204255-11-8

Basic information

• Product Name: Oseltamivir phosphate
• Synonyms: Osteltamivir phosphate;(3R,5S)-ethyl 4-acetamido-5-amino-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate phosphate;Oseltamivir phosphat;Oseltamivir Phosphate (200 mg);Oselt;OseltaMivir Acid-D3 Phosphate;OseltaMivir phosphate (TaMiflu);(3R,4R,5S)-ethyl 4-acetaMido-5-aMino-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate phosphate
• CAS NO: 204255-11-8
• Molecular Formula: C₁₆H₂₈N₂O₄*H₃O₄P
• Molecular Weight: 410.4
• Product Categories: Intermediates & Fine Chemicals;Pharmaceuticals;Ring Systems;Oseltamivir;Influenza Viruses;Amines;Anti-virals;apis;Tamiflu;API
• Mol File: 204255-11-8.mol
• Article Data: 49

Chemical Properties

• Melting Point: 196-198°C
• Boiling Point: 473.3 °C at 760 mmHg
• Flash Point: 240 °C
• Appearance: white to beige/
• Density: 1.08g/cm3
• Storage Temp.: -20°C Freezer
• Solubility: H2O: soluble30mg/mL, clear
• CAS DataBase Reference: Oseltamivir phosphate(CAS DataBase Reference)
• NIST Chemistry Reference: Oseltamivir phosphate(204255-11-8)
• EPA Substance Registry System: Oseltamivir phosphate(204255-11-8)

Safety Data

• HazardClass: IRRITANT
• Hazardous Substances Data: 204255-11-8(Hazardous Substances Data)

Usage

Anti-influenza virus

Oseltamivir phosphate is a kind of anti-influenza drugs, under the trade name Tamiflu. Its appearance exhibits as white to yellowish-white powder. It can be divided into type A (alpha) and B (Beta) selective inhibitor of the influenza virus neuraminidase and can prevent the release of virus from infected cells, through inhibiting the activity of the influenza virus neuraminidase, thus achieving the purpose of control of influenza symptoms. Clinically it can be used for treatment of the type A influenza and type B influenza in adults and children of 1 year old or over 1 year old as well as the clinical prevention of influenza A and B in adult and adolescent of 13 year old or over 13 years old. Oseltamivir phosphate can subject to rapid metabolism into oselatamivr carboxylate after gastrointestinal absorption with 75% of the total oral administrated dose participating in the systemic circulation in the from of oselatamivr carboxylate. The active ingredient of this drug is a potent and unique neuraminidase inhibitors acting on all the processes of influenza virus infection, preventing the replication of all clinically relevant influenza virus strains A or B strain. It has obvious inhibitory effect even in nanomolar concentration in vitro. It has ben observed in vitro that the active metabolite can inhibit the growth of influenza virus as well as in vivo that it can inhibit the replication and pathogenicity of influenza virus. This product, through inhibiting the release of virus from infected cells, can reduce the spread of influenza A or B virus.The above information is edited by the lookchem of Dai Xiongfeng.

Uses

Different sources of media describe the Uses of 204255-11-8 differently. You can refer to the following data:
1. Oseltamivir Phosphate is an orally active inhibitor of influenza virus neuraminidase; converted in vivo to the active acid metabolite. An antiviral drug. It is a COVID19-related research product.
2. Oseltamivir phosphate (Tamiflu) is a competitive neuraminidase inhibitor. The prodrug oseltamivir phosphate (Tamiflu) is itself not virally effective; however, once in the liver, it is converted by natural chemical processes, hydrolysed hepatically to its

Description

Oseltamivir phosphate (Tamiflu) was launched in the US and Switzerland for the treatment of influenza infections by all common strain viruses. It is an oral anti-viral drug approved for the treatment of acute, uncomplicated influenza in patients 2 weeks of age and older whose flu symptoms have not lasted more than two days. This product is approved to treat Type A and B influenza; however, the majority of patients included in the studies were infected with type A, the most common in the U.S. Efficacy of Tamiflu in the treatment of influenza in subjects with chronic cardiac disease and/or respiratory disease has not been established.

Chemical Properties

White Cyrstalline Solid. It is freely soluble in water.

Originator

Gilead (US)

Definition

ChEBI: Oseltamivir phosphate is a phosphate salt. It contains an oseltamivir. It is an acetamido cyclohexene that is a structural homolog of SIALIC ACID and inhibits NEURAMINIDASE.

Preparation

Oseltamivir phosphate (Tamiflu) has been synthesized from cis-2,3-bis(hydroxymethyl)aziridine. After protection of the cis-2,3-bis(hydroxymethyl)aziridine with a Boc group, desymmetrization provided a chiral aziridine, which was a key intermediate to install the required stereogenic center containing a nitrogen atom. Allylation and ring closing metathesis are the key reactions to obtain the cyclic product that was successfully converted to the desired oseltamivir phosphate. DOI: 10.1021/jo3015853It can also be obtained by a novel 12-step synthesis from (-)-quinic acid.

Brand name

Tamiflu (Roche).

Therapeutic Function

Antiviral

General Description

receptor site showed clearly that additional binding sitesexist for the C-5 acetamido carbonyl group and the arginineresidue at position 152 of the receptor site. In addition, the C-2 carboxyl group of sialic acid binds to Arg 118, Arg 292, andArg 371. Position C-6 is capable of undergoing a hydrophobicinteraction with various amino acids, including Glu, Ala,Arg, and Ile. Maximum binding to neuraminidase occurswhen the C-6 substituent is substituted with a nonpolar chain.In oseltamivir, this nonpolar group is 3-pentyl. An importantfeature of oseltamivir is the ethyl ester, which makes the drugorally efficacious. This drug is the first orally active agent foruse against influenza A and B. It is also indicated for the treatmentof acute illness. If administered within 2 days after theonset of influenza symptoms, the drug is effective.

Biochem/physiol Actions

Oseltamivir phosphate is an influenza viral neuraminidase inhititor. Oseltamivir phosphate, an antiviral, is used clinically to treat influenza A and influenza B, and to prevent flu after exposure. Oseltamivir phosphate is hydrolyzed in the liver to its active form, oseltamivir carboxylate, which is an inhibitor of influenza viral neuraminidases essential for viral replication. Oseltamivir has a broad spectrum of activity against a range of influenza A and B subtypes with IC50 values for neuraminidases measured from less than 1 nM to approximately 30 nM, depending on the virus subtype.

Clinical Use

Oseltamivir was approved as the first orally administered neuraminidase inhibitor used against influenza A and B viruses. The drug is indicated for the treatment of uncomplicated acute illness caused by influenza infection.

Side effects

Side effects with oseltamivir are minor, consist of nausea and vomiting, and occur primarily in the first two days of therapy.

Veterinary Drugs and Treatments

Although, there is no research published (at the time of writing— January 2007) documenting oseltamivir safety or efficacy in dogs or cats, there is much interest and discussion regarding its potential for the adjunctive treatment of parvovirus infections in dogs. It may be of benefit for adjunctive treatment of other viral infections, particularly those with associated secondary bacterial components, but research or experience is lacking. A recent study performed in horses, experimentally infected with equine influenza A (H3N8), documented some efficacy in the attenuation of clinical signs (pyrexia), viral shedding, and secondary bacterial pneumonias (Yamanaka, Tsujimura et al. 2006).Because oseltamivir is the primary antiviral agent proposed for treatment or prophylaxis for an H5N1 influenza (“bird flu”) pandemic in humans, its use in veterinary patients is controversial, particularly due to concerns of adequate drug supply for the human population and the potential for influenza virus resistance development. In 2006, the FDA banned the extra-label use of oseltamivir and other influenza antivirals in chickens, turkeys and ducks. At the time of writing, its use is still allowed in mammal veterinary patients, but veterinarians should use the drug prudently and be cognizant of these public health concerns.

Metabolism

Oseltamivir is readily absorbed from the GI tract following oral administration. It is a prodrug that is extensively metabolized in the liver, undergoing ester hydrolysis to the active carboxylic acid. Two oxidative metabolites also have been isolated, with the major oxidation product being the ω-carboxylic acid.

Mode of action

Oseltamivir Phosphate is the phosphate salt of oseltamivir, a synthetic derivative prodrug of ethyl ester with antiviral activity. By blocking neuraminidases on the surfaces of influenza viruses, oseltamivir interferes with host cell release of complete viral particles.

