CN101376642A - Carbapenem penicillin ertapenem intermediate, and preparation and use thereof - Google Patents

Abstract

The invention discloses an intermediate shown in formula IV for synthesizing carbapenem penicillin ertapenem; and a preparation method thereof: in a non-polar solvent, the compound shown in formula III is mixed with PNZ L- The activated ester of hydroxyproline can be condensed, wherein PNZ L-hydroxyproline is shown in formula IX; and its application in the preparation of carbapenem penicillin ertapenem. Among them, PMB is (see figure (1)); PNZ is (see figure (2)). The compound of the present invention can produce the side chain of ertapenem, and then produce ertapenem. The reaction conditions of each step in this route are mild, can be carried out at room temperature, the cost is low, and it is easy to apply to industrial production. The preparation method of the intermediate of the present invention is easy to operate, simple in experimental conditions, does not need expensive reagents, has high yield and is environmentally friendly.

Description

Intermediate of carbapenem penicillin ertapenem and its preparation method and application

technical field

The invention belongs to the field of organic compound synthesis, and in particular relates to an intermediate of the carbapenem penicillin ertapenem, a preparation method and application thereof.

Background technique

Ertapenem (ertapenem, MK-0826, L-749, 345, trade name Invanz) is a new type of broad-spectrum carbapenem antibiotic developed by Merck Pharmaceutical Company of the United States. Stability, excellent pharmacokinetic parameters, good clinical therapeutic effect, good tolerance, few adverse reactions and long half-life can be administered once a day. It is clinically used to treat infections caused by moderately to severely sensitive bacteria in adults. Satisfactory curative effect can be obtained for acquired mixed infection. This product was first launched in the United States in November 2001, and then successively launched in the United Kingdom, Ireland, Israel and the Philippines.

US5478820 reports a synthetic method of ertapenem. The method has a long synthetic route, low yield, high price of some reagents, multi-step reaction requires column chromatography separation, and is not suitable for industrial production.

At present, in the synthetic method of ertapenem used in industrial production, the side chain synthesis part adopts "one-pot method". Related patents are US5872250 and US6180783. The reaction of this method needs to be carried out at a low temperature of -20°C, the industrial production conditions are relatively harsh, and the equipment requirements are high; and some reagents used are relatively expensive, such as diethylpropylethylamine and diphenylphosphoryl chloride.

Contents of the invention

The technical problem to be solved by the present invention is to overcome that the synthesis method of ertapenem in the prior art is not easy to be applied to industrial production, and the industrial method needs to be carried out at a low temperature of -20°C, the conditions are relatively harsh, and the equipment requirements are relatively high. To solve the problem of higher cost, a new intermediate compound and its preparation method and application are provided. The preparation of ertapenem from the intermediate compound has mild reaction conditions, can be carried out at room temperature, has lower cost, and is easy to apply to industrial production.

The intermediate of the present invention is shown in formula IV:

Formula IV

PNZ为

Among them, PMB is

PNZ is

The present invention also relates to a preparation method of the intermediate compound, which includes the following steps: in a non-polar solvent, the compound shown in formula III is condensed with the activated ester of PNZ L-hydroxyproline; wherein, PNZ L-hydroxyproline is shown in formula IX;

Formula III Formula IX

Among them, PMB is PNZ is

Wherein, the molar ratio of the compound shown in formula III and the activated ester of PNZ L-hydroxyproline is preferably less than or equal to 2 (excluding the situation where the molar ratio is 0), more preferably 1.01 ~1.1; the temperature of the reaction is preferably -10-0°C, more preferably -5-0°C; the time of the reaction is preferably 2-5 hours, more preferably 4 hours . The consumption of non-polar solvent can be 2 times of reactant molar weight.

Wherein, the activated ester of PNZ L-hydroxyproline can be prepared by the following method: in a non-polar solvent, under the action of an organic base, PNZ L-hydroxyproline (such as the compound shown in formula IX ) react with chloroformate; wherein, PNZ L-hydroxyproline is as shown in formula IX. Described organic base is preferably triethylamine, diisopropylethylamine or pyridine, more preferably triethylamine; The consumption of described organic base can be 1.5 of the molar weight of PNZL-hydroxyproline -3 times; described chloroformate is preferably methyl chloroformate, ethyl chloroformate, n-butyl chloroformate or isobutyl chloroformate; the consumption of described PNZ L-hydroxyproline is more Preferably, it is 1.5-3 times the molar amount of chloroformate; the reaction time can be 1-3 hours, preferably 2 hours; the reaction temperature can be -10°C-25°C, preferably 0°C.

