CN104230880B - The simple and convenient process for preparing of 2-((4R, 6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-yl) acetic acid esters - Google Patents
The simple and convenient process for preparing of 2-((4R, 6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-yl) acetic acid esters Download PDFInfo
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- 0 C*[C@](C)OC(C[C@@](CCCC[*@](C(CC1=CCCC=C1)C(CC1)=CC=C1I)C(C(C)C)=CC(Sc1ccccc1)=O)O)=* Chemical compound C*[C@](C)OC(C[C@@](CCCC[*@](C(CC1=CCCC=C1)C(CC1)=CC=C1I)C(C(C)C)=CC(Sc1ccccc1)=O)O)=* 0.000 description 1
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- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
- C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
Abstract
The present invention relates to the simple and convenient process for preparing of a kind of 2-((4R, 6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-yl) acetic acid esters (I). The present invention utilizes 3-cyano group propylene (II) and 3; 3-dialkoxy propionic ester (III) or 3-alkoxy acrylic ester (IV); under Louis acid catalysis, prepare 2-((4R; 6R)-6-cyanogen methyl-2-ester group methyl isophthalic acid; 3-dioxane-4-yl) acetic acid esters (V); after desolvation, directly carry out blocking group and transform preparation 2-((4R; 6R)-6-cyanogen methyl-2; 2-dimethyl-1; 3-dioxane-4-yl) acetic acid esters (VI), then through Raney Ni catalytic hydrogenation two-step reaction preparation (I). The present invention utilizes the equatorial bond stable form of hexatomic ring chair form structure to build chiral centre, does not use in addition chiral adjuvant, and raw material is easy to get, and reaction process is short, has avoided the asymmetric reduction of carbonyl, easy and environmental protection, and cost is low, is suitable for suitability for industrialized production.
Description
Technical field
The present invention relates to the synthetic method of a kind of 2-((4R, 6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-yl) acetic acid esters, this compound is systemThe important side chain of standby Atorvastatin calcium, belongs to Atorvastatin calcium intermediate synthesis technical field.
Background technology
Cardiovascular disease is the principal disease of a class serious harm human health, and Atorvastatin calcium is to be used for the treatment of hypercholesterolemia and the high fat of mixed typeThe choice drug of mass formed by blood stasis, coronary heart disease and headstroke. Atorvastatin calcium, Chinese commodity is called " Lipitor ", chemistry (3R, 5R)-7-[2-(4-fluorine by namePhenyl)-5-isopropyl-3-phenyl-4-(carbanilino) pyrroles-1-yl]-3,5-dihydroxy heptyl acid calcium salt, its chemical constitution is as follows:
Atorvastatin calcium since two thousand occupies global best-selling drugs first place always, and the optimization of its synthesis technique is always doubly for paying close attention to.
The more employing of the synthetic method Paal-Knorr synthetic method of Atorvastatin calcium, the core of Paal-Knorr synthetic method is important intermediate 2-(2-(4-Fluorophenyl)-2-oxo-1-phenethyl)-4-methyl-3-oxo-N-phenyl-pentanamide (VII) and 2-(4R, 6R)-6-aminoethyl-2,2-dimethyl-1,3-bis-The preparation of encircle-4-of oxygen six acetic acid esters (I), and utilize these two kinds of intermediates to obtain Atorvastatin lactone through Paal-Knorr reaction, then through hydrolysisObtain Atorvastatin calcium, and the synthetic of formula I side chain compound is the key of Atorvastatin calcium.