Clinical claims and research

Oseltamivir is the ethyl ester prodrug of GS-4071, the corresponding acid, which is one of the most potent inhibitors of both influenza A and B virus neuraminidase (sialidase) isoenzymes; these glycoproteins are expressed on the virion surface and are essential for virus replication for both A and B strains. Oseltamivir emerged as one of the first two neuraminidase inhibitors to reach the market. GS-4071 demonstrated a low (< 5%) oral bioavailability in animals due to a poor absorption from the gastrointestinal barrier; by incorporating a more lipophilic ester group, the oral bioavailabilty can reach 30 to 100% in mice, rats and dogs. Following oral administration of Oseltamivir in rats, a similar concentration of GS-4071 was found in the bronchoalveolar lining fluid and the plasma which indicated a good penetration of the active compound into the lower respiratory tract. In mice, chickens and ferrets, orally administered Oseltamivir was found to have significant inhibitory effects on A and B influenza infections in protecting against a lethal challenge of virus and lessening virus titer in the lungs or nasal washings. In several clinical trials with patients receiving oral capsules daily, Oseltamivir was shown to be effective in reducing significantly the duration and severity of the clinical symptoms, including fever, cough and general malaise, in both early treatment and prevention.

InChI:InChI=1/C16H28N2O4.H3O4P/c1-5-12(6-2)22-14-9-11(16(20)21-7-3)8-13(17)15(14)18-10(4)19;1-5(2,3)4/h9,12-15H,5-8,17H2,1-4H3,(H,18,19);(H3,1,2,3,4)/t13-,14+,15+;/m0./s1

Synthetic route

oseltamivir (196618-13-0) → oseltamivir phosphate (204255-11-8)

Conditions	Yield
With phosphoric acid In ethanol at 50℃; for 0.0166667h; Sonication;	98%
With phosphoric acid In ethanol at -18.8℃; for 17h;	89.9%
With phosphoric acid In ethanol at 50 - 55℃;	88.6%

ethyl (3R,4R,5S)-4-N-acetylamino-5-N,N-diallylamino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate → oseltamivir phosphate (204255-11-8)

Conditions	Yield
Stage #1: ethyl (3R,4R,5S)-4-N-acetylamino-5-N,N-diallylamino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate With palladium 10% on activated carbon; 2,2'-iminobis[ethanol] In ethanol at 68 - 78℃; for 8h; Stage #2: With phosphoric acid In ethanol at 45 - 55℃; Reagent/catalyst;	96.31%
With 1,3-dimethylbarbituric acid; phosphoric acid; palladium 10% on activated carbon; triphenylphosphine In ethanol at 55 - 78℃; Temperature; Reagent/catalyst; Large scale;	89%
Stage #1: ethyl (3R,4R,5S)-4-N-acetylamino-5-N,N-diallylamino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate With tetrakis(triphenylphosphine) palladium(0); 1,3-dimethylbarbituric acid In dichloromethane at 35℃; for 7h; Inert atmosphere; Stage #2: With phosphoric acid In ethanol at 48 - 52℃; for 2h;	85%

oseltamivir (204255-06-1) → oseltamivir phosphate (204255-11-8)

Conditions	Yield
Stage #1: oseltamivir With tributylphosphine; triphenylphosphine In ethanol; water at 50℃; for 3h; Stage #2: With phosphoric acid In ethanol	92%
Stage #1: oseltamivir With Lindlar's catalyst; hydrogen In ethanol at 20℃; under 760.051 Torr; for 16h; Stage #2: With phosphoric acid In ethanol; ethyl acetate at 50℃; for 0.5h;	91%
	91%

phosphoric acid (86119-84-8, 7664-38-2) + oseltamivir (196618-13-0) → oseltamivir phosphate (204255-11-8)

Conditions	Yield
In ethanol; water at 50 - 55℃; for 1.5 - 2h;	88%

(3R,4R,5S)-ethyl 4-acetamido-5-((tert-butoxycarbonyl)amino)-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate (367252-68-4) → oseltamivir phosphate (204255-11-8)

Conditions	Yield
With phosphoric acid In ethanol at 78℃; for 12h; Inert atmosphere;	83%
With phosphoric acid In ethanol at 0 - 78℃; for 15h; Inert atmosphere;	83%
With phosphoric acid In ethanol at 50℃; for 6h;	81%

(3R,4R,5S)-4-acetamido-5-allyloxycarbonylamino-1-ethoxycarbonyl-3-(3-pentyloxy)cyclohex-1-ene → oseltamivir phosphate (204255-11-8)

Conditions	Yield
Stage #1: (3S,4S,5S)-4-acetamido-5-allyloxycarbonylamino-1-ethoxycarbonyl-3-(3-pentyloxy)cyclohex-2-ene With 1,3-dimethylbarbituric acid; 5%-palladium/activated carbon; triphenylphosphine In ethanol at 80℃; for 1h; Stage #2: With phosphoric acid In ethanol at 50℃;	76%

tert-butyl [(1S,5R,6R)-6-acetylamino-3-cyano-5-(1-ethylpropoxy)cyclohex-3-en-1-yl]carbamate (891831-22-4) + ethanol (64-17-5) → oseltamivir phosphate (204255-11-8)

Conditions	Yield
Stage #1: tert-butyl [(1S,5R,6R)-6-acetylamino-3-cyano-5-(1-ethylpropoxy)cyclohex-3-en-1-yl]carbamate; ethanol With hydrogenchloride at 60℃; for 4h; Stage #2: With phosphoric acid at 4 - 50℃;	50%
Stage #1: tert-butyl [(1S,5R,6R)-6-acetylamino-3-cyano-5-(1-ethylpropoxy)cyclohex-3-en-1-yl]carbamate; ethanol With hydrogenchloride Stage #2: With sodium hydroxide Stage #3: With phosphoric acid

(2-oxo-2,3,3aβ,4α,5,7aβ-hexahydro-benzoxazol-4-yl)-carbamic acid tert-butyl ester → oseltamivir phosphate (204255-11-8)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: LiOH 1.2: NEt3 2.1: isobutyric anhydride; DMSO 3.1: Ni(cod)2; 1,5-cyclooctadiene 3.2: NBS; NEt3 4.1: LiAl(Ot-Bu)3H 5.1: DEAD; PPh3 5.2: 56 percent / BF3*OEt2 6.1: HCl 6.2: aq. NaOH 6.3: H3PO4 View Scheme

(1S,2R)-2-(acetylamino)-1-(tert-butoxycarbonylamino)-4-cyclohexen-3-one (930275-48-2) → oseltamivir phosphate (204255-11-8)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: Ni(cod)2; 1,5-cyclooctadiene 1.2: NBS; NEt3 2.1: LiAl(Ot-Bu)3H 3.1: DEAD; PPh3 3.2: 56 percent / BF3*OEt2 4.1: HCl 4.2: aq. NaOH 4.3: H3PO4 View Scheme

(6-acetylamino-5-hydroxy-cyclohex-3-enyl)-carbamic acid tert-butyl ester → oseltamivir phosphate (204255-11-8)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: isobutyric anhydride; DMSO 2.1: Ni(cod)2; 1,5-cyclooctadiene 2.2: NBS; NEt3 3.1: LiAl(Ot-Bu)3H 4.1: DEAD; PPh3 4.2: 56 percent / BF3*OEt2 5.1: HCl 5.2: aq. NaOH 5.3: H3PO4 View Scheme

tert-butyl [(1S,5R,6R)-6-acetylamino-3-cyano-5-hydroxycyclohex-3-en-1-yl]carbamate (927395-71-9) → oseltamivir phosphate (204255-11-8)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: DEAD; PPh3 1.2: 56 percent / BF3*OEt2 2.1: HCl 2.2: aq. NaOH 2.3: H3PO4 View Scheme

(6-acetylamino-3-cyano-5-oxo-cyclohex-3-enyl)-carbamic acid tert-butyl ester (930275-47-1) → oseltamivir phosphate (204255-11-8)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: LiAl(Ot-Bu)3H 2.1: DEAD; PPh3 2.2: 56 percent / BF3*OEt2 3.1: HCl 3.2: aq. NaOH 3.3: H3PO4 View Scheme

ethyl (3R,4R,5S)-4-amino-5-azido-3-(pentan-3-yloxy)cyclohex-1-ene-1-carboxylate (204255-04-9) → oseltamivir phosphate (204255-11-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: 0.98 kg / sodium bicarbonate / hexane / 1 h 2: 1.) hydrogen, 2.) phophoric acid / 1.) Raney nickel / 1.) ethanol, 16 h, 2.) ethanol, 55 65 deg C View Scheme
Multi-step reaction with 3 steps 1: sodium hydrogencarbonate / water; dichloromethane / 1 h / 20 °C 2: hydrogen / ethanol / 18 h / 760.05 Torr 3: phosphoric acid / acetone; ethanol / Reflux View Scheme
Multi-step reaction with 3 steps 1: pyridine / 1 h / 20 °C 2: hydrogen / ethanol / 10 h 3: phosphoric acid / ethanol / 3 h / 60 °C View Scheme

