CN103880770A - Method for preparing chiral 3-morpholine methanol and 3-morpholine formic acid compounds - Google Patents
Method for preparing chiral 3-morpholine methanol and 3-morpholine formic acid compounds Download PDFInfo
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Abstract
The invention discloses a novel method for preparing chiral 3-morpholine methanol and 3-morpholine formic acid compounds. The method comprises the following steps: taking chiral serine as an initial material to obtain a serine ester (III) from a catalyst by esterification; reacting with halogen acetyl halide under an alkaline condition to obtain a compound (IV); obtaining a compound (V) by hydroxyl protection; adding a reducing agent to restore the ester into alcohol (VI); carrying out cyclization under the alkaline condition to obtain a compound (VII); obtaining a target product chiral 3-morpholine methanol compound (I) by amide reduction, hydroxyl deprotection and N protection; obtaining a chiral 3-morpholine formic acid compound (II) by oxidation. The method has the advantages of being low in cost, friendly to environment, simple to operate, high in yield, high in product purity and the like, the used reagent is simple and safe, and an intermediate in the reaction of each step does not need to be further purified, so that the experiment operation is greatly simplified, the production cost is reduced, and the method is applicable to industrial production.
Description
Technical field
The present invention relates to fine chemical technology field, be specifically related to the new preparation process of a kind of chirality 3-morpholine methyl alcohol class and 3-morpholine formic acid compounds.
Background technology
3-morpholine methyl alcohol class (I) compound and 3-morpholine formic acid class (II) compound of chirality are broad-spectrum key medicine intermediates, and many pharmaceutical factories are all being used this series compound in new drug development.Existing synthetic technology exists that raw material costliness is not easy to obtain conventionally, technical sophistication, condition harshness, yield is extremely low, chiral purity is not high, be not suitable for the shortcomings such as industrial production.
Therefore the synthetic attention that is more and more subject to chemists of chirality 3-morpholine methyl alcohol class (I) compound and 3-morpholine formic acid class (II) compound.
Shanghai Chang Feng biological medicine Science and Technology Ltd. discloses one piece of patent about (S)-3 morpholine carboxylic acid new synthetic method for 2012, and its synthetic route is as shown in the formula described:
It is starting raw material that this synthetic route is used Serine, and route looks shorter, but this route need to use strong oxidizer perchloric acid, and this compound is abnormally dangerous, in addition, closes the impact of that step of ring due to ester group, amplifies yield very low, is not suitable for industrialization.
John D.DiMarco has equaled to disclose for 2006 one piece of patent that relates to (R)-N-Boc-3-morpholine methyl alcohol, and its synthetic route is as shown in the formula described:
This synthetic route is also that use Serine is starting raw material, and synthetic route is very short, but yield is extremely low above, and uses hypertoxic borine dimethyl sulphide and expensive palladium carbon catalyst, and this route is not suitable for suitability for industrialized production on the whole.
Summary of the invention
In view of this, the object of the invention is to provide a kind of with low cost, environmental friendliness, simple to operate, yield is high, product purity is high and the new preparation process of the chirality 3-morpholine methyl alcohol compounds of applicable suitability for industrialized production.
To achieve these goals, the invention provides following technical scheme:
The preparation method of chirality 3-morpholine methyl alcohol compounds of the present invention, can represent with following reaction formula:
In formula, R is C
1～C
8alkyl, C
1～C
6alkyl sulphonyl, C
1～C
4alkyl oxygen carbonyl, phenyl, phenylmethylene oxygen carbonyl, trityl, phenyl sulfonyl or the substituted-phenyl that comprises one or more halogens, nitro, alkyl, alkoxyl group; R
1for methyl, ethyl, n-propyl, normal-butyl, benzyl, the tertiary butyl or tert-pentyl; R
2for methoxyl methyl, trityl, trimethyl silicon based, t-Butyldimethylsilyl or tert-butyl diphenyl silica-based; X is chlorine or bromine.
The present invention is take chirality Serine as starting raw material; obtain serine ester (III) by catalyzer esterification; the serine ester (III) of gained reacts under alkaline condition with halogen acetyl halide and obtains compound (IV); compound (IV) obtains compound (V) through hydroxyl protection; compound (V) adds reductive agent that ester is reduced to alcohol (VI); alcohol (VI) ring closure reaction under alkaline condition obtains compound (VII), and compound (VII) obtains target product (I) through reduction of amide, hydroxyl deprotection, N protection.
Concrete, the preparation method of described chirality 3-morpholine methyl alcohol compounds comprises the steps:
(1) in reaction unit, add chirality Serine, alcohol and the first catalyzer, after mixing, 0～150 ℃ is reacted 1～24 hour, reaction solution is adjusted to weakly alkaline, after concentrated, obtain the compound (III) of saliferous, described chirality Serine and the mol ratio of alcohol are (30: 1)～(1: 30), and the first described catalyzer is any one in sulfuric acid, thionyl chloride, hydrochloric acid, phosphoric acid, sodium hydroxide;
Preferably, described alcohol is any one in methyl alcohol, ethanol, propyl alcohol, butanols, benzylalcohol.
