KR100794217B1 - An intermediate of 4-acetoxyazetidinone and a process for the preparation of the intermediate - Google Patents

Abstract

The present invention provides (3R, 4R) -4-acetoxy-3- [1'R] -1'-t-butyldimethylsilyloxyethyl-2-ase of formula 1 useful as an intermediate of carbapenem and penem antibiotics. A novel process for preparing tidinone, a novel intermediate produced in the process and a process for the preparation thereof:

Carbapenem, intermediate, preparation method, (3R, 4R) -4-acetoxy-3- [1'R] -1'-t-butyldimethylsilyloxyethyl-2-azetidinone

Description

{An intermediate of 4-acetoxyazetidinone and a process for the preparation of the intermediate}

The present invention provides (3R, 4R) -4-acetoxy-3- [1'R] -1'-t-butyldimethylsilyloxyethyl-2-ase of formula 1 useful as an intermediate of carbapenem and penem antibiotics. A novel process for preparing tidinone (hereinafter referred to as '4-acetoxyazetidinone'):

[Formula 1]

The present invention also relates to novel intermediates produced during the preparation of 4-acetoxyazetidinone and methods for their preparation.

Representative of carbapenem and penem antibiotics prepared from 4-acetoxyazetidinone of Formula 1 can be exemplified by the Imipenem compound of Formula 11:

The compound of Formula 11 exhibits a broad spectrum of antimicrobial activity against almost all bacteria including aerobic and anaerobic, and particularly has excellent activity against Gram-positive bacteria.

Compounds of formula (I), which are used as essential intermediates in preparing such medically important carbapenem and penem antibiotics, have been prepared by several methods as follows.

First, the method of Scheme 1 below to prepare the desired 4-acetoxyazetidinone using a low cost starting material (USP 5,081,239, USP 5,712,388).

In Scheme 1,

TBDMS means tert-butyldimethylsilyl,

R ₁ represents lower alkanes such as methyl and ethyl,

R < ₂ > represents lower alkanes, such as tert- butyl.

However, the method of Scheme 1 has the advantage of reducing the production cost by using a low-cost starting material, while using a hydrogen reaction that is difficult to industrialize, there is a problem that the metal catalyst used during the reaction is expensive.

Second is the method of Scheme 2 or 3, using expensive butanediol or methyl 3-hydroxybutanoate as starting material. See Scheme 2: J. Chem. Soc. Chem. Commun., 662 (1991), KR 0133930; See Scheme 3: KR 0032097].

In Scheme 3

TBDMS is as defined above,

TMS means trimethylsilyl.

The schemes 2 and 3 have a problem that the overall production cost increases due to the use of expensive starting materials. In addition, in the method of Scheme 2, butene compound is produced as a reaction intermediate by reacting lithium carbonate and DMF solvent at 80 ° C. As a result, butene compound has a low E / Z ratio of about 2.5 / 1. There is a problem of significantly reducing the production yield of.

Third, it is also the method of Scheme 4 to lower the production cost by using a low-cost starting material (cf. KR 0144378, KR 0205768, KR 0205769).

In Scheme 4, X represents a carboxyl, alkoxycarbonyl, cyano, substituted thio, sulfoxy, sulfonyl, substituted phosphoryl, substituted alkanyl, nitro, isonitrile, or acyl group.

However, in the method of Scheme 4, not only the strong base is used in the lactam ring formation process, but also it is not satisfactory as it is difficult to industrialize the deprotection process due to the problem of excessive reagent use and yield reduction.

In this regard, the present inventors conducted intensive research to compensate for the shortcomings of the existing methods for the synthesis of 4-acetoxyazetidinone of Chemical Formula 1, and as a result, according to the new production method described below, a low-cost starting material was used. It is possible to apply mild reaction conditions that are easy to industrialization, and to increase the E / Z isomer ratio of butene compound to about 5 / 1-24 / 1 and ultimately contribute to the yield improvement of the compound of Formula 1, and the present invention. To complete.