(1S,5R,6S)-5-(pentan-3-yloxy)-7-oxabicyclo[4.1.0]hept-3-ene-3-carboxylic acid ethyl ester (204254-96-6) → oseltamivir phosphate (204255-11-8)

Conditions	Yield
Multi-step reaction with 4 steps 1: 1.) sodium azide, ammonium chloride, 2.) trimethylphosphine / 1.) ethanol, water, 70-75 deg C, 18 h, 2.) acetonitrile, <38 deg C, 2 h 2: sodium azide, ammonium chloride / dimethylformamide / 18 h / 70 - 80 °C 3: 0.98 kg / sodium bicarbonate / hexane / 1 h 4: 1.) hydrogen, 2.) phophoric acid / 1.) Raney nickel / 1.) ethanol, 16 h, 2.) ethanol, 55 65 deg C View Scheme
Multi-step reaction with 6 steps 1.1: boron trifluoride diethyl etherate / 1.17 h / 0 °C 1.2: 4 h / 0 - 20 °C 1.3: 36 h / 20 °C 2.1: triethylamine; dmap / 1 h / 0 °C 3.1: sodium hydride / dichloromethane; dimethyl sulfoxide; mineral oil / 8 h / 20 °C 4.1: boron trifluoride diethyl etherate / dichloromethane / 0.37 h / -15 °C 5.1: caesium carbonate / dimethyl sulfoxide / 0.25 h / 80 °C 5.2: 0.33 h / 80 °C 6.1: phosphoric acid / ethyl acetate; ethanol / 2 h / 50 °C View Scheme
Multi-step reaction with 5 steps 1.1: sodium azide; ammonium chloride / water; ethanol / 8 h / 70 - 75 °C 1.2: 6 h / Reflux 2.1: sodium azide; ammonium chloride / N,N-dimethyl-formamide / 5 h / 8 - 85 °C 3.1: sodium hydrogencarbonate / water; dichloromethane / 1 h / 20 °C 4.1: hydrogen / ethanol / 18 h / 760.05 Torr 5.1: phosphoric acid / acetone; ethanol / Reflux View Scheme

ethyl-(1R,5R,6R)-5-(pentan-3-yloxy)-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylate (204255-02-7) → oseltamivir phosphate (204255-11-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium azide, ammonium chloride / dimethylformamide / 18 h / 70 - 80 °C 2: 0.98 kg / sodium bicarbonate / hexane / 1 h 3: 1.) hydrogen, 2.) phophoric acid / 1.) Raney nickel / 1.) ethanol, 16 h, 2.) ethanol, 55 65 deg C View Scheme
Multi-step reaction with 4 steps 1: sodium azide; ammonium chloride / N,N-dimethyl-formamide / 5 h / 8 - 85 °C 2: sodium hydrogencarbonate / water; dichloromethane / 1 h / 20 °C 3: hydrogen / ethanol / 18 h / 760.05 Torr 4: phosphoric acid / acetone; ethanol / Reflux View Scheme

ethyl (3aR,7R,7aR)-2,2-dimethyl-7-methanesulfonyloxy-3a,6,7,7a-tetrahydrobenzo[1,3]dioxole-5-carboxylate (204254-84-2) → oseltamivir phosphate (204255-11-8)

Conditions	Yield
Multi-step reaction with 6 steps 1: 95 percent / perchloric acid 2: 1.) BH3-SMe2, trimethylsilyl trifluoromethanesulfonate, 2.) potassium hydroden carbonate / 1.) dichloromethane, -20 - -10 deg C, 0.2 h, 2.) ethanol, water, 55-65 deg C, 1 h 3: 1.) sodium azide, ammonium chloride, 2.) trimethylphosphine / 1.) ethanol, water, 70-75 deg C, 18 h, 2.) acetonitrile, <38 deg C, 2 h 4: sodium azide, ammonium chloride / dimethylformamide / 18 h / 70 - 80 °C 5: 0.98 kg / sodium bicarbonate / hexane / 1 h 6: 1.) hydrogen, 2.) phophoric acid / 1.) Raney nickel / 1.) ethanol, 16 h, 2.) ethanol, 55 65 deg C View Scheme
Multi-step reaction with 7 steps 1.1: perchloric acid / 18 h 2.1: dimethylsulfide borane complex; trimethylsilyl trifluoromethanesulfonate / dichloromethane / 1 h / -30 - -20 °C 2.2: 12 h / 20 °C 2.3: 2 h / 55 - 65 °C 3.1: sodium azide; ammonium chloride / water; ethanol / 8 h / 70 - 75 °C 3.2: 6 h / Reflux 4.1: sodium azide; ammonium chloride / N,N-dimethyl-formamide / 5 h / 8 - 85 °C 5.1: sodium hydrogencarbonate / water; dichloromethane / 1 h / 20 °C 6.1: hydrogen / ethanol / 18 h / 760.05 Torr 7.1: phosphoric acid / acetone; ethanol / Reflux View Scheme

ethyl (3aR,7R,7aR)-2,2-dimethyl-7-methanesulfonyloxy-3a,6,7,7a-tetrahydrobenzo[1,3]dioxole-5-carboxylate (204254-90-0) → oseltamivir phosphate (204255-11-8)

Conditions	Yield
Multi-step reaction with 5 steps 1: 1.) BH3-SMe2, trimethylsilyl trifluoromethanesulfonate, 2.) potassium hydroden carbonate / 1.) dichloromethane, -20 - -10 deg C, 0.2 h, 2.) ethanol, water, 55-65 deg C, 1 h 2: 1.) sodium azide, ammonium chloride, 2.) trimethylphosphine / 1.) ethanol, water, 70-75 deg C, 18 h, 2.) acetonitrile, <38 deg C, 2 h 3: sodium azide, ammonium chloride / dimethylformamide / 18 h / 70 - 80 °C 4: 0.98 kg / sodium bicarbonate / hexane / 1 h 5: 1.) hydrogen, 2.) phophoric acid / 1.) Raney nickel / 1.) ethanol, 16 h, 2.) ethanol, 55 65 deg C View Scheme
Multi-step reaction with 6 steps 1.1: dimethylsulfide borane complex; trimethylsilyl trifluoromethanesulfonate / dichloromethane / 1 h / -30 - -20 °C 1.2: 12 h / 20 °C 1.3: 2 h / 55 - 65 °C 2.1: sodium azide; ammonium chloride / water; ethanol / 8 h / 70 - 75 °C 2.2: 6 h / Reflux 3.1: sodium azide; ammonium chloride / N,N-dimethyl-formamide / 5 h / 8 - 85 °C 4.1: sodium hydrogencarbonate / water; dichloromethane / 1 h / 20 °C 5.1: hydrogen / ethanol / 18 h / 760.05 Torr 6.1: phosphoric acid / acetone; ethanol / Reflux View Scheme
Multi-step reaction with 4 steps 1.1: caesium carbonate / N,N-dimethyl-formamide / 8 h / 90 - 100 °C 2.1: triethylsilane; titanium tetrachloride / dichloromethane / 2 h / -40 - -35 °C / Inert atmosphere 3.1: acetic acid; sulfuric acid / 1 h / 0 - 20 °C 4.1: 1,3-dimethylbarbituric acid; tetrakis(triphenylphosphine) palladium(0) / dichloromethane / 7 h / 35 °C / Inert atmosphere 4.2: 2 h / 48 - 52 °C View Scheme

(3R,4R,5S)-4-azido-5-tert-butoxycarbonylamino-3-(1-ethylpropoxy)cyclohex-1-enecarboxylic acid ethyl ester (367252-67-3) + phosphoric acid (86119-84-8, 7664-38-2) → oseltamivir phosphate (204255-11-8)

Conditions	Yield
With sodium hydroxide; hydrogen bromide; acetic anhydride; acetic acid; triethylamine; cobalt In ethanol; ethyl acetate; acetone

ethyl (3R,4R,5S)-4-(acetylamino)-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate tartrate → oseltamivir phosphate (204255-11-8)

Conditions	Yield
With phosphoric acid In ethanol; acetone at 25 - 30℃; for 1.5h;

