Synthesis of Fluorobenzene Derivatives Containing Cyclopropane Ring 2002
Synthesis of Fluorobenzene Derivatives Containing Cyclopropane Ring 2002
2002
Spiperone D 2 antagonist. Cyclopropylation Spiperone Cyclopropyl, Cyclopropyl Spiperone 2. 9 4-Fluorobenzaldehyde Dithianation (93%), homoallylation (95%), DithianeDeprotection (74%), Epoxidation (92%), Cyclopropanation (33%) Mesylation (78%)6. 2 Mesylate 9 1-Phenyl-1,3,8- triazaspiro[4,5]decan-4-one 36%.
Abstract Spiperone has very strong binding affinity toward dopamine D2 receptor as an antagonist. Siperone, one of 4-fluorobutyrophenone neurotransmitter series, has fluorophenyl group. By using cyclopropylation reaction developed in this laboratory, a compound 2 having cyclopropyl group was designed as a target compound. The key intermediate 9 was synthesized in six steps from commercially available 4-fluorobenzaldehtde via dithanation (93%), homoallylation reaction (95%), deprotection of dithiane (74%), epoxidation (92%), cyclopropylation (33%), and mesylation (79%). The target compound 2 was prepared from mesylate 9 and 1-phenyl-1,3,8-triazaspiro[4,5]decan-4- one in 36% yield.
II.,,..,...,.,.
.,..... + 180 2...
SPECT. PET SPECT. PET. SPECT PET., D 1, D 2, D 3, D 4, D 5. camp K + Ca 2+. [ 18 F]-6-fluoro- DPA [ 11 C]DPA. D 2 quinpirole, phenothiazinebutyrophenone. [ 11 C]raclopride[ 11 C]N-methyl spiperone. D 2 PET, 18 F [ 18 F]spiperone[ 18 F]NMSP
[ 18 F]N-fluoroalkylspiperone, [ 18 F]FIDA. [ 18 F]FIDA D 2. SPECT 2 -iodospiperone (2 -ISP)4-iodospiperone (40ISP) D 2. 2-Iodolisuride SPECT iodobenzamide [ 123 I]IBZM. D 2 cyclopropane spiperone. N NH N F Spiperone: 1 F N N N H Target : 2
III. H a S S H b S S c F F F 3 4 5 d e F F F 6 7 8 H f F Ms g F N N N H 9 2
2-(4-Fluorophenyl)-1,3-dithiane (4) H S S H F 3 4 F : tetrahyrofuran (5 ml)1,3-propanedithiol (800 ml, 8.00 mmol) 0 o C borontrifluoride diethyletherate (1.00 ml, 8.00 mmol). 4-Fluorophenylaldehyde (710 ml, 7.00 mmol) 1 refluxing. TLC,. sodium bicarbonate methylene chloride (20 ml)3. Sodium sulfate. 4 (1.40 g, 93%) EtAcHexene. borontrifluoride diethyletherate.. 4.
. 1 H NMR (200 MHz, CDCl 3 ) δ 7.40-7.47 (m, 2H, Ar), 6.97-7.06 (m, 2H, Ar), 5.14 (s, 1H, CH), 2.85-3.13 (m, 4H, 2CH 2 ), 1.87-2.23 (m, 2H, CH 2 ); 13 C NMR (50 MHz, CDCl 3 ) δ 162.54 (d, J = 246.2 Hz), 135.06, 129.53 (d, J = 8.4 Hz), 115.62 (d, J = 21.7 Hz), 50.50, 32.06, 25.00; MS (CI) m/z 215 (MH + ). 2-(4-Fluorophenyl)-1-(1,3-dithian-2-yl)-4-pentene (5) S S H S S F 4 5 F : THF (5 ml)2-(4-fluorophenyl)-1,3-dithiane (300 mg, 1.40 mmol) 78 o C 1.6 M n-buthyllithium (1.05 ml, 1.68 mmol) 10. 4-Bromo-1-butene (140 µl, 1.40 mmol). -78 2.. methylene chloride (20 ml)
3. sodium sulfate. 5 (357 mg, 95%) flash chromatography (5% EtAc/Hx) oil. n-buthyllithium.. 1,3-dithiane. 1 H NMR (200 MHz, CDCl 3 ) δ 7.82-7.93 (m, 2H, Ar), 6.99-7.11 (m, 2H, Ar), 5.57-5.76 (m, 1H, CH), 4.85-4.97 (m, 2H, CH 2 ), 2.65-2.71 (m, 4H, 2CH 2 ), 1.90-2.12 (m, 6H, 3CH 2 ); 13 C NMR (50 MHz, CDCl 3 ) δ 164.10, 159.19, 137.30, 130.76, 130.60, 115.38, 114.96, 58.01, 44.16, 28.08, 27.53, 25.12; MS (CI) m/z 269 (MH + ). 1-(4-Fluorophenyl)pent-4-en-1-one (6) S S c F 5 F 6
