CN101891665A - (3S,4S)-4-acetyl-3-((R)-1-hydroxyethyl)-2-azetidinone and its preparation method - Google Patents

Abstract

The invention provides (3S, 4S)-4-acetyl-3-((R)-1-hydroxyethyl)-2-azetidinone and a preparation method thereof. The present invention also provides its intermediate (2R, 3R)-N-benzhydryl-N-(2-oxopropyl) epoxybutyramide (I) and (3S, 4S)-1-benzidine Base-3-((R)-1-hydroxyethyl)-4-acetyl-2-azetidinone (II) and its preparation method. The method of the invention has the advantages of cheap and easy-to-obtain raw materials, high yield, simple operation, environmental friendliness and easy realization of large-scale production.

Description

(3S, 4S)-4-acetyl-3-((R)-1-hydroxyethyl)-2-azetidinone and its preparation method

technical field

The invention relates to the field of medicinal chemistry, in particular to the compound (3S, 4S)-4-acetyl-3-((R)-1-hydroxyethyl)-2-azetidinone and a preparation method thereof. Involving its intermediates (2R, 3R)-N-benzhydryl-N-(2-oxopropyl) epoxybutanamide and (3S, 4S)-1-benzhydryl-3-((R )-1-hydroxyethyl)-4-acetyl-2-azetidinone and its preparation method.

Background technique

Penem and carbapenem antibiotics are atypical β-lactam antibiotics developed in the 1970s. It has strong antibacterial effect and is stable to β-lactamase. It occupies an important position in the current clinical anti-infection treatment, especially in the treatment of infections caused by drug-resistant bacteria.

(3R, 4R)-3-((R)-1-tert-butyldimethylsiloxyethyl)-4-acetoxy-2-azetidinone (4-AA for short) is the preparation of Penicillium The key intermediate of alkene and carbapenem antibiotics, its structural formula is as shown in formula (VI):

There are many reports on the synthesis of 4-AA, J Chem Soc Chem Com, 1992, 662-664; J OrgChem, 1992, 57: 4232-4237; Chem Pharm Bull 1992, 40: 1094-1097; Tetrahedron Lett, 1982, 23: 2293 -2296；Tetrahedron Lett，1986，27：4961-4964；Tetrahedron Lett，1988，29：1409-1412；Tetrahedron Lett，1998，39：7779-7782；WO9807691；EP0774463；EP167154；JP5239019；JP4173776；JP4173795；JP2134349都The preparation method of 4-AA was reported.

The 4-AA molecule contains three chiral centers, which is difficult to synthesize. How to introduce three chiral centers and stereoselectively form the β-lactam ring is the key to the synthesis.

The natural chiral source L-threonine is used as the starting material to introduce two chiral centers, and then the third chiral center is constructed in the subsequent reaction. This method has been reported as follows:

J Am Chem Soc, 1985, 1438-1439

This route needs to pass through the unstable 2,3-epoxybutyric acid intermediate, and the stereoselectivity of forming the β-lactam ring is not high, and the deprotection needs to use cerium ammonium nitrate which is harmful to the environment, and the obtained benzoyloxy The compound also needs to be reacted with potassium acetate to give 4-AA.

(2) Tetrahedron, 1984, 1795-1802

This route avoids the unstable 2,3-epoxybutyric acid intermediate, but the condensation to form the amide compound uses more expensive DCC, and the yield of the β-lactam ring is low. The highly toxic substance dimethyl cadmium is also used in the route.

(3) Eur J Org Chem, 2006, 3755-3766

Compared with methods (1) and (2), method (3) has easy-to-obtain raw materials and is easy to operate, but has the following problems: 1. The starting material needs to use methyl cyclopropyl ketone, which is not easily available in the market. 2. Due to the high water solubility of the deprotected product, it is soluble in water together with p-toluenesulfonic acid and is not easy to separate. 3. The obtained cyclopropylformyl compound must be transformed with acetate to obtain 4-AA.

Contents of the invention

In order to improve the synthetic technique of (3R, 4R)-3-((R)-1-tert-butyldimethylsiloxyethyl)-4-acetoxy-2-azetidinone, taking into account cost and In order to improve the reaction yield under the condition of safe operation, the present invention is proposed.

