Trifluoromethylpyrroloindolecarboxylic acid ester and process for production thereof

A trifluoromethylpyrroloindolecarboxylic acid ester intermediate represented by general formula (3):

• ##STR148## (where R is a lower alkyl group of C.sub.1 .about.C.sub.4 ;
• R.sub.7 is a hydrogen atom or a protective group for an amino group;
• R.sub.8 is a hydrogen atom or a protective group for a hydroxyl group;
• Y is a hydroxyl group, a protective group for a hydroxyl group, a halogen atom, an arylsulfonyloxy group, a lower alkylsulfonyloxy group, a haloalkylsulfonyloxy group, or an azide).

A process of deprotecting a compound represented by general formula (3a) below:

• ##STR150## (where R is a lower alkyl group of C.sub.1 .about.C.sub.4 l;
• R.sub.9 is a protective group for an amino group;
• Y is a halogen atom, an arylsulfonyloxy group, a lower alkylsulfonyloxy group, a haloalkylsulfonyloxy group, or an azide) to form a compound represented by general formula (3b) or a salt thereof:
• ##STR151## (where R and Y are the same as defined above), and subsequently acylating or imidoylating the compound of formula (3b) to produce a compound represented by general formula (3c) below:
• ##STR152## (where R.sup.1 is selected from the group consisting of .alpha.-amino acid residue, ##STR153## (X.sup.1, X.sup.2 and X.sup.3 are independently a hydrogen atom, OH, OR.sup.3 (R.sup.3 is a linear or branched lower alkyl group of C.sub.1 .about.C.sub.6, or an aryl group), OCOR.sup.3 (R.sup.3 is the same as above), CHO, NO.sub.2, ##STR154## (R.sup.4 and R.sup.5 are independently a hydrogen atom, a linear or branched lower alkyl group of C.sub.1 .about.C.sub.6, or an aryl group (R.sup.3 is the same as above)), ##STR155## (X.sup.4, X.sup.5, and X.sup.6 are independently a hydrogen atom, OR.sup.3, or ##STR156## (R.sup.3, R.sup.4, and R.sup.5 are the same as above)), ##STR157## (R.sup.4, and R.sup.5 are the same as above), ##STR158## (R.sup.4, and R.sup.5 are the same as above), Z.sup.1 is O, S, or NR.sup.4 (R.sup.4 is the same as above), n is 0.about.2), ##STR159## (X.sup.7 is O, S, or NH, X.sup.8 is CH or N (X.sup.1, X.sup.2, X.sup.3, and Z.sup.1 are the same as above)), ##STR160## (X.sup.9, and X.sup.10 are independently CH or N (X.sup.1, X.sup.2, X.sup.3, X.sup.8, and Z.sup.1 are the same as above)), ##STR161## (X.sup.11, and X.sup.12 are independently CH or N (X.sup.1, X.sup.2, X.sup.3, X.sup.7, and Z.sup.1 are the same as above)), ##STR162## (R.sup.6 is represented by the above formula a, b, c, or d (X.sup.1, X.sup.2, X.sup.7, X.sup.8, and Z.sup.1 are the same as above)), ##STR163## (X.sup.13 is O, S, or NH;
• X.sup.14 is CH or N (X.sup.1, X.sup.2, X.sup.4, X.sup.5, X.sup.6, X.sup.7, X.sup.8, and Z.sup.1 are the same as above)), and ##STR164## (W is --(CH.sub.2).sub.m --, --(CH.sub.2).sub.m --Z.sup.2 --(CH.sub.2).sub.n --, or ##STR165## (Z.sup.1 is the same as above), Z.sup.2 is S, O, or NH, and m and n are independently 0.about.16);
• and R and Y are as defined above).

