CN108503609B

CN108503609B - Method for preparing optically pure (R) -4-n-propyl-dihydrofuran-2 (3H) -ketone

Info

Publication number: CN108503609B
Application number: CN201710101572.2A
Authority: CN
Inventors: 马良; 徐征波
Original assignee: Beijing Ai Bestcomm Pharmaceutical Ltd By Share Ltd
Current assignee: Beijing Ai Bestcomm Pharmaceutical Ltd By Share Ltd
Priority date: 2017-02-24
Filing date: 2017-02-24
Publication date: 2019-12-24
Anticipated expiration: 2037-02-24
Also published as: CN108503609A

Abstract

The invention relates to a method for producing optically pure (R) -4-n-propyl-dihydrofuran-2 (3H) -one. The method takes optically pure (S) -3-n-pentanoyl-4-substituted oxazole-2-ketone as a raw material, and prepares the optically pure (R) -4-n-propyl-dihydrofuran-2 (3H) -ketone through the steps of alkylation reaction with an alkene or alkyne reagent, reduction removal of chiral auxiliary groups, oxidation of double bonds or triple bonds and the like. The preparation method provided by the invention has the advantages of easily available raw materials, low price, high total yield, high optical purity of the obtained product and simple reaction conditions and operation process.

Description

Method for preparing optically pure (R) -4-n-propyl-dihydrofuran-2 (3H) -ketone

Technical Field

The invention relates to a method for producing optically pure (R) -4-n-propyl-dihydrofuran-2 (3H) -one.

Background

The preparation of 2-oxo-pyrrolidin-1-yl and its use as a medicament are described in the international patent application publication WO01/62726, particularly for the treatment of neurological disorders. In particular, (2S) -2- ((4R) -2-oxo-4-n-propyl-1-pyrrolidinyl) butanamide (also known as bwaitan) is disclosed by european patent No. EP0162036 as a protective agent for the treatment and prevention of hypoxic and ischemic lesions of the central nervous system, and bwaitan preparations made from it as a raw material have been approved by the European Medicines Administration (EMA) as an adjuvant therapy for the treatment of partial seizures in epileptic patients over 16 years of age.

(2S) -2- ((4R) -2-oxo-4-n-propyl-1-pyrrolidinyl) butanamide (R) -4-n-propyl-dihydrofuran-2 (3H) -one

Benoit M.Kenda et al (J.Med.chem.2004,47, 530-. Since racemic 4-n-propyl-dihydrofuran-2 (3H) -ketone is used, the obtained product is a pair of diastereoisomers, and because the isomers have similar properties with the main component and are difficult to remove by a conventional recrystallization method, the qualified product can be obtained only by preparation and separation through a chiral column. Patent CN105646319 reports a method for preparing optically pure (R) -4-n-propyl-dihydrofuran-2 (3H) -one, and a method for preparing bravaracetam using the same. Because the optically pure (R) -4-n-propyl-dihydrofuran-2 (3H) -ketone is used, the chiral purity of the obtained product is high, and therefore, the high-optical-purity brivaracetam can be obtained without chiral preparation and separation.

At present, the preparation methods of optically pure (R) -4-n-propyl-dihydrofuran-2 (3H) -ketone reported in the literature have seven synthetic routes.

Kosugi, H et al (J.chem.Soc.Perkin Trans.I.1989,935-943.) report a synthetic route to optically pure (R) -4-n-propyl-dihydrofuran-2 (3H) -one. The method not only is not easy to purchase the starting material, but also uses a precious metal rhodium catalyst and a metal tin catalyst with high toxicity, so the method is not suitable for industrial production. The route is as follows:

mukaiyama, T et al (Chemistry letters.1980,635-638.) reported a synthetic route to optically pure (R) -4-n-propyl-dihydrofuran-2 (3H) -one. The method takes chiral seven-membered ring as starting material, and chiral lactone is obtained through addition, methylation, removal and hydrolysis reaction. The route not only adopts a complex intermediate as a starting material, is not easy to be purchased commercially, but also produces more byproducts and has poor atom economy, thus being not suitable for industrial production. The route is as follows:

a synthetic route for optically pure (R) -4-n-propyl-dihydrofuran-2 (3H) -one was reported by Chamberlin, R et al (J.O.C.1993,58, 2725-2737.). The method takes disubstituted chiral oxazoline ketone and bromoacetyl chloride as starting materials, obtains chiral lactone through seven steps of reaction, uses highly toxic mercury reagent in the last step, has long route and serious environmental pollution, and is not suitable for industrial production. The route is as follows:

