2 '-chloroaniline tartaroyl amino acid 17.5g (67.3mmol; With respect to 1-amino-2-vinyl cyclopropanecarboxylic acid ethyl ester is 0.52 mole doubly), add the 0.01g optical purity more than 99%ee (1R, 2S)-1-amino-2-vinyl cyclopropanecarboxylic acid ethyl ester (2S; 3S)-2 '-chloroaniline tartramide hydrochlorate as crystal seed after, stirred 30 minutes.In room temperature in the slurry of gained, add (2S, 3S)-2 '-chloroaniline tartaroyl amino acid 17.5g (67.3mmol, with respect to 1-amino-2-vinyl cyclopropanecarboxylic acid ethyl ester be 0.52 mole doubly), in stirring at room 20 hours.Filter the mixture of gained in room temperature, wash the crystal that leaches with the mixed solvent of the 2-propyl alcohol of the toluene of 10g and 0.50g.Crystal to washing carries out drying under reduced pressure, thus obtained 24.2g (58.3mmol) (1R, 2S)-1-amino-2-vinyl cyclopropanecarboxylic acid ethyl ester (2S, 3S)-2 '-chloroaniline tartramide hydrochlorate.Yield is 46%.
(1R with gained; 2S)-1-amino-2-vinyl cyclopropanecarboxylic acid ethyl ester (2S; 3S)-2 '-part of chloroaniline tartramide hydrochlorate handles with diethylamine under following optical purity analysis condition; Confirmed to obtain (1R, 2S)-optical purity of 1-amino-2-vinyl cyclopropanecarboxylic acid ethyl ester.Optical purity is 88%ee.To as diastereomeric salt (1R, 2S)-1-amino-2-vinyl cyclopropanecarboxylic acid ethyl ester (2S, 3S)-2 '-chloroaniline tartramide hydrochlorate carries out diethylamine to be handled, obtain thus (1R, 2S)-1-amino-2-vinyl cyclopropanecarboxylic acid ethyl ester.
24.2g (1R from gained; 2S)-1-amino-2-vinyl cyclopropanecarboxylic acid ethyl ester (2S; 3S)-2 '-and divide to take out 17.3g (41.7mmol) among the chloroaniline tartramide hydrochlorate, in room temperature flows into 34.6g ethanol in the crystal that branch takes out after, be heated to 62 ℃ and make dissolution of crystals.After the solution of gained is cooled to 58 ℃; Be (the 1R more than the 99%ee with optical purity; 2S)-and 1-amino-2-vinyl cyclopropanecarboxylic acid ethyl ester (2S, 3S)-2 '-chloroaniline tartramide hydrochlorate (optical purity＞, stir and made its pulp in 20 minutes 99%ee) as behind the crystal seed inoculation 0.01g.In 57 ℃ of heptane with 2 hours dropping 34.6g in this slurry.After being added dropwise to complete, be cooled to 15 ℃ with 10 ℃/hour speed of cooling, stirred 12 hours in 15 ℃ with 4.5 hours.Filter the crystal that leaches with the washing of the mixed solvent of 8.6g ethanol and 8.6g heptane in 15 ℃ of slurries to gained.Crystal to gained carries out drying under reduced pressure, obtained thus (1R, 2S)-1-amino-2-vinyl cyclopropanecarboxylic acid ethyl ester (2S, 3S)-2 '-chloroaniline tartramide hydrochlorate 14.0g (33.8mmol).The recrystallization yield is 81%.The total recovery that is got by 1-amino-2-vinyl cyclopropanecarboxylic acid ethyl ester is 37%.Through operation same as described above, confirmed (1R, 2S)-optical purity of 1-amino-2-vinyl cyclopropanecarboxylic acid ethyl ester.Optical purity＞99%ee.
