摘要:

1524 J.C.S. Perkin I Studies of Oxazolobenzodiazepines.t Part 7.l Synthesis of 3-Methyl-oxazolo[3,2-d] [IA]benzodiazepines and Configurational Studies of their Ketimi ne lntermed iates By Ryuji Tachikawa," Tetsuo Miyadera, Chihiro Tamura, Atsusuke Terada, Shunji Naruto, and Eiichi Nagamatsu, Central Research Laboratories, Sankyo Co., Ltd., 2-58, 1-chome, Hiromachi, Shinagawa-ku, Tokyo, Japan Some 3-substituted oxazolo[3,2-d] [1,4] benzodiazepines have been synthesized by a novel double-cyclization re- action, and the geometrical configurations of their ketimine intermediates have been investigated by n.m.r. spectro- scopy and X-ray analysis. In an earlier paper,2 we reported the synthesis and pharmacology of oxazolo[3,4-d] [1,4] benzodiazepines (A). Among numerous oxazolobenzodiazepines which were synthesized in our laboratories, the compounds possess- ing a 3-methyl group on the oxazolidine ring showed greater antibemegride activity than the unsubstituted compounds. The methyl-substituted oxazolobenzo-diazepines were, however, produced in poorer yields by a synthetic method involving a double-cyclization re-synthetic methods and found an alternative novel double-cyclization reaction.Treatment of 2- (2-bromoacet amido) -2',5-dichloro- benzophenone (2a) with morpholine in methylene chloride at room temperature gave 2-(2-morpholino-acetamido)-2',5-dichlorobenzophenone(3a). Heating of (3a) with an excess of 2-aminopropanol at 180-200 "C for 7 h followed by removal of the latter afforded the ketimine derivative (4a) as crystals of m.p.174-175 OC, action of 2-(2-hydroxy-l-methylethylamino)acetamido-whose elemental analysis was consistent with the formula benzophenone. With the aim of obtaining these com- Part 6, T. Miyadera, Y.Kawano, A. Terada, T. Kamioka, pounds in better yields, we have investigated various H. Takagi, and R. Tachikawa, Ann. Rep. Sankyo Res. Lab., 1973, 25, 69.t Formerly called benzo[6,7]-1,4-diazepino[5,4-b]oxazoles: T. Miyadera, A. Terada, M. Fukunaga, Y. Kawano, T. I.U.P.A.C.nomenclature requires the name given in the title and Kamioka, C. Tamura, H. Takagi, and R. Tachikawa, J. Medicin. text. Chem., 1971, 14, 520. C,,H,,Cl,N,O,. The i.r. spectrum exhibited the presence of the amide bond (1700 cm-l) and a C=N bond (1610 cm-l).The n.m.r. spectrum of (4a) showed two pairs of (A) doublets at 6 1.17 (J = 60 Hz) and 1.27 (J = 60 Hz) (nearly 1: 1)due to the methyl protons, and overlapping peaks arising from the morpholino-, hydroxyethyl, and methylene protons adjacent to the amide bond. The n.m.r. and U.V. spectra [235 (E 34 300), 268 (12 500),and 323 nm (4 SOO)] suggested that the ketimine (4a) might be a 1 : 1 mixture of syn-and anti-forms. The con-figurations of the ketimine isomers were investigated by correlating the u.v., i.r., and n.m.r. spectra with those of the corresponding ~ximes.~a-~ Our attempts to separate a mixture of syn-and anti-forms of (4a) have so far been unsuccessful but some other compounds such as (10a-i) and (101-n) were obtained as a single material as is described later.Although there is a possibility that the condensation product (4a) might exist as the tautomer (8)the presence of the latter was not dete~ted.