US 2004/0006238 A1 · Process to produce oxazolidinones

Abstract

The present invention includes a number of novel intermediates such as the (S)secondary alcohol of formula (VIIIA) X2—CH2—C*H(OH)—CH2—NH—CO—RN (VIIIA) and processes for production of pharmacologically useful oxazolidinones.

Claims53

Dependent claims

An (S)-secondary alcohol of formula (VIIIA)

X2—CH2—C*H(OH)—CH2—NH—CO—RN (VIIIA)
where:
(I) RN is C1-C5 alkyl;
(II) X2 is:
(A) —Cl,
(B) —Br,
(C) p-CH3-φ-SO2—,
(D) m-NO2-φ-SO2—.

5 more elements

A process for the production of an (S)-oxazolidinone-CH2—NH—CO—RN of formula (X)

Roxa-RING-CH2—NH—CO—RN (X)
where:
(I) RN is C1-C5 alkyl;
(II) Roxa is phenyl substituted with one —F and one substituted amino group;
which comprises:
(1) contacting a carbamate of formula (IX)
Roxa—NH—CO—O—CH2—X1 (IX)
where:
(I) X1 is:
(A) C1-C20 alkyl,
(B) C3-C7 cycloalkyl,
(C) φ- optionally substituted with one or two:
(1) C1-C3 alkyl,
(2) F—, Cl—, Br—, I—,
(D) CH2═CH—CH2—,
(E) CH3—CH═CH—CH2—,
(F) (CH3)2C═CH—CH2—,
(G) CH2═CH—,
(H) φ-CH═CH—CH2—,
(I) φ-CH2— optionally substituted on φ- with one or two —Cl. C1-C4 alkyl, —NO2, —CN, —CF3,
(J) 9-fluorenylmethyl,
(K) (Cl)3C—CH2—,
(L) 2-trimethylsilylethyl,
(M) φ-CH2—CH2—,
(N) 1-adamantyl,
(O) (φ)2CH—,
(P) CH≡C—C(CH3)2—,
(Q) 2-furanylmethyl,
(R) isobornyl,
(S) —H;
(II) Roxa is as defined above;
with an oxygenated amino reagent selected from the group consisting of:
(1) an (S)-secondary alcohol of the formula (VIIIA)
X2—CH2—C*H(OH)—CH2—NH—CO—RN (VIIIA)
where:
X2 is:
(A) —Cl,
(B) —Br,
(C) p-CH3-φ-SO2—,
(D) m-NO2-φ-SO2—;
(II) RN is as defined above;
or an (S)-epoxide of the formula (VIIIB)
—O#—CH2—C*#H—CH2—NH—CO—RN (VIIIB)
where:
(I) # indicates that the atoms marked with a (#) are bonded to each other resulting in the formation of a ring,
(II) RN is as defined above;
or an (S)-ester of the formula (VIIIC)
X2—CH2—C*H(O—CO—RN)—CH2—NH—CO—RN (VIIIC)
where:
(I) RN and X2 are as defined above;
in the presence of a lithium cation and a base whose conjugate acid has a pKa of greater than about 8.

48 more elements

A process for the production of an (S)-oxazolidinone-CH2—NH—CO—RN of formula (X)

