CN114181117A - Preparation method of peramivir intermediate - Google Patents
Preparation method of peramivir intermediate Download PDFInfo
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- CN114181117A CN114181117A CN202010966511.4A CN202010966511A CN114181117A CN 114181117 A CN114181117 A CN 114181117A CN 202010966511 A CN202010966511 A CN 202010966511A CN 114181117 A CN114181117 A CN 114181117A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
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- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
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Abstract
The invention discloses a preparation method of a peramivir intermediate, which comprises the following steps: adding (3aR, 4R, 6S, 6aS) -4- ((tert-butoxycarbonyl) amino) -3- (pentane-3-yl) -3a, 5, 6, 6 a-tetrahydro-4H-cyclopentane [ d ] isoxazole-6-carboxylic acid methyl ester and nickel chloride into a mixed solution of methanol and dichloromethane, and adding a methanol solution of sodium borohydride and sodium hydroxide, adding an aqueous solution of sodium nitrite, ethylenediamine tetraacetic acid and ammonia water after the reaction is finished, stirring and quenching, extracting, concentrating under reduced pressure, and crystallizing a mixed solvent of alcohol and water to obtain the peramivir intermediate (1S, 2S, 3S, 4R) -3- ((S) -1-amino-2-ethylbutyl) -4- ((tert-butoxycarbonyl) amino) -2-hydroxycyclopentane-1-carboxylic acid methyl ester.
Description
Technical Field
The invention relates to a preparation method of a drug intermediate, in particular to a preparation method of a peramivir intermediate (1S, 2S, 3S, 4R) -3- ((S) -1-amino-2-ethylbutyl) -4- ((tert-butyloxycarbonyl) amino) -2-hydroxycyclopentane-1-carboxylic acid methyl ester.
Background
Peramivir, english name: peramivir trihydrate, the chemical name of which is (1S, 2S, 3R, 4R, 1 ' S) -3- [ (1 ' -acetylamino-2 ' -ethyl) ] -4- [ [ (aminoimino) -methyl ] amino ] -2-carboxycyclopentane-1-carboxylic acid, is a cyclopentane derivative neuraminidase inhibitor developed by American Biocryst Pharmaceuticals, achieves the effect of preventing and treating influenza A and B by inhibiting the interaction between influenza neuraminidases and releasing and increasing the virus particles of tissue filial generation in host cells, has the advantages of good tolerance, small toxicity, suitability for injection and the like, and is an anti-influenza virus medicament with wide prospect. However, the production cost and price of the medicine are relatively high for different patients. With the gradual expansion of the market demand for anti-influenza drugs, new requirements for further process improvement and production cost reduction are also provided in the technology, and the work in this aspect is very meaningful for enterprises and society, while in the step of synthesizing the compound 2 by the compound 1, the system is complex because the system is a metal-catalyzed reduction reaction, and each synthesis route reported at present has own defects.
The synthetic methods that have been reported are mainly:
the synthetic route reported by the company Biocrystal Pharmaceutical in J.Med.chem.,2000,43,3482-3486 is as follows:
the specific method comprises the following steps: compound 1 is dissolved in methanol and reacted with hydrogen, 100psi hydrogen chloride, in the presence of platinum dioxide as a catalyst to form compound 2. Obviously, the method uses noble metal platinum and requires high-pressure reaction, which is not suitable for industrial scale production.
