WO2020168510A1

WO2020168510A1 - Method for preparing chiral butyrolactone

Info

Publication number: WO2020168510A1
Application number: PCT/CN2019/075688
Authority: WO
Inventors: 郭朋; 朱文峰
Original assignee: 上海博璞诺科技发展有限公司
Priority date: 2019-02-21
Filing date: 2019-02-21
Publication date: 2020-08-27

Abstract

Disclosed is a method for preparing chiral butyrolactone. Specifically, according to the method, compound (II) is used as a raw material to sequentially perform loop-opening, sulfonylation, substitution, and loop-closing reactions to obtain a chiral butyrolactone compound (I). In a synthesis method of the present invention, the raw materials used are cheap and readily available, the synthesis process is short, the operation is simple, the reaction process is safe and environmentally friendly, the chirality maintenance property is good, and the overall process is very suitable for industrial production.

Description

A kind of preparation method of chiral butyrolactone

Technical field

This application belongs to the field of medicinal chemistry, and specifically relates to a preparation method of the chiral butyrolactone intermediate of Buwaxitan.

Background technique

Brivaracetam, the chemical name is (S)-2-(R)-3-propylpyrrolidin-1-ylbutanamide. Buwaxitan is a third-generation anti-epileptic drug newly developed by the Belgian pharmaceutical giant (UCB). This drug can exert anti-epileptic effects by combining with synaptic vesicle protein 2A (SV2A). The results of clinical trials have shown that Buwaxitan can significantly reduce the frequency of partial seizures and improve the response rate. It has extensive anti-epileptic activity and high safety.

There are two chiral centers in the Buwaxitan structure, which is difficult to synthesize. However, with chiral butyrolactone (I) and (S)-2-aminobutanamide as main raw materials, the Buwaxitan API can be obtained by simple synthesis in 2 to 3 steps. (S)-2-Aminobutanamide is the main raw material of the marketed drug levetiracetam, and the market supply is sufficient. Therefore, chiral butyrolactone (I) has become a key intermediate in the synthesis of Buwaxitan.

At present, many literatures have reported the synthesis method of chiral butyrolactone (I).

In 2016, Arnaud Schülé et al. (Org. Process Res. Dev. 2016, 20, 1566-1575) published a method for obtaining optically pure Buwaxitan using a biocatalytic method. The enzymatic asymmetric hydrolytic resolution of racemic 2-n-propyl succinate methyl ester was used to obtain chiral products. The control of stereochemistry through biological methods makes it possible to scale up the production of chiral butyrolactone. However, the cumbersome raw material preparation method, the source of the enzyme and the preparation cost limit its practical application.

WO2016191435 discloses a synthetic method for preparing optically pure Buwaxitan, wherein the chirality of the n-propyl group on the butyrolactone is introduced by using chiral epichlorohydrin as a starting material, and the route cost is relatively low. However, since the chiral epoxy raw materials have two reaction sites, the synthesis of a five-membered ring and a three-membered ring requires strict control of the chirality; the entire route requires two high vacuum distillation operations. Therefore, there are certain difficulties in the actual enlargement of the route.

Huasheng Pharmaceutical discloses a synthetic method for preparing chiral butyrolactone intermediate I (CN107827844). The highly toxic sodium cyanide and the relatively expensive titanium triisopropoxy chloride are used in the route, and the route is not of high industrial value.

Ma Liang et al. (CN108503610) used a chiral auxiliary method to construct a butyrolactone chiral center, but other reaction steps used metal oxidation, and the atom utilization rate was not high.

Liu Xingxin et al. (CN107216276) also used a chiral auxiliary method to construct a butyrolactone chiral center, which also has the problem of low atom utilization and complicated steps.

Therefore, finding a synthetic method of chiral butyrolactone intermediate (I) with high yield, simple method, high chiral purity, low production cost, and suitable for industrial production is a technical problem that needs to be solved urgently in this field.

Summary of the invention

Aiming at the deficiencies in the prior art, the purpose of the present invention is to provide a method for synthesizing chiral butyrolactone (I) with high yield, simple method, high chiral purity, low production cost and suitable for industrial production.

