WO2008127070A1

WO2008127070A1 - Process for stereoselective preparation of 4-bma using a chiral auxiliary

Info

Publication number: WO2008127070A1
Application number: PCT/KR2008/002142
Authority: WO
Inventors: Dong Gyun Shin; Myeng Chan Hong; Won Koo Lee; Hyun Joon Ha; Seong Cheol Moon; Chung Hyun Song; Kyung Ho Lee; Chang Woan Han; Jong Hyek Kim; Byung Goo Lee; Yoon Seok Song
Original assignee: Daewoong Pharmaceutical Co., Ltd.; Daewoong Chemical Co., Ltd.
Priority date: 2007-04-16
Filing date: 2008-04-16
Publication date: 2008-10-23
Also published as: KR100886347B1; KR20080093315A; JP5180289B2; CN101675031B; JP2010524923A; CN101675031A

Abstract

The present invention relates to a process for preparing (3R,4S)-3-[[[R]-V-t- butyldimethylsilyloxy] ethyl] -4- [(/?)- l'-carboxyethyl]-2-azetidinone [4-BMA: formula (6)], a key intermediate for the synthesis of carbapenem and penem antibiotics. Specifically, the present invention relates to a process comprising first, the preparation of a chiral auxiliary from cheap L-Valinol, and then the preparation of 4-BMA in high yield and high selectivity, under industrially mild conditions.

Description

PROCESS FOR STEREOSELECTIVE PREPARATION OF 4-BMA USING A CHIRAL AUXILIARY

TECHNICAL FIELD

The present invention relates to a new process for stereoselectively preparing a compound of the following formula (6):

in which R represents hydrogen or a hydroxy-protecting group, particularly, (3R,4S)-3- [ [[R] - 1' -t-butyldimethylsilyloxy] ethyl] -A- [(R)- 1 "-carboxyethyl] -2-azetidinone (beta- methylazetidin-2-one; 4-BMA), which is useful as an intermediate for the synthesis of penems or carbapenems. The present invention also relates to a new process for preparing a compound of the following formula (3):

that can be effectively used as a chiral auxiliary for stereoselectively preparing the compound of formula (6) in high yield under mild conditions.

BACKGROUND ART The compound of formula (6) has been known in the art as an intermediate for the synthesis of 1 β-methylcarbapenem which exhibits potent antibacterial activity. Many types of carbapenems can be prepared from the compound of formula (6), a typical example of which is Meropenem of the following formula (7):

Meropenem (1\

The compound of formula (7), whose common name is Meropenem, exhibits a broad spectrum of antibacterial activity against gram-positive and gram-negative strains. In particular, it has an excellent antimicrobial effect in controlling gram-negative strains and metalactamase-producing strains. Also, the presence of the beta-methyl group makes Meropenem to have better stability against dehydropeptidase-1 (DHP-I) in the kidney compared to the existing carbapenem antibacterial agent of Imipenem (Antimicrobial Agents and Chemotheraphym 33, 215-222 (1989)). Thus, in contrast to Imipenem, Meropenem does not have to be administered along with cilastatin to maintain stability in the body, and can be administered alone.

Various methods for preparing the compound of formula (6), a key intermediate for manufacturing important medicines, such as carbapenem and penem antibiotics, have been developed. In earlier researches, 1 "-position hydrogen atom in the acetic acid residue at 4-position of the betamethyl compound was removed by a strong base, and methyl group was introduced thereto [Heterocycles, 21, 29(1984)]. However, this method posed problems of essentially using lithium diisopropylamide that is difficult to handle, and of having to be carried out under an extremely low temperature, such as -78 ^°C . There is also the disadvantage that the compound having lα-methyl group of the following formula (6a):

was produced in large amounts as a by-product (β/α=4/l).

Several approaches have been tried to overcome such problems, and the most advantageous was to introduce β-methyl group using a chiral auxiliary. The following have been used as the chiral auxiliaries for preparing the compound of formula (6) [Tetrahedron 52, 331-375, (1996)].

Tanabe Seiyaku

Sagami/Sumitomo Sankyo

Bristol-Myers Merck Lederle Japan

In most methods for preparing chiral auxiliaries for the synthesis of the 4-BMA, propionyl group is introduced as an acyl group. A halide compound, which is not easy to handle, such as propionyl bromide, is used for introducing propionyl group, and a metal catalyst, such as n-butyllithium, is used for the coupling reaction (JP2789190, DE3632916, US5104984, KR940008748).

