CN1747932A - Process for preparing pyridine-substituted amino ketal derivatives - Google Patents
Process for preparing pyridine-substituted amino ketal derivatives Download PDFInfo
- Publication number
- CN1747932A CN1747932A CNA2004800034784A CN200480003478A CN1747932A CN 1747932 A CN1747932 A CN 1747932A CN A2004800034784 A CNA2004800034784 A CN A2004800034784A CN 200480003478 A CN200480003478 A CN 200480003478A CN 1747932 A CN1747932 A CN 1747932A
- Authority
- CN
- China
- Prior art keywords
- formula
- ion
- acetylpyridine
- hydroxide
- processing step
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- 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
- C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
-
- 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
- C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
-
- 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
- C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
- C07D213/46—Oxygen atoms
- C07D213/50—Ketonic radicals
-
- 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
- C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
- C07D213/46—Oxygen atoms
- C07D213/51—Acetal radicals
-
- 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
- C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
- C07D213/53—Nitrogen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Catalysts (AREA)
Abstract
The present invention relates to an efficient process for preparing derivatives of 1-(pyridinyl)-1, 1-dialkoxy-2-aminoethane of the formula (I), with which compounds of the formula (I) can be prepared in high purity and yield and in the form of the free base without isolating the acetylpyridine oxime of the formula (XI) which is a critical product from a safety point of view as a solid.
Description
The invention provides the method for the dialkoxy ethylamine derivative that the pyridyl of a kind of preparation formula (I) replaces and intermediate in the methods of the invention.
Formula (I) compound is the intermediate in the preparation active constituents of medicine.For example United States Patent (USP) 5,792, and 871 have described wherein the pyridine group is substituted and R ' is (C at 3
1-C
3) derivative synthetic of formula (I) compound of alkyl.According to US 5,792,871, can begin to obtain formula (II) compound by these derivatives.
In addition, formula (I) compound as the structural unit of the Pyridinylimidazoles derivative of preparation formula (III) (J.Am.Soc., 1938,753-755):
R wherein " be H, SH.
The Pyridinylimidazoles derivative of formula (III) is used to prepare new macrolide antibiotic again, for example Ketek (US 5,635,485).
The currently known methods of preparation formula (I) compound is based on the effect of the p-toluenesulfonic esters of alkali metal alcohol salt pair ketoxime in alcoholic solution, for example the amino ketal derivatives of formula (I) is present in (F.M ller:Amine durch Umlagerungsreaktionen (Neber-Umlagerung) [amine (Neber reaction) that rearrangement reaction generates] in the preparation of cyclic amino ketone with intermediate, Houben-Weyl 11/1:Stickstoffverbindungen II[nitrogen compound II] (1957), the 903-905 page or leaf).
The 1-(pyridyl)-1 of formula (I), the preparation of 1-dialkoxy-2-ethylamine derivative is described in United States Patent (USP) 5,792, in 871, it uses the 1-(3-pyridyl)-1 by the formula (IV) of following three one step process, 1-diethoxy-2-aminoethane dihydrochloride as an example:
In the method, the 3-acetylpyridine of formula V is at first used hydrochloric acid hydroxylammonium oximate in methyl alcohol.The 3-acetylpyridine oxime of gained formula (VI) converts pyrido to by a plurality of distillation sequences and also add fresh pyridine (water-content＜5mol%) and dry by solvent change.
In addition, drying is directly carried out and carried out in the same manner to oximate in pyridine.Make the mixture of the 3-acetylpyridine oxime hydrochloride of gained formula (VI) and pyridine and the toluene sulfonyl chloride reaction of formula (VII) then, obtain the 3-acetylpyridine tolylsulfonyl oxime of formula (VIII), the latter is with the mixture precipitation of water and separate.
The tolylsulfonyl oxime and the potassium ethylate of gained formula (VIII) are reacted with Neber reaction in ethanol, obtain amino ketal.Gained tosic acid sylvite is mixing with hydrogenchloride in being dissolved in ether with methyl tertiary butyl ether dilution after-filtration and with filtered solution.This makes the 1-(3-pyridyl)-1 of formula (IV), and 1-diethoxy-2-aminoethane dihydrochloride precipitates with orange solids.
According to US 5,792,871, the purity of institute's separated product since the existence of unknown impuritie only can by
1H and
13C NMR data estimation is＞95%.For further reaction, amino ketal dihydrochloride (IV) is suspended in water and mix, to prepare the amino ketal of the required free alkali form of further linked reaction with sodium hydroxide solution.