The technical purpose of the present invention is achieved through the following technical solutions:

The first aspect of the present invention provides a method for preparing chiral butyrolactone represented by formula (I), the method comprising the steps:

(1) In an inert solvent, in the presence of an ethyl Grignard reagent and a catalyst, compound (II) is subjected to a ring-opening reaction to form compound (III);

(2) Perform a sulfonylation reaction between compound (III) and a sulfonylating reagent in an inert solvent in the presence of a base to form compound (IV) or a mixture containing compound (IV);

(3) Reacting compound (IV) or a mixture containing compound (IV) with compound (V) in an inert solvent under alkaline conditions for substitution reaction; after the completion of the substitution reaction, the reaction mixture is subjected to acidic conditions Ring-closing reaction to form compound (I);

Wherein, L is a C _1-4 alkyl sulfonate group or a halogenated C _1-4 alkyl sulfonate group; R is a C _1-6 alkyl group.

In another preferred embodiment, R is methyl, ethyl, propyl, isopropyl or tert-butyl.

In another preferred embodiment, L is a triflate group.

In another preferred embodiment, in step (1), the ethyl Grignard reagent is ethyl magnesium bromide or ethyl magnesium chloride.

In another preferred example, in step (1), the reaction molar ratio of the compound (II) and the ethyl Grignard reagent is 1: (1 to 2.0); preferably 1: (1.2 to 1.6).

In another preferred example, in step (1), the catalyst is cuprous iodide, ketone bromide, cuprous cyanide or ketone dimethyl sulfide bromide.

In another preferred example, in step (1), the reaction molar ratio of the compound (II) and the catalyst is 1:(0.01-0.2); preferably 1:(0.05-0.15).

In another preferred example, in step (1), the reaction temperature is -80 to 0°C; preferably -78 to -60°C or -40 to -20°C.

In another preferred example, in step (1), the reaction time is 0.5 to 5 hours.

In another preferred example, in step (1), the inert solvent is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, and toluene.

In another preferred example, in step (1), in an inert solvent, first add compound (II) and a catalyst, and then add (preferably dropwise) a solution of ethyl Grignard reagent, and then perform a ring-opening reaction to form Compound (III).

In another preferred example, in step (1), the reaction temperature is -78 to -60°C.

In another preferred example, in step (1), in an inert solvent, first add a solution of ethyl Grignard reagent and a catalyst, and then add (preferably dropwise) compound (II), and then perform a ring-opening reaction to form Compound (III).

In another preferred example, in step (1), the reaction temperature is -40 to -20°C.

In another preferred example, in step (1), after the ring-opening reaction is completed, the reaction mixture is quenched, separated, extracted and concentrated to obtain compound (III), which is directly used in the next reaction.

In another preferred embodiment, in step (1), after the ring-opening reaction is completed, a saturated aqueous ammonium chloride solution is added dropwise to the reaction mixture, and an organic solvent (such as methyl tert-butyl ether, petroleum ether, etc.) is used for the aqueous phase. ) Extraction, the organic phase is washed with water, dried and concentrated to obtain compound (III), which is directly used in the next reaction.

In another preferred example, in step (2), in an inert solvent, first add compound (III) and a base; then add (preferably dropwise) a sulfonylation reagent for sulfonylation reaction, thereby forming compound (IV) Or a mixture containing compound (IV).

In another preferred example, in step (2), first dissolve compound (III) in an inert solution, and then add a base and a sulfonylation reagent in sequence.

In another preferred example, in step (2), the reaction molar ratio of compound (III) to the sulfonylating reagent is 1:(1 to 1.2).

In another preferred example, in step (2), the reaction molar ratio of compound (III) and base is 1:(1~1.5).

In another preferred example, in step (2), the reaction temperature is -20 to 30°C; preferably -10 to 0°C.

In another preferred example, in step (2), the reaction time is 1 to 24 hours; preferably 1 to 2 hours.

In another preferred example, in step (2), the base is one or more of triethylamine, pyridine, diisopropylethylamine, and 4-dimethylaminopyridine (DMAP).

In another preferred embodiment, in step (2), the inert solvent is one of dichloromethane, ethyl acetate, dichloroethane, isopropyl acetate, tetrahydrofuran, methyl tert-butyl ether or Many kinds.

In another preferred example, in step (2), after the sulfonylation reaction is completed, the reaction mixture is filtered to obtain a filtrate containing compound (IV), and the filtrate is directly used in the next reaction.

In another preferred example, in step (2), the sulfonylation reagent is selected from the group consisting of C _1-4 alkyl sulfonate chloride, halogenated C _1-4 alkyl sulfonate chloride, C _{1- 4} alkyl sulfonic anhydride, halogenated C _1-4 alkyl sulfonic anhydride, or a combination thereof.