olof Ceder et al (Acta Chemica Scandinavica, Series B: Organic Chemistry and biochemistry, 1977,31,189-192.) reported a synthetic route to optically pure (R) -4-n-propyl-dihydrofuran-2 (3H) -one. The method takes chiral substituted cyclohexenone as a starting material, and chiral lactone is prepared by reduction, oxidation and electrolytic reaction. The route not only adopts the chiral intermediate which is not easy to be purchased commercially as the starting material, but also obtains the product through the electrolytic reaction, and has high cost and reaction conditions which are not suitable for large-scale production. The route is as follows:

patent CN105646319 reports a route to optically pure (R) -4-n-propyl-dihydrofuran-2 (3H) -one. The method uses diphenyl malonate and (R) -epichlorohydrin as starting materials to obtain chiral lactone through ring closing, Grignard reaction and decarboxylation. Although the starting materials are easily purchased, the decarboxylation reaction in the third step needs to be carried out at 130 ℃ or higher, the reaction time is long, and the racemization of the product can occur under long-term heating conditions, which affects the purity of the product. The route is as follows:

patent CN105837535 reports a route to prepare optically pure (R) -4-n-propyl-dihydrofuran-2 (3H) -one. The method uses valeryl chloride, chiral oxazoline ketone and 2-bromoacetic acid tert-butyl ester as starting materials to obtain chiral lactone through condensation, substitution, reduction and hydrolysis reaction. The intermediates in the route are purified by column chromatography, so that the cost is high and the operation is complicated. The route is as follows:

arnaud Sch ü l et al (org. Process Res. Dev.2016,20,1566-1575.) report a route for the preparation of optically pure (R) -4-n-propyl-dihydrofuran-2 (3H) -one starting from racemic substituted malonates by enzymatic resolution to give the (R) -isomer, which is then reduced and cyclized to give the chiral lactone.

To overcome the problems in the reported routes, the present inventors designed a new preparation method of optically pure (R) -4-n-propyl-dihydrofuran-2 (3H) -one and verified its feasibility by experiments. The new process route has the advantages of easily obtained starting materials, high reaction yield, capability of recycling byproducts in the reaction, simple operation, good enantioselectivity and the like, and has wide industrial application prospect.

Disclosure of Invention

The invention provides a simple and economical process for the preparation of optically pure (R) -4-n-propyl-dihydrofuran-2 (3H) -one.

A process for preparing optically pure (R) -4-n-propyl-dihydrofuran-2 (3H) -one comprising the steps of:

1) preparing an optically pure (R) -2-substituted pentanol compound represented by the formula (V);

2) in the formula (V), double bonds or triple bonds are oxidized and closed under the oxidation condition to obtain optically pure (R) -4-n-propyl-dihydrofuran-2 (3H) -ketone, and the configuration of a chiral center is not changed in the reaction process of converting the formula (V) into the formula (I);

r is-CH ═ CR¹R²or-C.ident.CR³，R¹、R²、R³Independently of each other is hydrogen, C_1-20Alkyl or substituted C_1-20Alkyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, heterocycloalkyl or substituted heterocycloalkyl.

The oxidation reagent system adopted by the oxidation is step-by-step oxidation of sodium periodate-ruthenium chloride, sodium periodate-potassium permanganate, potassium permanganate or osmium tetroxide/NMO/sodium periodate.

When the oxidation reagent system adopted by the oxidation is sodium periodate-ruthenium chloride, the reaction solvent is water and acetonitrile, and the reaction temperature is-10 ℃ to 40 ℃.

The molar ratio of the formula (V) to the sodium periodate is 1: 4-10, and the molar ratio of the formula (V) to the catalyst ruthenium chloride is 1: 0.01-0.5.

Preferably R¹Is hydrogen, R²、R³Is hydrogen, C_1-20Alkyl or substituted C_1-20Alkyl, aryl or substituted aryl;

preferably, R is-CH ═ CH₂or-C.ident.CH.

