CN104163808B - A kind of preparation method of 2-((4R, 6S)-6-substituent methyl-2-substituting group-1,3-dioxane-4-base) acetic ester - Google Patents
A kind of preparation method of 2-((4R, 6S)-6-substituent methyl-2-substituting group-1,3-dioxane-4-base) acetic ester Download PDFInfo
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- CN104163808B CN104163808B CN201410403294.2A CN201410403294A CN104163808B CN 104163808 B CN104163808 B CN 104163808B CN 201410403294 A CN201410403294 A CN 201410403294A CN 104163808 B CN104163808 B CN 104163808B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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 preparation method of a kind of 2-((4R, 6S)-6-substituent methyl-2-substituting group-1,3-dioxane-4-base) acetic ester.The present invention utilizes substituted ethylene and 3,3-dialkoxy propionic ester or 3-alkoxy acrylic ester, prepares 2-((4R, 6S)-6-substituent methyl-2-ester group methyl isophthalic acid, 3-dioxane-4-base) acetic ester under Louis acid catalysis; Then by hydrolysis, protect into ring and obtain 2-((4R; 6S)-6-chloromethyl-2-substituted-phenyl-1; 3-dioxane-4-base) ethyl acetate; again hydrolysis and with carbonyl compound Ⅹ or the Ⅺ one-tenth ring protection of its contracting glycol; obtain 2-((4R; 6S)-6-substituent methyl-2-substituting group-1,3-dioxane-4-base) acetic ester.The present invention utilizes the stable form of six-ring chair structure equatorial bond to build chiral centre, does not use chiral adjuvant in addition.Raw material of the present invention is easy to get, and reaction process is short, and avoids the asymmetric reduction of carbonyl, does not use inflammable and explosive reductive agent, easy and environmental protection, is suitable for large-scale industrial and produces.
Description
Technical field
The present invention relates to the synthetic method of a kind of 2-((4R, 6S)-6-substituent methyl-2-substituting group-1,3-dioxane-4-base) acetic ester, belong to the chemical technical field of organic synthesis of the side chain intermediate of statins antilipemic medicine.
Background technology
Cardiovascular diseases is the principal disease of a class serious harm human health, and the cardiovascular and cerebrovascular cause of disease mainly comes from atherosclerotic arteriosclerosis, shows as hyperlipidemia more, causes coronary heart disease and hypertension.Statins becomes the Representative Cultivars of current cardiovascular medicament because of its efficient and low toxic side effect, wherein atorvastatincalcuim, rosuvastain calcium, fluvastatin and pitavastatin are the primary drug of statins.Especially the arteries that hardened of rosuvastain calcium reversible, obtains U.S. FDA approval in August, 2003, at present more than 60 country's listings, has the report for foodstuff additive, is described as in the world " superstatin ".
The synthesis of statins is always noticeable, has lot of documents to report the preparation of above statins, mainly comprises parent nucleus and the two-part synthesis of chiral side chain.For rosuvastain calcium; European patent EP 0521471 and patent W02004052867 use full substituted pyrimidines aldehyde (II) to carry out Wittig olefination, deprotection, asymmetric reduction with the Wittig reagent of chirality C6 side chain (III), and hydrolysis salifying prepares Rosuvastatin salt.And III is for raw material with the 3-tertiary butyl dimethyl Si base Pyroglutaric acid of high price, 3-Stereocenter is set up with stoichiometric chiral adjuvant (-)-Benzyl Amygdalate, and use inflammable and explosive morpholine boron at carbonyl reduction steps, cost is high, is worth without industrial production.
The method that patent document W00049014 uses that full pyrimidine Mu He phosphonium salt (IV) replaced is reacted by Wittig-Horner with chirality C6 side chain aldehyde (V), Rosuvastatin sodium is prepared in deprotection, hydrolysis.The preparation of chirality C6 side chain aldehyde (V) uses (S)-epoxy chloropropane and sodium cyanide reaction, and inflammable and explosive morpholine boron reducing carbonyl, and severe reaction conditions, is difficult to scale operation.
Patent document CN102219780 utilizes full substituted pyrimidines aldehyde (II) and chirality C6 tetrazole sulfone ester Julia-Kocienski olefination, the amination of fragrant core nucleophilic substitution, deprotection salify to prepare Rosuvastatin sodium.And chirality C6 tetrazole sulfone ester side chain reaction scheme is long, cost is high, and Atom economy is poor, and severe reaction conditions, without practical value.
The preparation method of above rosuvastain calcium all needs corresponding side chain, namely has the open loop side chain that 4,6-bis-replaces-1,3-dioxane chiral ring side chain or its deprotection, and corresponding pyrimidine derivatives condensation.Have at present the chiral side chain preparation method of industrial value be by (S)-epoxy chloropropane, (R)-3-hydroxyl-4-bromobutyrate, (R)-3-hydroxyl-4-benzyloxy butyronitrile, (S)-4-chloro-3-hydroxyl butyronitrile or L MALIC ACID one of them as substrate, introduce first chiral centre, then generate second chiral centre through the asymmetric reduction of condensation, carbonyl.Then ketal protects into ring, then prepares corresponding Ce Lian phosphonium salt or side chain aldehyde.Above method cost of material is higher, and not easily obtain, route is long, and operation requires high, and each step product mostly is oily matter, is difficult to purifying, and factors causes chiral side chain to become the bottleneck of restriction statins synthesis.Therefore research and develop easy low consumption, safety and environmental protection and be easy to industrialized chiral side chain synthetic method, most important to the production of statins.