The present invention provides a new method for preparing compounds of formula (1) which are usefully used as intermediates in the preparation of carbapenem or penem antibiotics.

The present invention also provides a novel intermediate produced in the process of preparing a compound of formula (1) and a method for preparing the same.

The novel method for preparing 4-acetoxyazetidinone according to the present invention exhibits the advantage of producing the target compound in high yield even under economic and mild reaction conditions compared to the existing method.

Hereinafter, the configuration of the present invention will be described in more detail.

First, the present invention is to react the compound of formula 8 in the presence of powdered potassium hydroxide in an organic solvent to prepare a compound of formula 9, and to react the compound of formula 9 with chlorosulfonyl isocyanate to prepare a compound of formula 10 And reacting the compound of Formula 10 in the presence of N-bromosuccinimide and acetic acid in a solvent.

[Formula 1]

Wherein TBDMS represents tert-butyldimethylsilyl,

X represents halogen, particularly preferably chloro,

Ph represents phenyl.

In the method for preparing the compound of Formula 1, the process of preparing the compound of Formula 9 from the compound of Formula 8 is a part of the characteristic configuration of the method.

That is, in the conventional method for preparing the compound of Formula 9 from the compound of Formula 8 (see J. Antibiotics 43: 1608-1610, 1990), lithium halides such as lithium bromide, lithium iodide, and lithium chloride together with lithium carbonate It is reported that the butene compound of the formula (9) is obtained at a ratio of E / Z = 2.5 / 1 as the reaction is carried out. In addition, when alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide are used as bases, the compound of formula 9 can be obtained at a ratio of about E / Z = 4/1, but at the same time, unwanted impurities -20% is generated. However, according to the present invention, when the powder is used by grinding potassium hydroxide, a compound of formula 9 may be prepared in high yield and high E / Z ratio. If potassium hydroxide is used in granules or flakes rather than in powder form, the reaction does not proceed, and in performing the reaction, it is preferable to add 5 to 6 equivalents of powdered potassium hydroxide based on the compound of Formula 8 to complete the reaction.

On the other hand, the organic solvent used in the reaction can be used without limitation as long as the solvent does not dissolve the powdered potassium hydroxide, using this to reflux for 2 to 24 hours high yield of more than 90% and E / Z = 5/1 A compound of formula 9 can be obtained with an isomer ratio of -24/1. The organic solvent is preferably used at least one selected from the group consisting of tetrahydrofuran, hexane, isopropyl ether, dimethylformamide, dimethyl sulfoxide, and acetone. In the case of using a solvent in which potassium hydroxide is dissolved, most of the side reactions may proceed, and the production of impurities may be accompanied.

Process for preparing a compound of formula 10 from the compound of Formula 9 is described can be carried out according to a known method [see:: J. Antibiotics 41 1685, 1988 ], for preparing a compound of formula (I) from compounds of formula (10) The procedure can be carried out with reference to what is disclosed in KR 0132532.

The compound of formula 8 used as a starting material in the method for preparing a compound of formula 1 is prepared by reducing the compound of formula 5 in the presence of calcium chloride and sodium borohydride in a solvent to prepare a compound of formula 6 The compound of formula 6 may be prepared by reacting the compound of formula 6 with tosyl chloride in the presence of a base and a catalyst, and reacting the compound of formula 7 with benzenethiol sodium in a solvent. Accordingly, the present invention also provides a method for preparing the compound of Formula 8.

[Formula 8]

Wherein TBDMS represents tert-butyldimethylsilyl,

Me represents methyl,

Ts represents chum,

X represents halogen, particularly preferably chloro.

In the above method for preparing the compound of Formula 8, the reaction for preparing the compound of Formula 6 by reducing the compound of Formula 5 is a part constituting the characteristic configuration of the method. As a result of repeated experiments by the present inventors, when using other conventional reducing agents, there is a problem that many impurities are generated and thus the yield is lowered, but lower alcohols having 1 to 8 carbon atoms such as isopropanol or tetrahydrofuran It was found that the reaction of calcium chloride and sodium borohydride as a reducing agent in a solvent yielded the desired compound of formula 6 in a high yield of 90% or more. In this reaction, it is preferable to use 2 to 3 equivalents of calcium chloride and 2 to 3 equivalents of sodium borohydride based on the compound of formula (5). The reaction is usually carried out for 6 to 9 hours at a temperature of 0 to 25 ℃.