In another preferred embodiment, in step (2), the sulfonylation reagent is selected from the group consisting of trifluoromethanesulfonic acid chloride, trifluoromethanesulfonic anhydride or a combination thereof.

In another preferred example, in step (3), the alkaline conditions are conditions in the presence of organic bases.

In another preferred embodiment, the organic base is one or more of sodium methoxide, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide.

In another preferred example, in step (3), the acidic conditions are conditions in which an acidic solution exists.

In another preferred embodiment, the acidic solution is one or more of sulfuric acid solution, hydrochloric acid solution, phosphoric acid solution, and trifluoroacetic acid solution.

In another preferred example, in step (3), the acidic solution is an acidic aqueous solution.

In another preferred example, in step (3), the time for carrying out the substitution reaction under alkaline conditions is 2-24 hours; preferably 10-14 hours.

In another preferred example, in step (3), the temperature for the substitution reaction under alkaline conditions is 0 to 70°C; preferably 0 to 5°C.

In another preferred example, in step (3), the time for the ring-closure reaction under acidic conditions is 12 to 36 hours; preferably 20 to 25 hours.

In another preferred example, in step (3), the temperature for the ring closure reaction under acidic conditions is 80-100°C; preferably 90-100°C.

In another preferred embodiment, in step (3), the inert solvent is ethylene glycol dimethyl ether or tetrahydrofuran.

In another preferred example, in step (3), the reaction molar ratio of the compound (IV) to the compound (V) is 1: (1 to 1.2).

In another preferred embodiment, in step (3), after the ring-closure reaction is completed, the reaction mixture is extracted (for example, with an organic solvent such as methylene chloride), and the organic phase is washed with water, dried and concentrated to obtain compound (I) Crude product: The crude product is distilled under reduced pressure to obtain pure compound (I).

In another preferred example, in step (3), the filtrate containing compound (IV) obtained in step (2) is reacted with compound (V) in an inert solvent under alkaline conditions for substitution reaction; After completion, the reaction mixture is subjected to a ring-closure reaction under acidic conditions, thereby forming compound (I).

In another preferred example, in step (3), the organic base and compound (V) are first added to an inert solvent, and then compound (IV) or a mixture containing compound (IV) is added (preferably dropwise) to perform substitution reaction ; After the substitution reaction is over, an acidic solution is added to carry out a ring-closure reaction to form compound (I).

In another preferred example, in step (3), the organic base and compound (V) are first added to the inert solvent, and then (preferably added dropwise) the filtrate containing compound (IV) obtained in step (2) is added for substitution. Reaction: After the substitution reaction is over, an acidic solution is added to carry out a ring-closure reaction to form compound (I).

In another preferred example, the time for the substitution reaction is 2-24 hours; preferably 10-14 hours.

In another preferred example, the temperature of the substitution reaction is 0-30°C; preferably 0-5°C.

In another preferred example, the time for the ring closure reaction is 12 to 36 hours; preferably 20 to 25 hours.

In another preferred example, the temperature of the ring closure reaction is 80-100°C; preferably 90-100°C.

In another preferred embodiment, the acidic solution is an acidic aqueous solution.

Compared with the prior art, the technical solution of the present invention has the following beneficial effects:

The present invention provides a new method for preparing chiral butyrolactone (I), an intermediate compound of Buwaxitan. In the preparation method of chiral butyrolactone provided by the present invention, the raw materials used are cheap and easily available, the synthesis route is short, the operation is simple, the reaction process is safe and environmentally friendly, the chirality retention performance is good, and the overall process is very suitable for industrial production.

It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (such as the embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, I will not repeat them here.

detailed description

After a long period of in-depth research and development, the inventor unexpectedly discovered a method for preparing chiral butyrolactone (I), an intermediate of Buwaxitan. The method uses (R)-2-(tert-butoxymethyl) oxirane Alkane (compound (II)) is used as a raw material, and high-purity chiral butyrolactone (I) is obtained through ring opening, sulfonylation, substitution and ring closing reactions. Each step of the reaction involved in the method has simple operation and simple post-treatment, and finally high-purity chiral butyrolactone (I) can be obtained in a higher yield. The entire route is very conducive to industrial amplification. On this basis, the present invention has been completed.

the term

As used herein, the term "C _1-6 alkyl" means a linear or branched alkyl group having 1 to 6 carbon atoms. "C _1-4 alkyl" means a straight or branched alkyl group having 1 to 4 carbon atoms. For example, but not limited to, methyl, ethyl, propyl, isopropyl, tert-butyl, etc.