(2) in reaction unit, add compound (III), alkali (A) and solvent (a), under cooling, add halogen acetyl halide, at-78～50 ℃, react 1～24 hour, after reaction finishes, wash organic phase with saturated nacl aqueous solution, organic phase drying, the concentrated compound (IV) that to obtain, described compound (III) is (5: 1)～(1: 6) with the mol ratio of halogen acetyl halide;
Preferably, described halogen acetyl halide is chloroacetyl chloride or bromoacetyl bromide.
Preferably, described alkali (A) is at least one in triethylamine, pyridine, DMAP, morpholine, sodium carbonate, salt of wormwood, sodium bicarbonate, sodium hydride, sodium hydroxide, potassium hydride KH, potassium hydroxide.
Preferably, described solvent (a) is at least one in toluene, tetrahydrofuran (THF), ethylene dichloride, trichloromethane, methylene dichloride, methyl alcohol, ethanol, acetonitrile, ether, methyl tertiary butyl ether.
(3) in reaction unit, add compound (IV), alkali (B) and solvent (b), add protecting group reagent, at-20～60 ℃, react 1～24 hour, after reaction finishes, add saturated sodium-chloride water solution, organic solvent extraction, organic phase drying, the concentrated compound (V) that to obtain, described protecting group is any one in trimethylchlorosilane, TERT-BUTYL DIMETHYL CHLORO SILANE, tert-butyl diphenyl chlorosilane, chloromethyl methyl ether;
Preferably, described alkali (B) is at least one in triethylamine, pyridine, pyrazoles, DMAP, morpholine, sodium carbonate, salt of wormwood, sodium bicarbonate, sodium hydride, sodium hydroxide, potassium hydride KH, potassium hydroxide.
Preferably, described solvent (b) is dimethyl sulfoxide (DMSO), N, at least one in N-dimethylformamide, toluene, tetrahydrofuran (THF), ethylene dichloride, trichloromethane, methylene dichloride, acetonitrile, ether, methyl tertiary butyl ether.
(4) in reaction unit, add compound (V) and solvent (c), at-50～100 ℃, add the first reductive agent, after reaction finishes, cancellation adds water, organic extractant phase, organic phase drying, the concentrated compound (VI) that to obtain, the first described reductive agent is at least one in POTASSIUM BOROHYDRIDE, lithium borohydride, calcium borohydride, sodium borohydride, lithium aluminium hydride, sodium cyanoborohydride, diisobutyl aluminium hydride, sodium triacetoxy borohydride;
Preferably, described solvent (c) is at least one in water, methyl alcohol, ethanol, Virahol, propyl alcohol, the trimethyl carbinol, butanols, toluene, ether, methyl tertiary butyl ether, isopropyl ether, dioxane, tetrahydrofuran (THF), glycol dimethyl ether, diethylene glycol dimethyl ether.
(5) at-50～100 ℃, in reaction unit, add solvent (d), alkali (C) and compound (VI), stirring reaction 1～24 hour, after reaction finishes, cancellation adds water, add organic solvent extraction, organic phase drying, the concentrated compound (VII) that to obtain;
Preferably, described alkali (C) is at least one in triethylamine, pyridine, DMAP, morpholine, sodium ethylate, sodium tert-butoxide, sodium tert-amyl alcohol, sodium carbonate, salt of wormwood, sodium bicarbonate, sodium hydride, sodium hydroxide, potassium hydride KH, potassium hydroxide, lithium hydroxide.
Preferably, described solvent (d) is at least one in methyl alcohol, ethanol, Virahol, propyl alcohol, the trimethyl carbinol, butanols, toluene, ether, methyl tertiary butyl ether, isopropyl ether, dioxane, tetrahydrofuran (THF), glycol dimethyl ether, diethylene glycol dimethyl ether.
