LOPINAVIR

 
LOPINAVIR
(2S)-N-[(2S,4S,5S)-5-[2-(2,6-dimethylphenoxy)acetamido]-4-hydroxy-1,6-diphenylhexan-2-yl]-3-methyl-2-(2-oxo-1,3-diazinan-1-yl)butanamide
[1S-[1R*,(R*),3R*,4R*]]-N-[4-[[(2,6-dimethyl-phenoxy)acetyl]amino]-3-hydroxy-5-phenyl-1-(phenylmethyl)pentyl]tetrahydro-alpha-(1-methylethyl)-2-oxo-1(2H)-pyrimidineacetamide
(2S,3S,5S)-2-(-2,6- dimethylphenoxyacetyl)-amino-3-hydroxy-5-(2-(1-tetrahydropyrimid-2-onyl)-3- methylbutanoyl)amino-1 ,6-diphenylhexane
628.8008

Abbott Laboratories

CAS	192725-17-0

AHFS/Drugs.com	International Drug Names
MedlinePlus	a602015
Pregnancy cat.	C (US)
Legal status	POM (UK) ℞-only (US)

DrugSyn.org
US5914332
SYNONYMS

ABT-378, Aluviran, Koletra, ABT 378, 1mui, 2rkf, 2rkg, A 157378.0, RS-346

Molecular Formula: C₃₇H₄₈N₄O₅   Molecular Weight: 628.80082

Org. Proc. Res. Dev., 2000, 4 (4), pp 264–269

DOI: 10.1021/op990202j

http://pubs.acs.org/doi/abs/10.1021/op990202j
A large scale process for the synthesis of HIV protease inhibitor candidate ABT-378 has been developed which utilizes an intermediate common to the synthesis of ritonavir, Abbott’s first generation compound. The synthesis relies on the sequential acylation of this intermediate which is carried through as a mixture of diastereomers until the penultimate step. A synthesis of acid 5, derived from l-valine, is also reported.

[1S-[1R*(R*),3R*,4R*]]-N-[4-[[(2,6-dimethylphenoxy)acetyl]amino]-3-hydroxy-5-phenyl-1-(phenylmethyl)pentyl]tetrahydro-α-(1-methylethyl)-2-oxo-1(2H)-pyrimidineacetamide (2).

A 500-mL, three-necked, round-bottomed flask equipped with mechanical stirring, ……………………..DELETED…………………The solid product was washed with 30 mL of 1:1 EtOAc/heptane and dried in vacuo at 70 °C for 60 h, affording 18.8 g (89% yield) of ABT-378 2 as a colorless solid. Before crystallization crude 2 assayed as >93% pure by HPLC; after crystallization >99% purity was achieved.

mp (EtOAc), 124−127 °C. (uncorrected)

IR:  3413, 3335, 3289, 3060, 2966, 1671, 1650, 1624, 1545, 1520, 1453, 1189, 701 cm^-1.

¹H NMR (300 MHz):  δ 7.30−7.13 (m, 10H), 7.02−6.92 (m, 3H), 6.86 (v br s, 1H), 5.68 (br s, 1H), 4.25 (m, 1H), 4.19 (app d, J = 10 Hz, 2H), 4.19 (m, 2H), 3.78 (m, app d sept, 1H), 3.12 (m, 1H), 3.06 (m, 2H), 2.97 (d, J = 7.6 Hz, 2H), 2.88 (m, 1H), 2.81 (app ABX dd, J = 14, 5.2 Hz, 1H), 2.68 (app ABX, dd, J = 14, 9.5 Hz, 1H), 2.23 (m, 1H), 2.18 (s, 6H), 1.83 (s, 1H), 1.74 (m, 2H), 1.53 (m, 1H), 1.28 (m, 2H), 0.83 (app t, J = 7 Hz, 6H).

¹³C NMR (75 MHz):  δ 170.7, 168.8, 156.5, 154.2, 138.1, 138.0, 130.3, 129,3, 129.2, 129.0, 128.4, 128.2, 126.3, 126.0, 124.6, 70.2, 69.7, 63.1, 54.4, 48.7, 41.8, 41.1, 40.8, 40.0, 38.2, 25.4, 21.7, 19.6, 18.7, 16.1,

MS (ESI) 629 (M + H)⁺, 651 (M + Na)⁺.

Anal. Calcd for C₃₇H₄₈N₄O₅:  C, 70.66; H, 7.69; N 8.91. Found:  C, 70.26; H, 7.73; N 8.79.

[α]_d²⁰ = − 22.85 (c 0.4 MeOH).

• Crystallographic studies have shown, to our surprise, that 2 isolated by this crystallization method is not a solvate.
• The determination of the enantiomeric excess (% ee) for ABT-378 (2) can be done indirectly. Compound 17, which results from the acylation of 4 with the enantiomer of acid 5, is known to us, having been detected as an impurity in our process development.¹⁷ Compound 18 can only result from the acylation of the enantiomer of 4 (2R,3R,5R) with 5. The levels of 17/18 observed in 2 are typically <0.1%. Until there is a need for a more definitive assay, we assume this represents an upper limit to the amount of ent-2 present.

Enantiomeric excess is determined by HPLC (Chiracel OD column, elution with hexane: ethanol: trifluoroacetic acid (930:  70:  1). The desired l-isomer has a retention time of approximately 14 min; the d-isomer, 11.5 min.

References

1. “FDA Approved Drug Products: Kaletra”. Retrieved 30 April 2004.
2. KALETRA (lopinavir/ritonavir) capsules; (lopinavir/ritonavir) oral solution. Prescribing information. April 2009
3. Capparelli E, Holland D, Okamoto C, et al. (2005). “Lopinavir concentrations in cerebrospinal fluid exceed the 50% inhibitory concentration for HIV”. AIDS (London, England) 19 (9).
4. HIV drug used to reverse effects of virus that causes cervical cancer University of Manchester, 17 February 2014.

 

• Abbott: Kaletra (lopinavir/ritonavir) tablets

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