Method for preparing oseltamivir

Abstract

The invention relates to the technical field of pharmaceutical and chemical engineering, and particularly discloses a method for preparing oseltamivir, oseltamivir is prepared through thionyl chloride esterification, cyclization, Mitsunobu amino substitution, selective ring opening, TEMPO oxidation, transaminase enzyme catalysis, acylation and deprotection, esterification, oxidation and protection groups are classical reactions, then enzyme catalysis is combined for selective amino substitution, and the oseltamivir can be prepared. According to the present invention, the cheap shikimic acid is adopted as the starting material, the whole process is simple, the harmful material is not used, the enzyme catalysis reaction and the directional overturning group are adopted, the possibility of the compound racemization is substantially reduced, the operation is simple, and the yield of the whole process route is stable.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemical industry, and in particular to a method for preparing oseltamivir. Background Art

[0002] Currently, oseltamivir is one of the most commonly used drugs for the treatment of influenza. Although the structure of oseltamivir is very simple, it contains a six-carbon ring and α, β unsaturated esters, with three chiral centers and three functional groups on the ring. Therefore, its synthesis becomes very challenging.

[0003] In the prior art, the synthetic route uses shikimic acid as a raw material, undergoes esterification, ketal protection, mesylation, ketal exchange, silica gel reduction, intramolecular cyclization to generate an epoxy intermediate, and then the epoxy intermediate is subjected to azidation ring opening, epoxide resinization and azide reduction, a total of 11 steps, and oseltamivir is obtained with a total yield of 20%. This method uses relatively unsafe sodium folding and intermediates containing sodium folding, and the raw material shikimic acid is extracted from traditional Chinese medicine; the prior art CN111253276B provides a method for preparing oseltamivir phosphate by using ethyl (3R, 4R, 5S)-4-(tert-butylamino)-5-(diallylamino)-3-(pentane-3-oxy)cyclohexyl-1-ene-1-carboxylate as a starting material, and undergoes deprotection, acetylation reaction, and palladium catalysis in a total of three steps; the prior art CN111747861A provides a method for preparing oseltamivir phosphate by an azide process, which uses relatively unsafe sodium folding and intermediates containing sodium folding.

[0004] However, in the existing technology, the source of raw materials is limited and cannot meet large-scale demand, or the raw materials are expensive or the yield is low, which is not suitable for industrial production. Summary of the invention

[0005] The purpose of the present invention is to provide a method for preparing oseltamivir, aiming to solve the technical problems in the prior art that the raw material source is limited and cannot meet large-scale demand, or the raw material price is expensive, or the yield is low and is not suitable for industrial production.

[0006] To achieve the above object, the present invention adopts a method for preparing oseltamivir, comprising the following reaction equation:

[0007] The first step chemical reaction equation:

[0008] The second step chemical reaction equation:

[0009]

[0010] The third step chemical reaction equation:

[0011]

[0012] The fourth step chemical reaction equation:

[0013]

[0014] The fifth step chemical reaction equation:

[0015] The chemical reaction equation of the sixth step:

[0016]

[0017] The seventh step chemical reaction equation:

[0018]

[0019] Step 8 Chemical reaction equation:

[0020]

[0021] The steps include:

[0022] In the formula, Cpd1 is the starting material, and the Cpd2 intermediate shown in the formula is obtained by esterification of acid and alcohol;

[0023] In the formula, Cpd2 undergoes a ketal reaction, and a dehydrating agent and a catalyst are added to react to obtain the Cpd3 intermediate shown in the formula;

[0024] In the formula, Cpd3 reacts with phthalimide in a reaction solvent through a Mitsunobu amino substitution reaction to obtain the Cpd4 intermediate shown in the formula;

[0025] In the formula, Cpd4 is catalyzed by triethylsilane and Lewis acid in a reaction solvent, and selective ring opening is performed to obtain the Cpd5 intermediate shown in the formula;

[0026] In the formula, Cpd5 is oxidized by TEMPO in a reaction solvent to obtain the Cpd6 intermediate shown in the formula;

[0027] In the formula, Cpd6 is enzymatically catalyzed by transaminase to directionally convert the carbonyl group into a chiral amino group to obtain the Cpd7 intermediate shown in the formula;

[0028] In the formula, Cpd7 is subjected to an acetylation reaction with an acetylation agent in a reaction solvent to obtain the Cpd8 intermediate shown in the formula;

[0029] In the formula, Cpd8 is removed from phthalimide in a reaction solvent using a catalyst to obtain Cpd9 shown in the formula.

