CN100432047C - Synthesis process of peramivir as medicine for antagonizing influenza and bird flu virus - Google Patents

Abstract

The present invention relates to medicine compound, and discloses synthesis process of peramivir as medicine for antagonizing influenza and bird flu virus. The present invention synthesizes peramivir with Wins lactam and 2-ethyl butyl aldehyde as main materials and through an eight-step process. The preparation process of the present invention is simple, cheap in material and environment friendly, and has high yield, including single step reaction yield of 80-95 % and total yield up to 52.7 %.

Description

A kind of synthetic method of anti-influenza and avian influenza virus drug peramivir

technical field

The invention relates to the field of pharmaceutical compounds, in particular to a synthesis method of peramivir, an anti-influenza and avian influenza virus drug.

Background technique

Peramivir, the English name is peramivir, the chemical name is (±)-t-3-(1'-acetamido-2'-ethyl)butyl-c-4-guanidino-t-2-hydroxy Cyclopentyl-1-carboxylic acid, with a structure such as formula (I), is a cyclopentane derivative neuraminidase inhibitor jointly developed by the American BioCryst Pharmaceuticals company and the R.W.Johnson Institute of Drug Research. The drug can effectively inhibit the replication and transmission process of various influenza virus strains, has the advantages of good tolerance, low toxicity, etc., and is a very promising anti-influenza chemotherapeutic drug.

The current synthetic preparation method of peramivir mainly contains the patent of BioCryst Pharmaceuticals (International Patent Application PCT/US98126871, 17Dec, 1998.WO99/33781, 08July, 1999).

The chemical reaction formula of BioCryst Pharmaceuticals' patented method is as follows:

The method is to use Wens lactam as a raw material to obtain the final product through more than ten steps of reaction. Not only the steps are long and the yield is low (the total yield is less than 30%), but also expensive carbon dioxide is used in the catalytic hydrogenation process. Platinum is used as a catalyst, and highly toxic benzene cyanide is used in the preparation of aldoxime, and benzene is used as a solvent. The cost is high, the environmental protection requirements are high, the operation is difficult, and it is not suitable for industrial production.

Contents of the invention

The purpose of the present invention is to overcome the problems existing in the existing peramivir synthesis method, and provide a peramivir synthesis method with simple steps, low cost, safety and environmental protection.

In order to achieve the above object, the present invention adopts following synthetic method:

Specific steps are as follows:

1. Dissolve Wens lactam in anhydrous methanol, then continue to pass dry HCl gas at room temperature for 2 hours, then heat to 45°C and stir for 1 hour. After the reaction was complete, it was concentrated, crystallized, filtered and dried to obtain a white solid. This solid was the hydrochloride salt of methyl (±)-cis-4-aminocyclopent-2-ene-1-carboxylate.

2. Put the mixture of (±)-cis-4-aminocyclopent-2-ene-1-carboxylic acid methyl ester hydrochloride, NaHCO ₃ , BOC ₂ O into dichloromethane at a molar ratio of 1 : 0.5～2: 1～1.5. Stir at room temperature for 3 hours. Gas was released during the reaction. After the reaction, the organic layer was washed successively with water and saturated brine, and dried over anhydrous Na ₂ SO ₄ . After distilling off the solvent, an oil was obtained. Recrystallized from a mixed solution of n-hexane:ethyl acetate=95:5 to obtain (±)-cis-4-tert-butoxycarbonamidocyclopent-2-ene-1-carboxylic acid methyl ester as white crystals.

3. Dissolve hydroxylamine hydrochloride and potassium carbonate in water, and after there are no more bubbles, slowly add the ethanol (99%) solution of 2-ethylbutyraldehyde dropwise under ice bath. After the dropwise addition was completed, the mixture was stirred at room temperature for 2 hours. Then it was diluted with ice water, extracted with ether, the organic phase was washed with water, washed with saturated brine, dried over anhydrous NaSO ₄ , and concentrated to give 2-ethyl-butyraldehyde oxime as a colorless oily product.