(1S,5S,6R)-ethyl 7-acetyl-5-(tert-butoxycarbonylamino)-7-azabicyclo[4.1.0]hept-2-ene-3-carboxylate (891862-23-0) + 2-pentanol (584-02-1) → oseltamivir phosphate (204255-11-8)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: boron trifluoride diethyl etherate / 3 h / -20 °C / Inert atmosphere 2.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 2.2: 4 °C View Scheme

(1R,4R,5R)-4-iodo-6-oxabicyclo[3.2.1]octane-7-one (119719-61-8) → oseltamivir phosphate (204255-11-8)

Conditions	Yield
Multi-step reaction with 13 steps 1.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / toluene / 6 h / Reflux 2.1: potassium carbonate / 5 h / 20 °C 3.1: triphenylphosphine; diethylazodicarboxylate / toluene / 6 h / -20 °C / Inert atmosphere 4.1: 1,8-diazabicyclo[5.4.0]undec-7-ene; 2-hydroxyethanethiol / acetone / 3 h / 20 °C 5.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 6 h / 0 °C 6.1: titanium(IV) isopropylate; trimethylsilylazide / benzene / 2 h / 5 - 20 °C / Inert atmosphere 6.2: 1 h 7.1: triethylamine / dichloromethane / 0.5 h / 0 °C / Inert atmosphere 8.1: lithium diisopropyl amide / tetrahydrofuran; hexane / 0.75 h / -78 °C / Inert atmosphere 8.2: 0.5 h / -78 °C / Inert atmosphere 8.3: 0.5 h 9.1: pyridine; dihydrogen peroxide / dichloromethane / 0.5 h / 20 °C 10.1: triphenylphosphine / toluene / 3 h / Reflux 11.1: dmap; triethylamine / dichloromethane / 0 - 20 °C 12.1: boron trifluoride diethyl etherate / 3 h / -20 °C / Inert atmosphere 13.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 13.2: 4 °C View Scheme
Multi-step reaction with 12 steps 1.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / toluene / 6 h / Reflux 2.1: potassium carbonate / 5 h / 20 °C 3.1: triphenylphosphine; diethylazodicarboxylate / toluene / 6 h / -20 °C / Inert atmosphere 4.1: 1,8-diazabicyclo[5.4.0]undec-7-ene; 2-hydroxyethanethiol / acetone / 3 h / 20 °C 5.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 6 h / 0 °C 6.1: titanium(IV) isopropylate; trimethylsilylazide / benzene / 2 h / 5 - 20 °C / Inert atmosphere 6.2: 1 h 7.1: triethylamine / dichloromethane / 0.5 h / 0 °C / Inert atmosphere 8.1: lithium diisopropyl amide / tetrahydrofuran; hexane / 0.75 h / -78 °C / Inert atmosphere 8.2: 0.5 h / -78 °C / Inert atmosphere 8.3: 0.5 h 9.1: pyridine; dihydrogen peroxide / dichloromethane / 0.5 h / 20 °C 9.2: 3 h / Reflux 10.1: dmap; triethylamine / dichloromethane / 0 - 20 °C 11.1: boron trifluoride diethyl etherate / 3 h / -20 °C / Inert atmosphere 12.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 12.2: 4 °C View Scheme
Multi-step reaction with 13 steps 1.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / toluene / 6 h / Reflux 2.1: potassium carbonate / 5 h / 20 °C 3.1: triphenylphosphine; diethylazodicarboxylate / toluene / 6 h / -20 °C / Inert atmosphere 4.1: 1,8-diazabicyclo[5.4.0]undec-7-ene; 2-hydroxyethanethiol / acetone / 3 h / 20 °C 5.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 6 h / 0 °C 6.1: titanium(IV) isopropylate; trimethylsilylazide / benzene / 2 h / 5 - 20 °C / Inert atmosphere 6.2: 1 h 7.1: triethylamine / dichloromethane / 0.5 h / 0 °C / Inert atmosphere 8.1: lithium diisopropyl amide / tetrahydrofuran; hexane / 0.75 h / -78 °C / Inert atmosphere 8.2: 0.5 h / -78 °C / Inert atmosphere 8.3: 0.5 h 9.1: pyridine; dihydrogen peroxide / dichloromethane / 0.5 h / 20 °C 9.2: 24 h / 20 °C 10.1: triphenylphosphine / toluene / 3 h / Reflux 11.1: dmap; triethylamine / dichloromethane / 0 - 20 °C 12.1: boron trifluoride diethyl etherate / 3 h / -20 °C / Inert atmosphere 13.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 13.2: 4 °C View Scheme
Multi-step reaction with 13 steps 1.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / toluene / 6 h / Reflux 2.1: potassium carbonate / 5 h / 20 °C 3.1: triphenylphosphine; diethylazodicarboxylate / toluene / 6 h / -20 °C / Inert atmosphere 4.1: 1,8-diazabicyclo[5.4.0]undec-7-ene; 2-hydroxyethanethiol / acetone / 3 h / 20 °C 5.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 6 h / 0 °C 6.1: titanium(IV) isopropylate; trimethylsilylazide / benzene / 2 h / 5 - 20 °C / Inert atmosphere 6.2: 1 h 7.1: triethylamine / dichloromethane / 0.5 h / 0 °C / Inert atmosphere 8.1: lithium diisopropyl amide / tetrahydrofuran; hexane / 0.75 h / -78 °C / Inert atmosphere 8.2: 0.5 h / -78 °C / Inert atmosphere 8.3: 0.5 h 9.1: pyridine; dihydrogen peroxide / dichloromethane / 0.5 h / 20 °C 9.2: 3 h / Reflux 10.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / toluene / 24 h / 20 °C 11.1: dmap; triethylamine / dichloromethane / 0 - 20 °C 12.1: boron trifluoride diethyl etherate / 3 h / -20 °C / Inert atmosphere 13.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 13.2: 4 °C View Scheme

(1S,5S,6R)-ethyl 5-(tert-butoxycarbonylamino)-7-azabicyclo[4.1.0]hept-2-ene-3-carboxylate → oseltamivir phosphate (204255-11-8)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: dmap; triethylamine / dichloromethane / 0 - 20 °C 2.1: boron trifluoride diethyl etherate / 3 h / -20 °C / Inert atmosphere 3.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 3.2: 4 °C View Scheme

(1R,5R)-ethyl 5-hydroxycyclohex-3-enecarboxylate (1287204-65-2) → oseltamivir phosphate (204255-11-8)