Roxa-RING-CH2—NH—CO—RN (X)
where:
(I) RN is C1-C5 alkyl;
(II) Roxa is phenyl substituted with one —F and on substituted amino group which comprises:
(1) contacting a carbamate of formula (IX)
Roxa—NH—CO—O—CH2—X1 (IX)
where:
(I) X1 is:
(A) C1-C20 alkyl.
(B) C3-C7 cycloalkyl,
(C) φ- optionally substituted with one or two:
(1) C1-C3 alkyl,
(2) F—, Cl—, Br—, I—,
(D) CH2═CH—CH2—,
(E) CH3—CH═CH—CH2—,
(F) (CH3)2C═CH—CH2—,
(G) CH2═CH—,
(H) φ-CH═CH—CH2—,
(I) φ-CH2— optionally substituted on φ- with one or two —Cl, C1-C4 alkyl, —NO2, —CN, —CF3,
(J) 9-fluorenylmethyl,
(K) (Cl)3C—CH2—,
(L) 2-trimethylsilylethyl,
(M) φ-CH2—CH2—,
(N) 1-adamantyl,
(O) (φ)2CH—,
(P) CH≡C—C(CH3)2—,
(Q) 2-furanylmethyl,
(R) isobornyl,
(S) —H;
(II) Roxa is as defined above;
with a phthalimide reagent selected from th group consisting of:
(1) a phthalimide alcohol of the formula (IVC)
10
where:
(I) X2 is:
(A) —Cl,
(B) —Br,
(C) p-CH3-φ-SO2—,
(D) m-NO2-φ-SO2—;
(2) a phthalimide epoxide of the formula (IVD)
11
where # indicates that the atoms marked with a (#) are bonded to each other resulting in the formation of a ring to give the ring-phthalimide compound of formula (XI)
12
where Roxa is as defined above, in the presence of a lithium cation and a base whose conjugate acid has a pKa of greater than about 8,
(2) contacting the product of step (1) with aqueous acid,
(3) contacting the reaction mixture of step (2) with an acid anhydride of th formula O(CO—RN)2 where RN is as defined above or an acid halide of the formula RN—CO—X4 where X4 is —Cl or —Br and where RN is as defined above and a tri(alkyl)amine where alkyl is C1-C5.

43 more elements

A process for the production of an (S)—Roxa-RING-CH2—NH—CO—RN of the formula (X)

Roxa-RING-CH2—NH—CO—RN (X)
where:
(I) RN is C1-C5 alkyl;
(II) Roxa is phenyl substituted with one —F and one substituted amino group which comprises:
(1) contacting a carbamate of the formula (IX)
Roxa—NH—CO—O—X1 (IX)
where:
(I) X1 is
(A) C1-C20 alkyl,
(B) C3-C7 cycloalkyl,
(C) φ- optionally substituted with one or two:
(1) C1-C3 alkyl,
(2) F—, Cl—, Br—, I—,
(D) CH2═CH—CH2—,
(E) CH3—CH═CH —CH2—,
(F) (CH3)2C═CH—CH2—,
(G) CH2═CH—,
(H) φ-CH ═CH—CH2—,
(I) φ-CH2— optionally substituted on φ- with one or two —Cl, C1-C4 alkyl, —NO2, —CN, —CF3,
(J) 9-fluorenylmethyl,
(K) (Cl)3C—CH2—,
(L) 2-trimethylsilylethyl,
(M) φ-CH2—CH2—,
(N) 1-adamantyl,
(O) (φ)2CH—,
(P) CH≡C—C(CH3)2—,
(Q) 2-furanylmethyl,
(R) isobornyl,
(S) —H;
(II) Roxa is as defined above;
with a compound selected from the group consisting of a (S)-protected alcohol of the formula (IVA)
X2—CH2-C*H(OH)—CH2—N═CH—X0 (IVA)
where:
(I) X0 is:
(A) -φ,
(B) o-hydroxyphenyl,
(C) o-methoxyphenyl,
(D) p-methoxyphenyl;
(II) X2 is:
(A) —Cl,
(B) —Br,
(C) p-CH3-φ-SO2—,
(D) m-NO2-φ-SO2—;
and a (S)-3-carbon protected epoxide of the formula (IVB)
—O#—CH2—C*#H—CH2—N═CH—X0 (IVB)
where:
(I) # indicates that the atoms marked with a (#) are bonded to each other resulting in the formation of a ring,
(II) X0 is as defined above in th presence of a lithium cation and a base whose conjugate acid has a pKa of greater than about 8 to produce a (S)-protected oxazolidinone of the formula (XII)
Roxa-RING-CH2—N═CH—X0 (XII)
where X0 and Roxa are as defined above;
(2) contacting the reaction mixture of step (1) with aqueous acid to produce an (S)-oxazolidinone free amine of the formula (XIII) and
Roxa-RING-CH2—NH2 (XIII)
(3) contacting the product of step (2) with an acylating agent selected from the group consisting of an acid anhydride of the formula O(CO—RN)2 where RN is as defined above or an acid halide of the formula RN—CO—X4 where X4 is —Cl or —Br and where RN is as defined above and a tri(alkyl)amine where alkyl is C1-C5 where Roxa is as defined above.