At present, the synthetic method relatively with the I of industrial value is that by LDA, (two is different taking (3S)-4-cyano-3-hydroxy butyrate as raw materialPropyl group lithium amide) the de-proton condensation of-tert-butyl acetate, then generate cis diol compound through the selective reduction of diethyl methoxyl group borine-sodium borohydride,After two hydroxyl protections, reduction cyano group and obtaining. Reactions steps is loaded down with trivial details, and initiation material is difficult for obtaining, and uses LDA-tert-butyl acetate potential safety hazard large,Asymmetric reduction reaction requires ultralow temperature, operation inconvenience, and cost of material is high, is difficult to large-scale production. CN103614430A discloses oneThe synthetic method of Atorvastatin calcium intermediate, by bromo-(3S)-4-ethyl 3-hydroxybutanoate through the reduction of condensation, asymmetric living things catalysis, hydroxyl protection systemObtain [(4R, 6S)-6-bromomethyl-2,2-dimethyl-1,3-dioxane-4-yl] tert-butyl acetate, then at cuprous bromide and nitrogen-containing compound partUnder effect and after nitromethane condensation, make Atorvastatin calcium intermediate [(4R, 6R)-6-(2-amino-ethyl)-2,2-through raney ni catalysis hydro-reductionDimethyl-1,3-dioxane-4-yl] tert-butyl acetate. The method is used chiral raw material, and (3S)-the bromo-3-aldehyde radical of 4-ethyl butyrate is initiation material,Price is higher, is difficult for obtaining; When condensation, operation requirements is high, and LDA price is high; Asymmetric living things catalysis industrialization amplification reappearance is low; And nitroMethane condensation yield is lower, needs altogether 5 step reactions, and course of reaction is loaded down with trivial details.
Above-mentioned prior art problems cause formula I side chain compound to become the synthetic bottleneck of restriction Atorvastatin calcium, therefore need to research and develop onePlant easy low consumption, green safety and be easy to industrialized novel synthesis, for the industrialization of statins lays the foundation.
Summary of the invention
For the deficiencies in the prior art, the invention provides a kind of preparation method of easy formula I side chain compound, i.e. a kind of 2-((4R, 6R)-6-ammonia secondBase-2,2-dimethyl-1,3-dioxane-4-yl) simple and convenient process for preparing of acetic acid esters (I). " acetic acid esters " wherein comprises methyl esters, ethyl ester and tertiary fourthEster and other carbon four and the ester of carbon below four.
Technical scheme of the present invention is as follows:
A kind of preparation method of formula I compound 2-((4R, 6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-yl) acetic acid esters,
Wherein, R2 is methyl, ethyl, the tert-butyl group, carbon tetraalkyl or the following alkyl of other carbon four;
Comprise that step is as follows:
(1) 2-((4R, 6R)-6-cyanogen methyl-2,2-dimethyl-1,3-dioxane-4-yl) acetic acid esters (VI) is synthetic
Taking 3-cyano group propylene (II) as initiation material, with 3,3-dialkoxy propionic ester (III) or 3-alkoxy acrylic ester (IV), in solventIn, under Louis acid catalysis effect, in 10-100 DEG C of reaction production V compound, then through hydrolysis deprotection, wash with sodium sulfite aqueous solutionRemove free 2-formyl acetic acid ester, water layer extracts with toluene, gained organic layer under bronsted acid catalyst effect with acetone or 2,2-dialkoxy thirdAlkane annulation preparation formula VI compound;
(2) formula I compound is synthetic
Formula VI compound, in saturated ammonia alcoholic solution, under raney nickel catalyst exists, passes into hydrogen, through hydrogenating reduction cyano group, makes formula ICompound;
Reaction equation is as follows:
Wherein: R1For methyl, ethyl, isopropyl, n-pro-pyl, the tert-butyl group, isobutyl group
R2For methyl, ethyl, the tert-butyl group, carbon tetraalkyl or the following alkyl of other carbon four
Preferred according to the present invention, 3 described in step (1), 3-dialkoxy propionic ester is selected from 3,3-diethoxy ethyl propionate, 3,3-dimethoxyBase methyl propionate or 3, the 3-diethoxy propionic acid tert-butyl ester, described 3-alkoxy acrylic ester is selected from 3-methoxy acrylic acid ethyl ester, 3-ethoxy-cOlefin(e) acid ethyl ester, the 3-methoxy acrylic acid tert-butyl ester or 3-ethoxy propylene tert-butyl acrylate.
Preferred according to the present invention, lewis acid catalyst used in step (1), for conventional lewis acid, can be selected from boron trifluoride, three and fluoridizeAny in borate ether solution, bismuth trichloride, anhydrous zinc chloride, alchlor, anhydrous ferric trichloride, wherein preferred mass mark is 40-50%Boron trifluoride ether solution or anhydrous zinc chloride.
Preferred according to the present invention, in step (1), described lewis acid catalyst, 3,3-dialkoxy propionic ester or 3-alkoxy acrylic esterCompare for (0.05-0.5) with the amount of substance of 3-cyano group propylene: (2.0-2.5): 1.