The method for preparing the formula (V) in the step 1) comprises the following steps: A) the optically pure 3-n-valeryl-4-substituted oxazole-2-ketone shown in the formula (II) and an alkene or alkyne compound shown in the formula (III) and provided with a leaving group are subjected to alkyl substitution reaction in the presence of an alkaline reagent to generate a compound shown in the formula (IV), B) the compound shown in the formula (IV) is used for preparing optically pure 2-substituted pentanol (V) in the presence of a reducing agent, and simultaneously, a 4-substituted oxazole-2-ketone derivative shown in the general formula (VI) as a chiral auxiliary group is recovered, and in the reaction process, the stereo configuration of a newly generated chiral center in the formula (IV) is opposite to that of the chiral center in the formula (II);

x is substituted or unsubstituted C_1-20Alkyl radical, C_1-20Alkenyl, aryl, heteroaryl, heterocycloalkyl, arylalkyl or heteroarylalkyl, Y is selected from halogen, sulfonate group, -S⁺Me₂or-N₂ ⁺A leaving group of (1).

Preferably:

x is C_1-6Alkyl, substituted C_1-6Alkyl radical, C_2-6Alkenyl, aryl, heteroaryl, substituted aryl, arylalkyl, or substituted arylalkyl.

X is C_1-6Alkyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl, Y is fluorine, chlorine, bromine, iodine, mesyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy.

X is preferably methyl, ethyl, n-propyl, isopropyl, tert-butyl, benzyl, substituted benzyl, phenyl, substituted phenyl.

X is phenyl, isopropyl or benzyl, and Y is bromine, fluorine or chlorine.

The reducing agent is lithium borohydride, sodium borohydride, potassium borohydride, lithium tri-sec-butyl borohydride (L-select), lithium tri-tert-butoxyaluminum hydride or potassium tri-sec-butyl borohydride (K-select).

The molar ratio of the formula (IV) to the reducing agent is 1: 1.0-5.

The reduced reaction solvent of the formula (IV) is a single solvent or a mixed solvent of water, tetrahydrofuran, methanol, ethanol and isopropanol, and the reaction temperature is 0-100 ℃.

The base adopted in the alkylation is Lithium Diisopropylamide (LDA), Lithium Hexamethyldisilazide (LHMDS), potassium hexamethyldisilazide (KHMDS) and sodium hexamethyldisilazide (NHMDS).

The molar ratio of the dosage of the formula (II) to the dosage of the formula (III) is 1: 0.9-5, and the molar ratio of the dosage of the formula (II) to the dosage of the used alkali is 1: 0.9-3.

The alkylation reaction solvent is tetrahydrofuran or 2-methyltetrahydrofuran, and the alkylation reaction temperature is-80-20 ℃.

The formula (II) in the step A is prepared by adopting the following method: the compound shown in the formula (VI) reacts with n-pentanoic acid or n-valeryl chloride or mixed anhydride of n-pentanoic acid to obtain the compound.

The invention adopts optically pure (R) -2-alkynyl or alkenyl substituted amyl alcohol (V) to obtain the target product of the invention through oxidation ring closing. The overall reaction process is as follows:

step (1): optically pure (S) -3-n-pentanoyl-4-substituted oxazole-2-ketone shown in formula (II) and alkene or alkyne compound with leaving group shown in formula (III) are subjected to alkyl substitution reaction in the presence of alkaline reagent to generate a compound shown in a general formula (IV),

step (2): preparing optically pure (R) -2-substituted pentanol (V) from the compound shown in the formula (IV) in the presence of a reducing agent, and simultaneously recovering (S) -4-substituted oxazol-2-one derivatives as chiral auxiliary groups shown in the general formula (VI);

and (3): and (3) cyclizing the optically pure (R) -2-substituted pentanol (V) obtained in the step (2) under oxidizing conditions to obtain the optically pure (R) -4-n-propyl-dihydrofuran-2 (3H) -one.

The whole synthetic route is as follows:

the term "alkyl" as used herein is defined to include saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof and containing from 1 to 20 carbon atoms, acyclic alkyl radicals preferably containing from 1 to 6 carbon atoms and cyclic alkyl radicals preferably containing from 3 to 8 carbon atoms.

The term "alkenyl" as used herein is defined as an unsubstituted or substituted branched, unbranched or cyclic hydrocarbyl group or combination thereof having at least one double bond. Preferred alkenyl groups contain 2 to 4 carbons. The "alkenyl" moiety may be optionally substituted with 1-5 substituents independently selected from halogen, hydroxy, alkoxy, ester, acyl, cyano, acyloxy, carboxylic acid, amide or amino.

The term "aryl" as used herein includes groups derived from an aryl hydrocarbon by removal of one hydrogen atom, such as phenyl, naphthyl.

The term "heterocycloalkyl" as used herein denotes cyclic alkyl (cycloalkyl) groups containing at least one O, S and/or N atom interrupting the carbocyclic ring structure, such as tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholino and pyrrolidinyl groups.

