PERAMIVIR

CAS 330600-85-6

• Molecular FormulaC₁₅H₂₈N₄O₄
• Average mass328.407 Da

(1S,2S,3R,4R)-4-carbamimidamido-3-[(1S)-1-acetamido-2-ethylbutyl]-2-hydroxycyclopentane-1-carboxylic acid

• RWJ 270201
• RWJ-270201
• RWJ270201

Product Ingredients

NAME	DOSAGE	STRENGTH	ROUTE	LABELLER	MARKETING START	MARKETING END
Rapivab	Solution	600 mg/60mL	Intravenous	BioCryst Pharmaceuticals, Inc.	2014-12-20	Not applicable
Rapivab	Solution	600 mg/60mL	Intravenous	Seqirus USA Inc.	2014-12-20	Not applicable
Rapivab	Solution	10 mg	Intravenous	Biocryst Pharmaceuticals Inc	Not applicable	Not applicable

Drug Name：

Peramivir Hydrate

Research Code：

S-021812

Trade Name：

Rapiacta^® / Peramiflu^®

MOA：

Neuraminidase inhibitor

Indication：

Influenza infection

Status：

Approved

Company：

BioCryst (Originator) , Shionogi

Sales：

$21.6 Million (Y2015); 
$23.7 Million (Y2014);
$20 Million (Y2013);
$24.1 Million (Y2012);
$17.7 Million (Y2011);

ATC Code：

• US
• JP
• CN

Shionogi , GC Pharma and Seqirus , under license from BioCryst Pharmaceuticals (which licensed the program from the University of Alabama ), have developed and launched an iv formulation of the influenza neuraminidase inhibitor peramivir.

Peramivir hydrate was approved by Pharmaceuticals and Medicals Devices Agency of Japan (PMDA) on January 13, 2010, and approved by the U.S. Food and Drug Administration (FDA) on December 19, 2014. It was co-developed and co-marketed as Rapiacta^® by BioCryst and Shionogi in Japan.

Peramivir hydrate is a neuraminidase inhibitor, acting as a transition-state analogue inhibitor of influenza neuraminidase and thereby preventing new viruses from emerging from infected cells. It is indicated for the treatment of influenza A and B viral infections.

Rapiacta^® is available as injection solution for intravenous, containing 150 mg/300 mg Peramivir hydrate. The recommended dose is once a day by an intravenous drip infusion over a period of 15 minutes or longer.

Peramivir (trade name Rapivab) is an antiviral drug developed by BioCryst Pharmaceuticals for the treatment of influenza. Peramivir is a neuraminidase inhibitor, acting as a transition-state analogue inhibitor of influenza neuraminidase and thereby preventing new viruses from emerging from infected cells. It is approved for intravenous administration.^[1]

In October 2009, the U.S. Food and Drug Administration (FDA) issued an emergency use authorization (EUA) for the use of peramivir based on safety data from phase I, phase II, and limited phase III trial data. The emergency use authorization for peramivir expired in June 2010.^[2][3] On 19 December 2014, the FDA approved peramivir to treat influenza infection in adults.^[1]

Peramivir has also been approved in Japan and South Korea and is available in Japan as Rapiacta and in South Korea as Peramiflu.^[ As of 2015, it is the only intravenous option for treating swine flu.

Peramivir is an antiviral agent developed by Biocryst Pharmaceuticals to treat influenza A/B. The development of peramivir has been supported by the US Department of Health and Human Services as part of the government’s effort to prepare for a flu pandemic. Being an influenza virus neuraminidase inhibitor, peramivir works by preventing new viruses from emerging from infected cells. Due to the poor oral bioavailability, the oral formulation of the drug was previously abandoned by Johnson and Johnson Company. The injectable intravenous formulation of peramivir was approved by the FDA in September 2017 for the treatment of acute uncomplicated influenza to pediatric patients 2 years and older who have been symptomatic for no more than two days.

History

An intramuscular (IM) peramivir phase II study for seasonal influenza in 2008–2009 found no effect for the primary endpoint of improvement in the median time to alleviation of symptoms in subjects with confirmed, acute, uncomplicated influenza infection versus placebo.

In October 2009, it was reported that the experimental antiviral drug peramivir had been “life-saving” effective in intravenous treating 8 serious cases of swine flu.^[4] On October 23, the U.S. Food and Drug Administration (FDA) issued an Emergency Use Authorization for peramivir, allowing the use of the drug in intravenous form for hospitalized patients only in cases where the other available methods of treatment are ineffective or unavailable;^[5] for instance, if oseltamivir resistance develops and a person is unable to take zanamivir via the inhaled route. The U.S. government (department of Health and Human Services) gave BioCryst Pharmaceuticals more than $77 million to finish the Phase III clinical development of peramivir. In 2009 the department of Health and Human Services had already given about $180 million to the program.^[6] Biocryst also donated 1200 courses of treatment to the US department of Health and Human Services.^[7] The Emergency Use Authorization expired on June 23, 2010. In 2011 a phase III trial found the median durations of influenza symptoms were the same with 1 intravenous injection of peramivir against 5 days of oral oseltamivir for people with seasonal influenza virus infection.^[8]

