CN108503609A - A method of preparing optically pure (R) -4- n-propyls-dihydrofuran -2 (3H) -one - Google Patents
A method of preparing optically pure (R) -4- n-propyls-dihydrofuran -2 (3H) -one Download PDFInfo
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- CN108503609A CN108503609A CN201710101572.2A CN201710101572A CN108503609A CN 108503609 A CN108503609 A CN 108503609A CN 201710101572 A CN201710101572 A CN 201710101572A CN 108503609 A CN108503609 A CN 108503609A
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- ALZLTHLQMAFAPA-UHFFFAOYSA-N CC(C1)COC1=O Chemical compound CC(C1)COC1=O ALZLTHLQMAFAPA-UHFFFAOYSA-N 0.000 description 1
- 0 CCCCC(N([C@@](*)CO1)C1=O)=O Chemical compound CCCCC(N([C@@](*)CO1)C1=O)=O 0.000 description 1
- MWZQDRNDCQPZPQ-BHVGIWTPSA-O CCCCC1[OH+]C1N(C1O[C@H]1OC1)[C@]1(C)[U] Chemical compound CCCCC1[OH+]C1N(C1O[C@H]1OC1)[C@]1(C)[U] MWZQDRNDCQPZPQ-BHVGIWTPSA-O 0.000 description 1
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/32—Oxygen atoms
- C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
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Abstract
The present invention relates to a kind of methods preparing optically pure (R) 4 n-propyl dihydrofuran 2 (3H) ketone.This method is using 2 ketone of optically pure (S) 3 positive valeryl 4 substitution oxazoles as raw material; it is reacted by being alkylated with alkene or alkyne reagent; reduction removing chiral auxiliary, the oxidation of double or triple bonds and etc. be prepared and learn pure 2 (3H) ketone of (R) 4 n-propyl dihydrofuran.Preparation method raw material provided by the invention is easy to get, cheap, and total recovery is high, products therefrom optical purity is high, reaction condition and operating process are simple.
Description
Technical field
The present invention relates to a kind of methods preparing optically pure (R) -4- n-propyls-dihydrofuran -2 (3H) -one.
Background technology
The preparation method of 2- oxo-pyrroli -1- bases and the purposes as drug are in the world of publication number WO01/62726
It is described in patent application, is particularly suitable for treatment neurological disorders.Especially (2S) -2- ((4R) -2- oxos -4- positive third
Base -1- pyrrolidinyls) butyramide (also known as Bu Waxitan) disclosed by european patent number EP0162036 as protective agent treatment and pre-
Anti- CNS hypoxia and ischemic-type damage using it are Bu Waxitan preparations made of bulk pharmaceutical chemicals by European drug pipe
Reason office (EMA) approval is treated as adjuvant therapy medicaments for 16 years old or more epileptic's partial seizures.
(2S) -2- ((4R) -2- oxo -4- n-propyl -1- pyrrolidinyls) butyramide (R) -4- n-propyls-dihydrofuran -2
(3H) -one
Benoit M.Kenda et al. (J.Med.Chem.2004,47,530-549.) are described with the 4- of racemization positive third
The method that base-dihydrofuran -2 (3H) -one prepares 2- oxo-pyrroli -1- bases.Due to the use of 4- n-propyls-dihydro of racemization
Furans -2 (3H) -one, obtained product is a pair of of diastereoisomer, because isomers is similar to principal component property, it is difficult to logical
Conventional recrystallization method removal is crossed, therefore, it is necessary to can just obtain qualified product by chiral column preparative separation.Patent
CN105646319 report it is a kind of preparing optically pure (R) -4- n-propyls-dihydrofuran -2 (3H) -one, and prepared with it
The method of Bu Waxitan.Due to the use of optically pure (R) -4- n-propyls-dihydrofuran -2 (3H) -one, products obtained therefrom is chiral
Purity is high, it is therefore not necessary to can be obtained the Bu Waxitan of high-optical-purity by chiral preparative separation.
Currently, the preparation method of optically pure (R) -4- n-propyls-dihydrofuran -2 (3H) -one of document report shares seven
Synthetic route.
