close

Вход

Забыли?

вход по аккаунту

?

Investigations on the Pathway of the Fluorescence Reaction of a Pharmaceutically Important 13-Diamine with 2-Benzoylbenzaldehyde.

код для вставкиСкачать
Notes
Investigations on the Pathway of the Fluorescence Reaction of a
Pharmaceutically Important 1,3-Diamine with 2-Benzoylbenzaldehyde *
Reinhard Troschiitz” and Oliver Heinemann
Institut fur Pharmazie und Lebensmittelchemie der Friedrich-Alexander-Universitat,Erlangen-Numberg, Schuhstr. 19, D-91052 Erlangen, Germany
Key Words: Fluorescence reaction; deuteration experiments; reaction pathway; 2-benzoylbenzaldehyde; 1,j-diamine
Results and Discussion
Summary
The reaction of 2-benmyibenzd&hyde (1) with primary diamine
2, generated by reanangenlent and hydrolysis of Oxazepam, in
CD30D leads to intensely fluorescing deuterated isoindoloquinazolines 3 and 4. Reduction of ethyI 2-benzoylbenzoate (5) with
LiA1D4 followed by oxidation with Mn@ yields Z-benzoylbent[D]aldehyde (7). The condensation of 7 with diamine 2 leads
to isoindoloquinazoline12,free of deuterium.On the basis of these
experimentsa plausible pathway is proposed for the “fluorescence
reaction”.
Introduction
Phthalaldehyde represents a widely used reagent for the
fluorimetric assay of primary amines [14], especially biogenic amines such as histamine, tryptamine, and serotonin as
well as amino acids [5,61. The reaction of phthalaldehyde or
its analogue 2-benzoylbenzaldehyde (l),respectively, with
2-amino-5-chlorobenzhydrylamine(2), a primary 1,3diamine, obtained by rearrangement and hydrolysis from
Oxazepam, in CH30H at 20 “C gave rise to strongly fluorescent isoindoloquinazolines. This reaction enables a highly
specific TLC-fluorescence detection of Oxazepam and
Lorazepam L71.
In continuation of these investigations, special experiments
were set up to elucidate the pathway of this fluorescence
reaction.
In order to confirm our proposal of the reaction pathway,
an experiment in deuterated methanol was undertaken. The
reaction of 2-benzoylbenzaldehyde (1) with 2-amino-5-chlorobenzhydrylamine (2) in CD30D yielded the fluorescent
and deuterated compounds 3 and 4 as shown by ‘H-NMR and
MS data. The UV spectrum of 4 exhibits a maximum at h =
338 nm with some shoulders, attributed to the “azastilbene”
chromophore, which was not observed in 3. Consequently 4
is an isoindolo[l,2-b]quinazolinederivative and 3 is a derivative of isoindolo[2,1-a]quinazoline. The relative configuration of the deuterium-free congeners of 3 and 4 was
determined by NO experiments L71. Therefore, we assume that
the deuterated compounds 3 and 4 have, in all probability, the
same relative configuration. With regard to the phenyl
groups, 3 is trans- and 4 cis-configurated.
In order to prove or exclude an intramolecular hydride shift
during the formation of isoindoloquinazolines, a monodeuterated 2-benzoylbenzaldehyde (7) was used. Its preparation
started with the reduction of ethyl 2-benzoylbenzoate(5) with
LiAlD4 yielding the deuterated diol6 which was oxidized to
2-benzoylbenz[D]aldehyde (7) by MnO2 at 20 “C.
The deuterated ketoaldehyde 7 reacted with 2-amino-5chlorobenzhydrylamine (2) to give the solely isolated deuterium free isoindolo[ 1,2-b]quinazoline 12, as shown by
‘H-NMR and MS data. Compound 12 is identical with the
Ph
Ph
do
CHO
,.
+
+
Ph
1
2
Scheme 1
Arch. P h a n . P h a n . Med. Chem.
0 VCH Verlagsgesellschaft mbH, 0-6945 1 Weinheim, 1996
0365-6233/96/0505-0267$5.00 + .25/0
268
Troschutz and Heinemann
product obtained from the reaction of 2-benzoylbenzaldehyde (1) and 2 in methanol 17].