4. Put (±)-cis-4-tert-butoxycarbonamidocyclopent-2-ene-1-carboxylic acid methyl ester, 2-ethyl-butyraldehyde oxime in molar ratio of 1:3.5～7 In dichloromethane, NaOCl (9.4%) solution was slowly added dropwise in an ice bath and protected from light. After the dropwise addition, the reaction was continued for 0.5h, and then heated to room temperature for 7h. After the reaction was complete, it was washed with water, and the aqueous phase was extracted twice with dichloromethane. The organic phases were combined, washed with water successively, dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure to obtain a viscous liquid. Then it was recrystallized from a mixed solvent of petroleum ether: ethyl acetate (90:10) to obtain white crystals.

5. Transfer the above product into a hydrogenation reaction bottle, add a hydrogenation catalyst (PtO ₂ or palladium-activated carbon), concentrated hydrochloric acid and methanol, and slightly heat hydrogenation under pressure. After hydrogenation, blow N _{for half} an hour, pass the product through diatomaceous earth, distill the filtrate under reduced pressure to remove the solvent, and dry in vacuo to obtain a colorless or light yellow solid, which is (±)-t-3-(1'-amino- 2'-Ethyl)butyl-c-4-tert-butoxycarbonamido-t-2-hydroxycyclopentyl-r-1-carboxylic acid methyl ester hydrochloride.

(±)-t-3-(1'-amino-2'-ethyl)butyl-c-4-tert-butoxycarbonamido-t-2-hydroxycyclopentyl-r-1-carboxylic acid The hydrochloride of methyl ester was dissolved in dichloromethane, anhydrous acetic anhydride was added, and stirred at room temperature for 16h. After the reaction was complete, water was added, the organic layer was separated, the aqueous phase was extracted several times with dichloromethane, the organic phases were combined, washed with water and saturated brine successively, dried over anhydrous Na ₂ SO ₄ , and evaporated under reduced pressure to remove the solvent to obtain a white solid product ( ±)-t-3-(1'-acetamido-2'-ethyl)butyl-c-4-tert-butoxycarbonamido-t-2-hydroxycyclopentyl-r-1-carboxylic acid methyl ester.

6. Dissolve the above product in anhydrous ether, pass dry hydrogen chloride gas under reflux for 0.5h, stir at room temperature for 10 hours, and filter to obtain a white or yellowish white solid, namely (±)-t-3-(1'- Acetamido-2'-ethyl)butyl-c-4-amino-t-2-hydroxycyclopentyl-r-1-carboxylic acid methyl ester hydrochloride.

Dissolve this intermediate, N,N-1,3-di-tert-butoxycarbonyl-2-methyl-2-isothiourea and mercuric chloride in DMF, and stir at room temperature for 20 hours. Dilute with ethyl acetate to produce a white precipitate, filter, discard the filter residue, wash the filtrate with water and saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a yellow sticky solid. The white solid product (±)-t-3-(1'-acetamido-2'-ethyl)butyl-c-4 was obtained by column separation with petroleum ether:ethyl acetate=3:7～1:1 -(N,N-1",3"-di-tert-butoxycarbonyl)guanidino-t-2-hydroxycyclopentyl-r-1-carboxylic acid methyl ester.

7. Add (±)-t-3-(1'-acetamido-2'-ethyl)butyl-c-4-(N,N-1",3"-di-tert-butoxycarbonyl)guanidine Dissolve methyl-t-2-hydroxycyclopentyl-r-1-carboxylate in a mixed solvent (THF:ethanol=1:1), and slowly add 1M sodium hydroxide solution dropwise. Stir at room temperature for 3 hours, evaporate the solvent, add a little water, adjust to weak acidity with ice 1M hydrochloric acid solution, and extract with ethyl acetate. The obtained organic phase was washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a white solid (±)-t-3-(1'-acetamido-2'-ethyl)butyl-c-4-( N,N-1",3"-di-tert-butoxycarbonyl)guanidino-t-2-hydroxycyclopentane-r-1-carboxylic acid.