2. The report of the research of the toxic drugs of the military medical academy of sciences in CN101367750B shows that the synthetic route is as follows:
the specific method comprises the following steps: preparing a methanol solution of sodium hydroxide and sodium borohydride for later use, dissolving a compound 1 and nickel chloride hexahydrate in methanol, cooling to-10-5 ℃, keeping the temperature, slowly dropwise adding the methanol solution of sodium hydroxide and sodium borohydride, stirring after the addition, reacting, adding an aqueous solution of sodium nitrite, ammonium chloride and ammonia water, stirring at room temperature, performing suction filtration, washing, adding toluene and ammonia water into a filter cake, heating to 75-80 ℃, stirring and dissolving, separating, washing an organic phase with an aqueous solution of ammonia water and disodium ethylenediamine tetraacetate at 70-80 ℃, separating, cooling, stirring and crystallizing the organic phase, and finally obtaining a compound 2 with the final yield of 73.2%. Compared with the former method, the method is greatly improved, but the system is difficult to post-treat, the reduction time is longer, the solid-liquid separation time is longer, the material viscosity is larger, and the material transfer is difficult.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to provide a preparation method of peramivir intermediate (1S, 2S, 3S, 4R) -3- ((S) -1-amino-2-ethylbutyl) -4- ((tert-butoxycarbonyl) amino) -2-hydroxycyclopentane-1-carboxylic acid methyl ester, which solves the objective and practical problems existing in the preparation of the peramivir intermediate in the prior art and reduces the cost of industrial production.
The technical scheme is as follows: the preparation method of peramivir intermediate (1S, 2S, 3S, 4R) -3- ((S) -1-amino-2-ethylbutyl) -4- ((tert-butyloxycarbonyl) amino) -2-hydroxycyclopentane-1-carboxylic acid methyl ester provided by the invention comprises the following reaction:
the compound 1 and nickel chloride react with a methanol solution of sodium borohydride and sodium hydroxide in a mixed solvent of methanol and dichloromethane.
The preparation method also comprises the step of quenching reaction of aqueous solution of sodium nitrite, ethylenediamine tetraacetic acid and ammonia water.
The preparation method also comprises the steps of adding aqueous solution of sodium nitrite, ethylene diamine tetraacetic acid and ammonia water for quenching reaction, extracting, concentrating and crystallizing the mixed solvent of alcohol and water.
According to the preparation method, the nickel chloride is selected from anhydrous nickel chloride and hydrated nickel chloride, and preferably hydrated nickel chloride.
In the preparation method, the nickel chloride is nickel chloride hexahydrate.
According to the preparation method, the mass volume ratio of the compound 1 to the dichloromethane is selected from 1: 1-1: 10, preferably 1: 2-1: 8, more preferably 1:3 to 1: 5.
according to the preparation method, the molar ratio of the compound 1 to the nickel chloride is selected from 1: 0.05-1: 0.5, preferably 1: 0.1-1: 0.2.
according to the preparation method, the extraction solvent is dichloromethane.
Has the advantages that: compared with the prior art, the invention has the following remarkable characteristics: the method has the characteristics of simple operation, high raw material conversion rate, low byproduct content, simple subsequent purification treatment, low nickel-containing wastewater amount, obviously reduced production cost, suitability for industrial production and remarkable social and economic benefits.
Detailed Description
Example 1(1.1eq nickel chloride hexahydrate)
0.18g of sodium hydroxide, 6.41g of sodium borohydride and 60mL of methanol were added to a beaker and dissolved with stirring.
To a reaction flask were added 20.00g of Compound 1, 14.75g of nickel chloride hexahydrate, 60mL of dichloromethane, 20mL of methanol, and the temperature was lowered to-5 ℃. And (3) dropwise adding the prepared sodium borohydride and sodium hydroxide methanol solution at the temperature of-5 ℃ in the internal temperature, reacting for 15min at the temperature of-5 ℃, and stopping the reaction when TLC detects that the 1 point of the compound disappears.
19.79g of ethylenediamine tetraacetic acid, 11.68g of sodium nitrite, 20mL of ammonia water and 100mL of water were added to a beaker and dissolved by stirring.
Adding the prepared water solution of ethylene diamine tetraacetic acid, sodium nitrite and ammonia water into the reaction solution to quench the reaction, extracting with 200mL of dichloromethane, and separating the water phase; the organic phase is washed 1 time with 100mL of water and evaporated to dryness under reduced pressure. Methanol (200 mL) and water (100 mL) were added to the reaction solution, and the crystals were filtered and dried to obtain 14.58g of Compound 2. Purity: 97.44%, yield: 70.2 percent.
