NOVEL PROCEDURE FOR THE FORMATION OF 2H-BENZOTRIAZOLE BODIES AND CONGENERS
20220017527 · 2022-01-20
Inventors
Cpc classification
C07D249/20
CHEMISTRY; METALLURGY
International classification
Abstract
The present invention relates to a process for the preparation of 2H-benzotriazole compounds and congeners, novel 2H-benzotriazole compounds and congeners and their use as UV absorbers in coatings and bulk plastics.
Claims
1.-20. (canceled)
21. Process for the preparation of a benzotriazole compound according to the general formula (I): ##STR00071## wherein R.sub.1 is hydrogen, linear or branched C.sub.1-C.sub.24alkyl, linear or branched C.sub.2-C.sub.18alkenyl, C.sub.5-C.sub.12cycloalkyl, unsubstituted C.sub.7-C.sub.15phenylalkyl, C.sub.7-C.sub.15phenylalkyl with the phenyl moiety substituted once, twice, three times or four times with C.sub.1-C.sub.4alkyl, unsubstituted phenyl, phenyl substituted once, twice, three times or four times with C.sub.1-C.sub.4alkyl; R.sub.2 is, independently from R.sub.1, linear or branched C.sub.1-C.sub.24alkyl, linear or branched C.sub.2-C.sub.18alkenyl, C.sub.5-C.sub.12cycloalkyl, unsubstituted C.sub.7-C.sub.15phenylalkyl, C.sub.7-C.sub.15phenylalkyl with the phenyl moiety substituted once, twice, three times or four times with C.sub.1-C.sub.4alkyl, unsubstituted phenyl, phenyl substituted once, twice, or three times with C.sub.1-C.sub.4alkyl, wherein alkyl is optionally substituted by one or more —OH, —OCO—R.sub.3, —OR.sub.4, —NCO, —NH.sub.2 or combinations thereof, wherein R.sub.3 is hydrogen, linear or branched C.sub.1-C.sub.16alkyl, C.sub.5-C.sub.12cycloalkyl, linear or branched C.sub.3-C.sub.6alkenyl, phenyl, naphthyl or C.sub.7-C.sub.15phenylalkyl and R.sub.4 is hydrogen, linear or branched C.sub.1-C.sub.24 alkyl; —OR.sub.4, —C(O)OR.sub.4, —C(O)NHR.sub.4 or —C(O)NR.sub.4R.sub.4; —SR.sub.5, —NHR.sub.5, or —N(R.sub.5).sub.2, wherein R.sub.5 is C.sub.1-C.sub.20alkyl, C.sub.2-C.sub.20hydroxyalkyl; C.sub.3-C.sub.18alkenyl, C.sub.5-C.sub.12cycloalkyl, C.sub.7-C.sub.15phenylalkyl, unsubstituted phenyl, unsubstituted naphthyl, phenyl substituted once or twice with C.sub.1-C.sub.4alkyl, or naphthyl substituted once or twice with C.sub.1-C.sub.4alkyl; —(CH.sub.2).sub.m—CO—X.sub.1—(Z).sub.p—Y—R.sub.6, wherein X.sub.1 is —O— or —NR.sub.7—, Y is —O— or NR.sub.8— or a direct bond, Z is C.sub.2-C.sub.12alkylene, C.sub.4-C.sub.12alkylene interrupted by one to three nitrogen atoms, oxygen atoms or combinations thereof, C.sub.3-C.sub.12alkylene, butenylene, butynylene, cyclohexylene or phenylene, wherein each of which may be additionally substituted by a hydroxyl group; or a group selected from the following list of structures: ##STR00072## wherein * denotes a bond; or when Y is a direct bond, Z can additionally also be a direct bond; m is zero, 1 or 2; p is 1, or p is also zero when X and Y are —N(R.sub.7)— and —N(R.sub.8)—, respectively, R.sub.6 is hydrogen, C.sub.1-C.sub.12 alkyl, or —C(O)—C(R.sub.9)═C(H)R.sub.10, or when Y is —N(R.sub.8)—, forms together with R.sub.8 a group —C(O)—CH═CH—CO—, wherein R.sub.9 is hydrogen or methyl, and R.sub.10 is hydrogen, methyl or —CO—X.sub.1—R.sub.11, wherein R.sub.11 is hydrogen or C.sub.1-C.sub.12 alkyl, R.sub.7 and R.sub.8 independently of each other are hydrogen, C.sub.1-C.sub.12alkyl, C.sub.3-C.sub.12 alkyl interrupted by 1 to 3 oxygen atoms, cyclohexyl, unsubstituted C.sub.7-C.sub.15phenylalkyl, or C.sub.7-C.sub.15phenylalkyl with the phenyl moiety substituted once, twice, three times or four times with C.sub.1-C.sub.4alkyl and R.sub.7 together with R.sub.8 in case where Z is ethylene, also forms ethylene; A.sub.1, A.sub.2, A.sub.3 and A.sub.4 are defined to form a saturated or unsaturated, alicylic or heterocyclic, non-aromatic, aromatic or heteroaromatic ring in formula (I) by being, independently from each other, CH, CH.sub.2, CHR.sub.12, CR.sub.12, C(R.sub.12).sub.2, COH, COR.sub.12, CCO.sub.2H, CCO.sub.2R.sub.12, CNH.sub.2, CNHR.sub.12, CN(R.sub.12).sub.2, N, NR.sub.12, CO, C(SO.sub.2)R.sub.12 or C-Hal with Hal being F, Cl or Br, with R.sub.12 being defined independently for A.sub.1, A.sub.2, A.sub.3 and A.sub.4 by R.sub.1, R.sub.2 or R.sub.1 with one or more hydrogen atoms in R.sub.1 being optionally replaced by halogen, like F, Cl or Br; or A.sub.1, A.sub.2, A.sub.3 and A.sub.4 are defined to form a compound according to formula (II) having an additional ring defined by substituents B.sub.1, B.sub.2, B.sub.3 and B.sub.4, ##STR00073## wherein B.sub.1, B.sub.2, B.sub.3 and B.sub.4 form an additional five-membered or six-membered, saturated or unsaturated, alicylic or heterocyclic, non-aromatic, aromatic or heteroaromatic ring in formula (II) with B.sub.1, B.sub.2, B.sub.3 and B.sub.4 being, independently from each other, absent, CH, CH.sub.2, CHR.sub.12, CR.sub.12, C(R.sub.12).sub.2, COH, COR.sub.12, CCO.sub.2H, CCO.sub.2R.sub.12, CNH.sub.2, CNHR.sub.12, CN(R.sub.12).sub.2, N, NR.sub.12, or CO, with R.sub.12 being defined independently for B.sub.1, B.sub.2, B.sub.3 and B.sub.4 by R.sub.1, R.sub.2 or R.sub.1 with one or more hydrogen atoms in R.sub.1 being optionally replaced by halogen, like F, Cl or Br, the process comprising the step of converting the ortho-hydroxy diarylazo compound according to formula (III) to the benzotriazole compound according to formula (I) by oxidative ring closure in the presence of a metal salt, ##STR00074## characterized in that the oxidation with metal salt is carried out at a molar ratio of metal salt to diarylazo compound (III) from 0.001 to 4.5.