As used herein, the term "halo" refers to iodo, bromo, chloro or fluoro. The "halogenation" can be monohalogenation, polyhalogenation (such as dihalogenation, trihalogenation, etc.) or perhalogenation (that is, all hydrogen atoms of the group are replaced by halogen atoms).

As used herein, the term "halogen atom" refers to an iodine atom, a bromine atom, a chlorine atom, or a fluorine atom.

As used herein, the term "sulfonate group" means "-S(=O) ₂ O-" with the structure as

Shown.

As used herein, the term "sulfonyl" means "-S(=O) ₂ -" with the structure as

Shown.

among them,

Indicates that this bond is connected to other groups in the compound structure.

Chiral butyrolactone

The chiral butyrolactone, an intermediate of Buwaxitan of the present invention, is named (R)-4-n-propyl-dihydro-3H-furan-2-one, and its structure is as shown in formula (I). It can be represented by formula (I'), and formula (I) and formula (I') can be used interchangeably.

The chiral center exists in the R configuration, and the R configuration is determined according to the rules described in Pure. Appl. Chem. 45 (1976) 11-30.

Intermediate for the preparation of chiral butyrolactone

The present invention provides an intermediate compound for preparing chiral butyrolactone (I), the structure of which is shown in formula (A).

Wherein, R ₁ is hydrogen, C _1-4 alkylsulfonyl or halogenated C _1-4 alkylsulfonyl.

In another preferred embodiment, the intermediate compound is compound (III);

In another preferred embodiment, the intermediate compound is compound (IV);

Wherein, L is a C _1-4 alkylsulfonate group or a halogenated C _1-4 alkylsulfonate group.

Preparation method of intermediate for preparing chiral butyrolactone

The present invention provides a method for preparing compound (III), which includes step (1).

Step (1): At a certain temperature (for example -80～0℃; preferably -78～-60℃ or -40～-20℃), in an inert solvent, in an ethyl Grignard reagent (for example, ethyl bromide In the presence of magnesium or ethyl magnesium chloride) and a catalyst (such as cuprous iodide, ketone bromide, cuprous cyanide or ketone dimethyl sulfide bromide), compound (II) is subjected to a ring-opening reaction for a period of time (such as 0.5 to 5 hours), thereby forming compound (III);

In another preferred example, in step (1), the inert solvent is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, and toluene. The inert solvent is preferably an anhydrous solvent.

The present invention provides a method for preparing compound (IV), which includes step (2).

Step (2): At a certain temperature (for example, -20～30℃; preferably -10～0℃), in an inert solvent, in the presence of a base, the compound (III) is subjected to a sulfonylation reaction with a sulfonylation reagent A period of time (for example, 1 to 24 hours; preferably 1 to 2 hours) to form compound (IV) or a mixture containing compound (IV);

Among them, the preparation method of compound (III) is as described above.

In another preferred embodiment, in step (2), the base is an organic base (for example, one or more of triethylamine, pyridine, diisopropylethylamine, 4-dimethylaminopyridine (DMAP) ).

In another preferred example, in step (2), first dissolve compound (III) in an inert solution, and then add a base and a sulfonylating reagent in sequence.

Wherein, the mixture containing compound (IV) may be a filtrate containing compound (IV).

Preparation method of chiral butyrolactone

The present invention provides a preparation method of chiral butyrolactone, which comprises step (3).

Step (3): At a certain temperature (for example, 0～70℃; preferably 0～5℃), in an inert solvent, under alkaline conditions, compound (IV) or a mixture containing compound (IV) and compound (V) The reaction proceeds for a period of time (for example, 2-24 hours; preferably 10-14 hours); after the completion of the substitution reaction, the reaction mixture is heated at a certain temperature (for example, 80-100°C; preferably 90-100°C) Carry out the ring closure reaction for a period of time (for example, 12 to 36 hours; preferably 20 to 25 hours) under acidic conditions to form compound (I);

Among them, L is a C _1-4 alkylsulfonate group or a halogenated C _1-4 alkylsulfonate group (preferably a trifluoromethanesulfonate group); R is a C _1-6 alkyl group (preferably methyl , Ethyl, propyl, isopropyl or tert-butyl).

