A method of synthesis of phosphinic acids on the basis of hypophosphites: VII. Synthesis of pseudo-γ-aminobutanoyl peptides and other phosphinic analogs of γ-aminobutyric acid

Article abstract of DOI:10.1134/S107036320809003X

A method of synthesis of pseudo-γ-aminobutanoyl peptides and other phosphinic analogs of γ-aminobutyric acid from hypophosphites is suggested. Silyl phosphonites formed by in situ addition of bis-(trimethylsilyl) hypophosphite to the corresponding α-substituted acrylates, styrene, or vinyl phosphonate used as unsaturated components in the synthesis react in situ with N-(ω-bromoalkyl)phthalimides by an Arbuzov reaction scheme, affording ω-(phthalimido)alkylphosphinic acids possessing β-substituted β-(alkoxycarbonyl)ethyl, β-phenylethyl, or β- (diethoxyphosphinoyl)ethyl substituents. Acid hydrolysis of these reaction products gives the target aminophosphinic acids: phosphinic analogs of γ-aminobutyric acid.

Full text of DOI:10.1134/S107036320809003X

ISSN 1070-3632, Russian Journal of General Chemistry, 2008, Vol. 78, No. 9, pp. 1655–1661. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © V.V. Ragulin, 2008, published in Zhurnal Obshchei Khimii, 2008, Vol. 78, No. 9, pp. 1422–1428.
A Method of Synthesis of Phosphinic Acids
on the Basis of Hypophosphites:
VII.1 Synthesis of Pseudo-γ-Aminobutanoyl Peptides
and Other Phosphinic Analogs of γ-Aminobutyric Acid
V. V. Ragulin
Institute of Physiologically Active Compounds, Russian Academy of Sciences,
Severnyi pr. 1, Chernogolovka, Moscow oblast, 142432 Russia
Received April 5, 2008
Abstract―A method of synthesis of pseudo-γ-aminobutanoyl peptides and other phosphinic analogs of γ-
aminobutyric acid from hypophosphites is suggested. Silyl phosphonites formed by in situ addition of bis-
(trimethylsilyl) hypophosphite to the corresponding α-substituted acrylates, styrene, or vinyl phosphonate
used as unsaturated components in the synthesis react in situ with N-(ω-bromoalkyl)phthalimides by an
Arbuzov reaction scheme, affording ω-(phthalimido)alkylphosphinic acids possessing β-substituted β-(alkoxy-
carbonyl)ethyl, β-phenylethyl, or β-(diethoxyphosphinoyl)ethyl substituents. Acid hydrolysis of these reaction
products gives the target aminophosphinic acids: phosphinic analogs of γ-aminobutyric acid.
DOI: 10.1134/S107036320809003X
γ-Aminobutyric acid (GABA) is the main
inhibitory neuromediator in the central nervous system
[2–5]. At present three classes of actively studied
GABA receptors have been identified: a, b, and c. (3-
Aminopropyl)methylphosphinic acid (SK&F97541)
and 3-(aminopropyl)phosphonous acid (СGP27492)
are the strongest GABAb agonists [4, 5]. The main
disadvantage of these compounds is their low ability to
penetrate the hematoencephalic barrier. Therefore, the
most prospective approach to search for effective
ligands for GABAb receptors is synthesis of phos-
phinic GABA analogs containing lipophilic fragments,
which would promote development of orally active
compounds [5]. Of interest mat prove a new approach
to search for effective ligands for GABAb receptors on
the basis of phosphinic acid analogs of GABA-
peptides: pseudo-γ-aminobutanoyl peptides I.
This method is based on the transformation of
hydrophosphoryl compounds into silyl esters of
trivalent phosphorus acids. With hypophosphites, two
phosphorus–carbon bonds can be formed in a one-pot
process [6–11]. Our proposed one-pot procedure
makes use of hypophosphite and two equivalents of
haloalkane and leads to formation of symmetrical di-
alkylphosphinic acids via two consecutive Arbuzov-
type reactions, with silylation of a hydrophosphoryl
intermediate [6–9]. The development of this meth-
odology by using α,ω-dihaloalkanes in excess
hexamethylenedisilazane [10] or the high-boiling
mesitilene as a solvent [11] allowed preparation of
cyclic phosphinic acids.
