KR20000074884A - Process for the preparation of azetidinone derivatives - Google Patents

Abstract

PURPOSE: A preparation method of a (3R)-3-£(R)-1-(tert-butyldimethylsilyloxy)-ethyl|-2-azetidinone is provided. Thereby, (3R)-3-£(R)-1-(tert-butyldimethylsilyloxy)-ethyl|-2-azetidinone that is an intermediate used in synthesis of carbapenem antibiotics is produced economically in high yield by stereoselective method. CONSTITUTION: A preparation for an azetidinone derivative represented by the formula (I) comprises the following steps of: (a) reacting the compound, methyl (R)-3-hydroxy butyrate, of the formula (II) with a halomethylbenzylether to prepare dianion under the existence of additives and bases and stereoselectively alkylating the dianion, to produce an ester compound of the formula (III); (b) adding a silylation agent and a reductant to the ester compound, to produce a 1st alcohol of the formula (V), and then reacting a diphenylphosphoazide therewith, to produce an azide compound of the formula (VI); (c) reacting the azide compound with catalyst and an amine-protecting group, to produce aminoalcohol compound of the formula (VII) and then reacting oxidant therewith, to produce an amino acid compound of the formula (VIII); and (d) eliminating the amine-protecting group, and then performing lactamization, to produce a lactame ring.

Description

Process for the preparation of azetidinone derivatives

The present invention relates to (3R) -3-[(R) -1- (tert-butyldimethylsilyloxy) -ethyl] -2 represented by the following structural formula (I) which is the most widely used intermediate in the synthesis of carbapenem antibiotics: It relates to a stereoselective synthesis of -azetidinone {(3R) -3-[(R) -1- (tert-butyldimethylsilyloxy) -ethyl] -2-azetidinone}.

Wherein R is a tert-butyldimethylsilyl group.

As a method of synthesizing an azetidinone derivative represented by the above formula (I), a method using cycloaddition, a method using asymmetric aldol reaction, hydrogenation using Ru-BINAP catalyst And Yuki Gouseikgaku Kyokai Shi 1989, 47, 606-618 and Tetrahedron 1996, 52, 331-375.

However, the method of using cycloaddition has a problem in that stereoisomers are generated as by-products, and the method of using asymmetric aldol reaction or catalytic hydrogenation has a problem of using expensive asymmetric aids or catalysts.

In order to solve the problems of the prior art as described above, the inventors of the present invention provide a convenient and convenient solution without the use of expensive asymmetric aids or catalysts through stereoselective alkylation reactions using diions. We have developed a technique that can be adjusted accurately.

That is, an object of the present invention is to develop a technique for mass-producing a safe, economical and high yield of the compound of formula (I) from methyl (R) -3-hydroxy butyrate It is done.

The present invention is formed by reacting two molecules of lithium diisopropylamine (LDA) from methyl (R) -3-hydroxy butyrate of formula (II) Compounds of the following structural formula (III) were prepared by stereoselective alkylation of a double anion, followed by protecting the alcohol group with a silyl group to prepare the compound of the following structural formula (IV), and reducing the ester to alcohol to reduce the following formula ( Prepare the primary alcohol of V). The primary alcohol is converted to azide of the following structural formula (VI) through a substitution reaction and then reduced by catalytic hydrogenation using palladium. The prepared primary alcohol is prepared by preparing an amino acid of the following structural formula (산화) through an oxidation reaction and then deprotecting the protecting group of the amine to perform lactamization to prepare an azetidinone compound of the following structural formula (I). It relates to the method (Scheme 1).

Scheme 1.

Each step is described in more detail as follows.

The compound of formula (III) is prepared by carrying out the α-alkylation reaction using halomethylbenzylether (BOMCl or BOMBr) to the compound of formula (II). Preference is given to carrying out the α-alkylation reaction using a base and an additive. As the additive, hexamethylphosphoramide (HMPA), which is frequently used as an additive in the alkylation reaction of enolate, is preferably used, and diisopropylamine is preferably used as a base. .

