A simple and efficient synthesis of GYKI 52466 and GYKI 52895

Article abstract of DOI:10.1081/SCC-120002397

The synthesis of 1-(4-aminophenyl)-4-methyl-7,8-methylene-dioxy-5H-2,3-benzodiazepine (GYKI 52466, 1), the prototype of a series of noncompetitive AMPA receptor antagonists, and its 3,4-dihydroderivative (GYKI 52895, 2) is described. The title compounds have been prepared starting from safrole through a quite effective procedure.

Full text of DOI:10.1081/SCC-120002397

SYNTHETIC COMMUNICATIONS, 32(4), 527–533 (2002)
A SIMPLE AND EFFICIENT
SYNTHESIS OF GYKI 52466 AND
GYKI 52895
Maria Zappala,1 Silvana Grasso,1, Nicola Micale,1
*
Santina Polimeni,1 and Carlo De Micheli2
1Dipartimento Farmaco-Chimico, Universita di
Messina, Viale Annunziata, 98168 Messina, Italy
2Istituto di Chimica Farmaceutica, Universita di
Milano, Viale Abruzzi 42, 20131 Milano, Italy
ABSTRACT
The synthesis of 1-(4-aminophenyl)-4-methyl-7,8-methylene-
dioxy-5H-2,3-benzodiazepine (GYKI 52466, 1), the prototype
of a series of noncompetitive AMPA receptor antagonists,
and its 3,4-dihydroderivative (GYKI 52895, 2) is described.
The title compounds have been prepared starting from safrole
through a quite effective procedure.
The discovery of 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-
2,3-benzodiazepine (GYKI 52466, 1) as the prototype of selective non-
competitive AMPA receptor antagonists endowed with anticonvulsant1
and neuroprotective properties,2 induced a wide-ranging research activity
focused on 2,3-benzodiazepine derivatives.
*Corresponding author.
527
Copyright & 2002 by Marcel Dekker, Inc.
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ZAPPALA ET AL.
GYKI 52466 has proved to be useful as a tool to investigate the
physiological role of the AMPA receptor complex and its involvement
in a number of neurodegenerative pathologies. Only few details relating to
the preparation of 1 are available3 and no spectral data were reported in
literature.
As a part of our ongoing efforts to design new selective noncompeti-
tive AMPA receptor antagonists structurally related to GYKI 52466,4 we
now report a new and simple synthetic approach to compound 1 and to its
3,4-dihydroderivative (GYKI 52895, 2) which, at variance of 1, is a selective
dopamine uptake inhibitor.5
By using natural safrole (3) as starting material we have developed an
efficient reaction sequence which yielded GYKI 52466 (1) in 29% overall
yield (Scheme 1).
Alcohol 4 was synthesized in 96% yield from alkene 3 through an
oxymercuration–demercuration process. The preparation of methylketone
5 is thus straightforward and was accomplished in 75% yield by a pyridi-
nium chlorochromate (PCC) oxidation of alcohol 4. Friedel-Craft acylation
of 5 with 4-nitrobenzoic acid and subsequent reaction of intermediate
diketone 6 with an excess of hydrazine hydrate afforded 4-methyl-7,8-
methylenedioxy-1-(4-nitrophenyl)-5H-2,3-benzodiazepine 7, contaminated
by minor amounts of 3-methyl-6,7-methylenedioxy-1-(4-nitrophenyl)iso-
quinoline 8. A tin(II) chloride reduction of the nitro group of 7 yielded 1
in 80% yield. GYKI 52466 (1) was then submitted to a NaBH3CN reduction
to produce GYKI 52895 (2) in 83% yield.
EXPERIMENTAL SECTION
Melting points were determined on a Kofler hot stage apparatus and
are uncorrected. Elemental analyses were carried out on a Carlo Erba 1106