~ In contrast syn-and autti-configurational isomers were present as evidenced by the n.m.r. spectra of compounds (1Oi) and (lOj) which show no hydroxy-group but, instead, two kinds of methylene proton due to the syn-and anti-isomers respectively (see Table 2). Although structure (4a) was consistent with the physical data of the product, structure (9) was also a possibility. In order to confirm the structure as (4a), an alternative synthesis from 2-[2-amino-5-chloro-a-(2-chlorophenyl) benzylidenamino] propanol (5a) 3~ and an X-ray crystallographic analysis of the relating analogues were carried out; on the basis of these results (4a) was shown conclusively to be 2-[2-morpholinoacetamido-5-chloro-a-(2-chlorophen yl)benzylideneamino] propanol.Treatment of (5a) with morpholinoacetic acid in the presence of dicyclohexylcarbodi-imide gave (4a) which was identical in all respects with a sample obtained by the reaction of (3a) with 2-aminopropanol. The ketimine (4a)was methylated with methyl iodide to give the quaternary salt (6a) in quantitative yield. It appears that (6a) also exists as a 1: 1 mixture of syn-and anti-forms as is evident from the n.m.r. spectrum which exhibits two pairs of doublets at 6 1.19 and 1.23 (J = 6.0 Hz) assignable to the methyl group.Similarly, several other derivatives, (3), (4), and (6), (a) L. H. Sternbach, S. Kaiser, and E. Reeder, J. Amer. Chem. Soc., 1960, 82, 475; (b) S. C. Bell, G. L. Conklin, and A. J. Childress. 1. Ow. Chem., 1964. 29. 2368: (cl K. Memro. H. Tawada, aGd Y."Kuwada; J. Pharm: SOC.JapaN, 1973, 88, 1263. 1525 were synthesized ; their physicochemical properties are summarized in the Tables. The double-cyclization reaction of the quaternary salts (6a-d) leading to the oxazolobenzodiazepines (la-d) was examined under a variety of conditions to find that most suitable for ring closure. Heating of the quaternary salt (5a) in dimethylformamide (DMF) in the presence 1 IOR2 R' N-R4 (6) RL= CH(Me).CH20H (7) (c): R1=Br,R2=CL,R4=CH(Me)~CHZOH,R5~R6=~ (d): R'= Br, Rz= H ,R4= CH(Me)*CH20H,R5= R6= 3 SCHEME of CaCO, gave the desired product (la) in 70% yield, together with N-methylmorpholine.The structure of (la) was assigned on the basis of the mass, i.r., and n.m.r. spectra coupled with the elemental analysis; it T. Mivadera. A. Terada. C. Tamura, M. Yoshimoto, and R. Tachikawi, Ann..Rep. Sankyo Res. Lab., 1976, 28, 1. 1526 J.C.S. Perkin I was confirmed by comparison with an authentic sample above. To determine the configuration (syn or anti), prepared by the method reported previously.2 the n.m.r. and X-ray crystallographic analysis were TABLE1 Analysis (yo)Calc. (Found) Y.P. Yield 7(1) ( C) (%) Formula C H N c1 Br a 172-1 75 70 Cl,HI ,C1,N,O, 59.50 4.45 7.7 19.55 (59.5) (4.51) (7.63) (19.27)b 126-127 31 Ci&i &1NaO, 65.75 5.2 8.5 10.8 (65.49) (5.22) (8.50) (10.62) C 182-1 84 36 Cl,Hl,BrCIN,O, 53.0 3.95 6.85 8.7 19.6 (52.87) (3.94) (6.58) (8.76) (19.41)d 126-128 56 C1*H1,BrN,O, 57.9 4.6 7.5 21.4 (57.99) (4.50) (7.32) (21.18) Likewise, several oxazolobenzodiazepine derivatives performed.The methylene protons adjacent to the (la-d) bearing various substituents in the phenyl amide group showed a singlet and/or an AB type group were synthesized and the results are summarized quartet, and the amide proton exhibited a broad singlet in Table 1. at low field indicating the existence of the hydrogen bond TABLE2 N.m.r. spectral data and configurations of the ketimine (10) N.m.r.6 values (CDC1,) hI 3R1 R2 X* COCH,X (ratio) NHCO Config.t c1 c1 4-Mor s (3.31) 13.40 anti c1 H Pip s (3.29) 13.35 anti c1 c1 4-Mepz s (3.31) 13.35 anti c1 Me NMe, s (3.26) 13.50 anti c1 H OH s (4.28) 13.70 anti Br H OMe s (4.20) 13.80 anti Rr F NH, s (3.68) 13.34 anti Br H NMe, {E))c1 H NMe, 2: 1 13.80{: q (2.78,'3.13, J 18.0) 13.35 anti Br H NHEt c1 H SEt {: {: 2:3 13.00 [::::!'3.35, J 18.0) 5: 1 13.70i::::! 