(6) in reaction unit, add compound (VII) and solvent (e), add the second reductive agent under cooling, react 1～24 hour the cancellation that adds water, separatory, gained organic phase drying at-20～150 ℃, concentrate to obtain intermediate, described intermediate joins in solvent (f), add Deprotection reagent, at-20～150 ℃, react 1～24 hour, reaction solution adjusts pH value to alkalescence, adds alkali (d) and N protecting group reagent, react 1～24 hour, after finishing, reaction adds organic solvent, washing, organic phase drying, concentrate and to obtain chirality 3-morpholine methyl alcohol compounds (I) crude product, the purified target chiral product (I) that obtains of crude product, the second described reductive agent is lithium aluminium hydride, sodium borohydride, lithium aluminium hydride and aluminum chloride mixture, red aluminium, sodium borohydride and iodine mixture, sodium borohydride and boron trifluoride mixture, borine ethers complex compound or borine amine complex compound, described Deprotection reagent is tetrabutyl ammonium fluoride, boron trifluoride, hydrochloric acid, sulfuric acid or Potassium monofluoride, described N protecting group is fluorenes methoxy dicarbonyl chloride, to Methanesulfonyl chloride, trifluoroacetic anhydride, trityl chloride, tert-Butyl dicarbonate, chloroformic acid benzyl ester, phenyl aldehyde, Benzyl Chloride, cylite or diacetyl oxide.
Preferably, described alkali (d) is at least one in triethylamine, pyridine, DMAP, morpholine, sodium ethylate, sodium tert-butoxide, sodium tert-amyl alcohol, sodium carbonate, salt of wormwood, sodium bicarbonate, sodium hydride, sodium hydroxide, potassium hydride KH, potassium hydroxide, lithium hydroxide.
Preferably, described solvent (e) and solvent (f) are water, acetone, acetonitrile, tetrahydrofuran (THF), N, at least one in N-dimethylformamide.
Based on above-mentioned technical scheme, the present invention further provides a kind of new preparation process of chirality 3-morpholine formic acid compounds, compound (I) obtains compound (II) through peroxidation, be specially: first prepare compound (I), in reaction unit, add compound (I), alkali (e), the second catalyzer, solvent (g), under cooling, add oxygenant, at-20～80 ℃, react 1～24 hour, reaction finishes rear filtration, solid washing, liquid phase solvent extraction, water is adjusted to acidity, solvent extraction, organic phase drying, concentrate to obtain target chiral product (II).
Preferably, described oxygenant is at least one in Textone, calcium chlorite, potassium chlorite, potassium hypochlorite, clorox, Losantin.
Preferably, described alkali (e) is at least one in sodium carbonate, salt of wormwood, saleratus, sodium bicarbonate.
Preferably, the second described catalyzer is at least one in tetramethyl piperidine oxynitride, Australia's potassium, potassiumiodide.
Preferably, described solvent (g) is water, acetone, acetonitrile, tetrahydrofuran (THF), N, at least one in N-dimethylformamide.
Compared with prior art, that method provided by the invention has is with low cost, environmental friendliness, simple to operate, yield is high, product purity advantages of higher, agents useful for same is simple and safe, the intermediate of every step reaction is without further purification, greatly simplify experimental implementation, reduce production cost, be applicable to suitability for industrialized production.
Embodiment
Below in conjunction with the embodiment of the present invention, technical scheme of the present invention is described in detail, obviously, described embodiment is only the present invention's part embodiment, rather than whole embodiment.Based on the embodiment in the present invention, the every other embodiment that those of ordinary skills obtain under the prerequisite of not making creative work, belongs to the scope of protection of the invention.
Test raw materials used reagent and all can be buied by free market, its purity is chemical pure.
Embodiment 1
(1) Serine ethyl ester (S-(III)) is synthetic
5kg Serine joins in 50L dehydrated alcohol, and 0 ℃ splashes into the 4.6kg vitriol oil, adds 78 ℃ of reactions 12 hours.At 0 ℃, reaction solution is splashed in the saturated solution that 5kg sodium carbonate is made into, steam the mixture desolventizing, directly throw next step.
(2) synthesizing of (S)-2-chloracetyl amino-3-hydroxy-propionic acid ethyl ester (S-(IV))
In above-mentioned product, add 50L methylene dichloride, 5.8kg triethylamine; under ice bath, add 5.4kg chloroacetyl chloride; add room temperature reaction 12 hours; reaction solution 20L washing; organic phase after dried over sodium sulfate, concentrated 9kg (yield 90%) (S)-2-chloracetyl amino-3-hydroxy-propionic acid ethyl ester.
(3) synthesizing of (S)-2-chloracetyl amino-3-(trimethyl silicon based) oxygen base ethyl propionate (S-(V))
9kg (S)-2-chloracetyl amino-3-hydroxy-propionic acid ethyl ester, 4kg pyridine join in 90L tetrahydrofuran (THF); under ice bath, splash into 5kg trimethylchlorosilane; add room temperature reaction 6 hours; steam except tetrahydrofuran (THF); add 15L water; 15L dichloromethane extraction, organic phase through dried over sodium sulfate, concentrated 12.1kg (yield 100%) (S)-2-chloracetyl amino-3-(trimethyl silicon based) oxygen base ethyl propionate.