Kosugi, H et al. (J.Chem.Soc.Perkin Trans.I.1989,935-943.) report an optical voidness
(R) -4- n-propyls-dihydrofuran -2 (3H) -one synthetic route.The route is using chiral sulfoxide as starting material, through metal
Rhodium catalysis restores to obtain cis-form olefin, after obtain product with trichloro-acetic chloride cyclization, then dechlorinated and desulfurization under zinc powder catalysis,
Not only starting material is not easy to buy this method, and uses valuable metal rhodium catalyst and the prodigious metal tin catalyst of toxicity,
Therefore it is unsuitable for industrialized production.Route is as follows：
Mukaiyama, T et al. (Chemistry Letters.1980,635-638.) report one it is optically pure
(R) synthetic route of -4- n-propyls-dihydrofuran -2 (3H) -one.The route is using chiral heptatomic ring as starting material, warp
Addition methylates, removes and hydrolysis obtains asymmetric lactone.The route is not only with complicated intermediate as starting material
Material is not easy commercialization purchase, and generates more by-product, and Atom economy is poor, therefore is unsuitable for industrialized production.Route is such as
Under：
Chamberlin, R et al. (J.O.C.1993,58,2725-2737.) are reporting optically pure (R) -4- just
The synthetic route of propyl-dihydrofuran -2 (3H) -one.The route is using disubstituted chiral oxazoline ketone and bromoacetyl chloride as rising
Asymmetric lactone is prepared through the reaction of seven steps in beginning material, and the mercury reagent of severe toxicity is also used in final step, and route is long and to environment dirt
Dye is serious, therefore, is unsuitable for industrialized production.Route is as follows：
Olof Ceder et al. (Acta Chemica Scandinavica, Series B:Organic Chemistry
And Biochemistry.1977,31,189-192.) report optically pure (R) -4- n-propyls-dihydrofuran -2
The synthetic route of (3H) -one.The route is using chiral substituted cyclohexene acid as starting material, through reduction, oxidation, cell reaction system
It is standby to obtain asymmetric lactone.The route is not only with being not easy the chiral intermediate that buys of commercialization as starting material, and finally
Product is obtained through cell reaction, of high cost, reaction condition is also unsuitable for producing greatly.Route is as follows：
Patent CN105646319 reports a kind of optically pure (R) -4- n-propyls-dihydrofuran -2 (3H) -one of preparing
Route.The route is obtained using diphenyl malonate and (R)-epoxychloropropane as starting material through cyclization, grignard reaction and decarboxylation
Asymmetric lactone.Although starting material is easy to buy, third step decarboxylic reaction needs are carried out at 130 DEG C or more, and when reaction
Between it is longer, racemization may occur under the conditions of long-time heating for product, influence product purity.Route is as follows：
Patent CN105837535 reports a kind of optically pure (R) -4- n-propyls-dihydrofuran -2 (3H) -one of preparing
Route.The route using valeric chloride, chiral oxazoline ketone and 2- bromo-acetic acid tert-butyls as starting material, through condensation, substitution, reduction and
Hydrolysis obtains asymmetric lactone.Intermediate in the route all passes through column chromatography and purifies, of high cost, cumbersome.Route is such as
Under：
Arnaud Sch ü l é et al. (Org.Process Res.Dev.2016,20,1566-1575.) reports a kind of system
The route of standby optically pure (R) -4- n-propyls-dihydrofuran -2 (3H) -one.The route is with the substitution malonate of racemization
Beginning material obtains (R) type isomers after enzyme is split, and asymmetric lactone is obtained by reduction and cyclization.Because enzymatic is to reacting item
Part requires harshness, and expensive, and therefore, the route cost is higher.Route is as follows：
In order to overcome the problems, such as to have reported in route, the present inventor designs new optically pure (R) -4- n-propyls-dihydro
Furans -2 (3H) -one preparation method, and pass through its feasibility of experimental verification.New technology route is easy to get with starting material, instead
High income is answered, the advantages that by-product in reaction can recycle, easy to operate, and enantioselectivity is good has extensive work
Industry application prospect.
Invention content
The present invention provides a kind of system of simple and economically optically pure (R) -4- n-propyls-dihydrofuran -2 (3H) -one
Preparation Method.
A method of optically pure (R) -4- n-propyls-dihydrofuran -2 (3H) -one is prepared, is included the following steps：
1) the amylalcohol compound of optical voidness (R) -2- substitutions shown in formula (V) is prepared；
2) double or triple bonds oxidative cyclization is obtained optically pure (R) -4- n-propyls-dihydro by formula (V) under oxidative conditions
Furans -2 (3H) -one, and be converted into the reaction process of formula (I) in formula (V), chiral centre configuration does not change；
The R is-CH=CR1R2Or-C ≡ CR3, R1、R2、R3Stand alone as hydrogen, C1-20Alkyl or substituted C1-20Alkyl, virtue
Base or substituted aryl, heteroaryl or substituted heteroaryl, Heterocyclylalkyl or substituted Heterocyclylalkyl.
The oxidising agent system that the oxidation uses is sodium metaperiodate-ruthenic chloride, sodium metaperiodate-potassium permanganate, permanganic acid
Potassium or osmium tetroxide/NMO/ sodium metaperiodate step-by-step oxidations.
When the oxidising agent system that the oxidation uses is sodium metaperiodate-ruthenic chloride, reaction dissolvent is water and acetonitrile, reaction
Temperature is -10 DEG C~40 DEG C.
The formula (V) and the molar ratio of sodium metaperiodate are 1:4~10, the molar ratio of formula (V) and catalyst ruthenic chloride
It is 1:0.01~0.5.
It is preferred that R1It is hydrogen, R2、R3It is hydrogen, C1-20Alkyl or substituted C1-20Alkyl, aryl or substituted aryl；
It is preferred that R is-CH=CH2Or-C ≡ CH.
The method and step of preparation formula (V) is in the step 1)：A) the optically pure positive valeryl -4- of 3- shown in formula (II) take
Dai oxazole -2- ketone with shown in formula (III) carry leaving group alkene or acetylene hydrocarbon compound sent out in the presence of alkaline reagent
Raw alkyl substitution generates formula (IV) compound represented, B) compound shown in formula (IV) existing for reducing agent under the conditions of
The amylalcohol (V) of optically pure 2- substitutions is prepared, while recycling the oxazole-replaced such as the 4- for leading to chiral auxiliary that formula (VI) is shown as
2- ketone derivatives, and during the reaction, the spatial configuration of newly-generated chiral centre and the hand in formula (II) in formula (IV)
Property centered cubic configuration is opposite；
X is substituted or unsubstituted C1-20Alkyl, C1-20Alkenyl, aryl, heteroaryl, Heterocyclylalkyl, aryl alkyl or miscellaneous
Aryl alkyl, Y are selected from halogen, sulfonate ester group ,-S+Me2Or-N2 +Leaving group.
