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Download organic chemistry organic chemistry and more Lecture notes Organic Chemistry in PDF only on Docsity! Dual-Acting Small Molecules: Subtype-Selective Cannabinoid Receptor 2 Agonist/Butyrylcholinesterase Inhibitor Hybrids Show Neuroprotection in an Alzheimer’s Disease Mouse Model By Mohammad Sudqi Hamdan Organic pharmaceutical Chemistry Journal of Medicinal Chemistry 20080 pubs.acs.org/jmc Dual-Acting Small Molecules: Subtype-Selective Cannabinoid Receptor 2 Agonist/Butyrylcholinesterase Inhibitor Hybrids Show Neuroprotection in an Alzheimer’s Disease Mouse Model Philipp Spatz, Sophie A. M. Steinmuller, Anna Tutov, Eleonora Poeta, Axelle Morilleau, Allison Carles, Marie H. Deventer, Julian Hofmann, Christophe P. Stove, Barbara Monti, Tangui Maurice,* and Michael Decker* | Cite This: J. Med. Chem. 2023, 66, 6414-6435 E Read Online \\ (i) (a) oxalyl chloride, DMF, 0 °C, 1 h; (b) diethylamine, TEA, 0 °C to rt, 4 h; Were eee ee on othe —CO, x ye uly Hey | chlovde baie ef oxely ar ae sinnios OB) > Sie ie Cf oO cP - aff va Ae - alin c hou 2  OBn O NH oe Z wr ) 2-(4-(benzyloxy)phenyl)acetic acid, HBTU, TEA, DMF, rt, 3 h; NN. / =N —_ Ce N PFg ty 6 Nt : - ~ O ha oO” NY NS o oO N’ CLs N Cc Oo ao N [oN R yess oO N pa ea N \ J f —\ \ SS ne oN aN R ° RL \ HBTU t | Vos oO yd JL UR H2N—R = ait ‘ = *activated leaving group ‘ N=N | ed: = ! \ Urea Byproduct  OBn (v) acetic acid, 130 °C, 3 h; Scheme 2. Synthesis of Hybrid Set 2 (20a-e)“ HO NO. , MOMO NO, , MOMO NO, ,; NH» i, i, io _ii_, vy 78% : 66% y 99% N 59% 16 17 I 18 H 0 A 2 MOMO. NH ort vl 72% 4 aE Nr Mae R= o t mh H 19 21a-e D “Reagents and conditions: (i) MOMCI, potassium carbonate, DIPEA, acetone, 0 °C to rt, 4h; (ii) isopentylamine, TEA, EtOH, 55 °C, overnight (iii) hydrogen, Pd/C, EtOH, rt, overnight; (iv) 2-(4-ethoxyphenyl acetic acid, HBTU, TEA, DMF, rt, 2 h; (v) (a) acetic acid, 130 °C, 2h; (b trifluoro acetic acid, rt, 30 min; (vi) (a) cyclopropyl isocyanate, TEA, rt, overnight or (b) carbamoyl chlorides, NaH, THF, rt, 12 h or (c) 4 nitrophenylazetidine carboxylate, tert-butoxide, THF, 55 °C, 12 h. (i) MOMCl, potassium carbonate, DIPEA, acetone, 0 °C to rt, 4 h; MOMO NO, MOMO NO» _——— > wr & ' N 16 17 ro (ii) isopentylamine, TEA, EtOH, 55 °C, overni (v) (a) acetic acid, 130 °C, 2 h; (b) trifluoro acetic acid, rt, 30 min; (vi) (a) cyclopropyl isocyanate, TEA, rt, overnight or (b) carbamoyl chlorides, NaH, THF, rt, 12 h or (c) 4-nitrophenylazetidine carboxylate, tert-butoxide, THF, 55 °C, 12 h. Reduction of nitro group 2. Fe (Bechamp reduction), Sn or Zn + Acid • The use of (Metal) under acidic conditions (HCl / HOAc, NH4Cl)) • The Mechanism proceeds via electron transfer to give radical anions followed by protonation 3. SnCl2 + HCl The use of tin(II) chloride (SnCl2) provides a mild method for reducing nitro groups to amines in the presence of other reducible groups • Sodium sulfide can be a useful alternative for substrates where hydrogenation or acidic conditions are not compatible.  • Na2S can sometimes selectively reduce one nitro group in the presence of other nitro groups.  • Na2S generally does not reduce aliphatic nitro groups. 5. Zinnin reaction (Na2S) and Sulfur (S) rift a 70H ss O=N-S~ = Os, OH OH N-S-on a oO Hen Jo ; Ho"o:H OF O -H»,O a 4 ros i e. Os, 0" 5 ~ Na, Sg S.oy OH Son OH He + ars H On S-o4 OyS-220 - HO . “OH O OH OH : Geis Ho WA— HO isle HO {s)5 IV-b Tea aa Hoo) Hi fe) ay O5R 0H oe C8 oi! OH o un eso SSK O OH $ a Q=S-0- Vv OH vi H*| : HO, JH - Jou N oO. /N 6 Oo 0=S-0 o VII IX 2CsHsNO2 + 6S + 6NaOH ——+ 2CgHsNHz + 3NayS203 + HzO  H HO. 7 OH > UNG ss: Ne a Ar yt O ' TT ; N“O aa OH Ar On il Hees Ar _ I OH~ OH Hy O. \S u Ar . IV a ° oH Ss S=0 é or Ss” ~OH or | § ; Sy 9 N-Ar S=$=0 GaN HoH OH -s7=*oH Vv ! + EON OH Ar vi CgHsNO, + NaS. + HZO CgHsNH» + NaS203