(4) synthesizing of (R)-2-chloracetyl amino-3-(trimethyl silicon based) oxygen base propyl alcohol (R-(VI))
10kg (S)-2-chloracetyl amino-3-(trimethyl silicon based) oxygen base ethyl propionate joins in 80L tetrahydrofuran (THF); under room temperature, add 4kg POTASSIUM BOROHYDRIDE in batches; react 24 hours; the cancellation that adds water reaction; steam except tetrahydrofuran (THF); add 10L water, 15L dichloromethane extraction, organic phase through dried over sodium sulfate, concentrated 7.6kg (yield 90%) (R)-2-chloracetyl amino-3-(trimethyl silicon based) oxygen base propyl alcohol.
(5) synthesizing of (R)-5-(((trimethyl silicon based) oxygen base) methyl) morpholine-3-ketone (R-(VII))
7kg (R)-2-chloracetyl amino-3-(trimethyl silicon based) oxygen base propyl alcohol joins in 50L tetrahydrofuran (THF); under ice bath, add 1.5kg50% sodium hydride in batches; react 5 hours; after reaction finishes, adding 20L shrend goes out; steam except tetrahydrofuran (THF); water 15L dichloromethane extraction, organic phase is through dried over sodium sulfate, concentrated (R)-5-of 5.3kg (yield 90%) (((trimethyl silicon based) oxygen base) methyl) morpholine-3-ketone that to obtain.
(6) synthesizing of (S)-N-tertbutyloxycarbonyl-3-morpholine methyl alcohol (S-(I))
5kg (R)-5-(((trimethyl silicon based) oxygen base) methyl) morpholine-3-ketone joins in 30L tetrahydrofuran (THF), under room temperature, add two (dimethoxy oxyethyl group) the sodium aluminate toluene solutions of 8.5kg70%2-hydrogen, back flow reaction 12 hours, under cooling, splash into 6.5kg concentrated hydrochloric acid, reflux 5 hours.Be cooled to room temperature, separatory, water 20L dichloromethane extraction, organic phase evaporate to dryness after dried over sodium sulfate obtains intermediate. and intermediate joins in 30L tetrahydrofuran (THF), add 7.5kg tetrabutyl ammonium fluoride, room temperature reaction 5 hours, cooling, under ice bath, add 6.2kg triethylamine and 5.4kg tert-Butyl dicarbonate, room temperature reaction 24 hours.Organic phase is washed with 10L, and water 10L dichloromethane extraction merges organic phase, through dried over sodium sulfate, concentrated 4kg (yield 78%) (S)-N-Boc-3-morpholine methyl alcohol.
Characterization of The Products data are as follows: Mp80 ℃; Optically-active+60.4 (c1.1, CHCl
3); 1H NMR (300MHz, CDCl
3) δ 1.47 (9H, s, OC (CH
3)
3), 2.22 (1H, br s, OH), 3.17 (Ha, td, J=12.7,3.2Hz, NCHaHb), 3.46 (Ha, td, J=11.8,3Hz, COCHaHb), 3.57 (Hb, dd, J=11.9,3.6Hz, COCHaHb), 3.87 (5H+Hb, m, COCH
2, NCH, CH
2-hydroxyl, NCHaHb).
Embodiment 2
(1) D-Ser ethyl ester (R-(III)) is synthetic
5kg Serine joins in 50L dehydrated alcohol, and 0 ℃ splashes into 4.5kg phosphoric acid, adds 78 ℃ of reactions 12 hours.At 0 ℃, reaction solution is splashed in the saturated solution that 5kg sodium carbonate is made into, steam the mixture desolventizing, directly throw next step.
(2) synthesizing of (R)-2-chloracetyl amino-3-hydroxy-propionic acid ethyl ester (R-(IV))
In above-mentioned product, add 50L methylene dichloride, 5.8kg triethylamine; under ice bath, add 9.6kg acetobrom Australia; add room temperature reaction 12 hours; reaction solution 20L washing; organic phase after dried over sodium sulfate, concentrated 9.2kg (yield 91%) (R)-2-chloracetyl amino-3-hydroxy-propionic acid ethyl ester.
(3) synthesizing of (R)-2-chloracetyl amino-3-(trimethyl silicon based) oxygen base ethyl propionate (R-(V))
9.2kg (R)-2-chloracetyl amino-3-hydroxy-propionic acid ethyl ester, 5.2kg triethylamine join in 92L tetrahydrofuran (THF); under ice bath, splash into 5kg trimethylchlorosilane; add room temperature reaction 6 hours; steam except tetrahydrofuran (THF); add 15L water; 15L dichloromethane extraction, organic phase through dried over sodium sulfate, concentrated 12kg (yield 99%) (R)-2-chloracetyl amino-3-(trimethyl silicon based) oxygen base ethyl propionate.