8. Put the above product, trifluoroacetic acid, and Et ₃ SiH into dichloromethane, stir at room temperature for 24 hours, distill off the solvent under reduced pressure, wash the obtained dry matter with ether to obtain a yellow solid, and then pass methanol: water = 1: 1 was recrystallized from a mixed solvent to obtain white crystals (±)-t-3-(1'-acetamido-2'-ethyl)butyl-c-4-guanidino-t-2-hydroxycyclopentyl- 1-Carboxylic acid, namely peramivir.

Compared with the prior art, the present invention adopts the following beneficial effects: the present invention is aimed at the deficiencies of the existing peramivir synthetic method, and uses cheap palladium carbon as the catalyst in the catalytic hydrogenation process; Ethanol and potassium carbonate replaced highly toxic benzene cyanide and benzene, which achieved the purpose of reducing production costs, avoiding the use of highly toxic raw materials, and reducing pollution; the synthesis steps were changed from more than ten steps to eight steps, which simplified the synthesis steps; In addition, the synthesis method of the present invention has mild reaction conditions, simple equipment, easy operation and high yield. The single-step reaction reaches 80%-95%, and the total yield can reach 52.7%.

Description of drawings

Fig. 1 is the ¹ HNMR spectrogram of (±)-cis-4-tert-butoxycarbonamidocyclopent-2-ene-1-carboxylic acid methyl ester;

Fig. 2 is the MS spectrogram of (±)-cis-4-tert-butoxycarbonamidocyclopent-2-ene-1-carboxylic acid methyl ester;

Figure 3 is (±)-4-tert-butoxycarbonamido-3-(1'-ethyl)propyl-4,5,6,6a-4H-3aH-cyclopentyl[d]isoxazole- ¹ HNMR spectrum of methyl 6-carboxylate;

Figure 4 is (±)-4-tert-butoxycarbonamido-3-(1'-ethyl)propyl-4,5,6,6a-4H-3aH-cyclopentyl[d]isoxazole- The MS spectrum of methyl 6-carboxylate;

Figure 5 is (±)-t-3-(1'-acetamido-2'-ethyl)butyl-c-4-tert-butoxycarbonamido-t-2-hydroxycyclopentyl-r- ¹ HNMR spectrum of methyl 1-carboxylate;

Figure 6 is (±)-t-3-(1'-acetamido-2'-ethyl)butyl-c-4-tert-butoxycarbonamido-t-2-hydroxycyclopentyl-r- The MS spectrum of 1-methyl carboxylate;

Figure 7 is (±)-t-3-(1'-acetamido-2'-ethyl)butyl-c-4-(N,N-1", 3"-di-tert-butoxycarbonyl)guanidine The ¹ HNMR spectrum of methyl-t-2-hydroxycyclopentyl-r-1-carboxylate;

Figure 8 is (±)-t-3-(1'-acetamido-2'-ethyl)butyl-c-4-(N,N-1", 3"-di-tert-butoxycarbonyl)guanidine The MS spectrum of base-t-2-hydroxycyclopentyl-r-1-carboxylic acid methyl ester;

Figure 9 is (±)-t-3-(1'-acetamido-2'-ethyl)butyl-c-4-(N,N-1", 3"-di-tert-butoxycarbonyl)guanidine The ¹ HNMR spectrum of base-t-2-hydroxycyclopentyl-r-1-carboxylic acid;

Figure 10 is (±)-t-3-(1'-acetamido-2'-ethyl)butyl-c-4-(N,N-1", 3"-di-tert-butoxycarbonyl)guanidine The MS spectrum of base-t-2-hydroxycyclopentyl-r-1-carboxylic acid;

Figure 11 is the ¹ HNMR spectrum of peramivir;