[0030] Among them, in the step of preparing Cpd1 into Cpd2, the alcohol solvent can be any one of methanol, ethanol, and isopropanol, and the acid solvent can be any one of acetic acid, oxalic acid, dichlorothionyl, concentrated sulfuric acid, concentrated hydrochloric acid, and phosphoric acid, and the reaction temperature is 20 to 80°C.

[0031] Among them, in the step of preparing Cpd2 into Cpd3, the dehydrating agent can be any one of triethyl orthoformate, triethyl borate and trimethyl phosphate, and the catalyst can be any one of benzenesulfonic acid, p-toluenesulfonic acid and concentrated sulfuric acid.

[0032] Among them, in the Mitsunobu amino substitution reaction, the amino group is protected by a protecting group during the reaction, the protecting group used is phthalimide, and the equivalent range used is 1 to 2 equivalents.

[0033] Among them, in the step of preparing Cpd4 into Cpd5, the solvent used can be any one of dichloromethane, acetonitrile, tetrahydrofuran and methyl tert-butyl ether, the catalyst used can be any one of zinc dichloride, aluminum chloride, ferric chloride, titanium tetrachloride and boron trifluoride ether, and the amount of the catalyst used ranges from 1 to 1.5 equivalents.

[0034] In the step of converting Cpd5 into Cpd6, the oxidation catalyst used may be any one of TEMPO, copper oxide, iron oxide and titanium dioxide.

[0035] Among them, in the step of converting Cpd6 into Cpd7, the enzyme solution used in the enzyme-catalyzed reaction is a directed aminotransferase.

[0036] In the step of converting Cpd7 to Cpd8, the acetylating agent is any one of acetic anhydride, ethyl formate and acetyl chloride, and the amount of the acetylating agent added is 5 to 10 equivalents.

[0037] Wherein, in the step of converting Cpd8 into Cpd9, the catalyst used for deprotection can be any one of hydrazine hydrate, sodium borohydride and hydrochloric acid, and the added amount is 2 to 5 equivalents.

[0038] The method for preparing oseltamivir of the present invention has the following beneficial effects: oseltamivir is prepared through thionyl chloride esterification, cyclization, Mitsunobu amino substitution, selective ring opening, TEMPO oxidation, transaminase catalysis, acylation and deprotection, wherein esterification, oxidation and protecting group are all classical reactions, and then enzyme catalysis is combined to selectively add amino groups to obtain chiral compounds, and finally hydrazine hydrate is used for deprotection to obtain target compounds. The present invention uses cheap shikimic acid as a starting material, has a simple overall process, does not use highly hazardous materials, uses enzyme catalysis reaction, and directionally flips the groups, thereby greatly reducing the possibility of compound racemization, is simple to operate, and has a stable yield in the overall process route. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0040] Figure 1 It is a chemical reaction equation of a method for preparing oseltamivir of the present invention. DETAILED DESCRIPTION

[0041] See also Figure 1 The present invention provides a method for preparing oseltamivir, comprising the following reaction equation:

[0042] The first step chemical reaction equation:

[0043]

[0044] The second step chemical reaction equation:

[0045]

[0046] The third step chemical reaction equation:

[0047]

[0048] The fourth step chemical reaction equation:

[0049]

[0050] The fifth step chemical reaction equation:

[0051] The chemical reaction equation of the sixth step:

[0052]

[0053] The seventh step chemical reaction equation:

[0054]

[0055] Step 8 Chemical reaction equation:

[0056]

[0057] Further, the following steps are included:

[0058] In the formula, Cpd1 is the starting material, and the Cpd2 intermediate shown in the formula is obtained by esterification of acid and alcohol;

[0059] In the formula, Cpd2 undergoes a ketal reaction, and a dehydrating agent and a catalyst are added to react to obtain the Cpd3 intermediate shown in the formula;

[0060] In the formula, Cpd3 reacts with phthalimide in a reaction solvent through a Mitsunobu amino substitution reaction to obtain the Cpd4 intermediate shown in the formula;

[0061] In the formula, Cpd4 is catalyzed by triethylsilane and Lewis acid in a reaction solvent, and selective ring opening is performed to obtain the Cpd5 intermediate shown in the formula;

[0062] In the formula, Cpd5 is oxidized by TEMPO in a reaction solvent to obtain the Cpd6 intermediate shown in the formula;

[0063] In the formula, Cpd6 is enzymatically catalyzed by transaminase to directionally convert the carbonyl group into a chiral amino group to obtain the Cpd7 intermediate shown in the formula;

[0064] In the formula, Cpd7 is subjected to an acetylation reaction with an acetylation agent in a reaction solvent to obtain the Cpd8 intermediate shown in the formula;

[0065] In the formula, Cpd8 is removed from phthalimide in a reaction solvent using a catalyst to obtain Cpd9 shown in the formula.