Summary of the invention
For the deficiencies in the prior art, the invention provides a kind of preparation method of easy C6 chiral side chain, refer in particular to a kind of preparation method with 2-((4R, 6S)-6-substituent methyl-2-substituting group-1, the 3-dioxane-4-base) acetic ester of formula I.
Generalformulaⅰcompound comprises I a, I b and I c.The preparation of statins can be directly used in after I a compound recrystallization.
I b of the high-optical-purity prepared by I a compound can be directly used in the preparation of statins, also can be transformed by protecting group, and for preparing market demand contains the substituent chiral side chain of different 2-, i.e. chiral side chain I c of high antimer.
Technical scheme of the present invention is as follows:
A kind of preparation method of 2-((4R, 6S)-6-substituent methyl-2-substituting group-1,3-dioxane-4-base) acetic ester, comprises step as follows:
(1) 2-((4R, 6S)-6-substituent methyl-2-ester group methyl isophthalic acid, 3-dioxane-4-base) acetic ester (I synthesis a)
In aprotic polar solvent, make substituted ethylene (VI) and 3,3-dialkoxy propionic ester (VII) or 3-alkoxy acrylic ester (VIII) under lewis acidity catalyst action in 10-100 DEG C of reaction, the 2-((4R of production I a, 6S)-6-substituent methyl-2-ester group methyl isophthalic acid, 3-dioxane-4-base) acetic ester; The preparation of statins can be directly used in after this compound recrystallization;
(2) (I b) and purifying to generate 2-((4R, 6S)-6-chloromethyl-2-substituted-phenyl-1,3-dioxane-4-base) ethyl acetate
In a solvent, make 2-((4R, 6S)-6-substituent methyl-2-ester group methyl isophthalic acid, 3-dioxane-4-base) (I a) under Protic Acid Catalyzed effect for acetic ester, 10-80 DEG C of reaction 0.5-8 hour, hydrolysis, with the 2-formyl radical acetic ester that aqueous solution of sodium bisulfite washing removing generates, layering, obtain crude product 3R, the organic solvent solution of 5S-6-substituting group-3,5-dihydroxyl n-hexoate, then with substituted benzaldehyde Ⅸ, under Protic Acid Catalyzed effect, reflux carries out into ring protection reaction; With the substituted benzaldehyde Ⅸ that aqueous solution of sodium bisulfite washing removing is excessive, organic phase is dry, filter, recycling design, methyl tert-butyl ether recrystallization, (I b) for ethyl acetate to obtain the 2-((4R, 6S)-6-chloromethyl-2-substituted-phenyl-1,3-dioxane-4-base) of high-optical-purity.
(3) 2-((4R, 6S)-6-substituent methyl-2-substituting group-1,3-dioxane-4-base) acetic ester (I synthesis c)
In a solvent, (I b) under Protic Acid Catalyzed effect, reacts 0.5-8 hour, hydrolysis in 10-80 DEG C to make 2-((4R, 6S)-6-chloromethyl-2-substituted-phenyl-1,3-dioxane-4-base) ethyl acetate.With the substituted benzaldehyde Ⅸ that aqueous solution of sodium bisulfite washing removing open loop generates, layering, obtains the 3R of high-optical-purity; 5S-6-substituting group-3; 5-dihydroxyl n-hexoate solution, then with carbonyl compound Ⅹ or its contracting glycol Ⅺ, carries out into ring protection reaction under Protic Acid Catalyzed effect.The aqueous solution of sodium bisulfite washing excessive carbonyl compound Ⅹ of removing or its contracting glycol Ⅺ, organic phase is dry, filter, recycling design, underpressure distillation obtains the 2-((4R of high-optical-purity, 6S)-6-substituent methyl-2-substituting group-1,3-dioxane-4-base) (I c) for acetic ester.
Reaction scheme is as follows:
Wherein: R
1for Cl-, Br-, I-,
me
3siO-, CH
3sO
3-
R
2for CH
3-, CH
3cH
2-,
R
3, R
4for H, C
1--C
4alkyl or
R
5for CH
3-, CH
3cH
2-or other C
3-C
4alkyl
R
6for Cl-,-NO
2(ortho position, a position or contraposition)
R is CH
3-, CH
3cH
2-
Above process prepares I b of high-optical-purity by " one kettle way "; then the chemical compounds I derivative that a series of substituting group of preparation is different can be derived; this derivative enantiomeric excess value is high; both the preparation of statins can be directly used in; also can be transformed by protecting group, for preparing market demand contains the substituent chiral side chain of different 2-.
Preferred according to the present invention, the vinylcarbinol that the substituted ethylene (VI) described in step (1) is propylene halide or hydroxyl protection, wherein preferably chlorallylene, allyl methyl sulphonate, allyl acetic acid ester and 3-tri-silyloxy propylene.Described propylene halide is selected from chlorallylene, 3-bromopropylene or 3-iodopropylene, preferred 2-propenyl chloride and 3-bromopropylene.Wherein allyl methyl sulphonate, allyl acetic acid ester and 3-tri-silyloxy propylene are by prior art preparation, and all the other are commercially available prod.