The following Reaction Scheme 1 is an example of a method for preparing the chiral auxiliary:

Reaction Scheme 1

NaH _r γ^c

The method of Reaction Scheme 1 was developed by Sumitomo. The problem with this method comes from using n-butyllithium and sodium hydride, which cannot be easily applied to industrial mass production of the chiral auxiliary. Further, propionyl chloride used as an acylating agent is not easy to handle since it is unstable under moisture and air (USP5231179).

For the coupling reaction of a (3i?,4i?)-4-acetoxy-3-[(i?)-l'((t- butyldimethylsilyl)oxy) ethyl] -2-azetidinone (4-AA) with the chiral auxiliary, trimethylchlorosilane (TMSCl) / lithium diisopropylamide (LDA), tintriflate [Sn(OTf)₂], diethylborotriflate (Et₂BOTf) / zinc bromide (ZnBr₂), tert-butyldimethylsilyltriflate (TBDMSOTf) / zinc chloride (ZnCl₂), LDA-Zr(Cp)₂Cl₂, etc. have been used (EP0974582, US5104984, J. AM. Chem. Soc, 1986, 108, 4675, etc.). However, these substances are explosive metal catalysts, or should be used in an extremely low temperature (-78 "C) reaction. Thus, it is difficult and uneconomical to use them industrially. The following Reaction Scheme 2 is an example of a method for preparing 4-BMA using a chiral auxiliary:

Reaction Scheme 2

The method of Reaction Scheme 2 was published by Merck Co. in J. Am. Chem.

Soc 1986, 108, 4675-4676, and it is a coupling reaction using diethylborotriflate (Et₂B- OTf), diisopropylethylamine (DIPEA) and zinc bromide (ZnBr₂). However, even in said coupling reaction for preparing 4-BMA, a boron compound that is not easy to handle and is rarely commercially available is used under the reaction temperature of -78 ^°C .

As summarized above, several methods for preparing 4-BMA have been reported, but a method suitable for preparing the desired compound in high yield and high selectivity using substances that are easy to handle in industrial production has not yet been developed.

DETAILED DESCRIPTION OF THE INVENTION

Thus, the present inventors have extensively studied to resolve the demerits of the earlier methods for the synthesis of 4-BMA of formula (6). As a result, they succeeded in preparing a chiral auxiliary from cheap starting material in high yield under mild conditions, and in obtaining good quality 4-BMA of β/α ratio being 99.5/0.5 or more and a high yield of 70% or more by coupling the chiral auxiliary with the 4- AA also under mild conditions, and then completed the present invention.

Thus, one of the objects of the present invention is to provide a new process for preparing the 4-BMA of formula (6) that can be effectively used as an intermediate for preparing carbapenem or penem antibiotics.

Another object of the present invention is to provide a new process for preparing the chiral auxiliary of formula (3) that is effectively used for stereoselectively preparing the compound of formula (6).

The present invention will be explained in detail below.

BEST MODE FOR CARRYING OUT THE INVENTION

First, the present invention relates to a process for preparing the 4-BMA compound of formula (6):

in which R represents hydrogen or a hydroxy-protecting group, preferable one of which is the organic silyl group, such as t-butyldimethylsilyl, t-butyldiphenylsilyl, triethylsilyl, trimethylsilyl, etc. and particularly preferable is t-butyldimethylsilyl, which comprises the steps of coupling the chiral auxiliary of formula (3):

with an azetidinone compound of formula (4):

in which R is as defined above, using titanium chloride (TiCl₄) in the presence of an organic base and a solvent, and hydrolyzing a compound of formula (5):

in which R is as defined above, that is obtained from the coupling reaction.

The process for preparing the 4-BMA compound according to the present invention can be depicted as the following Reaction Scheme 3:

Reaction Scheme 3

As explained in detail above, various chiral auxiliaries have been used for preparing the compound of formula (5). Particularly, the earlier processes used the reagents, such as trimethylchlorosilane (TMSCl) / lithium diisopropylamide (LDA), tintriflate [Sn(OTf)₂], diethylborotriflate (Et₂BOTf) / zinc bromide (ZnBr₂), tert- butyldimethylsilyltriflate (TBDMSOTf) / ZnCl₂, LDA-Zr(Cp)₂Cl₂, etc., in the coupling reaction of the chiral auxiliary of formula (3) with the 4- AA of formula (4). Use of such reagents, however, causes some disadvantages due to the risk of explosion from the use of metal reagents and low temperature reaction. Thus, the earlier processes could not be easily applied to industrial production, and also showed poor selectivity of β/α.