Preferred according to the present invention, solvent described in step (1) is the utmost points such as oxolane, 2-methyltetrahydrofuran, methoxyl group pentamethylene or tolueneProperty aprotic solvent.
Preferred according to the present invention, in step (1), the temperature of lewis acid catalytic reaction is 20-90 DEG C, and further preferable reaction temperature is 40-75 DEG C.
Preferred according to the present invention, in step (1), the lewis acid catalytic reaction time is 1-10 hour. Further the preferred reaction time is that 4-6 is littleTime.
Preferred according to the present invention, the bronsted acid catalyst described in step (1) is the sulfuric acid, benzene sulfonic acid of mass fraction 98% or to methylbenzene sulphurAcid.
Preferred according to the present invention, described in step (1), hydrolysising reacting temperature is 10-80 DEG C, and further preferable reaction temperature is 20-50 DEG C.
Preferred according to the present invention, the hydrolysis time 0.5-8 hour of step (1). Further preferred 4-6 hour.
Preferred according to the present invention, step (1) bronsted acid catalyst is (0.005-0.1) with the amount of substance ratio of 3-cyano group propylene: 1. FurtherPreferably (0.01-0.05): 1.
Preferred according to the present invention, the saturated ammonia alcoholic solution described in step (2) refers under normal temperature and pass into ammonia to saturated in C1-C4 alcohol;Wherein more preferably methyl alcohol or ethanol of C1-C4 alcohol. The preparation of alcohol ammonia saturated solution, for example can be direct at normal temperatures and pressures by prior artPass into ammonia to constant weight. Conventional saturated ammonia methanol solution, saturated rear mass concentration approximately 35%.
Preferred according to the present invention, in step (2), in formula VI compound, described catalyst Raney Ni consumption is 5-30% mass ratio.
Preferred according to the present invention, the hydrogenating reduction temperature of step (2) is 20-80 DEG C, reaction time 1-12 hour. Further preferred hydrogenation alsoFormer temperature is 40-60 DEG C, reaction time 5-8 hour. Hydrogen Vapor Pressure is 10-20 atmospheric pressure.
Initial feed 3-cyano group propylene of the present invention can be commercial, also can prepare by prior art. The invention provides following preferred 3-cyano group thirdThe preparation method of alkene:
In toluene solvant, TBAB catalyst exist under, by the sodium cyanide solution of chlorallylene or 3-bromopropene and 25-35wt% mixClose, chlorallylene or 3-bromopropene are 1:(1.0-1.1 with Cymag amount of substance ratio); Be warming up to 50-60 DEG C of reaction 5-6 hour. React complete,Be cooled to room temperature. Layering, toluene extraction 2-3 time, merges organic phase for water layer, successively with the sulfurous acid iron of 2wt% wash, saturated sodium-chloride waterSolution washing, gained organic layer is used anhydrous sodium sulfate drying again, filters, and reclaims toluene, and decompression distillation obtains 3-cyano group propylene.
According to the present invention, a most preferred technical scheme, a kind of formula I compound 2-((4R, 6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-Base) preparation method of acetic acid esters, step is as follows:
The preparation of step 1:3-cyano group propylene
In 1000 ml flasks, add 300 grams of toluene, 76.5 grams of (1.0 moles) chlorallylenes, 1.0 grams of TBABs, 170 gram 30%Sodium cyanide solution, be warming up to 60 DEG C reaction 6 hours. React complete, be cooled to room temperature. Layering, toluene extracting twice for water layer is (each80 grams of toluene), merge organic phase, the sulfurous acid iron washing of 50 gram 2%, 50 grams of saturated sodium-chloride water solution washings, 15 grams of anhydrous sulphur for organic layerDry 4 hours of acid sodium, filters, and reclaims toluene, and decompression distillation (45-55 DEG C/10 millimetres of mercury) obtains 61.8 grams of colourless transparent liquids. Purity 99.5%(GC), yield 91.3%.