As the reaction conditions, tetrahydrofuran (THF) was used as a solvent, 1.4 equivalents of halomethylbenzyl ether and 1.8 equivalents of HMPA were used, and the amount of lithium diisopropylamine (LDA) was 1.7, 2.0, 2.2, 2.4. The reaction yield and stereoselectivity were investigated as the equivalent weight increased (Table 1). Reaction yield analysis was performed using HPLC, and the diastereomeric ratio (d.r) was determined using GC. The results showed that the overall reaction yield improved significantly when using HMPA as an additive. As a result of examining the reaction pattern according to the equivalent amount of the used base, the reaction yield gradually increased as the amount of the base was increased, indicating that only a very small amount of starting material remained when using 2.4 equivalents of the base. However, when the diastereomeric ratio using GC was examined, the use of 1.7 and 2.0 equivalent bases showed very good stereoselectivity of 25: 1 or more, but the amount of base used was excessive. In some cases, the selectivity gradually decreased, and the use of 2.4 equivalents resulted in a significant increase in the amount of syn form products at a ratio of 4: 1.

Table 1. α-alkylation of methyl (R) -3-hydroxy butyrate

LDA (equivalent) Conversion (%) Reaction yield (%) d.r. (anti: syn) 1.7 68 60> 25: 12.0 76 70> 25: 12.2 82 75 12: 12.4 84 78 4: 1

Here, the conversion rate is expressed as a percentage (%) by measuring the amount before and after the reaction with respect to the structural formula (II) as a reactant.

As a result, it was found that HMPA significantly increased the reactivity of alkylation, and the reaction yield improved as the amount of base used increased, but the diastereoselectivity decreased when the excess base was used. Could know.

Based on the above results, beta-hydroxy ester (III) having a benzyloxymethyl group substituted at the α-position by stereoselectively alkylating methyl (R) -3-hydroxy butyrate under conditions optimized using HMPA The secondary alcohol formed was protected with silyl group in 90% yield using tert-butyldimethylsilylchloride or triisopropyl chloride and imidazole on dimethylformamide (DMF), and then ester ) Diisobutyl aluminum hydride (DIBAL-H, 1.5 M toluene solution) as a reducing agent to give the alcohol (V) in 86% yield. At this time, even when the reaction was carried out at -10 ℃ instead of -78 ℃ could obtain the same results without side reactions.

To convert compound (V) to β-amino acid, a precursor for lactamization, it is necessary to convert primary alcohols to amines. The most common method used is to replace alcohols with leaving groups and then to aza via nucleoatesis. How to introduce id. Thus, compound (V) was mesylated using pyridine with methanesulfonyl chloride or p-toluenesulfonyl chloride, etc.) and then at 60 ° C. with sodium azide on DMF. The reaction was carried out for 48 hours to obtain azide in 75% yield. However, this method has a disadvantage in that the reaction time is very long when introducing azide and the explosive azide compound is heated to 60 ° C. or higher. Therefore, Mitsunobu conditions are used and the azide reagent is preferably used. As azide, diphenylphosphoazide (DPPA), which shows solubility in an organic solvent, was used to introduce azide in high yield when reacted at tetrahydrofuran for 2 hours at room temperature.

The obtained azide (VI) was subjected to catalytic hydrogenation in order to reduce to amine and to deprotect the benzyl group, which is an alcohol protecting group, to obtain amine-protected amino alcohol (VII) in a yield of 82.4%. In the reduction reaction, Pd / C or the like is used as the catalyst, and palladium hydroxide is more preferably used. In addition, the reduced amine was protected with a conventional amine protecting group in the reactor. In particular, a tert-butyloxycarbonyl (BOC) group is preferable as the amine protecting group. The alcohol thus obtained was oxidized to an amino acid compound using NaIO ₄ and a catalytic amount of RuCl ₃ .