Figure 12 is the MS spectrum of peramivir;

Detailed ways

Example 1

1. Add 5 grams of Vince lactam and 50 ml of methanol into a 250ml three-neck flask with magnetic stirring, reflux condenser, and drying tube, then continue to pass dry HCl gas at room temperature for 2 hours, then heat to 45°C and stir for 2 hours. The solvent was distilled off under reduced pressure to obtain a light yellow viscous substance. 100 ml of diethyl ether was added to the viscous substance, and stirred at room temperature for 2 hours. A white precipitate precipitated out, which was filtered and dried to obtain a white solid product. This solid is the hydrochloride salt of methyl (±)-cis-4-aminocyclopent-2-ene-1-carboxylate.

Yield 7.7 g, Yield: 95.2%

2. 2.05 grams (11.5mmol) of gained hydrochloride, NaHCO ₃ 0.81 grams (8.1mmol), BOC ₂ O2.61 grams (11.9mmol), methylene chloride 50ml, drop in the round bottom flask of 250ml, then room temperature Stir for 3 hours. Thin-layer chromatography monitored the reaction endpoint. After the reaction was completed, wash with water, separate the organic layer, extract the aqueous layer twice with dichloromethane, combine the organic phases, wash with water, wash with saturated brine, dry over anhydrous Na ₂ SO ₄ , and evaporate the solvent under reduced pressure to obtain an oily substance. The oil was rinsed with a mixed solution of n-hexane: ethyl acetate = 95:5 to obtain white crystals (±)-cis-4-tert-butoxycarbonamidocyclopent-2-ene-1-carboxylate acid methyl ester (1).

Yield: 2.62 g, Yield: 94.6%

Melting point: 36°C

Elemental analysis: C ₁₂ H ₁₉ NO ₄ MW: 241.12

Calculated: C 59.72 H 7.88 N 5.80 O 26.54

Analytical value: C 59.57 H 8.62 N 5.65 O 26.31

The ¹ HNMR and MS spectra of the product are shown in Fig. 1 and Fig. 2 .

3. Dissolve 3.0 grams of hydroxylamine hydrochloride in 25 ml of water, and then add 4 grams of potassium carbonate therein. After no more bubbles were generated, 25 ml of a solution of 2-ethylbutyraldehyde (4 g) in ethanol (99%) was slowly added dropwise under an ice bath. After the dropwise addition was completed, the mixture was stirred at room temperature for 1 hour. It was then diluted to 500ml with ice water, extracted three times with ether, washed with water, washed with saturated brine, dried over anhydrous NaSO ₄ , and concentrated to give 3 g of a colorless oily substance, namely 2-ethylbutyraldehyde oxime.

4. Put 5.18 grams (0.021mol) of (1) and 7.25 grams (0.063mol) of 2-ethylbutyraldehyde oxime into 20.7ml of dichloromethane, and slowly add NaOCl (9.4% ) 38.6 g (0.048 mol) solution. After the dropwise addition, the reaction was continued for half an hour, and then heated to room temperature for 8 hours. Thin-layer chromatography monitored the reaction endpoint. After the reaction was completed, the organic phase was separated, and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, washed with water, dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure. Recrystallize from a mixed solvent of petroleum ether: ethyl acetate (90:10) to obtain 7.1 g of white crystals, namely (±)-4-tert-butoxycarbonamido-3-(1'-ethyl)propyl -4,5,6,6a-methyl 4H-3aH-cyclopentyl[d]isoxazole-6-carboxylate (3). Yield: 95.4%

Melting point: 107～108℃

Elemental analysis: C ₁₈ H ₃ 0N ₂ O ₅ MW: 354.21

Calculated: C 60.98 H 8.47 N 7.90 O 22.58

Analytical value: C 60.29 H 8.32 N 7.75 O 22.41

^{The 1} HNMR and MS spectra of the product are shown in Fig. 3 and Fig. 4 .