This reduction reaction has not been used at all in many known production methods for the 4-acetoxyazetidinone of formula (1), but has been found to be very efficient by the inventors, and moreover, formula (6) prepared through this reduction reaction The compound of itself is a novel compound. It is therefore another object of the present invention to provide a novel compound of formula (6).

The process of preparing the compound of Formula 7 from the compound of Formula 6, and preparing the compound of Formula 8 therefrom can be easily carried out with reference to known reaction conditions ( J. Antibiotics 41: 1685, 1988). In brief, triethylamine, pyridine, tributylamine, etc. may be used as a base in the process of synthesizing the compound of Chemical Formula 7, and Dabco (1,4-diazabicyclo- [2,2,2) may be used as a catalyst. ] -Octane), DMAP (N, N-dimethylaminopyridine, etc.), of which Dabco can be used as a catalyst to obtain a compound of formula 7 in high yield in a short reaction time. When used, since it is difficult to remove after the reaction and also affects the following reaction, it is preferable to use 1 to 1.1 equivalents based on the compound of formula 6. In addition, the solvent is dimethylformamide, dimethylacetate in the process of synthesizing the compound of formula 8. At least one selected from amide and tetrahydrofuran may be used, and the reactant benzenethiol sodium may be used in an amount of 1 to 1.5 equivalents based on the compound of Formula 7. It is preferable in terms of lowering the pure water produced.

The compound of formula 5 used as a starting material in the method for preparing a compound of formula 8 may be obtained by reacting the compound of formula 4 with t-butyldimethylsilyl chloride (TBDMSCl) in the presence of a base.

Wherein Me represents methyl,

X represents halogen, particularly preferably chloro.

In this case, at least one selected from imidazole, triethylamine, and pyridine may be used as the base, and imidazole is preferably used. t-butyldimethylsilylchloride is preferably used in the amount of 1 to 1.1 equivalents based on the compound of formula (4). The reaction is usually carried out for 10 to 12 hours at a temperature of 0 to 25 ℃.

On the other hand, the compound of formula 4

i) reacting a compound of formula 2 with NaNO ₂ and a hydrofluoric acid or sodium halide to substitute an amino group with a halogen group to prepare a compound of formula 3, wherein the compound of formula 3 is methylated with methanol and acetyl chloride Or

ii) methylation of the compound of formula 3 with methanol and acid,

iii) reacting a compound of formula 3 with sodium acetate (SA) or sodium ethylhexanoate (SEH) to prepare a compound of formula 3a, wherein the compound of formula 3a is methylated with dimethylsulfate or methyl halide It can manufacture by.

Wherein X represents halogen, particularly preferably chloro.

The reaction for preparing the compound of Formula 3 from the compound of Formula 2 may be easily carried out through a known Sandmeyer reaction (see J, Org, Chem., 57, 4325, 1991). Briefly describing the Sandmeyer reaction, NaNO ₂ used as a diazotizing agent is first changed to nitrous acid (HNO ₂ ), and then the amino group (-NH ₂ ) of the compound of Formula 2 is changed to a diazo group (-N ₂ ). It is substituted by the halogen atom which is a nucleophile of hydrohalic acid or sodium halide. Hydrogen halides usable in this reaction include HCl, and sodium halides include NaBr. Particularly preferred in the present invention is the substitution of chloro groups with HCl. NaNO ₂ used in the diazotization of the reaction is preferably used in an amount of 2 to 3 equivalents based on the compound of Formula 2, since an excessive amount of impurities are used. Hydrogen halide or sodium halide used for the substitution is based on the compound of Formula 2. It is preferable to use 2-3 equivalents.