The term "heteroaryl" as used herein represents an "aryl" as defined above containing at least one O, S and/or N interrupting the carbocyclic ring structure, such as pyridyl, furyl, pyrrolyl, thienyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidinyl, quinolinyl, isoquinolinyl, isobenzofuryl, benzothienyl, pyrazolyl, indolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benzothiazolyl or benzoxazolyl.

The term "halogen" as used herein includes chlorine atom, bromine atom, iodine atom, fluorine atom.

The term "hydroxy" as used herein represents a group of formula-OH.

The term "carboxyl" as used herein represents a group of formula-COOH.

The term "sulfonic acid" as used herein represents a compound of formula-SO₃H is a group shown in the specification.

The term "sulfonamide" as used herein represents a compound of the formula-SO₂NH₂The radicals shown, in which 1 or 2 hydrogen atoms may be optionally substituted by "alkyl", "aryl", "heteroaryl" and/or "heterocycloalkyl", or substituted-SO as defined above₂NH₂。

The term "acyl" as used herein represents a group of formula RCO-, wherein R is "alkyl", "aryl", "heteroaryl" or "heterocycloalkyl", or a substituted RCO-as defined above.

The term "ester" as used herein represents a group of formula-COOR, wherein R is "alkyl", "aryl", "heteroaryl" or "heterocycloalkyl", or a substituted-COOR as defined above.

The term "alkoxy" as used herein represents a group of formula-OR, wherein R is "alkyl" OR "heterocycloalkyl", OR substituted as defined above.

As used herein, the term "aryloxy" represents a group of formula-OR, wherein R is "aryl" OR "heteroaryl", OR substituted as defined above.

The term "acyloxy", as used herein, represents a group of formula RCOO-, wherein R is "alkyl", "aryl", "heteroaryl" or "heterocycloalkyl", or a substituted RCOO-group as defined above.

Procedure for the inventionThe term "alkylsulfonyl" denotes-SO₂R wherein R is "alkyl" or "heterocycloalkyl", or substituted-SO as defined above₂And R group.

The term "arylsulfonyl" as used herein represents a compound of the formula-SO₂R wherein R is "aryl" or "heteroaryl", or substituted-SO as defined above₂And R group.

As used herein, the term "alkylsulfinyl" represents a group of formula-SO-R, wherein R is "alkyl" or "heterocycloalkyl", or a substituted-SO-R group as defined above.

As used herein, the term "arylsulfinyl" represents a group represented by the formula-SO-R, where R is "aryl" or "heteroaryl", or a substituted-SO-R group as defined above.

The term "esteroxy" as used herein represents a group of formula-OCOOR, wherein R is "alkyl", "aryl", "heteroaryl" or "heterocycloalkyl", or a substituted-OCOOR group as defined above.

The term "amido" as used herein represents a compound of formula-CONH₂A group shown wherein 1 or 2 hydrogen atoms may be optionally substituted by "alkyl", "aryl", "heteroaryl" and/or "heterocycloalkyl", or substituted-CONH as defined above₂A group.

The term "amidooxy" as used herein represents a compound of the formula-OCONH₂The group shown, in which 1 or 2 hydrogen atoms may be optionally substituted by "alkyl", "aryl", "heteroaryl" and/or "heterocycloalkyl", or substituted-OCONH as defined above₂A group.

The compounds of formula (II) used in the present invention may be prepared by any suitable method.

The (S) -3-n-pentanoyl-4-substituted oxazol-2-ones of formula (II) are preferably prepared by a process comprising: the compound shown in the formula (VI) reacts with n-pentanoic acid or n-valeryl chloride or mixed anhydride of n-pentanoic acid to obtain the compound.

When X is benzyl, the recrystallization solvent of the compound shown as the formula (II) is selected from a single solvent of n-heptane, n-hexane, petroleum ether, ethyl acetate and methyl tert-butyl ether or a mixed solvent of two or three of the solvents. Most preferably selected from n-heptane, n-hexane as the single solvent, or n-hexane/methyl tert-butyl ether as the mixed solvent.

In the method of the present invention, the base used in the alkylation reaction in step (1) is selected from Lithium Diisopropylamide (LDA), Lithium Hexamethyldisilazide (LHMDS), potassium hexamethyldisilazide (KHMDS), sodium hexamethyldisilazide (NHMDS); preferably selected from Lithium Hexamethyldisilazide (LHMDS) or Lithium Diisopropylamide (LDA).