5. Transfer 1 g (2.8 mmol) of (3), 0.156 g of palladium-carbon, and 95.2 ml of methanol into a hydrogenation reaction bottle, and then add 0.5 ml of concentrated hydrochloric acid, in a hydrogen atmosphere of 100 to 150 psi, at a constant temperature of 45°C Stir vigorously for 24 hours, cool to room temperature, blow N _{for half} an hour, pass through diatomaceous earth, concentrate, and dry in vacuo to obtain 1.09 g of a colorless or light yellow solid, which is (±)-t-3-(1'-amino- 2'-Ethyl)butyl-c-4-tert-butoxycarbonamido-t-2-hydroxycyclopentyl-r-1-carboxylic acid methyl ester hydrochloride.

1.09 g (2.78 mmol) of the obtained intermediate was dissolved in 80 ml of dichloromethane, and then 0.38 ml of Et ₃ N and 0.47 ml of anhydrous acetic anhydride were added in sequence, and stirred at room temperature for 16 h. After the reaction was complete, 20ml of water was added, the organic layer was separated, the aqueous phase was extracted three times with 20ml of dichloromethane, the organic phases were combined, washed with water and saturated brine successively, dried over anhydrous Na ₂ SO ₄ , and the solvent was removed by distillation under reduced pressure to obtain 1.06 g White solid, namely (±)-t-3-(1'-acetamido-2'-ethyl)butyl-c-4-tert-butoxycarbonamido-t-2-hydroxycyclopentyl- Methyl r-1-carboxylate (5), yield: 94.6%.

Melting point: 119～121℃

Elemental analysis: C ₂ 0H ₃₆ N ₂ O ₆ MW: 400.26

Calculated: C 59.96 H 8.99 N 6.99 O 23.98

Analytical value: C 59.67 H 8.72 N 7.05 O 23.81

^{The 1} HNMR and MS spectra of the product are shown in Fig. 5 and Fig. 6 .

6. Add 1.5 g (3.75 mmol) of (5) and 200 ml of diethyl ether into a 500 ml three-neck flask with magnetic stirring and a reflux condenser. After complete dissolution, continue to pass dry HCl gas for 15 minutes, stir at room temperature for 10 hours, and heat to reflux for 2 hours. The reaction endpoint was monitored by thin-layer chromatography. After the reaction is completed, filter to obtain a white solid (±)-t-3-(1'-acetamido-2'-ethyl)butyl-c-4-amino-t-2-hydroxycyclopentyl-r - the hydrochloride salt of methyl 1-carboxylate.

The resulting hydrochloride 1.1 grams (3.26mmol), triethylamine 0.85ml (8.45mmol), 1,3-di-tert-butoxycarbonyl-2-methyl-2-isothiourea 0.94 grams (3.26mmol), Mercury chloride 0.88 g (3.26 mmol) was added in 50 ml of DMF, and stirred at room temperature for 16 hours. After the reaction was completed, it was diluted with five times the volume of ethyl acetate to precipitate a white precipitate, which was filtered, and the filtrate was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a yellow sticky solid. Using petroleum ether: ethyl acetate = 3:7 ~ 1:1 to separate the column to obtain 1.3 g of white solid, which is (±)-t-3-(1'-acetamido-2'-ethyl)butyl -c-4-(N,N-1", 3"-di-tert-butoxycarbonyl)guanidino-t-2-hydroxycyclopentyl-r-1-carboxylic acid methyl ester (6), yield 83% .

Melting point: 167°C

Elemental analysis: C ₂₆ H ₄₆ N ₄ O ₈ MW: 542.56

Calculated: C 57.51 H 8.48 N 10.32 O 23.59

Analytical value: C 57.53 H 8.16 N 10.35 O 23.33

^{The 1} HNMR and MS spectra of the product are shown in Fig. 7 and Fig. 8 .