Described in step (1), 3,3-dialkoxy propionic esters (VII) are 3,3-diethoxy ethyl propionate, 3,3-dimethoxy methyl propionate or 3,3-diethoxy propanoic acid tert-butyl ester.3-alkoxy acrylic ester (VIII) is 3-diethoxy ethyl acrylate, 3-methoxypropene acid methyl esters or 3-diethoxy propene tert-butyl acrylate.
Preferred according to the present invention, lewis acid catalyst used in step (1) is boron trifluoride, boron trifluoride ether solution, Trichlorobismuthine, Zinc Chloride Anhydrous, aluminum chloride, FERRIC CHLORIDE ANHYDROUS, wherein preferred boron trifluoride ether solution and Zinc Chloride Anhydrous.
Preferred according to the present invention, in step (1), lewis acid catalyst, formula VII or formula VIII are (0.01-0.3) with the amount of substance ratio of formula VI compound: (2.0-2.8): 1, preferred proportion is (0.05-0.15): (2.0-2.5): 1.
Preferred according to the present invention, the aprotic polar solvent in step (1) is tetrahydrofuran (THF), 2-methyltetrahydrofuran, methoxyl group pentamethylene, DMF, N,N-dimethylacetamide or toluene.
Preferred according to the present invention, the temperature of reaction of step (1) is 20-90 DEG C, and further preferable reaction temperature is 40-75 DEG C.Preferred according to the present invention, the reaction times 1-10 hour of step (1).The temperature of reaction of most preferred step (1) is 60 DEG C of reactions 4 hours.
Preferred according to the present invention, the solvent described in step (2) is one in toluene, hexanaphthene, normal hexane, sherwood oil (boiling range 60-90 DEG C) or its mixture.
Preferred according to the present invention, substituted benzaldehyde Ⅸ described in step (2) is phenyl aldehyde, 3-nitrobenzaldehyde, 3-chlorobenzaldehyde or its corresponding phenyl aldehyde two acetal, 3-nitrobenzaldehyde two acetal, 3-chlorobenzaldehyde two acetal, wherein preferred 3-benzyl chloride formaldehyde, 3-nitrobenzaldehyde, 3-nitrobenzaldehyde two acetal or 3-chlorobenzaldehyde two acetal, described alcohol particular methanol and ethanol.
Preferred according to the present invention, the bronsted acid catalyst described in step (2) is 98wt% sulfuric acid, Phenylsulfonic acid or p-methyl benzenesulfonic acid.The amount of substance of bronsted acid catalyst and formula VI compound is than being (0.005-0.1): 1.
Preferred according to the present invention, the hydrolysis temperature of reaction of step (2) is 15-50 DEG C, and reaction 2-8 hour, further preferable reaction temperature is 20-50 DEG C.
Preferred according to the present invention, the one-tenth ring protection temperature of reaction of step (2) is 10-120 DEG C, and reaction 1-6 hour, further preferable reaction temperature is 50-100 DEG C.
The solvent phase of the solvent described in step (3) and step (2) is same.
Preferred according to the present invention, step (3) hydrolysis temperature of reaction is 15-50 DEG C, and reaction 2-8 hour, further preferable reaction temperature is 20-50 DEG C.Most preferred hydrolysis temperature 35 DEG C reaction 4 hours.In hydrolysis reaction, the consumption of bronsted acid catalyst is 2-((4R, 6S)-6-chloromethyl-2-substituted-phenyl-1,3-dioxane-4-base) ethyl acetate (I 0.5-5% b) (amount of substance than).
Preferred according to the present invention, the carbonyl compound described in step (3) is ketone or its corresponding two acetals that acetone, butanone, mibk etc. have general formula Ⅹ, described alcohol particular methanol and ethanol.
Preferred according to the present invention, step (3) preferred according to the present invention, the one-tenth ring protection temperature of reaction of step (3) is 10-120 DEG C, reaction 1-6 hour, and further preferable reaction temperature is 50-100 DEG C; Most preferred temperature of reaction 60 DEG C reaction 4 hours.In annulation, the consumption of bronsted acid catalyst is 2-((4R, 6S)-6-chloromethyl-2-substituted-phenyl-1,3-dioxane-4-base) ethyl acetate (I 0.5-5% b) (amount of substance than).
Preferred according to the present invention, the different chemical compounds I of serial substituting group is as one of following:
2-((4R, 6S)-6-chloromethyl-2-ethoxycarbonylmethyl group-1,3-dioxane-4-base) ethyl acetate;
2-((4R, 6S)-6-brooethyl-2-ethoxycarbonylmethyl group-1,3-dioxane-4-base) ethyl acetate;
2-((4R, 6S)-6-chloromethyl-2-ethoxycarbonylmethyl group-1,3-dioxane-4-base) tert.-butyl acetate;
2-((4R, 6S)-6-brooethyl-2-ethoxycarbonylmethyl group-1,3-dioxane-4-base) tert.-butyl acetate;
2-((4R, 6S)-6-acetyl-o-methyl-2-ethoxycarbonylmethyl group-1,3-dioxane-4-base) ethyl acetate;
2-((4R, 6S)-6-three silyloxy methyl-2-ethoxycarbonylmethyl group-1,3-dioxane-4-base) ethyl acetate;
2-((4R, 6S)-6-methylsulfonyl methyl-2-ethoxycarbonylmethyl group-1,3-dioxane-4-base) ethyl acetate;
2-((4R, 6S)-6-chloromethyl-2,2-dimethyl-1,3-dioxane-4-base) ethyl acetate;
2-((4R, 6S)-6-chloromethyl-2,2-dimethyl-1,3-dioxane-4-base) tert.-butyl acetate;
2-((4R, 6S)-6-brooethyl-2-methyl-2-ethyl-1,3-dioxane-4-base) ethyl acetate;
2-((4R, 6S)-6-brooethyl-2,2-dimethyl-1,3-dioxane-4-base) tert.-butyl acetate;
2-((4R, 6S)-6-chloromethyl-2-(3-chloro-phenyl-)-1,3-dioxane-4-base) ethyl acetate.