In contrast, the process of the present invention uses titanium chloride that is comparatively cheap, and the reaction is carried out in a conventional organic base and solvent at 0^°C to room temperature. In the process, the chiral auxiliary is dissolved in a solvent and cooled to 0 ^°C , titanium chloride is added in drops, and then an organic base is added in drops. After stirring for about 1 h, the 4- AA is added, and the reaction is carried out at room temperature to produce the desired compound of formula (5).

As the solvent, methylene chloride, dichloroethane, chloroform, etc., preferably methylene chloride can be used. The solvent is used in an amount which is 5-50 times, preferably 15-25 times, greater with respect to the 4- AA compound of formula (4). The organic base includes triethylamine (TEA), diisopropylethylamine (DIPEA), diethylamine

(DEA), butylamine, etc., preferably diisopropylethylamine (DIPEA). The organic base is used in the amount of 0.8-5 eq., preferably 1-2 eq., with respect to the 4-AA compound of formula (4). Titanium chloride is used in the amount of 1-3 eq., preferably 1.3-1.7 eq., with respect to the 4-AA compound of formula (4). If small amounts of titanium chloride are used, the reaction cannot be completed.

The suitable temperature when the organic base and titanium chloride are added should be between -20-10^°C, preferably -5-5 ^°C . The chiral auxiliary is used in the amount of 1-2 eq., preferably 1.2-1.4 eq., with respect to the 4-AA compound of formula (4). The suitable reaction temperature after adding even the 4-AA compound of formula (4) should be between 15-25 ^°C . The reaction proceeds very slowly when the temperature falls below this range, and the amount of impurities produced increases when the temperature is 25 ^°C or higher. The appropriate reaction time should be within 3 h, and the reaction should be completed within 2 h, if possible. The longer the reaction time, the more impurities produced, and therefore, it is preferable that the reaction be completed within 2 h.

The compound of formula (5) is hydrolyzed according to a method known in the art to produce the 4-BMA compound (see J Am. Chem. Soc, 1986, 108, 4675).

Preferably, the desired 4-BMA compound is obtained by the hydrolysis using hydrogen peroxide and lithium hydroxide.

Preparation of the desired 4-BMA compound according to the above explained process of the present invention produced a high yield of 70% or more and high selectivity of β/α ratio of 99.5/0.5 or more as calculated from the 4-AA compound of formula (4).

The earlier methods (US 5104984, EP0974582) using the same chiral auxiliary produced β/α ratios of 84/16 or 78/22 and yields of 89 or 21% even when drastic reaction conditions that cannot be industrially applied were used. The comparison of such results shows that the process of the present invention is more improved one that can be easily applied in industrial production, and at the same time, can result in excellent selectivity and yield.

The present invention also relates to a new process for preparing the compound of formula (3) used as a chiral auxiliary in the above process for preparing the 4-BMA compound. The chiral auxiliary of formula (3) can be prepared by a process comprising the steps of reacting the compound of formula ( 1 ) (L- Valinol) :

in the presence of a base and diethylcarbonate to produce the compound of formula (2):

and reacting the compound of formula (2) with propionic acid anhydride in the presence of an organic base, a solvent and a Lewis acid.

The process for preparing the chiral auxiliary of formula (3) from the compound of formula (1) can be depicted as the following Reaction Scheme 4:

Reaction Scheme 4

The compound of formula (2) can be easily synthesized by reacting the L-Valinol of formula (1) with a base and diethylcarbonate at a high temperature. The reaction time may be shortened by controlling the amount of base under the same conditions. The amount of base used should be 0.1-2 eq., preferably 0.5-1 eq., with respect to L-Valinol.

The bases that can be used include potassium carbonate, sodium hydride, potassium hydride, sodium carbonate, sodium bicarbonate, etc., preferably potassium carbonate and sodium carbonate. The reaction temperature is 80-150 ^°C , preferably 110~130^°C or the reflux temperature of the solvent. Usually, 4-24 h, preferably 10-14 h, is required for completing the reaction.

The earlier methods for preparing the compound of formula (3) from the compound of formula (2) usually used an acyl halide, such as propionyl chloride, and the coupling reaction of propionyl chloride with the compound of formula (2) was performed using a strong base, such as n-butyllithium or sodium hydride. The disadvantage of having to use a strong base is that the reaction had to be performed under an extremely low temperature (-78 ^°C). Also, the earlier methods are not desirable to be applied industrially due to the risk of explosion of the metal reagents and the instability of propionyl chloride in the presence of moisture.

On the other hand, in the present invention, the compound of formula (3) is prepared under mild conditions. Specifically, conventional organic bases are used instead of the explosive metal reagents. And, the stable propionic acid anhydride is used instead of the acyl halides, such as propionyl chloride, that are not stable in air and moisture.