In order to perform the lactamization of the amine-protected amino acid, the BOC of the amine was removed using trifluoroacetic acid (TFA), but when the solvent was not used, the alcohol protecting group TBDMS was also removed. Therefore, to prevent this, BFA was removed using TFA diluted to 20% with dichloromethane (MC), and then concentrated, and lactamation reaction was attempted without any purification. Amide formation reaction was attempted in the synthesis of beta-lactam under a variety of conditions, but triphenylphosphine-dipyridyldisulfide-acetonitrile (Ph ₃ P- (PyS) ₂ -used by Ohno et al. In 1981. Since the CH ₃ CN) condition is widely used as the best reaction, the acid remaining by the deprotection reaction performed above was neutralized with triethylamine, and then lactamization was performed using this method. Stirred at 60 ° C. for 12 hours to synthesize azetidinone compound (I) in a yield of 81%.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, the present invention is not limited thereto.

Example 1 Preparation of (2R, 3R) -methyl 2-[(benzyloxy) methyl] -3-hydroxy-butyrate

28 ml (0.20 mol) of diisopropylamine was added to 455 ml of THF, cooled to 0 ° C., and 131.3 ml (0.21 mol) of n-BuLi (1.6 M hexane solution) was added dropwise. After stirring for 1 hour, cooled to -78 ℃ and 11.812g (0.1mol) methyl (R) -3-hydroxybutyrate dissolved in 228ml of THF was slowly added dropwise and stirred for 30 minutes. 18.6 ml (0.14 mol) of benzyloxymethyl chloride dissolved in 32 ml (1.84 mol) of hexamethylphosphoamide (HMPA) was added dropwise and stirred at -78 ° C for 2.5 hours. 200 ml of saturated NH ₄ Cl aqueous solution was added, the organic layer was separated and the water layer was extracted with ether (100 ml × 3 times). The combined organic layers were washed with brine, dried over MgSO ₄ , concentrated under reduced pressure and separated by column (development). Solvent: EtOAc / n-Hexane, 1: 1) afforded 16.7 g of colorless oil benzyl ether (III). (70%)

R _f = 0.38 (EtoAc / n-Hexane, 1: 1)

¹ H NMR (CDCl ₃ , 300 MHz) δ 1.22 (d, 3H, CH ₃ C, J = 6.5 Hz), 2.75 (q, 1H, CHC = O, J = 6 Hz), 2.81 (br s, 1H, OH) , 3.74 (s, 3H, CH ₃ OC = O), 3.76 (abx, 1H, HCHO, J = 9.4, 6.0 Hz), 3.77 (abx, 1H, HCHO, J = 9.4, 6.0 Hz), 4.13 (dq, 1H, CHOSi, J = 6.0, 6.5 Hz), 4.51 (ab, 1H, HCHPh, J = 11.6 Hz), 4.52 (ab, 1H, CHCPh, J = 11.6 Hz), 7.25-7.4 (m, 5H, PhH)

[α] ²⁵ _D -7.935 ° (c 1.01, CHCl ₃ )

Example 2 Preparation of Methyl (2R, 3R) -2-[(benzyloxy) methyl] -3- (tert-butyldimethylsilyloxy) butyrate

Dissolve 15 g (62.95 mmol) of benzyl ether (III) in 100 ml of N, N-dimethylformamide (N, N-DMF), and 11.4 g (75.54 mmol) of tert-butylchlorodimethylsilane. 5.14 g (75.54 mmol) of dazol was added and stirred for 5 hours. After completion of the reaction, the reaction solution was diluted with a mixture of 400 ml of ether and 100 ml of 10% -HCl, and then the organic layer was separated and washed with 100 ml of H ₂ O and 100 ml of saturated NaHCO ₃ . The organic layer was dried over MgSO ₄ , concentrated under reduced pressure, and separated by column (developing solvent: Hexane / EtOAc, 15: 1) to give 18.5 g (83.4%) of a colorless transparent oily silyl ether (IV). .