The conditions of methanol / acetylchloride or methanol / acid can be used to methylate the compound of formula 3 to produce the compound of formula 4. In particular, sulfuric acid, hydrochloric acid and the like can be used as the acid in the latter method, and sulfuric acid is preferably used. The reaction is preferably carried out for 3 to 5 hours in the temperature range of 60 to 70 ℃.

On the other hand, the compound of formula 3 can be converted to the corresponding sodium salt (formula 3a) to obtain a solid, and for this purpose the compound of formula 3 is reacted with sodium acetate (SA) or sodium ethylhexanoate (SEH) . Since SA or SEH is difficult to remove when used in excess, it is preferable to use 1 to 2 equivalents based on the compound of Formula 3. Reaction of the solid compound of formula 3a with dimethylsulfate or methyl halide as a methylating agent gives a compound of formula 4. As methyl halide, methyl iodide, methyl bromide, or methyl chloride is preferably used. The methylating agent is preferably used in the amount of 1 to 1.5 equivalents based on the compound of the formula 3a, and also preferably the reaction is carried out in a solvent such as dimethylformamide. The methylation reaction is preferably carried out for 2 to 4 hours in the temperature range of 0 to 25 ℃.

The compound of each step produced through the reaction can be purified in a pure state by conventional purification methods, for example, column chromatography or recrystallization, if necessary.

In order to help the understanding of the present invention, the entire process of preparing the desired compound of Formula 1 from the compound of Formula 2 is shown in Scheme 5 below.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, these examples are only for the understanding of the present invention, and the scope of the present invention is not limited by them in any sense.

Definitions of abbreviations used herein, including the following examples, are as follows.

EA: ethyl acetate

MeOH: Methanol

AcCl: Acetylchloride

DMF: Dimethylformamide

DMSO: Dimethyl Sulfoxide

DMS: Dimethyl Sulfate

TBDMSCl: t-butyldimethylsilylchloride

IPA: Isopropanol

IPE: Isopropyl Ether

MC: methylene chloride

TEA: triethylamine

Dabco: 1,4-diazabicyclo- [2,2,2] -octane

TsCl: tosyl chloride

CSI: chlorosulfonyl isocyanate

NBS: N-bromosuccinimide

Example 1: Preparation of (2S, 3R) -2-chloro-3-hydroxybutanoic acid (3) (Step 1)

Hydrochloric acid (150 mL) was added to water (25 mL) at 0 ° C, and starting material L-threonine (50 g) was added thereto. NaNO ₂ (70 g) was dissolved in water (110 mL) at 0 ° C. and added over 4 hours. Extracted three times with EA (250 mL), the organic layers were combined, dried over MgSO ₄ , and distilled to give the title compound (58 g, 99% yield) as an oil.

1 H NMR (300 MHz, CDCl 3) δ: 4.5 (d, 1H), 4.3 (m, 1H), 1.2 (d, 3H)

Example 2: Preparation of Sodium (2S, 3R) -2-Chloro-3-hydroxybutanoate (3a) (Steps 1-2)

To the ethyl acetate extract obtained in Example 1 was added sodium acetate (15 g) and reacted for 2 hours to obtain the title compound quantitatively.

Example 3: Preparation of (2S, 3R) -methyl-2-chloro-3-hydroxybutanoate (4) (Step 2-1)

Compound (3) (58 g) of Example 1 was dissolved in MeOH (240 mL) and cooled to 0 ° C. AcCl (0.9eq) (26 mL) was added slowly and stirred overnight. MeOH of the reaction solution was distilled off, EA (500 mL) was added, and the mixture was washed with brine (100 mL). The organic layer was dried over MgSO ₄ and distilled to obtain the title compound (52 g, yield 82%).