(4) synthesizing of (S)-2-chloracetyl amino-3-(trimethyl silicon based) oxygen base propyl alcohol (S-(VI))
10kg (R)-2-chloracetyl amino-3-(trimethyl silicon based) oxygen base ethyl propionate joins in 80L tetrahydrofuran (THF); under room temperature, add 3.8kg sodium borohydride in batches; react 24 hours; the cancellation that adds water reaction; steam except tetrahydrofuran (THF); add 10L water, 15L dichloromethane extraction, organic phase through dried over sodium sulfate, concentrated 8kg (yield 92%) (S)-2-chloracetyl amino-3-(trimethyl silicon based) oxygen base propyl alcohol.
(5) synthesizing of (S)-5-(((trimethyl silicon based) oxygen base) methyl) morpholine-3-ketone (S-(VII))
7kg (S)-2-chloracetyl amino-3-(trimethyl silicon based) oxygen base propyl alcohol joins in 50L anhydrous methanol; under ice bath, add 1.7kg sodium methylate in batches; react 5 hours; after reaction finishes, adding 20L shrend goes out; steam except methyl alcohol; water 15L dichloromethane extraction, organic phase is through dried over sodium sulfate, concentrated (S)-5-of 5.5kg (yield 92%) (((trimethyl silicon based) oxygen base) methyl) morpholine-3-ketone that to obtain.
(6) synthesizing of (R)-N-tertbutyloxycarbonyl-3-morpholine methyl alcohol (R-(I))
5kg (S)-5-(((trimethyl silicon based) oxygen base) methyl) morpholine-3-ketone joins in 30L diethylene glycol dimethyl ether, under room temperature, add 1.5kg lithium aluminium hydride, back flow reaction 12 hours, under cooling, splash into 6.5kg concentrated hydrochloric acid, reflux 5 hours.Be cooled to room temperature, separatory, water 20L dichloromethane extraction, organic phase evaporate to dryness after dried over sodium sulfate obtains intermediate. and intermediate joins in 30L tetrahydrofuran (THF), add 7.5kg tetrabutyl ammonium fluoride, room temperature reaction 5 hours, cooling, under ice bath, add 3kg triethylamine and 5.4kg tert-Butyl dicarbonate, room temperature reaction 24 hours.Organic phase is washed with 10L, and water 10L dichloromethane extraction merges organic phase, through dried over sodium sulfate, concentrated 4kg (yield 78%) (R)-N-Boc-3-morpholine methyl alcohol.
Characterization of The Products data are as follows: Mp80 ℃; Optically-active-60.4 (c1.1, CHCl
3); 1H NMR (300MHz, CDCl
3) δ 1.47 (9H, s, OC (CH
3)
3), 2.22 (1H, br s, OH), 3.17 (Ha, td, J=12.7,3.2Hz, NCHaHb), 3.46 (Ha, td, J=11.8,3Hz, COCHaHb), 3.57 (Hb, dd, J=11.9,3.6Hz, COCHaHb), 3.87 (5H+Hb, m, COCH
2, NCH, CH
2-hydroxyl, NCHaHb).
Embodiment 3
(1) Serine ethyl ester (S-(III)) is synthetic
5kg Serine joins in 50L dehydrated alcohol, and 0 ℃ passes into 1kg HCl, adds 78 ℃ of reactions 12 hours.At 0 ℃, reaction solution is splashed in the saturated solution that 5kg sodium carbonate is made into, steam the mixture desolventizing, directly throw next step.
(2) synthesizing of (S)-2-chloracetyl amino-3-hydroxy-propionic acid ethyl ester (S-(IV))
In above-mentioned product Serine ethyl ester (S-(III)), add 50L acetonitrile, 5.8kg pyridine; under ice bath, add 5.4kg chloroacetyl chloride; add room temperature reaction 12 hours; reaction solution 20L washing; organic phase after dried over sodium sulfate, concentrated 9.2kg (yield 91%) (S)-2-chloracetyl amino-3-hydroxy-propionic acid ethyl ester.
(3) synthesizing of (S)-2-chloracetyl amino-3-(trimethyl silicon based) oxygen base ethyl propionate (S-(V))
9kg (S)-2-chloracetyl amino-3-hydroxy-propionic acid ethyl ester, 4kg diisopropylethylamine join in 90LDMF; under ice bath, splash into 5kg trimethylchlorosilane; add room temperature reaction 6 hours; add 90L water; 3 × 15L dichloromethane extraction, organic phase through dried over sodium sulfate, concentrated 12.5kg (yield > 100%) (S)-2-chloracetyl amino-3-(trimethyl silicon based) oxygen base ethyl propionate.
(4) synthesizing of (R)-2-chloracetyl amino-3-(trimethyl silicon based) oxygen base propyl alcohol (R-(VI))
10kg (S)-2-chloracetyl amino-3-(trimethyl silicon based) oxygen base ethyl propionate joins 80L anhydrous methanol; under room temperature, add 3.8kg sodium borohydride in batches; react 24 hours; the cancellation that adds water reaction; steam except methyl alcohol; add 10L water, 15L dichloromethane extraction, organic phase through dried over sodium sulfate, concentrated 7.8kg (yield 92%) (R)-2-chloracetyl amino-3-(trimethyl silicon based) oxygen base propyl alcohol.
