Methods of making dihydropyrone HIV protease inhibitors

Details Methods of making dihydropyrone HIV protease inhibitors Methods of making dihydropyrone HIV protease inhibitors

2000-10-31

2002-04-30

Dentz, Bernard (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C558S234000, C558S241000, C560S308000

Reexamination Certificate

active

06380400

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to methods of making dihydropyrone HIV protease inhibitors.
BACKGROUND OF THE INVENTION
Despite efforts to discover effective treatments or a cure, human immuno-deficiency virus (HIV) infection and the disease acquired immunodeficiency syndrome (AIDS) continue to haunt modem society. One way of combating HIV infection and AIDS has been to administer to an affected patient a compound that inhibits the viral enzyme HIV protease, which is required by the virus to reproduce. Some compounds that inhibit HIV protease are currently being marketed to treat HIV infection and AIDS and have been shown to be most effective when used in combination with other compounds that can be used to treat HIV infection and AIDS. The dihydropyrones represent a new chemical class of HIV protease inhibitors. The present invention provides a commercially viable method for making dihydropyrone HIV protease inhibitors. In particular, the present invention relates to the synthesis of (S)-6-[2-(4-Aminophenyl)-ethyl]-3-(2-tert-butyl-4-hydroxymethyl-5-methylphenylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one; (S)-3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one; (S)-3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one; and (S)-3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-6-cyclopentyl-4-hydroxy-6-[2-(3-hydroxy-phenyl)-ethyl]-5,6-dihydro-pyran-2-one. See, U.S. Pat. No. 5,789,440, U.S. patent application Ser. No. 08/885,743 and U.S. patent application titled “HIV Protease Inhibitors” filed on the same day as the present application listing Boyer, Fred et al. as inventors, which applications and patents are hereby incorporated by reference.
SUMMARY OF THE INVENTION
The present invention provides the compounds dimethylthiocarbamic acid O-(2-tert-butyl-4-formyl-5-methylphenyl) ester;
Dimethylthiocarbamic acid S-(2-tert-butyl-4-formyl-5-methylphenyl) ester;
Dimethylthiocarbamic acid S-(2-tert-butyl-4-hydroxymethyl-5-methylphenyl) ester;
(+/−)-1-Hydroxy-4-methyl-1-(4-nitrophenyl)pentan-3-one;
(+/−)-1-Acetoxy-4-methyl-1-(4-nitrophenyl)pentan-3-one or [Acetic acid 4-methyl-1-(4-nitro-phenyl)-3-oxo-pentyl ester].
1-(4-N-A acetylaminophenyl)-4-methylpentan-3-one or [N-[4-(4-methyl-3-oxo-pentyl)-phenyl]-acetamide].
(+/−)-3-[2-(4-N-Acetylaminophenyl)ethyl]-3-hydroxy-4-methylpentanoic acid or [3-[2-(4-acetylamino-phenyl)-ethyl]-3-hydroxy-4-methyl-pentanoic acid].
(+/−)-3-Hydroxy-3-isopropyl-5-(4-nitrophenyl)-4-pentenoic acid benzyl ester or [3-hydroxy-3-isopropyl-5-(4-nitro-phenyl)-pent-4-enoic acid benzyl ester];
(+/−)-3-Hydroxy-3-isopropyl-5-(4-nitrophenyl)-4-pentenoic acid benzyl ester;
(+/−)-3-[2-(4-Aminophenyl)ethyl]-3-hydroxy-4-methylpentanoic acid;
(S)-3-[2-(4-Acetylaminophenyl)ethyl]-3-hydroxy-4-methylpentanoic acid;
(S)-3-[2-(4-Acetylaminophenyl)ethyl]-3-hydroxy-4-methylpentanoic acid (S)-N-benzyl-&agr;-methylbenzylamine salt;
(S)-6-[2-(4-Acetylaminophenyl)ethyl]-4-hydroxy-6-isopropyl-5,6-dihydropyran-2-one;
(S)-5-[2-(4-Acetylaminophenyl)ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoic acid ethyl ester;
(S)-N-(4-{2-[5-(2-tert-Butyl-4-hydroxymethyl-5-methylphenylsulfanyl)-4-hydroxy-2-isopropyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl}phenyl)acetamide;
N-(5-tert-Butyl-2-methyl-4-thiocyanatophenyl)carbamic acid tert-butyl ester; and
Toluene-4-thiosulfonic acid S-(4-tert-butoxycarbonylamino-2-tert-butyl-5-methylphenyl) ester.
The present invention provides a method of making compounds of Formula I
wherein
R
a
and R
b
are independently C
1
-C
6
alkyl;
R
d
is hydrogen, C
1
-C
6
alkyl, or halogen;
R
3
is C
2
-C
8
cycloalkyl or C
1
-C
6
alkyl; and
