合成路线1

After protection of (S)-adamantylglycine (I) as the tert-butyl carbamate (II) with Boc2O and K2CO3, hydroxylation of the adamantane ring using KMnO4 in hot aqueous KOH gives the alcohol (III) (1). Alternatively, the Boc-protected amino acid (III) can be prepared by treatment of (3-hydroxyadamantyl)glycine (IV) with Boc2O and NaOH. Subsequent coupling of N-Boc-(S)-(3-hydroxyadamantyl)glycine (III) with (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide (V) using either EDC/HOBt or methanesulfonyl chloride and Hunig’s base produces amide (VI) (1-6). After protection of the hydroxyl group of (VI) with triethylsilyl triflate, the silylated carboxamide (VII) is dehydrated to the corresponding nitrile (VIII) by treatment with POCl3 and imidazole in pyridine. Deprotection of (VIII) employing trifluoroacetic acid in CH2Cl2 then gives saxagliptin (1). Scheme 1.
Alternatively, direct dehydration of unsilylated carboxamide (VI) with trifluoroacetic anhydride in the presence of pyridine or NaOH produces nitrile (IX), which undergoes acidic Boc group cleavage to furnish saxagliptin (2-6). Scheme 1.
In a related strategy, (3-hydroxyadamantyl)glycine (IV) is protected with either ethyl trifluoroacetate and potassium methoxide or dodecyl trifluorothioacetate and NaOH to give the trifluoroacetamide (X), which is further esterified with trifluoroacetic anhydride in isopropyl acetate to yield the N,O-bis(trifluoroacetyl) derivative (XI). After conversion of (XI) to the corresponding acid chloride (XII) by means of Vilsmeier reagent, condensation with the bicyclic carbonitrile (XIII) leads to amide (XIV). Hydrolysis of the trifluoroacetate ester (XIV) with NaHCO3 in MeOH provides (XV), from which the N-trifluoroacetyl group is reductively removed by means of NaBH4 to yield saxagliptin. Alternatively, the title compound is directly produced by treatment of the bis(trifluoroacetyl)-protected precursor (XIV) with NaBH4 in EtOH (7). Scheme 1.

合成路线2

The intermediate (S)-adamantylglycine (I) can be prepared as follows. Reduction of adamantane-1-carboxylic acid (XVI) using LiAlH4 in THF gives the primary alcohol (XVII), which is oxidized to aldehyde (XVIII) under Swern conditions. Adamantane-1-carbaldehyde (XVIII) is then condensed with (R)-phenylglycinol (XIX) and KCN in the presence of NaHSO3 to yield the chiral aminonitrile (XX). After acidic hydrolysis of nitrile (XX) to the corresponding amino acid (XXI), the chiral auxiliary group is removed by hydrogenolysis over Pearlman’s catalyst to furnish intermediate (I) (1, 6). Scheme 2.

合成路线3

The preparation of the hydroxylated adamantane (IV) is shown in Scheme 3. 1-Adamantyl bromide (XXII) is condensed with 1,1,2-tris(trimethylsilyloxy)ethylene (XXIII) by means of ZnCl2 in CH2Cl2 to afford the adamantylglycolic acid (XXIV), which is esterified to (XXV) utilizing a solution of acetyl chloride in MeOH. After Swern oxidation of (XXV) to the corresponding keto ester (XXVI), hydroxylation of the adamantane ring by means of HNO3/H2SO4 provides (XXVII). Alkaline hydrolysis of ester (XXVII) leads to the oxoacetic acid (XXVIII), which is converted to the target (S)-amino acid (IV) by reductive amination with phenylalanine dehydrogenase (3).

合成路线4

The bicyclic carboxamide (V) can be obtained as follows. Esterification of L-pyroglutamic acid (XXIX) with ethanolic H2SO4 followed by protection with Boc2O gives 1-Boc-5-oxoproline ethyl ester (XXXI). After reduction of (XXXI) with LiBHEt3, the obtained hemiaminal (XXXII) is dehydrated to the dehydroproline derivative (XXXIII) employing trifluoroacetic anhydride, DMAP and DIEA. Subsequent hydrolysis of ethyl ester (XXXIII) by means of LiOH leads to the carboxylic acid (XXXIV), which is converted to the corresponding carboxamide (XXXV) via activation with methanesulfonyl chloride, followed by reaction with ammonia. Simmons-Smith cyclopropanation of (XXXV) using diiodomethane and diethylzinc gives the bicyclic derivative (XXXVI), which is then deprotected under acidic conditions to furnish (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide (V) (2, 3). Scheme 4.

合成路线5

合成路线6

合成路线7