3.30, J 18.0)c1 H 4-Mepz4-MOr q (2.70, 3.10, J 18.0) q (2.76, 3.11, J 18.0) q (2.69, 2.91, J 18.0) 9.99 syn(31 H Br 9.15 SYn-NHEt NMe, 9.25 SYn s = Singlet and q = AB type quartet. * 4-MOr == 4-morpholino, Pip = piperidyl, 4-Mepz = 4-methylpiperazinyl. t With respect to the amido-substituted phenyl group.A plausible mechanism for the formation of oxazolo-benzodiazepines (I) from the quaternary salts (6) is shown in (7). As previously noted cis- and trans-isomers of (1) are possible and the n.m.r. spectrum of (la) showed it to be one of these. An X-ray analysis confirmed that it was the cis-isomer. Since some of the ketimines (3) possessed excellent tranquilizing activity comparable to that of the oxazolo- benzodiazepines (1) it appeared of interest to test the pharmacology of these and investigate the configuration of the syn-and anti-forms. The ketimine derivatives were prepared by the usual method mentioned above (A and B in the Scheme) and the results are summarized in Tables 2 and 6. Of these compounds, (log) showed excellent tranquilizing activity and the details of the pharmacology of the ketimines will be described elsewhere.The ketimines would also have syn-and/or anti-configuration with respect to -C=N bond as described in deuteriated chloroform, methanol, benzene, or dimethyl sulphoxide (DMSO) in the n.m.r. spectra. For example, the methylene protons of (10 h) showed a singlet at 6 3.21 in CDC1, and the amide proton revealed a broad singlet at 6 13.35. When a CDC1, solution of anti-(lOh) was set aside for 24 h at room temperature there was a decrease of the singlet at 6 3.21 due to the methylene protons and the concurrent appearance of a new AB type quartet at 6 2.70 and 3.06 (J = 18.0 Hz) (nearly 1 : 1); this was ascribed to the formation of an equilibrium mixture of anti-and syn-forms.In contrast, the n.m.r. spectrum of syn-(lOl) showed a broad singlet at 6 9.99 due to the amide proton and an AB type quartet at 6 2.70 and 3.10 (J = 18.0 Hz) for the methylene protons ; this decreased with the appearance of new singlet at 6 3.05 due to the anti-form (synlanti ca. 1 : 1) when the solution was set aside at room tem- perature in CDC1, for 24 h. It is noteworthy that the methylene protons of (10h) and (101) appeared as a singlet and an AB type quartet, 1978 respectively, immediately upon their dissolution in CDC1,. This suggests that (10h) and (101) exist either N H -CO* C H2- N-0n H CI (8) (9) NH*CO*CH,X (10) as the anti- or syn-form in the solid and as an equilibrium mixture in solution.Based on the spectral data of the methylene protons and the amide proton forming the hydrogen bond, (10h) and (101) were assumed to be anti-and syn-forms respectively. Since hydrogen bonding between the amide hydrogen and nitrogen atoni of CN bond is more likely in (10h) it is reasonable that the methylene peak should show a singlet in the n.m.r. spectrum. On the other hand, whilst hydrogen bonding in sy.n-(lOl) may be disfavoured the formation of a five-membered ring with the substituted-amino nitrogen 5Yn anti X = NR, ,OR,SR atom may be easier; this would explain the AB type quartet for the methylene protons on the five-membered ring. To confirm the structure of (10h) and (101), an X-ray crystallographic study was carried out and their struc- tures were unambiguously determined to be anti and syn, respectively, as shown in Figures 1 and 2.EXPERIMENTAL lH N.m.r. spectra were recorded with a Varian T60 spectrometer with SiMe, as internal standard. 1.r. and U.V. spectra were taken with Hitachi 215 and Cary 14 spectrophotometers, respectively. General Procedure for the Preparation of 2-[(N-.Substituted-amino)acetamido]benzophenones (3).