: 2-(4-Fluorophenyl)-1-(1,3-dithian2-yl)-4-pentene (2.08 g, 7.75 mmol) 40mL cooper (II) oxide (740 mg, 9.30 mmol), copper chloride (2.50 g, 18.60 mmol). 1.27 ml of N,N-dimethylformamide. 75 o C 90. Ethyl acetate. saturated sodium bicarbonate, brine. sodium sulfate. 6 (1.02 g, 74%) flash chromatography (5% EtAc/Hx) oil. oil bath 75. Workup DMF saturated ammonium chloride ammonium chloridedmf. 1 H NMR (200 MHz, CDCl 3 ) δ 7.96-8.03 (m, 2H, Ar), 7.08-7.17 (m, 2H, Ar), 5.80-6.00 (m, 1H, CH), 4.99-5.13 (m, 2H, CH 2 ), 3.05 (t, 2H, J = 7.3 Hz, CH 2 ), 2.49 (q, 2H, J = 6.7 Hz, CH 2 ); 13 C NMR (50 MHz, CDCl 3 ) δ 197.63, 165.54 (d, J = 253.0 Hz), 137.03, 133.20 (d, J = 3.1 Hz), 130.51 (d, J = 9.1 Hz), 115.53 (d, J = 22.0 Hz), 115.26, 37.50, 27.96; MS (CI) m/z 179 (M+1 + ).
1-(4-Fluorophenyl)-3-oxiranyl-propan-1-one (7) F 6 d F 7 : Chloroform (7mL) 60 m- CPBA (462mg, 2.06mmol), sodium bicarbinate (289mg, 3.44mmol) 1-(4-fluorophenyl) -pent-4-en-1-one (306mg, 1.72mmol). 5. saturated sodium carbonate methylene chloride saturated sodium bicarbonate, brine. sodium sulfate,. 7 (306mg, 92%)flash chromatography (40% EtAc/Hx (1% TEA)) oil. Epoxide 1% epoxide.
1 H NMR (200 MHz, CDCl 3 ) δ 7.94-8.04 (m, 2H, Ar), 7.05-7.18 (m, 2H, Ar), 3.30-3.15 (m, 3H, 3CH), 2.76-2.81 (m, 1H, CH), 2.51-2.55 (m, 1H, CH), 2.11-2.26 (m, 1H, CH), 1.69-2.09 (m, 1H, CH); 13 C NMR (50 MHz, CDCl 3 ) δ 197.32, 165.72 (d, J = 253.0 Hz), 133.10, 130.58 (d, J = 9.5 Hz), 115.67 (d, J = 21.6 Hz), 51.43, 47.29, 34.40, 26.64; MS (CI) m/z 195 (MH + ). (4-Fluorophenyl)-(2-hydroxymethyl)cyclopropyl methanone (8) F F H 7 8 : Acetonitrile (1 ml)1-(4-fluorophenyl)-3-oxiranyl-propan- 1-one (47 mg, 0.24 mmol) tetra-nbutylammonium fluoride hydrate (92 mg, 0.29 mmol)triethyl amine (41 µl, 0.29 mmol). pressure bottle 120 o C 4. ethyl acetate3brine.
Na 2 S 4. 8 (15 mg, 33%)flash column chromatography (40% EtAc/hexane) oil. 1 H NMR (200 MHz, CDCl 3 ) δ 7.95-8.06 (m, 2H, Ar), 7.02-7.16 (m, 2H, Ar), 3.71-3.82 (m, 1H, CH), 3.45-3.54 (m, 1H, CH), 2.94 (s, 1H, H), 2.55-2.63 (m, 1H, CH), 1.80-1.95 (m, 1H, CH), 1.37-1.47 (m, 1H, CH), 1.00-1.09 (m, 1H, CH); 13 C NMR (50 MHz, CDCl 3 ) δ 198.02, 165.60 (d, J = 252.7 Hz), 134.07, 130.63 (d, J = 9.1 Hz), 115.51 (d, J = 21.7 Hz), 64.27, 27.60, 22.59, 15.54; MS (CI) m/z 195 (MH + ). 4-Fluorophenyl-(2-methanesulfonyloxycyclopropyl) methanone (9) F H F Ms 8 9 : methylene chloride (3 ml) 4-fluorophenyl-(2-hydroxy methyl-cyclopropyl)methanone (116 mg, 0.60 mmol) 0 o C
triethylamine (125 ml, 0.90 mmol) methanesulfonyl chloride (56 ml, 0.72 mmol)30 min. methylene chloride3. Na 2 S 4. 9 (127 mg, 78%) flash column chromatography (40% EtAc/hexane). TLC plate TLC plate34. 9. 1 H NMR (200 MHz, CDCl 3 ) δ 7.98-8.08 (m, 2H, Ar), 7.07-7.18 (m, 2H, Ar), 4.35-4.43 (m, 1H, CH), 4.02-4.14 (m, 1H, CH), 3.00 (s, 3H, CH 3 ), 2.69-2.78 (m, 1H, CH), 1.94-2.08 (m, 1H, CH), 1.48-1.57 (m, 1H, CH), 1.08-1.19 (m, 1H, CH); 13 C NMR (50 MHz, CDCl 3 ) δ 196.37, 165.77 (d, J = 253.4 Hz), 133.65, 130.75 (d, J = 9.5 Hz), 115.66 (d, J = 21.7 Hz), 71.53, 37.89, 23.15, 23.04, 15.58; MS (CI) m/z 273 (M+1 + ).