Wherein, described compound shown in formula III can be prepared by following method:

(1) In an aprotic organic solvent, under the catalysis of an organic base reagent, react the compound shown in formula I with 4-methoxybenzyl chloride.

Formula I

Wherein, the molar ratio of the compound represented by formula I to 4-methoxybenzyl chloride is preferably 1:1.5 to 1:3, more preferably 1:1.5 to 1:2, and most preferably It is 1.8-1.9; Described aprotic organic solvent is preferably toluene, methylene dichloride, ethyl acetate, tetrahydrofuran, ether or isopropyl ether, more preferably dichlorotoluene; The consumption of aprotic organic solvent It can be twice the dissolved amount; the organic base reagent is preferably triethylamine, diisopropylethylamine or pyridine, more preferably triethylamine; the amount of the organic base reagent is preferably as 1.5-2 times the molar weight of the compound shown in formula I; the temperature of the reaction is preferably 40-60°C, more preferably 40-45°C, and most preferably 45°C; the temperature of the reaction The time is preferably 1 to 10 hours, more preferably 3 to 7 hours, most preferably 4 to 5 hours. After the reaction, it can be extracted with CH ₂ Cl ₂ and water, and the CH ₂ Cl ₂ layers can be combined, dried, filtered, and concentrated to obtain a solid product, which can be further purified by recrystallization.

(2) In an alcoholic solvent, the compound shown in formula II is heated and reacted under the action of stannous chloride dihydrate, and then the pH is adjusted to alkalinity with an inorganic base to obtain the compound shown in formula III compound of.

Formula II

Among them, PMB is

Wherein, the amount of the stannous chloride dihydrate is preferably 4 to 6 times the molar amount of the compound shown in formula II; the alcohol solvent is preferably methanol, ethanol, n-propanol or Virahol; The consumption of alcoholic solvent can be twice of reactant molar weight; The temperature of described reaction is preferably 40-75 ℃, more preferably 50-55 ℃; The time of described reaction is shorter It is preferably 30-60 minutes, more preferably 30-45 minutes; the inorganic base is preferably sodium hydroxide or potassium hydroxide, and the specific operation can make the inorganic base into a concentration of about 8-15% by mass The aqueous solution or alcohol solution is used; the said alkaline is preferably pH ≥ 9, more preferably pH = 10-11. After adjusting the reaction system to be alkaline, it can be extracted with ether and water, and the ether layers are combined, dried, filtered, and concentrated to obtain a solid product.

The present invention also relates to the application of the intermediate of the present invention in the preparation of the carbapenem penicillin ertapenem. The intermediate (formula III) of the present invention can be synthesized by the following route to prepare the ertapenem side chain:

Formula II Formula III

Formula IV Formula V

Formula VI

Formula VII

PNZ为

Ms为甲磺酰基；Among them, PMB is

PNZ is

Ms is methylsulfonyl;

Ac is acetyl; Et is ethyl; iBu is isobutyl.

Ertapenem can be further synthesized by the following route:

The reagents and raw materials used in the present invention are all commercially available.

The positive progress effect of the present invention is that: the intermediate of the present invention can produce the side chain of ertapenem, and then ertapenem can be produced. The reaction conditions of each step in this route are mild, can be carried out at room temperature, the cost is low, and it is easy to apply to industrial production. The preparation method of the intermediate of the present invention is easy to operate, simple in experimental conditions, does not need expensive reagents, has high yield and is environmentally friendly.

Detailed ways

The present invention is further illustrated below by means of examples, but the present invention is not limited to the scope of the examples.

Reference Examples Preparation of formula III compound

Formula I compound (26.5g, 157.9mmol) in CH ₂ Cl ₂ 350ml, add NEt ₃ (32g, 316.1mmol), dropwise add 4-methoxybenzyl chloride (PMBCl) (44.4g, 283.6mmol) at room temperature , heated up to 45°C, and reacted for 3 hours. Extracted with CH ₂ Cl ₂ and water, combined CH ₂ Cl ₂ layers were dried with anhydrous NaSO ₄ , filtered, and the filtrate was concentrated to give a light yellow solid (Formula II) (41.5 g, yield 91.5%, purity >99%).