Principle of the present invention:
Prins reaction refers to that alkene and aldehyde generate corresponding 4-and replaces-1,3-dioxane, 1,3-dihydroxy compound and vinylcarbinol mixture under Protic Acid Catalyzed effect, and chemical equation is as follows:
The present invention is with Prins reaction for foundation, and by Optimal reaction conditions, utilize corresponding replacement alkene and aldehyde derivatives under Louis acid catalysis, remove ether, highly selective generates 1,3-dioxane, prepares Statins chiral side chain.The present invention utilizes substituted ethylene and 3,3-dialkoxy propionic ester or 3-alkoxy acrylic ester are starting raw material, prepare chiral side chain I in a mild condition, this side chain I can be exchanged into the preparation of corresponding Wittig reagent for rosuvastain calcium, also can through cyaniding, reduction preparation 2-((4R, 6S)-6-amino-ethyl-2,2-dimethyl-1,3-dioxane-4-base) acetic ester, for the synthesis of atorvastatin calcium.The present invention utilizes the equatorial bond stable form of six-ring chair structure to set up chiral centre, raw materials used cheap and easy to get, does not use chiral adjuvant.And avoid carbonyl reduction, do not use inflammable and explosive reductive agent, reaction process shortens dramatically, easy and environmental protection.
With chlorallylene and 3,3-diethoxy ethyl propionate for example, reaction mechanism is as follows:
Technical characterstic of the present invention and excellent results:
The invention describes the preparation method of a kind of 2-((4R, 6S)-6-substituent methyl-2-substituting group-1,3-dioxane-4-base) acetic ester (I).Comprise and utilize substituted ethylene and 3,3-dialkoxy propionic ester or 3-alkoxy acrylic ester, highly selective preparationⅠcompound under Louis acid catalysis, then through hydrolysis with become ring protection and prepare I of high-optical-purity.Utilize the stable form of six-ring chair structure equatorial bond, build two chiral centres easily simultaneously.By becoming conversion and the recrystallization method of ring protection group, the chiral side chain that high antimer is excessive can be obtained.Raw material of the present invention is easy to get, and reaction process is short, easy and environmental protection, is suitable for large-scale industrial and produces.
Embodiment
The embodiment of the following stated describes the present invention in detail, but the present invention is not limited only to following examples.
Per-cent % in embodiment is mass percent, except special instruction.
Embodiment 1 to embodiment 3 is the preparation of raw material.Embodiment 4 is the preparation of a complete I c compound, and embodiment 5 to embodiment 10 is the preparation of I a compound.
The preparation of embodiment 1:3-tri-silyloxy propylene
In 1000 milliliters of reaction flasks, add 400 grams of methylene dichloride, 58.0 grams of (1.0 moles) vinylcarbinols, 114.0 grams of (1.05 moles) trimethylchlorosilanes, 85.0 grams of pyridines, be warming up to 30 DEG C of reactions 2 hours.React complete, be down to 20 DEG C, filter, with 50 grams of washed with dichloromethane filter cakes, merging filtrate, recycling design, underpressure distillation (75-85 DEG C/15 mmhg) obtains 123.9 grams of 3-trimethylsiloxy group propylene, colourless transparent liquid, yield 95.2%.
The preparation of embodiment 2:3-acetoxypropen
In 1000 milliliters of reaction flasks, add 400 grams of methylene dichloride, 58.0 grams of (1.0 moles) vinylcarbinols, 82.5 grams of (1.05 moles) Acetyl Chloride 98Min.s, are cooled to negative 5 DEG C, drip 106.0 grams of triethylamines, drip to finish to be warming up to 20 DEG C of reactions 4 hours.React complete, be down to 0 DEG C, filter, 50 grams of washed with dichloromethane filter cakes, merging filtrate, after normal pressure reclaims methylene dichloride, underpressure distillation (65-72 DEG C/15 mmhg) obtains 98.1 grams of colourless transparent liquid 3-acetoxypropen, yield 98.1%.
Embodiment 3: the preparation of allyl methyl sulphonate
In 1000 milliliters of reaction flasks, add 400 grams of methylene dichloride, 58.0 grams of (1.0 moles) vinylcarbinols, 120.2 grams of (1.05 moles) methylsulfonyl chlorides, are cooled to negative 5 DEG C, drip 106.0 grams of triethylamines, drip to finish to be warming up to 20 DEG C of reactions 6 hours.React complete, be down to 0 DEG C, filter, 50 grams of washed with dichloromethane filter cakes, merging filtrate, after normal pressure reclaims methylene dichloride, underpressure distillation (85-95 DEG C/15 mmhg) obtains 127.0 grams of 3-allyl methyl sulphonates, is light yellow transparent liquid, yield 93.4%.