It is preferred that：
X is C1-6Alkyl, substituted C1-6Alkyl, C2-6Alkenyl, aryl, heteroaryl, substituted aryl, aryl alkyl or
Substituted aryl alkyl.
X is C1-6Alkyl, aryl, substituted aryl, aryl alkyl or substituted aryl alkyl, Y are fluorine, chlorine, bromine, iodine, methylsulfonyl
Oxygroup, trifluoro-methanesulfonyl oxy, tolysulfonyl oxygroup.
The preferred methyl of X, ethyl, n-propyl, isopropyl, tertiary butyl, benzyl, substituted benzyl, phenyl, substituted-phenyl.
X is phenyl, isopropyl or benzyl, and Y is bromine, fluorine, chlorine.
The reducing agent is lithium borohydride, sodium borohydride, potassium borohydride, 3-sec-butyl lithium borohydride (L-
Selectride), three tertiary butyoxy lithium aluminium or three sec-butyl potassium borohydrides (K-selectride).
The formula (IV) and the dosage molar ratio of reducing agent are 1:1.0~5.
The reaction dissolvent that the formula (IV) is reduced be water, tetrahydrofuran, methanol, ethyl alcohol, isopropanol single solvent or and
Water mixed solvent, reaction temperature are 0~100 DEG C.
The alkali used that is alkylated is lithium diisopropylamine (LDA), lithium hexamethyldisilazide (LHMDS), six
Two silicon substrate potassamide (KHMDS) of methyl, sodium hexamethyldisilazide (NHMDS).
The formula (II) and the dosage molar ratio of formula (III) are 1:0.9~5, the dosage molar ratio of formula (II) and alkali used
It is 1:0.9~3.
The alkylated reaction dissolvent is tetrahydrofuran or 2- methyltetrahydrofurans, and alkylated reaction temperature is -80
~20 DEG C.
Formula (II) is made with the following method in the step A：Compound shown in formula (VI) and positive valeric acid or n-amyl chloride
Or the mixed anhydride reaction of positive valeric acid is made.
The amylalcohol (V) that the present invention is replaced using optically pure (R) -2- alkynyls or alkenyl, oxidized cyclization obtain the present invention
Target product.Overall process is as follows：
Step (1)：The optically pure positive valeryl -4- substitution oxazole -2- ketone of (S) -3- and formula (III) institute shown in formula (II)
Alkyl substitution occurs in the presence of alkaline reagent for the alkene with leaving group or acetylene hydrocarbon compound shown, generates general formula
(IV) compound represented,
Step (2)：Optically pure (R) -2- substitutions are prepared under the conditions of compound shown in formula (IV) is existing for reducing agent
Amylalcohol (V), while recycling the oxazole -2- ketone derivatives replaced such as (the S) -4- for leading to chiral auxiliary that formula (VI) is shown as；
Step (3)：Making the amylalcohol (V) that optically pure (R) -2- replaces obtained by step (2), cyclization is made under oxidative conditions
Optical voidness (R) -4- n-propyls-dihydrofuran -2 (3H) -one.
Entire synthetic route is as follows：
Term used herein " alkyl " is defined as including with straight chain, branch or cyclic moieties or combinations thereof and containing 1
The saturation monovalent hydrocarbon of~20 carbon atoms, acyclic alkyl groups preferably comprise 1~6 carbon atom, and cyclic alkyl preferably comprises 3~
8 carbon atoms.
Term used herein " alkenyl " be defined as having at least one double bond it is unsubstituted or substituted it is branched, do not prop up
Change or cyclic hydrocarbon group or combinations thereof.Preferred alkenyl includes 2~4 carbon." alkenyl " structure division can be optionally by independence
1-5 substituent group substitution selected from halogen, hydroxyl, alkoxy, ester, acyl group, cyano, acyloxy, carboxylic acid, amide or amino.
Term used herein " aryl " includes that aryl hydrocarbon sloughs a hydrogen atom and the group that generates, such as phenyl, naphthalene
Base.
Term used herein " Heterocyclylalkyl " represents the ring containing at least one O, S and/or N Atomic Break carbocyclic ring structure
Shape alkyl (naphthenic base), such as tetrahydrofuran base, THP trtrahydropyranyl, piperidyl, piperazinyl, morpholine subbase and pyrrolidinyl.
Term used herein " heteroaryl " represents above-mentioned containing at least one O, S and/or N Atomic Break carbocyclic ring structure
" aryl " of definition, such as pyridyl group, furyl, pyrrole radicals, thienyl, isothiazolyl, imidazole radicals, benzimidazolyl, tetrazolium
Base, pyrazinyl, pyrimidine radicals, quinolyl, isoquinolyl, isobenzofuran-base, benzothienyl, pyrazolyl, indyl, iso-indoles
Base, purine radicals, carbazyl, isoxazolyls, thiazolyl, oxazolyls, benzothiazolyl or benzoxazolyl.
Term used herein " halogen " includes chlorine atom, bromine atom, iodine atom, fluorine atom.
Group shown in term used herein " hydroxyl " representative formula-OH.
Group shown in term used herein " carboxyl " representative formula-COOH.
Term used herein " sulfonic acid " representative formula-SO3Group shown in H.