Aforesaid method has some shortcomings to expanding technical scale in proportion to: at first, the gained intermediate separately must be by the distillation sequence drying.Secondly; the 3-acetylpyridine tolylsulfonyl oxime intermediate of formula (VIII) be very easy to decompose when the above standing storage of room temperature and discharges big energy (resolution of 3-acetylpyridine tolylsulfonyl oxime is about 1000J/g; also referring to F.M ller:Amine durchUmlagerungsreaktionen (Neber-Umlagerung); Houben-Weyl 11/1:Stickstoffverbindungen II (1957), the warning that relevant tolylsulfonyl ketoxime ester stores in the 903-905 page or leaf).The 3rd, Zhi Bei 1-(3-pyridyl)-1 in this way, 1-diethoxy-2-aminoethane dihydrochloride (IV) is polluted by by product, and this point is by strong painted the confirmation.The 4th, in order to obtain free 1-(3-pyridyl)-1,1-diethoxy-2-ethylamine, isolating salt (IV) must discharge with auxiliary alkali in additional step.The 5th, in this procedure, want the conversion solvent usually.Solvent mixture must very expensively be handled once more then, and this causes environmental pollution.
The objective of the invention is to find the more efficient and safer method of a kind of synthesis type (I) compound.
Therefore the present invention provides the 1-pyridyl-1 of a kind of preparation formula (I), the method for 1-dialkoxy-2-ethylamine derivative, wherein R
1And R
2Be (C independently of one another
1-C
6) alkyl, wherein alkyl can be straight chain or branching, or R wherein
1And R
2Form wherein R with Sauerstoffatom
1And R
2Be (C together
2-C
4) cyclic ketal of alkylidene group, and wherein pyridyl preferably is substituted in the 3-position in 2-, 3-or 4-position, and this method comprises:
In processing step (a), add at the same time or subsequently and comprise M
N+Mineral alkali use down hydroxylammonium compound water solution example hydrochloric acid hydroxylammonium or sulfuric acid hydroxylammonium or aqueous hydroxylamine that the acetylpyridine of formula V is transformed the acetylpyridine oxime metal-salt of an accepted way of doing sth (IX), wherein n is 1 or 2 and M during n=1
N+Be alkaline-earth metal ions during for alkalimetal ion or n=2, preferred Li
+, Na
+, K
+Or Ca
2+
R
1And R
2(C preferably respectively does for oneself
1-C
6) alkyl.Preferred especially R
1And R
2Identical and (the C that respectively does for oneself
1-C
6) alkyl.(C
1-C
6) alkyl for example is methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-or n-hexyl.
Contain (C
2-C
4) cyclic ketal of alkylidene group for example is [1,3] dioxolane or [1,3] diox group.
This preparation can be by single component or polycomponent metered charge and is carried out in batches or continuously.Can solution or suspension separation or further machining type (IX) compound.
M
N+For example be Li
+, Na
+, K
+Or Ca
2+Comprise M
N+Mineral alkali for example be basic metal or alkaline earth metal hydroxides, basic metal or alkaline earth metal carbonate or basic metal or alkali metal bicarbonates or its mixture, preferred lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, yellow soda ash, sodium bicarbonate or salt of wormwood.
For the 100mol acetylpyridine, preferably use 98-120mol azanol or hydroxylammonium compound, more preferably 99-101mol; And also have 200-300mol to comprise M
+Mineral alkali, more preferably 200-220mol, perhaps 100-150mol comprises M
2+Mineral alkali, more preferably 100-110mol.
In processing step (b), the aqueous solution, aq suspension or the separate solid of acetylpyridine metal-salt of formula (IX) and the solution that contains the tosic acid derivative (X) of leavings group Y are reacted in the suitable solvent of water-insoluble or slightly water-soluble:
Wherein Y is F, Cl or Br, and preferred Cl obtains the acetylpyridine tolylsulfonyl oxime of formula (XI):
This is reflected in the two-phase mixture of water and suitable water-insoluble solvent and carries out, and optional one or more phase-transfer catalysts that use of this reaction carry out, described catalyzer for example is a quaternary ammonium Huo phosphonium salt, the quaternary ammonium salt of preferred formula (XII) or formula (hydrate of the salt of XIII) De phosphonium salt or formula (XII) or formula (XIII):
R wherein
3-R
10Identical or different and be independently of one another:
A) (the C of straight chain or branching
1-C
20) alkyl,
B) benzyl, or
C) phenyl and
X-is a negatively charged ion, for example fluorion, chlorion, bromide anion, iodide ion, hydroxide ion, hydrogen sulfate ion, tetrafluoroborate ion, acetate ion, trifluoromethanesulfonic acid radical ion, nitrate ion, hexafluoro-antimonic acid radical ion.
Reaction in two-phase mixture preferably uses one or more phase-transfer catalysts to carry out, but also can not use phase-transfer catalyst and carry out.
Processing step (b) can carry out in batches or continuously, preferably carries out continuously, and will see it is that crucial formula (XI) compound concentrations remains on low-level this moment from security standpoint.Mixture by separating obtained solvent of the ordinary method that is separated and water then.Water contains the used metal-salt of dissolved.Water is infeeded in the biopurification.Randomly, can water be washed one or many and merge solvent phase and further processing together with suitable water-insoluble solvent subsequently.Solvent phase contains formula (XI) compound.
In processing step (b), the 3-acetylpyridine oximate for 100mol formula (IX) preferably uses 0.1-50mol, the phase-transfer catalyst of preferred 0.2-10mol.