The method for preparing compound (IV) or the mixture containing compound (IV) is as described above.

In another preferred example, in step (3), the organic base and compound (V) are first added to an inert solvent, and then compound (IV) or a mixture containing compound (IV) is added (preferably dropwise) to carry out the substitution reaction ; After the substitution reaction is over, an acidic solution is added to carry out a ring-closure reaction to form compound (I).

The method for preparing the compound (II) in the present invention can be prepared by any method known in the art. The method shown in the following step (4) can also be used.

Step (4): At a certain temperature (for example, 0～35℃; preferably 10～30℃), in an inert solvent, in a catalyst (for example, boron trifluoride, boron trifluoride tetrahydrofuran, boron trifluoride acetonitrile) In the presence of one or more), the compound (VI) is reacted with tert-butanol for a period of time (for example, 1 to 24 hours; preferably 1 to 5 hours) to form compound (II);

In another preferred example, step (4) includes the steps: in an inert solvent, first add tert-butanol and a catalyst; then add (preferably dropwise) compound (VI) for substitution reaction, thereby forming compound (II).

In another preferred embodiment, in step (4), the inert solvent is one or more of dichloromethane, dichloroethane, tetrahydrofuran, and acetonitrile.

In another preferred example, in step (4), after the reaction is completed, the reaction mixture is separated into layers, and the organic phase is washed with water, dried and concentrated to obtain compound (II).

The chiral butyrolactone prepared by the invention has high chemical purity and can be used as a pharmaceutical intermediate to prepare the drug Buwaxitan. The method for preparing Buwaxitan from chiral butyrolactone can be any method known in the art.

The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods that do not indicate specific conditions in the following examples usually follow the conventional conditions or the conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are weight percentages and parts by weight.

The detection method of the compound of the present invention includes the following:

NMR conditions: NMR spectra were recorded on a BRUKER AC 250 Fourier transform NMR spectrometer equipped with an Aspect 3000 computer and a 5mm ¹ H/ ¹³ C dual probe. The compound was studied in DMSO-d ⁶ (or CDCl ₃ ) solution at a probe temperature of 313K. Lock the instrument on the deuterium signal of DMSO-d ⁶ (or CDCl ₃ ). The chemical shift is expressed in ppm from the magnetic field downstream of the TMS as the internal standard.

GC conditions: Chromatographic column Agilent HP-5 (30m*320um*0.25um) detector FID temperature is 180℃, inlet temperature is 150℃, carrier gas is nitrogen, column constant flow rate is 1ml/min, split ratio is 20:1; running time is 18.83min, of which the initial temperature is 30℃, keep for 5 minutes, at a rate of 15℃/min from 30℃ to 145℃, keep for 0min, at a rate of 30℃/min, from 145℃ to 180 ℃, keep for 5min.

Chiral GC conditions (Compound I): Chromatographic column Macherey-Nagel Lipodex E type (25m*250um), detector FID temperature is 220℃, inlet temperature is 200℃, carrier gas is helium, column constant pressure is 60kPa , The split ratio is 100:1; the running time is 68min, in which the initial temperature is 70℃, keep for 1 minute, and at a rate of 1℃/min from 70℃ to 122℃, keep for 15min.

HPLC conditions: Chromatographic column Agilent Eclipse plus-C18, 4.6*50mm, 5um; in 3.5 minutes, 95% 0.1% H ₃ PO ₄ aqueous solution and 5% acetonitrile to 5% 0.1% H ₃ PO ₄ aqueous solution and 95 Gradient elution of% acetonitrile, 5% 0.1% H ₃ PO ₄ aqueous solution and 95% acetonitrile continue to elute for 1.5 minutes. The flow rate is set to 2.0 mL/min. The column temperature was set at 35°C. The detection wavelength is 210nm.

Chiral HPLC conditions (Buwaxitan): Column Daicel AD-H column, 4.6*250mm, 5um; mobile phase A is n-hexane, mobile phase B is ethanol, isocratic elution, elution ratio is mobile phase A : Mobile phase B=80%:20%, flow rate is 1ml/min, column temperature is 30°C, detection wavelength is 210nm, injection volume is 5ul, and running time is 20min.

