Synthesis method of cefdil intermediate I

Abstract

The invention relates to the technical field of synthesis of drug intermediates, in particular to a synthesis method of a cefdil intermediate I. The preparation method comprises the following steps: adding (Z)-(2-amino-4-thiazolyl)-2-(t-butyloxycarboryl isopropoxyimino) thiobenzothiazole acetate and 7-amino-3-chloromethyl-3-cefazoline-4-carboxylic acid p-methoxybenzyl hydrochloride into an organic solvent, and reacting under the action of an alkaline reagent, so as to obtain the cefdil intermediate I. According to the method, isopropanol or tert-butyl alcohol is used as a reaction solvent, N, N-diisopropylethylamine is used as an alkaline reagent, and the low-temperature reaction is controlled, so that the yield of the ceftidil intermediate I is increased and reaches up to 82% or above, and meanwhile, the product purity is obviously improved; column chromatography purification is not needed in post-treatment, operation is simple, and the method is suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical intermediate synthesis, and in particular to a method for synthesizing a cefiderocol intermediate I. Background Art

[0002] Cefiderocol, developed by the Japanese pharmaceutical company Shionogi and marketed under the brand name Fetroja, has been approved for marketing by the U.S. FDA and the European Medicines Agency (EMA). The U.S. Food and Drug Administration (FDA) has approved the drug for the treatment of complicated urinary tract infections and hospital-acquired pneumonia. Cefiderocol is a novel injectable siderophore cephalosporin developed specifically for the treatment of multidrug-resistant (MDRO) infections. It exhibits broad-spectrum in vitro antibacterial activity against Gram-negative bacteria, including multidrug-resistant pathogens. Its structural formula is as follows: .

[0003] Cefiderocol intermediate I is a key intermediate in the synthesis of Cefiderocol, and its structure is as follows: .

[0004] Patent WO2016035847A1 discloses the following synthesis process: starting with 7-amino-3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester hydrochloride (ACLE•HCl), the 7-side chain is activated to methanesulfonic anhydride, which is then coupled with the starting material. The 1-sulfoxide S-isomer of the cephem nucleus of the coupled intermediate is then oxidized and introduced into the 3-side chain. Deprotection and purification are then performed using sulfuric acid and anisole. Crystallization is then performed by adding refined sulfuric acid and p-toluenesulfonic acid to obtain a hydrate crystal of a mixed salt of p-toluenesulfonic acid and sulfuric acid of the target compound. The synthetic route is as follows: .

[0005] Patent WO2016035847A1 uses (Z)-(2-(tert-butyloxycarbonyl)-substituted aminothiazol-4-yl)-2-(tert-butyloxycarbonyl)isopropoxyiminoacetic acid (Boc-AT in the above formula) as the starting material, which is condensed with ACLE•HCl to produce the amino-Boc-protected intermediate I (Boc-Intermediate I in the above formula). The reaction process involves first activating the carboxylic acid group of Boc-AT with the toxic reagent methanesulfonyl chloride, followed by condensation with ACLE•HCl. If the amino group in Boc-AT is not protected, the following side reactions will occur. Therefore, the purpose of pre-protecting the amino group in Boc-AT with Boc is to prevent the amino group from reacting with methanesulfonyl chloride and to prevent the amino group on the thiazole ring of (Z)-(2-aminothiazol-4-yl)-2-(tert-butyloxycarbonyl)isopropoxyiminoacetic acid (AT-TBA, also known as cephalosporin) from reacting with the methylene chloride in ACLE•HCl.

[0006] .

[0007] Patent WO2016035847A1 prepares intermediate I. AT-TBA first uses Boc to protect the amino group and then uses methanesulfonyl chloride to activate the carboxyl group. This synthesis method not only increases the reaction steps, but also has a low yield of Boc-intermediate I prepared by condensation reaction with GCLE.