(5) synthesizing of (R)-5-(((trimethyl silicon based) oxygen base) methyl) morpholine-3-ketone (R-(VII))
7kg (R)-2-chloracetyl amino-3-(trimethyl silicon based) oxygen base propyl alcohol joins in 50L dehydrated alcohol; under ice bath, add 2kg sodium ethylate in batches; react 5 hours; after reaction finishes, adding 20L shrend goes out; steaming desolventizes; water 15L dichloromethane extraction, organic phase is through dried over sodium sulfate, concentrated (R)-5-of 5.4kg (yield 91%) (((trimethyl silicon based) oxygen base) methyl) morpholine-3-ketone that to obtain.
(6) synthesizing of (S)-N-tertbutyloxycarbonyl-3-morpholine methyl alcohol (S-(I))
5kg (R)-5-(((trimethyl silicon based) oxygen base) methyl) morpholine-3-ketone joins in 30L glycol dimethyl ether, under room temperature, add 2kg sodium borohydride, back flow reaction 24 hours, splashes into 6.5kg concentrated hydrochloric acid, reflux 5 hours under cooling.Be cooled to room temperature, filter, solid is washed with 10L methylene dichloride, filtrate separatory, water 20L dichloromethane extraction, organic phase evaporate to dryness after dried over sodium sulfate obtains intermediate. under intermediate room temperature, joins in 10L tetrahydrofuran (THF) and 5L concentrated hydrochloric acid, room temperature reaction 5 hours, cooling, under ice bath, add 6kg sodium hydroxide and 5.4kg tert-Butyl dicarbonate, room temperature reaction 24 hours.Dichloromethane extraction 20L, organic phase through dried over sodium sulfate, concentrated 4kg (yield 78%) (S)-N-Boc-3-morpholine methyl alcohol.
(7) synthesizing of (R)-N-Boc-3-morpholine formic acid (R-(II))
2kg (S)-N-Boc-3-morpholine methyl alcohol, 1.5kg sodium bicarbonate, 143g tetramethyl piperidine oxynitride join in 5L tetrahydrofuran (THF), under room temperature, splash into 13kg10% sodium chlorite aqueous solution, add room temperature reaction 12 hours, reaction solution 2L petroleum ether extraction, water hydrochloric acid is adjusted pH value to 5,10L dichloromethane extraction, organic phase through dried over sodium sulfate, concentrated 2kg (yield 95%) (R)-N-Boc-3-morpholine formic acid.
Characterization of The Products data are as follows: mp181 ℃; Optically-active+73 (c1.1, MeOH); 1H NMR (300MHz, DMSO-d6) d1.37,1.47 (9H, two s, OC (CH
3)
3), 2.99 (Ha, td, J=12.7,3.7Hz, NCHaHb), 3.17 (0.5Ha, td, J=12.4,3.3Hz, NCHaHb), 3.37 (Ha, m, COCHaHb), 3.55 (2Hb, m, COCHaHb, NCHaHb), 3.78 (Hc, td, J=14.7,3.3Hz, COCHcHd), 4.15 (Hd, t, J=11.6Hz, COCHcHd), 4.31 (1H, dd, J=15.2,2.7Hz, NCH).
To those skilled in the art, obviously the invention is not restricted to the details of above-mentioned one exemplary embodiment, and in the situation that not deviating from spirit of the present invention or essential characteristic, can realize the present invention with other specific form.Therefore, no matter from which point, all should regard embodiment as exemplary, and be nonrestrictive, scope of the present invention is limited by claims rather than above-mentioned explanation, is therefore intended to all changes that drop in the implication and the scope that are equal to important document of claim to include in the present invention.
In addition, be to be understood that, although this specification sheets is described according to embodiment, but be not that each embodiment only comprises an independently technical scheme, this narrating mode of specification sheets is only for clarity sake, those skilled in the art should make specification sheets as a whole, and the technical scheme in each embodiment also can, through appropriately combined, form other embodiments that it will be appreciated by those skilled in the art that.