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GYKI 52466 AND GYKI 52895
529
Scheme 1. a) Hg(OAc)2/NaBH4, THF, rt, 2 h; b) PCC/CH2Cl2, rt, 6h; c) P 2O5/
CH2Cl2, rt, 8 h; d) NH2NH2, EtOH, rt, 1 h; e) SnCl2, EtOH, 70ꢁC, 1 h; f ) NaBH3CN,
MeOH/HCl, rt, 1 h.
elemental analyses for C, H, and N, and the results are within ꢀ0.4% of the
theoretical values. Merck silica gel 60 F254 plates were used for analytical
TLC; column chromatography was performed on Merck silica gel 60
(70–230 mesh). 1H and 13C NMR spectra were recorded in CDCl3 by
1
means of a Varian Gemini-300 spectrometer. Complete H and 13C assign-
ments were made by using direct and long-range heteronuclear chemical
shift correlation experiments (HETCOR and LR-HETCOR) carried out
by using the standard software package. Chemical shifts are expressed in
d (ppm) relative to TMS and coupling constants (J) in Hz. All exchangeable
protons were confirmed by addition of D2O. Mass spectra were recorded
under positive electrospray ionization (ESI þ) with a ThermoQuest LCQ

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ZAPPALA ET AL.
mass spectrometer. The relative abundance of the ions is reported in
brackets.
1-(3,4-Methylenedioxyphenyl)propan-2-ol (4): Safrole (3) (3.1 g,
19.1 mmol) was gradually added to a stirred solution of Hg(OAc)2 (6.25 g,
19.1 mmol) in THF (57 ml)/H2O (19 ml). After stirring for 1 h at room tem-
perature, the yellow color disappeared. The reaction mixture was alkalinized
(3 N NaOH, 20 ml) then a solution of NaBH4 (360 mg, 9.5 mmol) in 3 N
NaOH (20 ml) was added dropwise. After 1 h the reaction mixture was
saturated with NaCl, the organic layer separated and the aqueous layer
was further extracted with EtOAc (4 Â 60 ml). The combined organic
extracts were then washed with water (3 Â 25 ml) and the solution dried
over anhydrous Na2SO4. After evaporation of the solvents under vacuum,
alcohol 4 (3.3 g, 96%) was obtained as clear viscous oil. An analytical
sample of 4 was obtained by a silica gel column chromatography using
cyclohexane/EtOAc (6: 4) as eluant.
Compound 4: Rf (cyclohexane/EtOAc, 6: 4) 0.46; 1H NMR: 1.14 (d, 3H,
J ¼ 6.3 Hz, CH3), 2.58 (d, 2H, J ¼ 6.6 Hz, CH2), 2.84 (br s, 1H, OH) 3.86(m,
1H, CH), 5.82 (s, 2H, OCH2O), 6.57–6.70 (m, 3H, Ar); 13C NMR: 22.22
(CH3), 44.94 (CH2), 68.34 (CH), 100.38 (OCH2O), 107.73 (C-2), 109.31
(C-5), 121.83 (C-6), 132.12 (C-1), 145.56 (C-4), 147.15 (C-3); MS (ESI þ):
181 (Mþ þ 1, 17), 136(54), 135 (100), 106(18), 77 (42); Anal. Calcd. for
C10H12O3: C, 66.65, H, 6.71. Found: C, 66.74; H, 6.58.
3,4-Methylenedioxyphenylacetone (5): A mixture of 4 (2.9 g, 16mmol)
and PCC (6.9 g, 32.1 mmol) in dichloromethane (100 ml) was magnetically
stirred at room temperature overnight. The slurry was filtered through a
Celite pad and the residue washed with dichloromethane (2 Â 60 ml). The
clarified solution was washed with water (2 Â 50 ml), dried (Na2SO4) and
then concentrated at reduced pressure to yield 5 (2.1 g, 75%) as a light
brown oil.
Compound 5: Rf (cyclohexane/EtOAc, 6: 4) 0.56; 1H NMR: 2.14 (s, 3H,
CH3), 3.59 (s, 2H, CH2), 5.93 (s, 2H, OCH2O), 6.62–6.77 (m, 3H, Ar);
13C NMR: 28.74 (CH3), 50.05 (CH2), 100.71 (OCH2O), 108.06(C-2),
109.42 (C-5), 122.17 (C-6), 127.54 (C-1), 146.32 (C-4), 147.53 (C-3); MS
(ESI þ): 179 (Mþþ 1, 37), 135 (100), 122 (61), 102 (50), 91 (80); Anal.
Calcd. for C10H10O3: C, 67.41, H, 5.66. Found: C, 67.68; H, 5.93.
2-(4-Nitrobenzoyl)-4,5-methylenedioxyphenylacetone (6): To a stirred
solution of 5 (1.07 g, 6.0 mmol) in 1,2-dichloroethane (100 ml) was added
4-nitrobenzoic acid (1.3 g, 7.7 mmol) followed by phosphorous pentoxide
(8 g, 56.3 mmol). The mixture was stirred at room temperature overnight,
then water (60 ml) was cautiously added. The organic layer was separated
and sequentially treated with 10% NaOH (60 ml), brine (50 ml) and water
(2 Â 50 ml). The organic phase was dried (Na2SO4) and the solvent removed

