128
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 1, January, 2001
Reznik et al.
Table 2. Hypotensive and α-adrenolytic activity of some of the
compounds obtained
and the residue was distilled in vacuo to give compound 2c
(52.0 g, 67%).
2-(2-Fluorophenoxy)ethyl bromide (10).
A mixture of
Dosea
∆p
pA2
c
Com-
pound /mg kg
2-fluorophenol (112 g, 1 mol) and 1,2-dibromoethane (376 g,
2 mol) in 200 mL of water was heated to boiling, and a solution
of NaOH (40 g, 1 mol) in 500 mL of water was added dropwise
with stirring. The reaction mixture was refluxed for 7 h, and the
organic layer was separated, dried with MgSO4, and distilled to
give compound 10 (111 g, 51%).
O,S-Diethyl (3-chloropropyl)thiophosphonate (8a). Ethyl
chloro(3-chloropropyl)phosphonate (11a) (26.65 g, 0.13 mol)
was added dropwise at 1013 °C to a solution of ethanethiol
(8.06 g, 0.13 mol) and triethylamine (13.15 g, 0.13 mol) in
150 mL of anhydrous benzene. Then the reaction mixture was
heated at 60 °C for 4 h. The precipitate that formed was filtered
1
over the time (min)b
1
5
30
60
120
3a
2.50
1.25
1.25
1.25
1.25
0.5
52
40
52
36
46
45
46
60
49
47
41
20
14
35
20
29
25
8
16
8
15
23
15
41
23
8
9
6.3
6.3
7.4
6.2
7.8
7.8
6.6
3b
3c
3f
27
16
29
22
10
27
20
22
10
18
11
34
23
22
16
13
3h
3i
2.5
2.5
25
20
32
24
29
20
16
7
off, the filtrate was concentrated, and the residue was distilled
to give thiophosphonate 8a (13.8 g, 46%). IR (KBr), ν/cm
1040 (POC), 1224 (P=O).
9a
9b
9c
1.0
1.5
2.5
4.5
1
:
By analogy, ethyl (3-chloropropyl)(dimethylamido)phos-
phonate (8b) and ethyl (3-chloropropyl)(diethylamido)phos-
phonate (8c) were obtained from phosphonate 11a and di-
methyl- or diethylamine, respectively. The reaction of (3-
chloropropyl)phenylphosphoryl chloride (11b) with dimethyl-
amine yielded N,N-dimethyl-(3-chloropropyl)phenylphos-
phinamide (8d).
a Intravenous injection into rabbits.
b ∆p is the reduction in blood pressure (% from the initial level).
c Determined in the vessels of a rabbit's isolated ear.
ride 11b were obtained by the action of PCl5 on phosphonate 1a
and phosphinate 1c, respectively.
Ethyl chloro(3-chloropropyl)phosphonate (11a). Phospho-
rus pentachloride (104.1 g, 0.5 mol) was added in small portions
at 3035 °C to a solution of diethyl (3-chloropropyl)phos-
phonate (1a) (107.4 g, 0.5 mol) in 350 mL of anhydrous CCl4.
The reaction mixture was refluxed for 2 h until PCl5 was
completely dissolved. The solvent and POCl3 were removed in
vacuo (10 Torr), and the residue was distilled to give compound
11a (48.2 g, 47%).
O,O-Diisopropyl (3-chloropropyl)phosphonate (1b). Tri-
isopropyl phosphite (50 g, 0.24 mol) was added dropwise at
135140 °C to 1,3-bromochloropropane (75 g, 0.48 mol). The
reaction mixture was heated at this temperature for 3 h, with
removal of PriBr (20.1 g, 68%). The excess of 1,3-bromo-
chloropropane was removed, and the residue was distilled in
vacuo to give compound 1b (16.2 g, 28%). By analogy, ethyl
(3-chloropropyl)phenylphosphinate (1c) was obtained from di-
ethyl phenylphosphonite and 1,3-bromochloropropane in 62%
yield.
(3-Chloropropyl)phenylphosphoryl chloride (11b) was ob-
tained by analogy with compound 11a from ethyl (3-chloro-
propyl)phenylphosphinate (1c) and PCl5.