7. Dissolve 0.5 g (0.9 mmol) of (6) in a mixed solvent of 13 ml (THF: ethanol = 1: 1), slowly add 5 ml (5 mmmol) of 1M sodium hydroxide solution dropwise, stir at room temperature for 3 hours, reduce The solvent was distilled off under pressure, 6ml of water was added, adjusted to weak acidity with iced 1M hydrochloric acid solution, and then extracted with ethyl acetate. The obtained organic phase was washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 0.45 g of a white solid, namely (±)-t-3-(1'-acetamido-2'-ethyl)butyl -c-4-(N, N-1", 3"-di-tert-butoxycarbonyl)guanidino-t-2-hydroxycyclopentyl-r-1-carboxylic acid (7), yield: 95%

Melting point: 219～220℃

Elemental analysis: C ₂₅ H ₄₄ N ₄ O ₈ MW: 528.32

Calculated: C 56.78 H 8.33 N 10.60 O 24.23

Analytical value: C 56.67 H 8.12 N 10.55 O 24.31

The ¹ HNMR and MS spectra of the product are shown in Figure 9 and Figure 10 .

8. Put 0.30 g (0.56 mmol) of (7), 1.9 ml of trifluoroacetic acid, and 0.5 ml of Et ₃ SiH into 32 ml of dichloromethane, stir at room temperature for 12 hours, evaporate the solvent under reduced pressure, and obtain dry matter in 20 ml of After washing with ether, 0.17 g of a yellow solid was obtained. The solid product was passed through a silica gel column with a mixed solution of chloroform: methanol = 7: 3 ~ 1: 1, and the resulting crude product was recrystallized with a mixed solution of methanol: water = 1: 1 to obtain 0.15 g of a white solid, namely (±)-t-3-(1'-acetamido-2'-ethyl)butyl-c-4-guanidino-t-2-hydroxycyclopentyl-1-carboxylic acid (8), namely For peramivir. Yield: 82.3%

Melting point: >251°C

Elemental analysis: C ₁₅ H ₂₈ N ₄ O ₄ MW: 328.24

Calculated: C 54.84 H 8.53 N 17.06 O 19.50

Analytical value: C 54.67 H 8.52 N 17.11 O 19.31

The ¹ HNMR and MS spectra of the product are shown in Figure 11 and Figure 12 .

Claims (9)

1. a synthetic method of peramivir, is characterized in that comprising the steps: (1) Dissolving Wens lactam in an alcoholic solution, catalyzed by hydrochloric acid for ring-opening esterification to obtain hydrochloric acid of (±)-cis-4-aminocyclopent-2-ene-1-carboxylic acid methyl ester salt, the reaction formula is as follows (2) Put (±)-cis-4-aminocyclopent-2-ene-1-carboxylic acid methyl ester hydrochloride and di-tert-butyl dicarbonate into a two-phase system composed of alkaline solution and organic solvent , Vigorously stirred and reacted to obtain (±)-cis-4-tert-butoxycarbonamidocyclopent-2-ene-1-carboxylic acid methyl ester, the reaction formula is as follows:

(3) 2-ethylbutyraldehyde reacts with hydroxylammonium hydrochloride in the alcohol-carbonate system to prepare 2-ethylbutyraldehyde oxime, and the reaction formula is as follows: (4) Put (±)-cis-4-tert-butoxycarbonamidocyclopent-2-ene-1-carboxylic acid methyl ester and 2-ethylbutyraldehyde oxime into an organic solvent, and the reaction occurs under alkali catalysis. Cycloaddition reaction to produce (±)-4-tert-butoxycarbonamido-3-(1'-ethyl)propyl-4,5,6,6a-4H-3aH-cyclopentyl[d] Isoxazole-6-carboxylic acid methyl ester, the reaction formula is as follows:

(5) (±)-4-tert-butoxycarbonamido-3-(1'-ethyl)propyl-4,5,6,6a-4H-3aH-cyclopentyl[d]isoxazole - Catalytic hydrogenation of methyl 6-carboxylate in alcohol solution to obtain (±)-t-3-(1'-amino-2'-ethyl)butyl-c-4-tert-butoxycarbonamido- The hydrochloride salt of t-2-hydroxycyclopentyl-r-1-carboxylic acid methyl ester; then the resulting product is acetylated to generate the intermediate product (±)-t-3-(1'-acetamido- 2'-Ethyl)butyl-c-4-tert-butoxycarbonamido-t-2-hydroxycyclopentyl-r-1-carboxylic acid methyl ester, the reaction formula is as follows: (6) Intermediate product (±)-t-3-(1'-acetamido-2'-ethyl)butyl-c-4-tert-butoxycarbonamido-t-2-hydroxycyclopentyl- r-1-carboxylate methyl ester de-BOC protected in ether to get (±)-t-3-(1'-acetamido-2'-ethyl)butyl-c-4-amino-t-2- The hydrochloride salt of methyl hydroxycyclopentyl-r-1-carboxylate; put the obtained product and N,N-1,3-di-tert-butoxycarbonyl-2-methyl-2-isothiourea into inorganic salt In a reaction system composed of an alkaline organic solvent, the reaction is vigorously stirred to obtain (±)-t-3-(1'-acetamido-2'-ethyl)butyl-c-4-(N,N -1", 3"-di-tert-butoxycarbonyl)guanidine-t-2-hydroxycyclopentyl-r-1-carboxylate methyl ester, the reaction formula is as follows:

(7) (±)-t-3-(1'-acetamido-2'-ethyl)butyl-c-4-(N,N-1", 3"-di-tert-butoxycarbonyl) Guanidino-t-2-hydroxycyclopentyl-r-1-carboxylic acid methyl ester is put into a reaction system composed of alcohol, organic solvent, and aqueous sodium hydroxide solution to obtain (±)-t-3-(1 '-Acetamido-2'-ethyl)butyl-c-4-(N,N-1",3"-di-tert-butoxycarbonyl)guanidino-t-2-hydroxycyclopentane-r- 1-carboxylic acid, the reaction formula is as follows: (8) (±)-t-3-(1'-acetamido-2'-ethyl)butyl-c-4-(N,N-1", 3"-di-tert-butoxycarbonyl) Guanidino-t-2-hydroxycyclopentane-r-1-carboxylic acid is dissolved in an inert solvent, and the final product peramivir is obtained by removing BOC under organic strong acid and organosilane catalysis, and the reaction formula is as follows:

2. according to the described synthetic method of claim 1, it is characterized in that the alcohol described in step (1) is methyl alcohol. 3. The synthesis method according to claim 1, characterized in that the base in step (2) is NaHCO ₃ or Na ₂ CO ₃ , and the organic solvent is dichloromethane or hexane. 4. The synthesis method according to claim 1, characterized in that the alcohol in step (3) is methanol or ethanol, and the carbonate is Na ₂ CO ₃ or K ₂ CO ₃ . 5. according to the described synthetic method of claim 1, it is characterized in that the described solvent of step (4) is methylene dichloride, hexane or heptane, and described alkali is triethylamine or sodium hypochlorite. 6. according to the described synthetic method of claim 1, it is characterized in that the described alcohol of step (5) is methyl alcohol, and described catalyzer is platinum dioxide or palladium-activated carbon, and used acylating agent is acetic anhydride. 7. according to the described synthetic method of claim 1, it is characterized in that the ether described in step (6) is ether, and described inorganic salt is mercuric chloride, and described alkali is triethylamine or ethylenediamine. 8. according to the described synthetic method of claim 1, it is characterized in that the alcohol described in step (7) is ethanol, and described organic solvent is THF. 9. according to the described synthetic method of claim 1, it is characterized in that the inert solvent described in step (8) is dichloromethane, and described organic acid is trifluoroacetic acid, and described organosilane is triethylsilane.

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