1 H NMR (300 MHz, CDCl 3) δ: 4.3-4.2 (m, 1H), 3.8 (s, 3H), 1.3 (d, 3H)

Example 4: Preparation of (2S, 3R) -methyl-2-chloro-3-hydroxybutanoate (4) (Step 2-2)

Compound (3) of Example 1 (56.5 g) was dissolved in MeOH (226 mL), cooled to 0 ° C., sulfuric acid (5.4 mL) was slowly added thereto, and the mixture was refluxed for 3 hours. After cooling to room temperature, MeOH was distilled and water (56 mL) and EA (150 mL) were added thereto and the layers were separated. The lower layer was extracted twice with EA (150 mL), and then the organic solution was collected and washed with 5% aqueous saturated sodium bicarbonate solution (56 mL), followed by brine (56 mL). The combined organic layers were dried over MgSO ₄ and distilled to obtain the title compound (53 g, yield 85%).

Example 5: Preparation of (2S, 3R) -Methyl-2-chloro-3-hydroxybutanoate (4) (Steps 2-3)

Compound (3a) (5 g) of Example 2 was dissolved in DMF (20 mL) and DMS (4.7 mL) was added at 0 ° C. After stirring for 3 hours at room temperature, EA (40 mL) and water (40 mL) were added and extracted. The organic layer was washed with brine (40 mL), dried over MgSO ₄ , and distilled to obtain the title compound (3.9 g, yield 82%).

Example 6: Preparation of (2S, 3R) -Methyl-3- (tert-butyldimethylsilyloxy) -2-chloro-butanoate (5) (Step 3)

Compound (4) (52 g) obtained in any one of Examples 3 to 5 was added to DMF (100 mL) and stirred, imidazole (45.5 g) was added at 0 ° C, and stirred for 30 minutes. TBDMSCl (53 g) was added to the reaction solution and reacted overnight, and then cooled to 0 ° C. 3N HCl (250 mL) was added followed by extraction three times with hexane (250 mL), washed with saturated sodium bicarbonate solution (250 mL) and brine (250 mL), the organic layer was dried over MgSO ₄ , distilled off and titled Compound (86 g, yield 95%) was obtained.

¹ H NMR (300 MHz, CDCl 3) δ: 4.2 (m, 1H), 4.1 (d, 1H), 3.7 (s, 3H), 1.2 (d, 3H), 0.8 (s, 9H), 0.1 (d, 6H )

Example 7a: Preparation of (2S, 3R) -3- (tert-butyldimethylsilyloxy) -2-chlorobutan-1-ol (6) (Step 4)

Compound (5) of Example 6 (86 g) was added to IPA (960 mL) and stirred, followed by addition of CaCl ₂ (102 g) and NaBH ₄ (23.3 g). The reaction solution was stirred for 32 hours, filtered through celite and distilled. Water (960 mL) was added, extraction was performed three times with EA (400 mL), and the organic layers were combined, dried over MgSO ₄ , and distilled to obtain the title compound (69 g, 90% yield).

¹ H NMR (300 MHz, CDCl 3) δ: 4.1 (m, 1H), 3.8 (m, 2H), 3.7 (m, 1H), 1.2 (d, 3H), 0.8 (s, 9H), 0.1 (s, 6H )

Example 7b: Preparation of (2S, 3R) -3- (tert-butyldimethylsilyloxy) -2-chlorobutan-1-ol (6) (Step 4)

Compound (5) (88 g) of Example 6 was added to THF (176 mL) and stirred, followed by addition of CaCl ₂ (73.13 g) / NaBH 4 (24.95 g). After stirring for 10 hours, filtered, water (400 mL) was added and the layers separated. The aqueous layer was extracted twice with hexane (200 mL). The combined organic layers were washed with brine (200 mL), dried and distilled to afford the title compound (70 g, 89% yield).

