Synthesis

Synthesis of AIMSA
Reaction scheme part 2

 

Reaction scheme part 1:
The commercially available N-acetyl-neuraminic acid 1 is the starting reagent for the most direct approach to the synthesis of 4-guanidino-Neu5Ac2en (Relenza). In reaction scheme 113 the steps for the conversion of N-acetyl-neuraminic acid 1 to its 4-amino analogue is shown. Step 1 is the addition of methanolic HCl (MeOH and HCl gas), which produces the methyl ester of 1, followed by acetic anhydride in pyridine with 4-(dimethylamino)pyridine catalysis, which produces the penta-acetoxy compound, 2. In step 2, 2 is converted into the oxazoline 3 at high yield using trimethylsilyl trifluoromethanesulfonate (TMSOTf) in ethyl acetate at 52oC. In step 3, the azido compound, 4, is produced by the reaction of 3 with trimethylsilyl azide in tert-butyl alcohol at 80oC. In step 4 catalytic sodium methoxide in methanol was used to remove the acetate protecting groups from 4 to give triol 5. The 4-amino analogue, 6 was made in step 5, by hydrolysis using triethylamine in water, hydrogenolysis with a Lindlar catalyst and finally the addition of Dowex 2 * 8 resin. The triethylamine salt of the 6 was made during hydrogenolysis  and the purpose of the Dowex 2 * 8 resin was to desalt this intermediate. The chemical names of the compounds are:
1: N-acetyl-neuraminic acid
2: 5- Acetamido- 3,5- dideoxy- D- glycero- þ- D- galacto- 2- nonulo- pyranosonic acid methyl ester
3: Methyl (3aR, 4R, 7aR)- 2- Methyl- 4- [(1'S, 2'R)- 1', 2', 3' - triacet- oxypropyl]- 3a, 7a- dihydro- 4H- pyrano [3, 4-d] oxazole- 6- carboxlate.
4: 5- Acetamido- 7, 8, 9- tri- O- acetyl- 2, 6- anhydro- 4- azido- 3, 4, 5- trideoxy- D- glycero- D- galacto- non- 2- enonic acid methyl ester.
5: 5- Acetamido- 2, 6- anhydro- 4- azido- 3, 4, 5- trideoxy- D- glycero- D- galacto- non- 2- enonic acid methyl ester.
6: 5- Acetamido- 4- amino- 2, 6- anhydro- 3, 4, 5- trideoxy- D- glycero- D- galacto- non- 2- enonic acid.

Part one of reaction scheme

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Synthesis of reactant necessary for part 2 of reaction:
Aminoiminomethane-sulfonic acid (AIMSA), 7, which is necessary for the conversion of compound 6 into Relenza, 9, is synthesised in Reaction scheme 214. The oxidizing solution necessary for the reaction is prepared by the addition of peracetic acid to 30% hydrogen peroxide and then conc. sulfuric acid. This is followed by acetic anhydride and, once the reaction has completed, methanol. Thiourea is dissolved in methanol and added slowly to the oxidizing solution.to produce compound 7. Note that any crystals that form are removed and that the reaction needs to be carried out under cooled conditions. See the reference source for more experimental details.

Synthesis of AIMSA

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Reaction scheme part 2:
Reaction scheme 3 shows the conversion of compound 6 into Relenza13. For route A, 3 mol equivalent of AIMSA, 7, and 3 mol equivalent of potassium carbonate are added in a portionwise manner to compound 6 over an eight hour period. A yield of about 48% of the crystalline product 8 should be obtained for this method. An alternative route is to treat compound 6 with 1.1 mol equivalent of cyanogen bromide in the presence of sodium acetate in methanol. Route B step 1 gives compound 9, which can be converted into the final product 8 by treating it with ammonium hydroxide and ammonium formate at 85oC. A 36% yield of the purified product can be obtained after purification with ion-exchange chromatography and crystallisation. The chemical names of the compounds in this scheme are:
8. 5- Acetamido- 2, 6- anhydro- 3, 4, 5- trideoxy- 4- guanidino- D- glycero- D- galacto- non- 2- enonic acid. (Relenza)
9. 5- Acetylamino- 2, 6- anhydro- 4- cyanoamino- 3, 4, 5- trideoxy- D- glycero- D- galacto- non- 2- enonic acid

Part 2 of reaction scheme