Claims (9)
1. a preparation method for chirality 3-morpholine methyl alcohol compounds, is characterized in that, comprises the steps:
(1) in reaction unit, add chirality Serine, alcohol and the first catalyzer, after mixing, 0～150 ℃ is reacted 1～24 hour, reaction solution is adjusted to weakly alkaline, after concentrated, obtain the compound (III) of saliferous, described chirality Serine and the mol ratio of alcohol are (30: 1)～(1: 30), and the first described catalyzer is any one in sulfuric acid, thionyl chloride, hydrochloric acid, phosphoric acid, sodium hydroxide;
(2) in reaction unit, add compound (III), alkali (A) and solvent (a), under cooling, add halogen acetyl halide, at-78～50 ℃, react 1～24 hour, after reaction finishes, wash organic phase with saturated nacl aqueous solution, organic phase drying, the concentrated compound (IV) that to obtain, described compound (III) is (5: 1)～(1: 6) with the mol ratio of halogen acetyl halide;
(3) in reaction unit, add compound (IV), alkali (B) and solvent (b), add protecting group reagent, at-20～60 ℃, react 1～24 hour, after reaction finishes, add saturated sodium-chloride water solution, organic solvent extraction, organic phase drying, the concentrated compound (V) that to obtain, described protecting group is any one in trimethylchlorosilane, TERT-BUTYL DIMETHYL CHLORO SILANE, tert-butyl diphenyl chlorosilane, chloromethyl methyl ether;
(4) in reaction unit, add compound (V) and solvent (c), at-50～100 ℃, add the first reductive agent, after reaction finishes, cancellation adds water, organic extractant phase, organic phase drying, the concentrated compound (VI) that to obtain, the first described reductive agent is at least one in POTASSIUM BOROHYDRIDE, lithium borohydride, calcium borohydride, sodium borohydride, lithium aluminium hydride, sodium cyanoborohydride, diisobutyl aluminium hydride, sodium triacetoxy borohydride;
(5) at-50～100 ℃, in reaction unit, add solvent (d), alkali (C) and compound (VI), stirring reaction 1～24 hour, after reaction finishes, cancellation adds water, add organic solvent extraction, organic phase drying, the concentrated compound (VII) that to obtain;
(6) in reaction unit, add compound (VII) and solvent (e), add the second reductive agent under cooling, react 1～24 hour the cancellation that adds water, separatory, gained organic phase drying at-20～150 ℃, concentrate to obtain intermediate, described intermediate joins in solvent (f), add Deprotection reagent, at-20～150 ℃, react 1～24 hour, reaction solution adjusts pH value to alkalescence, adds alkali (d) and N protecting group reagent, react 1～24 hour, after finishing, reaction adds organic solvent, washing, organic phase drying, concentrate and to obtain chirality 3-morpholine methyl alcohol compounds (I) crude product, the purified target chiral product (I) that obtains of crude product, the second described reductive agent is lithium aluminium hydride, sodium borohydride, lithium aluminium hydride and aluminum chloride mixture, red aluminium, sodium borohydride and iodine mixture, sodium borohydride and boron trifluoride mixture, borine ethers complex compound or borine amine complex compound, described Deprotection reagent is tetrabutyl ammonium fluoride, boron trifluoride, hydrochloric acid, sulfuric acid or Potassium monofluoride, described N protecting group is fluorenes methoxy dicarbonyl chloride, Tosyl chloride, trifluoroacetic anhydride, trityl chloride, tert-Butyl dicarbonate, chloroformic acid benzyl ester, phenyl aldehyde, Benzyl Chloride, Australia's benzyl or diacetyl oxide,
In formula, R is C
1～C
8alkyl, C
1～C
6alkyl sulphonyl, C
1～C
4alkyl oxygen carbonyl, phenyl, phenylmethylene oxygen carbonyl, trityl, phenyl sulfonyl or the substituted-phenyl that comprises one or more halogens, nitro, alkyl, alkoxyl group; R
1for methyl, ethyl, n-propyl, normal-butyl, benzyl, the tertiary butyl or tert-pentyl; R
2for methoxyl methyl, trityl, trimethyl silicon based, t-Butyldimethylsilyl or tert-butyl diphenyl silica-based; X is chlorine or bromine.
2. preparation method according to claim 1, is characterized in that: in step (1), described alcohol is any one in methyl alcohol, ethanol, propyl alcohol, butanols, benzylalcohol.
3. preparation method according to claim 1, is characterized in that: in step (2), described halogen acetyl halide is chloroacetyl chloride or Australia's acetyl bromide; Described alkali (A) is at least one in triethylamine, pyridine, DMAP, morpholine, sodium carbonate, salt of wormwood, sodium bicarbonate, sodium hydride, sodium hydroxide, potassium hydride KH, potassium hydroxide; Described solvent (a) is at least one in toluene, tetrahydrofuran (THF), ethylene dichloride, trichloromethane, methylene dichloride, methyl alcohol, ethanol, acetonitrile, ether, methyl tertiary butyl ether.