Conditions	Yield
Multi-step reaction with 11 steps 1.1: triphenylphosphine; diethylazodicarboxylate / toluene / 6 h / -20 °C / Inert atmosphere 2.1: 1,8-diazabicyclo[5.4.0]undec-7-ene; 2-hydroxyethanethiol / acetone / 3 h / 20 °C 3.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 6 h / 0 °C 4.1: titanium(IV) isopropylate; trimethylsilylazide / benzene / 2 h / 5 - 20 °C / Inert atmosphere 4.2: 1 h 5.1: triethylamine / dichloromethane / 0.5 h / 0 °C / Inert atmosphere 6.1: lithium diisopropyl amide / tetrahydrofuran; hexane / 0.75 h / -78 °C / Inert atmosphere 6.2: 0.5 h / -78 °C / Inert atmosphere 6.3: 0.5 h 7.1: pyridine; dihydrogen peroxide / dichloromethane / 0.5 h / 20 °C 8.1: triphenylphosphine / toluene / 3 h / Reflux 9.1: dmap; triethylamine / dichloromethane / 0 - 20 °C 10.1: boron trifluoride diethyl etherate / 3 h / -20 °C / Inert atmosphere 11.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 11.2: 4 °C View Scheme
Multi-step reaction with 10 steps 1.1: triphenylphosphine; diethylazodicarboxylate / toluene / 6 h / -20 °C / Inert atmosphere 2.1: 1,8-diazabicyclo[5.4.0]undec-7-ene; 2-hydroxyethanethiol / acetone / 3 h / 20 °C 3.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 6 h / 0 °C 4.1: titanium(IV) isopropylate; trimethylsilylazide / benzene / 2 h / 5 - 20 °C / Inert atmosphere 4.2: 1 h 5.1: triethylamine / dichloromethane / 0.5 h / 0 °C / Inert atmosphere 6.1: lithium diisopropyl amide / tetrahydrofuran; hexane / 0.75 h / -78 °C / Inert atmosphere 6.2: 0.5 h / -78 °C / Inert atmosphere 6.3: 0.5 h 7.1: pyridine; dihydrogen peroxide / dichloromethane / 0.5 h / 20 °C 7.2: 3 h / Reflux 8.1: dmap; triethylamine / dichloromethane / 0 - 20 °C 9.1: boron trifluoride diethyl etherate / 3 h / -20 °C / Inert atmosphere 10.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 10.2: 4 °C View Scheme
Multi-step reaction with 11 steps 1.1: triphenylphosphine; diethylazodicarboxylate / toluene / 6 h / -20 °C / Inert atmosphere 2.1: 1,8-diazabicyclo[5.4.0]undec-7-ene; 2-hydroxyethanethiol / acetone / 3 h / 20 °C 3.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 6 h / 0 °C 4.1: titanium(IV) isopropylate; trimethylsilylazide / benzene / 2 h / 5 - 20 °C / Inert atmosphere 4.2: 1 h 5.1: triethylamine / dichloromethane / 0.5 h / 0 °C / Inert atmosphere 6.1: lithium diisopropyl amide / tetrahydrofuran; hexane / 0.75 h / -78 °C / Inert atmosphere 6.2: 0.5 h / -78 °C / Inert atmosphere 6.3: 0.5 h 7.1: pyridine; dihydrogen peroxide / dichloromethane / 0.5 h / 20 °C 7.2: 24 h / 20 °C 8.1: triphenylphosphine / toluene / 3 h / Reflux 9.1: dmap; triethylamine / dichloromethane / 0 - 20 °C 10.1: boron trifluoride diethyl etherate / 3 h / -20 °C / Inert atmosphere 11.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 11.2: 4 °C View Scheme
Multi-step reaction with 11 steps 1.1: triphenylphosphine; diethylazodicarboxylate / toluene / 6 h / -20 °C / Inert atmosphere 2.1: 1,8-diazabicyclo[5.4.0]undec-7-ene; 2-hydroxyethanethiol / acetone / 3 h / 20 °C 3.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 6 h / 0 °C 4.1: titanium(IV) isopropylate; trimethylsilylazide / benzene / 2 h / 5 - 20 °C / Inert atmosphere 4.2: 1 h 5.1: triethylamine / dichloromethane / 0.5 h / 0 °C / Inert atmosphere 6.1: lithium diisopropyl amide / tetrahydrofuran; hexane / 0.75 h / -78 °C / Inert atmosphere 6.2: 0.5 h / -78 °C / Inert atmosphere 6.3: 0.5 h 7.1: pyridine; dihydrogen peroxide / dichloromethane / 0.5 h / 20 °C 7.2: 3 h / Reflux 8.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / toluene / 24 h / 20 °C 9.1: dmap; triethylamine / dichloromethane / 0 - 20 °C 10.1: boron trifluoride diethyl etherate / 3 h / -20 °C / Inert atmosphere 11.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 11.2: 4 °C View Scheme

(1R,5S)-ethyl 5-(N-(tert-butoxycarbonyl)-4-nitrophenylsulfonamido)cyclohex-3-enecarboxylate (1287204-66-3) → oseltamivir phosphate (204255-11-8)

Conditions	Yield
Multi-step reaction with 10 steps 1.1: 1,8-diazabicyclo[5.4.0]undec-7-ene; 2-hydroxyethanethiol / acetone / 3 h / 20 °C 2.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 6 h / 0 °C 3.1: titanium(IV) isopropylate; trimethylsilylazide / benzene / 2 h / 5 - 20 °C / Inert atmosphere 3.2: 1 h 4.1: triethylamine / dichloromethane / 0.5 h / 0 °C / Inert atmosphere 5.1: lithium diisopropyl amide / tetrahydrofuran; hexane / 0.75 h / -78 °C / Inert atmosphere 5.2: 0.5 h / -78 °C / Inert atmosphere 5.3: 0.5 h 6.1: pyridine; dihydrogen peroxide / dichloromethane / 0.5 h / 20 °C 7.1: triphenylphosphine / toluene / 3 h / Reflux 8.1: dmap; triethylamine / dichloromethane / 0 - 20 °C 9.1: boron trifluoride diethyl etherate / 3 h / -20 °C / Inert atmosphere 10.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 10.2: 4 °C View Scheme
Multi-step reaction with 10 steps 1.1: 1,8-diazabicyclo[5.4.0]undec-7-ene; 2-hydroxyethanethiol / acetone / 3 h / 20 °C 2.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 6 h / 0 °C 3.1: titanium(IV) isopropylate; trimethylsilylazide / benzene / 2 h / 5 - 20 °C / Inert atmosphere 3.2: 1 h 4.1: triethylamine / dichloromethane / 0.5 h / 0 °C / Inert atmosphere 5.1: lithium diisopropyl amide / tetrahydrofuran; hexane / 0.75 h / -78 °C / Inert atmosphere 5.2: 0.5 h / -78 °C / Inert atmosphere 5.3: 0.5 h 6.1: pyridine; dihydrogen peroxide / dichloromethane / 0.5 h / 20 °C 6.2: 3 h / Reflux 7.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / toluene / 24 h / 20 °C 8.1: dmap; triethylamine / dichloromethane / 0 - 20 °C 9.1: boron trifluoride diethyl etherate / 3 h / -20 °C / Inert atmosphere 10.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 10.2: 4 °C View Scheme
Multi-step reaction with 10 steps 1.1: 1,8-diazabicyclo[5.4.0]undec-7-ene; 2-hydroxyethanethiol / acetone / 3 h / 20 °C 2.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 6 h / 0 °C 3.1: titanium(IV) isopropylate; trimethylsilylazide / benzene / 2 h / 5 - 20 °C / Inert atmosphere 3.2: 1 h 4.1: triethylamine / dichloromethane / 0.5 h / 0 °C / Inert atmosphere 5.1: lithium diisopropyl amide / tetrahydrofuran; hexane / 0.75 h / -78 °C / Inert atmosphere 5.2: 0.5 h / -78 °C / Inert atmosphere 5.3: 0.5 h 6.1: pyridine; dihydrogen peroxide / dichloromethane / 0.5 h / 20 °C 6.2: 24 h / 20 °C 7.1: triphenylphosphine / toluene / 3 h / Reflux 8.1: dmap; triethylamine / dichloromethane / 0 - 20 °C 9.1: boron trifluoride diethyl etherate / 3 h / -20 °C / Inert atmosphere 10.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 10.2: 4 °C View Scheme
Multi-step reaction with 9 steps 1.1: 1,8-diazabicyclo[5.4.0]undec-7-ene; 2-hydroxyethanethiol / acetone / 3 h / 20 °C 2.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 6 h / 0 °C 3.1: titanium(IV) isopropylate; trimethylsilylazide / benzene / 2 h / 5 - 20 °C / Inert atmosphere 3.2: 1 h 4.1: triethylamine / dichloromethane / 0.5 h / 0 °C / Inert atmosphere 5.1: lithium diisopropyl amide / tetrahydrofuran; hexane / 0.75 h / -78 °C / Inert atmosphere 5.2: 0.5 h / -78 °C / Inert atmosphere 5.3: 0.5 h 6.1: pyridine; dihydrogen peroxide / dichloromethane / 0.5 h / 20 °C 6.2: 3 h / Reflux 7.1: dmap; triethylamine / dichloromethane / 0 - 20 °C 8.1: boron trifluoride diethyl etherate / 3 h / -20 °C / Inert atmosphere 9.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 9.2: 4 °C View Scheme

ethyl (5S)-5-((tert-butoxycarbonyl)amino)cyclohex-3-ene-1-carboxylate (1287204-67-4) → oseltamivir phosphate (204255-11-8)