The one-pot procedure employing acrylates and
other unsaturated compounds for forming the first
phosphorus–carbon bond and haloalkanes in an
Arbuzov-type reaction for forming the second
phosphorus–carbon bond gave unsymmetrical
dialkylphosphinic acids [12–15]. The development of
this procedure by using dibromoethane and subsequent
simultaneous dehydrobromination and esterification of
In this work we suggest a synthesis of pseudo-γ-
aminobutanoyl peptides I and other phosphinic GABA
analogs as a development of the method of synthesis of
functionally substituted phosphinic acids
hypophosphites [6–11].
from
the intermediate acid with
provided vinylphosphinates of various structure [14–
triethyl orthofomate
1
For communication VI, see [1].
1655

1656
RAGULIN
17]. The latter compounds were found to be useful
objects for Michael addition of the amino acid
function; in this way, phosphinotricin and its analogs
[14], as well as γ-aminophosphinic acids (pseudo-γ-
glutamyl peptides) could be synthesized [15–17].
phosphorus–carbon bond, followed by the application
of N-(ω-bromoalkyl)phthalimides for forming the
second
phosphorus–carbon
bond. Such
a
methodology provides a new approach to new
effective ligands for GABAb receptors, specifically
phosphinic pseudo-γ-butanoyl peptides I or GABA-
pseudopeptides which are analogs of GABA-peptides
II (peptide isosters), where one peptide bond is
substituted by a hydrolytically stable methylenephos-
phoryl fragment.
The present work is devoted to further development
of this methodology over the application of activated
unsaturated compounds for forming the first
NH2
OH
3
R
NH2
HO
O
1
HO
O
P
2
N
H
O
R
O
I
II
Such substitution is a suitable imitation of a
substrate in the transition state of biological processes
involving at least two different classes of hydrolytic
enzymes: Zn–metalloproteinases and aspartic acid
proteinases [18–20]. The use in this procedure of
appropriately α-substituted acrylates allows synthesis
of corresponding pseudopeptides [19–21]. For
example, with ethyl acrylate as the unsaturated
component, pseudo-γ-aminobutanoylglycine {γ-Abu-ψ
(PO2CH2)Gly} (Iа) could be obtained; with ethyl
metacrylate, pseudo-γ-aminobutanoylalanine {γ-Abu-
ψ(PO2CH2)Ala} (Ib); with ethyl α-isobutylacrylate,
pseudo-γ-aminobutanoylvaline {γ-Abu-ψ(PO2CH2)
Val} (Ic); and with dimethyl itaconate, pseudo-γ-
aminobutanoylaspartate {γ-Abu-ψ(PO2CH2)Asp} (Id)
(Scheme 1).
For the unsaturated components we applied α-
substituted acrylates, styrene, and diethyl
vinylphosphonate. Bis(trimethylsilyl) hypophosphite
(III) adds in situ to the C=C bond of these compounds
to afford bis(trimethylsilyl) esters of [2-(ethoxycar-
Scheme 1.
X
OSiMe3
OSiMe3
P
(Me3Si)2NH
Y
[HP(OSiMe3)2]
H2POONH4
X
Y
IVа−IVe, IVi
III
(а) Br−(CH2)n−NPhth
(b) EtOH
O
O
O
P
(CH2)n
NH2
P
(CH2)n
N
HCl
A
B
X
OH
OH
O
Y
Iа−Ii
Vа−Vi
A = COOH, n = 3, B = H (Ia), Me (Ib), i-Bu (Ic), CH2C(O)OH (Id); A = Ph, B = H, n = 2 (Ie), n = 3 (If); n = 4 (Ih); A = P
(O)(OH)2, B = H, n = 3 (Ii); X = C(O)OEt, n = 3, Y = H (Va), Me (Vb), i-Bu (Vc); X = C(O)OMe, n = 3, Y = CH2C(O)
OMe, (Vd); X = Ph, Y = H, n = 2 (Ve), n = 3 (Vf), n = 4 (Vh); X = P(O)(OEt)2, Y = H, n = 3 (Vi).
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 78 No. 9 2008

A METHOD OF SYNTHESIS OF PHOSPHINIC ACIDS…: VII.