In 2012 BioCryst reported that it should halt enrollment on its study for intravenous peramivir in potentially life-threatened people after an interim analysis led trial monitors to conclude that it would be futile to continue and the trial should be terminated. The difference between peramivir and control group (oral oseltamivir) for the primary endpoint, clinical or virologic, was small.^[9] In 2013 the Biomedical Advanced Research and Development Authority (BARDA/HHS) released new funding under the current $234.8 million contract to enable completion of a New Drug Application filing for intravenous (IV) peramivir.^[10]

According to a research report published in June 2011, a new variant of swine flu had emerged in Asia with a genetic adaptation (a S247N neuraminidase mutation) giving some resistance to oseltamivir and zanamivir, but no significant reduction in sensitivity to peramivir.^[11][12] But a H274Y virus mutation showed resistance to oseltamivir and peramivir, but not to zanamivir, and only in N1 neuraminidases.^[13] Ultimately 3.2% (19/599) of A(H1N1)pdm09 viruses collected between 2009 and 2012 had highly reduced peramivir inhibition due to the H275Y NA mutation.^[14]

BioCryst Pharmaceuticals submitted a new drug application (NDA) to the U.S. Food and Drug Administration (FDA) for intravenous peramivir in December 2013.^[15] Peramivir (Rapivab) was approved for intravenous administration in December 2014.^[1][16]

Route 1

Reference：1. WO9933781A1 / US6562861B1.

Route 2

Reference：1. CN102372657A.

2. J. Med. Chem. 2000, 43, 3482-3486.

Route 3

Reference：1. CN102633686A.

Route 4

Reference：1. J. Med. Chem. 2001, 44, 4379-4392.

Route 5

Reference：1. WO2012145932A1.

PATENT

peramivir’s product case, WO9933781 ,

hold SPC protection in the EU states until December 2023, and contain one of the Orange Book (OB) listed patents, US6562861 , that was due to expire in the US in December 2023. In January 2021, the US FDA’s OB was seen to list patents describing peramivir that expire in 2027.

PATENT

WO-2021002689

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=9917F9BB2C7486012996DFDDFB205C4A.wapp2nA?docId=WO2021002689&tab=FULLTEXT

Process for preparing an inhibitor of neuraminidase infection ie peramivir trihydrate crystal from the free form of the drug ie peramivir. Discloses the use of peramivir trihydrate in treating influenza infection. Represents the first PCT filing from CKD Bio Corp that focuses on peramivir; however, this case was first seen as a Korean national filing that is published in February 2020.

Accordingly, the present inventors have made intensive research efforts to develop a manufacturing method suitable for manufacturing excellent pharmaceuticals and quality control standards (GMP) without using toxic solvents such as activated carbon and methanol in the manufacture of ferramivir trihydrate.

Example 1: Feramivir trihydrate ((1S,2S,3R,4R)-3-[(S)-1-acetylamido-2-ethylbutyl]-4-guanidino-2-hydroxycyclo Preparation of pentane-1-carboxylic acid trihydrate) (1)

[100]

[101]

[102]

In a 500.0 L capacity reactor (1S,2S,3R,4R)-3-[(S)-1-acetylamido-2-ethylbutyl]-4-guanidino-2-hydroxycyclopentane-1-carboxylic acid (Peramivir) 30.0 kg was added and suspended in 240.0 L of purified water. The reaction was heated to about 95° C. to completely dissolve the suspension, followed by stirring, followed by natural cooling. When the temperature of the reaction product was 85° C., 45.0 L of 1-propanol was slowly added thereto, followed by natural cooling to 25° C. with stirring. At this time, crystal grains of ferramivir trihydrate were generated at about 40°C. When the temperature of the reactor reached 25° C. through natural cooling, the mixture was stirred for about 12 hours for a phase change of the crystalline form A. In addition, the temperature of the reactor was cooled to 5° C. and further stirred for about 3 hours. After completion of the reaction, filtration and washing with 15.0 L of a 10% 1-propanol solvent were performed once. The filtered solid cake was placed in a vacuum dryer with an internal humidity of about 40% in which a purified water bowl was placed under the vacuum dryer, and the solid cake was dried at 40° C. for about 12 hours. After completion of drying, ferramivir trihydrate was obtained (yield: 95.0%, purity: 99.9%, moisture: 14.5%).

[103]

[104]

¹ H NMR (500 MHz, D ₂ O, δ): 4.30-4.27 (m, 2H), 3.79-3.74 (m, 1H, -CH), 2.65-2.63 (m, 1H, -CH), 2.48-1.45 (m, 1H, -CH), 2.16-2.12 (m, 1H, -CH), 1.88 (s, 3H, -CH ₃ ), 1.75-1.71 (m, 1H, -CH), 1.41-1.36 (m, 3H), 0.95-0.91 (m, 2H), 0.87-0.84 (t, 3H, -CH ₃ ), 0.82-0.79 (t, 3H, -CH ₃ ); ¹³ C NMR (500 MHz, D ₂ O, δ): 181.671, 173.686, 155.584, 75.368, 55.201, 54.091, 50.314, 49.933, 43.409, 34.015, 22.780, 21.887, 20.942, 12.128, 11.276; LC-MS (m/z, C ₁₅ H ₂₈ N ₄ O ₄ ): calcd for 329.21, found; 329.5.