-To a solution of 2-bromoacetamidobenzophenone (2) (33.0mmol) in CH,Cl, (70 ml) the appropriate amine (80 mmol) was added with ice cooling. After being stirred for 30 min at 3-5 "C and then for 5 h at room temperature, the reaction mixture was poured into ice-water and extracted with CH,Cl,.The combined CH2C1, layers were washed with H,O, dried (Na,SO,), and evaporated under reduced pressure to give a solid. Recrystallization from ethanol gave the product (Table 3). General Procedure for the Preparation of the Ketimines (4). -Method A. A mixture of 2-[(N-substituted amino)- acetamido]benzophenone (3) (10 mmol) and 2-amino-propanol (40 mmol) was heated at 180-200 "C for 4 h, after which excess of the latter was removed slowly under reduced pressure. The residue was dissolved in CH,Cl,, washed with H,O, dried (Na,SO,), and evaporated under reduced pressure to give a solid. Recrystallization from benzene gave the product (Table 4). Method B. To a solution of 2-amino-a-phenylbenzyl-ideneaminopropanol (5)(10 mmol) and the appropriate N- substituted aminoacetic acid ( 10 mmol) in tetrahydrofuran (THF) (60 ml) was added dicyclohexylcarbodi-imide ( 11 mmol) with ice cooling.Stirring of the reaction mixture was continued for 2 h at 3-5 "C after which it was poured FIGURE1 into saturated aqueous NaCl and THF layer separated. THF was evaporated under reduced pressure and the residue was dissolved in CH,Cl,. The CH,Cl, layer was washed with H,O, dried (Na,SO,), and evaporated to give a solid which was recrystallized from benzene to give the product (Table 4). General Procedure for the Preparation of the Quaternary B FIGURE2 Salts (6).-To a solution of the ketimine (4) (4.5 nimol) in CH,Cl, (20 ml) was added methyl iodide (10.0 g) at room 1528 J.C.S.Perkin I temperature. The reaction mixture was refluxed for 15 h, under reduced pressure to give a solid. Recrystallization and then CH,Cl, and excess of methyl iodide were distilled from the suitable solvent gave the product (Table 6). TABLE3 2-[ (N-Substituted amino)acetamido]benzophenone (3) Analysis (%) Calc. (Found) Yield h \r (3) R' R2 R5,R6 M.P. ("C) (%) Formula C HN c1 Br (4 c1 c1 CCH212O[CH212 133 96 C19H18C12N203 58.02 4.58 7.12 18.06 (58.0) (7.1) (18.5)(b) c1 H [CH214 90-9 1 90 C19H19C1N202 66.57 'b:i'5 8.17 10.34 (66.3) (5.7) (7.85) (10.5)(4 €31 c1 [CH215 141-142 93 C20H20BrC1N202 55.13 4.63 6.43 8.14 18.34 (55.0) (4.7) (6.4) (8.15) (18.15)(4 Br H [CH2la 88-89 91 C20H21BrN2O2 65.04 5.73 7.58 21.63 (65.1) (5.7) (7.5) (21.7) off under reduced pressure to give a solid ; recrystallization Method B.To a solution of N-substituted-(2-amino-of this from ethanol afforded the product (Table 5). a-phenyl) benzy1idene)amine (10 mmol) and the appropriate General Procedure for the Preparation of OxazoZo[3,4-d]-substituted acetic acid (10 mmol) in THF (60 ml) was added [1,4]benzodiazepines (1).-A mixture of the quaternary salt dicyclohexylcarbodi-imide(11 mmol) with ice-water cool-(6) (2.0 mmol), CaCO, (2.3 mmol), and dimethylformamide ing; stirring was continued for 2 h at 3-5 "C. The re- (DMF) (10 ml) was heated at 105-110 "C with stirring for action mixture was then poured into saturated aqueous TABLE 4 2-[ (2-Substituted amino)acetamido-a-phenylbenzylideneamino]propanol (4) Analysis (%) (4) R1 R2 R6,H6 Method M.p.