A process for the preparation of a methoxymethyl ether (MOM) protected C3 side chain of cefditoren

Abstract

The application discloses a preparation method of a novel MOM-protected C3 side chain of cefodizime, and belongs to the technical field of pharmaceutical synthesis intermediates. The method is as follows: 2-chloro-3,4-dihydroxybenzaldehyde is used as raw material, and chloromethyl methyl ether (MOMCl) or bromomethyl methyl ether (MOMBr) is used to protect two phenolic hydroxyl groups. After the aldehyde group is oxidized into a carboxylic acid by using a Pinnick method, the carboxylic acid is condensed with 2-chloroethylamine to obtain an amide, and finally, the amide is reacted with tetrahydropyrrole to obtain the target product: 2-chloro-3,4-bis(methoxymethoxy)-(2-(pyrrol-1-yl)ethyl)benzamide. N The application has mild reaction conditions and simple operation, and is suitable for industrialized production of cefodizime.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical intermediate synthesis, and specifically to a method for preparing a MOM-protected C3-position side chain of cefodil. Background Technology

[0002] Cefiderocol, a fifth-generation cephalosporin, is a novel siderophore cephalosporin antibiotic developed exclusively by Shionogi Pharmaceutical Co., Ltd. of Japan (trade name: Fetroja). The structure of cefiderocol consists of a cephalosporin core, a C7 side chain, and a C3 side chain. The C7 side chain is similar to that of ceftazidime, and its carboxyl group improves cefiderocol's permeability to the bacterial outer membrane; while the aminothiazole group, oxime, and dimethyl group enhance cefiderocol's antibacterial activity. The C3 side chain ends with a catechol group. Cefiderocol utilizes the two hydroxyl groups to chelate with ferric ions to form a complex, which is then taken up by bacteria via iron transporters into the periplasmic space and binds to penicillin-binding protein 3 (PBP3), blocking peptidoglycan cross-linking. This method of drug intake via iron transporters is likened to a "Trojan horse." This method effectively circumvents the resistance barrier of Gram-negative bacteria. Cefdil was the first approved antibiotic with siderophore function. Its lyophilized powder for injection was approved by the US FDA on November 14, 2019, and the EU EMA on April 23, 2020, for the treatment of complicated urinary tract infections, hospital-acquired bacterial pneumonia, and ventilator-associated bacterial pneumonia caused by susceptible Gram-negative microorganisms in adults aged 18 years or older.

[0003] The chlorocatechol group at the C3 end of cefdil's side chain is a key structure for chelating ferric ions. In the synthesis of cefdil, the two hydroxyl groups of the catechol need to be protected. Shionogi's published patents (CN102203100B) and other related patents (CN202111007933.X, CN202311039968.0, CN202311071628.6, CN202410044682.X) all use 4-methoxybenzyl (PMB) to protect the two hydroxyl groups of the catechol. Because the PMB protecting group has a large molecular weight, protecting both hydroxyl groups simultaneously increases the molecular weight of the intermediate. In practice, the intermediate containing PMB also has poor solubility, affecting the yield of the homogeneous reaction. Furthermore, during the final deprotection, the C3 side chain needs to lose two molecules of the PMB protecting group, which reduces atom economy and increases the difficulty of subsequent product purification. Summary of the Invention

[0004] The objective of this invention is to provide a novel synthetic method for the C3 side chain of cefdil, in which MOM replaces PMB to protect the catechol group at the end of the C3 side chain. To achieve the above objective, the present invention designs the following synthetic route:

[0005] The specific synthesis steps are as follows: (1) Dissolve the raw material 2-chloro-3,4-dihydroxybenzaldehyde in dichloromethane, add 3 times the amount of base, and then add 2.5 times the amount of bromomethyl methyl ether through a funnel. Stir the reaction for 1-2 hours to obtain intermediate I. (2) Dissolve compound I in tetrahydrofuran, and add a mixed solution of NaClO2 and NaH2PO4 while stirring. After reacting for 1 hour, carboxylic acid II can be obtained. The molar ratio of each component in the reaction is 1:5:10. (3) Dissolve compound II in dichloromethane, add triethylamine, and then add 2-chloroethylamine salt and condensing agent in sequence while stirring. Stir at room temperature for about 1-2 hours to obtain intermediate III. The molar ratio of each component in the reaction is 1:4:1.5:1.5. (4) Dissolve compound III in tetrahydropyrrole, and stir overnight at room temperature to obtain target compound IV. The feed ratio of substrate III to tetrahydropyrrole in the reaction is 1 (g):2-4 (mL).