Thus, the reaction can be carried out at room temperature.

As the solvent, tetrahydrofuran (THF), dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMAc), acetonitrile (AN), etc., preferably tetrahydrofuran (THF) or acetonitrile (AN), can be used. The amount of solvent used is 2~10 times, preferably 3~5 times, greater than the compound of formula (2). The organic base used includes triethylamine (TEA), diisopropylethylamine (DIPEA), t- butylamine, diethylamine (DEA), etc., preferably triethylamine (TEA), and should be used in the amount of 1~3 eq., preferably 1-1.3 eq., with respect to the compound of formula (2). As the Lewis acid for activating the reactants, lithium chloride (LiCl), aluminum chloride (AlCl₄), aluminum bromide (AlBr₄), iron tetrachloride (FeCl₄), zinc bromide (ZnBr₂), zinc chloride (ZnCl₂), trifluoroborane (BF₃), magnesium bromide (MgBr₂), preferably lithium chloride (LiCl) can be used. The amount of Lewis acid used should be 0.5-3 eq., preferably 1-1.5 eq., with respect to the compound of formula (2).

After adding all the reactants, the reaction is carried out for 1-10 h, preferably 1-2 h. The reaction temperature is between 0~50 ^°C , preferably 20-30 ^°C .

The chiral auxiliary of formula (3) obtained according to the above improved process produced a high yield of about 99% with respect to the compound of formula (2).

The present invention is more specifically explained by the following examples. However, these examples are intended to illustrate the present invention and should in no way be construed to limit the scope of the present invention.

Example 1: Preparation of (S)-4-isoporpyloxazolidin-2-one (2)

The starting material L-Valinol (15Og) was added to diethylcarbonate (227m#), and potassium carbonate (2Og) was then added while the mixture was stirred at room temperature. The reaction solution was refluxed for 5 h at 120~130^°C . The reaction solution was cooled to 0^°C, 1.5N hydrochloric acid (450m#) and ethyl acetate (450m#) were added, and the resulting two phases were separated. The aqueous phase was extracted twice with ethyl acetate (450m£), and the organic phase was washed with aqueous sodium chloride solution (450m#), phase-separated, dried, filtered and distilled. Isopropylether (225m£) was added to produce crystals to which n-hexane (225ml) was added. The mixture was stirred for 1 h at 0 ^°C , which was then filtered and dried to produce the title compound (17Og, Yield 85%).

¹H NMR (300MHz, CDCl₃) δ 4.4 (t, IH), 4.1 (m, IH), 3.6 (q, IH), 1.7 (m, IH), 0.98 (dd, 6H)

Example 2: Preparation of (S)-4-isopropyl-3-propionyloxazolidin-2-one (3)

The compound (2) prepared in Example 1 (10Og) was dissolved in tetrahydrofuran (300m#), and cooled to 0^°C . Lithium chloride (36g) was added, triethylamine (10Ig) was then slowly added, and the resulting mixture was stirred for 30 min. Propionic acid anhydride (106g) was slowly added over a 30 min. time period. The reaction mixture was slowly warmed to room temperature, and stirred for 1-1.5 h. The reaction solution was cooled, IN aqueous sodium chloride solution (300m#) was added, and the mixture was stirred for 30 min. Ethyl acetate (300mf) was added, the phases were separated, and extracted once again by ethyl acetate (300m£). After washing with 1.5 N hydrochloric acid (300m£), the organic phase was washed once again with aqueous sodium chloride solution (300m#), dried, filtered and distilled to produce the title compound (142g, Yield

%). 1H NMR (300MHz, CDCl₃) δ 4.4 (m, IH), 4.3-4.2 (m, 2H), 2.97 (m, 2H), 2.3 (m,

IH), 1.2 (t, 3H), 0.93 (dd, 6H)

Example 3: Preparation of (S)-3-((R)-2-(3-((R)-l-(t- butyldimethylsilyloxy)ethyl)-4-oxoazetidin-2-yl)propanoyl)-4-isopropyloxazolidin-2- one (5)

The compound (3) prepared in Example 2 (44g) was dissolved in methylene chloride (890ml), and cooled to 0^°C . Titanium chloride (55g) was slowly added. After 1 h, diisopropylethylamine (4Og) was added and then 4-AA (50g) was added. The resulting mixture was reacted for 3 h at room temperature and cooled. Water (890ml) was added to separate the phases. 1.5N hydrochloric acid (500ml) was added thereto. The phases were separated, and washed with aqueous sodium bicarbonate solution once again, washed with aqueous sodium chloride solution (100ml), dried over magnesium sulfate and distilled to produce the title compound contaminated with some impurities (95g).