According to the first aspect of the present invention, it provides a compound of formula (III) [(3S,4S)-4-acetyl-3-((R)-1-hydroxyethyl)-2 having the following structural formula -azetidinone]:

Formula (III) compound can be used as synthetic (3R, 4R)-3-((R)-1-tert-butyldimethylsiloxyethyl)-4-acetoxyl group-2-azetidinone ( 4-AA) intermediates. The synthetic route is as follows:

According to the technical scheme of the present invention, the above-mentioned (III) compound is prepared by using the following two compounds as key intermediates:

A compound [(2R, 3R)-N-benzhydryl-N-(2-oxopropyl) epoxybutyramide] with the following structural formula (I):

as well as,

A compound of formula (II) having the following structural formula [(3S,4S)-1-benzhydryl-3-((R)-1-hydroxyethyl)-4-acetyl-2-azetidinone] :

The above-mentioned compound of formula (I) and compound of formula (II) are key intermediates for preparing the compound of formula (III).

According to a second aspect of the present invention, it also provides a method for preparing the above-mentioned compound of formula (III), which comprises the following steps:

a) The formula (IV) compound (2R, 3R)-2,3-epoxybutyric acid sodium with the following structural formula is activated by acid chloride, and a base is added in an organic solvent to neutralize the formula (V) compound 1-benzhydryl Amino-2-propanone is condensed to obtain a compound of formula (I);

b) ring-closing the compound of formula (I) in an organic solvent under the catalysis of a base to obtain the compound of formula (II);

(I) (II)

c) removing the benzhydryl protecting group from the compound of formula (II) in an organic solvent under the action of a halogenating agent and silica gel or protonic acid to obtain the compound of formula (III).

Wherein in step a) the present invention slowly adds the activating reagent dropwise into the suspension composed of sodium epoxybutyrate (IV) and a suitable solvent, converts it into epoxybutyryl chloride and then adds alkali and compound (V) to react to generate formula (I ) compound. Suitable activating reagents are acid chlorides selected from one or more of the following: acetyl chloride, thionyl chloride, oxalyl chloride, pivaloyl chloride, isobutyl chloroformate, 2,4,6-trichlorobenzoyl chloride. Suitable bases are selected from one or more of the following: dimethylamine, diethylamine, diisopropylamine, N-methylaniline, piperidine, pyrrole, pyridine, morpholine, diisopropylethylamine, triethylamine Amine, N,N-dimethylaniline, N-ethylpiperidine, N-methylmorpholine, N-ethylpyrrolidine, N,N,N'N'-tetramethylethylenediamine. Suitable solvents are selected from one or more of the following: halogenated hydrocarbons, alkanes, esters, diethyl ether, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, benzene, toluene, xylene, acetonitrile. Wherein, the amount of compound (V) is 1 to 2 times that of compound (IV), and the amount of activating reagent is 1 to 2 times that of compound (IV), and the added base acts as an acid-binding agent to react with the hydrogen chloride produced in the reaction to promote reaction conversion. The amount of base used is 1 to 5 times that of compound (IV). The reaction temperature is -50°C to 40°C, preferably -20 to 25°C.

Wherein step b) in the present invention, the compound of formula (I) is ring-closed in an organic solvent under the catalysis of a base to obtain the compound of formula (II), and the suitable base is selected from one or more of the following substances: lithium hexamethyldisilazide , Sodium Hexamethyldisilazide, Lithium Diisopropylamide. Suitable solvents are selected from one or more of the following: halogenated hydrocarbons, alkanes, esters, tetrahydrofuran, diethyl ether, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, benzene, toluene, xylene, acetonitrile. Among them, the compound (I) generates an enol formula under the action of a base and then attacks the carbon on the epoxy, and the ring is closed to generate the compound (II). The amount of base used is 1 to 2 times that of the compound of formula (I). The reaction temperature is -20°C to 40°C, preferably -20°C to 25°C.

Wherein step c) the present invention dissolves the compound of formula (II) in a suitable organic solvent, generates a halide under the action of a halogenating agent, then reacts with water and converts it into a hydroxyl compound, and deprotects it under the action of silica gel or protonic acid group to obtain the compound of formula (III). Suitable halogenating agents are selected from one or more of the following: N-chlorosuccinimide, N-bromosuccinimide. N-bromosuccinimide is preferred. Suitable solvents are selected from one or more of the following: aliphatic ketones, aromatic ketones, alkanes, haloalkanes, acetonitrile, tetrahydrofuran, diethyl ether, isopropyl ether, methyl tert-butyl ether, benzene, toluene, xylene, and the like. Protic acid is inorganic acid, organic acid, for example, it can be selected from one or more of the following acids: hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, acetic acid, formic acid and the like. The amount of the halogenating agent is 1-2 times that of the compound of formula (II), and the amount of silica gel or protonic acid is 1-5 times that of the compound of formula (II). The reaction temperature is 0°C to 100°C, preferably 20 to 80°C.