[105]

[106]

Example 2: Feramivir trihydrate ((1S,2S,3R,4R)-3-[(S)-1-acetylamido-2-ethylbutyl]-4-guanidino-2-hydroxycyclo Preparation of pentane-1-carboxylic acid trihydrate) (2)

[107]

[108]

[109]

To a 500.0L reactor (1S,2S,3R,4R)-3-[(S)-1-acetylamido-2-ethylbutyl]-4-guanidino-2-hydroxycyclopentane-1-carboxylic acid 30.0 kg of (Peramivir) was added and suspended in 240.0 L of purified water. The reaction mixture is heated to about 95° C. to completely dissolve the suspension, followed by stirring, followed by natural cooling. When the temperature of the reaction product was 85°C, 45.0L of 2-propanol was slowly added thereto, and the mixture was naturally cooled to 25°C with stirring. At this time, crystal particles of ferramivir trihydrate are generated at about 40°C. When the temperature of the reactor reached 25° C. through natural cooling, the mixture was stirred for about 12 hours for a phase change of the crystalline form A. In addition, the temperature of the reactor was cooled to 5° C. and further stirred for about 3 hours, followed by filtration and washing with 15.0 L of 10% 2-propanol solvent once after the reaction was completed. The filtered solid cake is placed in a vacuum dryer with an internal humidity of about 40% in which a bowl of purified water is placed under the vacuum dryer, and the solid cake is dried at 40°C for about 12 hours. After completion of drying, ferramivir trihydrate was obtained (yield: 95.5%, purity: 99.9%, moisture: 14.6%).

[110]

[111]

¹ H NMR (500 MHz, D ₂ O, δ): 4.30-4.27 (m, 2H), 3.79-3.74 (m, 1H, -CH), 2.65-2.63 (m, 1H, -CH), 2.48-1.45 (m, 1H, -CH), 2.16-2.12 (m, 1H, -CH), 1.88 (s, 3H, -CH ₃ ), 1.75-1.71 (m, 1H, -CH), 1.41-1.36 (m, 3H), 0.95-0.91 (m, 2H), 0.87-0.84 (t, 3H, -CH ₃ ), 0.82-0.79 (t, 3H, -CH ₃ ); ¹³ C NMR (500 MHz, D ₂ O, δ): 181.671, 173.686, 155.584, 75.368, 55.201, 54.091, 50.314, 49.933, 43.409, 34.015, 22.780, 21.887, 20.942, 12.128, 11.276; LC-MS (m/z, C ₁₅ H ₂₈ N ₄ O ₄ ): calcd for 329.21, found; 329.5.

Example 3: Feramivir trihydrate ((1S,2S,3R,4R)-3-[(S)-1-acetylamido-2-ethylbutyl]-4-guanidino-2-hydroxycyclo Preparation of pentane-1-carboxylic acid trihydrate) (3)

[121]

[122]

In a 500.0 L reactor (1S,2S,3R,4R)-3-[(S)-1-acetylamido-2-ethylbutyl]-4-guanidino-2-hydroxycyclopentane-1-carboxylic acid 30.0 kg of (Peramivir) was added and suspended in 240.0 L of purified water. The reaction was heated to about 95° C. to completely dissolve the suspension, followed by stirring, and natural cooling was performed. When the temperature of the reaction product was 85° C., 45.0 L of 1-pentanol was slowly added thereto, and the mixture was naturally cooled to 25° C. with stirring. At this time, crystal grains of ferramivir trihydrate were generated at about 40°C. When the temperature of the reactor reached 25° C. through natural cooling, the mixture was stirred for about 12 hours for a phase change of the crystalline form A. In addition, the temperature of the reactor was cooled to 5° C. and further stirred for about 3 hours. After completion of the reaction, filtration and washing with 15.0 L of a 10% 1-pentanol solvent were performed once. The filtered solid cake was placed in a vacuum dryer with an internal humidity of about 40% in which a purified water bowl was placed under the vacuum dryer, and the solid cake was dried at 40°C for about 12 hours. After completion of drying, ferramivir trihydrate is obtained (yield: 95.1%, purity: 99.9%, moisture: 14.1%).

[123]

¹ H NMR (500 MHz, D ₂ O, δ): 4.30-4.27 (m, 2H), 3.79-3.74 (m, 1H, -CH), 2.65-2.63 (m, 1H, -CH), 2.48-1.45 (m, 1H, -CH), 2.16-2.12 (m, 1H, -CH), 1.88 (s, 3H, -CH ₃ ), 1.75-1.71 (m, 1H, -CH), 1.41-1.36 (m, 3H), 0.95-0.91 (m, 2H), 0.87-0.84 (t, 3H, -CH ₃ ), 0.82-0.79 (t, 3H, -CH ₃ ); ¹³ C NMR (500 MHz, D ₂ O, δ): 181.671, 173.686, 155.584, 75.368, 55.201, 54.091, 50.314, 49.933, 43.409, 34.015, 22.780, 21.887, 20.942, 12.128, 11.276; LC-MS (m/z, C ₁₅ H ₂₈ N ₄ O ₄ ): calcd for 329.21, found; 329.5.