22. The process according to claim 21, wherein the process comprises the additional step of preparing the ortho-hydroxydiarylazo compound according to formula (III) by reacting the 1,2-phenylenediamine compound ((IV) with an ortho-nitrosophenol compound (V) in the presence of a Lewis acid to obtain the diarylazo compound according to formula (III). ##STR00075##
23. The process according to claim 22, wherein reacting the 1,2-phenylenediamine compound (IV) with the ortho-nitrosophenol compound (V) is carried out in the presence of a Lewis acid selected from B(OR).sub.3, BF.sub.3, BF.sub.3—OEt.sub.2, Al(OR).sub.3, Al.sub.2O.sub.3, LiOR, LiF, Si(OR).sub.4, and Ti(OR).sub.4, wherein R is linear or branched C.sub.1-C.sub.18alkyl, perfluoro-alkyl, or phenyl, wherein phenyl is optionally substituted once, twice or three times with linear or branched C.sub.1-C.sub.6 alkyl or fluoride atom; B(O(O)CR).sub.3, Al(O(O)CR).sub.3, LiO(O)CR, or Ti(O(O)CR).sub.4, wherein R is linear or branched C.sub.1-C.sub.17alkyl, perfluoro-alkyl or phenyl, wherein phenyl is optionally substituted once, twice or three times with linear or branched C.sub.1-C.sub.6 alkyl or fluoride, or mixtures thereof.
24. The process according to claim 23, wherein the Lewis acid is selected from B(OR).sub.3, and LiOR, wherein R is linear or branched C.sub.1-C.sub.18alkyl, perfluoro-alkyl or phenyl, wherein phenyl is optionally substituted once, twice or three times with linear or branched C.sub.1-C.sub.6 alkyl or fluoride atom; B(O(O)CR).sub.3, Al(O(O)CR).sub.3, and LiO(O)CR, wherein R is linear or branched C.sub.1-C.sub.17alkyl, perfluoro-alkyl or phenyl, wherein phenyl is optionally substituted once, twice or three times with linear or branched C.sub.1-C.sub.6alkyl or fluoride, and B(O(O)CR).sub.3, wherein R is linear or branched C.sub.1-C.sub.17alkyl or phenyl, wherein phenyl is optionally substituted once, twice or three times with linear or branched C.sub.1-C.sub.6alkyl or fluoride.
25. The process according to claim 21, wherein the metal salt is selected from a transition metal salt comprising the cation Cu.sup.1+/2+, Mn.sup.(2+)-(7+), Fe.sup.2+/3+, Ni.sup.2+/4+, Ru.sup.3+ or Co.sup.2+/3+, Zn.sup.2+.
26. The process according to claim 21, wherein the oxidation with metal salt is carried out under atmospheric conditions.
27. The process according to claim 21, wherein the oxidation with a sub-stoichiometric amount of metal salt is carried out in the presence of an oxygen releasing agent, like hydrogen peroxide and/or urea peroxide.
28. The process according to claim 21, wherein the oxidation with a sub-stoichiometric amount of metal salt is carried out in the presence of at least one atmosphere of air or oxygen.
29. The process according to claim 21, wherein oxidation is carried out with a metal salt complexed by a ligand, wherein the ligand is selected from NR.sub.3, wherein R is H or linear or branched C.sub.1-C.sub.17alkyl, unsubstituted phenyl, or phenyl substituted once, twice or three times with linear or branched C.sub.1-C.sub.6alkyl, bidentate amines, like for instance R.sub.2N(CH.sub.2).sub.nNR.sub.2, wherein R is linear or branched C.sub.1-C.sub.17alkyl, unsubstituted phenyl, phenyl substituted once, twice or three times with C.sub.1-C.sub.6alkyl, aromatic amines, like pyridine, pyrimidine, N-alkylimidazoles and the like.
30. The process according to claim 21, wherein the counterion in the metal salt is selected from SO.sub.4.sup.2−; HSO.sub.4.sup.−, O(O)CR, wherein R is linear or branched C.sub.1-C.sub.17alkyl, perfluoro-alkyl, unsubstituted phenyl, phenyl substituted once, twice or three times with linear or branched C.sub.1-C.sub.6alkyl, acetylacetonate (acac), CN.sup.−, halides, and mixtures thereof.
31. The process according to claim 21, wherein in the compound according to formula (I), ##STR00076## R.sub.1 and R.sub.2 are defined as in claim 21, and A.sub.1, A.sub.2, A.sub.3 and A.sub.4 form another six-membered aromatic ring with A.sub.1, A.sub.2, A.sub.3 and A.sub.4 being defined independently from each other by aromatic ═C(H)—, aromatic ═C(R.sub.12)—, aromatic ═C(OH)—, aromatic ═C(OR.sub.12)—, aromatic ═C(CO.sub.2H)—, aromatic ═C((SO.sub.2)R.sub.12)— and aromatic ═C(CO.sub.2R.sub.12)—, wherein R.sub.12 is defined independently for A.sub.1, A.sub.2, A.sub.3 and A.sub.4 by R.sub.1, R.sub.2 or R.sub.1 with one or more hydrogen atoms in R.sub.1 being optionally replaced by halogen, like F, Cl and Br.
32. The process according to claim 31, wherein the compound is selected from the following list of structures: ##STR00077## ##STR00078## ##STR00079## ##STR00080##
33. The process according to claim 21, wherein in the compound according to formula (I), ##STR00081## R.sub.1 and R.sub.2 are defined as in claim 21, and A.sub.1, A.sub.2, A.sub.3 and A.sub.4 form another six-membered heteroaromatic or non-aromatic, heterocyclic ring containing one or two additional nitrogen atoms in formula (I) with A.sub.1, A.sub.2, A.sub.3 and A.sub.4 being defined independently from each other by one or two aromatic nitrogen(s) ═N—, or non-aromatic ═N—R.sub.12, together with non-aromatic —C(O)—, aromatic ═C(H)—, aromatic ═C(R.sub.12)—, aromatic ═C(OH)—, aromatic ═C(OR.sub.12)—, aromatic ═C(CO.sub.2H)—, aromatic ═C((SO.sub.2)R.sub.12)— and/or aromatic ═C(CO.sub.2R.sub.12)—, wherein R.sub.12 is defined independently for A.sub.1, A.sub.2, A.sub.3 and A.sub.4 by R.sub.1, R.sub.2 or R.sub.1 with one or more hydrogen atoms in R.sub.1 being optionally replaced by halogen, like F, Cl and Br.