Chiral oxazolinones (compounds of formula IV), referred to as evans prosthetic groups, are a common class of chiral prosthetic groups. After N-acylation of the prosthetic group, the selectivity of the newly formed chiral center can be well controlled if an alkyl side chain is introduced at the alpha position of the side chain amide. The reaction mechanism is that under the condition of low temperature, lithium diisopropylamide and other bases and a substrate form an enol form, and then the enol form reacts with halogenated alkane, so that the reaction enantioselectivity is good, and the optical purity of the obtained product is high.

In the research process, the applicant finds that in the novel route of the invention, the novel compound shown in the formula IV is prepared by using the compound shown in the formula II and the compound shown in the formula III, when the reaction is carried out at low temperature, the chiral center contained in the compound shown in the formula II can induce the construction of the novel chiral center stereospecifically, the generation of diastereoisomer is not observed, the reaction stereoselectivity is very good, the amount of the diastereoisomer generated in the reaction process is very small, in addition, the reaction does not generate by-products with similar structures, and the conversion rate is high. Therefore, the problems of poor reaction selectivity and low yield in the prior art are solved to a great extent.

In the method of the present invention, the reducing agent used in the reduction reaction in step (2) is selected from lithium aluminum hydride, lithium borohydride, sodium borohydride, potassium borohydride, lithium aluminum tri-tert-butoxyhydride, lithium tri-sec-butylborohydride (L-select), potassium tri-sec-butylborohydride (K-select); preferably selected from sodium borohydride, potassium borohydride, lithium borohydride; most preferably selected from sodium borohydride, potassium borohydride.

In the research process, the applicant finds that in the novel route of the invention, the novel compound shown in the formula V is prepared by using the compound shown in the formula IV, the chemical selectivity of the reaction is very good, the reduction site only occurs on the amido bond of the oxazolinone, no other by-product is observed, and the compound shown in the formula VI can be recovered by recrystallization after the reaction, so that the atom economy is greatly improved, and the cost is reduced.

Rong Gao et al (Synlett.2015,26, 661-.

In the method, the oxidizing reagent used in the oxidation reaction in the step (3) is selected from sodium periodate-ruthenium chloride, sodium periodate-potassium permanganate, potassium permanganate or osmium tetroxide/NMO/sodium periodate by step oxidation. Preferably selected from sodium periodate-ruthenium chloride.

When the oxidation reagent system adopted by the oxidation is sodium periodate-ruthenium chloride, the reaction solvent is water and acetonitrile, and the reaction temperature is-10-40 ℃.

The molar ratio of the formula (V) to sodium periodate is 1: 4-10, and the molar ratio of the formula (V) to the catalyst ruthenium chloride is 1: 0.01-0.5.

In the method of the present invention, the molar ratio of the formula (II) to the formula (III) in the step (1) is 1:0.9 to 5, preferably 1:1.1 to 1.5.

In the method of the present invention, the molar ratio of the formula (II) in the step (1) to the used base is 1:0.9 to 3, preferably 1:1.0 to 1.5.

In the method of the present invention, the molar ratio of the formula (IV) to the reducing agent in step (2) is 1:1.0 to 5, preferably 1:1.0 to 2.0.

In the method of the present invention, the reaction solvent for the alkylation in step (1) is tetrahydrofuran, 2-methyltetrahydrofuran.

In the method of the present invention, the reaction solvent for the reduction in step (2) is a mixed solvent of water/tetrahydrofuran, water/methanol, and water/ethanol.

In the method of the present invention, the reaction solvent for the oxidation in step (3) is a mixed solvent of acetonitrile and water.

In the method, in the oxidation reaction in the step (3), when the oxidation reagents are sodium periodate and ruthenium chloride, the molar ratio of the sodium periodate to the formula (V) is 4-10: 1; preferably 5-7: 1.

In the method of the present invention, in the oxidation reaction in step (3), when the oxidizing reagents are sodium periodate and ruthenium chloride, the molar ratio of ruthenium chloride to formula (V) is 0.01 to 0.5:1, preferably 0.04 to 0.1: 1.

In the method, the reaction temperature of alkylation in the step (1) is-80-20 ℃.

In the method, the reaction temperature of the reduction in the step (2) is 0-100 ℃.

In the method, the reaction temperature of the oxidation in the step (3) is-10-40 ℃, and preferably 10-30 ℃.

The process of the invention is particularly suitable for preparing 4-n-propyl-dihydrofuran-2 (3H) -one in the (R) configuration. The term (R) as used herein refers to a compound which: it has an enantiomeric composition of more than 50%, preferably more than 90%.