Based on these experiments the following reaction path is
proposed:
Initially the N,N-acetal 8 is formed from the ketoaldehyde
7 and the 1,3-diamine 2, cyclizing intramolecularly to a
1 0-hydroxyisoindoloquinazolinederivative 9. After protonation of the hydroxy group in 9, a carbenium-immonium ion
10 is generated, transforming into a reactive 1-aminoisoindole intermediate 11 after elimination of DO. 11 contains a
vinylogous enamine structure, which is responsible for the
nucleophilic reactivity at C-10. Protonation of C-10 by
methanol and elimination of the N-H proton gives rise to
10,I2-dihydroisoindolo[ I ,2-b]quinazoline 12, containing no
deuterium.
The observed incorporation of deuterium, as outlined in
Scheme 1, can be plausibly explained by a reaction of a
nucleophilic 1-aminoisoindole intermediate of type 11 with
a deuteron from C D 3 0 D .
do
Z)H@
1)
LIAID4, Et20 A
COOEt
5
1
I
78 mg (0.33 mmol) of 2 and 69 mg (0.33 mmol) of 2-benzoylbenzaldehyde
(1) were dissolved in CD30D. Under nitrogen and absence of light the
mixture was gently stirred at 20 “C for 3 h. The mixture was reduced to 113
of its volume and set aside. After 10 h the precipitated solid was chromatographed by MPLC on silica gel (CHCI31CH3OH 98:2).
Yield 31 mg (23%) colorless powder.- mp 166-167 ”C.- IR (KBr): v =
3066 cm-’, 3015 (Ar), 2970, 2938 (CH), 1619-1490 (C=N, C=C).- UV
(CH3OH): hman(log E) = 240.8 nm (4.20), 297.4 (3.70), 3 10.4 (3.63);addition
of HCI 252.6 (4.10), 297.4 nm (3.70), 320.0 (3.66).- ‘H-NMR (250.14 MHz,
CDC13):6=6.02ppm(s, 1H,5-H),6.57(d,J=9Hz3IH, l-H),7.02(dd,Ji
=9 Hz, J 2 = 2.5 Hz, IH, 2-H), 7.13 (d,J = 2.5 Ha, IH, 4-H), 7.20-7.45 (m,
13H, 8-H, 9-H, 10-H, 2’-H-6‘-H, 2”-H-6”-H), 7.93-7.97 (m, IH, 7-H).- MS
(70 eV): m/z (%) = 4091407 (7/22) [M’], 3331331 (31/100) [M+-C6Hs].
(IOSR,12RS)-[IO-D]-2-Chloro-lO,12-diphenylIO,l2-dihydroisoindolo
[1,2-b]quinazoline (4)
Isolated as a further compound from the reaction of 1 and 2.
Yield 36 mg (27%) colorless crystals.- mp 176-178 T - IR (KBr): v =
3034 cm-’ (Ar), 2922,2859 (CH), 1626-1494 (C=N, C=C).- UV (CH30H):
hmax (log &) = 245.0nm(4.25), 325.0 (sh, 3.88), 338.1 (3.97), 350.0 (sh, 3.90),
371.4 (sh, 3.54); addition of HCI 257.2 (4.13), 313.6 (3.92).- ‘H-NMR
(250.14 MHz, CDC13): 6 = 5.77 ppm (s, IH, 12-H), 6.55 (dd, J I = 2.5 Hz, Jz
= 1 Hz, IH, LH), 6.70 (br. s, IH, 2”-H-6”-H), 6.81-7.03 (m, 9H, 9-H,
2’-H4’-H, 3”-H-S”-H), 7.19 (dd, JI = 8 Hz, J2 = 2.5 Hz, IH, 3-H), 7.30 (d,
J = 8 H z , IH,4-H),7.41 (ddd,Ji=7.5Hz,J2=6Hz,J3=1.5Hz,1H,8-H),
7.52 (ddd, J i =J2 = 7.5 Hz,J3 = 1.5 Hz, lH, 7-H), 8.11 (br d, J = 7.5 Hz, lH,
6-H).- MS (70 eV): d z (5%) = 4091407 (7122) [M’], (311100) [M+-CsHsl.