The example of the quaternary ammonium salt of formula (XII) is a 4 bromide, tetramethyl ammonium chloride, etamon chloride, normal-butyl triethyl ammonium chloride, methyl triisopropyl ammonium chloride, methyl three normal-butyl chlorination ammonium (Aliquat
175), methyl three normal-butyl bromination ammoniums, methyl three normal-butyl monoammonium sulfates, methyl tetrabutylammonium chloride, methyl three n-octyl chlorination ammonium (Aliquat
336), methyl n-octyl ammonium hydroxide, methyl trioctylphosphine ammonium chloride, methyl trioctylphosphine ammonium hydroxide, dimethyl benzyl (C8-C18) alkyl ammomium chloride, four n-propyl chlorination ammoniums, triethyl hexyl ammonium chloride, triethyl n-octyl chlorination ammonium, triethyl n-octyl bromination ammonium, the positive decyl brometo de amonio of triethyl, triethyl n-hexadecyl brometo de amonio, the phenyl triethyl ammonium chloride, ethyl three n-octyl bromination ammoniums, tetrabutylammonium chloride, tetra-n-butyl ammonium bromide, tetrabutylammonium chloride, 4-n-butyl ammonium hydrogen sulfate, Tetramethylammonium iodide, the Tetramethylammonium hydroxide pentahydrate, Tetramethylammonium hydroxide, methyl triethyl brometo de amonio, the tetramethyl ammonium chloride monohydrate, 4 bromide, Tetramethylammonium iodide, the tetramethyl-ammonium tetrafluoroborate, (n-hexyl) trimethylammonium bromide, phenyl trimethyl ammonium chloride, phenyl trimethylammonium ammonium iodide, benzyl trimethyl ammonium chloride, benzyltrimethylammonium iodide, benzyltrimethylammonium hydroxide, (n-octyl) trimethylammonium bromide, (n-nonyl) trimethylammonium bromide, four n-propyl bromination ammoniums, phenyl triethyl iodate ammonium, (positive decyl) trimethylammonium bromide, benzyltriethylammoinium chloride, benzyl triethyl ammonium bromide, benzyl triethyl ammonium ammonium tetrafluoroborate, benzyl triethyl ammonium ammonium hydroxide, (dodecyl) trimethyl ammonium chloride, (dodecyl) trimethylammonium bromide, benzyl three n-propyl chlorination ammoniums, tetra-n-butyl ammonium bromide, tetrabutylammonium iodide, the tetra-n-butyl ammonium acetate, 4-n-butyl ammonium hydrogen sulfate, 4-n-butyl ammonium hydroxide, the tetra-n-butyl trifluoromethanesulfacid acid ammonium, (n-tetradecane base) trimethyl ammonium chloride, (n-tetradecane base) trimethylammonium bromide, (n-hexadecyl) trimethylammonium bromide, four n-pentyl chlorination ammoniums, four n-pentyl iodate ammoniums, benzyl three normal-butyl chlorination ammoniums, benzyl three normal-butyl bromination ammoniums, (n-hexadecyl) pyridinium chloride monohydrate, (n-hexadecyl) pyridinium bromide monohydrate, four n-hexyl brometo de amonios, four n-hexyl monoammonium sulfates, four n-octyl bromination ammoniums, four dodecyl ammonium iodides or four dodecyl ammonium nitrate.
The example of the phosphonium salt of formula (XIII) is four normal-butyl chlorination Phosphonium, 4-phenyl phosphonium bromide, methyl three n-octyl chlorination Phosphonium, first base three phenyl phosphonium bromides, ethyl three n-octyl bromination Phosphonium, four normal-butyl bromination Phosphonium, the tetraphenyl phosphonium chloride, tetraphenyl phosphonium iodide, tetraphenyl Liu Fu Ti Suan Phosphonium, tetraphenyl four fluorine boron acid Phosphonium, (n-hexadecyl) three normal-butyl bromination Phosphonium or trityl group triphenyl phosphonium chloride.
Water immiscibility or slightly water-soluble or water-insoluble suitable solvent for example are aliphatic series or aromatic hydrocarbons, and it is not substituted or by one or more (C
1-C
4) alkyl such as methyl, or one or more substituting group that is selected from fluorine, chlorine and bromine replaces preferred toluene, dimethylbenzene (pure isomer or isomer mixture), ethylbenzene, heptane or methylene dichloride.Also suitable is the mixture of above-mentioned suitable solvent.
For 1mol tosic acid derivative (X), preferably use the 0.6-1.1kg suitable solvent.In the reaction of the acetylpyridine oximate of 100mol formula (IX), preferably use 99-150mol, more preferably 100-110mol tosic acid derivative (X).
The term two-phase mixture refer to the water of two kinds of liquid phases-comprise acetylpyridine oximate (IX) and comprise the solvent phase of tosic acid derivative (X)-mixture.When using phase-transfer catalyst, this catalyzer may reside in water or the solvent phase, or is allocated between the two-phase.Ordinary method by technological operation in batches or continuously stirs and/or the mixing two-phase mixture, thereby guarantees the well distributed of each phase.