PATENT

https://patents.google.com/patent/WO2012145932A1/en

Peramivir has the chemical name of

(1^,2^,3^, 4R)-3-[(l_lS)-l-acetamido-2-ethyl-butyl] -4-(diaminomethylideneamino)- 2-hydroxy-cyclopentane-l-carboxylicacid, and has the following structure:

(I)

[0003] Peramivir is currently being developed as an antiviral drug, and in particular, for treatment of influenza. Acting as a neuraminidase inhibitor, peramivir can efficiently inhibit the replication of all type of influenza viruses. Peramivir can be administered via injection, and is known to be well-tolerated and cause only mild adverse effect.

[0004] Several processes relating to the preparation of peramivir are disclosed in CN1227466, CN1282316, and WO01/00577A1.

[0005] As shown in Scheme 1, CN 1227466 discloses a process comprising ring-opening of chiral 2-azabicyclo [2.2.1] hept-5-en-3-one, followed by

amino-protecting reaction, Diel- Alder conjugate cycloaddition, reduction, acetylation, guanidylation and finally hydrolyzation to yield peramivir. The major drawback of this process is the use of highly expensive starting material 1. In addition, this process is not suitable for scale-up.

Scheme 1

[0006] WO2009021404 discloses a method comprising reacting

N-Boc-protected chiral 2-azabicyclo [2.2.1] hept-5-en-3-one and

2-ethylbutylaldehyde as starting material to prepare peramivir as illustrated in Scheme 2.

Scheme 2

eram v r

EXAMPLES

Example 1

1 (liS’,4_J/?)-methyl-4-(2,3-bis(ieri-butoxycarbonyl)guanidino)cyclopent-2-ene- carboxylate (13)

11 12 13 [0063] To a mixture of (lS^R^methyl 4-aminocyclopent-2-enecarboxylate tartaric acid salt 11 ( 7.29 g, 25 mmol) in dichloromethane (150 mL), was added Et₃N (9 mL, 65 mmol) at 0 °C, and the resulting mixture was stirred for 15 min. To this, tert-butyl (lH-pyrazol-l-yl)methylenedicarbamate 12 was added. After addition, the reaction was monitored for completion by TLC ( PE: EtOAc=5 : 1 ) . The organic layers were washed with water and brine and dried over anhydrous Na₂S0₄. The mixture was filtered and concentrated to give 13 as a white solid, which was used in the next step without further purification.

[0064] MS (M+l ) : 384.

[0065] ‘H NMR (400 MHz, CDC1₃) δ 11.49 (s, 1H), 8.53 (d, J= 8.4 Hz, 1H), 5.94 – 5.83 (m, 2H), 5.38 – 5.31 (m, 1H), 3.73 (s, 3H), 3.56 – 3.44 (m, 1H), 2.60 (dt, J= 14.0, 8.5 Hz, 1H), 1.94 (dt, J= 13.9, 4.7 Hz, 1H), 1.50 (d, J= 7.4 Hz, 18H) (See attached Chart 1)

Example 2

2 (3a_J/?,4_J/?,6iS’,6aiS -methyl-4-(2,3-bis(ieri-butoxycarbonyl)guanidino)-3-(pentan -3-yl)-4,5,6,6a-tetrahydro-3aH-cyclopenta[d]isoxazole-6-carboxylate (5)

14 85% a) Preparation of 2-Ethyl-N-hydroxybutanimidoyl chloride (14):

[0066] Hydroxylamine hydrochloride (7.2g, 0.1 mol) was dissolved in water (7 mL). Toluene (27 mL) was added, followed by addition of 2-ethylbutylraldehyde (lOg, 0.1 mol). The two-phase mixture was stirred vigorously while cooling.

Sodium hydroxide solution (ca.30%, 14.6g, O. l lmol) was added slowly (addition is very exothermic) to maintain a temperature between 15-25 °C. The mixture was stirred for 60 min, then allowed to stand to separate the layers. The organic extract was washed with water and brine, dried over Na₂S0₄, and directly used in the next step.

