CN109180704B - Synthesis method of cefditoren pivoxil - Google Patents
Synthesis method of cefditoren pivoxil Download PDFInfo
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- CN109180704B CN109180704B CN201811373495.7A CN201811373495A CN109180704B CN 109180704 B CN109180704 B CN 109180704B CN 201811373495 A CN201811373495 A CN 201811373495A CN 109180704 B CN109180704 B CN 109180704B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
- C07D501/06—Acylation of 7-aminocephalosporanic acid
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
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Abstract
The invention relates to a method for synthesizing cefditoren pivoxil, which comprises the steps of reacting D-7ACA with an oxidizing reagent to obtain a compound 1; performing silanization protection on the compound 1 to obtain a compound 2; iodination of 4-methylthiazole-5-methanol and NaI under the catalysis of a small amount of sulfuric acid, and then adding triphenylphosphine for reaction to obtain a compound 3; adding the compound 3 into the feed liquid of the compound 2 for reaction, concentrating, adding methanol and a small amount of concentrated hydrochloric acid for deprotection, and crystallizing to obtain cefditoren mother nucleus; reacting 7-ATCA and AE active ester under an alkaline condition, and crystallizing to obtain a wet cefditoren sodium product; and adding iodomethyl pivalate to the wet cefditoren sodium product in the presence of a phase transfer catalyst for reaction, and crystallizing to obtain a cefditoren pivoxil crude product. In the method, single solvents are respectively used for synthesizing the compound 1, the cefditoren sodium and the cefditoren pivoxil, so that the recovery and the reuse are convenient; the synthetic method has the advantages of simple and convenient operation steps, high product conversion rate, small impurities and low production cost, and is suitable for industrial production of cefditoren pivoxil.
Description
Technical Field
The invention relates to a method for synthesizing cefditoren pivoxil, and belongs to the technical field of chemical drug synthesis.
Background
Cefditoren Pivoxil, the third generation oral cephalosporin, was first introduced by the japanese mingming combo-zuki society. The product is marketed in Japan in month 4 of 1994, and in China in month 4 of 2001, under the name of Meieke. Research shows that cefditoren pivoxil has obvious treatment effect on community-acquired respiratory tract infection caused by five main pathogenic bacteria, namely streptococcus pneumoniae, haemophilus influenzae, streptococcus pyogenes, staphylococcus aureus and moraxella catarrhalis.
Cefditoren Pivoxil (Cefditoren Pivoxil) is chemically 2, 2-dimethylpropionyloxymethyl (6R,7R) -7- [ (Z) -2- (2-amino-4-thiazolyl) -2-methoxyiminoacetylamino]-3- [ (Z) -2- (4-methyl-1, 3-thiazol-5-yl) vinyl]-8-oxo-5-thia-1-azabicyclo [4.2.0]Octyl-2-ene-2-carboxylic acid ester of the formula C25H28N6O7S3Molecular weight of 620.73, and structural formula as follows:
the current main preparation methods of cefditoren pivoxil comprise:
US20060173175a1 discloses a method for preparing cefditoren pivoxil, wherein GCLE is used as an initial raw material, the pH is adjusted by alkali in the presence of sodium iodide and triphenylphosphine, the mixture is layered, subjected to contact reaction, and then reacted with 4-methyl-5-thiazole formaldehyde, the obtained product is deprotected and then reacted with AE active ester to obtain cefditoren acid, and the cefditoren acid is reacted with iodomethyl pivalate to obtain cefditoren pivoxil. Similar patents are for example chinese patent No. cn20131069883. x, CN 201610082151.5. However, the yield of cefditoren pivoxil prepared by the method is low, and the cost of cefditoren pivoxil prepared by using GCLE as a starting material is high.
Chinese patent document CN201610080402.6 discloses a method for synthesizing cefditoren, which comprises the steps of taking 7-ATCA as an initial raw material, carrying out contact reaction on the 7-ATCA and MAEM in THF in the presence of TMEDA and sodium phosphate, then adding TEA and iodomethyl pivalate for reaction, and crystallizing to obtain cefditoren pivoxil. A similar patent is CN 201510567751.6. However, the method uses mixed organic alkali in the synthesis process, has higher environmental protection pressure, and has certain limitation in production by using the intermediate 7-ATCA as a starting material.