¹H NMR (300MHz, CDCl₃) δ 5.96 (s, IH), 4.44 (m, IH), 4.30 (m, 4H), 3.96 (m, IH), 3.05 (m, IH), 2.30 (m, IH), 1.25 (dd, 6H), 0.92 (m, 15H), 0.07 (d, 6H)

Example 4: Preparation of (S^^^-S-flf^l-l'-Z-butyldimethylsilyloxylethyl]^- [(/?)-l"-carboxyethyl]-2-azetidinone (6)

LiOHZH₂O₂

The compound (5) prepared in Example 3 (95g) was dissolved in acetone (350ml) and water (200ml). Hydrogen peroxide (50ml) was added thereto, and the mixture was stirred at 0^°C . Lithium hydroxide dihydrate (2Og) was dissolved in water (150ml), which was then added over a 30 min. time period. The reaction solution was stirred for 1 h, water (500ml) and methylene chloride (500ml) were added, and the phases were separated. The organic phase was distilled to produce the compound of formula (2) (2Og). The aqueous phase was adjusted to pH 2.5 using 6 N hydrochloric acid to produce a crystal. This crystal was filtered to produce the title compound having β/α ratio of 99.5/0.5 (37g, Yield 70% that was calculated from the 4- A A compound).

[4-BMA]

¹H NMR (300MHz, CDCl₃) δ 6.5 (br s, IH), 4.3 (m, IH), 3.97 (dd, IH), 3.05 (ddm, IH), 2.85 (m, IH), 1.29 (d, 3H), 1.22 (d, 3H), 0.89 (s, 9H), 0.08 (s, 6H)

[the corresponding α-isomer to 4-BMA]

¹H NMR (300MHz, CDCl₃) δ 6.5 (br s, IH), 4.2 (m, IH), 3.72 (dd, IH), 2.85 (ddm, IH), 2.65 (m, IH), 1.3 (d, 3H), 1.23 (d, 3H), 0.90 (s, 9H), 0.08 (s, 6H)

INDUSTRIAL APPLICABILITY

According to the processes of the present invention, the compound of formula (6), particularly, (5i?,¥5)-3-[[[R]-l'-t-butyldimethylsilyloxy]ethyl]-4-[(/?)-l"-carboxyethyl]-2- azetidinone (4-BMA), which is a key intermediate for the synthesis of carbapenem and penem antibiotics, can be prepared in high yield and high selectivity under industrially mild conditions.

Claims

1. A process for preparing a compound of formula (6):

in which R represents hydrogen or a hydroxy-protecting group, which comprises the steps of coupling a chiral auxiliary of formula (3):

with an azetidinone compound of formula (4):

in which R is as defined above, that is obtained from the coupling reaction.

2. The process of claim 1 wherein the organic base is selected from triethylamine (TEA), diisopropylethylamine (DIPEA), diethylamine (DEA) and butylamine.

3. The process of claim 1 wherein the solvent is selected from methylene chloride, dichloroethane and chloroform.

4. The process of claim 1 wherein the hydroxy-protecting group is an organic silyl group that is selected from the group consisting of t-butyldimethylsilyl, t-butyldiphenylsilyl, triethylsilyl and trimethylsilyl.

5. The process of claim 1 wherein the hydrolysis is carried out in the presence of hydrogen peroxide and lithium hydroxide.

6. A process for preparing the compound of formula (3):

which comprises the steps of reacting the compound of formula (1):

H₂N OH

(1) in the presence of a base and diethylcarbonate to produce the compound of formula (2):

7. The process of claim 6 wherein the Lewis acid used in the step of preparing the compound of formula (3) from the compound of formula (2) is selected from lithium chloride (LiCl), aluminum chloride (AlCl₄), aluminum bromide (AlBr₄), iron tetrachloride (FeCl₄), zinc bromide (ZnBr₂), zinc chloride (ZnCl₂), trifluoroborane (BF₃) and magnesium bromide (MgBr₂).

8. The process of claim 6 wherein the organic base used in the step of preparing the compound of formula (3) from the compound of formula (2) is selected from triethylamine (TEA), diisopropylethylamine (DIPEA), t-butylamine and diethylamine (DEA).

9. The process of claim 6 wherein the solvent used in the step of preparing the compound of formula (3) from the compound of formula (2) is selected from tetrahydrofuran (THF), dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMAc) and acetonitrile (AN).

0. The process of claim 1 wherein the compound of formula (3) that is prepared by the process of claim 6 is used.