[0008] T.G.C. Bird, J.C.A. Mould et al. reported in J. Med. Chem. 1992, 35, 2643-2651 a method for synthesizing cefiderocol intermediate I: TAEM and ACLE (1:1 molar ratio) were stirred in dichloromethane for 1 hour, followed by distillation of the solvent. The distillation residue was then passed through a silica gel column with dichloromethane / ethyl acetate (4:1 volume ratio). The yield of cefiderocol intermediate I obtained by this method was 69%. However, this method produced a high level of impurities, requiring column chromatography purification, resulting in a low yield and hindering industrial production.

[0009] In "Modification and Synthesis Design of Cefiderocol," Xu Jingjing reported using (Z)-(tert-aminothiazol-4-yl)-2-(tert-butyloxycarbonyl)isopropoxyiminoacetic acid (AT-BTA in the above formula) as the starting material. The carboxyl group was activated with methylsulfonyl chloride, followed by reaction with ACLE in N-methylmorpholine, extraction, drying, concentration, and column chromatography to obtain intermediate I in a yield of 71.7%. This method is complex, has difficult impurity control, requires column chromatography purification, and has low yields, making it unsuitable for industrial production. The synthetic route is as follows: . Summary of the Invention

[0010] The present invention aims to provide a method for synthesizing a cefiderocol intermediate I. The method uses (Z)-(2-amino-4-thiazolyl)-2-(tert-butoxycarbonylisopropyloxyimino)acetic acid thiobenzothiazolyl ester (TAEM) and 7-amino-3-chloromethyl-3-cephazoline-4-carboxylic acid p-methoxybenzyl hydrochloride (ACLE•HCl) as starting materials, uses isopropanol or tert-butanol as a reaction solvent, and controls the reaction at a low temperature to obtain the cefiderocol intermediate I. The yield of the cefiderocol intermediate I is improved, the synthesis route is shortened, and industrial production is easily realized.

[0011] The technical solution adopted by the present invention to solve the technical problem is: The synthesis method of the cefiderocol intermediate I comprises adding (Z)-(2-amino-4-thiazolyl)-2-(tert-butyloxycarbonylisopropyloxyimino)acetic acid thiobenzothiazolyl ester and 7-amino-3-chloromethyl-3-cephazoline-4-carboxylic acid p-methoxybenzyl hydrochloride to an organic solvent, and reacting under the action of an alkaline reagent to obtain the cefiderocol intermediate I.

[0012] in: The organic solvent is isopropyl alcohol or tert-butanol, preferably tert-butanol; the alkaline reagent is N,N-diisopropylethylamine.

[0013] The ratio of the organic solvent to 7-amino-3-chloromethyl-3-cephazoline-4-carboxylic acid p-methoxybenzyl hydrochloride is 8-10:1, wherein the organic solvent is measured in mL and the 7-amino-3-chloromethyl-3-cephazoline-4-carboxylic acid p-methoxybenzyl hydrochloride is measured in g.

[0014] The molar ratio of the alkaline reagent to 7-amino-3-chloromethyl-3-cephazoline-4-carboxylic acid p-methoxybenzyl hydrochloride is 2.0-2.5:1, preferably 2.3:1.

[0015] The molar ratio of 7-amino-3-chloromethyl-3-cephazoline-4-carboxylic acid p-methoxybenzyl hydrochloride to (Z)-(2-amino-4-thiazolyl)-2-(tert-butoxycarbonylisopropyloxyimino)acetic acid thiobenzothiazolyl ester is 1:1.05-1.1, preferably 1:1.05.

[0016] The reaction temperature is -10 to -2°C, preferably -5 to -2°C; the reaction time is 4 to 6 hours.

[0017] Preferably, the synthesis method of the cefiderocol intermediate I of the present invention comprises: adding TAEM and ACLE•HCl to an organic solvent, first cooling the mixture, and then adding an alkaline reagent to react; after the reaction is completed, adjusting the pH value, filtering, crystallizing, and drying to obtain the cefiderocol intermediate I.