4-Fluorophenyl- 17 -(2-fluoromethylcyclopropyl)methanone (2) F Ms F N N N H 9 : Acetonitrile (3mL) 4-fluorophenyl-(2-methane sulfonyloxycyclo-propyl)methanone (60 mg, 0.22 mmol) 1- phenyl-1,3,8 triazaspiro-[4,5]decan-4-one (51 mg, 0.22 mmol)triethyl amine (37 µl, 0.26 mmol) 120 o C 4 h. 2 (35 mg, 36%) flash column chromatography (5% MeH/CH 2 Cl 2 ) oil. 1 H NMR (200 MHz, CDCl 3 ) δ 8.09-8.17 (m, 2H, Ar), 7.49 (bs, 1H, NH), 2 7.27-7.35 (m, 2H, Ar), 7.10-7.18 (m, 2H, Ar), 6.85-6.99 (m, 3H, Ar), 4.75 (s, 2H, CH 2 ), 3.17 (bs, 4H, 2CH2), 2.81 (bs, 4H, 2CH 2 ), 1.74-1.81 (m, 3H, 3CH), 1.52-1.57 (m, 1H, CH), 1.15-1.30 (m, 2H, 2CH); 13 C NMR (50 MHz, CDCl 3 ) δ197.34, 177.26, 163.24, 142.63, 133.88, 130.92 (d, J = 9.1 Hz), 129.43, 119.56, 115.66, 115.65 (d, J = 21.6 Hz), 60.69, 59.31, 58.57, 49.62, 48.53, 28.21, 23.97, 17.86.
IV. Epoxide 7baseintramolecular cyclopropane 8. Spiperone 7. 2 35%, 80%. 9mesyl1-phenyl-1,3,8-triazaspiro[4,5]decan-4- one Spiperone 2. cyclopropane 2.
V. Spectrum Data
1 H NMR (200 MHz, CDCl 3 ) 2-4(4-Fluorophenyl)-1,3-dithiane(4)
13 C NMR (50 MHz, CDCl 3 ) 2-4(4- Fluorophenyl)-1,3-dithiane(4)
1 H NMR (200 MHz, CDCl 3 ) 2-(4-Fluorophenyl)-1-(1,3-dithian-2-yl)- 4-pentene (5)
13 C NMR (50 MHz, CDCl 3 ) 2-(4-Fluorophenyl)-1-(1,3-dithian-2-yl)- 4-pentene (5)
1 H NMR (200 MHz, CDCl 3 ) 1-(4-Fluorophenyl)pent-4-en-1-one (6)
13 C NMR (50 MHz, CDCl 3 ) 1-(4-Fluorophenyl)pent-4-en-1-one (6)
1 H NMR (200 MHz, CDCl 3 ) 1-(4-Fluorophenyl)-3-oxiranylpropan-1- one (7)
13 C NMR (50 MHz, CDCl 3 ) 1-(4-Fluorophenyl)-3-oxiranylpropan-1- one (7)
1 H NMR (200 MHz, CDCl 3 ) (4-Fluorophenyl)-(2-hydroxymethyl)cyclopropyl methanone (8)
13 C NMR (50 MHz, CDCl 3 ) (4-Fluorophenyl)-(2-hydroxymethyl)cyclopropyl methanone (8)
1 H NMR (200 MHz, CDCl 3 ) 4-Fluorophenyl-(2-methanesulfonyloxycyclopropyl) methanone (9)
13 C NMR (50 MHz, CDCl 3 ) 4-Fluorophenyl-(2-methanesulfonyloxycyclopropyl) methanone (9)
1 H NMR (200 MHz, CDCl 3 ) 4-Fluorophenyl-17 -(2-fluoromethyl cyclopropyl) methanone (2)
13 C NMR (50 MHz, CDCl 3 ) 4-Fluorophenyl-17-(2-fluoromethyl cyclopropyl) methanone (2)
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