CN102212040A - Novel preparation method for chiral 2-hydroxymethyl morpholine compounds - Google Patents
Novel preparation method for chiral 2-hydroxymethyl morpholine compounds Download PDFInfo
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Abstract
The invention discloses a novel preparation method for chiral 2-hydroxymethyl morpholine compounds (I), which comprises the following steps: carrying out reaction on chiral glycerin chlorohydrin used as a starting raw material and benzylamine to generate chiral 3-benzylamino-1,2-propanediol (II), acylating the chiral 3-benzylamino-1,2-propanediol (II) to generate a mixture of corresponding chiral N-haloacetyl-N-2,3-dihydroxypropyl-benzylamine (III) and chiral N-haloacetyl-N-(2-hydroxyl-3-haloacetylpropyl)-benzylamine (III'), carrying out cyclization, reduction and hydrogenation to obtain chiral 2-hydroxymethyl morpholine (Ia), and carrying out corresponding protection reaction on amino groups of the 2-hydroxymethyl morpholine (Ia) to generate chiral 2-hydroxymethyl-N-substituted-morpholine (I). The novel preparation method has the advantages of simple and safe used reagents, short steps, high reaction yield of each step, convenient purification of intermediate products and high purity of target products, and is especially suitable for industrial production.
Description
Technical field
The present invention relates to the preparation method of the 2-hydroxymethyl morpholine compounds (I) of chirality.
Background technology
The 2-hydroxymethyl morpholine of chirality comprises R configuration and two kinds of compounds of S configuration, is the key intermediate of synthetic many drug molecules, and is widely used in the new drug development as construction module.As Reboxetine, Viloxazine, Indeloxazine, Teniloxazine etc., these compounds by widely as depression, improve nervous system disorders medicines such as brain function.
Therefore synthesizing of the 2-hydroxymethyl morpholine of chirality more and more causes chemist's attention.
People such as Yanagisawa are at Heterocycles, have described the synthetic of chirality 2-methylol-N-tertbutyloxycarbonyl-morpholine on 1993,105.Wherein the synthetic route of S configuration of compound is as shown in the formula statement:
This route is with 1,2-and 5, and the D-N.F,USP MANNITOL of 6-propylidene protection is raw material, scission of link forms bimolecular aldehyde under the effect of oxygenant sodium periodate.Aldehyde and benzylamine form imines subsequently, after hydrogenation is reduced into amine.Amine generation acidylate is closed ring and is formed morpholinones after taking off propylidene.Morpholone mai obtains S configuration 2-methylol-N-benzyl morpholine through after the Li-Al hydrogen reduction, and with after form S configuration 2-hydroxymethyl morpholine after the catalytic hydrogenation, it is protected on amido and promptly obtains S configuration 2-methylol-N-tertbutyloxycarbonyl-morpholine.This method not only step is long, and needs to use strong oxidizer sodium periodate and dangerous Li-Al hydrogen, is not suitable for suitability for industrialized production.And some step also needs to purify by column chromatography, and this has also greatly limited the further application of this method.
In addition, the author has synthesized R configuration product again on the basis of above route, as shown in the formula expression:
The aldehyde that forms after the D-N.F,USP MANNITOL oxidation with the propylidene protection finally can obtain R configuration 2-methylol-N-tertbutyloxycarbonyl-morpholine through the reaction of 8 steps.This route is not only very loaded down with trivial details to be not suitable for industrialization, and target product purity is not high yet, can have 5% S configurational isomer.