The preparation of step 2:2-((4R, 6R)-6-cyanogen methyl-2,2-dimethyl-1,3-dioxane-4-yl) tert-butyl acetate
In 250 ml flasks, add 50 grams of oxolanes, 6.7 grams of (0.1 mole) 3-cyano group propylene, 48.0 grams of (0.22 moles) 3,3-diethylThe oxygen base propionic acid tert-butyl ester, the boron trifluoride ether solution of 3.4 grams of (20 mMs) mass fractions 47%, nitrogen replacement 3 times, is warming up to 60 DEG C insteadAnswer 6 hours (recovery ether). React complete, slightly cooling (30-40 DEG C), reclaims solvent, in residue, adds 100 grams of toluene, 10 grams of water,0.03 gram of benzene sulfonic acid, is warming up to 35 DEG C of reactions 4 hours. React complete, be cooled to 10 DEG C, add 120 gram of 10% aqueous solution of sodium bisulfite,Stir 1 hour, layering, toluene extracting twice for water layer (each 30 grams of toluene reclaim 2-formoxyl ethyl acetate by the water layer after extraction), closesAnd organic layer. Organic layer is gone in dry flask, add 12.5 grams of 2,2-dimethoxypropanes, 0.03 gram of benzene sulfonic acid, 40 DEG C are reacted 4 hours.Be cooled to room temperature, reaction liquid be added in the aqueous sodium carbonate of 50 gram 2%, stir 1 hour, layering, toluene extracting twice for water layer is (everyInferior 20 grams of toluene), merge organic phase, 5 grams of anhydrous sodium sulfate dryings 4 hours, filter, after toluene distillation, 80 grams of methyl tertiary butyl ethers for residueWith 1.0 grams of active carbon recrystallizations, obtain 21.3 grams of white solid 2-((4R, 6R)-6-cyanogen methyl-2,2-dimethyl-1,3-dioxane-4-yl) ethyl acetate,Fusing point 67-70 DEG C, purity 99.5% (HPLC), yield 79.3%.
The preparation of step 3:2-((4R, 6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-yl) tert-butyl acetate
In 250 milliliters of autoclave pressures, add 4.0 grams of (15 mMs) 2-((4R, 6R)-6-cyanogen methyl-2,2-dimethyl-1,3-dioxane-4-yl) acetic acidThe tert-butyl ester, 80 grams of saturated ammonia methanol solutions, 1.0 grams of Raney Nis, nitrogen replacement 2 times, passes into hydrogen, and a pressure 12-15 atmospheric pressure heats upTo 45 DEG C of reactions 6 hours. React complete, be cooled to 20 DEG C, filter, reclaim solvent, in residue, add 20 grams of acetone solutions, pass into dryDry hydrogen chloride gas, until solid is thoroughly separated out, filters, and filter cake is added in 30 grams of carrene and 30 gram of 5% sodium acid carbonate mixture to 20 DEG CStir 1 hour, layering, water layer dichloromethane extraction 2 times, combined dichloromethane layer, obtains 4.0 grams of colourless oil liquids after recovery solvent2-((4R, 6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-yl) tert-butyl acetate. Purity 99.4% (HPLC), yield 97.6%.
Technical characterstic of the present invention and excellent results:
The invention provides the simple and convenient process for preparing of a kind of 2-((4R, 6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-yl) acetic acid esters (I).Without chiral raw material, taking 3-cyano group propylene as initial feed with 3,3-dialkoxy propionic ester or 3-alkoxy acrylic ester, under Louis acid catalysisPreparation 2-((4R, 6R)-6-cyanogen methyl-2-ester group methyl isophthalic acid, 3-dioxane-4-yl) acetic acid esters (V) is straight through overprotection groups converted after desolvationConnect preparation 2-((4R, 6R)-6-cyanogen methyl-2,2-dimethyl-1,3-dioxane-4-yl) acetic acid esters (VI), then through Raney Ni catalytic hydrogenation preparation formula I sideChain compound, course of reaction shortens to two steps. Utilize the equatorial bond stable form of hexatomic ring chair form structure to build chiral centre, product is easy to recrystallizationPurifying feature, obtains 2-((4R, 6R)-6-aminoethyl-2, the 2-dimethyl-1,3-dioxane-4-yl) acetic acid esters of high-optical-purity.
The present invention does not use chiral adjuvant in addition, and raw material is easy to get, and reaction process is short, has avoided the asymmetric reduction of carbonyl, and easy and environmental protection is aobviousWork reduces production costs, and is suitable for large-scale industrial and produces.
Detailed description of the invention
The embodiment of the following stated describes the present invention in detail, but the present invention is not limited only to following examples. Various raw materials in embodiment, reagentConcentration " % " be mass percent, have special instruction except.