Conditions	Yield
Multi-step reaction with 9 steps 1.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 6 h / 0 °C 2.1: titanium(IV) isopropylate; trimethylsilylazide / benzene / 2 h / 5 - 20 °C / Inert atmosphere 2.2: 1 h 3.1: triethylamine / dichloromethane / 0.5 h / 0 °C / Inert atmosphere 4.1: lithium diisopropyl amide / tetrahydrofuran; hexane / 0.75 h / -78 °C / Inert atmosphere 4.2: 0.5 h / -78 °C / Inert atmosphere 4.3: 0.5 h 5.1: pyridine; dihydrogen peroxide / dichloromethane / 0.5 h / 20 °C 6.1: triphenylphosphine / toluene / 3 h / Reflux 7.1: dmap; triethylamine / dichloromethane / 0 - 20 °C 8.1: boron trifluoride diethyl etherate / 3 h / -20 °C / Inert atmosphere 9.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 9.2: 4 °C View Scheme
Multi-step reaction with 8 steps 1.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 6 h / 0 °C 2.1: titanium(IV) isopropylate; trimethylsilylazide / benzene / 2 h / 5 - 20 °C / Inert atmosphere 2.2: 1 h 3.1: triethylamine / dichloromethane / 0.5 h / 0 °C / Inert atmosphere 4.1: lithium diisopropyl amide / tetrahydrofuran; hexane / 0.75 h / -78 °C / Inert atmosphere 4.2: 0.5 h / -78 °C / Inert atmosphere 4.3: 0.5 h 5.1: pyridine; dihydrogen peroxide / dichloromethane / 0.5 h / 20 °C 5.2: 3 h / Reflux 6.1: dmap; triethylamine / dichloromethane / 0 - 20 °C 7.1: boron trifluoride diethyl etherate / 3 h / -20 °C / Inert atmosphere 8.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 8.2: 4 °C View Scheme
Multi-step reaction with 9 steps 1.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 6 h / 0 °C 2.1: titanium(IV) isopropylate; trimethylsilylazide / benzene / 2 h / 5 - 20 °C / Inert atmosphere 2.2: 1 h 3.1: triethylamine / dichloromethane / 0.5 h / 0 °C / Inert atmosphere 4.1: lithium diisopropyl amide / tetrahydrofuran; hexane / 0.75 h / -78 °C / Inert atmosphere 4.2: 0.5 h / -78 °C / Inert atmosphere 4.3: 0.5 h 5.1: pyridine; dihydrogen peroxide / dichloromethane / 0.5 h / 20 °C 5.2: 24 h / 20 °C 6.1: triphenylphosphine / toluene / 3 h / Reflux 7.1: dmap; triethylamine / dichloromethane / 0 - 20 °C 8.1: boron trifluoride diethyl etherate / 3 h / -20 °C / Inert atmosphere 9.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 9.2: 4 °C View Scheme
Multi-step reaction with 9 steps 1.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 6 h / 0 °C 2.1: titanium(IV) isopropylate; trimethylsilylazide / benzene / 2 h / 5 - 20 °C / Inert atmosphere 2.2: 1 h 3.1: triethylamine / dichloromethane / 0.5 h / 0 °C / Inert atmosphere 4.1: lithium diisopropyl amide / tetrahydrofuran; hexane / 0.75 h / -78 °C / Inert atmosphere 4.2: 0.5 h / -78 °C / Inert atmosphere 4.3: 0.5 h 5.1: pyridine; dihydrogen peroxide / dichloromethane / 0.5 h / 20 °C 5.2: 3 h / Reflux 6.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / toluene / 24 h / 20 °C 7.1: dmap; triethylamine / dichloromethane / 0 - 20 °C 8.1: boron trifluoride diethyl etherate / 3 h / -20 °C / Inert atmosphere 9.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 9.2: 4 °C View Scheme

(1R,3S,5S,6S)-ethyl 5-(tert-butoxycarbonylamino)-7-oxabicyclo[4.1.0]heptane-3-carboxylate (1287204-68-5) → oseltamivir phosphate (204255-11-8)

Conditions	Yield
Multi-step reaction with 8 steps 1.1: titanium(IV) isopropylate; trimethylsilylazide / benzene / 2 h / 5 - 20 °C / Inert atmosphere 1.2: 1 h 2.1: triethylamine / dichloromethane / 0.5 h / 0 °C / Inert atmosphere 3.1: lithium diisopropyl amide / tetrahydrofuran; hexane / 0.75 h / -78 °C / Inert atmosphere 3.2: 0.5 h / -78 °C / Inert atmosphere 3.3: 0.5 h 4.1: pyridine; dihydrogen peroxide / dichloromethane / 0.5 h / 20 °C 5.1: triphenylphosphine / toluene / 3 h / Reflux 6.1: dmap; triethylamine / dichloromethane / 0 - 20 °C 7.1: boron trifluoride diethyl etherate / 3 h / -20 °C / Inert atmosphere 8.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 8.2: 4 °C View Scheme
Multi-step reaction with 7 steps 1.1: titanium(IV) isopropylate; trimethylsilylazide / benzene / 2 h / 5 - 20 °C / Inert atmosphere 1.2: 1 h 2.1: triethylamine / dichloromethane / 0.5 h / 0 °C / Inert atmosphere 3.1: lithium diisopropyl amide / tetrahydrofuran; hexane / 0.75 h / -78 °C / Inert atmosphere 3.2: 0.5 h / -78 °C / Inert atmosphere 3.3: 0.5 h 4.1: pyridine; dihydrogen peroxide / dichloromethane / 0.5 h / 20 °C 4.2: 3 h / Reflux 5.1: dmap; triethylamine / dichloromethane / 0 - 20 °C 6.1: boron trifluoride diethyl etherate / 3 h / -20 °C / Inert atmosphere 7.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 7.2: 4 °C View Scheme
Multi-step reaction with 8 steps 1.1: titanium(IV) isopropylate; trimethylsilylazide / benzene / 2 h / 5 - 20 °C / Inert atmosphere 1.2: 1 h 2.1: triethylamine / dichloromethane / 0.5 h / 0 °C / Inert atmosphere 3.1: lithium diisopropyl amide / tetrahydrofuran; hexane / 0.75 h / -78 °C / Inert atmosphere 3.2: 0.5 h / -78 °C / Inert atmosphere 3.3: 0.5 h 4.1: pyridine; dihydrogen peroxide / dichloromethane / 0.5 h / 20 °C 4.2: 24 h / 20 °C 5.1: triphenylphosphine / toluene / 3 h / Reflux 6.1: dmap; triethylamine / dichloromethane / 0 - 20 °C 7.1: boron trifluoride diethyl etherate / 3 h / -20 °C / Inert atmosphere 8.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 8.2: 4 °C View Scheme
Multi-step reaction with 8 steps 1.1: titanium(IV) isopropylate; trimethylsilylazide / benzene / 2 h / 5 - 20 °C / Inert atmosphere 1.2: 1 h 2.1: triethylamine / dichloromethane / 0.5 h / 0 °C / Inert atmosphere 3.1: lithium diisopropyl amide / tetrahydrofuran; hexane / 0.75 h / -78 °C / Inert atmosphere 3.2: 0.5 h / -78 °C / Inert atmosphere 3.3: 0.5 h 4.1: pyridine; dihydrogen peroxide / dichloromethane / 0.5 h / 20 °C 4.2: 3 h / Reflux 5.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / toluene / 24 h / 20 °C 6.1: dmap; triethylamine / dichloromethane / 0 - 20 °C 7.1: boron trifluoride diethyl etherate / 3 h / -20 °C / Inert atmosphere 8.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 8.2: 4 °C View Scheme

(1S,3S,4R,5R)-ethyl 4-azido-3-(tert-butoxycarbonylamino)-5-hydroxycyclohexanecarboxylate (1287204-69-6) → oseltamivir phosphate (204255-11-8)

Conditions	Yield
Multi-step reaction with 7 steps 1.1: triethylamine / dichloromethane / 0.5 h / 0 °C / Inert atmosphere 2.1: lithium diisopropyl amide / tetrahydrofuran; hexane / 0.75 h / -78 °C / Inert atmosphere 2.2: 0.5 h / -78 °C / Inert atmosphere 2.3: 0.5 h 3.1: pyridine; dihydrogen peroxide / dichloromethane / 0.5 h / 20 °C 4.1: triphenylphosphine / toluene / 3 h / Reflux 5.1: dmap; triethylamine / dichloromethane / 0 - 20 °C 6.1: boron trifluoride diethyl etherate / 3 h / -20 °C / Inert atmosphere 7.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 7.2: 4 °C View Scheme
Multi-step reaction with 7 steps 1.1: triethylamine / dichloromethane / 0.5 h / 0 °C / Inert atmosphere 2.1: lithium diisopropyl amide / tetrahydrofuran; hexane / 0.75 h / -78 °C / Inert atmosphere 2.2: 0.5 h / -78 °C / Inert atmosphere 2.3: 0.5 h 3.1: pyridine; dihydrogen peroxide / dichloromethane / 0.5 h / 20 °C 3.2: 24 h / 20 °C 4.1: triphenylphosphine / toluene / 3 h / Reflux 5.1: dmap; triethylamine / dichloromethane / 0 - 20 °C 6.1: boron trifluoride diethyl etherate / 3 h / -20 °C / Inert atmosphere 7.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 7.2: 4 °C View Scheme