Temperature of reaction in processing step (b) is preferably 0-50 ℃ in batch program, more preferably 5-30 ℃, this temperature is 0-60 ℃ in continuous program, more preferably 5-40 ℃.
In processing step (c); the solvent phase of acetylpyridine tolylsulfonyl oxime that will comprise formula (XI) is after the drying or do not having to be metered under the drying in advance in the mixture of alkali metal alcoholates, alkali metal hydroxide, alkaline-earth alkoxides or alkaline earth metal hydroxides and alcohol, and wherein " alkoxide " is meant R
1O
-And/or R
2O
-And wherein alcohol is meant R
1OH and/or R
2OH, and R
1And R
2Suc as formula defining in (I) compound, and transform the 1-(pyridyl)-1 of an accepted way of doing sth (I), 1-dialkoxy-2-ethylamine derivative.
In processing step (c), the acetylpyridine tolylsulfonyl oxime for 100mol formula (XI) preferably uses the 99-500mol alkali metal alcoholates, more preferably 100-200mol; Or 99-500mol alkali metal hydroxide, more preferably 100-300mol; Or the 50-250mol alkaline-earth alkoxides, more preferably 50-100mol, or 50-250mol alkaline earth metal hydroxides, more preferably 50-150mol.
In processing step (c), preferably use alkali metal hydroxide or alkoxide, particularly lithium hydroxide, lithium methoxide, lithium ethoxide, sodium hydroxide, sodium methylate, sodium ethylate, potassium hydroxide, potassium methylate, potassium ethylate, cesium hydroxide, methyl alcohol caesium or ethanol caesium.
The introducing of required alkoxyl group is depended in the selection of alkoxide and/or alcohol.For example, in order to prepare 1-(pyridyl)-1,1-dimethoxy-2-ethylamine uses basic metal or mixture or alkali metal hydroxide the mixture in methyl alcohol of alkaline-earth metal methylate in methyl alcohol.In order to prepare wherein R
1And R
2Form compound 1-(pyridyl)-1-([1,3] the dioxolane)-2-ethylamine of cyclic ketal with Sauerstoffatom, for example use the alkali metal hydroxide in glycol.
For the acetylpyridine oxime tosylat of 1mol formula (XI), preferably use 0.3-3kg, the alcohol corresponding of preferred 0.5-1.5kg.For example, more preferably transform in 10-60 ℃ the temperature range at 0-90 ℃.
After reaction, at first steam and remove a part of solvent, so that the tosilate by product at room temperature is precipitated out.Distill by ordinary method.The solvent mixture that steaming removes (distillate) can directly be used further to processing step (c).
Remove tosic acid basic metal or alkaline earth salt by the conventional filtration method.Remaining solvent cut is by at barometric point or preferably under reduced pressure remove with ordinary method distillation.
Then by vacuum distilling or rectifying or by choose amino ketal derivatives wantonly by the distillation residue crystallization that obtains in the distillation in front with highly purified isolated in form formula (I).For example, can be by the distillation wherein R that purifies
1And R
2Respectively do for oneself formula (I) compound of methyl.
Productive rate in vacuum distilling or the rectifying can be chosen wantonly by add flux in distillation residue and improve.Its viscosity that is meant term " flux " reduces and therefore improves the flowing property of resistates to be distilled when being heated, but the while boiling point is significantly higher than the liquid or the waxy solid of product to be distilled.Used flux for example is molecular weight greater than 400 polyoxyethylene glycol (for example Polyethylene Glycol-600 or cetomacrogol 1000), paraffin (C
nH
2n+2, n＞15 wherein), polyvalent alcohol (alcohol with more than OH group, for example glycerine) or ester, for example sebacic acid two 2-ethyl esters.
Crystallization can be undertaken by ordinary method, uses or not with an organic solvent.Can use melt or solvent method.
The advantage of the inventive method at first is formula (I) compound with high purity and the very good direct separated free alkali of productive rate form; Secondly, the reaction conditions of selecting allows to carry out oximate and tosylation reaction with continuous program, this always only produces the intermediate of security-related on a small quantity formula (XI), and do not need to see crucial acetylpyridine tolylsulfonyl oxime with isolated in solid form from security standpoint, because after short time of lag, they directly change into the amino ketal of formula (I) in continuous device, the latter sees not crucial from security standpoint; The 3rd, formula (I) compound prepares with free alkali form and to be fit to plant-scale mode with high purity (greater than 97%) and productive rate (based on used acetylpyridine greater than 75%); The 4th, use the solvent that can directly be used further in this method with respective pure form or with form of mixtures, thereby make influence keep very little environment.