The preparation of embodiment 1:3-cyano group propylene
In 1000 ml flasks, add 300 grams of toluene, 76.5 grams of (1.0 moles) chlorallylenes, 1.0 grams of TBABs, 170 gram 30%Sodium cyanide solution, be warming up to 60 DEG C reaction 6 hours. React complete, be cooled to room temperature. Layering, toluene extracting twice for water layer is (each80 grams of toluene), merge organic phase, the sulfurous acid iron washing of 50 gram 2%, 50 grams of saturated sodium-chloride water solution washings, 15 grams of anhydrous sulphur for organic layerDry 4 hours of acid sodium, filters, and reclaims toluene, and decompression distillation (45-55 DEG C/10 millimetres of mercury) obtains 61.8 grams of colourless transparent liquids, purity 99.5%(GC), yield 91.3%.
The preparation of embodiment 2:3-cyano group propylene
The chlorallylene that replaces embodiment 1 with 121 grams of 3-bromopropenes, all the other obtain 62.6 grams of colourless transparent liquids, purity 99.6% with embodiment 1(GC), yield 93.5%.
The preparation of embodiment 3:2-((4R, 6R)-6-cyanogen methyl-2,2-dimethyl-1,3-dioxane-4-yl) ethyl acetate
In 250 ml flasks, add 50 grams of oxolanes, 6.7 grams of (0.1 mole) 3-cyano group propylene, 41.8 grams of (0.22 moles) 3,3-diethylOxygen base ethyl propionate, the boron trifluoride ether solution of 3.4 grams of (20 mMs) mass fractions 47%, nitrogen replacement 3 times, is warming up to 60 DEG C of reactions6 hours (recovery ether). React complete, slightly cooling (30-40 DEG C), reclaims solvent, adds 100 grams of toluene, 10 grams of water, 0.03 in residueGram benzene sulfonic acid, is warming up to 35 DEG C of reactions 4 hours. React complete, be cooled to 10 DEG C, add 120 gram of 10% aqueous solution of sodium bisulfite, stir 1Hour, layering, toluene extracting twice for water layer (each 30 grams of toluene reclaim 2-formoxyl ethyl acetate by the water layer after extraction), merges organicLayer. Organic layer is gone in dry flask, add 12.5 grams of 2,2-dimethoxypropanes, 0.03 gram of benzene sulfonic acid, 40 DEG C are reacted 4 hours.
Be cooled to room temperature, reaction liquid be added in the aqueous sodium carbonate of 50 gram 2%, stir 1 hour, layering, toluene extraction two for water layerInferior (each 20 grams of toluene), merge organic phase, and 5 grams of anhydrous sodium sulfate dryings 4 hours filter, after toluene distillation, and 80 grams of methyl for residueTertiary butyl ether and 1.0 grams of active carbon recrystallizations, obtain 18.7 grams of white solid 2-((4R, 6R)-6-cyanogen methyl-2,2-dimethyl-1,3-dioxane-4-yl)Ethyl acetate, fusing point 65-68 DEG C, purity 99.6% (HPLC), yield 77.6%.
The preparation of embodiment 4:2-((4R, 6R)-6-cyanogen methyl-2,2-dimethyl-1,3-dioxane-4-yl) ethyl acetate
Replace 3 of embodiment 3 with 31.5 grams of (0.22 mole) 3-ethoxy ethyl acrylates, 3-diethoxy ethyl propionate, all the other are identical, obtain18.2 grams of white solid 2-((4R, 6R)-6-cyanogen methyl-2,2-dimethyl-1,3-dioxane-4-yl) ethyl acetate, purity 99.4% (HPLC), yield75.5％。
The preparation of embodiment 5:2-((4R, 6R)-6-cyanogen methyl-2,2-dimethyl-1,3-dioxane-4-yl) ethyl acetate
With the oxolane of 25 grams of toluene and 25 grams of tetrahydrofuran compound replacement embodiment 2, all the other obtain 17.6 grams of whites solid with embodiment 3Body 2-((4R, 6R)-6-cyanogen methyl-2,2-dimethyl-1,3-dioxane-4-yl) ethyl acetate, purity 99.5% (HPLC), yield 73.0%.
The preparation of embodiment 6:2-((4R, 6R)-6-cyanogen methyl-2,2-dimethyl-1,3-dioxane-4-yl) ethyl acetate
The boron trifluoride ether solution that replaces embodiment 3 with 3.0 grams of anhydrous zinc chlorides, all the other obtain 17.9 grams of white solids with embodiment 32-((4R, 6R)-6-cyanogen methyl-2,2-dimethyl-1,3-dioxane-4-yl) ethyl acetate, purity 99.2% (HPLC), yield 74.3%.