Term used herein " sulfonamide " representative formula-SO2NH2Shown in group, wherein 1 or 2 hydrogen atom can appoint
Meaning ground is replaced by " alkyl ", " aryl ", " heteroaryl " and/or " Heterocyclylalkyl ", or replace as defined above-SO2NH2。
Group shown in term used herein " acyl group " representative formula RCO-, wherein R are " alkyl ", " aryl ", " heteroaryl
Base " or " Heterocyclylalkyl ", or the RCO- that replaces as defined above.
Group shown in term used herein " ester " representative formula-COOR, wherein R are " alkyl ", " aryl ", " heteroaryl "
Or " Heterocyclylalkyl ", or-the COOR that replaces as defined above.
Group shown in term used herein " alkoxy " representative formula-OR, wherein R are " alkyl " or " Heterocyclylalkyl ",
Or-the OR replaced as defined above.
Group shown in term used herein " aryloxy group " representative formula-OR, wherein R are " aryl " or " heteroaryl ", or
- the OR that person replaces as defined above.
Group shown in term used herein " acyloxy " representative formula RCOO-, wherein R are " alkyl ", " aryl ", " miscellaneous
Aryl " or " Heterocyclylalkyl ", or the RCOO- groups that replace as defined above.
Term used herein " alkyl sulphonyl " representative formula-SO2Group shown in R, wherein R are " alkyl " or " heterocycle
Alkyl ", the or-SO that replaces as defined above2R group.
Term used herein " aryl sulfonyl " representative formula-SO2Group shown in R, wherein R are " aryl " or " heteroaryl
Base ", the or-SO that replaces as defined above2R group.
Group shown in term used herein " alkyl sulphinyl " representative formula-SO-R, wherein R are " alkyl " or " miscellaneous
Naphthenic base ", the or-SO-R groups that replace as defined above.
Group shown in term used herein " aryl sulfonyl kia " representative formula-SO-R, wherein R are " aryl " or " miscellaneous
Aryl ", the or-SO-R groups that replace as defined above.
Group shown in term used herein " ester oxygroup " representative formula-OCOOR, wherein R are " alkyl ", " aryl ", " miscellaneous
Aryl " or " Heterocyclylalkyl ", the or-OCOOR groups that replace as defined above.
Term used herein " acylamino- " representative formula-CONH2Shown in group, wherein 1 or 2 hydrogen atom can be arbitrary
Ground is replaced by " alkyl ", " aryl ", " heteroaryl " and/or " Heterocyclylalkyl ", or-the CONH replaced as defined above2Base
Group.
Term used herein " acylamino- oxygroup " representative formula-OCONH2Shown in group, wherein 1 or 2 hydrogen atom can
Arbitrarily to be replaced by " alkyl ", " aryl ", " heteroaryl " and/or " Heterocyclylalkyl ", or replace as defined above-
OCONH2Group.
Compound can be prepared by any suitable method shown in formula (II) used in the present invention.
Positive valeryl -4- substitutions oxazole -2- the ketone of (S) -3- shown in formula (II) is preferably made of such method：Formula
(VI) compound shown in is made with positive valeric acid or the mixed anhydride reaction of n-amyl chloride or positive valeric acid.
Formula (II) compound represented in the present invention, when X be benzyl when, recrystallization solvent be selected from normal heptane, n-hexane,
Petroleum ether, ethyl acetate, methyl tertiary butyl ether(MTBE) single solvent or in which two or three of mixed solvent.Most preferably from normal heptane,
N-hexane single solvent or n-hexane/methyl tertiary butyl ether(MTBE) mixed solvent.
In the method for the invention, the alkali that step (1) alkylated reaction uses is selected from lithium diisopropylamine (LDA), six
Two silicon substrate lithium amide (LHMDS) of methyl, potassium hexamethyldisilazide (KHMDS), sodium hexamethyldisilazide (NHMDS)；
It is preferably selected from lithium hexamethyldisilazide (LHMDS) or lithium diisopropylamine (LDA).
Chiral oxazoline ketone (compound shown in formula IV) is referred to as Evans prothetic group, is a kind of common chiral auxiliary.Prothetic group
After N- acylations occur, if introducing alkyl side chain in the positions α of amide side chain, newly-generated chiral centre can be controlled well
Selectivity.Reaction mechanism is that under cryogenic, the alkali such as lithium diisopropylamine and substrate form enol form, afterwards and halogenated alkane
Reaction, reaction enantioselectivity is good, and products therefrom optical purity is high.
Applicant has found in the course of the research, in variation route of the invention, changes using shown in Formula II compound and formula III
It closes object and prepares compound shown in new formula IV, when reacting at low temperature, the chiral centre that Formula II compound contains can be stood
Body induces the structure of new chiral centre in specific manner, and the generation of diastereoisomer is not observed, and reaction stereoselectivity is non-
The amount of Chang Hao, the diastereoisomer generated in reaction process are seldom, in addition, the reaction does not generate the similar by-product of structure,
High conversion rate.Therefore, largely solve in the prior art that reaction selectivity is bad, the not high problem of yield.
In the method for the invention, the reducing agent that step (2) reduction reaction uses is selected from Lithium Aluminium Hydride, lithium borohydride, boron
Sodium hydride, potassium borohydride, three tertiary butyoxy lithium aluminium, 3-sec-butyl lithium borohydride (L-selectride), three sec-butyl boron
Hydrofining (K-selectride)；It is preferably selected from sodium borohydride, potassium borohydride, lithium borohydride；Most preferably from sodium borohydride, boron hydrogen
Change potassium.