PG is a protecting group selected from acetyl, formyl, propionyl, benzoyl, methyl carbamoyl, ethyl carbamoyl, benzyl carbamoyl, or trifluoroacetyl, or isobutyl carbamoyl,
the method comprising the step of reacting
wherein R
4
is tolyl, phenyl, or methyl, in the presence of a tertiary amine base to give
In a preferred embodiment of the method, the
is further reacted with a base to form
In another preferred embodiment, the reaction in the presence of a tertiary amine base is carried out in a low boiling point, polar, aprotic solvent.
In another preferred embodiment, the reaction in the presence of a tertiary amine base is carried out in acetonitrile or tetrahydrofuran.
In another preferred embodiment, the base is sodium hydroxide, potassium hydroxide, aqueous ammonia, or sodium methoxide.
In another preferred embodiment, the tertiary amine base is triethylamine.
In a more preferred embodiment, R
3
is
R
a
is
R
b
is —CH
3
, and R
d
is hydrogen.
In another more preferred embodiment, the tertiary amine base is triethylamine, and the solvent is acetonitrile.
Also provided is a method of making
wherein
R
3
is C
2
-C
8
cycloalkyl or C
1
-C
6
alkyl;
R
d
is hydrogen, C
1
-C
6
alkyl, or halogen; and
PG is a protecting group selected from acetyl, formyl, propionyl, benzoyl, methyl carbamoyl, ethyl carbamoyl, benzyl carbamoyl, trifluoroacetyl, or isobutyl carbamoyl,
the method comprising the steps of:
a. reacting
with carbonyl diimidazole to form
b. reacting the
with a compound of the formula
and MgCl
2
, to form
c. reacting the
with a base to form
In a preferred embodiment, the base is NaOH or KOH.
In a preferred embodiment,
is
and R
d
is hydrogen.
Also provided is a method of resolving
wherein
R
3
is C
2
-C
8
cycloalkyl or C
1
-C
6
alkyl;
R
d
is hydrogen, halogen, or C
1
-C
6
alkyl; and
PG is a protecting group selected from acetyl, formyl, propionyl, benzoyl, methyl carbamoyl, ethyl carbamoyl, benzyl carbamoyl, trifluoroacetyl, or isobutyl carbamoyl,
the method comprising the steps of:
a. treating
with (S)-N-benzyl-&agr;-methyl benzyl amine;
b. allowing crystals to form;
c. collecting the crystals; and
d. isolating
In a preferred embodiment,
Also provided is a method of making
wherein
R
3
is C
2
-C
8
cycloalkyl or C
1
-C
6
alkyl;
R
d
is hydrogen, halogen, or C
1
-C
6
alkyl; and
PG is a protecting group selected from acetyl, formyl, propionyl, benzyl, methyl carbamoyl, ethyl carbamoyl, benzyl carbamoyl, trifluoroacetyl, or isobutyl carbamoyl,
the method comprising the steps of:
a. reacting
to form
b. reacting
with acetic anhydride to form
c. reacting the
with H
2
to form
d. reacting the
with an acylating agent to form
e. reacting the
with benzyl acetate or C
1
-C
6
alkyl acetate to form
wherein R
c
is benzyl or C
1
-C
6
alkyl;
f. reacting the
with H
2
if R
c
is benzyl or aqueous base if R
c
is benzyl or C
1
-C
6
alkyl to provide
In a preferred embodiment, the acylating agent is acetic anhydride, formic acetic anhydride, methyl formate, ethyl formate chloroformate, benzyl chloroformate, or isobutyl chloroformate, trifluoroacetic anhydride.
In another preferred embodiment, the acylating agent is acetic anhydride.
In another preferred embodiment,
R
d
is hydrogen.
Also provided is a method of making
wherein R
4
is tolyl, phenyl, or methyl, and R
a
and R
b
are independently C
1
-C
6
alkyl, the method comprising the steps of:
a. reacting
with a Lewis acid catalyst, and tri-C
1
-C
6
alkyl orthoformate or dichloromethyl methyl ether to form
b. reacting
to give
c. heating
to produce
d. reacting
with a reducing agent to give
e. heating
with a base to give
f. reacting the
with a sulfonating agent R
4
SO
2
halogen to give
In a preferred embodiment of the method, the reducing agent is sodium borohydride or lithium borohydride.
In another preferred embodiment, the sulfonating agent R
4
SO
2
halogen is toluenesulfonyl chloride, benzenesulfonyl chloride, methanesulfonyl chloride, or toluenesulfonylbromide.
In another preferred embodiment, the Lewis acid ca

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