Chemical process for the preparation of intermediates to obtain n-formyl hydroxy-lamine compounds

A process for preparing a compound of formula (VIII)

• comprising Step A:
• contacting a compound of formula (I)
• with a compound of the formula (II)
• Y—O—NH2 (II)
• in a suitable solvent under conditions suitable to form a compound of the formula (III)
• followed by asymmetric hydrogenation Step B:
• contacting the compound of formula (III) with hydrogen in the presence of a chiral ligand and a catalytic amount of a hydrogenation catalyst in a suitable solvent and under conditions suitable to form a compound of the formula (IV)
• followed by Step C:
• contacting the compound of formula (IV) with a base such as a Grignard reagent in a suitable solvent under conditions suitable to form a compound of the formula (V)
• followed by Step D:
• contacting the compound of formula (V) with a compound of the formula (VI)
• in a suitable solvent, optionally in the presence of an activator under conditions suitable to form a compound of the formula (VII)
• followed by Step E:
• contacting the compound of formula (VII) with a formylating agent in a suitable solvent under conditions suitable to form the compound of formula (VIII):
• wherein
• X is —CH2—, —S', —CH(OH)—, —CH(OR)—, —CH(SH)—, —CH(SR)—, —CF2—, —C═N(OR)— or —CH(F)—;
• Y is a hydroxyl-protecting group;
• R is alkyl;
• R1 is aryl or heteroaryl;
• Ac is acetyl;
• each of R2, R3, and R10 independently is hydrogen or alkyl, or (R2 or R3) collectively form a C4-C7cycloalkyl;
• and
• n is 0-3, provided that when n is 0, X is —CH2—.

A process for preparing a compound of the formula (X)

• comprising Step 1:
• resolution of the compound of formula (XI):
• by contacting the compound of formula (XI) with (R)-α-methylbenzylamine in a suitable solvent to form the (R,R)-diasteromeric salt of formula (XII)
• followed by Step 2:
• contacting the compound of formula (XII) with a biphasic mixture of an aqueous mineral acid and an organic solvent to form the compound of formula (I),
• wherein
• each of R2, R3, R4 and R5 is, independently, hydrogen or alkyl;
• or R2 and R3, collectively, form a C4-C7cycloalkyl, provided that R′4 and R5 are different.

A process for preparing a compound of the formula (X′)

• comprising Step 1′:
• resolution of the compound of formula (XI):
• by contacting the compound of formula (XI′) with (S)-α-methylbenzylamine in a suitable solvent to form a (S,S)-diasteromeric salt of formula (XII′)
• followed by Step 2:
• contacting the compound of formula (XII′) with a biphasic mixture of an aqueous mineral acid and an organic solvent to form the compound of formula (X′).

A process for preparing a compound of the formula (XIII)

• comprising Step i:
• Contacting a compound of the formula (XIV)
• with an alkoxide of p-methoxybenzyl alcohol, in a suitable solvent under conditions to form a compound of formula (XV)
• followed by deprotection Step ii:
• contacting the compound of formula (XV) with a strong organic acid in a suitable solvent under conditions to form the compound of formula (XIII),
• wherein
• R4 is alkyl;
• Bn is benzyl;
• and
• Me is methyl.

The process for preparing a compound of formula (IX)

• wherein
• X is —CH2—, —S—, —CH(OH)—, —CH(OR)—, —CH(SH)—, —CH(SR)—, —CF2—, —C═N(OR)— or —CH(F)—;
• R1 is
• each of R2, R3, R4 and R5 independently is hydrogen or alkyl, or (R2 or R3) collectively form a C4-C7cycloalkyl, preferably R2, R3, R5 are hydrogen and R4 is n-butyl;
• n is 0-3,
• comprising:
• converting the compound of formula (XXV)
• wherein
• Y is a hydroxy-protecting group,
• to the compound of formula (IX) by removing the hydroxyl-protecting group by contacting the compound of formula (XXV) with molecular hydrogen at hydrogen partial pressures about less than 1 atm in the presence of a palladium catalyst in a suitable solvent.

The process for preparing a compound of formula (IX)

• wherein
• X is —CH2—, —S—, —CH(OH)—, —CH(OR)—, —CH(SH)—, —CH(SR)—, —CF2—, —C═N(OR)— or —CH(F)—;
• R1 is
• each of R2, R3, R4 and R5 independently is hydrogen or alkyl, or (R2 or R3) collectively form a C4C7cycloalkyl, preferably R2, R3, R5 are hydrogen and R4 is n-butyl;
• n is 0-3,
• comprising:
• converting the compound of formula (XXV)
• wherein
• Y is a hydroxyl-protecting group.
• to the compound of formula (IX) by removing the hydroxyl-protecting group by contacting the compound of formula (XXV) with a hydrogen transfer reagent comprising 4-methylmorpholine and formic acid in the presence of a palladium catalyst, in a suitable solvent.