Henegar is at JOC, described a kind of method of having described S configuration 2-methylol-N-tertbutyloxycarbonyl-morpholine on synthetic on 2008,3662.Its synthetic route is as shown in the formula statement:
This route uses the epoxy chloropropane of S configuration as raw material, and successive pass ring takes place under the effect of alkali the product that the ethanol generation ring-opening reaction that itself and benzamido group replace obtains and ring-opening reaction obtains a pair of compound.To the more excellent reactivity of secondary alcohol, carry out esterification by primary alconol on the hydroxyl of six-ring compound, formed compound salify under the weak base effect adds water layer, thereby separates with compounds with 7-member cycle.The back six-ring compound of purifying is deviate from ester group and is obtained key precursor after hydrolysis, it changes into S configuration 2-methylol-morpholine through the hydrogenation debenzylation, protects at last to obtain target product S configuration 2-methylol-N-tertbutyloxycarbonyl morpholine on its N nitrogen-atoms.This route need be with the epoxy chloropropane of expensive S configuration as raw material, and the intermediate that the first two steps reaction forms is all unstable, need now do existing usefulness, otherwise easily takes place rotten.Particularly unsettled intermediate can cause chiral carbon generation racemization, causes target product ee value to descend.Primary alconol can cause the compound of six-ring and seven-membered ring to produce to the intramolecularly ring-opening reaction of epoxy in addition, and both ratios not high (2/1), causes productive rate to descend greatly and has increased isolating difficulty.Everything has all limited its suitability for industrialized production.
Utilize the method also just like people such as Bergs at J.Med.Chem 1998,1934 introduced of epoxy compounds as raw material:
This route uses the benzyl glycidyl ether of R configuration or S configuration as raw material, and behind the benzylamine nucleophilic ring opening, resulting product acidylate takes place thereupon, closes ring and reduction and debenzylation, obtains the 2-hydroxymethyl morpholine of chirality.On nitrogen-atoms, protect the 2-methylol N-trityl morpholine that promptly gets chirality subsequently.Though this method route has shortened, and still exists the raw materials cost height, long reaction time, yield be not high, need problems such as column chromatography purification, and reducing amide need use hazardous agents such as Li-Al hydrogen, is not suitable for suitability for industrialized production.
Summary of the invention
The present invention has overcome the defective of above-mentioned prior art, and a kind of novel method for preparing the 2-hydroxymethyl morpholine compounds (I) of chirality is provided.That present method has is with low cost, environmental friendliness, reactions steps is short, simple to operate, yield is high, the product purity advantages of higher, is suitable for suitability for industrialized production.
The present invention comprises the steps: that specifically with the chirality glycerin chlorohydrin be starting raw material; generate the 3-benzamido group 1 of chirality respectively by the reaction of itself and benzylamine; 2-propylene glycol (II); resulting (II) reacts the N-halo ethanoyl-N-2 that generates corresponding chirality with chloroacetyl chloride or bromoacetyl bromide; the mixture of the N-halo ethanoyl-N-of 3-dihydroxypropyl-benzylamine (III) and chirality (2-hydroxyl-3-halogenated acetic acids ester group propyl group)-benzylamine (III '); resulting mixture (III) and (III ') generate the mixture of the 2-methylol-4-benzyl-morpholine-3-ketone (IV) of corresponding chirality and the 2-halogenated acetic acids ester group-4-benzyl-morpholine-3-ketone of chirality (IV ') through closing ring; resultant mixture (IV) and (IV ') are under reductive condition; all be converted into the 2-methylol-4-benzyl-morpholine (Ic) of corresponding chirality; resulting (Ic) generates the 2-hydroxymethyl morpholine (Ia) of corresponding chirality under hydrogenation conditions, resulting (Ia) generates the 2-methylol-N-replacement-morpholine (I) of corresponding chirality after carrying out corresponding protection on the amido.
Involved in the present invention to reaction can represent with following reaction formula:
R is C in the formula
1-C
8-alkyl, C
1-C
6-alkyl sulphonyl, C
1-C
4-alkyl oxygen carbonyl, phenyl, phenylmethylene oxygen carbonyl, triphenyl carbon back, phenyl sulfonyl can replace by one or more following bases on the phenyl: halogen, nitro, C
1-C
4-alkyl, C
1-C
4-alkoxyl group.X is chlorine or bromine.
3-benzamido group 1 from the corresponding chirality of chirality glycerin chlorohydrin preparation of the present invention, in the reaction of 2-propylene glycol (II), the mol ratio of chirality glycerin chlorohydrin and benzylamine is between 30: 1～1: 30, and temperature of reaction is 40～150 ℃.