34. The process according to claim 33, wherein the compound is selected from the following structures: ##STR00082##
35. The process according to claim 21, wherein the compound according to formula (I) is defined by the following formula (II) ##STR00083## wherein B.sub.1, B.sub.2, B.sub.3 and B.sub.4 form an additional five- or six-membered, saturated or unsaturated, alicylic or heterocyclic, non-aromatic, aromatic or heteroaromatic ring in formula (II) by B.sub.1, B.sub.2. B.sub.3 and B.sub.4 being, independently from each other, absent, CH, CH.sub.2, CHR.sub.12, CR.sub.12, C(R.sub.12).sub.2, COH, COR.sub.12, CCO.sub.2H, CCO.sub.2R.sub.12, CNH.sub.2, CNHR.sub.12, CN(R.sub.12).sub.2, N, NR.sub.12, or CO, with R.sub.12 being defined independently for B.sub.1, B.sub.2, B.sub.3 and B.sub.4 by R.sub.1, R.sub.2 or R.sub.1 with one or more hydrogen atoms in R.sub.1 being optionally replaced by halogen, like F, Cl or Br.
36. The process according to claim 35, wherein the compound according to formula (II), is defined by the following formula (VI), ##STR00084## wherein R.sub.1 and R.sub.2 are defined as in claim 21 and R.sub.12 is defined by R.sub.1, R.sub.2 or R.sub.1 with one or more hydrogen atoms in R.sub.1 being optionally replaced by halogen.
37. The process according to claim 35, wherein the compound according to formula (II) or (VI) is selected from the following structures: ##STR00085## ##STR00086##
38. A process for the preparation of the ortho-hydroxydiarylazo compound according to the general formula (III) ##STR00087## comprising the step of reacting the 1,2-phenylenediamine compound (IV) with an ortho-nitrosophenol compound (V) in the presence of a Lewis acid to obtain the diarylazo compound according to formula (III), wherein R.sub.1, R.sub.2, A.sub.1, A.sub.2, A.sub.3, and A.sub.4 and the Lewis acid are defined as in claim 22.
39. A benzotriazole compound selected from the group of compounds consisting of the following compounds: ##STR00088## ##STR00089## ##STR00090## ##STR00091## ##STR00092## ##STR00093## ##STR00094## ##STR00095##
40. Use of a benzotriazole compound according to claim 39 as ultraviolet (UV) absorber and/or visible light (VIS) absorber in a coating or bulk plastics.
Description
EXAMPLES
[0081] Preparative examples are given according the sequence outlined in scheme 4 for the claimed key steps II and III.
Example 1
[0082] ##STR00055##
[0083] In a dry argon atmosphere 0.100 g of oxime 2, 0.075 g of 1,2-phenylene diamine 1 and 0.200 ml triethyl-borate (B(OEt).sub.3) are dissolved in 4 ml dry THF and heated for 24 h at 60° C. After a TLC shows consumption of starting oxime the mixture is evaporated to dryness and the resulting residue purified by column chromatography (eluent: hexane-ethyl acetate: 10-1 vol/vol) to give 0.132 g (96%) of the diazo-amine intermediate 3.
[0084] .sup.1H-NMR (CDCl.sub.3; 300.13 MHz) in ppm (internal TMS-referenced): 1.40 (s, 9H); 1.50 (s, 9H); 6.06 (s broad NH.sub.2); 6.78 (dd, 1H); 6.85 (dt, 1H); 7.21 (dt, 1H); 7.41 (d, 1H); 7.63 (d, 1H); 7.72 (dd, 1H); 13.52 (s broad OH).
[0085] .sup.13C-NMR (CDCl.sub.3; 75.47 MHz) in ppm (internal TMS-referenced): 29.51; 31.49; 34.27; 35.29; 117.32; 117.58; 125.77; 127.00; 129.10; 131.49; 134.39; 136.46; 137.76; 141.20; 141.56; 149.88.
Comparative Example
[0086] Performing this reaction without the addition of B(OEt).sub.3 or performing the reactions in protic solvents, e.g. alcohols, results in the production of a series of side-products with only negligible amounts of compound 3. The TLC analysis of the coupling reaction of diamine 1 and oxime 2 is shown in
[0087] A mixture of 0.050 g of intermediate 3 and 0.190 g of CuSO.sub.4, dissolved in 0.250 ml water is dissolved in 3.00 ml ethanol, containing 0.50 ml of 28% ammonia solution and heated to reflux in air until intermediate 3 is consumed. The mixture is then evaporated to dryness and taken up in ethyl acetate and subsequently extracted with EDTA-solution and brine and dried over sodium sulfate. Filtration and evaporation leaves a residue which is purified over silica gel (eluent: hexane-ethyl acetate: 10-0.5 vol/vol) giving 0.043 g (86%) of benzotriazole 4.
[0088] .sup.1H-NMR (CDCl.sub.3; 300.13 MHz) in ppm (internal TMS-referenced): 1.42 (s, 9H); 1.50 (s, 9H); 7.45 (d, 1H); 7.49 (m, 2H); 7.96 (m, 2H); 8.32 (d, 1H); 11.56 (broad s, OH).
[0089] .sup.13C-NMR (CDCl.sub.3; 75.47 MHz) in ppm (internal TMS-referenced): 29.72; 31.37; 34.60; 35.71; 116.19; 117.58; 125.11; 125.22; 127.42; 138.62; 141.68; 142.65; 146.74.
Example 2
[0090] ##STR00056##
[0091] In a dry argon atmosphere 0.150 g of oxime 5, 0.070 g of 1,2-phenylene diamine 1 and 0.150 ml triethyl-borate are dissolved in 4 ml dry THF and heated for 24 h at 60° C. After a TLC shows consumption of starting oxime the mixture is evaporated to dryness and the resulting residue purified by column chromatography (eluent: hexane-ethyl acetate: 10-1 vol/vol) to give 0.171 g (92%) of the diazo-amine intermediate 6.
[0092] .sup.1H-NMR (CDCl.sub.3; 300.13 MHz) in ppm (internal TMS-referenced): 0.87 (s, 9H); 1.51 (s, 6H); 1.83 (s, 6H); 1.84 (s, 2H); 6.02 (broad s, NH.sub.2); 6.73 (dd, 1H); 6.79 (dt, 1H); 7.17 (dt, 1H); 7.22 (m, 1H); 7.31 (m, 4H); 7.58 (d, 1H); 7.60 (dd, 1H); 7.68 (d, 1H); 13.00 (broad s OH).
[0093] .sup.13C-NMR (CDCl.sub.3; 75.47 MHz) in ppm (internal TMS-referenced): 29.05; 29.73; 31.81; 32.50; 38.15; 42.43; 56.92; 117.24; 117.47; 125.21; 125.63; 126.94; 125.92; 128.47; 129.37; 131.47; 134.37; 136.67; 136.81; 138.82; 141.47; 149.07; 150.65.