The following examples are for the purpose of illustrating the invention only and are not meant to, or to be construed as, limiting the invention in any way. Conventional variations and modifications to the following examples may occur to those skilled in the art without departing from the spirit and scope of the invention.

Examples

Example 1: synthesis of (S) -4-benzyl-3-pentanoyl oxazole-2-one

Adding tetrahydrofuran (6.3L) into a reaction bottle, adding (S) -4-benzyl oxazole-2-ketone (422.0g), and cooling to-70 ℃; under the protection of nitrogen, keeping the internal temperature at-65 to-75 ℃, dropwise adding a 2.5M n-butyllithium (1.0L) solution, and keeping the temperature for half an hour after dropwise adding; keeping the internal temperature at-65-75 ℃, dropwise adding valeryl chloride (315.9g), reacting for half an hour after completing dropwise adding, detecting by TLC that (S) -4-benzyl oxazole-2-ketone disappears, and processing; raising the temperature to 0 ℃, adding 2L of saturated ammonium chloride aqueous solution, quenching butyl lithium, and separating phases. The organic phase is concentrated under reduced pressure to dryness, the concentrate is dissolved in 3L of dichloromethane and then washed twice with water (500 mL. times.2), and the organic phase is dried over 300.0g of anhydrous sodium sulfate for 2 hours; filtration and concentration to dryness under reduced pressure gave 621.3g of the title compound as a white solid.

¹H NMR(400MHz,CDCl₃)δ7.33(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°(c＝1.0g/100mL，CHCl₃).

Example 2: synthesis of (S) -4-benzyl-3- ((R) -2-n-propyl-pent-4-enoyl) oxazole-2-one

Tetrahydrofuran (50mL) was added to the reaction flask, and (S) -4-benzyl-3-pentanoyl oxazol-2-one (5.2g) was added and the temperature was reduced to-70 ℃; under the protection of nitrogen, keeping the internal temperature between-65 ℃ and-75 ℃, dropwise adding 1.0M of tetrahydrofuran solution (24mL) of LHMDS, and keeping the temperature for reaction for 1 hour after the dropwise adding is finished; keeping the internal temperature at-65-75 ℃, dropwise adding 3.0g of allyl bromide, keeping the temperature for reaction for 2 hours after the dropwise adding is finished, and detecting the disappearance of the raw materials by TLC (thin layer chromatography) for treatment; heating to 0 deg.C, adding 50mL saturated ammonium chloride aqueous solution, separating phases, extracting the aqueous phase with ethyl acetate (50mL), combining organic phases, and concentrating under reduced pressure; concentrated to dryness, dissolved in 50mL of dichloromethane and then washed with water (25 mL. times.2), and the organic phase dried over 10.0g of anhydrous sodium sulfate for 2 hours; filtration and concentration under reduced pressure gave 5.8g of the title compound as a pale yellow oil.

(S) -4-benzyl-3- ((R) -2-n-propyl-pent-4-enoyl) oxazol-2-one:¹H NMR(400MHz,CDCl₃)δ7.33(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°(c＝1.0g/100mL，CHCl₃).

example 3: synthesis of (S) -4-benzyl-3- ((R) -2-n-propyl-pent-4-alkynoyl) oxazole-2-one

Tetrahydrofuran (50mL) was added to the reaction flask, and (S) -4-benzyl-3-pentanoyl oxazol-2-one (5.2g) was added and the temperature was reduced to-70 ℃; under the protection of nitrogen, keeping the internal temperature between-65 ℃ and-75 ℃, dropwise adding 1.0M of tetrahydrofuran solution (24.0mL) of LHMDS, and keeping the temperature for reaction for 1 hour after dropwise adding; keeping the internal temperature at-65-75 ℃, dropwise adding propargyl bromide (3.1g), keeping the temperature for reacting for 2 hours after dropwise adding, and detecting the disappearance of the raw materials by TLC (thin layer chromatography) for treatment; raising the temperature to 0 ℃, adding 25mL of saturated ammonium chloride aqueous solution, carrying out phase separation, and concentrating the organic phase under reduced pressure. The concentrate is dissolved in 50mL of dichloromethane and then washed with water (25 mL. times.2), and the organic phase is dried over 10.0g of anhydrous sodium sulfate for 2 hours; filtration and concentration under reduced pressure gave 6.1g of the title compound as a pale yellow oil.