*6
6:
\
OH
g
Ph
(5RS,1IRS)-[11-D]-3-Chloro-5,Il-diphenyl-5,Il-dihydroi.soindolo12,I-a]quinazoline(3)
D
2-(Hydroxy[Dr]methyl)-diphenyl[D]methanol(6)
0 U
D
C
I
]
7
Ph
10
I-.
1
1
+ CHBOH
12
Scheme 2
1.0 g (3.9 mmol) of ethyl 2-benzoylbenzoate (10) was dissolved in
absolute ether (25 ml) and added over 1 h to a refluxing suspension of 1.0 g
(23.8 mmol) of LiAID4 in EtzO (50 ml). After 3 h the suspension was cooled,
hydrolyzed with ice water and acidified with diluted sulfuric acid and
extracted 3 times with 30 ml of EtzO; the organic layer was dried over
NazS04 and evaporated in vucuo. The resulting oil was chromatographed by
MPLC on silica gel (CHCb1CH30H 9:l).
Yield 626 mg (74%) colorless powder.- mp 72-73 “C.- IR (KBr): v =
3624cm-’ (OH), 3027, 3013 (Ar), 2945, 2899 (CD, CDz), 1603-1449
(C=C).- UV (CH30H): h,,, (log E) = no stimulation.- ‘H-NMR (360.14
MHz, [D6]DMSO): 6 = 5.08 ppm (s, IH, CDz-OH, D20-exchdnge), 5.75 (s,
IH, CD-OH, Dz0 exchange), 7.15-7.33 (m, 9H, Haromat).-MS(70 eV): d z
(%) = 198 (64) [M+-HDO], 197 (100).
2-Renzoylbenz[D]aldehyde(I)
0.5 g (2.3 mmol) of 2-hydroxy[D2]methyl-diphenyl[D]methanol( 6 ) was
dissolved in 50 ml of CH2C12 and gently stirred at 20 “C with 5.0 g
(57.5 mmol) of MnOz for 12 h. After filtration the crude brown residue was
extracted 3 times with CHzCIz (20 ml). The organic layer was dried over
Na2SOq and evaporated in vucuo to yield a residue, which was chromatographed by MPLC on silica gel (CHzCIz).
Yield 285 mg (58%) colorless powder.- mp 66-68 “C.- 1R (KBr): v =
3066 cm-I, 3024, 3016 (Ar), 1710, 1673 (C=O), 1597-1486 (C=C).- UV
(CH30H): hman(log E) = 248.4 nm (3.77).- ‘H-NMR (250.14 MHz, CDC13):
6 = 7.44-8.06 ppm (m, 9H, Haromat).- MS (70 eV): d z (%) = 21 1 (96) [M’],
182(100).
Experimental
(IOSR,12R,S)-2-Chloro-lO,
12-diphenyl-10,12-dihydroisoindolo[12-b]-qu
inazoline (12)
I
General: Mp: Buchi 530 (uncorr.).- Fl-IR: Perkin-Elmer 1740.- UV:
Perkin-Elmer Lambda 5.- ‘H-NMR and ”C-NMR: Bruker AM 360; Bruker
AC 250; Jeol FX 90 Q (standard: TMS).- EI-MS: Finnigan MAT TSQ 70.High Resolution EI-MS: Varian MAT 31 1 A or Varian MAT 312.- Silica
gel for MPLC: silica gel 60 Macherey Nagel & Co.
Prepared according to 3 from 123 mg (0.6 mmol) of 2 and 126 mg (0.6
mmol) of 7 in methanol.
Yield 93 mg ( 38 %).- mp 176-177 “C ( 175-177 “C ref.”’).
Arch. Phum. Phumz. Med. Chem. 329,267-269 (1966)
269
Fluorescence Reaction of a n Important I ,3-Diamine
References
*
Dedicated to Prof. Dr. G. Rucker, Bonn, on the occasion of his 65th
birthday.
[ 11 W.B. Shelley, L. Juhlin, J. Chromatogr. 1966,22, 130-138.
[2] D. Turner, S.L. Wightman, J. Chromatogr. 1 9 6 8 , 3 2 , 315-322.
[3]
[4] H.E. Geissler, E. Mutschler, Arzneim. Forsch. 1976,26, 75-78.