< optical purity analysis condition >
Chromatographic column: CHIRALCEL (registered trademark) AD-RH (4.6 * 150mm, 5 μ m)
Moving phase: A=0.1% diethylamine-water, B=0.1% diethylamine-methyl alcohol, A/B=60/40
Flow: 0.7mL/ minute
Detector: UV215nm
RT: (1R, 2S) type=6.7 minute, (1S, 2R) type=10.8 minute
(1R, 2S)-1-amino-2-vinyl cyclopropanecarboxylic acid ethyl ester (2S, 3S)-2 '-chloroaniline tartramide hydrochlorate
1H-NMR(DMSO-d
6，400MHz)δppm；9.42(1H，S)，8.36(1H，dd，J＝1.5，7.8Hz)，7.52(1H，dd，J＝1.5，8.3Hz)，7.39-7.30(1H，m)，7.16-7.08(1H，m)，5.64-5.53(1H，m)，5.22(1H，?dd，J＝2.0，17.1Hz)，5.02(1H，dd，J＝2，0，10.3Hz)，4.46(1H，d，J＝2，0Hz)，436(1H，d，J＝2.0Hz)，4.13-4.04(2H，m?)，2.03-1.95(1H，m)，1.43(1H，dd，J＝4.9，7.3Hz)，1.32(1H，dd，J＝4.9，9.3Hz)，1.20(3H，t，J＝6.8Hz)
13C-NMR?(DMSO?-d
6，100MHz)δppm：173.4，172.0，170.6，134.9，134.1，129.2，127.8，124.8，122.2，120.6，116.4，73.5，71.8，60.6，42.0，34.0，21.8，14.2
Fusing point: 123,1 ℃
(1R, 2S)-manufacturing of 1-amino-2-vinyl cyclopropanecarboxylic acid ethyl ester Hemisulphate
Will be by (the 1R of the 12.7g (30.7mmol) of recrystallization gained; 2S)-1-amino-2-vinyl cyclopropanecarboxylic acid ethyl ester (2S; 3S)-2 '-chloroaniline tartramide hydrochlorate mixes with the toluene of 31.8g; After cooling off this mixture to 14 ℃, drip make 1.29g dissolution of sodium hydroxide in 50.9g water and the aqueous solution.After being added dropwise to complete, in the mixture of gained, add 6.4g water, after 30 minutes, carry out separatory, divide and take out organic layer in 13 ℃ of stirrings.In the water layer of gained, add the toluene of 25.5g, extract again.The organic layer that merges gained, this organic layer of 10% aqueous sodium carbonate washing with 12.7g carries out drying with sal epsom to the organic layer that washs.Organic layer is cooled to 11 ℃ stirs, with the mixed solution that in this organic layer, dripped 1.45g (14.2mmol) sulfuric acid and 12.7g cyclopentyl-methyl ether in 3.5 hours.In 10 ℃ stirred the mixture 11 hours after, the slurry of gained is cooled to 3 ℃, further stirred 3.5 hours.Cross filter pulps in 3 ℃, wash the crystal that leaches with the mixed solvent of 6.4g toluene and 1.3g cyclopentyl-methyl ether.Crystal to gained carries out drying under reduced pressure, obtained thus (1R, 2S)-1-amino-2-vinyl cyclopropanecarboxylic acid ethyl ester Hemisulphate.Yield is 92%.Operation through same as described above confirmed (1R, 2S)-optical purity of 1-amino-2-vinyl cyclopropanecarboxylic acid ethyl ester.Optical purity＞99%.
1H-NMR?(CD
3OD，400MHz)δppm；5.88-5.75(1H，m)，5.38(1H，dd，J＝1.5，17.1Hz)，517(1H，dd，J＝1.5，10.3Hz).4.32-4.22(2H.q.J?＝6.8Hz)，2.56-2.47(1H.m).1.86(1H，dd.J＝6.4，10.2Hz)，1.70(1H，dd，J＝6，4，8.3Hz).1.30(3H，t，J＝6，8Hz)
13C-NMR(CD
3OD，100MHz)δppm，169.0，133.3，119.6，63.5，41.2，31.6，20.0，14.5
Utilizability on the industry
According to the present invention, can be with high-optical-purity and make useful optical activity 1-amino-2-vinyl cyclopropanecarboxylic acid ethyl esters such as synthetic intermediate efficiently as antiviral drug.
Claims (6)
1. the optically active 1-amino-2-vinyl cyclopropanecarboxylic acid ethyl ester shown in the formula (3) or the method for manufacture of its mirror image isomer or their acid salt,
It is characterized in that, comprise following operation:
Make (the 1R of the 1-amino-2-vinyl cyclopropanecarboxylic acid ethyl ester that contains shown in the formula (1); 2S) isomer and (1S; 2R) the reaction of the optically active aniline tartramide acid cpd shown in mixture of isomers and the formula (2) and generate the operation of the mixture of diastereomeric salt
In the formula (2); Ar representes to replace or non-substituted phenyl; This substituting group be 1～3 respectively independently carbonatoms be that 1～12 alkyl, carbonatoms are that 3～12 naphthenic base, carbonatoms are that 1～12 alkoxyl group, carbonatoms are 3～12 cycloalkyloxy, halogen atom, nitro, cyanic acid or trifluoromethyl; * represent unsymmetrical carbon
With one of them diastereomeric salt isolating operation from another diastereomeric salt,
Through isolating diastereomeric salt is handled the operation of decomposing diastereomeric salt with acid or alkali.
2. method of manufacture according to claim 1, wherein, Ar is the 2-chloro-phenyl-.
3. method of manufacture according to claim 1 and 2, wherein, 2 unsymmetrical carbons in optically active aniline tartramide acid cpd are the S configuration.
4.1-the optical resolution method of amino-2-vinyl cyclopropanecarboxylic acid ethyl ester; It is characterized in that; Comprise (the 1R that makes the 1-amino-2-vinyl cyclopropanecarboxylic acid ethyl ester that contains shown in the formula (1); 2S) isomer and (1S, 2R) operation of the optically active aniline tartramide acid cpd reaction shown in mixture of isomers and the formula (2);
In the formula (2); Ar representes to replace or non-substituted phenyl; This substituting group be 1～3 respectively independently carbonatoms be that 1～12 alkyl, carbonatoms are that 3～12 naphthenic base, carbonatoms are that 1～12 alkoxyl group, carbonatoms are 3～12 cycloalkyloxy, halogen atom, nitro, cyanic acid or trifluoromethyl, * representes unsymmetrical carbon.