R _f = 0.5 (Hexane / EtOAc, 10: 1)

¹ H NMR (CDCl ₃ , 300 MHz) δ 0.0 (s, 6H, (CH ₃ ) ₂ Si), 0.82 (s, 9H, (CH ₃ ) ₃ C), 1.12 (d, 3H, CH ₃ , J = 6Hz ), 2.7-2.8 (m, 1H, CHC), 3.6-3.7 (m, 2H, CH ₂ O), 3.74 (s, 3H, CH ₃ O), 4.03 (dq, 1H, CHOSi, J = 6.6 Hz) , 4.43 (s, 2H, CH ₂ Ph), 7.24 (s, 5H, PhH)

[α] ²⁵ _D -8.899 ° (c 1.03, CHCl ₃ )

Example 3 Preparation of (2R, 3R) -2-[(benzyloxy) methyl] -3- (tert-butyldimethylsilyloxy) butanol

12.68 g (36 mmol) of silyl ether (IV) was dissolved in 120 ml of ether, cooled to -78 ° C, and 52.8 ml (79.2 mmol) of DIBAL (1.5 M in Toluene) was added dropwise and stirred for 1 hour. 2.4 ml of methanol was added after completion of the reaction, and the temperature was raised to room temperature. The reaction solution was dissolved in 150 ml of saturated potassium sodium tartrate aqueous solution and stirred for 1 hour. The organic layer was separated and the water layer was extracted with ether (50ml × 2 times). The combined organic layers were washed with brine, dried over MgSO ₄ , concentrated under reduced pressure, and separated by column (developing solvent: Hexane / EtOAc, 6: 1). 10 g of colorless transparent oily alcohol (V) was obtained. (85.7%)

R _f = 0.25 (Hexane / EtOAc, 10: 1)

¹ H NMR (CDCl ₃ , 500 MHz) δ 0.08 (d, 6H, (CH ₃ ) ₂ Si), 0.88 (s, 9H, (CH ₃ ) ₃ C), 1.23 (d, 3H, CH ₃ C, J = 6.5 Hz), 1.71 to 1.74 (m, 1H, CHC), 3.63 (q, 1H, CH ₂ OBn, J = 6.5, 9 Hz), 3.69 (q, 1H, CH ₂ OBn, J = 6.5, 9.5 Hz), 3.74 (q, 1H, CH ₂ OH, J = 4, 11.5 Hz), 4.0 (q, 1H, CH ₂ OH, J = 4, 11 Hz), 4.15 to 4.20 (dq, 1H, CHOSi, J = 6.5 Hz, 3.5 Hz), 4.49 to 4.55 (q, 2H, CH ₂ Ph), 7.27 to 7.37 (m, 5H, PhH)

¹³ C NMR (CDCl ₃ , 125 MHz) δ-4.45, -3.66, 18.55, 22.68, 26.47, 47.50, 62.93, 69.76, 71.29, 74.15, 128.38, 128.45, 129.12, 138.86

IR (neat) 3453, 2955, 2930, 2891, 2857, 1468, 1366, 1254 cm ^-1

[α] ²⁸ _D -8.271 ° (c 0.7133, CHCl ₃ )

MS (EI) 325 (M ⁺ )

Example 4 Preparation of (2R, 3R) -2-[(benzyloxy) methyl] -3- (tert-butyldimethylsilyloxy) butane azide

Dissolve 1 g (3.1 mmol) of alcohol (V) in 10 ml of tetrahydrofuran, add 1.62 g (6.2 mmol) of triphenylphosphine and 0.97 ml (6.2 mmol) of diethylazodicarboxylate. Then 1.33 ml (6.2 mmol) diphenylphosphoazide was slowly added dropwise and stirred at room temperature for 2 hours. After completion of the reaction, 20 ml of water was added thereto, diluted, and extracted with ether (20 ml × 2). The combined organic layers were washed with brine, dried over MgSO ₄ , concentrated under reduced pressure, separated by column (developing solvent: Hexane / EtOAc, 10: 1) to obtain 1.02 g of azide (VI) as a colorless transparent oily product. (94.7%)

R _f = 0.6 (Hexane / EtOAc, 6: 1)

¹ H NMR (CDCl ₃ , 500 MHz) δ 0.04 (d, 6H, (CH ₃ ) ₂ Si), 0.88 (s, 9H, (CH ₃ ) ₃ C), 1.23 (d, 3H, CH ₃ C, J = 6.5 Hz), 1.18 (m, 1H, CHC), 3.38 (q, 1H, CH ₂ N ₃ , J = 7.1, 12.2 Hz), 3.45 (q, 1H, CH ₂ OBn, J = 6.0, 9.1 Hz), 3.51 (q, 1H, CH ₂ N ₃ , J = 7.1, 4.8 Hz), 3.53 (q, 1H, CH ₂ OBn, J = 5.1, 9.1 Hz), 3.98 (m, 1H, CHOSi), 4.46 to 4.53 ( q, 2H, CH ₂ Ph), 7.26 to 7.37 (m, 5H, PhH)