1657
bonyl)ethyl]phosphonous (IVa), [2-(ethoxycarbonyl)
propyl]phosphonous acid (IVb), [2-(ethoxycarbonyl)-
4-methylpentyl]phosphonous acid (IVc), [2,3-bis
(methoxycarbonyl)propyl]phosphonous acid (IVd), [2-
phenylethyl]phosphonous acid (IVe), and [2-
(diethoxyphosphinoyl)ethyl]phosphonous (IVi) acids
(Scheme 1).
propylphosphinate (Vi) (Scheme 2), gave a sym-
metrical bis[β-(diethoxyphosphinoyl)ethyl]phosphinate
(VI). The latter can be formed as a result of 1,2- or,
more probably, 1,4-addition of the second vinyl phos-
phonate molecule to intermediate bis(trimethylsilyl)-
[2-(diethoxyphosphinoyl)ethyl]phosphonite (IVi). The
product of this reaction can have the structure of silyl
phosphinate VII (Scheme 2, 1,4-addition) which can
be partially dealkylated due to reaction with
bromotrimethylsilane. The presence of the latter in the
reaction mixture is associated with the occurrence of
the target Arbuzov-type reaction of silyl ester IVi with
N-(3-bromopropyl)phthalimide, leading to unsym-
metrical phosphinate Vi. Therefore, after alcoholysis,
the reaction mixture containing silyl and ethyl esters
was treated with triethyl orthoformate, and both the
target phosphinate Vi and by-product symmetrical
ethyl bis[2-(diethoxyphophinoyl)ethyl]phosphinate
(VI) were isolated as ethyl esters by chromatography
on silica gel.
Silyl phosphonites IVa–IVd enter in situ an
Arbuzov-type reaction with N-(3-bromopropyl)
phthalimide to form 2-substituted [2-(alkoxycarbonyl)
ethyl][3-(phthalimido)propyl]phosphinic acids Va–Vd
(Scheme 1) whose hydrolysis provides 2-substituted
[2-(hydroxycarbonyl)ethyl][3-aminopropyl]phosphinic
acids Ia–Id.
The reactions of α-substituted acrylates with bis-
(trimethylsilyl) hypophosphite (III) were conducted
under mild conditions to suppress formation of bis-
adducts which, as we showed earlier [13], become the
main products at a certain reagent ratio and
temperature. In the case of styrene, the reaction
proceeded unidirectionally [12, 14, 22] to form bis-
(trimethylsilyl) (2-phenylethyl)phosphonite (IVe)
which reacted in situ reacts with the corresponding N-
(ω-bromoalkyl)phthalimide, affording target phos-
phinates Ve–Vh.
Hydrolysis of ω-phthalimidoalkylphosphinic acids
Va–Vi affords ω-aminoalkylphosphinic acids Ia–Ii
(Schemes 1 and 2) which can be considered as GABA
analogs, potential ligands for GABAb receptors con-
taining both lipophilic and hydrophilic substituents at
the phosphorus atom.
Thus, we suggested a general synthesis of
The reaction with diethyl vinylphosphonate
unsymmetrical ω-aminoalkylphosphinic acids, include-
provides, along with the target γ-(phthalimido)
Scheme 2.
HP(OSiMe3)2
III
O
P
O
O
SiMe3
O
O
OSiMe3
P
(EtO)2P(O)CH=CH2
(EtO)2P(O)CH=CH2
P
P
P
OEt
EtO
EtO
SiMe3
OSiMe3
OEt
OEt
OEt
IVi
VII
(a) Br−(CH2)3NPhth
−Me3SiBr
(b) EtOH
(a) EtOH
(b) CH(OEt)3
(c) CH(OEt)3
NPhth
NH2
OEt
P
O
O
O
P
O
O
O
P
P
P
HCl
EtO
EtO
P
P
OEt
HO
O
OEt
OH
OEt
OEt
OH
OEt
VI
Vi
Ii
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 78 No. 9 2008

1658
RAGULIN
ing pseudo-γ-aminobutanoyl peptides, starting from
ammonium hypophosphite.