Applicant has found in the course of the research, in variation route of the invention, is prepared using formula IV compound represented
The chemo-selective of compound shown in new Formula V, the reaction is very good, restores the amido bond of site Jin Fa Sheng oxazolinones
On, other by-products are not observed, and Formula IV compound can be recycled by recrystallizing after reacting, substantially increased in this way
Atom economy reduces cost.
Rong Gao et al. (Synlett.2015,26,661-665.) is reported to be aoxidized using sodium metaperiodate-ruthenic chloride
γ-alkene can directly obtain the disubstituted butyrolactone of cyclization product β, β-, and this method is selectively good, high income, and grasp
Make easy.
In the method for the invention, the oxidising agent used in step (3) oxidation reaction be selected from sodium metaperiodate-ruthenic chloride,
Sodium metaperiodate-potassium permanganate, potassium permanganate or osmium tetroxide/NMO/ sodium metaperiodate step-by-step oxidations.It is preferably selected from sodium metaperiodate-chlorine
Change ruthenium.
When the oxidising agent system that the oxidation uses is sodium metaperiodate-ruthenic chloride, reaction dissolvent is water and acetonitrile, reaction
Temperature is -10~40 DEG C.
The formula (V) is 1 with the molar ratio with sodium metaperiodate:4~10, the molar ratio of formula (V) and catalyst ruthenic chloride
Example is 1:0.01-0.5.
In the method for the invention, the dosage molar ratio of formula (II) and formula (III) is 1 in step (1):0.9~5, preferably
1:1.1~1.5.
In the method for the invention, formula (II) and the dosage molar ratio of alkali used are 1 in step (1):0.9~3, preferably 1:
1.0~1.5.
In the method for the invention, formula (IV) and the dosage molar ratio of reducing agent are 1 in step (2):1.0~5, preferably 1:
1.0~2.0.
In the method for the invention, step (1) alkylated reaction dissolvent is tetrahydrofuran, 2- methyltetrahydrofurans.
In the method for the invention, the reaction dissolvent of step (2) reduction is water/tetrahydrofuran, water/methanol, water/ethyl alcohol
Mixed solvent.
In the method for the invention, the reaction dissolvent of step (3) oxidation is the mixed solvent of acetonitrile and water.
In the method for the invention, step (3) oxidation reaction, when oxidising agent is sodium metaperiodate and ruthenic chloride, high iodine
The molar ratio of sour sodium and formula (V) is 4~10:1；It is preferred that 5~7:1.
In the method for the invention, step (3) oxidation reaction, when oxidising agent is sodium metaperiodate and ruthenic chloride, chlorination
The molar ratio of ruthenium and formula (V) is 0.01~0.5:1, preferably 0.04~0.1:1.
In the method for the invention, step (1) alkylated reaction temperature is -80~20 DEG C.
In the method for the invention, the reaction temperature of step (2) reduction is 0~100 DEG C.
In the method for the invention, the reaction temperature of step (3) oxidation is -10~40 DEG C, preferably 10~30 DEG C.
The method of the present invention is particularly suitable for preparing 4- n-propyls-dihydrofuran -2 (3H) -one of (R) configuration.It is used herein
Term (R) refer to such compound：It has 50% or more, more preferable 90% or more enantiomter composition.
It is that example only plays the purpose illustrated the present invention below, does not mean in any way or be construed to pair
The limitation of the present invention.Those skilled in the art can do following embodiment in no more than the spirit and scope of the present invention conventional change
It changes and improves.
Embodiment
Embodiment 1：(S) synthesis of -4- benzyls -3- valeryls Ji oxazole -2- ketone
Tetrahydrofuran (6.3L) is added in reaction bulb, (S) -4- Bian Ji oxazole -2- ketone (422.0g) is added, be cooled to -
70℃；It under nitrogen protection, is kept for Nei Wen -65~-75 DEG C, a concentration of 2.5M n-BuLis (1.0L) solution is added dropwise, drop finishes, heat preservation
React half an hour；It is kept for Nei Wen -65~-75 DEG C, valeric chloride (315.9g) is added dropwise, drop finishes, and reacts half an hour, and TLC detects (S) -
4- Bian Ji oxazole -2- ketone disappears, processing；0 DEG C is risen to, 2L saturated aqueous ammonium chlorides are added, butyl lithium, split-phase is quenched.Decompression
Organic phase is concentrated, is concentrated to dryness, concentrate 3L dichloromethane dissolves, and (500mL × 2) is then washed with water twice, organic phase
It is dried 2 hours with 300.0g anhydrous sodium sulfates；Filtering, is concentrated to dryness, obtains 621.3g target compounds, solid for white
Body.
1H NMR(400MHz,CDCl3) δ 7.33 (t, J=7.2Hz, 2H), 7.28 (d, J=7.3Hz, 1H), 7.21 (d, J
=7.2Hz, 2H), 4.67 (ddd, J=10.6,7.1,3.6Hz, 1H), 4.26-4.08 (m, 2H), 3.29 (dd, J=13.4,
3.1Hz, 1H), 3.04-2.84 (m, 2H), 2.77 (dd, J=13.3,9.6Hz, 1H), 1.68 (ddd, J=16.9,11.0,
6.1Hz, 2H), 1.41 (dt, J=15.0,7.7Hz, 2H), 0.96 (t, J=7.4Hz, 3H) .MS (ESI):m/z 262.1[M+
H]+.[α]D 20+ 54.0 ° of (c=1.0g/100mL, CHCl3).