50 more elements

A process for the production of an (S)-Roxa-RING-CH2—NH—CO—RN of the formula (X)

Roxa-RING—CH2—NH—CO—RN (X)
where:
(I) RN is C1-C5 alkyl;
(II) Roxa is phenyl substituted with one —F and one substituted amino group which comprises:
(1) contacting a carbamate of the formula (IX)
Roxa-NH—CO—O—CH2—X1 (IX)
where:
(I) X1 is:
(A) C1-C20 alkyl,
(B) C3-C7 cycloalkyl,
(C) φ- optionally substituted with one or two:
(1) C1-C3 alkyl,
(2) F—, Cl—, Br—, I—,
(D) CH2═CH—CH2—,
(E) CH3—CH═CH—CH2—,
(F) (CH3)2C═CH—CH2—,
(G) CH2═CH—,
(H) φ-CH═CH—CH2—,
(I) φ-CH2— optionally substituted on φ- with one or two —Cl, C1-C4 alkyl, —NO2, —CN, —CF3,
(J) 9-fluorenylmethyl,
(K) (Cl)3C—CH2—,
(L) 2-trimethylsilylethyl,
(M) φ-CH2—CH2—,
(N) 1-adamantyl,
(O) (φ)2CH—,
(P) CH≡C—C(CH3)2—,
(Q) 2-furanylmethyl,
(R) isobornyl,
(S) —H;
(II) Roxa is as defined above;
with an (S)-3-carbon amino alcohol (V) wh re X2 is as defined above in the presence of a lithium cation and a base whose conjugate acid has a pKa of greater than about 8 to produce an (S)-oxazolidinone free amine of the formula (XIII)
Roxa-RING-CH2—NH2 (XIII)
where Roxa is as defined above, and
(2) acylating the (S)-oxazolidinone free amine (XIII) with an acylating agent selected from the group consisting of an acid anhydride of the formula O(CO—RN)2 where RN is as defined above or an acid halide of the formula RN—CO—X4 where X4 is —Cl or —Br and where RN is as defined above and a tri(alkyl)amine where alkyl is C1-C5.

31 more elements

Dependencies are inferred from the claim text.

Facts

Application

10/607,697Filed 27 Jun 2003

Priority

7 Nov 1997

Published

8 Jan 2004

Term ends

Not estimatedThe source records don’t support an estimate.

Classification20 codes

C07C 213/04
Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same…: by…
C07C 233/18
With the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom: having the carbon atom of…
C07C 251/24
Containing imino groups: having carbon atoms of imino groups bound to carbon atoms of six-membered aromatic rings
C07C 271/28
With the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring: to a carbon atom of a…

Family

Application60/064,738Us provisional application · filed 7 Nov 1997

Application09/170,776Division · filed 13 Oct 1998

Application09/546,357Division · filed 10 Apr 2000

Application09/927,007Division · filed 9 Aug 2001

Application10/047,705Division · filed 15 Jan 2002

Application10/271,861Division · filed 16 Oct 2002

Application10/352,533Division · filed 28 Jan 2003

Application10/422,334Division · filed 24 Apr 2003

Application10/607,697Division · filed 27 Jun 2003

US 2002/0032348 A1Published application

US 2002/0095054 A1Published application