[0006] Features and beneficial effects of the present invention: This invention presents a novel method for synthesizing the C3 side chain of cefdil. Replacing the PMB protecting group with the MOM protecting group to protect the two phenolic hydroxyl groups of the chlorocatechol group reduces the molecular weight of the C3 side chain, increases its solubility, and results in a cefdil precursor with higher atom economy after deprotection. The reaction conditions in this invention are mild, the yield is high, and it is suitable for industrial production. Attached Figure Description

[0007] Figure 1-2 These are the 1H and 1C NMR spectra of the MOM-protected C3 side chain IV. Figure 3-4 The results show the proton NMR and high-resolution mass spectra of the cefidil precursor prepared using the MOM-protected C3 side chain. Detailed Implementation

[0008] The present invention will be further illustrated by the following examples, but the present invention is not limited to the examples implemented. Anything that does not depart from the spirit of the present invention should be included within the scope of protection of the present invention.

[0009] Step 1. Synthesis of 2-chloro-3,4-bis(methoxymethoxy)benzaldehyde (I): 2-Chloro-3,4-dihydroxybenzaldehyde (8 g, 46.4 mmol) was dissolved in 30 mL of dichloromethane, resulting in a brown suspension. Triethylamine (25 mL) was then added, turning the solution a dark brown transparent liquid. Finally, bromomethyl methyl ether (7.6 mL, 93 mmol) was slowly added dropwise through a constant-pressure funnel under ice-water bath conditions. During this addition, a large amount of white fumes were produced, and the solution turned a brown transparent liquid. After the addition was complete, the mixture was stirred at room temperature for 1-2 hours until the reaction was complete. A saturated ammonium chloride aqueous solution was added to remove the alkali from the solution. The aqueous and organic phases were separated. The organic phase was washed twice with water and brine, respectively, and finally dried over anhydrous sodium sulfate. The solution was filtered and concentrated to obtain a brownish-yellow oily crude product. The crude product was recrystallized from ethyl acetate and petroleum ether to give 8.6 g of a pale yellow flocculent product, with a product yield of 71%. 1 H NMR (400 MHz, CDCl3) δ 10.36 (s, 1H), 7.70 (d, J =8.8 Hz, 1H), 7.16 (d, J = 8.8 Hz, 1H), 5.28 (s, 2H), 5.20 (s, 2H), 3.67 (s, 3H), 3.50 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 189.0, 156.1, 143.0, 132.9, 127.5, 125.9, 113.9, 99.0, 94.9, 58.0, 56.8.

[0010] Step 2. Synthesis of 2-chloro-3,4-bis(methoxymethoxy)benzoic acid (II): Intermediate I (8.35 g, 32.1 mmol) was dissolved in 100 mL of tetrahydrofuran. While stirring in an ice bath, 100 mL of a mixed solution of NaClO2 (14.5 g, 160 mmol) and NaH2PO4 (38.4 g, 320 mmol) was added dropwise. The reaction was continued for one hour, and the solution was concentrated under reduced pressure. The mother liquor was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was evaporated. The resulting yellow solid was recrystallized from ethyl acetate and petroleum ether to give 7.3 g of a white flocculent product, with a yield of 82.0%. 1 HNMR (400 MHz, d-DMSO) δ 13.08 (s, 1H), 7.57 (d, J = 8.8 Hz, 1H), 7.17 (d, J=8.8 Hz, 1H), 5.31 (s, 2H), 5.14 (s, 2H), 3.55 (s, 3H), 3.41 (s, 3H). 13 C NMR (100 MHz, d-DMSO) δ 166.2, 152.9, 142.9, 127.3, 126.7, 125.0, 113.7, 98.3, 94.5, 57.3, 56.2.

[0011] Step 3. Synthesis of 2-chloro-N-(2-chloroethyl)-3,4-bis(methoxymethoxy)benzamide (III): Compound II (10 g, 36.2 mmol) was dissolved in 100 mL of dichloromethane, and triethylamine (20 mL, 144 mmol), 2-chloroethylamine hydrochloride (6.26 g, 54 mmol), and the condensing agent HATU (20.53 g, 54 mmol) were added sequentially. After stirring at room temperature for about 30 min, 50 mL of saturated sodium sulfate solution was added, followed by extraction three times with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain an oily product. The crude product was recrystallized from ethyl acetate and petroleum ether to give 8.8 g of pale yellow flocculent product III, with a product yield of 72%. 1 H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 8.8,1H), 7.10 (d, J = 8.8 Hz, 1H), 6.69 (s, 1H), 5.22 (s, 2H), 5.17 (s, 1H), 3.77-3.80 (m, 4H), 3.71-3.73 (m, 4H), 3.65 (s, 3H), 3.48 (s, 3H).