A process of protecting the hydroxyl group of a compound represented by general formula (3c) with a biologically decomposable substituent ##STR166## (where R is a lower alkyl group of C.sub.1 .about.C.sub.4 ;

• R.sup.1 is selected from the group consisting of .alpha.-amino acid residue, ##STR167## (X.sup.1, X.sup.2, and X.sup.3 are independently a hydrogen atom, OH, OR.sup.3 (R.sup.3 is a linear or branched lower alkyl group of C.sub.1 .about.C.sub.6, or an aryl group), OCOR.sup.3 (R.sup.3 is the same as above), CHO, NO.sub.2, ##STR168## (R.sup.4 and R.sup.5 are independently a hydrogen atom, a linear or branched lower alkyl group of C.sub.1 .about.C.sub.6, or an aryl group (R.sup.3 is the same as above), ##STR169## (X.sup.4, X.sup.5, and X.sup.6 are independently a hydrogen atom, OR.sup.3, or ##STR170## (R.sup.3, R.sup.4, and R.sup.5 are the same as above)), ##STR171## (R.sup.4, and R.sup.5 are the same as above), ##STR172## (R.sup.4, and R.sup.5 are the same as above), Z.sup.1 is O, S, or NR.sup.4 (R.sup.4 is the same as above), n is 0.about.2), ##STR173## (X.sup.7 is O, S, or NH, X.sup.8 is CH or N (X.sup.1, X.sup.2, X.sup.3, and Z.sup.1 are the same as above)), ##STR174## (X.sup.9, and X.sup.10 are independently CH or N (X.sup.1, X.sup.2, X.sup.3, X.sup.8, and Z.sup.1 are the same as above)), ##STR175## (X.sup.11, and X.sup.12 are independently CH or N (X.sup.1, X.sup.2, X.sup.3, X.sup.7, and Z.sup.1 are the same as above)), ##STR176## (R.sup.6 is represented by the above formula a, b, c, or d (X.sup.1, X.sup.2, X.sup.7, X.sup.8, and Z.sup.1 are the same as above)), ##STR177## (X.sup.13 is O, S, or NH;
• X.sup.14 is CH or N (X.sup.1, X.sup.2, X.sup.4, X.sup.5, X.sup.6, X.sup.7, X.sup.8, and Z.sup.1 are the same as above)), and ##STR178## (W is --(CH.sub.2).sub.m --, --(CH.sub.2).sub.m --Z.sup.2 --(CH.sub.2).sub.n --, or ##STR179## (Z.sup.1 is the same as above), Z.sup.2 is S, O, or NH, and m and n are independently 0.about.16);
• and Y is a halogen atom, an arylsulfonyloxy group, a lower alkylsulfonyloxy group, a haloalkylsulfonyloxy group, or an azide to produce a compound of general formula (3d):
• ##STR180## (where R.sup.10 is a biologically decomposable substituent selected from the group consisting of N,N-di(lower alkyl) carbamoyl group, piperidinocarbonyl group which may be substituted with piperidino group, or (4-alkyl-1-piperazinyl) carbonyl group which alkyl may be substituted with hydroxyl group, di(lower alkyl)amino group and hydroxy alkoxy group, and R, R.sup.1 and Y are as defined above.

A process of ring closure of a compound represented by general formula (3c) in the presence of a basic catalyst:

• ##STR181## (where R is a lower alkyl group of C.sub.1 .about..sub.4 ;
• R.sup.1 is selected from the group consisting of .alpha.-amino acid residue, ##STR182## (X.sup.1, X.sup.2 and X.sup.3 are independently a hydrogen atom, OH, OR.sup.3 (R.sup.3 is a linear or branched lower alkyl group of C.sub.1 .about.C.sub.6, or an aryl group), OCOR.sup.3 (R.sup.3 is the same as above), CHO, NO.sub.2, ##STR183## (R.sup.4 and R.sup.5 are independently a hydrogen atom, a linear or branched lower alkyl group of C.sub.1 .about.C.sub.6, or an aryl group (R.sup.3 is the same as above)), ##STR184## (X.sup.4, X.sup.5, and X.sup.6 are independently a hydrogen atom, OR.sup.3, or ##STR185## (R.sup.3, R.sup.4, and R.sup.5 are the same as above), ##STR186## (R.sup.4, and R.sup.5 are the same as above)), ##STR187## (R.sup.4, and R.sup.5 are the same as above), Z.sup.1 is O, S, or NR.sup.4 (R.sup.4 is the same as above), n is 0.about.2), ##STR188## (X.sup.7 is O, S, or NH, X.sup.8 is CH or N (X.sup.1, X.sup.2, X.sup.3, and Z.sup.1 are the same as above)), ##STR189## (X.sup.9, and X.sup.10 are independently CH or N (X.sup.1, X.sup.2, X.sup.3, X.sup.8, and Z.sup.1 are the same as above)), ##STR190## (X.sup.11, and X.sup.12 are independently CH or N (X.sup.1, X.sup.2, X.sup.3, X.sup.7, and Z.sup.1 are the same as above)), ##STR191## (R.sup.6 is represented by the above formula a, b, c, or d (X.sup.1, X.sup.2, X.sup.7, X.sup.8, and Z.sup.1 are the same as above)), ##STR192## (X.sup.13 is O, S, or NH;
• X.sup.14 is CH or N (X.sup.1, X.sup.2, X.sup.4, X.sup.5, X.sup.6, X.sup.7, X.sup.8, and Z.sup.1 are the same as above)), and ##STR193## (W is --(CH.sub.2).sub.m --, --(CH.sub.2).sub.m --Z.sup.2 --(CH.sub.2).sub.n --, or ##STR194## (Z.sup.1 is the same as above), Z.sup.2 is S, O, or NH, and m and n are independently 0.about.16);
• and Y is a halogen atom, an arylsulfonyloxy group, a lower alkylsulfonyloxy group, a haloalkylsulfonyloxy group, or an azide to produce a compound of general formula (4a):
• ##STR195## (where R and R.sup.1 are as defined above).