The compound represented by formula II (40.93g, 142.47mmol) was dissolved in SnCl _{2 ·} 2H ₂ O (161.0g, 712.37mmol) in 300ml of ethanol, the temperature was raised to 50°C, and the reaction was carried out until all solids were dissolved. Adjust the pH to 11 with 15% NaOH alcohol solution, extract with ether and water, combine the ether layers, dry over anhydrous NaSO ₄ , filter, and concentrate the filtrate to give a light yellow solid (Formula III) (33.84 g, 92.3%).

Example 1 (2S, 4R)-4-hydroxyl-1-(4-nitrobenzyloxycarbonyl)-2-[3-(4-methoxybenzyl)phenylcarbamoyl]pyrrolidine (formula IV )Synthesis

PNZ L-hydroxyproline (5.00g, 16.12mmol) in CH ₂ Cl ₂ 80ml, add NEt ₃ (2.45g, 24.17mmol), and add ClCOOCH ₃ (3.30g, 24.17mmol) dropwise at -8°C-10°C , reacted for 1 h to obtain the activated ester of PNZL-hydroxyproline (6.61 g, 16.10 mmol). The compound represented by formula III (8.29 g, 32.24 mmol) was added in one portion, and the reaction was continued for 2 h. Wash successively with 1N HCl, saturated NaClaq and saturated NaHCO ₃ aq, combine CH ₂ Cl ₂ layers for use, dry over anhydrous NaSO ₄ , filter, and concentrate the filtrate to obtain 8.23 g of white powdery solid (Formula IV), with a yield of 92.9%. Melting point: 180-182°C.

NMR (CDCl ₃ ) δ: 2.01 (m, 2H); 2.33 (s, 1H); 3.34 (m, 1H); 3.56 (m, 2H) 3.74 (s, 3H); 4.40 (m, 1H); s, 2H); 5.51(s, 2H); 6.70(m, 2H); 7.10(m, 2H), 7.28(m, 1H); 7.44(m, 2H); 7.68(m, 1H); 7.90(m , 1H); 8.00(s, 1H); 8.05(m, 2H); 8.40(s, 1H)

MS (CI): 549

Example 2 (2S, 4R)-4-hydroxyl-1-(4-nitrobenzyloxycarbonyl)-2-[3-(4-methoxybenzyl)phenylcarbamoyl]pyrrolidine (formula IV )Synthesis

PNZ L-hydroxyproline (17.91g, 57.72mmol) in CH ₂ Cl ₂ 120ml, add diisopropylethylamine (8.19g, 63.49mmol), add ClCOOi-Bu ( 7.96g, 58.30mmol), and reacted for 4h to obtain the activated ester of PNZ L-hydroxyproline (23.66g, 57.70mmol). The compound represented by formula III (125.00 g, 58.30 mmol) was added at one time, and the reaction was continued for 2 h. Wash with 1N Hclaq, saturated NaClaq and saturated NaHCO ₃ aq successively, combine the CH ₂ Cl ₂ layers for use, dry over anhydrous NaSO ₄ , filter, and concentrate the filtrate to obtain a white powdery solid (Formula IV) (26.7, 94.2%). Melting point: 175-178°C.

Example 3 (2S, 4R)-4-hydroxyl-1-(4-nitrobenzyloxycarbonyl)-2-[3-(4-methoxybenzyl)phenylcarbamoyl]pyrrolidine (formula IV )Synthesis

PNZ L-hydroxyproline (17.91g, 57.72mmol) in CH ₂ Cl ₂ 120ml, add pyridine (5.02g, 63.49mmol), add ClCOOn-Bu (7.96g, 58.30mmol) dropwise at 0°C- -5°C , and reacted for 1 h to obtain the activated ester of PNZL-hydroxyproline (23.67 g, 57.71 mmol). The compound represented by formula III (125.00 g, 58.30 mmol) was added in one portion, and the reaction was continued for 5 h. Wash with 1N Hclaq, saturated NaClaq and saturated NaHCO ₃ aq successively, combine the CH ₂ Cl ₂ layers for use, dry over anhydrous NaSO ₄ , filter, and concentrate the filtrate to obtain a white powdery solid (Formula IV) (29.52 g, 93.5%). Melting point: 175-178°C.