[0067] N-Chlorosuccinimide (NCS) (13.3g, 0.1 mol) was suspended in dimethylformamide (DMF) (17ml) and cooled to about 10 °C. The toluene solution prepared above (3 .15 mol) was added dropwise with sufficient cooling to maintain the reaction temperature betweenlO-25°C. After addition, the reaction was monitored by TLC until completion of the reaction. Water (100ml) was added slowly (slightly exothermic) while maintaining the temperature at 15-25 °C. The two-phase mixture was stirred for 15 min at 15-25 °C and the layers were separated. The water layer was extracted with toluene (10ml) and the organic layer washed with water (3 X 20ml) and brine, dried over Na₂S0₄, and directly used in the next step. b)

Preparation of (3a_J/?,4_J/?,6iS’,6aiS -methyl-4-(2,3-bis(ieri-butoxycarbonyl)-guan idine)-3 -(pentan-3 -yl)-4,5,6,6a-tetrahy dro-3 aH-cy clopenta [d] is oxazole-6- carboxylate (15)

[0068] 13 (from example 1, 9.2g, 0.024 mol) was dissolved in toluene (100 mL) and triethylamine (10. Og, 0.099 mol) and the reaction mixture was heated to 60-70 °C. 2- Ethyl-N-hydroxylbutanimidoyl chloride 14 (from example 2a, 14.8 g, 0.099 mol) in toluene (40 mL) was added to the above solution. A white solid

(triethylammonium chloride) was formed. After addition, the reaction was

monitored for completion by TLC ( PE: EtOA_c=3 : 1. The reaction mixture was cooled to 20-25 °C, the precipitate was removed by filtration and the filter cake was washed with toluene (50 g). The organic filtrate was washed with water, brine, and dried over anhydrous Na₂S0₄. The mixture was filtered and concentrated by rotary evaporation. The resulting residue was purified by silica gel flash column

chromatography using PE/EtOAc (30 : 1-4: 1, v/v) to give 15 as a white solid.

[0069] Yield : 10.0 g (85%).

[0070] MS (M+l ) :497.

[0071] ‘H NMR (400 MHz, CDC1₃) δ 11.29 (s, 1H), 8.55 (d, J= 6.4 Hz, 1H), 5.30 (dd, J= 9.1, 1.5 Hz, 1H), 4.53 (d, J= 4.8 Hz, 1H), 3.78 (s, 3H), 3.70 (d, J = 9.1 Hz, 1H), 3.25 (t, J= 5.4 Hz, 1H), 2.93 – 2.84 (m, 1H), 2.20 (dd, J= 7.6, 3.7 Hz, 2H), 1.87 – 1.60 (m, 4H), 1.49 (d, J= 5.0 Hz, 18H), 0.95 (t, J= 7.4 Hz, 3H), 0.87 (t, J= 7.5 Hz, 3H). (See attached Chart 2)

Example 3 3. (1^,2^,3^,4^)-ιη6ίΗγ1-3-(1-306ίαιηΐάο-2-6ίΗγ1 υίγ1)-4-(2,3- Ϊ8(ί^ί- butoxycarb -onyl) guanidino)-2-hydroxycyclopentanecarboxylate (16):

[0072] Compound 15 ( from example 2, 5.0 g, 10.08 mmol) and nickel chloride hexahydrate (2.5g, 10.5 mmol) were dissolved in methanol (40 mL). The green solution was cooled to -15 °C, while a suspension formed. Sodium borohydride

( 0.456 g, 12 mmol) was added to the reaction mixture at -10 to -5 °C (reaction is highly exothermic). A black suspension was formed along with gas evolution.

After complete addition of the sodium borohydride solution, the reaction mixture was stirred until TLC showed 15 was fully consumed. A solution of acetic

anhydride ( 15g, 0.13 mol) was added slowly and maintained the reaction temperature at 0-5 °C, the reaction mixture was stirred for 2-12 h at 0 °C (The black solution change into green solution ), The pH of the mixture was adjusted to ~9 by addition of 25% aq. ammonium hydroxide. The mixture was concentrated by rotary evaporator. The resulting residue was diluted with water (30 mL) and extracted with EtOAc (50 mL><3). The combined organic extracts were washed with water and brine and dried over anhydrous Na₂S0₄. The mixture was filtered and concentrated by rotary evaporation. The residue was purified by flash chromatography using DCM/Methanol (100:0 to 100:2, v/v) to give 16 as a white solid. [0073] Yield: 3.8 g (71%).

[0074] MS (M+l ) : 543.

[0075] ‘H NMR (400 MHz, CDC1₃) δ 11.39 (s, 1H), 8.72 (d, J= 9.9 Hz, 1H), 8.59 (d, J= 8.5 Hz, 1H), 4.53 – 4.39 (m, 1H), 4.26 (d, J= 16.4 Hz, 2H), 3.96 (t, J = 10.2 Hz, 1H), 3.71 (s, 3H), 2.90 – 2.75 (m, 1H), 2.53 (dt, J= 13.6, 8.8 Hz, 1H), 2.10 (s, 3H), 2.03 (d, J= 6.3 Hz, 1H), 1.90 – 1.76 (m, 1H), 1.38 (dd, J= 73.9, 7.9 Hz, 18H), 1.25 (ddd, J= 15.2, 13.1, 7.3 Hz, 4H), 0.79 (t, J= 7.3 Hz, 3H), 0.75 (dd, J = 14.1, 6.9 Hz, 3H). (See attached Chart 3)

Example 4

4. (1^,2^,3^,4^)-3-(1-306ίαιηΐάο-2-6ίΗγ1 υίγ1)-4-(2,3- Ϊ8(ί^ί- butoxycarbonyl)gu -anidino)-2-hydroxycyclopentanecarboxylic acid (17)