mixture was then cooled to 25–30°С, and 0.036 mol of
freshly distilled α-substituted acrylate was slowly
added dropwise. After stirring at 40°С for 2–3 h
followed by adding 0.036 mol of N-(3-bromopropyl)
phthalimide, the mixture was stirred under reflux for 6-
7 h and cooled to room temperature. Alcohol, 30 ml,
was then slowly added dropwise with vigorous
stirring, and the mixture was refluxed for 20–30 min,
after which alcohol-insoluble admixture were filtered
off. The alcohol solution was evaporated, and the oily
residue was partitioned between 30–40 ml of ethyl
acetate and 10 ml of 0.1 N aqueous HCl. The organic
layer was additionally washed with water (10 ml),
dried over MgSO4, and evaporated in a vacuum. The
residue was dissolved in chloroform and passed
through a bed of Celite (20–30 ml), evaporated, and
the residue was subjected to chromatography on silica
gel (eluents chloroform and chloroform–isopropanol,
20:1–2) to isolate 2-substituted [2-(alkoxycarbonyl)-
ethyl][3-(phthalimindo)propyl]phosphinic acid Va–
Vd. Commonly, acids V were used for preparing target
amino acids I without further purification.
EXPERIMENTAL
1
The H and 31P NMR spectra were registered on
Bruker DPX-200 and Bruker CXP-300 Fourier
spectrometers against internal TMS and external 85%
H3PO4. The melting points measured on a Boetius-
PHMK device or in a block in an open capillary.
All reactions with silyl hypophosphites or
intermediate phosphonous acids were performed
under argon. All solvents were thoroughly dried. TLC
analysis of individual compounds and reaction
mixtures was carried out on Silufol (eluent
chloroform–acetone, 5–7 : 1), Alufol (Kavalier), and
Merck glass plates [UV-254 silica, layer thickness
0.2 mm; eluents ethanol–25% aqueous ammonia (4 : 1),
isobutanol–acetic acid–water (4 : 1 : 1), or, with amino
acids, pyridine–acetic acid–water–isobutanol (1 : 3 :
5 : 5)]. Amino acid were detected after spraying plates
with ninhydrin, followed by drying at 110°С.
Aminophos-phinic acids I were purified by ion-
exchange chromato-graphy on Dowex 50WX8-200
(H+) (Lancaster) and KUIKhT (H+) (Russian Institute
of Chemical Technology). Column chromatography of
ω-(phthal-imido)alkylphosphinic acids V was carried
out on Silpearl and Chemapol L100/160 silica gels.
Compounds V was purified by column chromato-
graphy on Celite filter aid (Lancaster) or a mixture of
Chemapol L100/160 silica gel and Brockmann neutral
alumina (80–90 : 20–10, by weight).
[2-(Ethoxycarbonyl)ethyl][3-(phthalimido)pro-
pyl]phosphinic acid (Va) was isolated pure and
characterized after additional crystallization from
ether. Yield 53% (per ammonium hypophosphite), mp
94–97°С. 1H NMR spectrum (CD3OD), δ, ppm : 1.15 t
(3Н, СН3), 1.72 m (2Н, CH2), 1.90 m (4Н, 2CH2), 2.47
m [2H, CH2C(O)], 3.66 t (2Н, СН2N), 4.00 q (2Н,
1
СН2O), 7.75 m (4Н, Ph). H NMR spectrum (CDCl3,
δ, ppm) : 1.23 t (3Н, СН3), 1.75 m (2Н, CH2), 2.02 m
(4Н, 2CH2), 2.60 m [2H, CH2C(O)], 3.77 t(2Н, СН2N),
4.10 q (2Н, СН2O), 6.85 br.s (1Н, POOH), 7.70 m
(2Н, Ph), 7.82 m (2Н, Ph). 31Р NMR spectrum, δP,
ppm: 52.9 (CD3OD), 57.9 (CDCl3). Found, %: C
54.52; 54.60; H 5.61, 5.58; P 8.65, 8.51. C16H20NO6P.
Calculated, %: C 54.39; H 5.71; P 8.77.
Ammonium hypophosphite was prepared by the
procedure in [23]. Hypophosphorus acid, potassium
phthalimide, hexamethyldisilazane, ethyl acrylate and
methacrylate, dimethyl itaconate, and styrene are
supplied by C-Reactor (Lancaster), ethyl α-isobutyl-
acrylate was purchased from Khimeks (St. Petersburg).
Diethyl vinylphosphonate was prepared by the earlier
described procedure using triethyl orthoformate for
esterification and dehydrobromination of bromoethyl-
phosphonic acid [24]. N-(2-Bromoethyl )-, N-(3-
bromopropyl)- and N-(4-bromobutyl)phthalimides were
synthesized as described in [25].