Example 2(0.05eq nickel chloride hexahydrate)
0.17g of sodium hydroxide, 6.44g of sodium borohydride and 60mL of methanol were added to a beaker and dissolved with stirring.
To a reaction flask were added 20.00g of Compound 1, 0.67g of nickel chloride hexahydrate, 60mL of dichloromethane, 20mL of methanol, and the temperature was lowered to 20 ℃. And (3) dropwise adding the prepared sodium borohydride and sodium hydroxide methanol solution at the temperature of-5 ℃ in the internal temperature, reacting for 15min at the temperature of-5 ℃, and stopping the reaction when TLC detects that the 1 point of the compound disappears.
1.98g of ethylenediamine tetraacetic acid, 3.89g of sodium nitrite, 20mL of ammonia water and 100mL of water are added to a beaker and dissolved by stirring.
Adding the prepared water solution of ethylene diamine tetraacetic acid, sodium nitrite and ammonia water into the reaction solution to quench the reaction, extracting with 200mL of dichloromethane, and separating the water phase; the organic phase is washed 1 time with 100mL of water and evaporated to dryness under reduced pressure. Methanol (200 mL) and water (100 mL) were added to the reaction solution, and the crystals were filtered and dried to obtain 14.84g of Compound 2. Purity: 97.31%, yield: 71.4 percent.
Example 3(0.2eq nickel chloride hexahydrate)
0.17g of sodium hydroxide, 6.47g of sodium borohydride and 60mL of methanol were added to a beaker and dissolved with stirring.
20.00g of Compound 1, 2.68g of nickel chloride hexahydrate, 60mL of dichloromethane and 20mL of methanol were added to a reaction flask and the temperature was reduced to-5 ℃. And (3) dropwise adding the prepared sodium borohydride and sodium hydroxide methanol solution at the temperature of-5 ℃ in the internal temperature, reacting for 15min at the temperature of-5 ℃, and stopping the reaction when TLC detects that the 1 point of the compound disappears.
3.63g of ethylenediamine tetraacetic acid, 3.92g of sodium nitrite, 20mL of ammonia water and 100mL of water were added to a beaker and dissolved by stirring.
Adding the prepared water solution of ethylene diamine tetraacetic acid, sodium nitrite and ammonia water into the reaction solution to quench the reaction, extracting with 200mL of dichloromethane, and separating the water phase; the organic phase is washed 1 time with 100mL of water and evaporated to dryness under reduced pressure. Methanol (200 mL) and water (100 mL) were added to the reaction solution, and the crystals were filtered and dried to obtain 15.90g of Compound 2. Purity: 97.56%, yield: 76.7 percent.
Example 4(1.1eq of Nickel chloride comparative experiment 1) without addition of dichloromethane
0.18g of sodium hydroxide, 6.43g of sodium borohydride and 100mL of methanol were added to a beaker and dissolved with stirring.
20.00g of Compound 1, 14.79g of nickel chloride hexahydrate and 100mL of methanol were added to a reaction flask and the temperature was reduced to-5 ℃. And (3) dropwise adding the prepared sodium borohydride and sodium hydroxide methanol solution at the temperature of-5 ℃ in the internal temperature, reacting for 15min at the temperature of-5 ℃, and stopping the reaction when TLC detects that the 1 point of the compound disappears.
19.81g of ethylenediamine tetraacetic acid, 11.65g of sodium nitrite, 20mL of ammonia water and 100mL of water were added to a beaker and dissolved by stirring.