In summary, the starting materials of the present invention can be synthesized from cheap and easy-to-obtain L-threonine and chloroacetone. When removing the benzhydryl protecting group, instead of using acids such as PTSA, silica gel is used, and the reaction is mild. The treatment is simple and the product is easy to purify. And in the end, 4-AA can be directly obtained without reacting with acetate, and the route is concise.

Detailed ways

The present invention will be further described below in conjunction with examples, but these examples do not constitute any limitation to the present invention.

Embodiment 1: the preparation of (2R, 3R)-N-benzhydryl-N-(2-oxopropyl) epoxybutanamide (formula (I) compound)

In a 250 mL four-neck round bottom flask equipped with a magnetic stirrer and a thermometer, add 7.9 g of sodium (2R,3R)-2,3-epoxybutyrate and 100 mL of tetrahydrofuran. After cooling to -15°C, add 3.7 mL of oxalyl chloride dropwise, stir at this temperature for 2 hours, add 5.3 mL of anhydrous pyridine, 6.4 g of 1-benzhydrylamino-2-propanone, stir for 1 hour and then rise to Stirring was continued at room temperature for 2 hours, 100 mL of ethyl acetate was added, washed with 5% sodium bicarbonate solution, the organic phase was washed with brine after liquid separation, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated, and the compound (I) was obtained by silica gel column chromatography 7.2 g, yield 85.6%.

MS: 324.2 (M+H);

¹ HNMR: (400MHz, CDCl ₃ ) 1.18(3H, m), 2.13(3H, s), 2.93(1H, m), 3.47(1H, m), 4.38(1H, s), 6.16(1H, s) , 7.10-7.33 (10H, m).

Embodiment 2: the preparation of (2R, 3R)-N-benzhydryl-N-(2-oxopropyl) epoxybutyramide (formula (I) compound)

In a 250 mL four-necked round bottom flask equipped with a magnetic stirrer and a thermometer, 7.9 g of sodium (2R,3R)-2,3-epoxybutyrate and 100 mL of dichloromethane were added. After cooling to -20°C, add 4.9 g of thionyl chloride dropwise, stir at this temperature for 2 hours, add 10.5 g of triethylamine, 6.4 g of 1-benzhydrylamino-2-propanone, and stir for 1 hour Heat up to reflux reaction for 2 hours, add 100mL ethyl acetate, wash with 5% sodium bicarbonate solution, wash the organic phase with brine after liquid separation, dry over anhydrous magnesium sulfate, evaporate the solvent after filtration, and obtain compound (I )7.2g, yield 82.0%.

MS: 324.2 (M+H);

¹ HNMR: (400MHz, CDCl ₃ ) 1.18(3H, m), 2.13(3H, s), 2.93(1H, m), 3.47(1H, m), 4.38(1H, s), 6.16(1H, s) , 7.10-7.33 (10H, m).

Example 3: (3S, 4S)-1-benzhydryl-3-((R)-1-hydroxyethyl)-4-acetyl-2-azetidinone (compound of formula (II)) preparation of

In a 500 mL four-necked round bottom flask equipped with a magnetic stirrer and a thermometer, 7.0 g of the compound of formula (I) and 250 mL of dichloromethane were added. After cooling to -20°C, add LDA (1mol/L) 26.4mL dropwise, heat up to reflux for 3 hours after the dropwise addition, add 1N HCl 30mL, ethyl acetate 150mL, and use 5% sodium bicarbonate solution for the organic phase after liquid separation Washing, washing with brine, drying over anhydrous magnesium sulfate, filtering and distilling off the solvent, silica gel column chromatography to obtain compound (II) 5.4g, yield 77.4%.

MS: 324.2(M+H), 346(M+Na)

¹ HNMR: (400MHz, CDCl ₃ ) 1.28(3H, m), 1.80(3H, s), 2.96(1H, m), 4.24(1H, m), 4.56(1H, s), 5.90(1H, s) , 7.25-7.33 (10H, m)

Example 4: (3S, 4S)-1-benzhydryl-3-((R)-1-hydroxyethyl)-4-acetyl-2-azetidinone (compound of formula (II)) preparation of

In a 500 mL four-neck round bottom flask equipped with a magnetic stirrer and a thermometer, add 7.0 g of the compound of formula (I) and 250 mL of tetrahydrofuran. After cooling to -15°C, add LiHMDS (1mol/L) 26.4mL dropwise, rise to room temperature and react for 3 hours after the dropwise addition, add 1N HCl30mL, ethyl acetate 150mL, and wash the organic phase with 5% sodium bicarbonate solution after liquid separation , washed with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated to remove the solvent. Silica gel column chromatography gave 5.6 g of compound (II), with a yield of 80.3%.