[3-(Phthalimido)propyl]phosphinic acids Va-Vd were
subjected to acid hydrolysis in 30–40 ml of 8 N HCl
for 13–15 h. The reaction mixture was extracted with
benzene, toluene, or chloroform (2 × 20 ml), the acidic
aqueous phase was evaporated, and the residue was
passed through a cation-exchange column (eluent 0.5–
1.0 N HCl). Fractions with a positive ninhydrin
reaction were collected and evaporated, and the residue
was crystallized from a mixture of acetone and 0.5–1.0 N
HCl. Free amino acids I were isolated by treatment of
the residue with excess propylene oxide in aqueous
alcohol.
Synthesis of pseudo-γ-aminobutanoyl peptides
Iа–Id with α-substituted acrylates as unsaturated
component. A mixture of 0.036 mol of ammonium
hypophosphite and 0.072 mol of hexamethyldisilazane
was stirred under reflux for 2 h [26, 27]. The reaction
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A METHOD OF SYNTHESIS OF PHOSPHINIC ACIDS…: VII.
1659
phthalimide was added in one portion at 25–30ºС
under argon. After stirring for an additional 8–10 h and
cooling to room temperature, 30–40 ml of alcohol was
slowly added dropwise with vigorous stirring. The
mixture was refluxed for 20–30 min, filtered, and
evaporated in a vacuum. The residue was partitioned
between 30 ml of chloroform and 10 ml of 0.1 N
aqueous HCl. The organic layer was washed with
water (2 × 10 ml), dried over MgSO4, concentrated in a
vacuum, and filtered through a bed (20–30 ml) of
Celite or a mixture of silica gel and alumina (eluent
chloroform). The eluate was evaporated in a vacuum
and additionally passed through silica gel (eluent
chloroform and chloroform–isopropanol, 20 : 1) to
isolate (2-phenylethyl)(ω-phthalimidoalkyl)phosphinic
acid Ve–Vh. Commonly, acids V were further used for
preparing target amino acids I without additional
purification. [2-(Phtalylimido)ethyl]- and [3-(phthal-
imido)propyl](2-phenylethyl)phosphinic acids Ve and
Vf were isolated pure and characterized after
additional crystallization.
(3-Aminopropyl)(2-carboxyethyl)phosphinic
acid (Ia) [pseudo-γ-aminobutanoylglycine γ-Abu-ψ-
(PO2CH2)Gly]. Yield 83% (per Vа), mp 135–137°С
1
(0.5 N HCl : acetone). H NMR spectrum (D2O), δ,
ppm : 1.55 m (2Н, СН2), 1.78 m (4Н, 2CH2P), 2.47 d t
[2H, CH2C(O)], 2.98 t (2Н, СН2N). 31P NMR spectrum
(D2O), δP, ppm : 43.7. Found, %: C 31.23; 31.31; H
6.48, 6.43; P 13.11, 13.23. C6H14NO4P·HCl. Cal-
culated, %: C 31.11; H 6.53; P 13.37.
(3-Aminopropyl)(2-carboxypropyl)phosphinic
acid (Ib) [pseudo-γ-aminobutanoylalanine γ-Abu-ψ-
(PO2CH2)Ala]. Yield 43% (per ammonium hypo-
1
phosphite), mp 121–123°С (0.5 N HCl + acetone). H
NMR spectrum (D2O), δ, ppm : 1.20 d (3Н, СН3; JHMe
7.33 Hz), 1.80 m (5Н, CH2CH2+ one of CHCH2P
protons), 2.15 d.d.d (1H, second of CHCH2P protons),
2.75 m (1Н, СНCOO), 2.95 t (2H, CH2N). 31P NMR
spectrum (D2O), δP, ppm : 53.3. Found, %: C 34.11;
34.17; H 7.08, 7.13; P 12.73, 12.77. C7H16NO4P · HCl.
Calculated, %: C 34.23; H 6.98; P 12.61.
(3-Aminopropyl)(2-carboxy-4-methylpentyl)-
phosphinic acid (Ic) [pseudo-γ-aminobutanoylvaline-
γ-Abu-ψ(PO2CH2)Val]. Yield 47% (per ammonium
hypophosphite), mp 117–119°C (1 N HCl + acetone).