[0018] Cool down to -10~0℃.

[0019] After the reaction is completed, the pH value is adjusted to 5.0-6.0 with hydrochloric acid at 0-10°C.

[0020] The synthetic route of the present invention is as follows: .

[0021] The beneficial effects of the present invention are as follows: The present invention uses TAEM as a starting material, and conducts a condensation reaction with ACLE•HCl to obtain cefiderocol intermediate I. The present invention adopts the active thioester method to introduce an amide bond. Active thioesters are an important type of intermediate in organic synthesis. The active thioester method is used to carry out the aminoacylation reaction. Since -SR is a good leaving group, the reaction conditions are mild, the yield is high, and production conversion is easy to achieve. The amino group in TAEM is no longer protected, and it is directly reacted with ACLE•HCl to prepare cefiderocol intermediate I. The reaction selectivity is good, the protection and deprotection process of the amino group in the active ester of the side chain acid is omitted, and the reaction steps are reduced. In addition, the starting material TAEM is also an active ester of the side chain acid of ceftazidime, which is widely available and cheaply available on the market, providing convenient conditions for the implementation of this route and helping to reduce the production cost of this route.

[0022] The present invention uses isopropyl alcohol or tert-butyl alcohol as a reaction solvent, ensuring that the by-product benzo[D]thiazole-2-thiol does not dissolve in the reaction system, avoiding a side reaction between the methylene chloride group in ACLE•HCl and the by-product benzo[D]thiazole-2-thiol, thereby improving the yield of the cefiderocol intermediate I. At the same time, the present invention strictly controls the reaction temperature between -10 and -2°C. When the reaction temperature is lower than -10°C, the reaction is significantly slowed down, affecting production efficiency. When the reaction temperature is higher than -2°C, the solubility of the by-product benzo[D]thiazole-2-thiol in the system increases, which will promote a nucleophilic substitution side reaction between the benzo[D]thiazole-2-thiol and the methylene chloride group in ACLE•HCl, thereby reducing the product yield. In addition, the present invention uses N,N-diisopropylethylamine as an alkaline reagent to provide the alkaline environment required for the reaction. N,N-diisopropylethylamine has strong alkalinity, effectively removing protons from ACLE•HCl while enhancing the nucleophilic activity of the amino group. Furthermore, the large steric hindrance of N,N-diisopropylethylamine reduces the occurrence of other side reactions, further improving the yield of cefiderocol intermediate I. After completion of the reaction, cefiderocol intermediate I can be obtained by acidification, filtration, crystallization, and drying, and the post-processing operation is simple.

[0023] In the reaction process of TAEM and ACLE•HCl of the present invention, tert-butanol or isopropanol is used as a reaction solvent, N,N-diisopropylethylamine is used as an alkaline reagent, and the reaction temperature is strictly controlled between -10°C and -2°C, thereby achieving the preparation of cefiderocol intermediate I and improving the yield of cefiderocol intermediate I to as high as over 82%. At the same time, the purity of the product is significantly improved. Moreover, the post-treatment of the present invention does not require column chromatography purification, the operation is simple, and the method is suitable for industrial production. DETAILED DESCRIPTION

[0024] The present invention is further described below with reference to the following examples.