[0094] Replacing the B(OEt).sub.3 by 2.5 g of basic Al.sub.2O.sub.3 and the THF by 2 ml of xylene and heating this mixture to 140° C. for 48 h gives after the usual work-up 0.089 mg of diazo compound 6 and 0.300 g of starting oxime 5.
[0095] According the procedure given for the preparation of compound 4 in example 1, triazole 7 is obtained from 0.007 g (0.016 mmol) of intermediate amine 6 and 0.020 g (0.122 mmol) CuSO.sub.4 in 100% (0.007 g). In this comparative example, 7.73 equivalents of copper salt are used.
[0096] .sup.1H-NMR (CDCl.sub.3; 300.13 MHz) in ppm (internal TMS-referenced): 0.88 (s, 9H); 1.57 (s, 6H); 1.89 (s, 6H); 1.91 (s, 2H); 7.23 (m, 1H); 7.34 (m, 4H); 7.45 (m, 2H); 7.68 (d, 2H); 7.88 (m, 2H); 8.41 (d, 1H); 11.49 (s broad 1H).
[0097] .sup.13C-NMR (CDCl.sub.3; 75.47 MHz) in ppm (internal TMS-referenced): 29.79; 31.92; 32.00; 32.52; 38.49; 42.82; 57.01; 117.30; 117.51; 125.22; 125.32; 125.52; 126.53; 127.39; 127.94; 137.80; 140.40; 142.61; 146.06; 150.84.
[0098] More favorably, triazole 7 is obtained according the conditions listed in Table 1. As is has been observed, base-sensitive functional groups, e.g. cyclic amides or esters in various desired benzotriazole compounds, do not survive the conditions applied for the oxidative cyclization given in example 1 for the synthesis of the benzotriazole body without significant degradation.
TABLE-US-00001 TABLE 1 Yield for the ring closure reaction of the amine 6 to the benzotriazole compound 7 depending on the amount of catalyst run Cu-salts Conditions* 7 [%] 1 4.1 eq Cu(OAc).sub.2 2 ml pyr-5 ml THF, 70° C, mol sieves 50 2 1.0 eq Cu(OAc).sub.2 2 ml pyr-5 ml THF, 70° C 100 3 0.5 eq Cu(OAc).sub.2 2 ml pyr-5 ml THF, 70° C 100 4** 0.02 eq Cu(OAc).sub.2 2 ml pyr-10 ml THF, 70° C 100 5 1.0 eq Cu(OAc).sub.2 5 eq TMEDA***- 5 ml THF, 70° C 100 6 1.0 eq Cu(acac).sub.2 2.5 eq TMEDA***- 1 ml pyr-5 ml THF, 70° C, 48 7 1.0 eq Cu(OAc).sub.2 5.0 eq MIA****- 5 ml THF, 70° C 100 *0.050 g of amine 6 is used, refluxed until educt is consumed; **0.200 g of amine 6 is reacted; ***N,N,N,N-tetramethylethylenediamine; **** methylimidazole;
Example 3
[0099] ##STR00057##
[0100] According to the procedure given for the preparation of compound 3 in example 1, diamine 8 (0.164 g) is treated with 0.328 g of oxime 5 and 0.300 ml B(OEt).sub.3 to yield 0.329 g (70%) of compound 9 as a mixture of two stereo isomers (78/22). The isomers are subsequently combined and cyclized in the following procedure.
[0101] .sup.1H-NMR (CDCl.sub.3; 300.13 MHz) in ppm (internal TMS-referenced): for main isomer: 0.85 (s, 9H); 1.50 (s, 6H); 1.84 (s, 6H); 1.87 (s, 2H); 5.56 (broad s, NH.sub.2); 6.75 (d, 1H); 7.23 (m, 1H); 7.33 (m, 4H); 7.37 (dd, 1H); 7.66 (d, 1H); 7.69 (d, 1H); 7.87 d, 1H); 12.55 (broad OH). .sup.13C-NMR (CDCl.sub.3; 75.47 MHz) in ppm (internal TMS-referenced): for main isomer: 29.68; 31.83; 31.98; 32.50; 38.19; 42.44; 56.88; 117.44; 119.95; 122.10; 125.33; 125.58:127.00; 127.58; 128.00; 129.35; 133.90; 136.60; 137.10; 140.28; 143.15; 149.16; 150.48.
[0102] .sup.19F-NMR (CDCl.sub.3; 282.41 MHz): −61.44 main isomer; −63.14 minor isomer.
[0103] According to the procedure given in example 2 for the cyclization of compound 6 run 2, 0.300 g of azo-amine 9 (mixture of isomers) are cyclized to yield 0.270 g (91%) of benzotriazole 10.
[0104] .sup.1H-NMR (CDCl.sub.3; 300.13 MHz) in ppm (internal TMS-referenced): 0.83 (s, 9H); 1.46 (s, 6H); 1.84 (s, 6H); 1.88 (s, 2H); 7.21 (m, 1H); 7.30 (m, 4H); 7.64 (dd, 1H); 7.69 (d, 1H); 7.99 (d 1H); 8.25 (broad s, 1H); 8.37 (d, 1H); 11.13 (broad s, OH).
[0105] .sup.13C-NMR (CDCl.sub.3; 75.47 MHz) in ppm (internal TMS-referenced): 29.71; 31.77; 31.96; 32.48; 28.48; 42.82; 56.93; 116.16; 117.46; 118.72; 121.99; 123.54; 125.05; 125.26; 125.47; 127.33; 127.93; 138.12; 140.77; 141.52; 143.02; 146.24; 150.60.
Example 4
[0106] ##STR00058##
[0107] According to the procedure given for the preparation of compound 3 in example 1, diamine 11 (0.250 g) is treated with 0.430 g of oxime 2 and 0.620 ml B(OEt).sub.3 to yield 0.460 g (71%) of compound 12.
[0108] .sup.1H-NMR (CDCl.sub.3; 300.13 MHz) in ppm (internal TMS-referenced): 1.38 (s, 9H); 1.52 (s, 9H); 2.25 (s, 3H); 2.26 (s, 3H); 5.55 (broad, NH.sub.2); 6.76 (s, 1H); 7.38 (d, 1H); 7.50 (s, 1H); 7.65 (d, 1H); 12.95 (broad OH).
[0109] .sup.13C-NMR (CDCl.sub.3; 75.47 MHz) in ppm (internal TMS-referenced): 18.71; 19.96; 29.51; 31.49; 34.28; 35.26; 119.53; 119.97; 125.29; 126.89; 127.96; 128.74; 133.99; 136.57; 137.59; 141.19; 141.43; 150.02.
[0110] According the procedure given in example 2 for the cyclization of compound 6 run 3, 0.460 g of azo-amine 12 are cyclized to yield 0.282 g (62%) of benzotriazole 13.