Example 1

Synthesis of (R)-2-(tert-butoxymethyl) oxirane

In a 1-L three-necked flask, 160 g of tert-butanol, 7.56 g of boron trifluoride tetrahydrofuran and 500 mL of dichloromethane were added. After adding 50 g of (S)-epichlorohydrin dropwise, the mixture was stirred at 15 to 25°C for 4 hours. Concentrate to remove solvent and excess tert-butanol. The concentrate was dissolved in 250 mL of methyl tert-butyl ether, added to 20% sodium hydroxide solution and stirred at 15-25°C for 14 hours. After standing for layering, the organic phase was washed with water, dried, and concentrated to obtain 60 g of the target compound with a yield of 85%.

Example 2

Synthesis of (R)-1-(tert-butoxy)pentan-2-ol

In a 1L three-necked flask, 50g of (R)-2-(tert-butoxymethyl)oxirane, 3.44g of cuprous cyanide and 500mL of anhydrous tetrahydrofuran were added. After cooling to -78°C, 169 mL of 3.4M ethylmagnesium bromide 2-methyltetrahydrofuran solution was added dropwise to the system, and the temperature was controlled not to exceed -60°C. After slowly raising the temperature to -20°C within 4 hours, 300 mL of saturated ammonium chloride aqueous solution was added dropwise. After dripping, let it stand and separate, and the aqueous phase was extracted once with methyl tert-butyl ether. The organic phases are combined, washed with water, dried, and concentrated to obtain 60 g of the target compound with a GC purity of 95% and a yield of 97%.

Example 3

Synthesis of (R)-1-(tert-butoxy)pentan-2-ol

In a 1 L three-necked flask, 169 mL of a 3.4M 2-methyltetrahydrofuran solution of ethylmagnesium bromide, 7.9 g of ketone dimethyl sulfide bromide and 300 mL of anhydrous tetrahydrofuran were added. After cooling to -20°C, 50 g of (R)-2-(tert-butoxymethyl) ethylene oxide liquid was added dropwise while maintaining this temperature. After dripping and continuing to stir for 1 hour, 300 mL of saturated ammonium chloride aqueous solution was added dropwise. After dripping, let it stand and separate, and the aqueous phase was extracted once with methyl tert-butyl ether. The organic phases were combined, washed with water, dried, and concentrated to obtain 55 g of the target compound with a GC purity of 97% and a yield of 89%.

1H NMR(CDCl3,400MHz): δ=3.75-3.65(m,1H), 3.36(dd,J=8.8,3.2Hz,1H), 3.14(dd,J=8.8,8.0Hz,1H), 2.48(d ,J=2.8Hz,1H),1.55-1.30(m,4H),1.19(s,9H),0.92ppm(t,J=6.4Hz,3H).

Example 4

Synthesis of (R)-1-(tert-butoxy)pent-2-yl trifluoromethanesulfonate

In a 1-L three-necked flask, 30 g of (R)-1-(tert-butoxy)pentan-2-ol, 15.5 g of pyridine and 300 mL of dichloromethane were added. After cooling to -10°C, 54.9 g of trifluoromethanesulfonic anhydride liquid was added dropwise while maintaining the temperature. After stirring for 1 hour at -10°C, the reaction solution was filtered to remove insoluble materials, and the filtrate was directly put into the next step.

Example 5

Synthesis of (R)-1-(tert-butoxy)pent-2-yl methanesulfonate

In a 1L three-necked flask, add 30 g of (R)-1-(tert-butoxy)pentan-2-ol, 28.4 g of triethylamine, 2.29 g of DMAP and 300 mL of dichloromethane. After cooling to 0°C, 21.4 g of methanesulfonyl chloride was added dropwise while maintaining this temperature. After stirring for 2 hours at 15-20°C, the reaction solution was washed twice with 150 ml of water, the organic phase was dried and concentrated to obtain 42 g of the target product with a yield of 94%.

1H NMR (CDCl3, 400MHz): δ = 4.70-4.60 (m, 1H), 3.48-3.38 (m, 2H), 3.04 (s, 3H), 1.70-1.51 (m, 2H), 1.50-1.34 (m, 2H), 1.15 (s, 9H), 0.91 ppm (t, J = 7.2 Hz, 3H).