(1S,3S,4S,5S)-ethyl 3-azido-5-(tert-butoxycarbonylamino)-4-hydroxycyclohexanecarboxylate (1287204-70-9) → oseltamivir phosphate (204255-11-8)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: triethylamine / dichloromethane / 0.5 h / 0 °C / Inert atmosphere 2.1: lithium diisopropyl amide / tetrahydrofuran; hexane / 0.75 h / -78 °C / Inert atmosphere 2.2: 0.5 h / -78 °C / Inert atmosphere 2.3: 0.5 h 3.1: pyridine; dihydrogen peroxide / dichloromethane / 0.5 h / 20 °C 3.2: 3 h / Reflux 4.1: dmap; triethylamine / dichloromethane / 0 - 20 °C 5.1: boron trifluoride diethyl etherate / 3 h / -20 °C / Inert atmosphere 6.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 6.2: 4 °C View Scheme
Multi-step reaction with 7 steps 1.1: triethylamine / dichloromethane / 0.5 h / 0 °C / Inert atmosphere 2.1: lithium diisopropyl amide / tetrahydrofuran; hexane / 0.75 h / -78 °C / Inert atmosphere 2.2: 0.5 h / -78 °C / Inert atmosphere 2.3: 0.5 h 3.1: pyridine; dihydrogen peroxide / dichloromethane / 0.5 h / 20 °C 3.2: 3 h / Reflux 4.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / toluene / 24 h / 20 °C 5.1: dmap; triethylamine / dichloromethane / 0 - 20 °C 6.1: boron trifluoride diethyl etherate / 3 h / -20 °C / Inert atmosphere 7.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 7.2: 4 °C View Scheme

(1S,3S,4R,5R)-ethyl 4-azido-3-(tert-butoxycarbonylamino)-5-(trimethylsilyloxy)cyclohexanecarboxylate (1287204-71-0) → oseltamivir phosphate (204255-11-8)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: lithium diisopropyl amide / tetrahydrofuran; hexane / 0.75 h / -78 °C / Inert atmosphere 1.2: 0.5 h / -78 °C / Inert atmosphere 1.3: 0.5 h 2.1: pyridine; dihydrogen peroxide / dichloromethane / 0.5 h / 20 °C 3.1: triphenylphosphine / toluene / 3 h / Reflux 4.1: dmap; triethylamine / dichloromethane / 0 - 20 °C 5.1: boron trifluoride diethyl etherate / 3 h / -20 °C / Inert atmosphere 6.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 6.2: 4 °C View Scheme
Multi-step reaction with 6 steps 1.1: lithium diisopropyl amide / tetrahydrofuran; hexane / 0.75 h / -78 °C / Inert atmosphere 1.2: 0.5 h / -78 °C / Inert atmosphere 1.3: 0.5 h 2.1: pyridine; dihydrogen peroxide / dichloromethane / 0.5 h / 20 °C 2.2: 24 h / 20 °C 3.1: triphenylphosphine / toluene / 3 h / Reflux 4.1: dmap; triethylamine / dichloromethane / 0 - 20 °C 5.1: boron trifluoride diethyl etherate / 3 h / -20 °C / Inert atmosphere 6.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 6.2: 4 °C View Scheme

oseltamivir phosphate (204255-11-8) → oseltamivir acid

Conditions	Yield
With sodium hydroxide In methanol at 20℃; for 0.5h;	100%
With sodium hydroxide In water at 20℃; for 4h;	96%
Stage #1: oseltamivir phosphate With sodium hydroxide In 1,4-dioxane; water at 20℃; for 24h; Inert atmosphere; Stage #2: In 1,4-dioxane; water Inert atmosphere;	88%

oseltamivir phosphate (204255-11-8) → oseltamivir (196618-13-0)

Conditions	Yield
With sodium hydrogencarbonate In water at 20℃; for 0.0833333h; Inert atmosphere;	98%
Stage #1: oseltamivir phosphate In dichloromethane; water at 25 - 30℃; for 0.166667h; Stage #2: With ammonia In dichloromethane; water pH=9 - 10; Stage #3: In n-heptane at 25 - 30℃; for 1h; Purification / work up;
Stage #1: oseltamivir phosphate In dichloromethane; water at 25 - 30℃; for 0.166667h; Stage #2: With ammonia In dichloromethane; water pH=9 - 10; Stage #3: In n-heptane; toluene at 20 - 30℃; for 3.5h; Purification / work up;
In dichloromethane; water at 20℃; for 0.75h;

di-tert-butyl dicarbonate (24424-99-5) + oseltamivir phosphate (204255-11-8) → (3R,4R,5S)-ethyl 4-acetamido-5-((tert-butoxycarbonyl)amino)-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate (367252-68-4)

Conditions	Yield
Stage #1: oseltamivir phosphate With sodium hydrogencarbonate In water Stage #2: di-tert-butyl dicarbonate With triethylamine	98%
Alkaline conditions;	98%
With triethylamine In methanol at 20℃; for 12h;	96.3%

N,N'-bis( tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine (152120-54-2, 862686-58-6, 1143572-00-2) + oseltamivir phosphate (204255-11-8) → ethyl (3R,4R,5S)-4-acetamido-5-[N2,N3-bis(tert-butoxycarbonyl)guanidino]-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate

Conditions	Yield
With triethylamine In acetonitrile at 20℃; for 18h;	98%
With amine In tetrahydrofuran

tert-butyl N-({[(tert-butoxy)carbonyl]amino}methanethioyl)carbamate (145013-05-4) + oseltamivir phosphate (204255-11-8) → (3R,4R,5S)-5-[[(1Z)-[[(tert-butoxy)carbonyl]amino]([[(tert-butoxy)carbonyl]imino])methyl]amino]-4-acetylamino-3-(pentan-3-yloxy)cyclohex-1-ene-1-carboxylic acid ethyl ester (208720-81-4)

Conditions	Yield
With triethylamine; mercury dichloride In N,N-dimethyl-formamide at 20℃;	98%

tert-butyldicarbonate (34619-03-9) + oseltamivir phosphate (204255-11-8) → (3R,4R,5S)-ethyl 4-acetamido-5-((tert-butoxycarbonyl)amino)-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate (367252-68-4)

Conditions	Yield
With triethylamine In methanol at 20℃; for 12h;	96.3%

acetic anhydride (108-24-7) + oseltamivir phosphate (204255-11-8) → (3R,4R,5S)-4-acetylamino-5-acetylamino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid ethyl ester (1191921-01-3)

Conditions	Yield
Stage #1: oseltamivir phosphate With dmap; triethylamine In dichloromethane Stage #2: acetic anhydride In dichloromethane	94%

5-(3,5-difluorophenyl)furan-2-carbaldehyde + oseltamivir phosphate (204255-11-8) → ethyl (3R,4R,5S)-4-acetamido-5-(((5-(3,5-difluorophenyl)furan-2-yl)methyl)amino)-3-(pentan-3-yloxy)cyclohex-1-ene-1-carboxylate

Conditions	Yield
With sodium tris(acetoxy)borohydride In ethanol at 20℃;	89%

oseltamivir phosphate (204255-11-8) → C16H28N2O4*H3O4P

Conditions	Yield
In ethanol; water at 65 - 75℃; for 8h;	86.9%

propionic acid (802294-64-0) + oseltamivir phosphate (204255-11-8) → (3R,4R,5S)-ethyl 4-acetamido-5-(propionamido)-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate

Conditions	Yield
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃;	86%

(phenylthio)acetic acid chloride (7031-27-8) + oseltamivir phosphate (204255-11-8) → C24H34N2O6S

Conditions	Yield
With dihydrogen peroxide In acetonitrile at 60℃; for 1h;	86%

4-diphenylsulfonyl chloride (1623-93-4) + oseltamivir phosphate (204255-11-8) → (3R,4R,5S)-5-(([1,1'-biphenyl]-4-sulfonamide))-4-acetamido-3-((pentan-3-yl)oxy)cyclohexene-1-ene-1-carboxylic acid ethyl ester

Conditions	Yield
With triethylamine In dichloromethane at 20℃; for 6h;	85%
With triethylamine In dichloromethane at 25 - 30℃; for 8h;	84.7%

4-Phenylbenzaldehyde (3218-36-8) + oseltamivir phosphate (204255-11-8) → (3R,4R,5S)-4-acetylamino-5-(([1,1'-biphenyl]-4-ylmethyl)amino)-3-(1-ethylpropyloxy)-1-cyclohexene-1-carboxylic acid ethyl ester

Conditions	Yield
With sodium cyanoborohydride In ethanol at 20℃; for 6h;	84%
Stage #1: 4-Phenylbenzaldehyde; oseltamivir phosphate In ethanol at 20℃; for 0.0833333h; Stage #2: With sodium cyanoborohydride In ethanol at 20℃; for 4h;	67%
With sodium cyanoborohydride In ethanol at 20℃; for 6h;