1H NMR spectrum (D2O), δ, ppm : 0.60 d (3Н, СН3;
JHMe 7.3 Hz), 0.64 d (СН3; JHMe 7.3 Hz), 1.15 m [1Н,
СН(СН3)2], 1.30 m [2Н, СН2CH(СН3)2], 1.55–1.80 m
(6Н, CH2CH2PСН2), 2.95 m (1Н, СНCOO), 3.05 t
(2H, CH2N). 31P NMR spectrum (D2O), δP, ppm : 50.3.
Found, %: C 39.11; 39.17; H 8.31, 8.33;P 10.03, 9.89.
C10H22NO4P · HCl · H2O. Calculated, %: C 39.29; H
8.24; P 10.13.
(2-Phenylethyl)[2-(phthalimido)ethyl]phosphinic
acid (Ve). Yield 43% [per N-(2-bromoethyl)phthal-
imide], mp 118–121°С (ether–alcohol). 1H NMR
spectrum (CDCl3), δ, ppm : 2.17 m (4Н, 2СН2P), 2.94
m (2Н, CH2), 3.97d. t (2Н, CH2), 7.25 m (5H, Ph),
7.67 m (2Н, Ph), 7.82 m (2Н, Ph), 10.18 br.s (1Н,
POOH). 31Р NMR spectrum, δP, ppm: 55.0 (CDCl3),
42.6 (D2O + NaOD, pH 10). Found, %: C 62.81;
62.67; H 5.31, 5.51; P 8.83, 8.71. C18H18NO4P.
Calculated, %: C 62.97; H 5.28; P 9.02.
(2-Phenylethyl)[3-(phthalimido)propyl]phos-
phinic acid (Vf). Yield 47% [per N-(3-bromopropyl)-
phthalimide], mp 112–113°С (ether–alcohol). 1H NMR
spectrum (DMSO-d6 : CCl4, 1:3), δ, ppm: 1.58 m (2Н,
СН2), 1.83 m (4Н, 2СН2P), 2.78 m (2Н, CH2), 3.63 t
(2Н, CH2N), 7.22 m (5H, Ph), 7.80 m (4Н, Ph). 31Р
NMR spectrum, δP, ppm: 49.0 (DMSO + CCl4, 1:3).
Found, %: C 62.81; 62.67; H 5.31, 5.51; P 8.83, 8.71.
C18H18NO4P. Calculated, %: C 62.97; H 5.28; P 9.02.
(3-Aminopropyl)(2,3-dicarboxypropyl)phos-
phinic acid (Id) [pseudo-γ-aminobutanoylaspartate γ-
Abu-ψ(PO2CH2)Asp]. Yield 37% (per ammonium
1
hypophosphite), mp 215−217°С (H2O : EtOH). H
NMR spectrum (D2O, δ, ppm): 1.40−1.95 m (6Н,
3СН2), 2.60 m (СН2СОО), 2.90 t (CH2N), 2.90 m
(СHCOO). 31P NMR spectrum (D2O), δP, ppm: 42.2.
Found, %: C 35.29; 35.17; H 6.78, 6.83; P 11.33,
11.37. C8H16NO6P · H2O. Calculated, %: C 35.43; H
6.69; P 11.42.
Compounds V were subjected to acid hydrolysis in
40–50 ml of 8 N HCl for 13–15 h. After cooling, the
reaction mixture was extracted with 15–20 ml of
benzene, touene, or chloroform. The acidic aquoues
phase was evaporated, and the residue was passed
through a cation-exchange column (eluent 0.5–1.0 N
HCl). Fractions with a positive ninhydrin reaction were
collected, evaporated, and the residue was crystallized
from an acetone–0.5 N HCl mixture.
Synthesis of (ω-aminoalkyl)(2-phenylethyl)phos-
phinic acids Ie-Ih with styrene as unsaturated
component. A mixture of 0.036 mol of ammonium
hypophosphite, 0.036 mol of freshly distilled styrene,
and 0.072 mol of hexamethyldisilazane [12, 14, 22]
was stirred under reflux for 2 h. The reaction mixture
was then cooled, and 0.030 mol of N-(ω-bromoalkyl)-
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RAGULIN
1.28 t (3H, СН3), 1.32 t (6H, 2СН3), 1.80 m (2Н, СН2),
1.98 m (6Н, 3СН2P), 3.74 t (2Н, СН2N), 4.07 m (6Н,
3СН2O), 7.72 m (2Н, 2СН), 7.82 m (2Н, 2СН). 31P
NMR spectrum (CDCl3), δP, ppm: 31.1 d [1Р, P(OEt)2,
JPP 68.3 Hz], 55.3 d (1Р, CH2PCH2, JPP 68.3 Hz).