[0012] Step 4. Preparation of 2-chloro-3,4-bis(methoxymethoxy)-N-(2-(pyrrolo-1-yl)ethyl)benzamide (IV) Compound III (15 g, 44.4 mmol) was dissolved in 30 mL of tetrahydropyrrole and stirred overnight at room temperature. 200 mL of water was added to the reaction mixture, followed by extraction three times with ethyl acetate. The combined organic phases were washed 1-2 times with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. Recrystallization from ethyl acetate and petroleum ether yielded a pale yellow needle-like or flocculent solid. The solid was filtered, and 12 g was collected, yielding a product of 74%. 1 H NMR (400 MHz, CDCl3) δ7.34 (d, J= 8.8,1H), 7.08 (d, J = 8.8 Hz, 1H), 6.85 (s, 1H), 5.21 (s, 2H), 5.16 (s, 2H), 3.64(s, 3H), 3.53 (q, J = 10.8, 6.0 Hz, 2H), 3.47 (s, 3H), 2.69 (t, J = 6.0 Hz, 2H), 2.54 (t, J = 1.6 Hz, 4H), 1.76 (t, J = 1.6 Hz, 4H). 13 C NMR (100 MHz, CDCl3) δ 166.5, 152.4, 143.2, 130.2, 126.1, 125.4, 114.4, 99.0, 95.1, 58.0, 56.5, 54.3, 53.8, 38.6, 23.6.

[0013] The above description of the embodiments is merely to illustrate the technical concept and features of the present invention, and is intended to enable those skilled in the art to understand the content of the present invention and implement it accordingly. It should not be construed as limiting the scope of protection of the present invention. Equivalent changes or modifications made by those skilled in the art based on the spirit and essence of the present invention should be within the scope of protection of the present invention.

Claims

1. A method for preparing a MOM-protected C3 side chain of cefdil, comprising the following steps: (i) Synthesis of 2-chloro-3,4-bis(methoxymethoxy)benzaldehyde (I): using 2-chloro-3,4-dihydroxybenzaldehyde as a raw material, reacting it with halomethyl methyl ether under alkaline catalysis via a Williamson reaction to obtain MOM-protected I, wherein the reaction feed ratio is 1.0:2.5:3.0 for the molar ratio of raw material:alkali:halomethyl methyl ether; (ii) Synthesis of 2-chloro-3,4-bis(methoxymethoxy)benzoic acid (II): using the Pinnick oxidation method, with sodium chlorite as the oxidant and sodium dihydrogen phosphate as the buffer solution, the aldehyde is oxidized to a carboxylic acid. The molar ratio of raw material I to sodium chlorite and sodium dihydrogen phosphate is 1.0:5.0:10.0; (III) Synthesis of 2-chloro-N-(2-chloroethyl)-3,4-bis(methoxymethoxy)benzamide (III): Intermediate II is amidated with 2-chloroethylamine hydrochloride under alkaline conditions using a condensing agent to obtain the product. The molar ratio of intermediate II to 2-chloroethylamine: condensing agent and base is 1:1.5:1.5:4; (IV) Preparation of 2-chloro-3,4-bis(methoxymethoxy)-N-(2-(pyrrolo-1-yl)ethyl)benzamide (IV): Intermediate III is dissolved in tetrahydropyrrole as solvent and stirred at room temperature for 8 hours to obtain the target product.

2. The method according to claim 1, characterized in that, The halomethyl methyl ether mentioned in step (i) is chloromethyl methyl ether or bromomethyl methyl ether. The base is sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, triethylamine, or diisopropylethylamine.

3. The method according to claim 1, characterized in that, The oxidation method described in step (ii) is the Pinnick method, using sodium chlorite as the oxidant and sodium dihydrogen phosphate as the buffer solution.

4. The method according to claim 1, characterized in that, The condensing agent mentioned in step (iii) is one or more of the following: methanesulfonyl chloride, p-toluenesulfonyl chloride, phosphorus oxychloride, oxaloyl chloride, thionyl chloride, dicyclohexylcarbodiimide (DCC), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), and 1-hydroxybenzotriazole (HOBt).

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