(S) -4-benzyl-3- ((R) -2-n-propyl-pent-4-ynoyl) oxazol-2-one:¹H NMR(400MHz,CDCl₃)δ7.29(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°(c＝0.9g/100mL，CHCl₃).

example 4: synthesis of (R) -2-n-propyl-4-en-1-pentanol

Tetrahydrofuran (8.0mL) and water (2.0mL) were added to the reaction flask, (S) -4-benzyl-3- ((R) -2-n-propyl-pent-4-enoyl) oxazol-2-one (1.2g) and sodium borohydride (0.3g) was added in portions. Keeping the temperature for reaction for 2 hours; TLC detects the disappearance of the raw material and processes; saturated ammonium chloride (6.0ml) was added dropwise thereto and quenched at an internal temperature of not higher than 30 ℃. Separating, extracting the water phase with methyl tert-butyl ether (10.0mL), combining the organic phases, distilling under reduced pressure at 40 ℃, and concentrating under reduced pressure to dryness. Adding methyl tert-butyl ether/n-hexane (2.8mL,2:1, v/v) into the concentrate, cooling to 0-10 ℃, stirring for 1 hour, separating out a solid, filtering, recovering (S) -4-benzyl oxazole-2-ketone to obtain 0.35g, concentrating the filtrate to dryness, and performing column chromatography to obtain 0.44g of the target compound which is colorless oily matter.

(R) -2-n-propyl-4-en-1-pentanol:¹H NMR(400MHz,Chloroform-d)δ5.83(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°(c＝1.0g/100mL，CHCl₃).

example 5: synthesis of (R) -2-n-propyl-4-yne-1-pentanol

Tetrahydrofuran (8.0ml) and water (2.0ml) were added to a reaction flask, (S) -4-benzyl-3- ((R) -2-n-propyl-pent-4-ynoyl) oxazol-2-one (1.2g) and sodium borohydride (0.3g) was added in portions. Keeping the temperature for reaction for 2 hours; TLC detects the disappearance of the raw material and processes; saturated ammonium chloride (6.0ml) was added dropwise thereto and quenched at an internal temperature of not higher than 30 ℃. Separating, extracting the water phase with methyl tert-butyl ether (10.0mL), combining the organic phases, distilling under reduced pressure at 40 ℃, and concentrating under reduced pressure to dryness. Methyl tert-butyl ether/n-hexane (3.0mL,2:1, v/v) was added to the concentrate, and the mixture was stirred for 1 hour at 0-10 ℃ to precipitate a solid, which was filtered to recover (S) -4-benzyl oxazol-2-one to give 0.38g, which was concentrated to dryness, and the filtrate was subjected to column chromatography to give 0.40g of the title compound as a colorless oil.

(R) -2-n-propyl-4-yne-1-pentanol:¹H NMR(400MHz,CDCl₃)δ3.66(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) Example 6: synthesis of (R) -4-n-propyl-dihydrofuran-2 (3H) -one

The method comprises the following steps:

acetonitrile (6.0mL) and water (1.0mL) were added to a reaction flask, (R) -2-n-propyl-4-en-1-pentanol (0.4g) was added, ruthenium chloride (32mg) was added at room temperature, and after dissolution, NaIO was added in portions at room temperature₄(4.0g), after the addition, the reaction was vigorously stirred at room temperature, and a solid precipitated, followed by reaction for 3 hours. TLC detection raw material disappearance, filtration, water (10.0mL), sodium bisulfite addition to make the solution pH 1-3, stirring for 1 hour, ethyl acetate addition (20.0mL), liquid separation, organic phase combination, saturated salt water washing, anhydrous sodium sulfate addition, drying, filtration and concentration to obtain crude product. Column chromatography of the concentrate gave 0.21g of the title compound as a colorless oil.

(R) -4-n-propyl-dihydrofuran-2 (3H) -one:¹H NMR(400MHz,Chloroform-d)δ4.42(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°(c＝1.22g/100mL，CHCl₃).

the method 2 comprises the following steps:

acetonitrile (6.0mL) and water (1.0mL) were added to a reaction flask, (R) -2-n-propyl-4-yn-1-pentanol (0.4g) was added, ruthenium chloride (31mg) was added at room temperature, and after dissolution, NaIO was added in portions at room temperature₄(4.0g), after the addition, the reaction was vigorously stirred at room temperature, and a solid precipitated, followed by reaction for 3 hours. TLC detection raw material disappearance, filtration, water (10.0mL), sodium bisulfite addition to make the solution pH 1-3, stirring for 1 hour, ethyl acetate addition (20.0mL), liquid separation, organic phase combination, saturated salt water washing, anhydrous sodium sulfate addition, drying, filtration and concentration to obtain crude product. Column chromatography of the concentrate gave 0.24g of the title compound as a colorless oil.