Above-mentioned 3-benzamido group 1 from the corresponding chirality of chirality glycerin chlorohydrin preparation, the reaction of 2-propylene glycol (II) is carried out under the alkali effect, and selected alkali is: triethylamine, diisopropyl ethyl amine, pyridine, morpholine, N-methylmorpholine, yellow soda ash, sodium bicarbonate, salt of wormwood, sodium hydroxide, potassium hydroxide.
The operating process of above-mentioned reaction from the corresponding chiral compounds (II) of chirality glycerin chlorohydrin preparation is roughly as follows:
In there-necked flask, mix chirality glycerin chlorohydrin, benzylamine and alkali.Under heated condition, reacted 1-24 hour subsequently.Promptly get compound (II) after concentrating.Compound (II) can directly be done next step reaction without purifying.
The 3-benzamido group 1 of chirality of the present invention; the N-halo ethanoyl-N-2 of the chirality that 2-propylene glycol (II) preparation is corresponding; in the reaction of the mixture of the N-halo ethanoyl-N-of 3-dihydroxypropyl-benzylamine (III) and chirality (2-hydroxyl-3-halogenated acetic acids ester group propyl group-benzylamine (III '); the 3-benzamido group 1 of chirality; the mol ratio of 2-propylene glycol (II) and halogen acetyl halide is between 2: 1～1: 6, and temperature of reaction is-78～50 ℃.
Described halogen acetyl halide can be chloroacetyl chloride or bromoacetyl bromide.
Above-mentioned 3-benzamido group-1 from chirality; the N-halo ethanoyl-N-2 of the chirality that 2-propylene glycol (II) preparation is corresponding; the reaction of the mixture of the N-halo ethanoyl-N-of 3-dihydroxypropyl-benzylamine (III) and chirality (2-hydroxyl-3-halogenated acetic acids ester group propyl group benzylamine (III ') is carried out under appropriate solvent, and selected solvent is: toluene, tetrahydrofuran (THF), methylene dichloride, trichloromethane, methyl alcohol, acetonitrile, ether.
Above-mentioned 3-benzamido group 1 from chirality; the N-halo ethanoyl-N-2 of the chirality that 2-propylene glycol (II) preparation is corresponding; the reaction of the mixture of the N-halo ethanoyl-N-of 3-dihydroxypropyl benzylamine (III) and chirality (2-hydroxyl-3-halogenated acetic acids ester group propyl group-benzylamine (III ') is carried out under the alkali effect, and selected alkali is: triethylamine, diisopropyl ethyl amine, pyridine, yellow soda ash, salt of wormwood, sodium hydroxide, potassium hydroxide, sodium methylate, sodium tert-butoxide, sodium hydride.
The operating process of the reaction of above-mentioned mixture from compound (II) preparation compound (III) and (III ') is roughly as follows:
Add compound (II) in there-necked flask, alkali and solvent under cooling, slowly add the halogen acetyl halide in system, react 1～24 hour under suitable temperature subsequently.After reaction finishes, add in the buck and system, extraction back organic phase reduces pressure after drying and removes the mixture that promptly gets compound (III) and (III ') behind the organic solvent.The mixture of compound (III) and (III ') can directly be done next step reaction without purifying.
N-halo ethanoyl-N-2 from chirality of the present invention; in the reaction of the mixture of the 2-methylol-4-benzyl-morpholine-3-ketone (IV) of the chirality that the mixture preparation of the N-halo ethanoyl-N-of 3-dihydroxypropyl-benzylamine (III) and chirality (2-hydroxyl-3-halogenated acetic acids ester group propyl group-benzylamine (III ') is corresponding and the 2-halogenated acetic acids ester group-4-benzyl-morpholine-3-ketone of chirality (IV '); be reflected at appropriate solvent and react under the effect of alkali, temperature of reaction is-45～45 ℃.
