Processes and intermediates for preparing retroviral...

Details Processes and intermediates for preparing retroviral... Processes and intermediates for preparing retroviral...

2001-08-29

2002-04-16

Ford, John M. (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

Reexamination Certificate

active

06372905

ABSTRACT:

TECHNICAL FIELD
The present invention relates to processes and intermediates employed in the synthesis of HIV protease inhibitors.
BACKGROUND OF THE INVENTION
Compounds that are inhibitors of human immunodeficiency virus (HIV) protease are useful for inhibiting HIV protease in vitro and in vivo and are useful for inhibiting an HIV infection. Examples of HIV protease inhibitors include the compound of formula I:
which is also known as ((2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)-amino-3-hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl)-3-methylbutanoyl)amino-1,6-diphenylhexane or lopinavir. Processes for preparing compounds of formula I and analogs thereof are provided in U.S. Pat. No. 5,914,332, issued Jun. 22, 1999, which is herein incorporated by reference.
An intermediate which is useful for preparing the compounds of formula I and analogs thereof is a compound of formula II:
wherein R
3
is loweralkyl, hydroxyalkyl or cycloalkylalkyl and P
1
and P
2
are independently selected from hydrogen and an N-protecting group. Preferred compounds of formula II are those wherein R
3
is loweralkyl, P
1
and P
2
are hydrogen or P
1
and P
2
are benzyl. More preferred compounds of formula II are those wherein R
3
is isopropyl and P
1
and P
2
are hydrogen or wherein R
3
is is isopropyl and P
1
and P
2
are benzyl.
Methods for the preparation of a compound of formula II are disclosed in U.S. Pat. No. 5,914,332. These methods involve the reaction of a compound of the formula III:
wherein P
1
is hydrogen or an N-protecting group and P
2
is an N-protecting group With a compound of the formula IV:
wherein R
3
is loweralkyl, hydroxyalkyl or cycloalkylalkyl; or a salt or an activated ester thereof.
Preferred compounds of the formula III are those wherein P
1
and P
2
are N-protecting groups. Most preferred compounds of the formula III are those wherein P
1
and P
2
are both benzyl. Most highly preferred is the compound of formula III that is (2S,3S,5S)-2-N,N-dibenzylamino-3-hydroxy-5-amino-1,6-diphenylhexane.
Preferred compounds of the formula IV are those wherein R
3
is loweralkyl. Most preferred compounds of the formula IV are those wherein R
3
is isopropyl. Also preferred are the acid chloride derivatives of the compounds of formula IV. Most highly preferred is the compound of formula IV that is 2S-(1-tetrahydro-pyrimid-2-only)-3-methyl butanoic acid and the compound of formula IV that is 2S-(1-tetrahydro-pyrimid-2-only)-3-methyl butanoyl chloride.
In the disclosed process, (2S,3S,5S)-2-N,N-dibenzylamino-3-hydroxy-5-amino-1,6-diphenylhexane is reacted with 2S-(1-tetrahydro-pyrimid-2-only)-3-methyl butanoyl chloride in a suitable solvent (ethyl acetate or ethyl acetate/DMF) with imidazole as a base. However, this process is not suited for large-scale production for many reasons, including unstable intermediates, low yields, and catalyst poisoning. In particular, the acid chloride is relatively unstable and the use of thionyl chloride to prepare the acid chloride leads to impurities that poison the catalyst used in a later reaction. In addition, some racemization of the amino acid side chain occurs under the reaction conditions used.
Thus, there is a continuing need for improved processes for preparing intermediates employed in the synthesis of HIV protease inhibitors, including compounds of formula I as defined hereinabove.
DISCLOSURE OF THE INVENTION
The present invention relates to processes and intermediates for preparing a compound of formula II:
wherein R
3
is loweralkyl, hydroxyalkyl or cycloalkylalkyl and P
1
and P
2
are independently selected from hydrogen and an N-protecting group comprising reacting a compound of the formula III:
wherein P
1
is hydrogen or an N-protecting group and P
2
is an N-protecting group with a compound of the formula V:
wherein R
3
is loweralkyl, hydroxyalkyl or cycloalkylalkyl and R
4
is a nitrogen-containing heterocycle, bonded through a ring nitrogen atom to the carbonyl group, selected from the group consisting of imidazolyl, pyrrolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, indolyl, benzimidazolyl and benzotriazolyl.
In a preferred process of the invention, P
1
and P
2
are N-protecting groups, R
3
is loweralkyl and R
4
is imidazolyl. In a most preferred process of the invention, P
1
and P
2
are both benzyl, R
3
is isopropyl and R
4
is imidazolyl.
In the process of the invention, the compound of formula III is reacted with the compound of formula V in a molar ratio of from about 1.0 moles of the compound of formula III to about 1.3 moles of the compound of formula V. A preferred ratio is from about 1.0 to about 1.2. A most preferred ratio is from about 1.0 to about 1.15.
Suitable solvents for the process of the invention are inert solvents, such as isopropyl acetate, ethyl acetate, tetrahydrofuran (THF), methyl t-butyl ether and the like. A preferred solvent for the process of the invention is ethyl acetate.
The process of the invention can be carried out at a temperature of from about 15° C. to about 100° C. The preferred temperature for the process of the invention is about the reflux temperature of the solvent. The most preferred temperature for the process of the invention is from about 75° C. to about 80° C.
The process of the invention is accelerated by the presence of water. The preferred amount of water present in the reaction mixture is from about 1% to about 3% (weight/volume), based on the ratio of the amount of water (in grams) to the total volume (in mL) of the reaction mixture.
The compound of formula V is prepared by reaction of carboxylic acid IV (about 1.00 moles) with carbonyldiimidazole (about 1.05 moles) in an inert, aprotic solvent such as isopropyl acetate, ethyl acetate, tetrahydrofuran (THF), methyl t-butyl ether and the like at a temperature of from about 15° C. to about 50° C. Preferably, carboxylic acid IV is reacted with R
4
—C(O)—R
4
, R
4
—C(S)—R
4
or R
4
—S(O)—R
4
wherein R
4
is defined as above (preferably, carbonyldiimidazole) in ethyl acetate at about 15° C.
While the compound of formula V can be isolated, preferably it is prepared and then reacted (without isolation and purification) with the compound of formula III in a one-pot process.
The compound of formula II wherein P
1
and P
2
are each benzyl can then be debenzylated and the resulting compound of formula II wherein P
1
and P
2
are each hydrogen (as the (S)-pyroglutamic acid salt) can be reacted with 2,6-dimethylphenoxyacetyl chloride (as disclosed in U.S. Pat. No. 5,914,332) to provide lopinavir.
The term “loweralkyl” as used herein refers to straight or branched chain hydrocarbon radicals containing from 1 to 6 carbon atoms. Representative examples of loweralkyl groups include groups such as, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl, and the like.
The term “cycloalkyl” as used herein refers to an aliphatic ring system having 3 to 10 carbon atoms and 1 or 2 rings. Representative cylcoalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornane, bicyclo[2.2.2]octane and the like.
The term “(cycloalkyl)alkyl” as used herein refers to a cycloalkyl group appended to a loweralkyl radical. Representative examples of (cycloalkyl)alkyl groups include groups such as, for example, cyclohexylmethyl, cyclopentylmethyl, cyclohexylethyl, cyclopentylethyl, and the like.
The term “N-protecting group” or “N-protected” as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undesirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in T. H. Greene and P. G. M. Wuts,
Protective Groups in Organic Synthesis,
2nd edition, John Wiley & Sons, New York (1991). N-protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, p

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