(I preparation c) of embodiment 4:2-((4R, 6S)-6-chloromethyl-2,2-dimethyl-1,3-dioxane-4-base) ethyl acetate
Reaction equation is as follows:
The product of step (1) is 2-((4R, 6S)-6-chloromethyl-2-ethoxycarbonylmethyl group-1,3-dioxane-4-base) ethyl acetate; The product of step (2) is 2-((4R, 6S)-6-chloromethyl-2-(3-chlorine) phenyl-1,3-dioxane-4-base) ethyl acetate, be through (3R, 5S)-6-chloro-3,5 dihydroxyl ethyl hexanoate crude products one pot obtain; Step (3) product is 2-((4R, 6S)-6-chloromethyl-2,2-dimethyl-1,3-dioxane-4-base) ethyl acetate, by (3R, 5S)-6-chloro-3,5 dihydroxyl ethyl hexanoate sterlings and acetone or 2,2-dialkoxy propane become ring to obtain.
(I preparation a) of step (1): 2-((4R, 6S)-6-chloromethyl-2-ethoxycarbonylmethyl group-1,3-dioxane-4-base) ethyl acetate
500 grams of tetrahydrofuran (THF)s are added in 1000 milliliters of reaction flasks, 76.5 grams of (1.0 moles) chlorallylenes, 418.0 grams of (2.2 moles) 3,3-diethoxy ethyl propionate, 13.6 grams of (0.08 mole) 47% boron trifluoride ether solutions, nitrogen replacement 3 times, is warming up to 60 DEG C of reactions, 4 hours (recovery ether).React complete, recycling design, be cooled to 20 DEG C, add 100 grams of water and 300 grams of ethyl acetate, layering, aqueous layer with ethyl acetate extracts, extract three times (each 30 grams of ethyl acetate), merge organic phase, 20 grams of anhydrous sodium sulfate dryings 4 hours, filter, reclaim ethyl acetate, obtain 2-((4R, 6S)-6-chloromethyl-2-ethoxycarbonylmethyl group-1,3-dioxane-4-base) ethyl acetate 267.5 grams, purity 98.2% (GC), yield 86.7%.
(I preparation b) of step (2): 2-((4R, 6S)-6-chloromethyl-2-(3-chlorine) phenyl-1,3-dioxane-4-base) ethyl acetate
200 grams of toluene are added in 500 milliliters of reaction flasks, 30.9 grams of (0.1 mole) 2-((4R, 6S)-6-chloromethyl-2-ethoxycarbonylmethyl group-1,3-dioxane-4-base) ethyl acetate, 300 grams of toluene, 30 grams of water, 0.3 gram of Phenylsulfonic 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, forwards to organic layer in 500 ml flasks, adds 14.1 grams of 3-chlorobenzaldehydes, 0.3 gram of Phenylsulfonic acid, reflux dehydration reaction 4 hours.Be cooled to room temperature, reaction liquid is added in the aqueous solution of sodium bisulfite of 50 gram 2%, stir 1 hour, layering, water layer toluene extracting twice (each 20 grams of toluene), merge organic phase, 5 grams of anhydrous sodium sulfate dryings 4 hours, filter, reclaim toluene, residuum 90 grams of methyl tert-butyl ether recrystallizations, obtain 2-((4R, 6S)-6-chloromethyl-2-(3-chlorine) phenyl-1,3-dioxane-4-base) ethyl acetate 28.8 grams, fusing point 68-70 DEG C, purity 99.8% (GC), yield 86.5%.
(I preparation c) of step (3): 2-((4R, 6S)-6-chloromethyl-2,2-dimethyl-1,3-dioxane-4-base) ethyl acetate
100 grams of toluene are added in 250 milliliters of reaction flasks, 16.7 grams of (0.05 mole) 2-((4R, 6S)-6-chloromethyl-2-(3-chlorine) phenyl-1,3-dioxane-4-base) ethyl acetate, 10 grams of water, 0.1 gram of Phenylsulfonic acid, is warming up to 35 DEG C of reactions 4 hours.React complete, be cooled to 10 DEG C, add 60 gram of 10% aqueous solution of sodium bisulfite, stir 1 hour, layering, forwards to organic layer in 250 ml flasks, adds 7.8 grams of 2,2-dimethoxypropanes, 0.1 gram of Phenylsulfonic acid, and 60 DEG C are reacted 4 hours.Be cooled to room temperature, reaction liquid is added in the aqueous solution of sodium bisulfite of 50 gram 2%, stir 1 hour, layering, water layer toluene extracting twice (each 20 grams of toluene), merge organic phase, 5 grams of anhydrous sodium sulfate dryings 4 hours, filter, after toluene distillation, underpressure distillation (135-150 DEG C/10 mmhg) obtains weak yellow liquid 2-((4R, 6S)-6-chloromethyl-2,2-dimethyl-1,3-dioxane-4-base) ethyl acetate 11.4 grams, purity 99.8% (GC), yield 91.2%.