Above-mentioned N-halo ethanoyl-N-2 from chirality; the reaction of the mixture of the 2-methylol-4-benzyl morpholine-3-ketone (IV) of the chirality that the mixture preparation of the N-halo ethanoyl-N-of 3-dihydroxypropyl benzylamine (III) and chirality (2-hydroxyl-3-halogenated acetic acids ester group propyl group benzylamine (III ') is corresponding and the 2-halogenated acetic acids ester group-4-benzyl morpholine-3-ketone of chirality (IV ') is carried out under the alkali effect, and selected alkali is: triethylamine; diisopropyl ethyl amine; pyridine; morpholine; N-methylmorpholine; piperidines; yellow soda ash; sodium bicarbonate; salt of wormwood; saleratus; sodium hydroxide; potassium hydroxide; sodium methylate; sodium ethylate; sodium tert-butoxide; potassium tert.-butoxide; sodium hydride.
Above-mentioned N-halo ethanoyl-N-2 from chirality; the reaction of the mixture of the 2-methylol-4-benzyl-morpholine-3-ketone (IV) of the chirality that the mixture preparation of the N-halo ethanoyl-N-of 3-dihydroxypropyl-benzylamine (III) and chirality (2-hydroxyl-3-halogenated acetic acids ester group propyl group-benzylamine (III ') is corresponding and the 2-halogenated acetic acids ester group-4-benzyl-morpholine-3-ketone of chirality (IV ') is carried out under appropriate solvent; selected solvent is: methylene dichloride; trichloromethane; tetrahydrofuran (THF); N, dinethylformamide; methyl-sulphoxide; acetonitrile; toluene; ether; isopropyl ether; methyl alcohol; ethanol.
It is roughly as follows that above-mentioned mixture from compound (III) and (III ') prepares the operating process of reaction of mixture of compound (IV) and (IV '):
The mixture that adds compound (III) and (III ') in there-necked flask, suitably alkali, and appropriate solvent was proper temperature reaction 1～24 hour.Add entry and organic solvent extracts in system, organic phase reduces pressure after drying and removes the mixture that promptly gets compound (IV) and (IV ') behind the organic solvent.The mixture of compound (IV) and (IV ') can directly be done next step reaction without purifying.
The present invention is under suitable reductive agent effect from the reaction of the 2-methylol-4-benzyl-morpholine (Ic) of the corresponding chirality of the mixture preparation of the 2-methylol-4-benzyl-morpholine-3-ketone (IV) of chirality and the 2-halogenated acetic acids ester group-4-benzyl-morpholine-3-ketone of chirality (IV '), and under suitable solvent, carry out.
Above-mentioned temperature of reaction is-20～150 ℃.
The selected reductive agent of reaction of the 2-methylol-4-benzyl-morpholine (Ic) of the chirality that the mixture preparation of the 2-halogenated acetic acids ester group-4-benzyl-morpholine-3-ketone of above-mentioned 2-methylol-4-benzyl-morpholine from chirality-3-ketone (IV) and chirality (IV ') is corresponding is: the mixing of the mixing of lithium aluminium hydride, lithium aluminium hydride and aluminum chloride, red aluminium, sodium borohydride, sodium borohydride and boron trifluoride ethers complex compound, the ethers complex compound of borine, the amine complex compound of borine.
The reaction of the 2-methylol-4-benzyl-morpholine (Ic) of the chirality that the mixture preparation of the 2-halogenated acetic acids ester group-4-benzyl-morpholine-3-ketone of above-mentioned 2-methylol-4-benzyl-morpholine from chirality-3-ketone (IV) and chirality (IV ') is corresponding is carried out under appropriate solvent, and selected solvent is: methylene dichloride, trichloromethane, tetracol phenixin, tetrahydrofuran (THF), dioxane, acetonitrile, toluene, dimethylbenzene, trimethylbenzene, ether, isopropyl ether, first uncle's ether, glycol dimethyl ether, diethylene glycol dimethyl ether, methyl alcohol.
It is roughly as follows that above-mentioned mixture from compound (IV) and (IV ') prepares the operating process of reaction of compound (Ic):
Mixture with compound (IV) and (IV ') in there-necked flask is dissolved in appropriate solvent, under ice bath reductive agent is added in the reaction system, reacts under proper temperature 1～24 hour.Add the shrend reaction system of going out after reaction finishes, and add organic solvent and extract, organic phase promptly gets compound (Ic) after reducing pressure after drying and removing organic solvent.Compound (Ic) can directly be done next step reaction without purifying, and also can purify by column chromatography or underpressure distillation.