4. preparation method according to claim 1, it is characterized in that: in step (3), described alkali (B) is at least one in triethylamine, pyridine, pyrazoles, DMAP, morpholine, sodium carbonate, salt of wormwood, sodium bicarbonate, sodium hydride, sodium hydroxide, potassium hydride KH, potassium hydroxide; Described solvent (b) is dimethyl sulfoxide (DMSO), N, at least one in N-dimethylformamide, toluene, tetrahydrofuran (THF), ethylene dichloride, trichloromethane, methylene dichloride, acetonitrile, ether, methyl tertiary butyl ether.
5. preparation method according to claim 1, it is characterized in that: in step (4), described solvent (c) is at least one in water, methyl alcohol, ethanol, Virahol, propyl alcohol, the trimethyl carbinol, butanols, toluene, ether, methyl tertiary butyl ether, isopropyl ether, dioxane, tetrahydrofuran (THF), glycol dimethyl ether, diethylene glycol dimethyl ether.
6. preparation method according to claim 1, it is characterized in that: in step (5), described alkali (C) is at least one in triethylamine, pyridine, DMAP, morpholine, sodium ethylate, sodium tert-butoxide, sodium tert-amyl alcohol, sodium carbonate, salt of wormwood, sodium bicarbonate, sodium hydride, sodium hydroxide, potassium hydride KH, potassium hydroxide, lithium hydroxide; Described solvent (d) is at least one in methyl alcohol, ethanol, Virahol, propyl alcohol, the trimethyl carbinol, butanols, toluene, ether, methyl tertiary butyl ether, isopropyl ether, dioxane, tetrahydrofuran (THF), glycol dimethyl ether, diethylene glycol dimethyl ether.
7. preparation method according to claim 1, it is characterized in that: in step (6), described alkali (d) is at least one in triethylamine, pyridine, DMAP, morpholine, sodium ethylate, sodium tert-butoxide, sodium tert-amyl alcohol, sodium carbonate, salt of wormwood, sodium bicarbonate, sodium hydride, sodium hydroxide, potassium hydride KH, potassium hydroxide, lithium hydroxide; Described solvent (e) and solvent (f) are water, acetone, acetonitrile, tetrahydrofuran (THF), N, at least one in N-dimethylformamide.
8. a preparation method for chirality 3-morpholine formic acid compounds, is characterized in that, comprises the steps:
First make chirality 3-morpholine methyl alcohol compounds (I) according to the preparation method described in claim 1～7 any one, in reaction unit, add compound (I), alkali (e), the second catalyzer, solvent (g), under cooling, add oxygenant, at-20～80 ℃, react 1～24 hour, reaction finishes rear filtration, solid washing, liquid phase solvent extraction, water is adjusted to acidity, solvent extraction, organic phase drying, the concentrated target chiral product (II) that to obtain
In formula, R is C
1～C
8alkyl, C
1～C
6alkyl sulphonyl, C
1～C
4alkyl oxygen carbonyl, phenyl, phenylmethylene oxygen carbonyl, trityl, phenyl sulfonyl or the substituted-phenyl that comprises one or more halogens, nitro, alkyl, alkoxyl group.
9. preparation method according to claim 8, is characterized in that: described oxygenant is at least one in Textone, calcium chlorite, potassium chlorite, potassium hypochlorite, clorox, Losantin; Described alkali (e) is at least one in sodium carbonate, salt of wormwood, saleratus, sodium bicarbonate; The second described catalyzer is at least one in tetramethyl piperidine oxynitride, Australia's potassium, potassiumiodide; Described solvent (g) is water, acetone, acetonitrile, tetrahydrofuran (THF), N, at least one in N-dimethylformamide.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101906097A (en) * | 2009-06-02 | 2010-12-08 | 首都医科大学 | 1,3-dioxane compounds as well as synthesizing method and medical application thereof |
| JP2011178779A (en) * | 2010-02-04 | 2011-09-15 | Daiichi Sankyo Co Ltd | Imidazopyridin-2-one derivative |
| CN102617503A (en) * | 2011-03-03 | 2012-08-01 | 上海常丰生物医药科技有限公司 | Novel synthetic method of (S)-3-morpholinyl carboxylic acid |
| WO2012120476A1 (en) * | 2011-03-10 | 2012-09-13 | Lupin Limited | Substituted morpholines as modulators for the calcium sensing receptor |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101906097A (en) * | 2009-06-02 | 2010-12-08 | 首都医科大学 | 1,3-dioxane compounds as well as synthesizing method and medical application thereof |
| JP2011178779A (en) * | 2010-02-04 | 2011-09-15 | Daiichi Sankyo Co Ltd | Imidazopyridin-2-one derivative |
| CN102617503A (en) * | 2011-03-03 | 2012-08-01 | 上海常丰生物医药科技有限公司 | Novel synthetic method of (S)-3-morpholinyl carboxylic acid |
| WO2012120476A1 (en) * | 2011-03-10 | 2012-09-13 | Lupin Limited | Substituted morpholines as modulators for the calcium sensing receptor |
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