[0066] Furthermore, in the step of converting Cpd1 into Cpd2, the alcohol solvent can be any one of methanol, ethanol, and isopropanol, and the acid solvent can be any one of acetic acid, oxalic acid, dichlorothionyl, concentrated sulfuric acid, concentrated hydrochloric acid, and phosphoric acid, and the reaction temperature is 20 to 80°C.

[0067] Furthermore, in the step of preparing Cpd2 into Cpd3, the dehydrating agent may be any one of triethyl orthoformate, triethyl borate and trimethyl phosphate, and the catalyst may be any one of benzenesulfonic acid, p-toluenesulfonic acid and concentrated sulfuric acid.

[0068] Furthermore, in the Mitsunobu amino substitution reaction, the amino group is protected with a protecting group during the reaction, the protecting group used is phthalimide, and the equivalent range used is 1 to 2 equivalents.

[0069] Furthermore, in the step of preparing Cpd4 into Cpd5, the solvent used may be any one of dichloromethane, acetonitrile, tetrahydrofuran and methyl tert-butyl ether, the catalyst used may be any one of zinc dichloride, aluminum chloride, ferric chloride, titanium tetrachloride and boron trifluoride ether, and the amount of the catalyst used may range from 1 to 1.5 equivalents.

[0070] Furthermore, in the step of converting Cpd5 into Cpd6, the oxidation catalyst used may be any one of TEMPO, copper oxide, iron oxide and titanium dioxide.

[0071] Furthermore, in the step of converting Cpd6 into Cpd7, the enzyme solution used in the enzyme-catalyzed reaction is a directed aminotransferase.

[0072] Furthermore, in the step of converting Cpd7 into Cpd8, the acetylating agent is any one of acetic anhydride, ethyl formate and acetyl chloride, and the amount of the acetylating agent added is 5 to 10 equivalents.

[0073] Furthermore, in the step of converting Cpd8 to Cpd9, the catalyst used for deprotection can be any one of hydrazine hydrate, sodium borohydride and hydrochloric acid, and the added amount is 2 to 5 equivalents.

[0074] In this embodiment,

[0075] Embodiment 1:

[0076] Preparation of Cpd2:

[0077] Add 200g of shikimic acid to the reaction bottle, add 1000mL of ethanol, protect with nitrogen, start stirring, prepare a constant pressure dropping funnel, weigh 13.66g of thionyl chloride, and slowly drip it into the reaction solution. Release heat to 38°C during the addition; after the addition is completed, heat up and reflux at 80-85°C for 4h. The reaction solution is milky white when the temperature is less than 80°C. Stable reflux at 80°C for 20-30min, the reaction solution gradually becomes clear, and after reacting for 4h, the reaction solution is cooled to 25-30°C, concentrated under reduced pressure, and concentrated into an oil to obtain 227.5g of a reddish-brown oil with a yield of 98%.

[0078] Embodiment 2:

[0079] Preparation of Cpd3:

[0080] 204g of triethyl orthoformate, 118g of 3-pentanone, 56mL of ethanol and 0.36g of p-toluenesulfonic acid were added to the reaction flask, and the mixture was stirred at room temperature for 3 hours under nitrogen protection. After reacting for 3 hours, the reaction solution was added to the Cpd2 prepared in the previous step, and stirred for another 2-3 hours at room temperature; after the reaction, 600mL of DCM and 200mL of tap water were added to the reaction flask, the mixture was stirred for 15 minutes and the layers were separated, saturated NaHCO3 was added to the organic phase, stirred for 15 minutes and separated, tap water was continued to be added to the organic phase, stirred for 15 minutes and separated, the aqueous phases were combined, and DCM was used for back extraction. The combined organic phases were collected, anhydrous sodium sulfate was added to the organic phase, dried and stirred, filtered to obtain a filtrate, and then concentrated under reduced pressure to obtain 285g of an oily substance, which solidified after standing, with a yield of 95%.