The present invention is under the effect of palladium carbon from the reaction of the 2-hydroxymethyl morpholine (VI) of the corresponding chirality of 2-methylol-4-benzyl-morpholine (Ic) preparation of chirality, and hydrogenation is carried out under appropriate solvent, and temperature of reaction is 0～85 ℃, and reaction pressure is 1～10 normal atmosphere.
The selected solvent of reaction of the 2-hydroxymethyl morpholine (VI) of the chirality that above-mentioned 2-methylol from chirality-4-benzyl-morpholine (Ic) preparation is corresponding is: water, formic acid, acetate, methyl alcohol, ethanol, tetrahydrofuran (THF), ethyl acetate.
The operating process of above-mentioned reaction from compound (Ic) preparation compound (Ia) is roughly as follows:
In there-necked flask, add compound (Ic), palladium carbon and appropriate solvent, under hydrogen environment, under suitable temperature and pressure, reacted 1～72 hour.After removing by filter metal reagent, removal of solvent under reduced pressure promptly gets compound (Ia).This mixture can directly be done next step reaction without purifying, also can be by underpressure distillation this compound of purifying.
The present invention is from the reaction of the 2-methylol-N-replacement-morpholine (I) of the corresponding chirality of 2-hydroxymethyl morpholine (Ia) preparation of chirality, the mol ratio of the 2-hydroxymethyl morpholine (Ia) of chirality and corresponding electrophilic reagent is between 2: 1～1: 4, and temperature of reaction is-10～70 ℃.
The above-mentioned 2-hydroxymethyl morpholine (Ia) from chirality prepares the reaction of the 2-methylol-N-replacement-morpholine (I) of corresponding chirality to carry out under the alkali effect, and selected alkali is: triethylamine, diisopropyl ethyl amine, yellow soda ash, sodium bicarbonate, salt of wormwood, sodium hydroxide, potassium hydroxide, sodium hydride, sodium tert-butoxide, potassium tert.-butoxide.
The above-mentioned 2-hydroxymethyl morpholine (Ia) from chirality prepares the reaction of the 2-methylol-N-replacement-morpholine (I) of corresponding chirality to carry out under appropriate solvent, selected solvent is: water, methyl alcohol, ethanol, methylene dichloride, trichloromethane, tetrahydrofuran (THF), toluene, N, dinethylformamide, methyl-sulphoxide, acetonitrile.
The operating process of above-mentioned reaction from compound (Ia) preparation compound (I) is roughly as follows:
In there-necked flask, compound (Ia), corresponding electrophilic reagent and alkali are dissolved in appropriate solvent, under proper temperature, reacted 1～24 hour.System water and organic solvent extract, and remove water layer.Decompression removes organic solvent and obtains compound (I) simultaneously.
The invention has the advantages that and use raw material cheap and easy to get, as R configuration glycerin chlorohydrin, S configuration glycerin chlorohydrin, benzylamine etc., by a series of nucleophilic substitution reactions, reduction reaction or further amido replacement, prepared the 2-hydroxymethyl morpholine compounds (I) of a series of chirality easily.Not only step is short, and the yield height of reaction of per step, and it is convenient to purify, and target product purity height extremely is fit to suitability for industrialized production.
The present invention be advantageous in that used reagent is simple and safe, the intermediate of per step reaction need not further purification, has simplified experimental implementation greatly, and cost reduces greatly, is fit to mass production.
In a word, the invention has the advantages that all reagent of use are easy to get cheapness.Reaction scheme is succinctly easy to operate, mild condition, and the yield height, all intermediates need not further purification, and target product purity is very high.So present invention is particularly suitable for suitability for industrialized production.