[0111] .sup.1H-NMR (CDCl.sub.3; 300.13 MHz) in ppm (internal TMS-referenced): 1.43 (s, 9H); 1.55 (s, 9H); 2.46 (s, 6H); 7.43 (d (1H); 7.68 (s, 2H); 8.29 (d, 1H); 11.14 (broad OH).
[0112] .sup.13C-NMR (CDCl.sub.3; 75.47 MHz) in ppm (internal TMS-referenced): 20.98; 29.61; 31.54; 34.58; 35.66; 115.93; 116.05; 124.57; 125.34; 138.10; 138.42; 141.52; 142.07; 146.48.
Example 5
[0113] ##STR00059##
[0114] According the procedure given for the preparation of compound 3 in example 1, diamine 14 (0.250 g) is treated with 0.330 g of oxime 2 and 0.480 ml B(OEt).sub.3 to yield 0.420 g (76%) of compound 15.
[0115] .sup.1H-NMR (CDCl.sub.3; 300.13 MHz) in ppm (internal TMS-referenced): 1.39 (s, 9H); 1.44 (s, 9H); 4.90 (broad s, NH.sub.2); 7.05 (broad d, 1H); 7.45 (d, 1H); 7.64 (d, 1H); 7.82 (s, 1H); 12.99 (broad s, OH).
[0116] .sup.13C-NMR (CDCl.sub.3; 75.47 MHz) in ppm (internal TMS-referenced): 29.44; 31.40; 34.31; 35.28; 119.35; 122.98; 125.35; 127.57 (2 C); 128.61 (2 C); 135.00; 136.75; 137.93; 141.81; 150.23.
[0117] According the procedure given in example 2 for the cyclization of compound 6 run 3, 0.390 g of azo-amine 15 are cyclized to yield 0.267 g (69%) of benzotriazole 16.
[0118] .sup.1H-NMR (CDCl.sub.3; 300.13 MHz) in ppm (internal TMS-referenced): 1.42 (s, 9H); 1.54 (s, 9H); 7.48 (d, 1H); 8.11 (s, 2H); 8.27 (d, 1H); 11.12 (OH).
[0119] .sup.13C-NMR (CDCl.sub.3; 75.47 MHz) in ppm (internal TMS-referenced): 29.56; 31.46; 34.61; 35.73; 116.24; 118.39; 124.92; 125.87; 132.40; 138.90; 141.51; 142.03; 146.78.
Example 6
[0120] ##STR00060##
[0121] According to the procedure given for the preparation of compound 3 in example 1, diamine 17 (0.200 g) is treated with 0.310 g of oxime 2 and 0.440 ml B(OEt).sub.3 to yield 0.235 g (49%) of compound 18.
[0122] .sup.1H-NMR (CDCl.sub.3; 300.13 MHz) in ppm (internal TMS-referenced): 1.38 (s, 9H); 1.49 (s, 9H); 4.21 (broad NH.sub.2); 6.83 (broad d, 1H); 7.46 (d, 1H); 7.65 (d, 1H); 7.88 (d, 1H); 8.44 (s, 1H); 12.97 (OH).
[0123] .sup.13C-NMR (CDCl.sub.3-CD.sub.3OD 75.47 MHz) in ppm (internal TMS-referenced): 33.28; 35.25; 38.10; 39.13; 120.72; 122.70; 129.34; 131.30; 136.49 (2 C); 136.82; 140.18; 141.70; 145.31; 149.43; 152.99; 172.69.
[0124] According the procedure given in example 2 for the cyclization of compound 6 run 3, 0.200 g of azo-amine 18 are cyclized to yield 0.125 g (63%) of benzotriazole 19.
[0125] .sup.1H-NMR (CDCl.sub.3-CD.sub.3OD; 300.13 MHz) in ppm (internal TMS-referenced): 1.38 (s, 9H); 1.49 (s, 9H); 7.44 (d, 1H); 7.95 (d, 1H); 8.12 (d, 1H); 8.28 (d, 1H); 8.73 (d, 1H).
[0126] .sup.13C-NMR (CDCl.sub.3-CD.sub.3OD 75.47 MHz) in ppm (internal TMS-referenced): 29.48; 31.39; 34.54; 35.66; 116.29; 117.34; 121.31; 124.99; 125.74; 127.75; 129.66; 138.74; 141.94; 142.19; 144.51; 146.71; 168.12.
Example 7
[0127] ##STR00061##
[0128] According to the procedure given for the preparation of compound 3 in example 1, diamine (0.690 g) is treated with 1.000 g of oxime 2 and 1.50 ml B(OEt).sub.3 to yield 1.100 g (80%) of compound 21.
[0129] .sup.1H-NMR (CDCl.sub.3; 300.13 MHz) in ppm (internal TMS-referenced): 1.39 (s, 9H); 1.50 (s, 9H); 6.66 (d, 1H); 6.93 (broad NH.sub.2); 7.44 (d, 1H); 7.58 (d, 1H); 8.14 (broad d, 1H); 8.80 (s, 1H); 13.23 (OH).
[0130] .sup.13C-NMR (CDCl.sub.3; 75.47 MHz) in ppm (internal TMS-referenced): 29.48; 31.45; 34.26; 35.34; 111.57; 126.09; 127.82; 131.02; 136.35; 138.13; 141.49; 146.06; 149.31; 149.76; 152.73.
[0131] According the procedure given in example 2 for the cyclization of compound 6 run 1—but refluxed for only 7 h—0.110 g of azo-amine 21 are cyclized to yield 0.100 g (92%) of benzotriazole 22.
[0132] .sup.1H-NMR (CDCl.sub.3; 300.13 MHz) in ppm (internal TMS-referenced): 1.42 (s, 9H); 1.54 (s, 9H); 7.52 (d, 1H); 7.82 (d, 1H); 8.33 (d, 1H); 8.57 (broad 1H); 9.57 (broad 1H); 11.41 (OH).
[0133] .sup.13C-NMR (CDCl.sub.3; 75.47 MHz) in ppm (internal TMS-referenced): 29.56; 31.45; 34.61; 35.76; 111.02; 116.61; 124.86; 126.48; 139.08; 142.15; 143.41; 144.29 (2 C); 144.83; 147.26.
Example 8
[0134] ##STR00062##
[0135] According the procedure given for the preparation of compound 3 in example 1, diamine 20 (0.070 g) is treated with 0.150 g of oxime 5 and 0.150 ml B(OEt).sub.3 to yield 0.150 g (83%) of compound 23.
[0136] .sup.1H-NMR (CDCl.sub.3; 300.13 MHz) in ppm (internal TMS-referenced): 0.83 (s 9H); 1.48 (s, 6H); 1.79 (s, 6H); 1.82 (s, 2H); 6.58 (d, 1H); 6.79 (NH.sub.2); 7.19 (m, 1H); 7.28 (m, 4H); 7.60 (s 2H); 8.08 (d, 1H); 8.67 (s, 1H); 12.69 (OH).