A process of addition of an acid to a compound represented by general formula (4a):

• ##STR196## (where R is a lower alkyl group of C.sub.1 .about.C.sub.4 ;
• R.sup.1 is selected from the group consisting of .alpha.-amino acid residue, ##STR197## (X.sup.1, X.sup.2 and X.sup.3 are independently a hydrogen atom, OH, OR.sup.3 (R.sup.3 is a linear or branched lower alkyl group of C.sub.1 .about.C.sub.6, or an aryl group), OCOR.sup.3 (R.sup.3 is the same as above), CHO, NO.sub.2, ##STR198## (R.sup.4 and R.sup.5 are independently a hydrogen atom, a linear or branched lower alkyl group of C.sub.1 .about.C.sub.6, or an aryl group (R.sup.3 is the same as above)), ##STR199## (X.sup.4, X.sup.5, X.sup.6 are independently a hydrogen atom, OR.sup.3, or ##STR200## (R.sup.3, R.sup.4, and R.sup.5 are the same as above)), ##STR201## (R.sup.4, and R.sup.5 are the same as above)), ##STR202## (R.sup.4, and R.sup.5 are the same as above), Z.sup.1 is O, S, or NR.sup.4 (R.sup.4 is the same as above), n is 0.about.2), ##STR203## (X.sup.7 is O, S, or NH, X.sup.8 is CH or N (X.sup.1, X.sup.2, X.sup.3, and Z.sup.1 are the same as above)), ##STR204## (X.sup.9, and X.sup.10 are independently CH or N (X.sup.1, X.sup.2, X.sup.3, X.sup.8, and Z.sup.1 are the same as above)), ##STR205## (X.sup.11, and X.sup.12 are independently CH or N (X.sup.1, X.sup.2, X.sup.3, X.sup.7, and Z.sup.1 are the same as above)), ##STR206## (R.sup.6 is represented by the above formula a, b, c, or d (X.sup.1, X.sup.2, X.sup.7, X.sup.8, and Z.sup.1 are the same as above)), ##STR207## (X.sup.13 is O, S, or NH;
• X.sup.14 is CH or N (X.sup.1, X.sup.2, X.sup.4, X.sup.5, X.sup.6, X.sup.7, X.sup.8, Z.sup.1 are the same as above)), and ##STR208## (W is --(CH.sub.2).sub.m --, --(CH.sub.2).sub.m --Z.sup.2 --(CH.sub.2).sub.n --, or ##STR209## (Z.sup.1 is the same as above), Z.sup.2 is S, O, or NH, and m and n are independently 0.about.16) to produce a compound of general formula (3c):
• ##STR210## (where Y is a halogen atom, an arylsulfonyloxy group, a lower alkylsulfonyloxy group, a haloalkylsulfonyloxy group, or an azide;
• and R and R.sup.1 are as defined above).