Embodiment
Further specify technical scheme of the present invention with specific embodiment below, but protection scope of the present invention is not limited thereto:
Embodiment one R-3-benzamido group 1,2-propylene glycol (R-(II)) synthetic
2.3 kilograms of S-glycerin chlorohydrins, 0.85 kilogram of sodium hydroxide and 3.3 kilograms of benzylamines are mixed in the reaction flask, are warming up to 105 ℃, reacted 5 hours.Unnecessary benzylamine is removed in decompression, and gained compound R-(II) need not further purification is directly used in next step reaction.
Embodiment two R-N-chloracetyl-N-2,3-dihydroxypropyl benzylamine (R-(III)) and N-chloracetyl-N-(2-hydroxyl-3-Mono Chloro Acetic Acid ester group propyl group-benzylamine (R-(III ')) mixture synthetic
The crude product of above compound R-(II) and 3 kilograms of triethylamines are dissolved in 15 liters of methylene dichloride.Under ice bath, Dropwise 5 .1 kilogram chloroacetyl chloride slowly drips off the back in room temperature reaction 6 hours.
Reaction system is washed with 12 premium on currency, and organic layer is removed the mixture that organic solvent gets 4.8 kilograms of compound Rs-(III) and R-(III ') behind anhydrous sodium sulfate drying.Be directly used in next step reaction.
Embodiment three R-2-methylol-4-benzyl-morpholine-3-ketone (R-(IV)) and R-2-Mono Chloro Acetic Acid ester group-4-benzyl-morpholine-3-ketone (R-(IV ')) mixture synthetic
The mixture of 4.8 kilograms of above compound Rs-(III) and R-(III ') is dissolved in 40 liters of tetrahydrofuran (THF)s.Under ice bath, add 1.5 kilogram of 50% sodium hydride in batches.Room temperature reaction is 2 hours subsequently.
Under ice bath, in reaction mixture, add 25 premium on currency cancellation reaction, with 5 liters of ethyl acetate extractions 3 times.Organic layer is removed the mixture that organic solvent gets 3.6 kilograms of compound Rs-(IV) and R-(IV ') behind anhydrous sodium sulfate drying.Be directly used in next step reaction.
Synthesizing of experimental example four R-2-methylol-4-benzyl-morpholine (R-(Ic))
Mixture and 1.3 kilograms of sodium borohydrides of above 3.6 kilograms of compound Rs-(IV) and R-(IV ') are dissolved in 25 liters of methyl alcohol, afterwards reaction system were refluxed 12 hours.
After being cooled to room temperature, after methyl alcohol is removed in decompression, slowly drip 15 premium on currency solution, use 15 liters of dichloromethane extraction water layers subsequently to system.Organic layer is removed organic solvent behind anhydrous sodium sulfate drying, 2.7 kilograms of compound Rs-(Ic).
Synthesizing of embodiment five R-2-hydroxymethyl morpholines (R-(Ia))
Above 2.7 kilograms of compounds (R-Ic) are dissolved in 26 liters of methyl alcohol, add 320 grams, 10% palladium carbon, under nitrogen atmosphere, under 70 degree, reacted 24 hours.
Remove by filter metal reagent, removal of solvent under reduced pressure.1.14 kilograms of compound Rs-(Ia).
Synthesizing of embodiment six R-2-methylol-N-tertbutyloxycarbonyl-morpholine (R-(Ib))
Above 1.14 kilograms of compound Rs-(Ia) and 2.54 kilograms of sodium hydroxide are dissolved in 6 premium on currency, slowly drip 6 premium on currency solution of 2.2 kilograms of dimethyl dicarbonate butyl esters under the room temperature, drip off back room temperature reaction 12 hours.
In system, add 5 liters of ethyl acetate extractions, remove water layer.Organic layer is behind anhydrous sodium sulfate drying, and organic solvent is removed in decompression, gets 1.9 kilograms of oily matter.Oily matter is dissolved in amount of ethyl acetate, under agitation subsequently, drips a large amount of methyl alcohol, solid is separated out.This solid is carried out recrystallization, and with its recrystallization in methyl alcohol, cooling obtains 1.54 kilograms of white solids, is target compound R-(Ib), purity 99.8%, ee:99.7%.