[0137] .sup.13C-NMR (CDCl.sub.3; 75.47 MHz) in ppm (internal TMS-referenced): 29.64; 31.74; 31.94; 32.46; 38.12; 42.41; 56.84; 111.42; 125.28; 125.55; 127.15; 127.93; 129.17; 136.55; 137.18; 140.11; 145.84; 148.91 (2 C); 149.45; 150.38; 152.95.
[0138] According the procedure given in example 2 for the cyclization of compound 6 run 2, 0.100 g of azo-amine 23 are cyclized to yield 0.077 g (77%) of benzotriazole 24.
[0139] .sup.1H-NMR (CDCl.sub.3; 300.13 MHz) in ppm (internal TMS-referenced): 0.86 (s, 9H); 1.55 (s, 6H); 1.83 (s, 6H), 1.89 (s, 2H); 7.20 (m, 1H); 7.30 (m, 4H); 7.73 (d, 1H); 7.79 (broad d, 1H); 8.40 (d, 1H); 8.55 (broad s, 1H); 9.53 (broad s, 1H); 11.09 (OH).
[0140] .sup.13C-NMR (CDCl.sub.3; 75.47 MHz) in ppm (internal TMS-referenced): 29.71; 31.77; 31.89; 32.50; 38.51; 42.84; 56.92; 111.05; 117.73; 124.95; 125.32; 125.46; 127.92; 127.97; 138.34; 140.98; 143.09; 144.08 (2 C); 144.89; 146.62; 150.47.
Example 9
[0141] ##STR00063##
[0142] According to the procedure given for the preparation of compound 3 in example 1, diamine 28 (0.100 g) is treated with 0.090 g of oxime 2 and 0.150 ml B(OEt).sub.3 to yield 0.128 g (73%) of compound 29.
[0143] .sup.1H-NMR (CDCl.sub.3; 300.13 MHz) in ppm (internal TMS-referenced): 0.98 (t, 3H); 1.33 (m, 2H); 1.39 (s, 9H); 1.49 (s, 9H); 1.74 (m, 2H); 3.69 (t, 2H); 6.77 (NH.sub.2); 7.25 (s, 1H); 7.48 (d, 1H); 7.63 (d, 1H); 8.17 (s, 1H); 12.99 (OH).
[0144] .sup.13C-NMR (CDCl.sub.3; 75.47 MHz) in ppm (internal TMS-referenced): 13.65; 20.12; 29.43; 31.38; 31.88; 34.30; 35.34; 37.95; 111.97; 120.04; 123.56; 125.57; 128.78; 134.19; 135.92; 136.65; 138.21; 141.87; 146.69; 150.31; 167.83; 167.86.
[0145] According to the procedure given in example 2 for the cyclization of compound 6 run 3, 0.120 g of azo-amine 29 are cyclized to yield 0.101 g (85%) of benzotriazole 30.
[0146] .sup.1H-NMR (CDCl.sub.3; 300.13 MHz) in ppm (internal TMS-referenced): 1.22 (t, 3H); 1.38 (m, 11H); 1.50 (s, 9H); 1.65 (m, 2H); 3.80 (t, 2H); 7.52 (d, 1H); 8.34 (d, 1H); 8.46 (s, 2H); 11.75 (OH).
[0147] .sup.13C-NMR (CDCl.sub.3; 75.47 MHz) in ppm (internal TMS-referenced): 13.84; 20.14; 29.55; 30.52; 31.44; 34.65; 35.77; 38.37; 114.71; 116.41; 124.86; 126.57; 130.11; 139.16; 142.31; 144.71; 147.00; 167.09.
Example 10
[0148] ##STR00064##
[0149] According to the procedure given for the preparation of compound 3 in example 1, diamine 28 (0.145 g) is treated with 0.200 g of oxime 5 and 0.215 ml B(OEt).sub.3 to yield 0.195 g (61%) of compound 31.
[0150] .sup.1H-NMR (CDCl.sub.3; 300.13 MHz) in ppm (internal TMS-referenced): 0.85 (s, 9H); 0.95 (t, 3H); 1.41 (m, 2H); 1.52 (s, 6H); 1.63 (m, 2H); 1.82 (s, 6H); 1.84 (s, 2H); 3.67 (t, 2H); 6.76 (NH.sub.2); 7.18 (m, 2H); 7.25 (m, 4H); 7.66 (m, 2H); 8.04 (s, 1H); 12.50 (OH).
[0151] .sup.13C-NMR (CDCl.sub.3; 75.47 MHz) in ppm (internal TMS-referenced): 13.68; 20.14; 29.04; 29.73; 31.91; 31.98; 32.49; 37.93; 38.18; 42.40; 56.80; 112.00; 119.78; 123.63; 125.36; 125.63; 126.85; 127.97; 130.05; 134.14; 135.77; 136.86; 137.34; 140.53; 146.74; 149.44; 150.25; 167.72; 167.91.
[0152] According the procedure given in example 2 for the cyclization of compound 6 run 3, 0.150 g of azo-amine 31 are cyclized to yield 0.125 g (83%) of benzotriazole 32.
[0153] .sup.1H-NMR (CDCl.sub.3; 300.13 MHz) in ppm (internal TMS-referenced): 0.88 (s, 9H); 0.99 (t, 3H); 1.44 (m, 2H); 1.54 (s, 6H); 1.75 (m, 2H); 1.84 (s, 6H); 1.89 (s, 2H); 3.78 (t, 2H); 7.20 (m, 1H); 7.29 (m, 4H); 7.72 (d, 1H); 8.37 (m, 3H); 11.00 (OH).
[0154] .sup.13C-NMR (CDCl.sub.3; 75.47 MHz) in ppm (internal TMS-referenced): 13.64; 20.14; 29.71; 30.52; 31.77; 32.50; 32.72; 38.36; 38.52; 42.48; 56.90; 114.63; 117.50; 124.94; 125.34; 125.43; 127.90; 127.98; 130.07; 138.32; 141.09; 144.67; 146.38; 150.45; 167.06.
Example 11
[0155] ##STR00065##
[0156] According to the procedure given for the preparation of compound 3 in example 1, diamine (0.200 g) are treated with 0.320 g of oxime 2 and 0.470 ml B(OEt).sub.3 to yield 0.040 g (11%) of compound 26.
[0157] .sup.1H-NMR (CDCl.sub.3; 300.13 MHz) in ppm (internal TMS-referenced): 1.40 (s, 9H); 1.50 (s, 9H); 6.50 (NH); 7.51 (d, 1H); 7.59 (d, 1H); 9.27 (NH); 13.19 (OH).
[0158] .sup.13C-NMR (CDCl.sub.3; 75.47 MHz) in ppm (internal TMS-referenced): 29.49; 31.36; 34.29; 35.44; 123.23; 126.76; 129.44; 136.04; 138.70; 141.89; 149.91; 155.01; 157.05; 160.55.