Chinese patent document CN201711429569.X discloses a preparation method of spore-tolan pivoxil, which takes 7-ACA as an initial raw material, and generates iodination and wittig reaction after silanization protection to generate cefditoren mother nucleus 7-ATCA; after amino protection of the Aminothiazolic acid Ethyl ester, in AlMe3The reaction product of cefditoren mother nucleus 7-ATCA under catalysis reacts with iodomethyl pivalate under the action of a phase transfer catalyst and an adsorbent, and is subjected to deamination protection to obtain cefditoren pivoxil. However, the method for preparing cefditoren pivoxil by the method is relatively complex in operation, low in yield, difficult to recover and high in environmental protection pressure due to the adoption of a mixed solvent in the synthesis process.
Therefore, the search for a method for preparing cefditoren pivoxil suitable for industrial production is a technical problem to be solved in the field. The invention is therefore proposed.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a preparation method of cefditoren pivoxil, which is suitable for large-scale industrial production. Dissolving D-7ACA in alkali at 0-20 ℃ by using water as a solvent, adding a proper amount of a cocatalyst, reacting with an oxidation reagent under the action of 2,2,6, 6-tetramethylpiperidine oxynitride (TEMPO), adjusting the pH to 3-4 by adding acid after the reaction is finished, and crystallizing to obtain a compound 1; carrying out silanization protection on the compound 1 in dichloromethane at 0-20 ℃ to obtain a feed liquid of a compound 2; adding 4-methylthiazole-5-methanol and NaI into dichloromethane, carrying out iodination under the catalysis of a small amount of sulfuric acid, adjusting the pH value to 8-9 by using triethylamine, and adding triphenylphosphine for reaction to obtain a compound 3 material liquid; adding the feed liquid of the compound 3 into the feed liquid of the compound 2 at the temperature of 0-10 ℃ for reaction, concentrating the reaction product after the reaction is finished, adding methanol and a small amount of concentrated hydrochloric acid, and performing deprotection and crystallization to obtain cefditoren mother nucleus 7-ATCA; using dichloromethane as a solvent, using a small amount of water as a catalyst, reacting 7-ATCA and AE active ester under an alkaline condition, performing post-treatment to obtain a cefditoren triethylamine salt aqueous solution, and adding sodium chloride solid for crystallization to obtain a cefditoren sodium wet product; taking dichloromethane and water as solvents, adding a cefditoren sodium wet product, adding iodomethyl pivalate in the presence of a phase transfer catalyst tetrabutylammonium bromide, reacting at the temperature of 0-20 ℃, layering after the reaction is finished, concentrating an organic phase, and adding water for crystallization to obtain a cefditoren pivoxil crude product.
In the method, single solvents are respectively used for synthesizing the compound 1, the cefditoren sodium and the cefditoren pivoxil, so that the recovery and the reuse are convenient; the synthesis method has the advantages of simple and convenient operation steps, high product yield, small impurities and low production cost, and is suitable for industrial production of cefditoren pivoxil.
Description of terms:
unless otherwise stated, D-7ACA, 7-ATCA, compound 1, compound 2 and compound 3 referred to in the invention refer to the corresponding compounds in the term description, and have the same reference relationship.