Synthesizing of embodiment seven S-2-methylol-N-tertbutyloxycarbonyl-morpholine (S-(Ib))
To be dissolved in 6 premium on currency with 1.14 kilograms of S-2-hydroxymethyl morpholines (S-(VI)) and 2.54 kilograms of sodium hydroxide that same procedure obtains, slowly drip 6 premium on currency solution of 2.2 kilograms of dimethyl dicarbonate butyl esters under the room temperature, drip off back room temperature reaction 12 hours.
In system, add 5 liters of ethyl acetate extractions, remove water layer.Organic layer is behind anhydrous sodium sulfate drying, and organic solvent is removed in decompression, gets 1.82 kilograms of oily matter.Oily matter is dissolved in amount of ethyl acetate, under agitation subsequently, drips a large amount of methyl alcohol, solid is separated out.This solid is carried out recrystallization, and with its recrystallization in methyl alcohol, cooling obtains 1.48 kilograms of white solids, is target compound S-(Ib), purity 99.4%, ee:99.9%.
Synthesizing of embodiment eight R-2-methylol-N-methyl-morpholine (R-(Id))
The 1 gram R-2-hydroxymethyl morpholine (R-(Ia)) and the 1.74 gram triethylamines that obtain are dissolved in 6 milliliters of methylene dichloride, slowly drip 6 milliliters of dichloromethane solutions of 1.21 gram methyl iodide under the room temperature, drip off back room temperature reaction 13 hours.
In system, add the extraction of 10 ml waters, remove water layer.Organic layer is behind anhydrous sodium sulfate drying, and organic solvent is removed in decompression, and the oily matter of gained carries out column chromatography.Obtain 0.73 gram R-(Id).
Embodiment nine R-2-methylol-N-p-toluenesulfonyl morpholine R-'s (Ie) is synthetic
The 1 gram R-2-hydroxymethyl morpholine R-(Ia) and the 1.74 gram triethylamines that obtain are dissolved in 6 milliliters of methylene dichloride, slowly drip 6 milliliters of dichloromethane solutions of 1.64 gram Tosyl chlorides under the room temperature, drip off back room temperature reaction 24 hours.
In system, add the extraction of 10 ml waters, remove water layer.Organic layer is behind anhydrous sodium sulfate drying, and organic solvent is removed in decompression, and the oily matter of gained carries out column chromatography.Obtain 1.63 gram R-(Ie).
Synthesizing of embodiment ten R-2-methylol-N-trityl morpholine (R-(If))
The 1 gram R-2-hydroxymethyl morpholine (R-(Ia)) and the 1.74 gram triethylamines that obtain are dissolved in 6 milliliters of methylene dichloride, slowly drip 6 milliliters of dichloromethane solutions of 2.5 gram Tosyl chlorides under the room temperature, drip off back room temperature reaction 4 hours.
In system, add the extraction of 10 ml waters, remove water layer.Organic layer is behind anhydrous sodium sulfate drying, and organic solvent is removed in decompression, and the oily matter of gained carries out column chromatography.Obtain 1.9 gram R-(If).
Claims (10)
1. plant the method for preparing chirality 2-hydroxymethyl morpholine compounds (I),
Its feature comprises chirality glycerin chlorohydrin and benzylamine (BnNH
2) reaction obtains chipal compounds (II),
The reaction of compound (II) and halogen acetyl halide obtains the mixture of chipal compounds (III) and chipal compounds (III '),
The mixture that ring obtains chipal compounds (IV) and chipal compounds (IV ') takes place to close in the mixture of chipal compounds (III) and chipal compounds (III ') under alkaline condition,
The mixture of chipal compounds (IV) and chipal compounds (IV ') obtains chipal compounds (Ic) after reduction,
Chipal compounds (Ic) obtains chipal compounds (Ia) through hydrogenation,
Chipal compounds (Ia) carries out corresponding protection on amido, generate corresponding chipal compounds (I).
2. according in the described method for preparing chipal compounds (II) of claim 1, it is characterized in that in the glycerin chlorohydrin of property and the mol ratio of benzylamine be 30: 1～1: 30.