Embodiment 1:
Preparation 1-(3-pyridyl)-1,1-dimethoxy-2-ethylamine, method 1
1 (a) makes 174g 40% hydrochloric acid hydroxylammonium solution, 121g 3-acetylpyridine and 245g 33% sodium hydroxide solution be metered into mode at 15-25 ℃ temperature range internal reaction with 3 components in reactor.Make the sodium salt solution and the reaction of 2g methyltributylammonichloride chloride of gained 3-acetylpyridine oxime.
1 (b) make then this solution in continuation method (via the method for recycling of the static mixer that has the part discharge) with the solution reaction of 193g Tosyl chloride and 655g toluene, be 35-38 ℃ up to internal temperature.Then with the gained two-phase mixture by disengaging zone and with solvent phase and aqueous phase separation.
1 (c) makes solvent phase flow directly into 940g methyl alcohol (or from the solvent distillatory methanol/toluene mixture first time, as follows) and in the initial charge solution of 216g 30% sodium methoxide solution.Temperature remains in the 20-40 ℃ of scope.Make reaction soln continue reaction other 5-10 hour.Under 70-90 ℃ and barometric point, from reaction mixture, steam methyl alcohol (solvent distillation for the first time) with azeotropic mixture with toluene.This azeotropic solvent mixture can be used further to (on seeing) in the above-mentioned reaction.After distillation, distillation residue are cooled to 25 ℃, leach the tosic acid sodium salt subsequently and use the 85g toluene wash.Be about 120-130 ℃ by distilling concentrated filtrate down up to internal temperature then in decompression (about 100-200 millibar).Then, the 10-20g Polyethylene Glycol-600 is added in the distillation residue and under the inner evaporator temperature of 1-10 millibar and 100-160 ℃, steam 1-(3-pyridyl)-1,1-dimethoxy-2-ethylamine with the water clear liquid via short column.Obtain 157.3g 1-(3-pyridyl)-1,1-dimethoxy-2-ethylamine, purity is 98-99% (by titration, HPLC-MS and NMR with the reference standard comparative determination).This is 85% of a theoretical value corresponding to productive rate, based on used 3-acetylpyridine.
Embodiment 2:
Preparation 1-(3-pyridyl)-1,1-dimethoxy-2-ethylamine, method 2
2 (a) make 174g 40% hydrochloric acid hydroxylammonium solution, 121g 3-acetylpyridine and 245g 33% sodium hydroxide solution be metered into mode with 3 components in reactor to react under 15-25 ℃ temperature.In the sodium salt solution of gained 3-acetylpyridine oxime, add the 2g methyltributylammonichloride chloride.
2 (b) make then this solution in continuation method (via the method for recycling of the static mixer that has the part discharge) with the solution reaction of 193g Tosyl chloride and 655g toluene, be 35-38 ℃ up to internal temperature.Make the gained two-phase mixture by the disengaging zone and with solvent phase and aqueous phase separation then.
2 (c) make solvent phase flow directly into 940g methyl alcohol (or from the solvent distillatory methanol/toluene mixture first time, as follows) and in the initial charge solution of 48g sodium hydroxide.Temperature remains 20-40 ℃.Make this reaction soln continue reaction other 5-10 hour.From reaction mixture, steam methyl alcohol (solvent distillation for the first time) with azeotropic mixture with toluene.This azeotropic solvent mixture can be used further to (on seeing) in the above-mentioned reaction.After distillation, distillation residue are cooled to 25 ℃, leach the tosic acid sodium salt then and use the 85g toluene wash.Concentrated filtrate is about 120-130 ℃ up to internal temperature by distilling down in decompression (about 100-200 millibar) then.Then, the 10-20g Polyethylene Glycol-600 is added in the distillation residue and under the inner evaporator temperature of 1-10 millibar and 100-160 ℃, steam 1-(3-pyridyl)-1,1-dimethoxy-2-ethylamine with the water clear liquid via short column.Obtain 148g 1-(3-pyridyl)-1,1-dimethoxy-2-ethylamine, purity is 98-99% (by titration, HPLC-MS and NMR with the reference standard comparative determination).This is 80% of a theoretical value corresponding to productive rate, based on used 3-acetylpyridine.
Claims (19)
1. the 1-(pyridyl)-1 of a preparation formula (I), the method for 1-dialkoxy-1-ethylamine derivative:
R wherein
1And R
2Be (C independently of one another
1-C
6) alkyl, wherein alkyl can be straight chain or branching, or R wherein
1And R
2Form wherein R with Sauerstoffatom
1And R
2Be (C together
2-C
4) cyclic ketal of alkylidene group, and wherein the pyridine group is in 2-, 3-or 4-position, and preferred 3-position is substituted, and this method comprises:
In processing step (a), comprise M in adding
N+Mineral alkali use down hydroxylammonium compound water solution or aqueous hydroxylamine that the acetylpyridine of formula V is transformed the acetylpyridine oxime metal-salt of an accepted way of doing sth (IX), wherein n is 1 or 2 and M
N+Be basic metal or alkaline-earth metal ions:
In processing step (b), the acetylpyridine metal-salt of formula (IX) and the solution that contains the tosic acid derivative (X) of leavings group Y are reacted in water immiscibility or slightly water-soluble or water-insoluble suitable solvent:
Wherein Y is F, Cl or Br, obtains the acetylpyridine tolylsulfonyl oxime of formula (XI):
This is reflected in the two-phase mixture of water and suitable solvent and carries out, optional one or more phase-transfer catalysts that use,
And in processing step (c); the acetylpyridine tolylsulfonyl oxime of formula (XI) is changed into the compound of formula (I) in the mixture of alkali metal alcoholates, alkali metal hydroxide, alkaline-earth alkoxides or alkaline earth metal hydroxides and alcohol, wherein " alkoxide " is meant R
1O
-And/or R
2O
-And wherein alcohol is meant R
1OH and/or R
2OH, and R
1And R
2Each defines formula (I) compound freely,
And carry out this method independently continuously or in batches for each processing step (a)-(c).