The chemical structural formula of hydroxymethyl-7-aminocephalosporanic acid (D-7ACA) is as follows:
molecular formula ═ C8H10N2O4S
Molecular weight of 230.241
(6R,7R) -7-amino-3- [ (1Z) -2- (4-methyl-5-thiazolyl) -vinyl ] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid (7-ATCA) having the formula:
molecular formula ═ C13H13N3O3S2
Molecular weight of 323.39062
The chemical structural formula of the compound 1 is as follows:
molecular formula ═ C8H8N2O4S
Molecular weight of 228.22512
The chemical structural formula of the compound 2 is as follows:
molecular formula ═ C14H24N2O4SSi2
Molecular weight of 372.58736
The chemical structural formula of the compound 3 is as follows:
molecular formula ═ C23H20NPS
Molecular weight of 373.450361
The technical scheme of the invention is as follows:
an industrialized method for synthesizing cefditoren pivoxil comprises the following steps:
(1) taking water as a solvent, dissolving D-7ACA by adding alkali, reacting with an oxidizing reagent under the action of 2,2,6, 6-tetramethylpiperidine oxynitride (TEMPO), and crystallizing to obtain a compound 1; performing silanization protection on the compound 1 to obtain a compound 2; adding 4-methylthiazole-5-methanol and NaI into dichloromethane, carrying out iodination under the catalysis of a small amount of sulfuric acid, adjusting the pH value to 8-9 by using triethylamine, and adding triphenylphosphine for reaction to obtain a compound 3; mixing the compound 3 with the feed liquid of the compound 2, carrying out deprotection and crystallization after reaction to obtain cefditoren mother nucleus 7-ATCA;
(2) using dichloromethane as a solvent, using a small amount of water as a catalyst, reacting 7-ATCA and AE active ester under an alkaline condition, performing post-treatment to obtain a cefditoren triethylamine salt aqueous solution, and adding sodium chloride solid for crystallization to obtain a cefditoren sodium wet product;
(3) taking dichloromethane and water as solvents, adding a cefditoren sodium wet product, adding iodomethyl pivalate in the presence of a phase transfer catalyst tetrabutylammonium bromide, reacting at the temperature of 0-20 ℃, layering after the reaction is finished, concentrating an organic phase, and adding water for crystallization to obtain a cefditoren pivoxil crude product.
According to the present invention, it is preferable that the base used for dissolving the D-7ACA in the step (1) is sodium hydroxide, sodium carbonate, sodium bicarbonate or potassium carbonate;
according to the invention, preferably, the cocatalyst used in the step (1) is potassium bromide or sodium bromide, and the molar ratio of the used cocatalyst to the D-7ACA is (0.1-10): 1;
according to the present invention, it is preferable that the oxidizing agent in step (1) is sodium hypochlorite, calcium hypochlorite or potassium hypochlorite;
according to the present invention, it is preferred that the silylation protecting agent in the step (1) is hexamethyldisilazane or trimethylchlorosilane.
According to the present invention, it is preferred that the molar ratio of 4-methylthiazole-5-methanol, NaI and triphenylphosphine in the preparation of compound 3 in step (1) is 1: (1.0-1.5): (1.0 to 1.1), more preferably 1:1.05: 1.
according to the invention, the volume ratio of the catalyst water to the dichloromethane in the step (2) is preferably (2.5-5): 100.
According to the present invention, it is preferred that the base used in the basic condition in step (2) is an organic base, further preferably diisopropylamine, diethylamine or triethylamine; the molar ratio of the organic base to the 7-ATCA is (1.0-1.5): 1, more preferably 1.2:1.
according to the invention, the volume ratio of water to dichloromethane in the reaction process in the step (3) is preferably (2-5): 1, and more preferably 3: 1;
according to the present invention, it is preferred that the phase transfer catalyst in step (3) is tetrabutylammonium bromide, tetrabutylammonium chloride or tetrabutylammonium hydrogen sulfate.
According to the present invention, it is preferred that the molar ratio of 7-ATCA to iodomethyl pivalate in step (3) is 1: (1.0 to 1.5), and more preferably 1: 1.2.
the synthetic process route of the method is as follows:
advantageous effects
1. The preparation method disclosed by the invention is simple to operate, has few reaction steps and is suitable for industrial production;
2. according to the preparation method, a single solvent dichloromethane is used during 7-ATCA synthesis, and dichloromethane and methanol are used during crystallization, so that the preparation method is easy to recycle and reuse, is beneficial to environmental protection, and reduces the production cost and the environmental protection expenditure;
3. according to the preparation method disclosed by the invention, the synthesis of cefditoren sodium and cefditoren pivoxil adopts a single solvent dichloromethane, the recovery is easy, the production cost and the environmental protection expenditure are reduced, the yield from D-7ACA to cefditoren pivoxil crude product is more than 84%, the yield from 7-ATCA to cefditoren pivoxil crude product is more than 94.5%, and the purity is more than 99.7%.
Drawings
Fig. 1 is a nuclear magnetic resonance hydrogen spectrum of cefditoren pivoxil prepared in example 1.
Fig. 2 is a nmr hydrogen spectrum of a cefditoren pivoxil standard control.
Detailed description of the preferred embodiments
The technical solutions of the present invention are further illustrated by the following examples, but the examples provided should not be construed as limiting the scope of the present invention.