(I preparation a) of embodiment 5:2-((4R, 6S)-6-chloromethyl-2-ethoxycarbonylmethyl group-1,3-dioxane-4-base) ethyl acetate
300 grams of tetrahydrofuran (THF)s are added in 1000 milliliters of reaction flasks, 38.3 grams of (0.5 mole) chlorallylenes, 158.4 grams of (1.1 moles) 3-ethoxy ethyl acrylates, 8.5 grams of (0.05 mole) 47% boron trifluoride ether solutions, nitrogen replacement 3 times, is warming up to 60 DEG C of reactions, 4 hours (recovery ether).React complete, recycling design, be cooled to 20 DEG C, add 50 grams of water and 150 grams of ethyl acetate, layering, aqueous layer with ethyl acetate extracts, extract three times (each 20 grams of ethyl acetate), merge organic phase, 10 grams of anhydrous sodium sulfate dryings 4 hours, filter, reclaim ethyl acetate, obtain 2-((4R, 6S)-6-chloromethyl-2-ethoxycarbonylmethyl group-1,3-dioxane-4-base) ethyl acetate 147.0 grams, purity 98.6% (GC), yield 85.2%.
(I preparation a) of embodiment 6:2-((4R, 6S)-6-chloromethyl-2-tert-Butoxycarbonylmethyl-1,3-dioxane-4-base) tert.-butyl acetate
100 grams of tetrahydrofuran (THF)s are added in 500 milliliters of reaction flasks, 7.7 grams of (0.1 mole) chlorallylenes, 48.0 grams of (0.22 moles) 3,3-diethoxy propanoic acid tert-butyl ester, 4.3 grams of (25 mmole) 47% boron trifluoride ether solutions, nitrogen replacement 3 times, is warming up to 60 DEG C of reactions, 4 hours (recovery ether).React complete, recycling design, be cooled to 20 DEG C, add 20 grams of water and 60 grams of ethyl acetate, layering, aqueous layer with ethyl acetate extracts, extract three times (each 20 grams of ethyl acetate), merge organic phase, 5 grams of anhydrous sodium sulfate dryings 4 hours, filter, reclaim ethyl acetate, obtain 2-((4R, 6S)-6-chloromethyl-2-tert-Butoxycarbonylmethyl-1,3-dioxane-4-base) tert.-butyl acetate 33.3 grams, purity 98.9% (GC), yield 91.3%.
(I preparation a) of embodiment 7:2-((4R, 6S)-6-chloromethyl-2-ethoxycarbonylmethyl group-1,3-dioxane-4-base) ethyl acetate
100 grams of tetrahydrofuran (THF)s are added in 500 milliliters of reaction flasks, 7.7 grams of (0.1 mole) chlorallylenes, 41.8 grams of (0.22 moles) 3,3-diethoxy ethyl propionate, 4.0 grams of (30 mmole) Zinc Chloride Anhydrouss, nitrogen replacement 3 times, is warming up to 60 DEG C of reactions, 4 hours (recovery ether).React complete, recycling design, be cooled to 20 DEG C, add 20 grams of water and 60 grams of ethyl acetate, layering, aqueous layer with ethyl acetate extracts, extract three times (each 20 grams of ethyl acetate), merge organic phase, 20 grams of anhydrous sodium sulfate dryings 4 hours, filter, reclaim ethyl acetate, obtain 2-((4R, 6S)-6-chloromethyl-2-ethoxycarbonylmethyl group-1,3-dioxane-4-base) ethyl acetate 25.1 grams, purity 98.1% (GC), yield 81.5%.
(I preparation a) of embodiment 8:2-((4R, 6S)-6-methylol-2-ethoxycarbonylmethyl group-1,3-dioxane-4-base) ethyl acetate
100 grams of tetrahydrofuran (THF)s are added in 500 milliliters of reaction flasks, 13.0 grams of (0.1 mole) 3-tri-silyloxy propylene, 31.7 grams of (0.22 mole) 3-ethoxy ethyl acrylates, 5.2 grams (30 mmole) 47% boron trifluoride ethanamidine solution, nitrogen replacement 3 times, is warming up to 60 DEG C of reactions, 4 hours (recovery ether).React complete, recycling design, be cooled to 20 DEG C, add 20 grams of saturated aqueous ammonium chlorides and 60 grams of ethyl acetate, layering, aqueous layer with ethyl acetate extracts, and extracts three times (each 20 grams of ethyl acetate), merges organic phase, 20 grams of anhydrous sodium sulfate dryings 4 hours, filter, reclaim ethyl acetate, obtain 2-((4R, 6S)-6-methylol-2-ethoxycarbonylmethyl group-1,3-dioxane-4-base) ethyl acetate 22.1 grams, purity 98.5% (GC), yield 76.3%.
(I preparation a) of embodiment 9:2-((4R, 6S)-6-acetyl-o-methyl-2-ethoxycarbonylmethyl group-1,3-dioxane-4-base) ethyl acetate
100 grams of tetrahydrofuran (THF)s are added in 500 milliliters of reaction flasks, 10.0 grams of (0.1 mole) 3-acetoxypropen, 41.8 grams of (0.22 moles) 3,3-diethoxy ethyl propionate, 5.2 grams (30 mmole) 47% boron trifluoride ethanamidine solution, nitrogen replacement 3 times, is warming up to 60 DEG C of reactions, 4 hours (recovery ether).React complete, recycling design, be cooled to 20 DEG C, add 20 grams of water and 60 grams of ethyl acetate, layering, aqueous layer with ethyl acetate extracts, extract three times (each 20 grams of ethyl acetate), merge organic phase, 20 grams of anhydrous sodium sulfate dryings 4 hours, filter, reclaim ethyl acetate, obtain 2-((4R, 6S)-6-acetyl-o-methyl-2-ethoxycarbonylmethyl group-1,3-dioxane-4-base) ethyl acetate 27.5 grams, purity 98.9% (GC), yield 82.7%.