Adding the prepared water solution of ethylene diamine tetraacetic acid, sodium nitrite and ammonia water into the reaction solution to quench the reaction, extracting with 200mL of dichloromethane, and separating the water phase; the organic phase is washed 1 time with 100mL of water and evaporated to dryness under reduced pressure. Methanol (200 mL) and water (100 mL) were added to the reaction solution, and the crystals were filtered and dried to obtain 14.40g of Compound 2. Purity: 96.39%, yield: 68.6 percent.
Example 5(0.2eq Nickel chloride hexahydrate comparative experiment 2) without dichloromethane
0.18g of sodium hydroxide, 6.43g of sodium borohydride and 100mL of methanol were added to a beaker and dissolved with stirring.
20.00g of Compound 1, 2.69g of nickel chloride hexahydrate and 80mL of methanol were added to a reaction flask and the temperature was reduced to-5 ℃. And (3) dropwise adding the prepared sodium borohydride and sodium hydroxide methanol solution at the temperature of-5 ℃ in the internal temperature, reacting for 15min at the temperature of-5 ℃, detecting more compound 1 by TLC, continuously stirring for 1h, detecting that the compound 1 by TLC is basically consistent with the compound 1 for 15min, and detecting by HPLC: compound 2: 29.23%, compound 1: 16.50%, other maximum single heteroatoms: 24.58 percent.
Example 6(0.2eq Nickel chloride hexahydrate, 1-fold methylene chloride experiment)
0.17g of sodium hydroxide, 6.44g of sodium borohydride and 60mL of methanol were added to a beaker and dissolved with stirring.
To a reaction flask were added 20.00g of Compound 1, 2.67g of nickel chloride hexahydrate, 20mL of dichloromethane, 20mL of methanol, and the temperature was lowered to-5 ℃. And (3) dropwise adding the prepared sodium borohydride and sodium hydroxide methanol solution at the temperature of-5 ℃ in the internal temperature, reacting for 15min at the temperature of-5 ℃, and stopping the reaction when TLC detects that the 1 point of the compound disappears.
3.64g of ethylenediamine tetraacetic acid, 3.96g of sodium nitrite, 20mL of ammonia water and 100mL of water were added to a beaker and dissolved by stirring.
Adding the prepared water solution of ethylene diamine tetraacetic acid, sodium nitrite and ammonia water into the reaction solution to quench the reaction, extracting with 200mL of dichloromethane, and separating the water phase; the organic phase is washed 1 time with 100mL of water and evaporated to dryness under reduced pressure. Methanol (200 mL) and water (100 mL) were added to the reaction solution, and the crystals were filtered and dried to obtain 14.74g of Compound 2. Purity: 95.96%, yield: 69.9 percent.
Example 7(0.2eq nickel chloride hexahydrate, 10 times the amount of methylene chloride test)
0.16g of sodium hydroxide, 6.35g of sodium borohydride and 60mL of methanol were added to a beaker and dissolved with stirring.
To a reaction flask were added 20.00g of Compound 1, 2.74g of nickel chloride hexahydrate, 200mL of dichloromethane, 20mL of methanol, and the temperature was lowered to-5 ℃. And (3) dropwise adding the prepared sodium borohydride and sodium hydroxide methanol solution at the temperature of-5 ℃ in the internal temperature, reacting for 15min at the temperature of-5 ℃, and stopping the reaction when TLC detects that the 1 point of the compound disappears.
3.69g of ethylenediamine tetraacetic acid, 3.99g of sodium nitrite, 20mL of ammonia water and 100mL of water are added into a beaker and stirred to be dissolved.
Adding the prepared water solution of ethylene diamine tetraacetic acid, sodium nitrite and ammonia water into the reaction solution to quench the reaction, extracting with 200mL of dichloromethane, and separating the water phase; the organic phase is washed 1 time with 100mL of water and evaporated to dryness under reduced pressure. Methanol (200 mL) and water (100 mL) were added to the reaction solution, and the crystals were filtered and dried to obtain 15.94g of Compound 2. Purity: 97.36%, yield: 76.7 percent.