("C) Yield (%) Formula r C Calc. (Found) h H N c1 Br \ (a) (a) (c) (d) (b) C1 C1 Br Br c1 C1 C1 C1 H €3 [CH2],0[CH2], [CH2],0[CH2j2 [CH2J5 [CH215 [CH216 A H A A A 174-175 174-175 194-195 139-140 156-157 61.4 57.0 52.8 63.0 79.3 C,2H26C1,N,03 C2,H2,BrCIN302 C2,H2,BrN302 C22H26CIN3O3 58.66 (66.25)56.05 (56.25)60.26 (60.75) (58.95) 66.10 5.55 (6.5)5.52 (5.45)6.15 (6.1) (5.75) 6.50 9.33 (10.65)8.53 (8.5)9.16 (9.05) (9.1) 10.50 15.77 (9.05)7.19 (7.2) (15.85) 8.89 16.22 (16.05)17.43 (17.4) 24 h. After cooling of the mixture the solvent was evapor- NaCl and the THF layer separated. The solvent was ated under reduced pressure, and the residue was dissolved evaporated under reduced pressure and the residue was in CH,Cl, and H,O.The CH,Cl, layer was separated and dissolved in CH,Cl,. The CH,Cl, layer was washed with the aqueous layer was extracted with CH,Cl,. The com- H,O, dried (Na,SO,), and evaporated to give a solid, re- bined CH,Cl, layers were washed with H,O, dried (Na,SO,), crystallization of which from a suitable solvent gave the and evaporated under reduced pressure to give a solid. product (Table 6). TABLE5 Quaternary salt (6) of 2-[ (%substituted amino)acetamido-cx-plienylbenzylideneamino]propanol Analysis (yo)Calc. (Found) Yield r -(6) R1 R2 R6,R6 M.p. ("C) (yo) Formula C H c1 Br 1 (a) C1 C1 0 209-211 98 C23H28C121N30, 46.62 4.73 11.99 24.45 (46.55) (4.8) (12.0) (24.65) (b) C1 H 0 207-210 97 C23H2gClIN302 50.97 5.35 6.55 23.46 (50.95) (5.35) (6.1) (24.05)(c) Br C1 0 208-209 97 C2,H30BrClIN302 45.41 4.76 5.58 12.59 19.99 (45.15) (4.8) (5.55) (12.7) (19.75)(d) Br H 0 199-200 95 C24H3,BrIN302 48.01 5.20 13.31 21.14 (47.9) (5.3) (13.5) (21.15) Recrystallization from ethanol gave the product (Table Crystallographic Analyses of the Ketimine (10h) and (101).1). -The ketimine (10h) was recrystallized from isopropyl General Procedure for the Preparation of the Ketirnines ether to give colourless prisms of m.p. 105-107 OC. (10).--Method A. A mixture of 2-(2-~ubstituted)acetamido-CrystaZ Data.-Ketimine (1Oh). Triclinic. Space group benzophenone ( 10 mmol) and the appropriate substituted Pi; a = 12.91,b = 19.57, c = 10.11, a = 92.96, = 66.42, amine (20-40 mmol) was heated at 170-200 "C for 4 h, y = 116.44, D, = 1.341 (2 = a), Do = 1.370; number of and the excess substituted amine was then removed slowly reflections 3 537.under reduced pressure. The residue was dissolved in Ketimine (101) was recrystallized from isopropyl ether to CH,Cl,, washed with H,O, dried (Na,SO,) , and evaporated afford colourless prisms of m.p. 115-116 "C. 1978 1529 Crystal Da.fa.-Ketimine (101). Monoclinic. Space structures were solved by a heavy-atom technique and group P2Jc; a = 9.94, b = 17.78, c = 12.67, cc = 90.0, refined bv block-diagonal least-squares procedure. The TABLE6 Method M.p. ("C) Yield(yo) Formula Analysis (%)Calc. (Found) L --------I C H N c1 Br F 5 125-126 85 57.78 5.31 9.62 16.25 111-1 12 78 (57.65)66.05 6.55(5.1) 10.50(9.8) (15.95)8.87 119-123 100-102 156-157 73 66 46 (65.9)63.82 (63.85)64.24 (64.5)61.84 (66%(3(6.5)5.14 (10.6)13.53 (13.8)11.23 8.41(11.2) 8.57 (8.45)9.49 10.66 (8.8) (9.4) 103-105 67 (61.6)55.25 (5.15)4.89 7.16(8.55) (10.55) 20.42 167-1 68 74 47 51.79(55.35) 4.34(44 10.65(7.0) (20.15)20.26 4.81 105-10 7 75 (51.5)57.42 5.78(4.45) (10.45)10.04 (20.3)19.10 (4.6) 110-111 64 35 (57.16)63.40 6.16(5.75) (10.4)11.67 9-86 (19.0) 125-127 47 (63.7)61.06 4.90(6.0) (11.65)9.28 (9.75) 17.66 78-79 64 (60.85)63.23 5.86(5.0) 7.76(9.25) 9.83 (17.6) 8.86 115-116 66 (63.4)63.67 6.55(5.75) 13.50(7.8) (9.66)8.55 (8.6) Oil 48 73 (63.5)63.52 (6.35)6.30 (13.5)10.10 8.53(8.6) 158-159 15 (63.45)66.37 6.08(6.3) (10.25)12.52 (8.8) 17.86 (56.25) (6.15) (12.65) (17.6) * R1, R2, R4 and X: see Table 2.-90.0, D,= 1.271 (Z = 4), Do = 1.30; conventional R values of (10h) and (101) were reduced to p = 104.76, y .-number of reflections 2 659. 0.10 and 0.087, respectively. Intensity data were collected on an automated Rigaku four-circle diffractometer with Mo-K, radiation. The [8/327 Received, 24th February, 19781

ISSN:1472-7781    

DOI:10.1039/P19780001524

出版商:RSC    

年代:1978

数据来源: RSC