MS: 324.2(M+H), 346(M+Na)

¹ HNMR: (400MHz, CDCl ₃ ) 1.28(3H, m), 1.80(3H, s), 2.96(1H, m), 4.24(1H, m), 4.56(1H, s), 5.90(1H, s) , 7.25-7.33 (10H, m)

Example 5: Preparation of (3S, 4S)-4-acetyl-3-((R)-1-hydroxyethyl)-2-azetidinone (compound of formula (III))

In a 500 mL four-neck round bottom flask equipped with a magnetic stirrer and a thermometer, add 5.0 g of the compound of formula (II), 4.1 g of chlorosuccinimide, 150 mL of dichloromethane, and 100 mL of water. Stir the reaction at room temperature overnight, wash the organic phase with 5% sodium bisulfite, add 10.0 g of p-toluenesulfonic acid, react at room temperature for 12 hours, evaporate the solvent after the reaction, add 200 mL of cold water, and concentrate the obtained filtrate under reduced pressure to obtain The crude product was subjected to silica gel column chromatography to obtain 1.9 g of compound (III), with a yield of 78.2%.

MS: 158(M+H)

¹ H-NMR: (400MHz, CDCl ₃ ) 1.23(3H, s), 1.77(3H, m), 3.18(1H, m), 3.65(1H, m), 4.22(1H, s), 4.30(1H, m), 4.81 (1H, s).

Example 6: Preparation of (3S, 4S)-4-acetyl-3-((R)-1-hydroxyethyl)-2-azetidinone (compound of formula (III))

In a 500 mL four-neck round bottom flask equipped with a magnetic stirrer and a thermometer, add 5.0 g of the compound of formula (II), 3.0 g of bromosuccinimide, 150 mL of dichloromethane, and 100 mL of water. Stir the reaction under light at room temperature overnight, wash the organic phase with 5% sodium bisulfite, evaporate dichloromethane, add 100mL tetrahydrofuran, add 10.0g silica gel, reflux reaction for 12 hours, filter to remove silica gel after the reaction, wash the silica gel with a small amount of methanol After combining the filtrates, the tetrahydrofuran was distilled off, 200 mL of water was added, washed with toluene (3×100 mL), separated, and the aqueous phase was concentrated under reduced pressure to obtain 2.1 g of compound (III), with a yield of 86.4%.

MS: 158(M+H)

¹ H-NMR: (400MHz, CDCl ₃ ) 1.23(3H, s), 1.77(3H, m), 3.18(1H, m), 3.65(1H, m), 4.22(1H, s), 4.30(1H, m), 4.81 (1H, s).

Example 7: Preparation of (3S, 4R)-3-((R)-1-hydroxyethyl)-4-acetoxy-2-azetidinone (compound of formula (VII))

In a 500 mL four-necked flask equipped with a magnetic stirrer and a thermometer, add 4.4 g of the compound of formula (III), 12.0 g of m-chloroperoxybenzoic acid, and 200 mL of dichloromethane. Stir at room temperature overnight, add 5% sodium bisulfite solution to wash after the reaction, wash with brine, dry over anhydrous magnesium sulfate, filter and distill off the solvent by silica gel column chromatography to obtain 4.2 g of compound (VII), with a yield of 87.5%.

MS: 196(M+Na), 214(M+Na+ _H2O ), 228(M+Na+ _CH3OH )

Example 8: (3R, 4R)-3-((R)-1-tert-butyldimethylsiloxyethyl)-4-acetoxy-2-azetidinone (4-AA) preparation

(c＝1.0，CHCl₃)。In a 500 mL four-neck flask equipped with a magnetic stirrer and a thermometer, add 4.2 g of the compound of formula (VII), 15.8 g of tert-butyldimethylchlorosilane, 21.6 g of imidazole, and 200 mL of DMF. Stir overnight at room temperature. After the reaction, 200 mL of ethyl acetate was added, washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated to remove the solvent by silica gel column chromatography to obtain 6.4 g of compound (VII), yield 91.8%, mp 106-108 °C,

(c=1.0, _CHCl3 ).