Claims

1. A process for preparing optically pure (R) 4-n-propyl-dihydrofuran-2 (3H) -one comprising the steps of:

(1) preparing an optically pure (R) -2-substituted pentanol (V) compound represented by the formula (V);

(2) in the formula (V), double bonds or triple bonds are oxidized and closed under the oxidation condition to prepare optically pure (R) -4-n-propyl-dihydrofuran-2 (3H) -ketone, and the configuration of a chiral center is not changed in the reaction process of converting the formula (V) into the formula (I);

r is-CH ═ CR¹R²or-C.ident.CR³，R¹、R²、R³Independently is hydrogen or C_1-20An alkyl group;

the method for preparing the formula (V) in the step (1) comprises the following steps: A) carrying out alkyl substitution reaction on optically pure (S) -3-n-pentanoyl-4-substituted oxazole-2-ketone shown in a formula (II) and an alkene or alkyne compound shown in a formula (III) and provided with a leaving group in the presence of an alkaline reagent to generate a compound shown in a formula (IV), wherein the stereo configuration of a newly generated chiral center in the formula (IV) is opposite to that of the chiral center in the formula (II) in the reaction process; B) preparing optically pure (R) -2-substituted pentanol (V) from the compound shown in the formula (IV) in the presence of a reducing agent, and simultaneously recovering (S) -4-substituted oxazol-2-one derivatives as chiral auxiliary groups shown in the general formula (VI),

x is C_1-20Alkyl radical, C_1-20Alkenyl, phenyl or benzyl, Y being selected from halogen, sulfonate groups, -S⁺Me₂or-N₂ ⁺The leaving group of (a) is,

the reducing agent is lithium borohydride, sodium borohydride or potassium borohydride;

the reaction solvent for reducing the formula (IV) is a mixed solvent of water/tetrahydrofuran, water/methanol or water/ethanol, the molar ratio of the formula (IV) to the reducing agent is 1: 1.0-2.0, and the reaction temperature is 0-100 ℃.

2. The process according to claim 1, wherein the oxidation is carried out using an oxidizing reagent system selected from the group consisting of sodium periodate-ruthenium chloride, sodium periodate-potassium permanganate, and osmium tetroxide-N-methyl-N-oxomorpholine-sodium periodate.

3. The method according to claim 2, wherein when the oxidizing reagent system used for the oxidation is sodium periodate-ruthenium chloride, the reaction solvent is a mixture of water and acetonitrile, the reaction temperature is-10 to 40 ℃, the molar ratio of the formula (V) to the sodium periodate is 1:4 to 10, and the molar ratio of the formula (V) to the catalyst ruthenium chloride is 1:0.01 to 0.5.

4. The method according to claim 3, wherein the reaction temperature is 10 to 30 ℃, the molar ratio of the formula (V) to the sodium periodate is 1:5 to 7, and the molar ratio of the formula (V) to the catalyst ruthenium chloride is 1:0.04 to 0.1.

5. The method of claim 1, wherein R¹Is hydrogen, R²、R³Is hydrogen or C_1-20An alkyl group.

6. The method of claim 5, wherein R is-CH ═ CH₂or-C.ident.CH.

7. The method of claim 1, X is C_1-6Alkyl, phenyl, or benzyl, Y is fluoro, chloro, bromo, iodo, methanesulfonyloxy, trifluoromethanesulfonyloxy, or p-toluenesulfonyloxy.

8. The process of claim 7, X is methyl, ethyl, n-propyl, isopropyl, t-butyl, benzyl, or phenyl.

9. The process according to claim 8, X is phenyl, isopropyl or benzyl and Y is bromine, fluorine or chlorine.

10. The process of claim 1, wherein the alkylation employs a base that is lithium diisopropylamide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, or sodium hexamethyldisilazide.

11. The method according to claim 10, wherein the alkylation reaction solvent is tetrahydrofuran or 2-methyltetrahydrofuran, the alkylation reaction temperature is-80-20 ℃, the molar ratio of the formula (II) to the formula (III) is 1: 0.9-5, and the molar ratio of the formula (II) to the base is 1: 0.9-3.

12. The method according to claim 11, wherein the molar ratio of the formula (II) to the formula (III) is 1: 1.1-1.5, and the molar ratio of the formula (II) to the base is 1: 1.0-1.5.