Embodiment 2：(S) -4- benzyls -3- ((R) -2- n-propyls-amyl- 4- enoyl-) oxazole -2- ketone synthesis
Tetrahydrofuran (50mL) is added in reaction bulb, (S) -4- benzyl -3- valeryl Ji oxazole -2- ketone (5.2g) is added,
It is cooled to -70 DEG C；It under nitrogen protection, is kept for Nei Wen -65~-75 DEG C, the tetrahydrofuran solution (24mL) of 1.0M LHMDS is added dropwise,
Drop finishes, insulation reaction 1 hour；It is kept for Nei Wen -65~-75 DEG C, allyl bromine (3.0g) is added dropwise, drop finishes, insulation reaction 2 hours, TLC
It detects raw material to disappear, processing；It rises to 0 DEG C, is added 50mL saturated aqueous ammonium chlorides, split-phase, water phase is with ethyl acetate (50mL)
Extraction merges organic phase, is concentrated under reduced pressure；It is concentrated to dryness, is dissolved with 50mL dichloromethane, (25mL × 2) are then washed with water, have
Machine mutually uses 10.0g anhydrous sodium sulfates to dry 2 hours；Filtering is concentrated under reduced pressure, obtains 5.8g target compounds, is faint yellow oily
Object.
(S) -4- benzyls -3- ((R) -2- n-propyls-amyl- 4- enoyl-) oxazole -2- ketone：1H NMR(400MHz,CDCl3)δ
7.33 (t, J=7.2Hz, 2H), 7.30-7.19 (m, 3H), 5.96-5.72 (m, 1H), 5.07 (dd, J=17.9,13.7Hz,
2H), 4.78-4.60 (m, 1H), 4.27-4.05 (m, 2H), 4.04-3.85 (m, 1H), 3.30 (dd, J=13.3,2.9Hz,
1H), 2.66 (dd, J=13.3,10.1Hz, 1H), 2.47 (dt, J=14.8,7.6Hz, 1H), 2.42-2.23 (m, 1H),
1.79-1.67 (m, 1H), 1.49 (dt, J=13.2,6.9Hz, 1H), 1.32 (dq, J=15.2,7.4Hz, 2H), 0.91 (t, J
=7.3Hz, 3H) .MS (ESI):m/z302.1[M+H]+.[α]D 19+ 34.0 ° of (c=1.0g/100mL, CHCl3).
Embodiment 3：(S) -4- benzyls -3- ((R) -2- n-propyls-amyl- 4- alkynes acyl group) oxazole -2- ketone synthesis
Tetrahydrofuran (50mL) is added in reaction bulb, (S) -4- benzyl -3- valeryl Ji oxazole -2- ketone (5.2g) is added,
It is cooled to -70 DEG C；It under nitrogen protection, is kept for Nei Wen -65~-75 DEG C, the tetrahydrofuran solution of 1.0M LHMDS is added dropwise
(24.0mL), drop finish, insulation reaction 1 hour；It is kept for Nei Wen -65~-75 DEG C, the third bromine of alkynes (3.1g) is added dropwise, drop finishes, insulation reaction
2 hours, TLC detected raw material and disappears, processing；0 DEG C is risen to, 25mL saturated aqueous ammonium chlorides are added, split-phase is concentrated under reduced pressure organic
Phase.Concentrate 50mL dichloromethane dissolves, and is then washed with water (25mL × 2), and organic phase is dried with 10.0g anhydrous sodium sulfates
2 hours；Filtering is concentrated under reduced pressure, obtains 6.1g target compounds, is pale yellow oil.
(S) -4- benzyls -3- ((R) -2- n-propyls-amyl- 4- alkynes acyl group) oxazole -2- ketone：1H NMR(400MHz,CDCl3)δ
7.29 (ddd, J=16.9,12.8,7.5Hz, 5H), 4.71 (ddt, J=10.4,7.0,3.4Hz, 1H), 4.29-4.10 (m,
2H), 4.10-3.94 (m, 1H), 3.32 (dd, J=13.5,3.2Hz, 1H), 2.78 (dd, J=13.4,9.6Hz, 1H), 2.67-
2.44 (m, 2H), 2.01 (t, J=2.6Hz, 1H), 1.77 (dt, J=15.2,7.1Hz, 1H), 1.58 (ddd, J=20.4,
13.3,6.9Hz,1H),1.47–1.28(m,3H),1.00–0.83(m,3H).MS(ESI):m/z 300.1[M+H]+.[α]D 19+
51.4 ° of (c=0.9g/100mL, CHCl3).
Embodiment 4：(R) synthesis of -2- n-propyls -4- alkene -1- amylalcohols
Tetrahydrofuran (8.0mL) and water (2.0mL) are added in reaction bulb, (S) -4- benzyls -3- ((R) -2- positive third are added
The amyl- 4- enoyl-s) oxazoles -2- ketone (1.2g) of base -, is added portionwise sodium borohydride (0.3g).It keeps reacting 2 hours at room temperature；TLC
It detects raw material to disappear, processing；Saturated ammonium chloride (6.0ml) is added dropwise under the conditions of temperature is not higher than 30 DEG C in control to be quenched.Liquid separation, water phase
It is extracted with methyl tertiary butyl ether(MTBE) (10.0mL), merges organic phase, be concentrated to dryness under the conditions of 40 DEG C.To concentrate
Middle addition methyl tertiary butyl ether(MTBE)/n-hexane (2.8mL, 2:1, v/v) it, is down to 0~10 DEG C to stir 1 hour, solid is precipitated, filter,
(S) -4- Bian Ji oxazole -2- ketone is recycled, obtains 0.35g, filtrate is concentrated to dryness, and 0.44g target compounds are obtained after column chromatography, are
Colorless oil.