Example 6

Synthesis of (R)-1-(tert-butoxy)pent-2-yl 4-nitrobenzene sulfonate

In a 1L three-necked flask, add 50g of (R)-1-(tert-butoxy)pentan-2-ol, 47.4g of triethylamine, 3.8g of DMAP and 500mL of dichloromethane. After cooling to 0°C, 69.1 g of p-nitrobenzenesulfonyl chloride was added in batches while maintaining this temperature. After stirring for 2 hours at 15-20°C, the reaction solution was washed twice with 150 ml of water, the organic phase was dried and concentrated to obtain a crude product. The crude product was separated by silica gel column chromatography (eluent: petroleum ether) to obtain 89 g of the product, HPLC purity: 98%.

1H NMR (CDCl3, 400MHz): δ = 8.35 (dt, J = 8.8, 6.0 Hz, 2H), 8.13 (dt, J = 8.8, 6.0 Hz, 2H), 4.72 (m, 1H), 3.42-3.35 (m ,2H),1.76-1.60(m,2H),1.45-1.25(m,2H),1.00(s,9H),0.89ppm(t,J=7.2Hz,3H).

Example 7

Synthesis of (R)-4-propyldihydrofuran-2(3H)-one

In a 500 mL three-necked flask, add 19.8 g of sodium tert-butoxide and 140 mL of ethylene glycol dimethyl ether. After cooling to 0-5°C, 27.2 g of dimethyl malonate was added dropwise to the system while maintaining this temperature. After stirring for 60 minutes, the (R)-1-(tert-butoxy)pent-2-yl trifluoromethanesulfonate solution obtained in Example 4 was added dropwise while maintaining 0-5°C. After dripping, continue stirring at 0～5°C for 20 hours. Then add 190 mL of a 2M sulfuric acid aqueous solution, gradually increase the temperature until the internal temperature reaches 90°C or more, and continue stirring for 24 hours. The reaction solution was extracted twice with 300 ml of dichloromethane, the organic phases were combined, washed with water, dried, and concentrated to obtain a crude product. The crude product was subjected to vacuum distillation to collect fractions at 45-55°C to obtain 11 g of the target product, with a GC purity of 97%, an ee value of 98%, and a yield of 46%.

1H NMR(CDCl3,400MHz): δ=4.34(dd,J=8.8,7.2Hz,1H), 3.85(dd,J=9.2,7.2Hz,1H), 2.42–2.62(m,2H), 2.18–2.05 (m,1H),1.48-1.34(m,2H),1.34-1.20(m,2H),0.86ppm(t,J=7.2Hz,3H)

Example 8

Synthesis of (R)-4-propyldihydrofuran-2(3H)-one

In a 500 mL three-necked flask, 11.7 g of potassium tert-butoxide and 100 mL of ethylene glycol dimethyl ether were added. After cooling to 0-5°C, 16.7 g of diethyl malonate was added dropwise to the system while maintaining this temperature. After stirring for 60 minutes, 30 g of (R)-1-(tert-butoxy)pent-2-yl 4-nitrobenzenesulfonate was added dropwise. After dripping, continue stirring for 12 hours at 0-5°C. No conversion was observed in the GC control.

Example 9 Preparation of Buwaxitan

In a 50 mL flask, add 16 mL of 33 wt% HBr acetic acid solution, and cool to 0-5°C. (R)-4-propyldihydrofuran-2(3H)-one 3g 3mL acetic acid solution was added dropwise. After dripping, the temperature was raised to 80°C. After stirring for 3 hours, the temperature was lowered to 20-25°C. After adding 30 mL of dichloromethane and 60 mL of water, the layers were separated. The aqueous phase was extracted twice with 30 mL of dichloromethane. The combined organic phase was washed twice with water (30 mL). The organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 4.9 g of crude (R)-3-(bromomethyl)hexanoic acid with a yield of 100%. The crude product is directly put into the next step without separation.

In a 50 mL flask, 4.9 g of the crude (R)-3-(bromomethyl)hexanoic acid obtained above and 20 mL of ethanol were added. After adding 0.5 mL of concentrated hydrochloric acid, the temperature was raised to 40°C and stirred for 21 hours. After cooling to 20°C, it was concentrated to remove ethanol. The residue was dissolved in 100 mL of ethyl acetate, and then washed with 50 mL of saturated sodium bicarbonate and 50 mL of water. The organic phase was concentrated to obtain 4.2 g of ethyl (R)-3-(bromomethyl)hexanoate with a yield of 76%. The crude product is directly put into the next step without separation.

