Preparation of betamethyl carbapenem intermediates

Details Preparation of betamethyl carbapenem intermediates Preparation of betamethyl carbapenem intermediates

1994-05-12

2001-06-05

Berch, Mark L. (Department: 1624)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06242596

ABSTRACT:

BACKGROUND OF THE INVENTION
A process for making a beta methyl carbapenem intermediate is disclosed. A compound of formula I:
is contacted in a non-reactive solvent with methyl Meldrum's acid and a base to produce a compound of formula III:
Compound III is treated in an aprotic solvent with a scavenging base, an alkali metal halide and a tri-organo silyl protecting compound for nitrogen to produce a compound of formula IV:
Compound IV may be reacted with a nucleophile Nu—X in a non-reactive solvent and base, and the mixture acidified to produce a compound of formula V.
Compound V may be reacted with mild acid to produce a compound of formula VI.
Numerous routes to beta-methyl carbapenem intermediates of formula VI have been cited in the literature:
Tetrahedron Letters,
Vol. 26, No. 39, pp 4739-4742, 1985;
J. Am. Chem. Soc.
1986, 108, 4673-4675;
Tetrahedron Letters,
Vol. 27, No. 19, pp 2149-2152, 1986;
Tetrahedron Letters,
Vol. 27, No. 51, pp 6241-6244, 1986;
Can. J. Chem
65, 2140 (1987);
J. Org. Chem.
1987, 52, 3174-3176;
J. Org. Chem.
1987, 52, 2563-2567;
J. Org. Chem.
1987, 52, 5491-5492;
Tetrahedron Letters,
Vol. 28, No. 1, pp 83-86, 1987;
Tetrahedron Letters,
Vol. 28, No. 5, pp 507-510, 1987;
Tetrahedron Letters,
Vol. 28, No. 17, pp 1857-1860, 1987;
Tetrahedron Letters,
Vol. 28, No. 52, pp 6625-6628, 1987;
Can. J. Chem.
66, 1400 (1988);
Can. J. Chem.
Vol. 66, (1988);
J. Chem. Soc. Chem. Commun.
1988;
J. Org. Chem.
1988, 53, 2131-2132;
J. Org. Chem.
1988, 53, 4154-4156;
Tetrahedron
Vol. 44, No. 8, pp 2149 to 2165, 1988;
Tetrahedron Letters,
Vol. 29, No. 1, pp 61-64, 1988;
Tetrahedron Letters,
Vol. 29, No. 49, pp 6461-6464, 1988;
Tetrahedron Letters,
Vol. 29, No. 48, pp 6345-6348, 1988;
Chemistry Letters,
pp 445-448, 1989;
J. Chem. Soc. Perkin Trans. I
1989;
J. Org. Chem.
1989, 54, 2103-2112;
Tetrahedron Letters,
Vol. 30, No. 1 pp 113-116, 1989;
Tetrahedron Letters,
Vol. 31, No. 2, pp 271-274, 1990;
Tetrahedron Letters,
Vol. 31, No. 4, pp 549-552, 1990;
Chem. Pharm. Bull.
39(9) 2225-2232 (1991);
Tetrahedron
Vol. 47, No. 16/17, pp 2801-2820, 1991;
Tetrahedron: Asymmetry
Vol. 2, No. 4, pp 255-256, 1991;
Tetrahedron Letters,
Vol. 32, No. 19, pp 2143-2144, 1991;
J. Org. Chem.
1992, 57, 2411-2418;
Tetrahedron
Vol. 48, No. 1, pp 55-66, 1992;
Previous methods to stereoselectively prepare &bgr;-methyl carbapenems include:
(1) hydrogenation of a 4-(2-propenyl) substituted azetidinone.
(2) stereoselective protonation of an enolate ion.
(3) reaction of 4-acetoxy azetidinone with a chiral enolate.
These methods required difficult multistep preparation of intermediates (1) and/or reagents (3), tedious manipulation of highly reactive intermediates at low temperature (2), or the use of expensive reagents (2,3).
The invention disclosed herein provides a versatile route to &bgr;-methyl intermediates (VI Scheme 1 with high stereoselectivity from readily available starting materials in four steps.
SUMMARY OF THE INVENTION
wherein R and P′ are protecting groups R
1
is a methylmalonic acid ester and Nu is a nucleophilic group. Process intermediates are also disclosed.
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, the invention concerns a process of making Beta-methyl carbapenem intermediates of formula VI
wherein
R is
(a) hydrogen,
(b) methyl, or
(c) a hydroxy protecting group such as tri-organo-silyl including tri-C
1-4
alkyl silyl, phenyl di C
1-4
alkyl silyl and diphenyl mono C
1-4
alkyl silyloxy including tert-butyl-dimethylsilyl; and isopropyl dimethylsilyl and
P′ is a nitrogen protecting group such as tri-organo-silyl, including tri-C
1-4
alkylsilyl, phenyl di C
1-4
alkyl silyl and diphenyl mono C
1-4
alkyl silyl including tert-butyl-dimethylsilyl; and isopropyldimethyl-silyl; comprising:
(a) contacting a compound of Formula I
R
1
is
(a)—O—C(O)—R″ wherein R″ includes C
1-6