Example 1 a process for the preparation of cefditoren pivoxil comprising the steps of:
(1) preparation of cefditoren mother nucleus: adding 200ml of water into a reaction bottle, adding D-7ACA50g at the temperature of 0-10 ℃, dropwise adding 7% sodium bicarbonate to adjust the pH value to be clear, adding 10g of sodium bromide and 2g of 2,2,6, 6-tetramethylpiperidine nitrogen oxide, dropwise adding 50ml of 10% sodium hypochlorite, reacting for 2-3 hours, dropwise adding 3N hydrochloric acid to adjust the pH value to be 3.5, and obtaining about 47.08g of a compound 1.
A: putting 100ml of dichloromethane into a reaction bottle, adding about 23.55g of compound 1, controlling the temperature to be 0-20 ℃, adding hexamethyldisilazane, carrying out reflux reaction for about 5 hours to obtain a feed liquid of compound 2, and keeping the temperature to be 0-10 ℃ for later use.
B: putting 100ml of dichloromethane into a reaction bottle, adding 14.4g (112mmol) of 4-methylthiazole-5-methanol, 14.7 g (118mmol) of NaI17.7 and a small amount of sulfuric acid, reacting at 0-10 ℃ for 2h, dropwise adding triethylamine to adjust the pH value to 8-9, adding 29.3g (112mmol) of triphenylphosphine, and reacting at 0-10 ℃ for 1 h to obtain a feed liquid of a compound 3, wherein the molar ratio of the 4-methylthiazole-5-methanol to the NaI to the triphenylphosphine is 1:1.05: 1.
And (3) adding the B into the A at the temperature of 0-10 ℃, reacting for 2 hours, vacuum-concentrating at 20 ℃, and then adding 300ml of methanol and 2ml of concentrated hydrochloric acid to obtain 32g of cefditoren mother nucleus (7-ATCA) with the yield of 96%.
(2) Preparation of cefditoren sodium wet product: putting 200ml of dichloromethane, 5ml of water, 20g (61.8mmol) of 7-ATCA (advanced telecom computing architecture), 23.4g of AE active ester into a reaction bottle, controlling the temperature to be 0-10 ℃, dropwise adding 7.5g (74.1mmol) of triethylamine, reacting for 2 hours after dropwise adding, adding 400ml of water into the feed liquid, layering, adding 100g of solid sodium chloride into a water phase at the temperature of 0-20 ℃, crystallizing, and filtering to obtain a wet cefditoren sodium product.
(3) Preparation of cefditoren pivoxil: adding 300ml of water and 120ml of dichloromethane into a reaction bottle, controlling the temperature to be 0-25 ℃, adding the cefditoren sodium wet product, stirring, adding 2g of tetrabutylammonium bromide and 17.95g (74.2mmol) of iodomethyl pivalate, stirring for reacting for 2h, layering, concentrating an organic phase, and then dropwise adding 500ml of water for crystallization to obtain 35.4g of cefditoren pivoxil crude product, wherein the yield is 95%, the purity is 99.85%, and the maximum nonspecific impurity is 0.02%.
The nmr hydrogen spectrum of cefditoren pivoxil obtained in this example is shown in fig. 1, and the nmr hydrogen spectrum of cefditoren pivoxil reference is shown in fig. 2.
1H-NMR(400MHz，DMSO-d6)δ：1.06(s，9H)，2.37(s，3H)，3.44(d，1H)，3.57(d，1H)，3.84(s，3H)，5.30(d，1H)，5.69(d，1H)，5.76(d，1H)，5.90(dd，1H)，6.32(d，1H)，6.75(d，1H)，6.75(s，1H)，7.24(s，2H)，8.94(s，1H)，9.70(d，1H)。
Embodiment 2 a process for the preparation of cefditoren pivoxil comprising the steps of:
(1) preparation of cefditoren mother nucleus: adding 200ml of water into a reaction bottle, adding D-7ACA50g at the temperature of 0-10 ℃, dropwise adding 7% sodium bicarbonate to adjust the pH value to be clear, adding 10g of sodium bromide and 2g of 2,2,6, 6-tetramethylpiperidine nitrogen oxide, dropwise adding 50ml of 10% sodium hypochlorite, reacting for 2-3 hours, dropwise adding 3N hydrochloric acid to adjust the pH value to be 3.5, and obtaining about 47.08g of a compound 1.