[0076] To a mixture of compound 16 ( from example 3, 2.0 g, 3.69 mmol) in MeOH/THF (1 : 1, v/v, 12 mL), was added aq. NaOH (IN, 7 mL) at room

temperature. After completion of the reaction (monitored by TLC,

DCM:MeOH=10: l, the mixture was concentrated by rotary evaporation. The resulting solution was neutralized to pH 7 using ice-cold 1 N HCl aq. solution and quickly extracted with EtOAc twice. The combined organic extracts were washed with water, brine, and dried over anhydrous Na₂S0₄. The mixture was filtered and the filtrate was concentrated by rotary evaporation. The resulting white foam was washed triturated by hexane, filtered, dried to give 17 as a white solid

[0077] Yield: 1.6 g (84%).

[0078] MS (M+l ) : 529 o

[0079] ‘H NMR (400 MHz, CDC1₃) δ 11.41 (s, 1H), 8.80 (d, J= 9.8 Hz, 1H), 8.62 (d, J= 8.3 Hz, 1H), 4.43 (dd, J= 23.3, 14.3 Hz, 2H), 4.00 (t, J= 9.8 Hz, 1H), 2.83 (s, 1H), 2.53 (dt, J= 16.9, 8.4 Hz, 1H), 2.14 (s, 3H), 1.91 (dd, J= 12.5, 6.0 Hz, 1H), 1.46 (dd, J = 30.1, 9.5 Hz, 18H), 1.47 – 1.14 (m, 6H), 0.97 – 0.69 (m, 6H). (See attached Chart 4)

Example 5

5. (1^,2^,3^,4^)-3-(1-306ίαιηΐάο-2-6ίΗγ1 υίγ1)-4^υαηΐ(1ΐηο-2- hydroxycyclopent -anecarboxylic acid (Peramivir I)

[0080] Compound 17 ( from example 4, 1.1 g, 2 mmol) was dissolved in aq. HC1 ( 6N, 6 mL, 36 mmol) at 0 °C. The mixture was stirred at room temperature overnight. The resulting solution was neutralized to pH 6-7 using ice-cold 1 N NaOH aq. solution. The mixture was concentrated to 1.5 ml by rotary evaporation. To this, methanol (20 mL) was added. The precipitate was filtered, and the filtrate was concentrated. The resulting white solid was recrystallized from

methanol/water (1 : 1, v/v) to give Peramivir I as a white solid.

[0081] Yield: 500 mg (73%).

[0082] MS (M+l ) : 329.

[0083] H NMR (400 MHz, D₂0) δ 4.21 (d, J= 10.6 Hz, 2H), 3.70 (dd, J= 14.6, 9.0 Hz, 1H), 2.57 (d, J= 4.8 Hz, 1H), 2.40 (dt, J= 17.7, 8.9 Hz, 1H), 2.14 – 2.01 (m, 1H), 1.81 (s, 3H), 1.75 – 1.58 (m, 1H), 1.31 (s, 3H), 0.78 (ddd, J= 21.6, 18.6, 6.8 Hz, 8H). (See attached Chart 5)

SYN

SYN

Method of synthesis

i. Lactan is dissolved I alcoholic solution, esterification by ring opening under HCl and acid catalysis.

ii. Compound formed is reacted with hydrochloride and tert-butyl dicarbonate.

iii. Reaction with oxammonium hydrochloride reactant salt in alcohol-carbonate system.

iv. Cycloaddition reaction takes place under base catalysis.

v. Hydrogenation in alcoholic solution to generate intermediate compound.

vi. Taking off BOC protect hydrochloride

vii. Two guanidine radicals are put in the reaction vessel, system made of alcohol, organic solvent, aqueous sodium hydroxide solution.

viii. Taking off BOC, product is obtained under organic acid.

 

SYN

https://www.tandfonline.com/doi/abs/10.1080/00397911.2012.729279?journalCode=lsyc20

Abstract

An improved and convenient synthetic route for the synthesis of peramivir has been developed with a total 34% yield. The process was improved from previous methods in three key reaction steps including 1,3-dipolar cycloaddition, reductive ring cleavage of the isoxazoline, and incorporation of the peripheral guanidino group. First, an activated sodium hypochlorite (Cl% = 10%) was employed for the catalytic 1,3-dipolar cycloaddition, and 61–68% yields were obtained. Second, the NaBH₄-NiCl₂ was used as a new reducing reagent instead of the expensive catalyst PtO₂. Most important, an innovative and environmentally friendly method of guanylation in the final step was developed using chloroformamidine hydrochloride as the amidino reagent, which avoided the use of the highlytoxic reagent of HgCl₂ and made the process greener.

Supplemental materials are available for this article. Go to the publisher’s online edition of Synthetic Communications® to view the free supplemental file.