[0025] Example 1 A reaction flask was added with tert-butyl alcohol (163 mL), ACLE•HCl (20.26 g, 0.05 mol), and TAEM (25.2 g, 0.0525 mol). Stirring was initiated and the mixture was cooled to -5-2°C. N,N-diisopropylethylamine (14.9 g, 0.115 mol) was added dropwise with controlled temperature control. The reaction was maintained at -5-2°C for 5 h, and the reaction progress was monitored by thin-layer chromatography. After the reaction, concentrated hydrochloric acid was added dropwise at 0-5°C to adjust the pH to 5.0-6.0. The mixture was stirred at this temperature for 20 min. The byproduct benzo[D]thiazole-2-thiol was removed by filtration, and the filtrate was collected. The filtrate was transferred to a reaction flask, controlled at 0-10°C, and 10 wt.% hydrochloric acid solution was added dropwise. The mixture was crystallized, filtered, washed with acetone and water, and dried under vacuum at 40°C to obtain 28.9 g of cefiderocol intermediate I with an 85.0% yield and 98.9% purity. Its NMR data are as follows: 1 HNMR (500 MHz, CDCl3): δ 7.98-7.96 (d, 1H), 7.36-7.34 (d, 2H), 6.91-6.88 (d, 2H), 6.87 (s, 1H), 6.55 (m, 2H), 5.98-5.96 (dd, 1H), 5.28-5.18 (m,2H), 5.05-5.03 (d, 1H), 4.56-4.52 (d, 1H), 4.47-4.43 (d, 1H), 3.81 (s, 3H),3.66-3.61 (d, 1H), 3.48-3.45 (d, 1H), 1.59 (s, 3H), 1.58 (s, 3H), 1.40 (s,9H).

[0026] Example 2 Isopropanol (183 mL), ACLE•HCl (20.26 g, 0.05 mol), and TAEM (26.3 g, 0.055 mol) were added to a reaction flask with stirring. The mixture was cooled to -10-5°C and N,N-diisopropylethylamine (12.9 g, 0.10 mol) was added dropwise with controlled temperature. The reaction was maintained at -10-5°C for 6 h, and the reaction progress was monitored by thin-layer chromatography. After the reaction, concentrated hydrochloric acid was added dropwise at 5-10°C to adjust the pH to 5.0-6.0. The mixture was stirred at this temperature for 20 min. The byproduct benzo[D]thiazole-2-thiol was removed by filtration, and the filtrate was collected. The filtrate was transferred to a reaction flask, controlled at 0-10°C, and 10 wt.% hydrochloric acid solution was added dropwise. The mixture was crystallized, filtered, washed with acetone and water, and dried under vacuum at 40°C to obtain 28.1 g of cefiderocol intermediate I with a yield of 82.6% and a purity of 97.9%.

[0027] Example 3 To a reaction flask, tert-butyl alcohol (202 mL), ACLE•HCl (20.26 g, 0.05 mol), and TAEM (25.8 g, 0.054 mol) were added. Stirring was initiated and the mixture was cooled to -8–3°C. N,N-diisopropylethylamine (16.1 g, 0.125 mol) was added dropwise with controlled temperature control. The reaction was maintained at -8–3°C for 4 h, and the reaction progress was monitored by thin-layer chromatography. After the reaction, concentrated hydrochloric acid was added dropwise at 2–6°C to adjust the pH to 5.0–6.0. ​​The mixture was stirred at this temperature for 20 min. The byproduct benzo[D]thiazole-2-thiol was removed by filtration, and the filtrate was collected. The filtrate was transferred to a reaction flask, controlled at 0–10°C, and 10 wt.% hydrochloric acid solution was added dropwise. The mixture was crystallized, filtered, washed with acetone and water, and dried under vacuum at 40°C to obtain 28.5 g of cefiderocol intermediate I with a yield of 83.8% and a purity of 98.4%.

[0028] Comparative Example 1 The "tert-butyl alcohol" in Example 1 was modified to "dichloromethane", and the remaining steps were the same as in Example 1. 19.1 g of cefiderocol intermediate I was obtained with a yield of 56.2% and a purity of 96.3%.

[0029] Comparative Example 2 The "tert-butyl alcohol" in Example 1 was modified to "ethanol", and the remaining steps were the same as in Example 1. 20.8 g of cefiderocol intermediate I was obtained with a yield of 61.2% and a purity of 96.5%.

[0030] Comparative Example 3 The "N,N-diisopropylethylamine" in Example 1 was modified to "triethylamine", and the remaining steps were the same as in Example 1. 25.6 g of cefiderocol intermediate I was obtained with a yield of 75.3% and a purity of 96.1%.