ESI-MS(m/z): 310(M+H+Na), 342(M+H+Na+ _CH3OH )

¹ H-NMR (CDCl ₃ ) δ: 0.07 (6H, s), 0.87 (9H, s), 1.26 (3H, m), 2.10 (3H, s), 3.18 (1H, m), 4.22 (1H, m ), 5.84(1H, m), 6.47(1H, s)

Claims (17)

1. (3S,4S)-4-acetyl-3-((R)-1-hydroxyethyl)-2-azetidinone, the structural formula of which is shown in formula (III).

2. an intermediate compound for synthesizing (3S, 4S)-4-acetyl-3-((R)-1-hydroxyethyl)-2-azetidinone described in claim 1, its The structural formula is shown in formula (I).

3. an intermediate compound for synthesizing (3S, 4S)-4-acetyl-3-((R)-1-hydroxyethyl)-2-azetidinone according to claim 1, its The structural formula is shown in formula (II).

4. A method for preparing a compound of formula (III) according to claim 1, comprising the steps of: a) adding a base to the compounds represented by formula (IV) and formula (V) under the activation of acid chloride, and condensing in an organic solvent to obtain the compound of formula (I);

b) ring-closing the compound of formula (I) in an organic solvent under the catalysis of a base to obtain the compound of formula (II); c) removing the benzhydryl protecting group from the compound of formula (II) in an organic solvent under the action of a halogenating agent, water, silica gel or protonic acid to obtain the compound of formula (III). 5. The method of claim 4, wherein, The acid chloride used in step a) is selected from one or more of the following substances: acetyl chloride, thionyl chloride, oxalyl chloride, pivaloyl chloride, isobutyl chloroformate, 2,4,6-trichlorobenzoyl chloride; The base is selected from one or more of the following substances: DBU, dimethylamine, diethylamine, diisopropylamine, N-methylaniline, piperidine, pyrrole, pyridine, morpholine, diisopropylethylamine , triethylamine, N,N-dimethylaniline, N-ethylpiperidine, N-methylmorpholine, N-ethylpyrrolidine, N,N,N'N'-tetramethylethylenediamine ; The solvent is selected from one or more of the following substances: halogenated hydrocarbons, alkanes, esters, diethyl ether, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, benzene, toluene, xylene, and acetonitrile. 6. The method according to claim 5, characterized in that, in the step a), the amount of compound (V) is 1 to 2 times that of compound (IV), and the amount of acid chloride used is 1 times that of compound (IV). ～2 times, the consumption of base is 1～5 times of compound (IV). 7. The method according to claim 5, characterized in that, the reaction temperature adopted in the step a) is -50°C to 40°C. 8. The method according to claim 7, characterized in that, the reaction temperature adopted in the step a) is -20-25°C. 9. The method according to claim 4 or 5, characterized in that, in step b), The base is selected from one or more of the following substances: lithium hexamethyldisilazide, sodium hexamethyldisilazide, lithium diisopropylamide; The solvent is selected from one or more of the following substances: halogenated hydrocarbons, alkanes, tetrahydrofuran, diethyl ether, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, benzene, toluene, xylene, and acetonitrile. 10. The method according to claim 9, characterized in that the amount of alkali used in the step b) is 1 to 2 times that of compound (I). 11. The method according to claim 9, characterized in that, the reaction temperature adopted in the step b) is -20°C to 40°C. 12. The method according to claim 11, characterized in that, the reaction temperature adopted in the step b) is -20-25°C. 13. The method according to claim 4 or 5, characterized in that, in step c), The halogenating agent is selected from one or more of the following substances: N-chlorosuccinimide, N-bromosuccinimide; The solvent is selected from one or more of the following substances: aliphatic ketones, aromatic ketones, alkanes, haloalkanes, acetonitrile, tetrahydrofuran, ether, isopropyl ether, methyl tert-butyl ether, benzene, toluene, xylene; The reaction uses silica gel or protic acid for deprotection The protonic acid is an inorganic or organic acid capable of donating protons, which is selected from one or more of the following acids: hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, acetic acid, formic acid. 14. The method according to claim 13, wherein the halogenating agent is N-bromosuccinimide. 15. The method according to claim 4 or 5, characterized in that, in step c), the amount of the halogenating agent used is 1 to 2 times that of the compound of formula (II), and the amount of silica gel or protonic acid is the amount of formula (II) ) compound 1 to 5 times. 16. The method according to claim 4 or 5, characterized in that, in step c), the reaction temperature used is 0°C-100°C. 17. The method according to claim 16, characterized in that, in step c), the reaction temperature used is 20-80°C.