A: putting 100ml of dichloromethane into a reaction bottle, adding about 23.55g of compound 1, controlling the temperature to be 0-20 ℃, adding hexamethyldisilazane, carrying out reflux reaction for about 5 hours to obtain a feed liquid of compound 2, and keeping the temperature to be 0-10 ℃ for later use.
B: putting 100ml of dichloromethane into a reaction bottle, adding 14.4g (112mmol) of 4-methylthiazole-5-methanol, 20.1g (134mmol) of NaI and a small amount of sulfuric acid, reacting at 0-10 ℃ for 2h, dropwise adding triethylamine to adjust the pH value to 8-9, adding 29.3g (112mmol) of triphenylphosphine, reacting at 0-10 ℃ for 1 h to obtain a feed liquid of a compound 3, wherein the molar ratio of the 4-methylthiazole-5-methanol to the NaI to the triphenylphosphine is 1:1.2:1,
and (3) adding the B into the A at the temperature of 0-10 ℃, reacting for 2 hours, vacuum-concentrating at 20 ℃, and then adding 300ml of methanol and 2ml of concentrated hydrochloric acid to obtain 32g of cefditoren mother nucleus (7-ATCA) with the yield of 96.2%.
(2) Preparation of cefditoren sodium wet product: putting 200ml of dichloromethane, 10ml of water, 7-ATCA20g (61.8mmol) and 23.4g of AE active ester into a reaction bottle, controlling the temperature to be 0-10 ℃, dropwise adding 5.45g (74.5mmol) of diethylamine, reacting for 2 hours after dropwise adding, adding 400ml of water into the feed liquid, demixing, adding 100g of solid sodium chloride into a water phase at the temperature of 0-20 ℃, crystallizing, and filtering to obtain a wet cefditoren sodium product.
(3) Preparation of cefditoren pivoxil: adding 300ml of water and 120ml of dichloromethane into a reaction bottle, controlling the temperature to be 0-25 ℃, adding the cefditoren sodium wet product, stirring, adding 1.73g of tetrabutylammonium chloride and 17.95g (74.2mmol) of iodomethyl pivalate, stirring for reacting for 2h, layering, concentrating an organic phase, and dropwise adding 500ml of water for crystallization to obtain 35.38g of cefditoren pivoxil crude product, wherein the yield is 94.95%, the purity is 99.8%, and the maximum non-specific impurity is 0.02%.
Embodiment 3 a process for the preparation of cefditoren pivoxil comprising the steps of:
(1) preparation of cefditoren mother nucleus: adding 200ml of water into a reaction bottle, adding D-7ACA50g at the temperature of 0-10 ℃, dropwise adding 7% sodium bicarbonate to adjust the pH value to be clear, adding 10g of sodium bromide and 2g of 2,2,6, 6-tetramethylpiperidine nitrogen oxide, dropwise adding 50ml of 10% sodium hypochlorite, reacting for 2-3 hours, dropwise adding 3N hydrochloric acid to adjust the pH value to be 3.5, and obtaining about 47.08g of a compound 1.
A: putting 100ml of dichloromethane into a reaction bottle, adding about 23.55g of compound 1, controlling the temperature to be 0-20 ℃, adding hexamethyldisilazane, carrying out reflux reaction for about 5 hours to obtain a feed liquid of compound 2, and keeping the temperature to be 0-10 ℃ for later use.
B: putting 100ml of dichloromethane into a reaction bottle, adding 14.4g (112mmol) of 4-methylthiazole-5-methanol, 20.1g (134mmol) of NaI and a small amount of sulfuric acid, reacting at 0-10 ℃ for 2h, dropwise adding triethylamine to adjust the pH value to 8-9, adding 32.3g (123mmol) of triphenylphosphine, and reacting at 0-10 ℃ for 1 h to obtain a feed liquid of a compound 3, wherein the molar ratio of the 4-methylthiazole-5-methanol to the NaI to the triphenylphosphine is 1:1.2: 1.1.
And (3) adding the B into the A at the temperature of 0-10 ℃, reacting for 2 hours, vacuum-concentrating at 20 ℃, and then adding 300ml of methanol and 2ml of concentrated hydrochloric acid to obtain 32g of cefditoren mother nucleus (7-ATCA) with the yield of 96.5%.