¹³ C NMR (CDCl ₃ , 125 MHz) δ-4.32, -3.53, 18.69, 22.23, 26.52, 47.27, 50.27, 67.25, 69.07, 73.97, 128.35, 128.40, 129.09, 138.91

IR (neat) 2956, 2931, 2893, 2858, 2099, 1458 cm ^-1

MS (EI) 350 (M ⁺ )

Example 5 Preparation of (2S, 3R) -2- [tert-butylcarbamoylmethyl] -3- (tert-butyldimethyl-silyloxy) butanol

0.89 g (2.55 mmol) of azide (VI) was dissolved in 10 ml of ethyl acetate, 100 mg of palladium hydroxide, and 0.834 g of di-tert-butoxycarbamate were added, followed by 1 Stir at room temperature under hydrogen at atmospheric pressure for 24 hours. After completion of the reaction, the reaction solution was filtered over celite, concentrated and separated by column (developing solvent: Hexane / EtOAc, 6: 1) to 0.7 g white N-Boc-protected alcohol (상의). Got. (82.4%)

R _f = 0.15 (Hexane / EtOAc, 6: 1)

¹ H NMR (CDCl ₃ , 500 MHz) δ 0.07 (d, 6H, (CH ₃ ) ₂ Si), 0.88 (s, 9H, (CH ₃ ) ₃ C), 1.2 (d, 3H, CH ₃ C, J = 6 Hz), 1.44 (s, 9H, O (CH ₃ ) ₃ ), 1.63 (m, 1H, CHC), 3.22 (dt, 1H), 3.30 (br, 1H), 3.49 (m, 1H), 3.62 (m , 2H), 3.96 (m, 1H, CHOSi), 5.02 (br, 1H, NH)

¹³ C NMR (CDCl ₃ , 125 MHz) δ-4.38, -3.54, 18.59, 22.40, 26.53, 29.05, 37.95, 48.45, 62.26, 69.86, 80.21, 158.10

IR (neat) 3410, 2956, 2931, 2891, 2859, 1695, 1511, 1470, 1391, 1367 cm ^-1

MS (EI) 334 (M ⁺ )

Example 6 Preparation of (2S, 3R) -2- [tert-butylcarbamoylmethyl] -3- (tert-butyldimethyl silyloxy) butanoic acid

540 mg of amino alcohol (VII) was dissolved in a mixed solvent of CH ₃ CN-CCl ₄ -H ₂ O (4 ml: 4 ml: 6 ml), 1.42 g (6.64 mmol) of sodium periodate (NaIO ₄ ) and ruthenium chloride (Rucl) ₃ ) 7.4 mg (2.2 mol%) was added, followed by reaction for 4 hours with vigorous stirring. After completion of the reaction, 10 ml of dichloromethane was added, diluted, and the water layer was separated and concentrated. Diethyl ether was added thereto, and the insoluble precipitate was filtered off over celite, concentrated again and separated by column (developing solvent: Hexane / EtOAc, 1: 1) to give 480 mg of white powdery amino acid (VIII). Got it. (85.3%)

R _f = 0.35 (Hexane / EtOAc, 1: 1)

¹ H NMR (CDCl ₃ , 500 MHz) rotamer δ 0.01, 0.11 (d, 6H, (CH ₃ ) ₂ Si), 0.90 (s, 9H, (CH ₃ ) ₃ C), 1.22 (d, 3H, CH ₃ C , J = 6.5 Hz), 1.43 (s, 9H, O (CH ₃ ) ₃ ), 2.64, 2.69 (br, 1H, CHCO), 3.23, 3.25 (br, 1H, CH ₂ N), 3.45, 3.50 (br , 1H, CH ₂ N), 4.13, 4.25 (br, 1H, CHOSi), 5.22, 6.23 (br, 1H, NH)