3. according in the described method for preparing chipal compounds (II) of claim 1, it is characterized in that selected alkali is triethylamine, diisopropyl ethyl amine, pyridine, morpholine, N-methylmorpholine, yellow soda ash, sodium bicarbonate, salt of wormwood, sodium hydroxide, potassium hydroxide.
4. chipal compounds N-chloro ethanoyl-N-(2-hydroxyl-3-chloracetic acid ester group propyl group)-benzylamine or chipal compounds N-bromo ethanoyl-N-(2-hydroxyl-3-monobromo-acetic acid ester group propyl group)-benzylamine (III ').
5. in the method according to the mixture of the described preparation chipal compounds of claim 1 (III) and chipal compounds (III '), it is characterized in that using chloroacetyl chloride or bromoacetyl bromide as acylating reagent.
6. chipal compounds 2-chloracetic acid ester group-4-benzyl-morpholine-3-ketone or 2-monobromo-acetic acid ester group-4-benzyl-morpholine-3-ketone (IV ').
7. in the method according to the mixture of the described preparation chipal compounds of claim 1 (IV) and chipal compounds (IV '), it is characterized in that selected alkali is: triethylamine, diisopropyl ethyl amine, pyridine, morpholine, N-methylmorpholine, piperidines, yellow soda ash, sodium bicarbonate, salt of wormwood, saleratus, sodium hydroxide, potassium hydroxide, sodium methylate, sodium ethylate, sodium tert-butoxide, potassium tert.-butoxide, sodium hydride.
8. in the method according to the mixture of claim 1 and the described preparation chipal compounds of claim 7 (IV) and chipal compounds (IV '), it is characterized in that selected solvent is: methyl chloride, trichloromethane, tetrahydrofuran (THF), N, dinethylformamide, methyl-sulphoxide, acetonitrile, toluene, ether, isopropyl ether, methyl alcohol, ethanol.
9. according in the described method for preparing chipal compounds (Ic) of claim 1, it is characterized in that selected reductive agent is: the mixing of the mixing of lithium aluminium hydride, lithium aluminium hydride and aluminum chloride, red aluminium, sodium borohydride, sodium borohydride and boron trifluoride ethers complex compound, the ethers complex compound of borine, the amine complex compound of borine.
10. according in the described method for preparing chipal compounds (Ic) of claim 1 and claim 9, it is characterized in that selected solvent is: methylene dichloride, trichloromethane, tetracol phenixin, tetrahydrofuran (THF), dioxane, acetonitrile, toluene, dimethylbenzene, trimethylbenzene, ether, isopropyl ether, first uncle's ether, glycol dimethyl ether, diethylene glycol dimethyl ether, methyl alcohol.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114213354A (en) * | 2021-12-30 | 2022-03-22 | 上海皓元生物医药科技有限公司 | Preparation method of trans-2- (substituted phenyl) -3-hydroxymethyl morpholine |
| CN115448907A (en) * | 2022-10-08 | 2022-12-09 | 赛隆药业集团股份有限公司 | Compound for treating peptic ulcer, intermediate and preparation method |
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| WO2008124575A1 (en) * | 2007-04-05 | 2008-10-16 | Smithkline Beecham Corporation | Renin inhibitors |
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| 马楠等: "N-Boc-(S)-二羟甲基吗啉的合成研究", 《化学试剂》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114213354A (en) * | 2021-12-30 | 2022-03-22 | 上海皓元生物医药科技有限公司 | Preparation method of trans-2- (substituted phenyl) -3-hydroxymethyl morpholine |
| CN114213354B (en) * | 2021-12-30 | 2023-04-25 | 上海皓元生物医药科技有限公司 | Preparation method of trans-2- (substituted phenyl) -3-oxymorphone |
| CN115448907A (en) * | 2022-10-08 | 2022-12-09 | 赛隆药业集团股份有限公司 | Compound for treating peptic ulcer, intermediate and preparation method |
| CN115448907B (en) * | 2022-10-08 | 2024-01-12 | 赛隆药业集团股份有限公司 | Compound for treating peptic ulcer, intermediate and preparation method thereof |
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| CN102212040B (en) | 2014-02-19 |
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