(2) Preparation of cefditoren sodium wet product: putting 200ml of dichloromethane, 5ml of water, 20g (61.8mmol) of 7-ATCA (advanced telecom computing architecture), 23.4g of AE active ester into a reaction bottle, controlling the temperature to be 0-10 ℃, dropwise adding 7.5g (74.1mmol) of triethylamine, reacting for 2 hours after dropwise adding, adding 400ml of water into the feed liquid, layering, adding 100g of solid sodium chloride into a water phase at the temperature of 0-20 ℃, crystallizing, and filtering to obtain a wet cefditoren sodium product.
(3) Preparation of cefditoren pivoxil: adding 300ml of water and 120ml of dichloromethane into a reaction bottle, controlling the temperature to be 0-25 ℃, adding the cefditoren sodium wet product, stirring, adding 2g of tetrabutylammonium bromide and 14.96g (61.8mmol) of iodomethyl pivalate, stirring for reacting for 2h, layering, concentrating an organic phase, and then dropwise adding 500ml of water for crystallization to obtain 35.65g of cefditoren pivoxil crude product, wherein the yield is 93%, the purity is 99.75%, and the maximum nonspecific impurity is 0.04%.
Embodiment 4 a process for the preparation of cefditoren pivoxil comprising the steps of:
(1) preparation of cefditoren mother nucleus: adding 200ml of water into a reaction bottle, adding D-7ACA50g at the temperature of 0-10 ℃, dropwise adding 7% sodium bicarbonate to adjust the pH value to be clear, adding 10g of sodium bromide and 2g of 2,2,6, 6-tetramethylpiperidine nitrogen oxide, dropwise adding 50ml of 10% sodium hypochlorite, reacting for 2-3 hours, dropwise adding 3N hydrochloric acid to adjust the pH value to be 3.5, and obtaining about 47.08g of a compound 1.
A: putting 100ml of dichloromethane into a reaction bottle, adding about 23.55g of compound 1, controlling the temperature to be 0-20 ℃, adding hexamethyldisilazane, carrying out reflux reaction for about 5 hours to obtain a feed liquid of compound 2, and keeping the temperature to be 0-10 ℃ for later use.
B: putting 100ml of dichloromethane into a reaction bottle, adding 14.4g (112mmol) of 4-methylthiazole-5-methanol, 112.8g (112mmol) of NaI and a small amount of sulfuric acid, reacting at 0-10 ℃ for 2h, dropwise adding triethylamine to adjust the pH value to 8-9, adding 29.3g (112mmol) of triphenylphosphine, and reacting at 0-10 ℃ for 1 h to obtain a feed liquid of a compound 3, wherein the molar ratio of the 4-methylthiazole-5-methanol to the NaI to the triphenylphosphine is as follows: 1:1:1.
And (3) adding the B into the A at the temperature of 0-10 ℃, reacting for 2 hours, vacuum-concentrating at 20 ℃, and then adding 300ml of methanol and 2ml of concentrated hydrochloric acid to obtain 32g of cefditoren mother nucleus (7-ATCA) with the yield of 95%.
(2) Preparation of cefditoren sodium wet product: putting 200ml of dichloromethane, 5ml of water, 20g (61.8mmol) of 7-ATCA (advanced telecom computing architecture), 23.4g of AE active ester into a reaction bottle, controlling the temperature to be 0-10 ℃, dropwise adding 7.5g (74.1mmol) of triethylamine, reacting for 2 hours after dropwise adding, adding 400ml of water into the feed liquid, layering, adding 100g of solid sodium chloride into a water phase at the temperature of 0-20 ℃, crystallizing, and filtering to obtain a wet cefditoren sodium product.
(3) Preparation of cefditoren pivoxil: adding 300ml of water and 120ml of dichloromethane into a reaction bottle, controlling the temperature to be 0-25 ℃, adding the cefditoren sodium wet product, stirring, adding 2g of tetrabutylammonium bromide and 20.94g (86.5mmol) of iodomethyl pivalate, stirring for reacting for 2h, layering, concentrating an organic phase, and then dropwise adding 500ml of water for crystallization to obtain 35.51g of cefditoren pivoxil crude product, wherein the yield is 95.3%, the purity is 99.7%, and the maximum nonspecific impurity is 0.03%.