(R) -2- n-propyls -4- alkene -1- amylalcohols：1H NMR (400MHz, Chloroform-d) δ 5.83 (ddt, J=
17.2,10.1,7.2Hz,1H),5.15–4.92(m,2H),3.66–3.45(m,2H),2.20–2.06(m,2H),1.61(p,J
=6.1Hz, 1H), 1.41-1.19 (m, 4H), 0.91 (t, J=6.9Hz, 3H) .MS (EI, 70eV)：m/e(rel.inten.)95
(15),81(61),69(80),57(67),55(100),54(57).[α]D 19+ 20.0 ° of (c=1.0g/100mL, CHCl3).
Embodiment 5：(R) synthesis of -2- n-propyls -4- alkynes -1- amylalcohols
Tetrahydrofuran (8.0ml) and water (2.0ml) are added in reaction bulb, (S) -4- benzyls -3- ((R) -2- positive third are added
The amyl- 4- alkynes acyl group) oxazoles -2- ketone (1.2g) of base -, is added portionwise sodium borohydride (0.3g).It keeps reacting 2 hours at room temperature；TLC
It detects raw material to disappear, processing；Saturated ammonium chloride (6.0ml) is added dropwise under the conditions of temperature is not higher than 30 DEG C in control to be quenched.Liquid separation, water phase
It is extracted with methyl tertiary butyl ether(MTBE) (10.0mL), merges organic phase, be concentrated to dryness under the conditions of 40 DEG C.To concentrate
Middle addition methyl tertiary butyl ether(MTBE)/n-hexane (3.0mL, 2:1, v/v) it, is down to 0-10 DEG C to stir 1 hour, solid is precipitated, filter, return
(S) -4- Bian Ji oxazole -2- ketone is received, 0.38g is obtained, filtrate is concentrated to dryness, and 0.40g target compounds are obtained after column chromatography, is nothing
Color grease.
(R) -2- n-propyls -4- alkynes -1- amylalcohols：1H NMR(400MHz,CDCl3) δ 3.66 (ddd, J=17.5,10.8,
5.7Hz, 2H), 2.38-2.20 (m, 2H), 1.97 (t, J=2.6Hz, 1H), 1.83-1.67 (m, 1H), 1.52 (s, 1H), 1.36
(dd, J=5.6,3.2Hz, 4H), 0.93 (dd, J=8.5,5.0Hz, 3H) .MS (EI, 70eV)：m/e(rel.inten.)126
(M+,2),111(1),93(73),83(67),79(65),69(100),55(75).[α]D 19+ 8.2 ° (c=0.5g/100mL,
CHCl3) embodiments 6：(R) synthesis of -4- n-propyls-dihydrofuran -2 (3H) -one
Method 1：
Acetonitrile (6.0mL) and water (1.0mL) are added in reaction bulb, (R) -2- n-propyl -4- alkene -1- amylalcohols are added
(0.4g) is added ruthenic chloride (32mg), keeps room temperature that NaIO is added portionwise after dissolving under room temperature4(4.0g), finishes, and keeps
Room temperature is vigorously stirred reaction, there is solid precipitation, reacts 3 hours.TLC detects raw material and disappears, and filtering adds water (10.0mL), adds Asia
Niter cake, it is 1-3 to make solution ph, is stirred 1 hour, again with full after adding ethyl acetate (20.0mL), liquid separation, organic phase to merge
It is primary with salt washing, anhydrous sodium sulfate drying is added, filtering and concentrating obtains crude product.Concentrate obtains 0.21g mesh through column chromatography
Compound is marked, is colorless oil.
(R) -4- n-propyls-dihydrofuran -2 (3H) -one：1H NMR (400MHz, Chloroform-d) δ 4.42 (t, J=
8.0Hz, 1H), 3.92 (dd, J=8.9,7.0Hz, 1H), 2.59 (ddt, J=22.4,15.2,8.0Hz, 2H), 2.18 (dd, J
=16.2,7.1Hz, 1H), 1.46 (q, J=7.0Hz, 2H), 1.34 (dtt J=14.4,7.1,4.6Hz, 2H), 0.94 (t, J
=7.3Hz, 3H) .MS (EI, 70eV)：m/e(rel.inten.)128(M+,4),110(2),97(29),70(55),69(42),
56(100),55(92).[α]D 19+ 6.50 ° of (c=1.22g/100mL, CHCl3).
Method 2：
Acetonitrile (6.0mL) and water (1.0mL) are added in reaction bulb, (R) -2- n-propyl -4- alkynes -1- amylalcohols are added
(0.4g) is added ruthenic chloride (31mg), keeps room temperature that NaIO is added portionwise after dissolving under room temperature4(4.0g), finishes, and keeps
Room temperature is vigorously stirred reaction, there is solid precipitation, reacts 3 hours.TLC detects raw material and disappears, and filtering adds water (10.0mL), adds Asia
Niter cake, it is 1-3 to make solution ph, is stirred 1 hour, again with full after adding ethyl acetate (20.0mL), liquid separation, organic phase to merge
It is primary with salt washing, anhydrous sodium sulfate drying is added, filtering and concentrating obtains crude product.Concentrate obtains 0.24g mesh through column chromatography
Compound is marked, is colorless oil.
