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Sitagliptin Januvia

Taken by mouth for type 2 diabetes. It blocks the enzyme that breaks down GLP-1, so the body's own signal to release insulin after a meal lasts longer. Sold as the phosphate salt.

  • DPP-4 inhibitor
  • FDA 2006
  • C16H15F6N5O · 407.32 g/mol
  • CAS 486460-32-6

Chemical resolution route

5 steps · 11% overall · 96% ee

The whole point of this route is that it installs the chiral amine without a noble metal. The enamine is reduced with cheap NaBH4 to give the racemate, and the two enantiomers are then separated with (−)-di-p-toluoyl-L-tartaric acid. That trades yield for cost: 11% overall against Merck's 52% first-generation process, but no rhodium or ruthenium, no high-pressure hydrogenation, and no need to strip precious metal out of the product stream. The separated filtrate still holds the S enantiomer at 90% ee, so neither half is thrown away.

Scale: laboratory scale, 5 to 10 g per step

2,4,5-Trifluorophenylacetic acid (8) no public CAS
+
Meldrum's acid (2,2-dimethyl-1,3-dioxane-4,6-dione) no public CAS
Step 1 87% isolated
CDI, dry THF
50 °C, 5 h
Meldrum's acid acts as the acyl anion equivalent · CDI replaces pivaloyl chloride here
Meldrum's acid adduct (9) no public CAS
Meldrum's acid adduct (9) no public CAS
+
3-(Trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (6) no public CAS
Step 2 67% isolated
i-Pr2NEt, isopropyl acetate
75–80 °C, 5 h
amide formation onto the triazolopyrazine, giving the β-ketoamide
β-Ketoamide (10) no public CAS
β-Ketoamide (10) no public CAS
Step 3 92% isolated
NH4OAc, aqueous NH3, MeOH
58 °C, then cooled
the enamine crystallises straight out of the mixture · 99 wt% by simple filtration
(Z)-Enamine (11) no public CAS
(Z)-Enamine (11) no public CAS
Step 4 60% isolated
NaBH4 with MsOH, THF / i-PrOH
−15 °C, 4.5 h
gives the racemate · NaBH4 alone does nothing (0% conversion); the acid additive is what makes it go, and MsOH was chosen over BF3·OEt2 on toxicity grounds
Racemic sitagliptin (13) no public CAS
Racemic sitagliptin (13) no public CAS
Step 5 33% isolated
(−)-Di-p-toluoyl-L-tartaric acid, MeOH / i-PrOH, 65 °C
then aq. NH3, then 85 wt% H3PO4, 78 °C
the tartrate of the R enantiomer crystallises out, is freed with ammonia, and is taken to the phosphate salt · 96% ee, 99 wt%
Sitagliptin phosphate (1) no public CAS
Ye, F.; Zhang, Z.; Zhao, W.; Ding, J.; Wang, Y.; Dang, X.
Two methods for the preparation of sitagliptin phosphate via chemical resolution and asymmetric hydrogenation
RSC Adv. 2021, 11, 4805–4809 · Scheme 2 · open access, CC BY-NC 3.0

Open the paper · DOI 10.1039/d0ra10273c Read the PDF

Asymmetric hydrogenation route

3 steps from the ketoamide · 7% ee

The same β-ketoamide is hydrogenated to the alcohol, the alcohol is turned into its mesylate, and ammonia then displaces the mesylate to give the amine with inversion. Compounds 14 and 15 were made here for the first time. The authors report it as an alternative rather than a better route: the optical purity collapses to 7% ee by the end, so the stereocentre set in the first step is largely lost in the displacement.

Scale: laboratory scale, 3 to 10 g per step

β-Ketoamide (10) no public CAS
Step 1 98% assay
[Ru(cymene)Cl]2 with (S)-Ts-DPEN, MeOH
H2 at 435 psi, 65 °C, 12 h
asymmetric reduction of the ketone · formic acid / Et3N as the hydrogen source did not work at all, even at 80 °C
(S)-Alcohol (14), first made in this work no public CAS
(S)-Alcohol (14), first made in this work no public CAS
Step 2 42% isolated
MsCl, Et3N, ethyl acetate
−10 °C, 2 h
the alcohol becomes a leaving group · 98 wt% after chromatography, but already only 7% ee
(S)-Mesylate (15), first made in this work no public CAS
(S)-Mesylate (15), first made in this work no public CAS
Step 3 33% isolated
NH3 in MeOH (13 wt%)
65 °C, 8 h at 145 psi, then H3PO4
ammonia displaces the mesylate, inverting the centre to R · 99 wt% but 7% ee
Sitagliptin phosphate (1) no public CAS
Ye, F.; Zhang, Z.; Zhao, W.; Ding, J.; Wang, Y.; Dang, X.
Two methods for the preparation of sitagliptin phosphate via chemical resolution and asymmetric hydrogenation
RSC Adv. 2021, 11, 4805–4809 · Scheme 3 · open access, CC BY-NC 3.0

Open the paper · DOI 10.1039/d0ra10273c Read the PDF

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