Example 8 (comparative experiment for toluene extraction crystallization)
0.18g of sodium hydroxide, 6.44g of sodium borohydride and 100mL of methanol were added to a beaker and dissolved with stirring.
20.00g of Compound 1, 14.71g of nickel chloride hexahydrate and 100mL of methanol were added to a reaction flask and the temperature was reduced to-5 ℃. And (3) dropwise adding the prepared sodium borohydride and sodium hydroxide methanol solution at the temperature of-5 ℃ in the internal temperature, reacting for 15min at the temperature of-5 ℃, and stopping the reaction when TLC detects that the 1 point of the compound disappears.
19.85g of ethylenediamine tetraacetic acid, 11.69g of sodium nitrite, 20mL of ammonia water and 100mL of water were added to a beaker and dissolved by stirring.
Adding the prepared aqueous solution of ethylene diamine tetraacetic acid, sodium nitrite and ammonia water into the reaction solution to quench the reaction, heating 140mL of toluene to 70-80 ℃ for extraction, and separating a water phase; the organic phase is washed 1 time with 100mL of water, cooled to room temperature, crystallized, filtered and dried to give 11.66g of Compound 2. Purity: 97.28%, yield: 56.1 percent. (higher viscosity of the material during suction filtration and more difficulty in transferring the material)
From the experimental results, it is clear that the reaction does not completely convert and the selectivity is poor when the amount of nickel chloride hexahydrate is reduced by using only methanol as a solvent. When equivalent amounts of nickel chloride hexahydrate are used, the reaction can be fully converted and the selectivity is better, which is consistent with literature reports. When a proper amount of dichloromethane is added into a reaction system for reaction, the reduction of the use amount of nickel chloride hexahydrate has no great influence on the conversion rate and the selectivity of the reaction. The reaction is proved to actually reduce the dosage of the nickel chloride, and the complete reaction can still be ensured only by adding a catalytic amount of the nickel chloride hexahydrate.
The extraction operation is carried out by using dichloromethane instead of methylbenzene in the reaction post-treatment process, the extraction can be completed at normal temperature, the high-temperature extraction operation is avoided, the process safety risk is reduced, the alcohol and water mixed system is used for crystallization, the fluidity of a crystalline liquid is good in the suction filtration process, and the problem that the material is difficult to transfer due to large viscosity is solved.
Claims (8)
1. A preparation method of peramivir intermediate methyl (1S, 2S, 3S, 4R) -3- ((S) -1-amino-2-ethylbutyl) -4- ((tert-butoxycarbonyl) amino) -2-hydroxycyclopentane-1-carboxylate is characterized by comprising the following steps:
the compound 1 and nickel chloride react with a methanol solution of sodium borohydride and sodium hydroxide in a mixed solvent of methanol and dichloromethane.
2. The method according to claim 1, further comprising a step of quenching the reaction with an aqueous solution of sodium nitrite, ethylenediaminetetraacetic acid, and aqueous ammonia.
3. The method according to claim 1, further comprising the steps of adding an aqueous solution of sodium nitrite, ethylenediaminetetraacetic acid, and aqueous ammonia to quench the reaction, extracting, concentrating, and crystallizing the alcohol-water mixed solvent.
4. The method according to claim 1, wherein the nickel chloride is selected from the group consisting of anhydrous nickel chloride and hydrated nickel chloride.
5. The method of claim 1, wherein the nickel chloride is nickel chloride hexahydrate.
6. The method according to claim 1, wherein the mass-to-volume ratio of compound 1 to dichloromethane is selected from 1:1 to 1: 10.
7. the method of claim 1, wherein the molar ratio of compound 1 to nickel chloride is selected from the group consisting of 1: 0.05-1: 0.5.
8. the method according to claim 3, wherein the extraction solvent is methylene chloride.
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| CN114853636B (en) * | 2022-05-27 | 2024-04-02 | 温州海鹤药业有限公司 | Preparation method of peramivir intermediate |
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