¹³ C NMR (CDCl ₃ , 125 MHz) δ-4.51, -3.87, 18.53, 21.08, 26.34, 29.07, 38.83, 52.80, 69.29, 80.16, 158.68, 175.63

IR (KBr) 3319, 3273, 2979, 2956, 2932, 2859, 1725, 1699, 1653, 1475, 1409, 1366 cm ^-1

MS (EI) 349 (M ⁺ )

Example 7 Preparation of (3R, 4S) -3-[(R) -1-((tert-butyl-dimethylsilyloxy) -ethyl] -2-azetidinone

300 mg (0.863 mmol) of amino acid (VIII) was dissolved in 2 ml of dichloromethane, and 0.5 ml of trifluoro acetic acid was added at 0 ° C., followed by stirring for 20 minutes. After completion of the reaction, the reaction solution was concentrated and dissolved in 17.3 ml of acetonitrile, 0.12 ml of triethylamine was added and stirred for 5 minutes. Then, 272 mg (1.036 mmol) of triphenyl phosphine and 22.82 mg (1.036 mmol) of 2-aldrithiol were added thereto, stirred at 60 ° C. for 12 hours, 10 ml of water was added thereto, and ethyl acetate (15 ml) was added. 2 ×). The combined organic layers were washed with brine, dried over MgSO ₄ , concentrated under reduced pressure, and separated by column (developing solvent: Hexane / EtOAc, 2: 1) to obtain 160 mg (81%) of azetidinone (I) as white crystals.

R _f = 0.25 (Hexane / EtOAc, 2: 1)

¹ H NMR (CDCl ₃ , 500 MHz) δ 0.08 (d, 6H, (CH ₃ ) ₂ Si), 0.88 (s, 9H, (CH ₃ ) ₃ C), 1.19 (d, 3H, CH ₃ C, J = 6.24 Hz), 3.23 (qt, 1H, CHCO), 3.29 (t, 1H, CH ₂ N, J = 5.1 Hz), 3.35 (q, 1H, CH ₂ N, J = 5.1, 2.55 Hz), 4.21 (m , 1H, CHOSi, J = 6.24, 4.54 Hz), 5.76 (br s, 1H, NH)

¹³ C NMR (CDCl ₃ , 125 MHz) δ -4.31, -3.56, 18.66, 22.25, 26.42, 38.34, 60.03, 65.96, 170.20

IR (neat) 3189, 2959, 2929, 2894, 2857, 1746, 1469, 1370 cm ^-1

[α] ²⁷ _D −74.2 ° (c 0.7, CHCl ₃ )

When the compound of formula I is prepared according to the method of the present invention, it is possible to prepare the compound of formula I in a high yield of 30% or more from the starting material methyl (R) -3-hydroxy butyrate. Selective alkylation using the steric structure facilitated efficient control of the two stereochemistry present in compound I. In particular, the problems of reaction yield and stereoselectivity in the α-hydroxymethylation of β-hydroxy ester were significantly improved by using HMPA as an additive.

Claims (4)

Preparing a ester compound of formula (III) by stereoselectively alkylating the compound of formula (II) with halomethylbenzylether in the presence of an additive and a base; Preparing an azide compound of formula (VI) by adding a silylating agent and a reducing agent to the ester compound to prepare a primary alcohol, and then reacting diphenylphosphoazide (DPPA); Reacting an azide compound with a catalyst and an amine protecting group to produce an aminoalcohol compound of formula (VII), and then reacting an oxidant to prepare an amino acid compound of formula (VIII), Removing the amine protecting group of the amino acid compound, and then performing a cyclization reaction to prepare a lactam ring finally a method for producing an azetidinone compound of formula (I) Wherein R is a tert-butyldimethylsilyl group. The method for producing an azetidinone compound according to claim 1, wherein the base is lithium diisopropylamine. The method for producing an azetidinone compound according to claim 1, wherein the additive is diphenylphophoazide. The method for producing an azetidinone compound according to claim 1, wherein the catalyst is palladium hydroxide.