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531
under reduced pressure to yield crude 6 which was purified by a silica gel
column chromatography (eluant: cyclohexane/EtOAc, 6: 4) to afford pure 6
(1.17 g, 60%) as colorless solid.
Compound 6: Rf (cyclohexane/EtOAc, 6: 4) 0.49; mp 151–154 ꢁC;
1H NMR: 2.25 (s, 3H, CH3), 4.01 (s, 2H, CH2), 6.06 (s, 2H, OCH2O),
6.76 (s, 1H, H-6), 6.81 (s, 1H, H-3), 7.91 (d, 2H, J ¼ 8.3 Hz, H-20,60), 8.31
(d, 2H, J ¼ 8.3 Hz, H-30,50); 13C NMR: 29.91 (CH3), 48.39 (CH2), 102.11
(OCH2O), 111.11 (C-6), 112.71 (C-3), 123.47 (C-30,50), 129.70 (C-1),
130.82 (C-20,60), 131.71 (C-2), 143.66 (C-10), 146.08 (C-4), 149.79 (C-40),
150.66 (C-3), 195.0 (C¼O), 205.40 (CH3C¼O); Anal. Calcd. for
C17H13NO6: C, 62.39; H, 4.00, N, 4.28. Found: C, 62.58; H, 3.76; H, 4.15.
4-Methyl-7,8-methylenedioxy-1-(4-nitrophenyl)-5H-2,3-benzodiazepine
(7) and 3-Methyl-6,7-methylenedioxy-1-(4-nitrophenyl)isoquinoline (8): To a
solution of 6 (1.095 g, 2.9 mmol) in EtOH (125 ml) was added hydrazine
hydrate (2.5 ml, 51.5 mmol) and the resulting mixture was stirred at room
temperature for 2 h. Ethanol was removed under vacuum and the residue
treated with water (80 ml) and extracted with chloroform (2 Â 50 ml). The
pooled organic extracts were dried (Na2SO4); the solvent was evaporated at
reduced pressure to yield a mixture of compounds 7 and 8. A silica gel
column chromatography (eluant: cyclohexane/EtOAc 6: 4) of the residue
gave 535 mg (50%) of 7 and 300 mg (32%) of 8.
Compound 7: Rf (cyclohexane/EtOAc, 6: 4) 0.33; mp 200–203 ꢁC;
1H NMR: 2.16(s, 3H, CH 3), 2.90 and 3.29 (dd, 2H, J ¼ 12.3 Hz, CH2), 6.04
(s, 2H, OCH2O), 6.65 (s, 1H, H-6), 6.77 (s, 1H, H-9), 7.85 (d, 2H, J ¼ 8.9 Hz,
H-20,60), 8.25 (d, 2H, J ¼ 8.9 Hz, H-30,50); 13C NMR: 22.18 (CH3), 38.55 (C-5),
101.96(OCH 2O), 106.51 (C-6), 108.87 (C-9),0122.68 (C-5a), 123.61 (C-30,50),
130.29 (C-20,60), 134.46(C-9a), 144.73 (C-1 ), 147.14 (C-7), 148.51 (C-40),
151.17 (C-8), 154.60 (C-4), 156.43 (C-1); Anal. Calcd. for C17H13N3O4:
C, 63.16; H, 4.05; N, 13.0. Found: C, 62.97; H, 4.26; N, 13.15.
ꢁ
Compound 8: Rf (cyclohexane/EtOAc, 6: 4) 0.56; mp 178–181 C;
1H NMR: 2.69 (s, 3H, CH3), 6.09 (s, 2H, OCH2O), 7.08 (s, 1H, H-5), 7.12
(s, 1H, H-8), 7.41 (s, 1H, H-4), 7.82 (d, 2H, J ¼ 8.9 Hz, H-20,60), 8.38 (d, 2H,
J ¼ 8.9 Hz, H-30,50); 13C NMR: 23.98 (CH3), 101.68 (OCH2O), 102.09 (C-5),
102.41 (C-8), 118.95 (C-4), 123.62 (C-30,50), 130.71 (C-20,60), 121.61 (C-4a),
136.26 (C-8a), 146.46 (C-10), 147.70 (C-6), 148.29 (C-40), 150.33 (C-7),
150.83 (C-3), 155.80 (C-1); MS (ESI þ): 309 (Mþþ 1, 22), 279 (20), 263
(100), 251 (12); Anal. Calcd. for C17H12N2O4: C, 66.23; H, 3.92; N, 9.09.
Found: C, 66.41; H, 3.87; N, 9.31.
1-(4-Aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine
(1): To a solution of 7 (460 mg, 1.42 mmol) in absolute EtOH (80 ml)ꢁtin(II)
chloride (1.6g, 6.8 mmol) was added. The mixture was heated at 70 C for
1 h. The solvent was removed in vacuo and the residue was treated with a