The preparation of embodiment 7:2-((4R, 6R)-6-cyanogen methyl-2,2-dimethyl-1,3-dioxane-4-yl) methyl acetate
With 32.5 grams of (0.22 moles) 3,3-dimethoxy methyl propionate replaces 3 of embodiment 3,3-diethoxy ethyl propionate, and all the other are identical,To 17.8 grams of white solid 2-((4R, 6R)-6-cyanogen methyl-2,2-dimethyl-1,3-dioxane-4-yl) methyl acetate, fusing point 59-61 DEG C, purity 99.7%(HPLC), yield 78.5%.
The preparation of embodiment 8:2-((4R, 6R)-6-cyanogen methyl-2,2-dimethyl-1,3-dioxane-4-yl) tert-butyl acetate
With 48.0 grams of (0.22 moles) 3, the 3-diethoxy propionic acid tert-butyl ester replaces 3 of embodiment 3,3-diethoxy ethyl propionate, and all the other are identical,Obtain 21.3 grams of white solid 2-((4R, 6R)-6-cyanogen methyl-2,2-dimethyl-1,3-dioxane-4-yl) tert-butyl acetate, fusing point 67-70 DEG C, purity99.5% (HPLC), yield 79.3%.
The preparation of embodiment 9:2-((4R, 6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-yl) tert-butyl acetate
In 250 milliliters of autoclave pressures, add 4.0 grams of (15 mMs) 2-((4R, 6R)-6-cyanogen methyl-2,2-dimethyl-1,3-dioxane-4-yl) acetic acidThe tert-butyl ester (embodiment 8 makes), 80 grams of saturated ammonia methanol solutions, 1.0 grams of Raney Nis, nitrogen replacement 2 times, passes into hydrogen (the about 12-15 of pressureAtmospheric pressure), be warming up to 45 DEG C of reactions 6 hours. React complete, be cooled to 20 DEG C, filter, reclaim solvent, in residue, add 20 gram thirdKetone dissolves, and passes into dry hydrogen chloride gas until solid is thoroughly separated out, and filters, and filter cake is added to 30 grams of carrene and 30 gram of 5% sodium acid carbonateIn mixture, 20 DEG C are stirred 1 hour, layering, dichloromethane extraction 2 times (each 10 grams), combined dichloromethane layer, recovery solvent for water layerAfter obtain 4.0 grams of colourless oil liquid 2-((4R, 6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-yl) tert-butyl acetate, purity 99.4%(HPLC), yield 97.6%.
Product is through nuclear-magnetism confirmation, and data are as follows:
1HNMR (solvent C DCl3,400MHz)δ:ppm
1.29 (unimodal, 9H), 1.41 (triplet, 3H), 1.52 (triplet, 3H), 2.1 (broad peak, 2H), 2.83 (multiplet, 2H),2.92 (multiplet, 2H), 3.22 (doublet, 2H), 4.13 (multiplet, 1H), 4.31 (quartet, 2H), 4.45 (multiplet,1H)。
The preparation of embodiment 10:2-((4R, 6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-yl) ethyl acetate
As described in Example 9, difference is: with 3.6 grams of (15 mMs) 2-((4R, 6R)-6-cyanogen methyl-2,2-dimethyl-1,3-dioxane-4-Base) ethyl acetate replaces 2-((4R, 6R)-6-cyanogen methyl-2, the 2-dimethyl-1,3-dioxane-4-yl) tert-butyl acetate of embodiment 9, and all the other are with implementingExample 9, obtains 3.6 grams of colourless oil liquid 2-((4R, 6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-yl) ethyl acetate, purity 99.6%(HPLC), yield 97.3%.
1HNMR (solvent C DCl3,400MHz)δ:ppm
1.30 (triplet, 3H), 1.42 (triplet, 3H), 1.51 (triplet, 3H), 2.6 (broad peak, 2H), 2.80 (multiplet, 2H),2.93 (multiplet, 2H), 3.19 (doublet, 2H), 3.71 (quartet, 2H), 4.11 (multiplet, 1H), 4.29 (quartet, 2H),4.41 (multiplet, 1H).