[0081] Embodiment 3:

[0082] Preparation of Cpd4:

[0083] Add the product Cpd3 from the previous step to the reaction bottle, add 2850 mL of benzene, stir evenly and then cool to 0-10°C, add 232.68 g of phthalimide and 27.65 g of triphenylphosphine, stir below 10°C for 30 min, then control the temperature and add 275.43 g of diethyl azodicarboxylate dropwise, after the addition is complete, heat to room temperature and react for 14 h, then heat to 40°C and react for 3 h, cool to room temperature after the reaction is complete, add ethyl acetate for extraction, collect the organic phase and concentrate under reduced pressure to obtain 337 g of Cpd4, with a yield of 80%.

[0084] Embodiment 4:

[0085] Preparation of Cpd5:

[0086] Add the product Cpd4 from the previous step to the reaction flask, add 2000mL of dichloromethane and stir evenly, then add 97.52g of triethylsilane and cool the reaction solution to -10 to -20°C, protect with nitrogen, prepare another reaction flask, dissolve 159g of titanium tetrachloride in 680mL of dichloromethane, pour into a constant pressure dropping funnel for standby use, control the temperature at -10 to -20°C and slowly add dropwise to the reaction flask, stir at this temperature for 1h, after the reaction is completed, slowly add 280mL of ice water to the reaction solution, control the temperature of the reaction solution at 0-5°C, stir and extract, wash the organic phase with saturated NaHCO3, collect the organic phase and concentrate under reduced pressure to obtain 286g of yellow oil with a yield of 85%.

[0087] Embodiment 5:

[0088] Preparation of Cpd6:

[0089] Add the product Cpd5 from the previous step to the reaction bottle, add 2860 mL of dichloromethane and stir evenly, then add 111.3 g of TEMPO and cool the solution to 0 to -5 ° C, protect with nitrogen, stir evenly and add 165.5 g of TCCA in batches under temperature control, and stir for 2 hours after the addition; after the reaction is completed, filter the reaction solution, rinse the filter cake with 500 mL of dichloromethane, add 5% sodium sulfite solution to the filtrate after filtration to quench the reaction, stir and perform separation extraction, collect the organic phase and concentrate under reduced pressure to obtain 227 g of Cpd6, with a yield of 80%.

[0090] Embodiment 6:

[0091] Preparation of Cpd7:

[0092] Add the product Cpd6 from the previous step to the reaction bottle, add 2250 mL of polyethylene glycol, start stirring, stir evenly, add 4500 mL of phosphate buffer solution to adjust the pH to 7-8, then add 382.5 g of isopropylamine, 22.5 g of pyridoxal phosphate and 9 g of transaminase in sequence, maintain the system pH at 7-8, react at room temperature 20-25°C for 48 hours, add 2N sodium hydroxide aqueous solution after the raw materials are consumed to adjust the pH to 10-12, stir evenly, add ethyl acetate for extraction, collect the organic phase and concentrate under reduced pressure to obtain 215 g of Cpd7 with a yield of 95%.

[0093] Embodiment 7:

[0094] Preparation of Cpd8:

[0095] Add the product Cpd7 from the previous step to the reaction bottle, start stirring, add 274g of acetic anhydride and 33g of anhydrous sodium acetate, heat the system to 110-116°C under nitrogen protection, and keep the temperature for 4h. After the reaction is qualified, cool the system to 45-50°C, add 500mL of ethyl acetate, stir for 20-30 minutes, add 250mL of water, continue to cool, extract after cooling to room temperature, collect the organic phase and concentrate under reduced pressure to obtain 210g of Cpd8 with a yield of 90%.

[0096] Embodiment 8:

[0097] Preparation of Cpd9:

[0098] The product Cpd8 from the previous step was added to the reaction flask, stirring was started, 1050 mL of ethanol and 95 g of hydrazine hydrate were added under nitrogen protection, and the reaction was refluxed for 24 h. After the insulation was completed, the system was cooled to room temperature, 200 mL of sodium hydroxide aqueous solution and 600 mL of dichloromethane were added for extraction, the organic phase was collected, and concentrated under reduced pressure to obtain 140 g of Cpd9 with a yield of 95%. The overall eight-step reaction yield was 41%.