2. as the desired method of claim 1, wherein pyridyl is substituted in the 3-position.
3. as claim 1 or 2 desired method, wherein R
1And R
2(C respectively does for oneself
1-C
6) alkyl.
4. as each desired method among the claim 1-3, wherein in processing step (a), use azanol, hydrochloric acid hydroxylammonium or sulfuric acid hydroxylammonium.
5. as each desired method among the claim 1-4, wherein in processing step (a), M
N+Be meant Li
+, Na
+, K
+Or Ca
2+
6. as each desired method among the claim 1-5, wherein in processing step (a), comprise M
N+Mineral alkali be lithium hydroxide, sodium hydroxide, yellow soda ash, sodium bicarbonate, potassium hydroxide, salt of wormwood or calcium hydroxide.
7. as each desired method among the claim 1-6, wherein in processing step (b), leavings group Y is Cl.
8. as each desired method among the claim 1-7, wherein in processing step (b), described phase-transfer catalyst be the quaternary ammonium salt of formula (XII) or formula (XIII) De phosphonium salt:
R wherein
3-R
10Identical or different and be independently of one another:
A) (the C of straight chain or branching
1-C
20) alkyl,
B) benzyl, or
C) phenyl and
X
-Be negatively charged ion, for example fluorion, chlorion, bromide anion, iodide ion, hydroxide ion, hydrogen sulfate ion, tetrafluoroborate ion, acetate ion, trifluoromethanesulfonic acid radical ion, nitrate ion, hexafluoro-antimonic acid radical ion, preferable methyl tributyl ammonium chloride.
9. as each desired method among the claim 1-8, wherein in processing step (c), use lithium hydroxide, lithium methoxide, lithium ethoxide, sodium hydroxide, sodium methylate, sodium ethylate, potassium hydroxide, potassium methylate, potassium ethylate, cesium hydroxide, methyl alcohol caesium or ethanol caesium.
10. as each desired method among the claim 1-9, wherein not drying and the acetylpyridine tolylsulfonyl oxime of use formula (XI) in advance in processing step (c).
11. the method for the acetylpyridine oxime metal-salt of preparation formula (IX):
Wherein n is 1 or 2 and M
N+Be alkalimetal ion or alkaline-earth metal ions, and wherein pyridyl is substituted at 2-, 3-or 4-position,
This method comprises:
Use aqueous hydroxylamine or hydroxylammonium compound water solution to comprise M in adding
N+Mineral alkali under with the acetylpyridine of formula V:
Transform the acetylpyridine oxime metal-salt of an accepted way of doing sth (IX),
And carry out this method continuously or in batches.
12. as the desired method of claim 11, wherein pyridyl is substituted in the 3-position.
13. as claim 11 or 12 desired method, wherein M
N+Be Li
+, Na
+, K
+Or Ca
2+
14. as each desired method among the claim 11-13, the wherein said M that comprises
N+Mineral alkali be lithium hydroxide, sodium hydroxide, yellow soda ash, sodium bicarbonate, potassium hydroxide, salt of wormwood or calcium hydroxide.
15. as each desired method among the claim 11-14, it carries out continuously.
16. the method for a preparation formula (XI) compound:
Wherein pyridyl is substituted at 2-, 3-or 4-position,
This method comprises:
Make the acetylpyridine metal-salt of formula (IX):
Wherein n is 1 or 2 and M
N+Be alkalimetal ion or alkaline-earth metal ions,
React in the suitable solvent of water-insoluble or slightly water-soluble with the solution of the tosic acid derivative (VII) that contains leavings group Y:
Wherein Y is F, Cl or Br, obtains the acetylpyridine tolylsulfonyl oxime of formula (XI),
This is reflected at and carries out in the two-phase mixture of water and suitable water-insoluble solvent and optionally use one or more phase-transfer catalysts, and carries out this method continuously or in batches.