(4-biphenylyl)acetic acid (5728-52-9) + oseltamivir phosphate (204255-11-8) → (3R,4R,5S)-5-(2-([1,1'-biphenyl]-4-yl)acetamido)-4-acetamido-3-((pentan-3-yl)oxy)cyclohexene-1-ene-1-carboxylic acid ethyl ester

Conditions	Yield
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 30℃; for 8h;	82.6%

p-toluenesulfonyl chloride (98-59-9) + oseltamivir phosphate (204255-11-8) → ethyl (3R,4R,5S)-4-acetamido-5-((4-methylphenyl)sulfonamido)-3-(pentan-3-yloxy)cyclohex-1-ene-1-carboxylate

Conditions	Yield
With triethylamine In dichloromethane at 20℃; for 6h;	80%

oseltamivir phosphate (204255-11-8) + 3-Phenylpropionic acid (501-52-0) → (3R,4R,5S)-ethyl 4-acetamido-5-(3-phenylpropionamido)-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate

Conditions	Yield
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃;	79%

oseltamivir phosphate (204255-11-8) + 3-(chloromethyl)-5-(4-chlorophenyl)-1,2,4-oxadiazole (73217-30-8) → C25H33ClN4O5

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 70℃; for 12h;	79%

5-(3,4-Dimethoxyphenyl)-2-furaldehyde (62427-25-2) + oseltamivir phosphate (204255-11-8) → ethyl (3R,4R,5S)-4-acetamido-5-(((5-(3,4-dimethoxyphenyl)furan-2-yl)methyl)amino)-3-(pentan-3-yloxy)cyclohex-1-ene-1-carboxylate

Conditions	Yield
With sodium tris(acetoxy)borohydride In ethanol at 20℃;	79%

benzenesulfonyl chloride (98-09-9) + oseltamivir phosphate (204255-11-8) → ethyl (3R,4R,5S)-4-acetamido-3-(pentan-3-yloxy)-5-(phenylsulfonamido)cyclohex-1-ene-1-carboxylate

Conditions	Yield
With triethylamine In dichloromethane at 20℃; for 6h;	79%

4-(Methylthio)benzaldehyde (3446-89-7) + oseltamivir phosphate (204255-11-8) → ethyl (3R,4R,5S)-4-acetamido-3-(sec-butoxy)-5-((4(methylthio)benzyl)amino)cyclohex -1-ene-1-carboxylate

Conditions	Yield
With sodium cyanoborohydride In ethanol at 20℃; for 6h;	77.3%

3-thiophene carboxaldehyde (498-62-4) + oseltamivir phosphate (204255-11-8) → ethyl (3R,4R,5S)-4-acetamido-3-(pentan-3-yloxy)-5-((thiophen-3-ylmethyl)amino)cyclohex-1-ene-1-carboxylate

Conditions	Yield
With sodium cyanoborohydride In methanol; ethanol at 20℃; for 6h;	77%
With sodium cyanoborohydride In ethanol at 20℃; for 6h;

4-nitrobenzaldehdye (555-16-8) + oseltamivir phosphate (204255-11-8) → (3R,4R,5S)-4-acetamido-5-((4-nitrobenzyl)amino)-3-((pentan-3-yl)oxy)cyclohexene-1-ene-1-carboxylic acid ethyl ester

Conditions	Yield
With sodium cyanoborohydride In methanol; ethanol at 20℃; for 6h;	77%
With sodium cyanoborohydride In ethanol at 30℃; for 5h;	76.3%

phenylacetic acid (103-82-2) + oseltamivir phosphate (204255-11-8) → (3R,4R,5S)-ethyl 4-acetamido-5-(phenylacetamido)-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate

Conditions	Yield
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃;	77%

(phenylthio)acetic acid chloride (7031-27-8) + oseltamivir phosphate (204255-11-8) → C24H34N2O7S

Conditions	Yield
With dihydrogen peroxide In acetonitrile at 60℃; for 24h;	77%

Upstream product

• 367252-67-3 (3R,4R,5S)-4-azido-5-tert-butoxycarbonylamino-3-(1-ethylpropoxy)cyclohex-1-enecarboxylic acid ethyl ester 
• 86119-84-8 phosphoric acid 
• 367252-68-4 (3R,4R,5S)-ethyl 4-acetamido-5-((tert-butoxycarbonyl)amino)-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate 
• 651324-04-8 (3R,4S,5R)-[5-(tert-butylamino)-4-hydroxy-3-(pent-3-yloxy)]cyclohex-1-ene-1-carboxylic acid ethyl ester 
• 757965-01-8 (1S,5R,6R)-5-(1-ethyl-propoxy)-7-oxa-bicyclo[4.1.0]hept-3-ene-3-carboxylic acid ethyl ester 
• 651324-07-1 ethyl (3R,4R,5S)-4-N-acetyl(1,1-dimethylethyl)amino-5-N,N-diallylamino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate 
• 651324-06-0 ethyl (3R,4R,5S)-5-N,N-diallylamino-4-(1,1-dimethylethyl)amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate 
• 1401454-81-6 (2R,3S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-3-((R)-3-(ethoxycarbonyl)-1-hydroxybut-3-en-1-yl)aziridine-1-carboxylate 
• 1132659-98-3 (3R,4S,5R)-4-amino-3-(1-ethyl-propoxy)-5-methanesulfonyloxy-cyclohex-1-enecarboxylic acid ethyl ester 
• 1402431-91-7 ethyl (3R,4R,5R)-4-acetylamino-5-amino-3-(pentan-3-yloxy)cyclohex-1-ene-1-carboxylate 
• 1401454-88-3 ethyl (3R,4S,5R)-4-(tert-butoxycarbonylamino)-3-(1-ethylpropoxy)-5-(methanesulfonyloxy)cyclohex-1-ene-1-carboxylate 
• 1401454-87-2 ethyl (1S,5R,6S)-7-(tert-butoxycarbonyl)-5-(methanesulfonyloxy)-7-azabicyclo[4.1.0]hept-2-ene-3-carboxylate 
• 1401454-86-1 tert-butyl (2S,3S)-2-ethenyl-3-{(1R)-3-(ethoxycarbonyl)-1-[(methylsulfonyl)oxy]but-3-en-1-yl}aziridine-1-carboxylate 
• 1401454-85-0 (2S,3R)-tert-butyl 2-((R)-3-(ethoxycarbonyl)-1-(methanesulfonyloxy)but-3-en-1-yl)-3-formylaziridine-1-carboxylate 

Downstream Products

• 196618-13-0 oseltamivir 
• 1191921-01-3 (3R,4R,5S)-4-acetylamino-5-acetylamino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid ethyl ester 
• 1191921-02-4 (3R,4R,5S)-ethyl 4-acetamido-5-(benzoylamido)-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate 
• 208720-81-4 (3R,4R,5S)-5-[[(1Z)-[[(tert-butoxy)carbonyl]amino]([[(tert-butoxy)carbonyl]imino])methyl]amino]-4-acetylamino-3-(pentan-3-yloxy)cyclohex-1-ene-1-carboxylic acid ethyl ester 

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Relevant articles and documents

Method for preparing oseltamivir phosphate

The invention discloses a method for preparing oseltamivir phosphate. The method comprises the following steps: reacting OSTW-5, an organic solvent and 1, 3-dimethyl barbituric acid in the presence of a palladium catalyst and heteropoly acid to obtain oseltamivir phosphate after the reaction is finished. In the method, the heteropoly acid is silicotungstic acid or silicomolybdic acid. The method is simple and convenient in process, the yield of oseltamivir phosphate obtained by the method is higher than that of oseltamivir phosphate obtained by an existing method and can reach 95%, the purity of oseltamivir phosphate can reach 98%, and the method has important application value.

Preparation method and intermediate of oseltamivir

The invention relates to a preparation method of oseltamivir (a compound shown as a formula I) and an intermediate of the oseltamivir. The method is implemented according to a route described in the specification. The method is convenient and safe to operate, high in yield, small in environmental pollution, suitable for industrial production and good in economic effect.

FLOW SYNTHESIS PROCESS FOR THE PRODUCTION OF OSELTAMIVIR

This invention provides for a flow synthesis process for producing Oseltamivir and pharmaceutically acceptable salts thereof from shikimic acid in particular but not exclusively to a flow synthesis process for producing Oseltamivir phosphate from shikimic acid in a nine-step flow synthesis that provides for superior reaction times and product yields compared to known methods.