Example 8: Preparation of (2S, 3R) -3- (tert-butyldimethylsilyloxy) -2-chlorobutyl-4-methylbenzenesulfonate (7) (Step 5)

Compound (6) (69 g) of Example 7 was added to MC (244 mL), stirred at 0 ° C, and TEA (71 mL) was added slowly. Dabco (0.61 g) was added and TsCl (50 g) was added followed by stirring at 0 ° C. for 3 hours. 1N HCl (244 mL) was added and the layers separated. The aqueous layer was removed and saturated aqueous sodium hydrogen carbonate solution (125 mL) was added to the MC layer, stirred, and the layers were separated. Brine (125 mL) was added to the MC layer, the layers were separated, and the organic layer was dried over MgSO ₄ and distilled to obtain the title compound (110 g, yield 97%).

¹ H NMR (300 MHz, CDCl 3) δ: 7.7 (d, 2H), 7.3 (d, 2H), 4.2 (dd, 1H), 4.0 (m, 2H), 3.7 (m, 1H), 2.3 (s, 3H ), 1.2 (d, 3H), 0.8 (s, 9H), 0.1 (d, 6H)

Example 9 Preparation of tert-butyl ((2R, 3S) -3-chloro-4- (phenylthio) butan-2-yloxy) dimethylsilane (8) (Step 6)

Compound (7) of Example 8 (110 g) was added to DMF (220 mL), stirred at 0 ° C., and benzenethiol sodium (47 g) was slowly added. Stirred at 0 ° C. for 1 hour, hexane (200 mL) and 1N NaOH (1000 mL) were added, followed by 30 min stirring and layer separation. Brine (1000 mL) was added to the hexane layer, and the layers were separated again. 1N HCl (1000 mL) was added to the hexane layer, followed by stirring and layer separation. MgSO ₄ was added to the organic layer, stirred for 1 hour, filtered, and distilled to obtain the title compound (87 g, yield 94%).

¹ H NMR (300 MHz, CDCl 3) δ: 7.4-7.2 (m, 5H), 4.2 (m, 1H), 3.8 (m, 1H), 3.5 (dd, 1H), 3.2 (dd, 1H), 1.2 (d , 3H), 0.9 (s, 9H), 0.1 (d, 6H)

Example 10a: Preparation of (R) -tert-butyldimethyl (4- (phenylthio) but-3-en-2-yloxy) silane (9) (Step 7)

Compound (8) (87 g) of Example 9 was added to THF (400 mL), and powdered KOH (87 g) was added thereto while stirring and refluxed for 2 hours, followed by cooling. Hexane (400 mL) and 1N HCl (170 mL) were added, stirred for 30 minutes and layered. Saturated aqueous sodium hydrogen carbonate solution (170 mL) was added to the hexane layer, and the layers were separated. Brine (170 mL) was added to the hexane layer, and the layers were separated. MgSO ₄ was added to the organic layer, stirred for 1 hour, filtered, and distilled to obtain the title compound (72 g, yield 92%, E / Z = 5/1).

¹ H NMR (300 MHz, CDCl 3) δ: 7.3-7.2 (m, 5H), 6.4 (dd, 0.85H), 6.12 (dd, 0.15H), 5.96 (dd, 0.85H), 5.91 (dd, 0.15H) , 4.7 (m, 0.15H), 4.3 (m, 0.85H), 1.2 (d, 3H), 0.8 (s, 9H), 0.1 (d, 6H)

Example 10b: Preparation of (R) -tert-butyldimethyl (4- (phenylthio) but-3-en-2-yloxy) silane (9) (Step 7)

Compound (8) (87 g) of Example 9 was added to hexane (400 mL), and powdered KOH (160 g) was added thereto under stirring, and refluxed for 21 hours, followed by cooling. 400 ml of water was added, stirred for 30 minutes, and the layers were separated. 170 mL of 1.5N HCl was added to the hexane layer, and after separating the layers, brine (170 mL) was added to the hexane layer, and the layers were separated. MgSO ₄ was added to the upper layer, stirred for 1 hour, filtered, and distilled to obtain the title compound (72 g, yield 92%, E / Z = 96: 4).