alkyl, allyl and substituted phenyl wherein the substituent is hydrogen, C
1-3
alkyl, halo, nitro, cyano or C
1-3
alkyloxy,
(b) —S(O)
n
—R
2
wherein n is 1 or 2, and R
2
is or an aromatic group such phenyl, biphenyl, naphthyl, said aromatic group optionally substituted with, for example halide, such as chloride or bromide, or C
1-4
alkyl,
(c) halo, including Cl and Br in a non-reactive solvent with 2,2,5-trimethyl-1,3-dioxan-4,6-dione and a base to yield a compound of Formula III:
For purposes of this specification protecting groups wherein R and P′ are intended to include but are not limited to tri-organosilyl as defined above; suitable alternatives are cited in Protecting Groups In Organic Synthesis, Theodora W. Green, John Wiley and Sons 1981.
For purposes of this specification non-reactive solvents are defined to include a broad spectrum of non-reacting solubilizing agents including aromatic solvents such as benzene, toluene and xylene; etheral solvents including diethyl ether, di-n-butyl and diisopentyl ethers, anisole, cyclic ethers such as tetrahydropyran, 4-methyl-1,3-dioxane, dihydropyran, tetrahydrofurfuryl, methyl ether, ethyl ether, furan, 2-ethoxytetrahydrofuran and tetrahydrofuran (THF) ester solvents including ethyl and isopropyl acetate; halo carbon solvents including mono or dihalo C
1-4
alkyl; alcohols, including C
1-6
alkanol; and C
6-10
linear, branched or cyclic hydrocarbon solvents including hexane and toluene; and nitrogen containing solvents including N,N-dimethylacetamide, N,N-dimethylformamide and acetonitrile.
For purposes of this specification bases are intended to include carbonates including alkali carbonates such as K
2
CO
3
and tertiary C
1-4
alkyl amines including triethyl amine.
The molar ratio of compound of formula I to methyl Meldrum's acid should be approximately 1 to 1 or greater. The molar ratio of compound of formula I to base should be approximately 0.8-1.2 to 1. The reaction may be conducted from approximately 0 to 60° C. preferably 40 to 50° C. The reaction is allowed to proceed until substantially complete in 1 minute to 20 hours, typically 14 hrs.
(b) contacting a compound of formula III in an aprotic solvent with a scavenging base, an alkali metal halide and a tri- organo halo silane to yield a compound of formula IV
For purposes of this specification, the aprotic solvent is intended to include N,N-diC
1-6
alkylcarbonylamide such as N,N-dimethyl formamide (DMF), toluene, tetrahydrofuran and dichloromethane. The scavenging base is intended to include pyrrole, pyridine, pyrrolidine, N,N diC
1-3
alkyl amino pyridine such as N,N-dimethyl amino pyridine tri-C
1-4
alkylamine such as triethylamine and imidazole. The alkali metal halide may include sodium, potassium or lithium as the metal, and iodine, bromine, or chlorine as the halide. The tri-organo halo silane is intended to include tri-C
1-4
alkyl halo silane, such as Butyldimethyl silyl chloride; phenyl di C
1-4
alkyl halo silane, and diphenyl C
1-4
alkyl halo silane, wherein halo is intended to include chloride, bromide and iodide. The ratio of formula III to silane should be approximately 1 to 1 or less. The molar ratio of silane to scavenging base should be approximately 1 to 1 or less. The ratio of silane to halide should be approximately 1 to 1 or less.
The reaction is conducted at 0 to 70° C., until essentially complete in 2-72 hours.
(c) contacting a compound of formula IV in a non-reactive solvent or C
1-6
alkanol with a base and nucleophile of formula NuX to yield after acidification a compound of formula V
The non-reactive solvent is as defined above.
For purposes of this specification C
1-6
alkanol shall include methyl, ethyl, propyl, isopropyl, butyl and siobutyl alcohol. The base shall include alkali hydroxide such as potassium lithium or sodium hydroxide and shall include alkali carbonate such as sodium or potassium carbonate. Acidification may be accomplished with any suitable acid such as a mineral acid including HCl, H
2
SO
4
or an organic acid such as acetic or formic acid.
The ratio of formula IV to base should be approximately 1 to 1 or less, and approxima

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