GRAPHICAL ABSTRACT

Practical synthesis of the anti-influenza drug RWJ-270201 (Peramivir) Emergency Use Authorization (EUA) for Intravenous (IV) peramivir

SYN

https://www.chemie.tu-darmstadt.de/media/ak_fessner/damocles_pdf/2016/Peramivir.pdf

Synthesis Synthesis of Peramivir. [2]

SYN

Peramivir – Synthetic Route 1

Synthetic Reference

Chand, Pooran; Kotian, Pravin L.; Dehghani, Ali; El-Kattan, Yahya; Lin, Tsu-Hsing; Hutchison, Tracy L.; Babu, Y. Sudhakar; Bantia, Shanta; Elliott, Arthur J.; Montgomery, John A. Systematic Structure-Based Design and Stereoselective Synthesis of Novel Multi-Substituted Cyclopentane Derivatives with Potent Anti-influenza Activity. Journal of Medicinal Chemistry. Volume 44. Issue 25. Pages 4379-4392. Journal. (2001).

Synthetic Reference

Jia, Fei; Hong, Juan; Sun, Ping-Hua; Chen, Jian-Xin; Chen, Wei-Min. Facile synthesis of the neuraminidase inhibitor peramivir. Synthetic Communications. Volume 43. Issue 19. Pages 2641-2647. Journal; Online Computer File. (2013).

Peramivir – Synthetic Route 3

Peramivir – Synthetic Route 4

Synthetic Reference

Li, Mingjie; Zhu, Quanming; Wang, Chunyan. A process for preparing peramivir. Assignee Shandong Luoxin Pharmacy Stock Co., Ltd., Peop. Rep. China. CN 103524383. (2014).

Synthetic Reference

Ge, Min; Li, Liang; Hu, Chunchen; Wang, Huaiqiu; Fu, Mingwei; Li, Lingchao. Synthesis of Peramivir via 3+2 ring closure. Assignee Acesys Pharmatech Ltd., Peop. Rep. China. CN 108997171. (2018).

SYN 1

WO 9933781

Ring opening of cis-2-azabicyclo[2.2.1]hept-5-en-3-one (I) with HCl in refluxing methanol gives cis-4-amino-2-cyclopentene-1-carboxylic acid (II), which is esterified with HCl/methanol, yielding the methyl ester (III). The protection of (III) with tert-butoxycarbonyl anhydride and triethylamine in dichloromethane affords carbamate (IV), which is cyclized with 2-ethyl-1-nitrobutane (V) by means of phenyl isocyanate in refluxing benzene to give the cyclopenta-oxazoline (VI). Ring opening of (VI) by hydrogenation with H2 over PtO2 in HCl/methanol yields amine (VII), which is acylated with acetic anhydride and triethylamine in dichloromethane to afford acetamide (VIII). The deprotection of (VIII) with HCl in ethyl ether gives the cyclopentylamine (IX), which is condensed with N,N’-bis(tert-butoxycarbonyl)-O-methylisourea (X) by means of HgCl2 in DMF to yield the protected guanidino compound (XI). Deprotection of the guanidino group of (XI) with trifluoroacetic acid in dichloromethane affords the methyl ester (XII), which is finally hydrolyzed with NaOH in THF/methanol.

SYN 2

J Med Chem 2000,43(19),3482

The stereospecific synthesis of BCX-1812(RWJ-270201) has been reported: Ring opening of (-)-2-azabicyclo[2.2.1]hept-5-en-3-one (I) with methanolic HCl gives the methyl ester (II), which is N-protected with Boc2O and TEA yielding the carbamate (III). Cyclization of (III) with 2-ethyl-1-nitrobutane (IV) by means of phenyl isocyanate and TEA affords the bicyclic compound (V) and other isomers. Compound (V) is isolated from the mixture and then hydrogenated with H2 over PtO2 in MeOH and a catalytic amount of HCl to provide amine (VI). Reaction of (VI) with acetic anhydride gives the acetamide (VII), which is Boc-deprotected with ethereal HCl yielding amine (VIII). The guanylation of (VIII) with pyrazolecarboxamidine hydrochloride (IX) and DIEA affords the guanidino derivative (X), which is finally hydrolyzed with NaOH to the desired (1S,2S,3R,4R,1’S)-diastereomer.

SYN 3

J Med Chem 2001,44(25),4379

The ring opening of (-)-2-azabicyclo [2,2,1]hept-5-en-3-one (I) with methanolic HCl gives the methyl ester (II), which is N-protected with Boc2O and TEA, yielding the carbamate (III). The cyclization of (III) with 2-ethyl-1-nitrobutane (IV) by means of phenyl isocyanate and TEA affords the bicyclic compound (V) along with other isomers that are separated by column chromatography. Compound (V) is hydrogenated with H2 over PtO2 in methanol to provide amine (VI), which is acylated with Ac2O, giving the acetamide (VII). N-Boc deprotection of (VII) by means of HCl in ethyl ether yields the amine (VIII), which is condensed with protected isothiourea (IX) by means of HgCl2 to afford the guanidine derivative (X). The hydrolysis of (X) with NaOH provides the carboxylic acid (XI), which is finally deprotected with trifluoroacetic acid to yield the target cyclopentanecarboxylic acid derivative.