17. as the desired method of claim 16, this method uses one or more phase-transfer catalysts to carry out, wherein said phase-transfer catalyst be the quaternary ammonium salt of formula (XII) or formula (XIII) De phosphonium salt:
R wherein
3-R
10Identical or different and be independently of one another:
A) (the C of straight chain or branching
1-C
20) alkyl,
B) benzyl, or
C) phenyl and
X
-Be negatively charged ion, for example fluorion, chlorion, bromide anion, iodide ion, hydroxide ion, hydrogen sulfate ion, tetrafluoroborate ion, acetate ion, trifluoromethanesulfonic acid radical ion, nitrate ion, hexafluoro-antimonic acid radical ion, preferable methyl tributyl ammonium chloride.
18. as claim 16 or 17 desired methods, wherein pyridyl is substituted in the 3-position.
19. as each desired method among the claim 16-18, it carries out continuously.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10305391A DE10305391A1 (en) | 2003-02-11 | 2003-02-11 | Preparation of 1-(pyridinyl)-1,1-dialkoxy-1-aminoethane derivatives involves reacting acetylpyridine tosyl oxime with mixture of alkali metal alkoxide or hydroxide or alkaline earth metal alkoxide or hydroxide with alcohol |
| DE10305391.3 | 2003-02-11 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1747932A true CN1747932A (en) | 2006-03-15 |
| CN100393701C CN100393701C (en) | 2008-06-11 |
Family
ID=32730947
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2004800034784A Expired - Fee Related CN100393701C (en) | 2003-02-11 | 2004-01-27 | Process for preparing pyridine-substituted amino ketal derivatives |
Country Status (20)
| Country | Link |
|---|---|
| EP (1) | EP1601648A2 (en) |
| JP (1) | JP4709741B2 (en) |
| KR (1) | KR101114893B1 (en) |
| CN (1) | CN100393701C (en) |
| AR (1) | AR043132A1 (en) |
| AU (1) | AU2004212038B2 (en) |
| BR (1) | BRPI0407349A (en) |
| CA (1) | CA2514255C (en) |
| CO (1) | CO5690583A2 (en) |
| DE (1) | DE10305391A1 (en) |
| HK (1) | HK1086007A1 (en) |
| IL (1) | IL169900A (en) |
| MX (1) | MXPA05007961A (en) |
| NO (1) | NO332353B1 (en) |
| NZ (1) | NZ541735A (en) |
| PL (1) | PL376654A1 (en) |
| RU (1) | RU2336271C2 (en) |
| TW (1) | TWI316054B (en) |
| WO (1) | WO2004072026A2 (en) |
| ZA (1) | ZA200505298B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115477926A (en) * | 2022-09-15 | 2022-12-16 | 江苏科技大学 | Phase change material and preparation method thereof |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4746669A (en) * | 1985-12-23 | 1988-05-24 | Merck & Co., Inc. | Substituted thiazoles as immunoregulants |
| US4798841A (en) * | 1987-03-31 | 1989-01-17 | Warner-Lambert Company | Tetrahydropyridine oxime cholinergic agents and method of treatment |
| US5792871A (en) * | 1996-07-22 | 1998-08-11 | Merck & Co., Inc. | Process for N-Boc-N-(R)-2(3-pyridyl)-2-hydroxy-ethyl)-N-2(4-aminophenyl)ethyl amine and 2-(4-aminophenyl)-N-2-(2(R)-hydroxy-2-phyridin-S-yl-ethyl)acetamide |
| FR2780973B1 (en) * | 1998-07-09 | 2001-10-05 | Hoechst Marion Roussel Inc | PROCESS FOR THE PREPARATION OF 4- (3-PYRIDINYL) -1H-IMIDAZOLE, AND THE INTERMEDIATES USED |
-
2003
- 2003-02-11 DE DE10305391A patent/DE10305391A1/en not_active Withdrawn
-
2004
- 2004-01-27 MX MXPA05007961A patent/MXPA05007961A/en active IP Right Grant
- 2004-01-27 NZ NZ541735A patent/NZ541735A/en not_active IP Right Cessation
- 2004-01-27 BR BR0407349-5A patent/BRPI0407349A/en not_active IP Right Cessation
- 2004-01-27 RU RU2005128281/04A patent/RU2336271C2/en not_active IP Right Cessation
- 2004-01-27 EP EP04705409A patent/EP1601648A2/en not_active Withdrawn
- 2004-01-27 WO PCT/EP2004/000640 patent/WO2004072026A2/en active Application Filing
- 2004-01-27 KR KR1020057014743A patent/KR101114893B1/en not_active IP Right Cessation
- 2004-01-27 CA CA2514255A patent/CA2514255C/en not_active Expired - Fee Related
- 2004-01-27 PL PL376654A patent/PL376654A1/en not_active Application Discontinuation
- 2004-01-27 JP JP2006501606A patent/JP4709741B2/en not_active Expired - Fee Related
- 2004-01-27 CN CNB2004800034784A patent/CN100393701C/en not_active Expired - Fee Related
- 2004-01-27 AU AU2004212038A patent/AU2004212038B2/en not_active Ceased
- 2004-02-09 AR ARP040100398A patent/AR043132A1/en not_active Application Discontinuation