Claims (16)
1. a kind of method preparing optically pure (R) 4- n-propyls-dihydrofuran -2 (3H) -one, includes the following steps：
(1) amylalcohol (V) compound of optical voidness (R) -2- substitutions shown in formula (V) is prepared；
(2) under oxidative conditions optical voidness (R) -4- n-propyls-dihydrofuran -2 is made in double or triple bonds oxidative cyclization by formula (V)
(3H) -one, and be converted into the reaction process of formula (I) in formula (V), chiral centre configuration does not change；
The R is-CH=CR1R2Or-C ≡ CR3, R1、R2、R3Stand alone as hydrogen, C1-20Alkyl or substituted C1-20Alkyl, aryl or
It is aryl, heteroaryl or the substituted heteroaryl, Heterocyclylalkyl or substituted Heterocyclylalkyl of substitution.
2. according to the method described in claim 1, the oxidising agent system that the oxidation uses is sodium metaperiodate-ruthenic chloride, height
Sodium iodate-potassium permanganate, potassium permanganate or osmium tetroxide/NMO/ sodium metaperiodate step-by-step oxidations.
3. according to the method described in claim 2, the oxidising agent system that the oxidation uses is when being sodium metaperiodate-ruthenic chloride,
Reaction dissolvent is the mixture of water and acetonitrile, and reaction temperature is -10~40 DEG C, the molar ratio of formula (V) and sodium metaperiodate
It is 1:4~10, formula (V) and the molar ratio of catalyst ruthenic chloride are 1:0.01~0.5.
4. according to the method described in claim 3, reaction temperature is 10~30 DEG C, the molar ratio of formula (V) and sodium metaperiodate
Example is 1:5~7, formula (V) and the molar ratio of catalyst ruthenic chloride are 1:0.04~0.1.
5. according to the method described in claim 1, wherein R1It is hydrogen, R2、R3It is hydrogen, C1-20Alkyl or substituted C1-20Alkyl, virtue
Base or substituted aryl.
6. according to the method described in claim 5, R is-CH=CH2Or-C ≡ CH.
7. according to the method described in claim 1, the method and step for preparing formula (V) in the step (1) is：A) shown in formula (II)
The optically pure alkene or alkynes (S) -3- positive valeryl -4- substitution oxazole -2- ketone and carry leaving group shown in formula (III)
Alkyl substitution occurs in the presence of alkaline reagent for compound, generates formula (IV) compound represented, and reacting
Cheng Zhong, the spatial configuration of newly-generated chiral centre is opposite with the chiral centre spatial configuration in formula (II) in formula (IV)；B) formula
(IV) amylalcohol (V) of optically pure (R) -2- substitutions is prepared under the conditions of compound shown in is existing for reducing agent, while being recycled such as
Oxazole -2- the ketone derivatives of (S) -4- substitutions of the be shown as chiral auxiliary of logical formula (VI),
X is substituted or unsubstituted C1-20Alkyl, C1-20Alkenyl, aryl, heteroaryl, Heterocyclylalkyl, aryl alkyl or heteroaryl
Alkyl, Y are selected from halogen, sulfonate ester group ,-S+Me2Or-N2 +Leaving group.
8. according to the method described in claim 7, X is C1-6Alkyl, aryl, substituted aryl, aryl alkyl or substituted aryl alkane
Base, Y are fluorine, chlorine, bromine, iodine, mesyloxy, trifluoro-methanesulfonyl oxy, tolysulfonyl oxygroup.
9. according to the method described in claim 8, X is methyl, ethyl, n-propyl, isopropyl, tertiary butyl, benzyl, substitution benzyl
Base, phenyl, substituted-phenyl.
10. according to the method described in claim 9, X is phenyl, isopropyl or benzyl, Y is bromine, fluorine, chlorine.
11. according to the method described in claim 7, the reducing agent be lithium borohydride, sodium borohydride, potassium borohydride, three Zhong Ding
Base lithium borohydride, three tertiary butyoxy lithium aluminium or three sec-butyl potassium borohydrides.
12. according to the method for claim 11, the reaction dissolvent that the formula (IV) is reduced be water, tetrahydrofuran, methanol,
One or more in ethyl alcohol, isopropanol, reaction temperature is 0~100 DEG C, and the formula (IV) and the dosage molar ratio of reducing agent are
1:0.5~5.
13. according to the method for claim 12, the reaction dissolvent that the formula (IV) is reduced is water/tetrahydrofuran, water/first
The mixed solvent of alcohol, water/ethyl alcohol, formula (IV) and the dosage molar ratio of reducing agent are 1:1.0~2.0.
14. according to the method described in claim 7, the alkali used that is alkylated is lithium diisopropylamine, two silicon of hexamethyl
Base lithium amide, potassium hexamethyldisilazide, sodium hexamethyldisilazide.
15. according to the method for claim 14, the alkylated reaction dissolvent is tetrahydrofuran or 2- methyl tetrahydrochysene furans
It mutters, alkylated reaction temperature is -80~20 DEG C, and the formula (II) and the dosage molar ratio of formula (III) are 1:0.9~5, formula
(II) it is 1 with the dosage molar ratio of alkali used:0.9~3.
16. according to the method for claim 15, the formula (II) and the dosage molar ratio of formula (III) are 1:1.1~1.5,
Formula (II) and the dosage molar ratio of alkali used are 1:1.0~1.5.
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| CN113717132A (en) * | 2021-08-31 | 2021-11-30 | 珠海润都制药股份有限公司 | Key intermediate of antiepileptic drug and preparation method thereof |
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