[0159] According the procedure given in example 2 for the cyclization of compound 6 run 2, 0.0.40 g of azo-amine 26 are cyclized to yield 0.038 g (95%) of benzotriazole 27.
[0160] .sup.1H-NMR (CDCl.sub.3; 300.13 MHz) in ppm (internal TMS-referenced): 1.39 (s, 9H); 1.51 (s, 9H); 7.50 (broad, 1H); 8.23 (broad 2H); 10.79 (OH).
Example 12
[0161] ##STR00066##
[0162] According to the procedure given for the preparation of compound 3 in example 1, diamine 28 (1.500 g) is treated with 2.500 g of oxime 2 and 3.75 ml B(OEt).sub.3 to yield 2.97 g (80%) of compound 29 as a mixture of isomers (ratio: 61-39).
[0163] .sup.1H-NMR (CDCl.sub.3; 300.13 MHz) in ppm (internal TMS-referenced): 1.41 (s, 9H); 1.50 (s, 9H); 6.16 (broad s, NH.sub.2); 6.77 (d, 1H); 6.80 (dd, 1H); 7.42 (d, 1H); 7.57 (d, 1H); 7.61 (dd, 1H); 13.52 (broad s, OH). Main isomer only.
[0164] .sup.13C-NMR (CDCl.sub.3; 75.47 MHz) in ppm (internal TMS-referenced): 29.49; 31.46; 34.27; 35.30; 116.60; 117.95; 125.70; 127.36; 130.36; 132.96; 136.39; 137.15; 137.96; 141.39; 142.31; 149.85.
Main Isomer Only
[0165] According the procedure given in example 2 for the cyclization of compound 6 run 3, 2.00 g of the isomeric mixture of azo-amine 29 as obtained above is cyclized to yield 1.50 g (76%) of benzotriazole 30.
[0166] .sup.1H-NMR (CDCl.sub.3; 300.13 MHz) in ppm (internal TMS-referenced): 1.42 (s, 9H); 1.54 (s, 9H); 7.44 (dd, 1H); 7.48 (d, 1H); 7.90 (d, 1H); 7.96 (d, 1H); 8.29 (d, 1H); 11.55 (broad s, OH).
[0167] .sup.13C-NMR (CDCl.sub.3; 75.47 MHz) in ppm (internal TMS-referenced): 29.57; 31.49; 34.59; 35.71; 116.18; 116.63; 118.76; 125.05; 125.50; 128.99; 133.33; 138.76; 141.17; 141.87; 143.01; 146.17.
Example 13
[0168] ##STR00067##
[0169] According to the procedure given for the preparation of compound 3 in example 1, diamine 31 as the dihydrogen chloride salt (3.00 g) is treated with 3.30 g of oxime 2 and 4.82 ml B(OEt).sub.3 to yield 4.20 g (84%) of compound 32 as a mixture of isomers (ratio: 85-15).
[0170] .sup.1H-NMR (CDCl.sub.3; 300.13 MHz) in ppm (internal TMS-referenced): 1.40 (s, 9H); 1.51 (s, 9H); 3.86 (s, 3H); 6.21 (d, 1H); 6.32 (broad s, NH.sub.2); 6.45 (dd, 1H); 7.37 (d, 1H); 7.95 (d, 1H); 7.627 (d, 1H); 13.48 (broad s, OH). Main isomer only.
[0171] .sup.13C-NMR (CDCl.sub.3; 75.47 MHz) in ppm (internal TMS-referenced): 29.55; 31.53; 34.26; 35.26; 55.40; 100.04; 105.58; 125.13; 125.95; 129.46; 131.75; 136.26; 137.54; 141.01; 143.50; 149.63; 162.36. Main isomer only
[0172] According the procedure given in example 2 for the cyclization of compound 6 run 3, 2.70 g of the isomeric mixture of azo-amine 32 as obtained above is cyclized to yield 2.50 g (91%) of benzotriazole 33.
[0173] .sup.1H-NMR (CDCl.sub.3; 300.13 MHz) in ppm (internal TMS-referenced): 1.43 (s, 9H); 1.55 (s, 9H); 3.94 (s, 3H); 7.17 (m, 2H); 7.43 (d, 1H); 7.82 (d, 1H); 8.26 (d, 1H); 11.55 (broad s, OH).
[0174] .sup.13C-NMR (CDCl.sub.3; 75.47 MHz) in ppm (internal TMS-referenced): 29.60; 31.54; 34.57; 35.67; 55.62; 94.29; 115.80; 118.39; 122.47; 124.54; 125.33; 138.46; 141.48; 143.72; 146.31; 159.59.
Preparation of Starting Oximes 2 and 5:
[0175] ##STR00068##
[0176] The nitroso-compound 2′ which is in a tautomeric equilibrium with the more stable oxime 2 is best obtained from commercial chinone A (V. T. Kasumov et al., Spectrochimica Acta A, 2000, 56, 841: not isolated and no yield given).
[0177] In an argon atmosphere, 20.00 g of the ortho-chinone A are dissolved in 450 ml/so-propanol and 24 ml of pyridine. After addition of 6.40 g of hydroxylamine hydrochloride salt, the mixture is heated to reflux for 3 h, cooled down, diluted with diethyl ether and subsequently extracted with 0.5 N hydrochloric acid, sat. hydrogen carbonate solution and brine. The organic phase is dried over sodium sulfate, filtered and evaporated giving 21.90 g (96%) of compound 2/2′. The crude material—without crystallization (96%)—was also conveniently used without significant adverse effects. Due to the tautomeric equilibrium the spectra are not well resolved.
[0178] .sup.1H-NMR (CDCl.sub.3; 300.13 MHz) in ppm (internal TMS-referenced): 1.35 (s, 9H); 1.40 (s, 9H); 5.52 (broad, 1H); 7.80 (broad, 1H).
##STR00069##
[0179] We obtained nitroso derivative 5′, which is also in equilibrium with its oxime taumer 5 by the two-step process depicted above, as the ortho-chinone B is currently not available on large scale, commercially, whereas phenol B is produced on a large ton scale.
[0180] According a published ortho-oxidation protocol for phenols (M. Uyanik et al. Molecules 2012, 17, 8604 or US2017/0066711) which claims to give directly the ortho-chinone products, 15.8 g of phenol B precursor are dissolved in 200 ml ethyl acetate. This solution is added to a clear—usually stirred for 24 h at room temperature—solution containing 30 g of commercial Oxone®, 6.7 g of potassium carbonate, 72 g of sodium sulfate, 1.6 g of phase transfer catalyst tetra n-butyl ammonium hydrogen sulfate and 0.84 g of active oxidative catalyst sodium 2-iodo-benzenesulfonate in 150 ml ethyl acetate. The reaction mixture is then vigorously stirred at room temperature until all starting phenol is consumed, filtered and extracted with water and brine. Evaporation of solvent gives a residue which is purified over silica gel (eluent: hexane-ethyl acetate 10-2) to yield 10.0 g (61%) of pure novel chinone B as a colorless syrupy mass.