¹ H NMR (300 MHz, CDCl 3) δ: 7.3-7.2 (m, 5H), 6.4 (dd, 0.92H), 6.12 (dd, 0.08H), 5.96 (dd, 0.92H), 5.91 (dd, 0.08H) , 4.7 (m, 0.15H), 4.3 (m, 0.85H), 1.2 (d, 3H), 0.8 (s, 9H), 0.1 (d, 6H)

Example 10c: Preparation of (R) -tert-butyldimethyl (4- (phenylthio) but-3-en-2-yloxy) silane (9) (Step 7)

Compound (8) of Example 9 (87 g) was added to IPE (400 mL), and powdered KOH (160 g) was added thereto while stirring, refluxed for 10 hours, and then cooled. 400 ml of water was added, stirred for 30 minutes, and the layers were separated. 170 mL of 1.5N HCl was added to the hexane layer, and after separating the layers, brine (170 mL) was added to the hexane layer, and the layers were separated. MgSO ₄ was added to the upper layer, stirred for 1 hour, filtered, and distilled to obtain the title compound (72 g, yield 92%, E / Z = 96: 4).

¹ H NMR (300 MHz, CDCl 3) δ: 7.3-7.2 (m, 5H), 6.4 (dd, 0.92H), 6.12 (dd, 0.08H), 5.96 (dd, 0.92H), 5.91 (dd, 0.08H) , 4.7 (m, 0.15H), 4.3 (m, 0.85H), 1.2 (d, 3H), 0.8 (s, 9H), 0.1 (d, 6H)

Example 11: Preparation of (3S, 4R) -3 ((R) -1- (tert-butyldimethylsilyloxy) ethyl) -4- (phenylthio) azetidin-2-one (10) (Step 8)

Compound (9) (72 g) in Example 10 was added to hexane / 1,4-dioxane (20/1) (720 mL) and stirred at room temperature. CSI (25 mL) was added to the reaction solution, and the mixture was stirred for 6 hours. After cooling the reaction solution to 0 ° C., Na ₂ SO ₃ (118 g) and NaHCO ₃ (39.3 g) were dissolved in water (1080 mL) and slowly added thereto, followed by 1 hour, and the temperature stirred at room temperature for 2-3 hours. The resulting crystals were filtered, the filtrate was separated and the filtrate was washed with brine (170 ml), the organic layer was cooled to −30 ° C. and the resulting solid was filtered and dried with the solid obtained first. The title compound (37 g, yield 45 %) Was obtained.

¹ H NMR (300 MHz, CDCl 3) δ: 7.4-7.3 (m, 5H), 6.2 (bs, 1H), 5.0 (d, 1H), 4.2 (d, 1H), 3.0 (m, 1H), 1.2 (d , 3H), 0.9 (s, 9H), 0.1 (d, 6H)

Example 12 Preparation of (3R, 4R) -4-acetoxy-3- [1'R] -1'-tert-butyldimethylsilyloxyethyl-2-azetidinone (step 9)

MC (300 mL), AcOH (23 mL), and NBS (15 g) were added to compound (10) (33 g) in Example 11, and the mixture was stirred for 5 hours. 10% Na ₂ S ₂ O ₃ aqueous solution (100 mL) was added to the reaction mixture, and the layers were separated. The organic layer was dried over MgSO ₄ , distilled, and crystallized with hexane at low temperature (-20 ° C.) to give the title compound (27 g, Yield 94%).

¹ H NMR (300 MHz, CDCl 3) δ: 6.5 (bs, 1H), 5.8 (d, 1H), 4.2 (m, 1H), 3.2 (m, 1H), 2.1 (s, 3H), 1.2 (d, 3H ), 0.86 (s, 9H), 0.1 (d, 6H)

Claims (3)

A compound of formula [Formula 6]

Wherein TBDMS represents tert-butyldimethylsilyl, X represents a halogen. The compound of claim 1, wherein X is chloro. A process for preparing a compound of formula 6 characterized in that the compound of formula 5 is reduced in the presence of calcium chloride and sodium borohydride in a solvent: [Formula 5]

[Formula 6]

Wherein TBDMS represents tert-butyldimethylsilyl, Me represents methyl, X represents a halogen.