Example 4 (2S, 4R)-4-hydroxyl-1-(4-nitrobenzyloxycarbonyl)-2-[3-(4-methoxybenzyl)phenylcarbamoyl]pyrrolidine (formula IV )Synthesis

PNZ L-hydroxyproline (17.91g, 57.72mmol) in CH ₂ Cl ₂ 120ml, add NEt ₃ (6.43g, 63.49mmol), add ClCOOCH ₂ CH ₃ (6.33g, 58.30 mmol), reacted for 1 h to obtain the activated ester of PNZ L-hydroxyproline (21.74 g, 53 mmol). The compound represented by formula III (125.00 g, 58.30 mmol) was added at one time, and the reaction was continued for 3.5 h. Wash successively with 1N Hclaq, saturated NaClaq and saturated NaHCO ₃ aq, combine the CH ₂ Cl ₂ layers for use, dry over anhydrous NaSO ₄ , filter, and concentrate the filtrate to obtain a white powdery solid (Formula IV) (30.33 g, 95.7%). Melting point: 175-178°C.

Application Examples [4R, 5S, 6S]-3-[[(3S, 5S)-5-[[(S-carboxytoluene)amino]carbonyl]-3-pyrrolidinyl]thio]-6-[( 1R)-1-Hydroxyethyl]-4-methyl-7-oxo-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid monosodium salt (ertapenem monosodium salt) preparation of

Formula I compound (26.5g, 157.9mmol) in CH ₂ Cl ₂ 350ml, add NEt ₃ (32g, 316.1mmol), dropwise add 4-methoxybenzyl chloride (PMBCl) (44.4g, 283.6mmol) at room temperature , heated up to 45°C, and reacted for 3 hours. Extracted with CH ₂ Cl ₂ and water, combined CH ₂ Cl ₂ layers were dried with anhydrous NaSO ₄ , filtered, and the filtrate was concentrated to give a light yellow solid (Formula II) (41.5 g, yield 91.5%, purity >99%).

The compound represented by formula II (40.93g, 142.47mmol) was dissolved in SnCl _{2 ·} 2H ₂ O (161.0g, 712.37mmol) in 300ml of ethanol, the temperature was raised to 50°C, and the reaction was carried out until all solids were dissolved. Adjust the pH to 11 with 15% NaOH alcohol solution, extract with ether and water, combine the ether layers, dry over anhydrous NaSO ₄ , filter, and concentrate the filtrate to give a light yellow solid (Formula III) (33.84 g, 92.3%).

PNZ L-hydroxyproline (17.91g, 57.72mmol) in CH ₂ Cl ₂ 120ml, add NEt ₃ (6.43g, 63.49mmol), add ClCOOi-Bu (7.96g, 58.30mmol) dropwise at 0°C - -5°C ), reacted for 4h, and obtained the activated ester of PNZ L-hydroxyproline (23.66g, 57.70mmol). The compound represented by formula III (125.00 g, 58.30 mmol) was added at one time, and the reaction was continued for 2 h. Wash with 1N Hclaq, saturated NaClaq and saturated NaHCO ₃ aq successively, combine the CH ₂ Cl ₂ layers for use, dry over anhydrous NaSO ₄ , filter, and concentrate the filtrate to obtain a white powdery solid (Formula IV) (26.7, 94.2%).

Formula IV compound (24.00g, 43.68mmol) in CH ₂ Cl ₂ 220ml, add NEt ₃ (6.63g, 65.51mmol), add MsCl (10.01g, 87.36mmol) dropwise at 0℃～-2℃, react for 2h . Extract with CH ₂ Cl ₂ and water, combine CH ₂ Cl ₂ layers for use, and concentrate to obtain off-white crystals (Formula V) (25.8 g, yield 94%, purity >95%).

Add AcSK (11.45 g, 100.35 mmol) to compound of formula V (25 g, 40.14 mmol) in DMF 90 ml and ethyl acetate 75 ml, heat to 50° C., and react for 9 h. Extract with ethyl acetate and water, combine the ethyl acetate layers, concentrate, and wash the brown semi-solid with methanol to obtain the product (formula VI) (22 g, yield 91%).