[0181] .sup.1H-NMR (CDCl.sub.3; 300.13 MHz) in ppm (internal TMS-referenced): 0.98 (s, 9H); 1.28 (s, 6H); 1.65 (s, 6H); 1.72 (s, 2H); 6.31 (d, 1H); 7.00 (d, 1H); 7.26 (m, 5H).
[0182] .sup.13C-NMR (CDCl.sub.3; 75.47 MHz) in ppm (internal TMS-referenced): 28.55; 28.99; 31.57; 32.56; 40.31; 42.35; 53.23; 123.66; 125.67; 126.18; 128.38; 135.20; 147.19; 148.27; 163.53; 179.58; 180.16.
[0183] 10.0 g of the chinone B are treated with 2.3 g of hydroxyl amine hydrochloride as described for the oxime 2 to give after work-up 8.8 g (85%) of syrupy chinoxime 5/5′.
[0184] .sup.1H-NMR (CDCl.sub.3; 300.13 MHz) in ppm (internal TMS-referenced): 0.91 (s, 9H); 1.44 (s, 6H); 1.73 (s, 6H); 1.78 (s, 2H); 7.17-7.32 (m, 5H); 7.67 (broad d, 1H); 7.77 (broad, 1H).
Starting Ortho-Diamino-Phthalimide 28:
[0185] ##STR00070##
[0186] Commercial amino phthalimide 30 is first alkylated according a published protocol (U.S. Pat. No. 3,980,634). 2.50 g of Amino-phthalimide 30 are dissolved in 25 ml of dry dimethylformamide containing 4.25 g of butyl iodide and 0.075 g of 18-crown-6 ether at room temperature. This mixture is then treated portion-wise with 4.45 g of potassium carbonate with vigorous stirring and stirred until all starting compound is consumed. The mixture is filtered, diluted with ethyl acetate and subsequently extracted with water and brine. Evaporation of organic solvent leaves 3.28 g (97%) of the butyl phthalimide 31 which is sufficiently pure for the next step.
[0187] .sup.1H-NMR (CDCl.sub.3; 300.13 MHz) in ppm (internal TMS-referenced): 0.92 (t, 3H); 1.33 (m, 2H); 1.62 (m, 2H); 3.62 (t, 2H); 6.81 (dd, 1H); 7.01 (d, 1H); 7.57 b (d, 1H).
[0188] .sup.13C-NMR (CDCl.sub.3; 75.47 MHz) in ppm (internal TMS-referenced): 13.64; 20.07; 30.74; 37.56; 108.43; 117.75; 120.57; 124.92; 134.96; 152.33; 168.69; 168.79.
[0189] The amine 31 is intermittently acylated to amide 32 to ensure clean ortho-nitration to compound 33.
[0190] 3.00 g of intermediate 31 are dissolved at room temperature in a mixture of 20 ml dichloromethane, 3.00 ml acetic anhydride and 4.00 ml of pyridine and stirred at room temperature until the starting amine 31 is consumed. The mixture is then diluted with ethyl acetate and extracted with 1 N hydrogen chloride solution, sat. sodium hydrogen carbonate solution and brine. Evaporation of solvent gives 3.50 g (100%) of the amide 32 as a yellow powder sufficiently pure for the next step.
[0191] .sup.1H-NMR (CDCl.sub.3; 300.13 MHz) in ppm (internal TMS-referenced): 0.90 (t, 3H); 1.29 (m, 2H); 1.60 (m, 2H); 2.19 (s, 3H); 3.64 (broad NH); 3.61 (t, 2H); 7.70 (d, 1H); 7.95 (dd, 1H); 7.98 (s (1H).
[0192] .sup.13C-NMR (CDCl.sub.3; 75.47 MHz) in ppm (internal TMS-referenced): 20.02; 22.09; 24.31; 30.50; 37.81; 113.88; 123.65; 124.22; 126.33; 133.43; 144.05; 168.20; 168.42; 169.72.
[0193] The N-acetylated phthalimide 32 is subsequently nitrated according published procedures (O. V. Shishkina et al. Rus. J. Gen. Chem. 1997, 67(5), 789). 10.0 g of the acetylated amide 32 are mixed at −10° C. into 15 ml of conc. sulfuric acid (d 1.84) with vigorous stirring. To this mixture are then added dropwise 4.8 ml of conc. nitric acid (d 1.51) and it is further stirred below −5° C. until the starting material is consumed. The mixture is then poured cautiously onto a mixture of ice/ethyl acetate and sodium hydrogen carbonate with vigorous stirring and pH adjusted to 8 by the addition of more sodium hydrogen carbonate. The organic phase is separated and evaporated. The residue is further purified by column chromatography on silica gel (eluent dichloromethane-ethyl acetate 20-1) to give 7.6 g (65%) nitro amide 33.
[0194] .sup.1H-NMR (CDCl.sub.3; 300.13 MHz) in ppm (internal TMS-referenced): 0.95 (t, 3H); 1.36 (m, 2H); 1.67 (m, 2H); 2.38 (s, 3H); 3.72 (t, 2H); 8.65 (s, 1H); 9.29 (s, 1H); 10.61 (NH).
[0195] .sup.13C-NMR (acetone-D.sub.6; 75.47 MHz) in ppm (internal TMS-referenced): 13.02; 19.77; 24.20; 30.22; 37.91; 116.90; 120.50; 125.60; 136.75; 139.06; 140.58; 165.76; 166.09; 169.29.
[0196] According a published procedure (A. R. Katrizky et al. J. Heterocycl. Chem. 1992, 29, 1519) 8.9 g of the nitro-amide 33 are dissolved in 100 ml acetone and 10 ml water at 40° C. and treated with 10 ml of conc. hydrogen chloride solution until all acetate is cleaved. The mixture is cooled to room temperature and extracted with dichloromethane, the organic phase washed subsequently with dat. Sodium hydrogen carbonate solution and brine. Evaporation yields 9.2 g (95%) of the corresponding nitro-amine as a yellow solid, which is processed further without purification. Hydrogenation of this material following published protocols (Y. A. Liu et al. J. Heterocycl. Chem. 2016, 53, 1630) gives the title diamine (95%) 28.
[0197] .sup.1H-NMR (acetone-D.sub.6; 300.13 MHz) in ppm (internal TMS-referenced): 0.95 (t, 3H); 1.34 (m, 2H); 1.58 (m, 2H); 3.54 (m, 2H); 5.05 (NH.sub.2); 7.05 (s, 2H).
[0198] .sup.13C-NMR (acetone-D.sub.6; 75.47 MHz) in ppm (internal TMS-referenced): 13.04; 19.77; 30.74; 36.63; 107.97; 123.01; 139.95; 169.20.