5. (1R, 2S)-salt of the optically active aniline tartramide acid cpd shown in 1-amino-2-vinyl cyclopropanecarboxylic acid ethyl ester and the formula (2),
In the formula (2); Ar representes to replace or non-substituted phenyl; This substituting group be 1～3 respectively independently carbonatoms be that 1～12 alkyl, carbonatoms are that 3～12 naphthenic base, carbonatoms are that 1～12 alkoxyl group, carbonatoms are 3～12 cycloalkyloxy, halogen atom, nitro, cyanic acid or trifluoromethyl, * representes unsymmetrical carbon.
(1R, 2S)-1-amino-2-vinyl Trimetylene-1-ethyl formate with (2S, 3S)-2 '-salt of chloroaniline tartaroyl amino acid.
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| JP2009193914A JP5476859B2 (en) | 2009-08-25 | 2009-08-25 | Process for producing optically active ethyl 1-amino-2-ethenylcyclopropane-1-carboxylate or acid addition salt thereof, and intermediate used in the process |
| JP2009-193914 | 2009-08-25 | ||
| PCT/JP2010/063950 WO2011024691A1 (en) | 2009-08-25 | 2010-08-12 | Process for preparation of optically active ethyl 1-amino-2-ethenylcyclopropanecarboxylate |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1315965A (en) * | 1998-08-10 | 2001-10-03 | 贝林格尔·英格海姆加拿大有限公司 | Hepatitis C inhibitor peptides |
| JP2006282606A (en) * | 2005-04-01 | 2006-10-19 | Sumitomo Chemical Co Ltd | Method of crystallizing (3s,4r)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine(+)-2'-chlorotartranyl acid monohydrate |
| JP2006282607A (en) * | 2005-04-01 | 2006-10-19 | Sumitomo Chemical Co Ltd | Purification method of (3s, 4r)-trans-4-(4-fluorophenyl)-3-hydroxymethyl piperidine (+)-2'-chlorotartranyl acid monohydrate |
| JP2006282605A (en) * | 2005-04-01 | 2006-10-19 | Sumitomo Chemical Co Ltd | Preparation method of (3s, 4r)-trans-4-(4-fluorophenyl)-3-hydroxymethyl piperidine (+)-2'-chlorotartranyl acid monohydrate and method for recovering optical resoluting agent |
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| JP4029992B2 (en) * | 1997-02-14 | 2008-01-09 | 大東化学株式会社 | Production of tartranic acid |
| JP3257779B2 (en) * | 1999-09-16 | 2002-02-18 | 住化ファインケム株式会社 | Method for producing tartanyl acids |
| JP4406482B2 (en) * | 1999-09-28 | 2010-01-27 | 株式会社デ・ウエスタン・セラピテクス研究所 | Process for producing optically active 2-aminocyclohexanol derivative |
| JP3780787B2 (en) * | 1999-11-09 | 2006-05-31 | 住友化学株式会社 | Method for precipitation of diastereomeric crystals |
| JP2004051604A (en) * | 2002-07-24 | 2004-02-19 | Sumitomo Chem Co Ltd | Production method of optically active 2-amino-2-(2-naphthyl)ethanols and intermediate thereof |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1315965A (en) * | 1998-08-10 | 2001-10-03 | 贝林格尔·英格海姆加拿大有限公司 | Hepatitis C inhibitor peptides |
| JP2006282606A (en) * | 2005-04-01 | 2006-10-19 | Sumitomo Chemical Co Ltd | Method of crystallizing (3s,4r)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine(+)-2'-chlorotartranyl acid monohydrate |
| JP2006282607A (en) * | 2005-04-01 | 2006-10-19 | Sumitomo Chemical Co Ltd | Purification method of (3s, 4r)-trans-4-(4-fluorophenyl)-3-hydroxymethyl piperidine (+)-2'-chlorotartranyl acid monohydrate |
| JP2006282605A (en) * | 2005-04-01 | 2006-10-19 | Sumitomo Chemical Co Ltd | Preparation method of (3s, 4r)-trans-4-(4-fluorophenyl)-3-hydroxymethyl piperidine (+)-2'-chlorotartranyl acid monohydrate and method for recovering optical resoluting agent |
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| PIERRE L.BEAULIEU,ET AL.: "Synthesis of (1R,2S)-1-Amino-2-vinylcyclopropanecarboxylic Acid (Vinyl-ACCA) Derivatives: Key Intermediates for the Preparation of Inhibitors of the Hepatitis C Virus NS3 Protease", 《J.ORG.CHEM.》, vol. 70, no. 15, 17 June 2005 (2005-06-17), pages 5869 - 5879, XP002686607, DOI: doi:10.1021/JO050468Q * |
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