The compound of formula VI (3.00 g, 4.94 mmol) was dissolved in 15 ml of dichloromethane, 0.4 g of concentrated sulfuric acid was added, the pH of the solution was 1.0, and the reaction was carried out at room temperature for 10 minutes. Add water to crystallize, and filter to obtain an off-white solid (Formula VII) (2.30 g, yield 82%).

(4R, 5S, 6S, 8R)-3-[(diphenoxyphosloyl)oxy-6-(1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo[3.2. 0]-hept-2-ene-2-carboxylic acid (4-nitrophenyl)methyl ester (0.595g, 1mmol) (commercially available) was dissolved in NMP+DMF10ml (v/v=3:1), Add (2S,4R)-1-(4-nitrobenzyloxycarbonyl)-2-(3-(4-methoxybenzyl)carbamoyl)pyrrolidine-4-thiol ( Formula VII) (0.565g, 1mmol) in NMP+DMF10ml (v/v=3:1) solution, cooled to -40°C, 10 minutes later quickly added DIPEA (0.38ml, 2.2mmol), reacted for 4 hours.

Add 20ml of deionized water treated with ultrasound and nitrogen bubbling into the hydrogenation reaction kettle, add anhydrous sodium bicarbonate (84mg, 1mmol), 10%Pd/C (0.29g, 0.2mmol), pour into the appeal The reaction solution was incubated at 20 atm for 5 hours.

Pd/C was removed by filtration, and the filtrate was treated with activated carbon in an ice-water bath and under the protection of nitrogen, and then extracted twice with cold ethyl acetate and isoamyl alcohol to obtain a solution. After filtration, the filtrate was concentrated, filtered, the solid was washed with ethanol and methyl acetate, and dried to obtain ertapenem monosodium salt (0.33 g, 66%).

Melting point: 262-263°C

1H NMR (CDCl ₃ ) δ: 1.17(d, 3H); 1.27(d, 3H); 2.20(m, 1H); 3.00(m, 1H); 3.31(m, 1H); 3.45(m, 2H); 3.80 (dd, 1H); 4.05(m, 1H); 4.20(m, 2H); 4.60(t, 1H); 7.47(t, 1H); 7.65(d, 1H); 7.71(d, 1H); 7.86( s, 1H)

MS (ESI): 476.0 (M+1), 498.1 (M+Na).

Claims (11)

1. The intermediate shown in formula IV for the synthesis of carbapenem penicillin ertapenem;

Formula IV Among them, PMB is

PNZ is

2. the preparation method of the intermediate shown in formula IV as claimed in claim 1, is characterized in that comprising the steps: in nonpolar solvent, with the compound shown in formula III and PNZ L-hydroxyproline Condensation reaction of the activated ester; Wherein, PNZ L-hydroxyproline is as shown in formula IX;

Formula III Formula IX Among them, PMB is

PNZ is

3. The method according to claim 2, characterized in that: the molar ratio of the compound shown in formula III to the activated ester of PNZL-hydroxyproline is less than or equal to 2. 4. The method according to claim 3, characterized in that: the molar ratio of the compound shown in formula III to the activated ester of PNZL-hydroxyproline is 1.01-1.1. 5. The method according to claim 2, characterized in that: the temperature of the reaction is -10-0°C. 6. The method according to claim 5, characterized in that: the temperature of the reaction is -5-0°C. 7. The method according to claim 2, characterized in that: the reaction time is 2-5 hours. 8. The method according to claim 2, characterized in that: the activated ester of the PNZ L-hydroxyproline is obtained by the following method: in a non-polar solvent, under the action of an organic base, the PNZ L -Hydroxyproline reacts with chloroformate; Wherein, PNZ L-hydroxyproline is as shown in formula IX. 9. The method according to claim 8, characterized in that: the organic base is triethylamine, diisopropylethylamine or pyridine. 10. The method according to claim 8, characterized in that: the chloroformate is methyl chloroformate, ethyl chloroformate, n-butyl chloroformate or isobutyl chloroformate. 11. The application of the intermediate shown in formula IV as claimed in claim 1 in the preparation of carbapenem penicillin ertapenem.