References

External links

• “Peramivir”. Drug Information Portal. U.S. National Library of Medicine.
• “Peramivir: Requirements for Administration under EUA”. Lifehugger. Archived from the original on 2011-07-13.
• “CDC H1N1 Flu – Termination of the Emergency Use Authorization (EUA) of Medical Products and Devices”. U.S. Centers for Disease Control and Prevention (CDC).
• Clinical trial number NCT00957996 for “Safety Study of IV Peramivir in Hospitalized Subjects With Confirmed or Suspected Influenza” at ClinicalTrials.gov
• “A Novel Anti-viral Drug for Influenza, RAPIACTA Launch” (PDF). Shionogi & Co., Ltd. January 26, 2010. Archived from the original (PDF) on 2013-05-22.

Peramivir

Clinical data
Trade names	Rapivab
AHFS/Drugs.com	Monograph
License data	US DailyMed: Peramivir
Pregnancy category	AU: B3
Routes of administration	Intravenous
ATC code	J05AH03 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) US: ℞-only EU: Rx-only
Pharmacokinetic data
Bioavailability	100% (IV)
Elimination half-life	7.7 to 20.8 hours (in patients with normal renal function)
Excretion	Kidney
Identifiers
IUPAC name[show]
CAS Number	330600-85-6  trihydrate: 1041434-82-5
PubChem CID	151164
DrugBank	DB06614
ChemSpider	135903
UNII	9ZS94HQO3B trihydrate: QW7Y7ZR15U
KEGG	D03829
ChEBI	CHEBI:85202
ChEMBL	ChEMBL332608
CompTox Dashboard (EPA)	DTXSID10904727
Chemical and physical data
Formula	C15H28N4O4
Molar mass	328.413 g·mol−1
3D model (JSmol)	Interactive image
SMILES[show]
InChI[show]
(what is this?)  (verify)

Influenza (Flu)
Types[show]
Vaccines[show]
Treatment[show]
Pandemics[show]
Outbreaks[show]
See also[show]
v t e

////////////////PERAMIVIR, RWJ 270201, RWJ-270201, RWJ270201M, BCX 1812, RWJ 270201

/////////////////

PERAMIVIR

(1S,2S,3S,4R)-3-[(1S)-1-acetamido-2-ethyl-butyl]-4- (diaminomethylideneamino)-2-hydroxy-cyclopentane- 1-carboxylic acid

8th, APRIL 2013

In the wake of the growing bird flu outbreak, China’s SFDA will fast-track approvals of a flu treatment – not a vaccine – known as peramivir (peramivir sodium chloride injection). The drug is a neuraminidase inhibitor, which works by preventing the virus from moving from an infected cell to infect other cells. Guangzhou Nanxin Pharma has been approved to produce the medicine, and it expects to begin distributing the drug in 30 days. Other China pharmas have also filed for approval to make the drug or conduct human clinical trials

Peramivir is an experimental antiviral drug developed by BioCryst Pharmaceuticals for the treatment of influenza. It has been authorized for the emergency use of treatment of certain hospitalized patients with known or suspected 2009 H1N1 influenza.^[1]

Peramivir is a neuraminidase inhibitor, acting as a transition-state analogue inhibitor of influenza neuraminidase and thereby preventing new viruses from emerging from infected cells.

The development of peramivir is supported by the US Department of Health and Human Services as part of the US government’s effort to prepare against the threat of an influenza pandemic.^[2]

Peramivir is already available in Japan as RAPIACTA (R) and also available in South Korea as PERAMIFLU. Peramivir is currently the only intravenous option for treating swine flu. The drug is in Phase III studies in US.^[3][4]

Use in treating Influenza A (H1N1) “Swine Flu”

In October 2009, it was reported that the experimental antiviral drug peramivir had been effective in treating serious cases of swine flu.^[5] On October 23, the U.S. Food and Drug Administration (FDA) issued an Emergency Use Authorization for Peramivir, allowing the use of the drug in intravenous form for hospitalized patients only in cases where the other available methods of treatment are ineffective or unavailable;^[6] for instance, if oseltamivir (Tamiflu) resistance develops and a person is unable to take Relenza via the inhaled route. The Emergency Use Authorization expired on June 23, 2010.

Biocryst also donated 1200 courses of treatment to the US department of Health and Human Services.^[7]

According to a research report published in June 2011, a novel variant of swine flu has emerged in Asia with a genetic adaptation giving some resistance to Roche’s (ROG.VX) Tamiflu and GlaxoSmithKline’s (GSK.L) Relenza, the two mainstay drugs used to tackle the disease. There was no significant reduction in sensitivity to Peramivir. ^[8]

Initial treatment courses are for 5 to 10 days duration. Treatment beyond 10 days is permitted depending on clinical presentation such as critical illness (e.g., respiratory failure or intensive care unit admission), continued viral shedding or unresolved clinical influenza illness.^[9]

• Peramivir: Requirements for Administration under EUA
• BioCryst Pharmaceuticals, Inc.
• Peramivir CDC/FDA EUA request form
• Peramivir Phase III Clinical Trials