- 2004-02-09 TW TW093102879A patent/TWI316054B/en not_active IP Right Cessation
-
2005
- 2005-06-30 ZA ZA200505298A patent/ZA200505298B/en unknown
- 2005-07-26 IL IL169900A patent/IL169900A/en not_active IP Right Cessation
- 2005-08-09 CO CO05078811A patent/CO5690583A2/en active IP Right Grant
- 2005-09-07 NO NO20054167A patent/NO332353B1/en not_active IP Right Cessation
-
2006
- 2006-05-25 HK HK06106012A patent/HK1086007A1/en not_active IP Right Cessation
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115477926A (en) * | 2022-09-15 | 2022-12-16 | 江苏科技大学 | Phase change material and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| EP1601648A2 (en) | 2005-12-07 |
| CA2514255C (en) | 2012-01-24 |
| CA2514255A1 (en) | 2004-08-26 |
| WO2004072026A2 (en) | 2004-08-26 |
| AR043132A1 (en) | 2005-07-20 |
| CO5690583A2 (en) | 2006-10-31 |
| JP4709741B2 (en) | 2011-06-22 |
| NO332353B1 (en) | 2012-09-03 |
| NZ541735A (en) | 2008-06-30 |
| JP2006518716A (en) | 2006-08-17 |
| IL169900A0 (en) | 2007-07-04 |
| CN100393701C (en) | 2008-06-11 |
| ZA200505298B (en) | 2008-01-30 |
| WO2004072026A3 (en) | 2004-09-30 |
| KR20050101205A (en) | 2005-10-20 |
| HK1086007A1 (en) | 2006-09-08 |
| AU2004212038B2 (en) | 2010-11-25 |
| PL376654A1 (en) | 2006-01-09 |
| KR101114893B1 (en) | 2012-03-06 |
| NO20054167L (en) | 2005-10-31 |
| TWI316054B (en) | 2009-10-21 |
| AU2004212038A1 (en) | 2004-08-26 |
| IL169900A (en) | 2010-12-30 |
| MXPA05007961A (en) | 2005-09-20 |
| TW200504020A (en) | 2005-02-01 |
| RU2336271C2 (en) | 2008-10-20 |
| BRPI0407349A (en) | 2006-01-10 |
| RU2005128281A (en) | 2006-02-10 |
| WO2004072026B1 (en) | 2004-11-18 |
| DE10305391A1 (en) | 2004-08-19 |
| NO20054167D0 (en) | 2005-09-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Landini et al. | Stability of quaternary onium salts under phase-transfer conditions in the presence of aqueous alkaline solutions | |
| CN1997636B (en) | Method for obtaining pure tetrahydrocannabinol | |
| CN103641811A (en) | Method for preparing cyclic carbonate | |
| JP2022535052A (en) | Method for producing hydroxymethylfurfural | |
| CN104262110A (en) | Method for preparing 4-tert-butyl-2-(alpha-methylbenzyl)phenol | |
| CN1747932A (en) | Process for preparing pyridine-substituted amino ketal derivatives | |
| CN102675152A (en) | Preparation method of intermediate glycol of antidepressant citalopram | |
| CN106380421A (en) | Synthetic method for Sacubitril | |
| WO2010001870A1 (en) | Process for producing diphenyl carbonate | |
| CN106316953A (en) | Synthetic method of 6-cyanophenanthridine compounds | |
| CN107674179A (en) | The method for preparing epoxy resin using D-pHPG production solid slag | |
| CN1266133C (en) | Process for preparing acetyl substituted nitrogen containing heterocyclic compound | |
| CN114478216A (en) | Novel synthesis method of 1-acetyl-1-chlorocyclopropane | |
| CN107434758B (en) | Method for synthesizing monobromo condensed ring aromatic hydrocarbon compound | |
| CN110105266A (en) | Synthetic method of one species specificity for the small molecule, anti-tumor drug of CYP2J2 | |
| CN104817589A (en) | Dialkyl phosphinic acid compound or salt thereof and preparation method thereof | |
| CN104496899B (en) | The synthetic method of the intermediate of Menglusitena | |
| CN109336743A (en) | A kind of synthetic method of Beta-bromo ether compound | |
| CN1569842A (en) | Process for preparing hexahydropyridazine-3-carboxylic acid derivatives | |
| CN101654433B (en) | Method for N-alkylation of 2-pyridone | |
| CN1639113A (en) | Method for producing 2-chloromethylphenyl acetic acid derivatives | |
| US20040158073A1 (en) | Process for preparing pyridine-substituted amino ketal derivatives | |
| CN101654432B (en) | Method for N-alkylation of 2-pyridone | |
| CN1696117A (en) | Method for preparing ion liquid in halogenated alkyl imidazole type | |
| CN117327008A (en) | Green synthesis process of dortefovir intermediate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1086007 Country of ref document: HK |
|
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: GR Ref document number: 1086007 Country of ref document: HK |
|
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20080611 Termination date: 20150127 |
|
| EXPY | Termination of patent right or utility model |