Comparative example 1
A process for the preparation of cefditoren pivoxil as in example 1 except that: when the acylation reaction is carried out in the step (2) without using water, 25.78g of cefditoren pivoxil is obtained in a yield of 69.2%.
Comparative example 2
A process for the preparation of cefditoren pivoxil as in example 1 except that: the same volume of methanol was used instead of water in the acylation reaction in step (2) to give 32.97g of cefditoren pivoxil in 88.5% yield.
Comparative example 3
A process for the preparation of cefditoren pivoxil as in example 1 except that: in the esterification reaction in the step (3), no phase transfer catalyst is used, so that 9.32g of cefditoren pivoxil is obtained with a yield of 25%.
Claims (11)
1. An industrialized method for synthesizing cefditoren pivoxil comprises the following steps:
(1) taking water as a solvent, adding a proper amount of cocatalyst, reacting D-7ACA with an oxidizing reagent under the action of 2,2,6, 6-tetramethylpiperidine oxynitride (TEMPO), and crystallizing to obtain a compound 1; performing silanization protection on the compound 1 to obtain a compound 2; adding 4-methylthiazole-5-methanol and NaI into dichloromethane, carrying out iodination under the catalysis of a small amount of sulfuric acid, adjusting the pH value to 8-9 by using triethylamine, and adding triphenylphosphine for reaction to obtain a compound 3; mixing the compound 3 with the feed liquid of the compound 2, carrying out deprotection and crystallization after reaction to obtain cefditoren mother nucleus 7-ATCA;
compound 1 Compound 2 Compound 3
(2) Using dichloromethane as a solvent, using a small amount of water as a catalyst, reacting 100, 7-ATCA and AE active ester in a volume ratio of water to dichloromethane of (2.5-5) under an alkaline condition, performing post-treatment to obtain a cefditoren triethylamine salt aqueous solution, and adding sodium chloride solid for crystallization to obtain a cefditoren sodium wet product;
(3) taking dichloromethane and water as solvents, adding a cefditoren sodium wet product, adding iodomethyl pivalate in the presence of a phase transfer catalyst tetrabutylammonium bromide, reacting at the temperature of 0-20 ℃, layering after the reaction is finished, concentrating an organic phase, and adding water for crystallization to obtain a cefditoren pivoxil crude product.
2. The industrial synthesis method of cefditoren pivoxil according to claim 1, wherein the base used for dissolving the D-7ACA in the step (1) is sodium hydroxide, sodium carbonate, sodium bicarbonate or potassium carbonate.
3. The industrial synthesis method of cefditoren pivoxil according to claim 1, wherein the cocatalyst used in step (1) is potassium bromide or sodium bromide.
4. The industrialized method for synthesizing cefditoren pivoxil according to claim 1, wherein the molar ratio of the cocatalyst amount to the D-7ACA in the step (1) is (0.1-10): 1.
5. the industrial synthesis method of cefditoren pivoxil according to claim 1, wherein the oxidizing agent in step (1) is sodium hypochlorite, calcium hypochlorite or potassium hypochlorite.
6. The industrial synthesis method of cefditoren pivoxil according to claim 1, wherein the silylation protective agent in step (1) is hexamethyldisilazane or trimethylchlorosilane.
7. The industrialized method for synthesizing cefditoren pivoxil according to claim 1, wherein the molar ratio of 4-methylthiazole-5-methanol, NaI and triphenylphosphine in the preparation of the compound 3 in the step (1) is 1: (1.0-1.5): (1.0-1.1).
8. The industrialized method for synthesizing cefditoren pivoxil according to claim 1, wherein the base used in the alkaline condition in the step (2) is an organic base, and the molar ratio of the organic base to 7-ATCA is (1.0-1.5): 1.
9. the industrial synthesis method of cefditoren pivoxil according to claim 1, wherein the organic base used in the basic condition in step (2) is diisopropylamine, diethylamine or triethylamine.
10. The industrial synthesis method of cefditoren pivoxil according to claim 1, wherein the volume ratio of water to dichloromethane in the reaction process in the step (3) is (2-5): 1.
11. The industrial synthesis method of cefditoren pivoxil according to claim 1, wherein the molar ratio of 7-ATCA to iodomethyl pivalate in step (3) is 1: (1.0-1.5).
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