(I preparation a) of embodiment 10:2-((4R, 6S)-6-MSM oxygen methyl-2-ethoxycarbonylmethyl group-1,3-dioxane-4-base) ethyl acetate
100 grams of tetrahydrofuran (THF)s are added in 500 milliliters of reaction flasks, 13.6 grams of (0.1 mole) 3-vinylcarbinol methanesulfonates, 41.8 grams of (0.22 moles) 3,3-diethoxy ethyl propionate, 5.2 grams (30 mmole) 47% boron trifluoride ethanamidine solution, nitrogen replacement 3 times, is warming up to 60 DEG C of reactions 4 hours, reclaims ether.React complete, recycling design, be cooled to 20 DEG C, add 20 grams of water and 60 grams of ethyl acetate, layering, aqueous layer with ethyl acetate extracts, extract three times (each 20 grams of ethyl acetate), merge organic phase, 20 grams of anhydrous sodium sulfate dryings 4 hours, filter, reclaim ethyl acetate, obtain 2-((4R, 6S)-6-MSM oxygen methyl-2-ethoxycarbonylmethyl group-1,3-dioxane-4-base) ethyl acetate 28.3 grams, purity 98.8% (GC), yield 76.9%.
Claims (11)
1. the preparation method of 2-((4R, 6S)-6-substituent methyl-2-substituting group-1, a 3-dioxane-4-base) acetic ester, comprises step as follows:
(1) 2-((4R, 6S)-6-substituent methyl-2-ester group methyl isophthalic acid, 3-dioxane-4-base) acetic ester (I synthesis a)
In aprotic polar solvent, make substituted ethylene (VI) and 3,3-dialkoxy propionic ester (VII) or 3-alkoxy acrylic ester (VIII) under lewis acidity catalyst action in 10-100 DEG C of reaction, the 2-((4R of production I a, 6S)-6-substituent methyl-2-ester group methyl isophthalic acid, 3-dioxane-4-base) acetic ester; The preparation of statins can be directly used in after this compound recrystallization;
(2) (I b) and purifying to generate 2-((4R, 6S)-6-chloromethyl-2-substituted-phenyl-1,3-dioxane-4-base) ethyl acetate
In a solvent, make 2-((4R, 6S)-6-substituent methyl-2-ester group methyl isophthalic acid, 3-dioxane-4-base) (I a) under Protic Acid Catalyzed effect for acetic ester, 10-80 DEG C of reaction 0.5-8 hour, hydrolysis, with the 2-formyl radical acetic ester that aqueous solution of sodium bisulfite washing removing generates, layering, obtain crude product 3R, the organic solvent solution of 5S-6-substituting group-3,5-dihydroxyl n-hexoate, then with substituted benzaldehyde Ⅸ, reflux Cheng Huan under Protic Acid Catalyzed effect; With the substituted benzaldehyde Ⅸ that aqueous solution of sodium bisulfite washing removing is excessive, organic phase is dry, filter, recycling design, methyl tert-butyl ether recrystallization, (I b) for ethyl acetate to obtain the 2-((4R, 6S)-6-chloromethyl-2-substituted-phenyl-1,3-dioxane-4-base) of high-optical-purity;
(3) 2-((4R, 6S)-6-substituent methyl-2-substituting group-1,3-dioxane-4-base) acetic ester (I synthesis c)
In a solvent, (I b) under Protic Acid Catalyzed effect, reacts 0.5-8 hour, hydrolysis in 10-80 DEG C to make 2-((4R, 6S)-6-chloromethyl-2-substituted-phenyl-1,3-dioxane-4-base) ethyl acetate; With the substituted benzaldehyde Ⅸ that aqueous solution of sodium bisulfite washing removing open loop generates, layering, obtains the 3R of high-optical-purity, 5S-6-substituting group-3,5-dihydroxyl n-hexoate solution, then with carbonyl compound Ⅹ or its contracting glycol Ⅺ, annulation under Protic Acid Catalyzed effect; The aqueous solution of sodium bisulfite washing excessive carbonyl compound Ⅹ of removing or its contracting glycol Ⅺ, organic phase is dry, filter, recycling design, underpressure distillation obtains the 2-((4R of high-optical-purity, 6S)-6-substituent methyl-2-substituting group-1,3-dioxane-4-base) (I c) for acetic ester;
Reaction scheme is as follows:
Wherein: R
1for Cl-, Br-, I-,
me
3siO-, CH
3sO
3-
R
2for CH
3-, CH
3cH
2-
R
3, R
4for H, C
1--C
4alkyl or
R
5for CH
3-, CH
3cH
2-or other C
3-C
4alkyl
R
6for Cl-,-NO
2
R is CH
3-, CH
3cH
2-.
2. 2-((4R as claimed in claim 1; 6S)-6-substituent methyl-2-substituting group-1; 3-dioxane-4-base) preparation method of acetic ester, it is characterized in that the substituted ethylene described in step (1) is the vinylcarbinol of chlorallylene, 3-bromopropylene and 3-iodopropylene or hydroxyl protection.