[0099] What is disclosed above is only a preferred embodiment of the present invention, and it certainly cannot be used to limit the scope of rights of the present invention. Ordinary technicians in this field can understand that all or part of the processes of the above embodiment and equivalent changes made according to the claims of the present invention still fall within the scope of the invention.

Claims

1. A method for preparing oseltamivir, characterized in that: Including the following reaction equation: The first step chemical reaction equation: The second step chemical reaction equation: The third step chemical reaction equation: The fourth step chemical reaction equation: The fifth step chemical reaction equation: The chemical reaction equation of the sixth step: The seventh step chemical reaction equation: Step 8 Chemical reaction equation:

2. A method for preparing oseltamivir according to claim 1, characterized in that: The steps include: In the formula, Cpd1 is the starting material, and the Cpd2 intermediate shown in the formula is obtained by esterification of acid and alcohol; In the formula, Cpd2 undergoes a ketal reaction, and a dehydrating agent and a catalyst are added to react to obtain the Cpd3 intermediate shown in the formula; In the formula, Cpd3 reacts with phthalimide in a reaction solvent through a Mitsunobu amino substitution reaction to obtain the Cpd4 intermediate shown in the formula; In the formula, Cpd4 is catalyzed by triethylsilane and Lewis acid in a reaction solvent, and selective ring opening is performed to obtain the Cpd5 intermediate shown in the formula; In the formula, Cpd5 is oxidized by TEMPO in a reaction solvent to obtain the Cpd6 intermediate shown in the formula; In the formula, Cpd6 is enzymatically catalyzed by transaminase to directionally convert the carbonyl group into a chiral amino group to obtain the Cpd7 intermediate shown in the formula; In the formula, Cpd7 is subjected to an acetylation reaction with an acetylation agent in a reaction solvent to obtain the Cpd8 intermediate shown in the formula; In the formula, Cpd8 is removed from phthalimide in a reaction solvent using a catalyst to obtain Cpd9 shown in the formula.

3. A method for preparing oseltamivir according to claim 2, characterized in that: In the step of converting Cpd1 into Cpd2, the alcohol solvent can be any one of methanol, ethanol, and isopropanol, and the acid solvent can be any one of acetic acid, oxalic acid, dichlorothionyl, concentrated sulfuric acid, concentrated hydrochloric acid, and phosphoric acid. The reaction temperature is 20 to 80°C.

4. A method for preparing oseltamivir according to claim 2, characterized in that: In the step of preparing Cpd2 into Cpd3, the dehydrating agent may be any one of triethyl orthoformate, triethyl borate and trimethyl phosphate, and the catalyst may be any one of benzenesulfonic acid, p-toluenesulfonic acid and concentrated sulfuric acid.

5. A method for preparing oseltamivir according to claim 2, characterized in that: In the Mitsunobu amino substitution reaction, the amino group is protected with a protecting group during the reaction, the protecting group used is phthalimide, and the equivalent range used is 1 to 2 equivalents.

6. A method for preparing oseltamivir according to claim 2, characterized in that: In the step of preparing Cpd4 into Cpd5, the solvent used can be any one of dichloromethane, acetonitrile, tetrahydrofuran and methyl tert-butyl ether, the catalyst used can be any one of zinc dichloride, aluminum chloride, ferric chloride, titanium tetrachloride and boron trifluoride ether, and the amount of the catalyst used ranges from 1 to 1.5 equivalents.

7. A method for preparing oseltamivir according to claim 2, characterized in that: In the step of converting Cpd5 into Cpd6, the oxidation catalyst used may be any one of TEMPO, copper oxide, iron oxide and titanium dioxide.

8. A method for preparing oseltamivir according to claim 2, characterized in that: In the step of converting Cpd6 into Cpd7, the enzyme solution used in the enzyme-catalyzed reaction is a directed aminotransferase.

9. A method for preparing oseltamivir according to claim 2, characterized in that: In the step of converting Cpd7 to Cpd8, the acetylating agent is any one of acetic anhydride, ethyl formate and acetyl chloride, and the amount of the acetylating agent added is 5 to 10 equivalents.

10. A method for preparing oseltamivir according to claim 2, characterized in that: In the step of converting Cpd8 to Cpd9, the catalyst used for deprotection can be any one of hydrazine hydrate, sodium borohydride and hydrochloric acid, and the added amount is 2 to 5 equivalents.

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