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ZAPPALA ET AL.
10% NaOH solution (30 ml), extracted with EtOAc (2 Â 30 ml) and dried
(Na2SO4). The solvent was removed under reduced pressure and the residue
was purified by crystallization from EtOH to give 332 mg (80%) of 1.
Compound 1: Rf (CHCl3/MeOH, 95 : 5) 0.28; mp 235–238ꢁC; 1H NMR:
2.12 (s, 3H, CH3), 2.99 and 3.20 (dd, 2H, J ¼ 12.1 Hz, CH2), 3.80 (br s, 2H,
NH2), 6.02 (m, 2H, OCH2O), 6.69 (d, 2H, J ¼ 8.5 Hz, H-30,50), 6.72 (s, 1H,
H-6), 6.80 (s, 1H, H-9), 7.50 (d, 2H, J ¼ 8.5 Hz, H-20,60); 13C NMR: 22.87
(CH3), 38.39 (C-5), 101.56(OCH 2O), 106.0 (C-6), 109.92 (C-9), 114.37
(C-30,50), 123.82 (C-5a), 129.06(C-1 0), 130.96(C-2 0,60), 134.14 (C-9a),
146.56 (C-7), 148.12 (C-40), 150.28 (C-8), 154.73 (C-4), 157.84 (C-1); Anal.
Calcd. for C17H15N3O2: C, 69.61; H, 5.15; N, 14.33. Found: C, 69.83; H,
5.34; N, 4.28.
1-(4-Aminophenyl)-3,4-dihydro-4-methyl-7,8-methylenedioxy-5H-2,3-benzo-
diazepine (2): To a solution of 1 (332 mg, 1.13 mmol) in MeOH (60 ml)/2 N
HCl (pH ¼ 3–4) NaBH3CN (35.1 mg, 5.61 mmol) was added. The mixture
was stirred at room temperature for 1 h and, after treatment with 10% KOH
(20 ml), was extracted with CHCl3 (2 Â 50 ml). The solvent was removed
in vacuo and the crude product was purified by silica gel column chromato-
graphy (eluant: CHCl3/MeOH 95 : 5) to afford 277 mg (83%) of 2.
Compound 2: Rf (CHCl3/MeOH, 95 : 5) 0.33; mp 116–118ꢁC; 1H NMR:
1.21 (d, 3H, J ¼ 6.2 Hz, CH3), 2.37 (dd, 2H, J ¼ 4.2 and 13.8 Hz, HA-5), 2.81
(dd, 2H, J ¼ 6.6 and 13.8 Hz, HB-5), 3.80 (br s, 2H, NH2), 4.11 (m, 1H, CH),
5.95 (m, 2H, OCH2O), 6.63 (d, 2H, J ¼ 8.7 Hz, H-30,50), 6.61 (s, 1H, H-6),
6.76 (s, 1H, H-9), 7.38 (d, 2H, J ¼ 8.7 Hz, H-20,60); 13C NMR: 20.85 (CH3),
38.62 (C-5), 63.43(C-4), 101.16 (OCH2O), 108.76(C-6), 109.28 (C-9), 114.41
(C-30,50), 128.18 (C-5a), 128.40 (C-10), 130.04 (C-20,60), 134.14 (C-9a), 145.76
(C-7), 147.66 (C-40), 147.99 (C-8), 163.35 (C-1); Anal. Calcd. for
C17H17N3O2: C, 69.14; H, 5.80; N, 14.23. Found: C, 68.95; H, 5.91; H, 14.49.
ACKNOWLEDGMENTS
This work was financially supported by CNR, 99.00987.CT03, (Rome,
Italy).
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Received in the Netherlands March 19, 2001

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