3. 2-((4R as claimed in claim 1,6S)-6-substituent methyl-2-substituting group-1,3-dioxane-4-base) preparation method of acetic ester, it is characterized in that lewis acid catalyst used in (1) is boron trifluoride, boron trifluoride ether solution, Trichlorobismuthine, Zinc Chloride Anhydrous, aluminum chloride or FERRIC CHLORIDE ANHYDROUS; Lewis acid catalyst, 3,3-dialkoxy propionic esters or 3-alkoxy acrylic ester are (0.05-0.5) with the amount of substance ratio of substituted olefine: (2.0-2.5): 1.
4. 2-((4R as claimed in claim 1,6S)-6-substituent methyl-2-substituting group-1,3-dioxane-4-base) preparation method of acetic ester, it is characterized in that the solvent in step (1) is tetrahydrofuran (THF), 2-methyltetrahydrofuran, methoxyl group pentamethylene, N, dinethylformamide, N,N-dimethylacetamide or toluene.
5. the preparation method of 2-((4R, 6S)-6-substituent methyl-2-substituting group-1,3-dioxane-4-base) acetic ester as claimed in claim 1, is characterized in that the temperature of reaction of step (1) is 20-90 DEG C.
6. the preparation method of 2-((4R, 6S)-6-substituent methyl-2-substituting group-1,3-dioxane-4-base) acetic ester as claimed in claim 1, is characterized in that the temperature of reaction of step (1) is 40-75 DEG C.
7. 2-((4R as claimed in claim 1; 6S)-6-substituent methyl-2-substituting group-1; 3-dioxane-4-base) preparation method of acetic ester, it is characterized in that the substituted benzaldehyde that the one-tenth ring protection described in step (2) is reacted used is 3-nitrobenzaldehyde or 3-chlorobenzaldehyde.
8. 2-((4R as claimed in claim 1,6S)-6-substituent methyl-2-substituting group-1,3-dioxane-4-base) preparation method of acetic ester, it is characterized in that solvent used in step (2) is one in the sherwood oil of toluene, hexanaphthene, normal hexane, boiling range 60-90 DEG C or its mixture, the catalyzer of the hydrolysis reaction described in step (2) is 98% sulfuric acid, Phenylsulfonic acid, p-methyl benzenesulfonic acid, and the amount of substance of catalyzer and substituted ethylene is than being (0.005-0.1): 1.
9. the preparation method of 2-((4R, 6S)-6-substituent methyl-2-substituting group-1,3-dioxane-4-base) acetic ester as claimed in claim 1, is characterized in that step (2) hydrolysis temperature of reaction is 15-50 DEG C.
10. 2-((4R as claimed in claim 1,6S)-6-substituent methyl-2-substituting group-1,3-dioxane-4-base) preparation method of acetic ester, it is characterized in that the carbonyl compound described in step (3) is acetone, butanone, mibk, said alcohol is methyl alcohol or ethanol.
11. 2-((4R as claimed in claim 1,6S)-6-substituent methyl-2-substituting group-1,3-dioxane-4-base) preparation method of acetic ester, its spy is that the hydrolysis temperature of reaction of step (3) is 15-50 DEG C, reaction 2-8 hour; The annulation temperature of step (3) is 50-100 DEG C.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050148784A1 (en) * | 2001-12-20 | 2005-07-07 | Inhee Lee | Process for the preparation of optically active 2-[6-substituted alkyl)-1,3-dioxan-4-yl]acetic acid derivatives |
| CN103387560A (en) * | 2013-07-04 | 2013-11-13 | 复旦大学 | Preparation method of 2-[(4R, 6S)-6-substitued methyl-2, 2-dimethyl-1, 3-dioxan]-acetate |
| CN103614430A (en) * | 2013-11-22 | 2014-03-05 | 苏州卫生职业技术学院 | Synthetic method of atorvastatin calcium intermediate |
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2014
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050148784A1 (en) * | 2001-12-20 | 2005-07-07 | Inhee Lee | Process for the preparation of optically active 2-[6-substituted alkyl)-1,3-dioxan-4-yl]acetic acid derivatives |
| CN103387560A (en) * | 2013-07-04 | 2013-11-13 | 复旦大学 | Preparation method of 2-[(4R, 6S)-6-substitued methyl-2, 2-dimethyl-1, 3-dioxan]-acetate |
| CN103614430A (en) * | 2013-11-22 | 2014-03-05 | 苏州卫生职业技术学院 | Synthetic method of atorvastatin calcium intermediate |
Non-Patent Citations (1)
| Title |
|---|
| Synthesis of ethyl and t-buytl(3R,5S)-dihydroxy-6-benzyloxy hexanoates via diastereo- and enantioselective microbial reduction;Zhiwei Guo,et al.;《Tetrahedron:Asymmetry》;20061231;1589-1602 * |
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Denomination of invention: A preparation method of 2 - ((4R, 6S) - 6-substituted methyl-2-substituent-1,3-dioxane-4-yl) acetate Effective date of registration: 20211130 Granted publication date: 20160406 Pledgee: Zhejiang Commercial Bank Co.,Ltd. Dongying Branch Pledgor: Xinfa pharmaceutical Co.,Ltd. Registration number: Y2021980013546 |