Claims (10)
1. the preparation method of a formula I compound 2-((4R, 6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-yl) acetic acid esters,
Ⅰ
Wherein, R2 is methyl, ethyl, the tert-butyl group or the following alkyl of other carbon four;
Comprise that step is as follows:
(1) 2-((4R, 6R)-6-cyanogen methyl-2,2-dimethyl-1,3-dioxane-4-yl) acetic acid esters (VI) is synthetic
Taking 3-cyano group propylene (II) as initiation material, with 3,3-dialkoxy propionic ester (III) or 3-alkoxy acrylic ester (IV), in solvent, under Louis acid catalysis effect, in 10-100 DEG C of reaction production V compound, then through hydrolysis deprotection, wash and remove free 2-formyl acetic acid ester with sodium sulfite aqueous solution, water layer extracts with toluene, gained organic layer under bronsted acid catalyst effect with acetone or 2,2-dialkoxy propane annulation preparation formula VI compound;
(2) formula I compound is synthetic
Formula VI compound, in saturated ammonia alcoholic solution, under raney nickel catalyst exists, passes into hydrogen, through hydrogenating reduction cyano group, makes formula I compound;
Reaction equation is as follows:
R2 is methyl, ethyl, the tert-butyl group or the following alkyl of other carbon four.
2. 2-((4R as claimed in claim 1,6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-yl) preparation method of acetic acid esters, it is characterized in that 3 described in step (1), 3-dialkoxy propionic ester is selected from 3,3-diethoxy ethyl propionate, 3,3-dimethoxy methyl propionate or 3, the 3-diethoxy propionic acid tert-butyl ester, described 3-alkoxy acrylic ester is selected from 3-methoxy acrylic acid ethyl ester, 3-ethoxy ethyl acrylate, the 3-methoxy acrylic acid tert-butyl ester or 3-ethoxy propylene tert-butyl acrylate.
3. 2-((4R as claimed in claim 1,6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-yl) preparation method of acetic acid esters, it is characterized in that in step (1), described lewis acid catalyst, 3,3-dialkoxy propionic ester or 3-alkoxy acrylic ester are (0.05-0.5) with the amount of substance ratio of 3-cyano group propylene: (2.0-2.5): 1.
4. 2-((4R as claimed in claim 1,6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-yl) preparation method of acetic acid esters, it is characterized in that solvent described in step (1) is oxolane, 2-methyltetrahydrofuran, methoxyl group pentamethylene or toluene.
5. the preparation method of 2-as claimed in claim 1 ((4R, 6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-yl) acetic acid esters, is characterized in that the temperature of lewis acid catalytic reaction in step (1) is 40-75 DEG C; The preferred reaction time is 4-6 hour.
6. 2-((4R as claimed in claim 1,6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-yl) preparation method of acetic acid esters, it is characterized in that the bronsted acid catalyst described in step (1) is sulfuric acid, benzene sulfonic acid or the p-methyl benzenesulfonic acid of mass fraction 98%.
7. 2-((4R as claimed in claim 1,6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-yl) preparation method of acetic acid esters, it is characterized in that the amount of substance of step (1) bronsted acid catalyst and 3-cyano group propylene is than being (0.005-0.1): 1.
8. 2-((4R as claimed in claim 1,6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-yl) preparation method of acetic acid esters, it is characterized in that the saturated ammonia alcoholic solution described in step (2) refers under normal temperature to pass into ammonia to saturated in C1-C4 alcohol.
9. 2-as claimed in claim 1 ((4R, 6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-yl) preparation method of acetic acid esters, it is characterized in that in step (2), in formula VI compound, described catalyst Raney Ni consumption is 5-30% mass ratio.
10. 2-((4R as claimed in claim 1,6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-yl) preparation method of acetic acid esters, the hydrogenating reduction temperature that it is characterized in that step (2) is 20-80 DEG C, reaction time 1-12 hour, Hydrogen Vapor Pressure is 10-20 atmospheric pressure.
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Denomination of invention: A simple preparation method of 2 - ((4R, 6R) - 6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-yl) acetate Effective date of registration: 20211130 Granted publication date: 20160504 Pledgee: Zhejiang Commercial Bank Co.,Ltd. Dongying Branch Pledgor: Xinfa pharmaceutical Co.,Ltd. Registration number: Y2021980013546 |