In a 100 mL flask, add 4.2 g of ethyl (R)-3-(bromomethyl)hexanoate, 40 mL of isopropyl acetate, 3.69 g of (S)-2-aminobutanamide hydrochloride, and four Butylammonium iodide 1.97g, sodium carbonate 5.65g. The temperature was raised to 88-90°C, and after 22 hours of stirring, the temperature was lowered to 25-30°C. The insoluble matter was removed by filtration, and the filter cake was washed with 40 mL of isopropyl acetate. The filtrate was transferred to a 100 mL flask and the temperature was raised to 60°C. Add 0.8 g of acetic acid, stir at 60°C for 1.5 hours, and then lower the temperature to 20-25°C. Remove insoluble matter by filtration. After adjusting the pH value of the filtrate to neutral with saturated sodium bicarbonate aqueous solution, the liquid was separated. After washing the organic phase with 40 mL of water, it was concentrated to obtain 2.7 g of crude Buwaxitan with a purity of 76%, an ee value of 98%, and a yield of 71.6%. The crude product was crystallized with methyl tert-butyl ether and petroleum ether to obtain 0.9 g of pure product, with a yield of 33%, a purity of 96%, and an ee value of 100%.

1H NMR(CDCl3,400MHz): δ=6.44(s,1H),5.73(s,1H), 4.45(dd,J=8.8,6.8Hz,1H),3.55(dd,J=8.8,7.6Hz,1H ), 2.98 (dd, J = 9.6, 6.9H, 1H), 2.51 (dd, J = 16.8, 8.8 Hz, 1H), 2.41-2.27 (m, 1H), 2.11 (dd, J = 16.4, 8.0 Hz, 1H),2.01-1.87(m,1H),1.74-1.68(m,1H),1.50-1.37(m,2H),1.37-1.24(m,2H),0.97-0.83ppm(m,6H)

All documents mentioned in the present invention are cited as references in this application, as if each document was individually cited as a reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims

A method for preparing chiral butyrolactone represented by formula (I), characterized in that the method comprises the steps:

(1) In an inert solvent, in the presence of an ethyl Grignard reagent and a catalyst, compound (II) is subjected to a ring-opening reaction to form compound (III);

(2) Perform a sulfonylation reaction between compound (III) and a sulfonylating reagent in an inert solvent in the presence of a base to form compound (IV) or a mixture containing compound (IV);

(3) Reacting compound (IV) or a mixture containing compound (IV) with compound (V) in an inert solvent under alkaline conditions for substitution reaction; after the completion of the substitution reaction, the reaction mixture is subjected to acidic conditions Ring-closing reaction to form compound (I);

Wherein, L is a C 1-4 alkyl sulfonate group or a halogenated C 1-4 alkyl sulfonate group; R is a C 1-6 alkyl group.
The preparation method according to claim 1, wherein R is methyl, ethyl, propyl, isopropyl or tert-butyl.
The preparation method according to claim 1, wherein L is a triflate group.
The preparation method according to claim 1, wherein in step (1), the ethyl Grignard reagent is ethyl magnesium bromide or ethyl magnesium chloride.
The preparation method according to claim 1, wherein in step (1), the catalyst is cuprous iodide, ketone bromide, cuprous cyanide or ketone dimethyl sulfide bromide.
The preparation method according to claim 1, wherein in step (2), in an inert solvent, first add compound (III) and a base; then add a sulfonylation reagent for sulfonylation reaction, thereby forming compound ( IV) or a mixture containing compound (IV).
The preparation method according to claim 1, wherein in step (2), the sulfonylation reagent is selected from the group consisting of C 1-4 alkyl sulfonate chloride, halogenated C 1-4 alkyl Sulfonic acid chloride, C 1-4 alkyl sulfonic anhydride, halogenated C 1-4 alkyl sulfonic anhydride, or a combination thereof.
The preparation method according to claim 1, wherein in step (3), the alkaline conditions are conditions in the presence of organic bases.
The preparation method according to claim 1, wherein, in step (3), the acidic condition is the condition in which an acidic solution exists.
The preparation method according to claim 1, characterized in that, in step (3), the organic base and compound (V) are first added to an inert solvent, and then compound (IV) or a mixture containing compound (IV) is added to perform Substitution reaction: After the completion of the substitution reaction, an acidic solution is added to carry out a ring-closure reaction to form compound (I).