[0031] Comparative Example 4 The "N,N-diisopropylethylamine" in Example 1 was modified to "N-methylmorpholine", and the remaining steps were the same as in Example 1. 26.3 g of cefiderocol intermediate I was obtained with a yield of 77.3% and a purity of 95.3%.

[0032] Comparative Example 5 The reaction temperature was maintained at -5 to -2°C in Example 1, which was modified to -13 to -11°C. The remaining steps were the same as those in Example 1. 19.8 g of cefiderocol intermediate I was obtained with a yield of 58.2% and a purity of 94.3%.

[0033] Comparative Example 6 The reaction temperature was maintained at -5 to -2°C in Example 1, which was modified to -1 to 1°C. The remaining steps were the same as those in Example 1. 21.7 g of cefiderocol intermediate I was obtained with a yield of 63.8% and a purity of 95.6%.

Claims

1. A synthetic method for a cefiderocol intermediate I, characterized in that: (Z)-(2-amino-4-thiazolyl)-2-(tert-butoxycarbonylisopropyloxyimino)acetic acid thiobenzothiazolyl ester and 7-amino-3-chloromethyl-3-cephazoline-4-carboxylic acid p-methoxybenzyl hydrochloride are added to an organic solvent and reacted under the action of an alkaline reagent to obtain cefiderocol intermediate I.

2. the synthetic method of cefiderocol intermediate I according to claim 1, is characterized in that: The organic solvent is isopropyl alcohol or tert-butyl alcohol, and the alkaline reagent is N,N-diisopropylethylamine.

3. the synthetic method of cefiderocol intermediate I according to claim 1, is characterized in that: The ratio of the organic solvent to 7-amino-3-chloromethyl-3-cephazoline-4-carboxylic acid p-methoxybenzyl hydrochloride is 8-10:1, wherein the organic solvent is measured in mL and the 7-amino-3-chloromethyl-3-cephazoline-4-carboxylic acid p-methoxybenzyl hydrochloride is measured in g.

4. the synthetic method of cefiderocol intermediate I according to claim 1, is characterized in that: The molar ratio of the alkaline reagent to 7-amino-3-chloromethyl-3-cephazoline-4-carboxylic acid p-methoxybenzyl hydrochloride is 2.0-2.5:

1.

5. the synthetic method of cefiderocol intermediate I according to claim 1, is characterized in that: The molar ratio of 7-amino-3-chloromethyl-3-cephazoline-4-carboxylic acid p-methoxybenzyl hydrochloride to (Z)-(2-amino-4-thiazolyl)-2-(tert-butoxycarbonylisopropyloxyimino)acetic acid thiobenzothiazolyl ester is 1:1.05-1.

1.

6. the synthetic method of cefiderocol intermediate I according to claim 1, is characterized in that: The reaction temperature is -10~-2°C, and the reaction time is 4~6 hours.

7. the synthetic method of cefiderocol intermediate I according to claim 6, is characterized in that: The reaction temperature is -5~-2℃.

8. the synthetic method of cefiderocol intermediate I according to claim 1, is characterized in that: (Z)-(2-amino-4-thiazolyl)-2-(tert-butoxycarbonylisopropyloxyimino)acetic acid thiobenzothiazolyl ester and 7-amino-3-chloromethyl-3-cephazoline-4-carboxylic acid p-methoxybenzyl hydrochloride are added to an organic solvent, the temperature is first cooled, and then an alkaline reagent is added to react; after the reaction is completed, the pH value is adjusted, the mixture is filtered, crystallized, and dried to obtain a cefiderocol intermediate I.

9. the synthetic method of cefiderocol intermediate I according to claim 8, is characterized in that: Cool down to -10~0℃.

10. The synthetic method of Cefiderocol intermediate I according to claim 8, wherein: After the reaction is completed, the pH value is adjusted to 5.0-6.0 with hydrochloric acid at 0-10°C.