Diethyl {3-[2-(2-methylphenoxy)ethylamino]propyl}phos-
phonate (3a). A solution of diethyl (3-chloropropyl)phosphonate
(1a) (16.1 g, 0.075 mol) and 2-(2-methylphenoxy)ethylamine
(2a) (11.3 g, 0.075 mol) in 250 mL of anhydrous BunOH was
refluxed with anhydrous K2CO3 (10.4 g, 0.075 mol) and stirring
for 20 h. The precipitate that formed was filtered off, and the
BunOH was removed. The product was extracted with benzene
(2½50 mL). Vacuum distillation gave compound 3a (7.6 g, 31%).
Compounds 3bi were synthesized by analogy with 3a from
the corresponding 3-chloropropyl derivatives of phosphorus ac-
ids 1ad and 2-aryloxyethylamines 2ac.
Diethyl 3-{benzyl[2-(2-methoxyphenoxy)ethyl]aminopro-
pyl}phosphonate (5). A solution of phosphonate 3b (8.6 g,
0.025 mol) and benzyl bromide (4.3 g, 0.025 mol) in 150 mL of
anhydrous BunOH was refluxed with anhydrous K2CO3 (3.5 g,
0.025 mol) and stirring for 24 h. The precipitate that formed
was filtered off, the butanol was removed, and the residue was
chromatographed on Al2O3 in ether. The yield of compound 5
was 2.52 g (23%). IR (KBr), ν/cm1: 1035 (POC), 1255
(P=O), 1598 (arom.), 3035, 3070 (=CH).
O,O-Diethyl (3-chloropropyl)thiophosphonate (1d). A solu-
tion of sodium diethyl thiophosphite (prepared from diethyl
thiophosphite (30.8 g, 0.2 mol) and sodium (4.6 g, 0.2 mol) in
200 mL of anhydrous EtOH) was added dropwise with stirring
at 3035 °C to a solution of bromochloropropane (47.5 g,
0.3 mol) in 100 mL of anhydrous EtOH. The reaction mixture
was refluxed for 4.5 h. The precipitate that formed was filtered
off, and the filtrate was concentrated in vacuo (10 Torr). The
product was extracted with ether (300 mL). The ethereal solu-
tion was washed with water and dried with MgSO4. The ether
was removed, and the residue was distilled in vacuo to give
compound 1d (27.15 g, 59%). B.p. 7374 °C (0.002 Torr),
20
20
d4 1.1436, nD 1.4871 (see Ref. 11).
2-(2-Fluorophenoxy)ethylamine (2c).
A mixture of
2-(2-fluorophenoxy)ethyl bromide (10) (109.5 g, 0.5 mol) and
potassium phthalimide (97.1 g, 0.55 mol) in 400 mL of DMF
was stirred at 9095 °C for 5 h and then poured into 700 mL of
water. The precipitate that formed was filtered off, washed with
hot water, dried, and added to a solution of hydrazine hydrate
(25 g, 0.5 mol) in 500 mL of anhydrous EtOH. The resulting
mixture was refluxed for 1 h, 18% HCl (125 mL) was added in
portions of 25 mL, and stirring was continued at 90100 °C for
1.5 h. The precipitate that formed was filtered off, and EtOH
was removed from the filtrate. A 20% aqueous solution of KOH
was added with stirring to the crystalline residue until pH 10 was
reached. The product was extracted with CHCl3 (2½100 mL),
the extract was dried with MgSO4, the solvent was removed,
Benzyl[3-(diethoxyphosphoryl)propyl]methyl[2-(2-methoxy-
phenoxy)ethyl]ammonium iodide (6). A solution of phosphonate
5 (2.18 g, 5 mmol) and MeI (0.78 g, 5.5 mmol) in 50 mL of
anhydrous ethyl methyl ketone was heated at 6570 °C for
13 h. Then the reaction mixture was poured into 200 mL of
anhydrous ether. The resulting oil was separated, and
reprecipitated with ether from anhydrous ethyl methyl ketone
(40 mL). The yield of compound 6 was 1.42 g (49%).
Reznik