[5] B. Algermissen, M. Nudel, E. Riedel, GIT Fachz. Lab. 1 9 8 9 , 9 , 783790.
[6] M. Roth, Anal. Chem. 1971,43,880-883.
171 .R. Troschiitz, 0. Heinemann, R. Waihel, J. Troschiitz, Arch. Pharm.
_
(Weinheim), 1995, 328, 557-563.
R.P. Maikel, F.P. Miller, Anal. Chem. 1966, 38(13), 1937-1938.
Received: January 25,1995 [FP089]
0 VCH Verlagsgesellschaft mbH, D-69451 Weinheim, 1996 -Printed in the Federal Republic of Germany
Anzeigenleitung: R.J. Roth, D-6945 I Weinheim - VCH Verlagsgesellschaft mbH (Geschaftsfiihrer: Hans Dirk Kohler), Postfach 10161, D-69451 Weinheim.
Alle Rechte, insbesondere die der Ubersetzung in fremde Sprachen, vorbehalten. Kein Teil dieser Zeitschrift darf ohne sebriftliche Genehmigung des Verlages in irgendeiner Form
- durch Fotokopie, Mikrofilm oder irgendein anderes Verfahren - reproduziert oder in eine von Maschinen, insbesondere von Datenverarbeitungsmaschinen verwendbare Sprache
iibertragen oder iibersetzt werden.- All rights reserved (including those of translation into foreign languages). No part of this issue may be reproduced in any form - photoprint,
microfilm, or any other means - nor transmitted or translated into a machine language without the permission in writing of the publishers.- Von einzelnen Beitragen oder Teileu
von ihnen diirfen nur einzelne Vervielfaltigungsstcke fur den personlichen und sonstigen eigenen Gehrauch hergestellt werden. Die Weitergabe von Vervielfiltigungen, gleichgiiltig
zu welehem Zweck sie hergestellt werden, ist eine Urheberrechtsverletzung. Der Inhalt dieses Heftes wurde sorgfaltig erarbeitet. Dennoch iibemehmen Autoren, Herausgeher,
Redaktion und Verlag fiir die Richtigkeit von Angaben, Hinweisen und Ratschlagen sowie fur eventuelle Druckfehler keine Haftung. This journal was carefully produced in all its
parts. Nevertheless, authors, editors and publishers do not warrant the information contained therein to be free of errors. Readers are advised to keep in mind that statements, data,
illustrations, procedural details or other items may inadvertently be inaccurate.- Die Wiedergahe von Gerbrduchsnamen, Handelsnamen,Warenbezeiehnungen u. dgl. in dieser
Zeitschrift berechtigt nicht LU der Annahme, daR solche Namen ohne weiteres von jedermann benutzt werden diirfen. Es handelt sich haufig um gesetzlich eingetragene Warenzeichen,
auch wenn sie in dieser Zeitschrift nicht als solche gekennzeichuet siud. Druck und Buchbinder: Druck Partner Riibelmann GmbH, D-69502 Hemsbach.- Unverlangt zur Rezension
eingehende Biicher werden nicht zuriickgesandt.
Valid for users in the USA: The appearance of the code at the bottom of the first page of an article in this journal (serial) indicates the copyright owner’s consent that copies of the
article may be made for personal or internal use, or for the personal or internal use of specific clients. This consent is given on the condition, however, that copier pay the stated per
copy fee throught the Copyright Clearance Center, Inc., for copying beyond that permitted by Sections 107 for 108 of the U S . Copyright Law. This consent does not extend to
other kinds of copying, such as copying for General distribution, for advertising or promotional purposes, for creating new collective work, or for resale. For copying from back
volumes of this journal see >>Permissionsto Photo-Copy: Publisher’s Fee Lista of the CCC.
Printed on chlorine- and acid-free paper/Gedmckt auf saurefreiem und chlorfrei gebleichtem Papier
Arch. Phamz. Pharm. Med. Chem. 329,267-269 (1966)
Документ
Категория
Без категории
Просмотров
1
Размер файла
257 Кб
Теги
investigation, reaction, fluorescence, benzoylbenzaldehyde, importance, pathways, pharmaceutical, diamine
1/--страниц
Пожаловаться на содержимое документа