Subsequent elution with a chloroform–isopropanol
mixture (19:1) gave 0.6 g (16% per ammonium
hypophosphite) of ethyl bis[2-(diethoxyphosphinoyl)-
ethyl]phosphinate (VI) as a light yellow oil. 1H NMR
spectrum (CDCl3, δ, ppm): 1.28 t (15Н, 5СН3), 1.92 m
(8Н, 4CH2P), 4.03 m (10Н, 5CH2O). 31P NMR
spectrum (CDCl3, δP, ppm): 30.8 d [2P, P(OEt)2, JPP
69.0 Hz], 54.5 t (1P, CH2PCH2, JPP 69.0 Hz). Found,
%: C 39.77, 39.61; H 8.10, 8.13; P 21.53, 21.71.
C14H33O8P3. Calculated, %: C 39.82; H 7.88; P 22.00.
(2-Aminoethyl)(2-phenylethyl)phosphinic acid (Ie),
hydrochloride. Yield 83% (per Ve), mp 173–175°С
(1 N HCl : acetone). 1H NMR spectrum (D2O), d, ppm:
1.95 m (4Н, 2СН2P), 2.75 m (2Н, CH2), 3.07 m (2H,
СН2N), 7.21 m (5Н, Ph). 31P NMR spectrum (D2O), δP,
ppm: 54.4. Found, %: C 47.77, 47.50; H 6.39, 6.43; P
12.31, 12.17. C10H16NO2P · HCl. Calculated, %: C
48.11; H 6.86; P 12.41.
(3-Aminopropyl)(2-phenylethyl)phosphinic acid
(If), hydrochloride. Yield 78%, (per Vf), mp 169–
1
171°С (1N HCl : acetone). H NMR spectrum (D2O +
DCl), d, ppm: 0.95 m (4Н, 2СН2), 1.30 m (2Н, CH2),
1.98 m (2Н, CH2), 2.12 t (2Н, CH2N), 6.43 m (5Н,
Ph). 31P NMR spectrum (D2O + DCl), δP, ppm: 58.5.
Found, %: C 49.83, 49.94; H 7.30, 7.33; P 11.69,
11.61. C11H18NO2P · HCl. Calculated, %: C 50.10; H
7.26; P 11.75.
(3-Aminopropyl)[2-(dihydroxyphosphinoyl)-
ethyl]phosphinic acid (Ii). A mixture of 3 g of ester
Vi and 30 ml of 6 N HCl was refluxed for 11 h, cooled
to room temperature, and phthalic acid was filtered off.
The aqueous phase was extracted with benzene (3 ×
15 ml), evaporated, and the residue was passed
through a cation-exchanger column (eluent 0.5 N
HCl). Fractions with a positive ninhydrin reaction were
collected and evaporated, and the target amino acid
was crystallized from aqueous acetone. Yield 1.4 g
(71% per Vi), mp 183–188°С (foaming), 271–273°С
(melting with decomposition). 1H NMR spectrum
(D2O, pH 1), δ, ppm: 1.77 m (8Н, СН2), 2.92 t
(CH2N). 1H NMR spectrum (D2O, pH 9), δ, ppm: 1.27
m (2Н, СН2), 1.42 m (4Н, СН2), 1.65 m (2Н, СН2),
2.83 t (CH2N). 31P NMR spectrum (D2O, pH 1), δP,
ppm: 28.4 d (1Р, P(OH)2, JPP 66.4 Hz), 54.4 d (1Р,
CH2PCH2, JPP 66.4 Hz). 31P NMR spectrum (D2O, pH
9), δP, ppm: 22.3 d [1Р, P(OH)2, JPP 62.7 Hz], 46.7 d
(1Р, CH2PCH2, JPP 62.7 Hz). Found, %: C 20.83,
20.91; H 6.37, 6.11; N 4.83, 4.91, P 21.57, 21.53.
C5H15NO5P2 · HCl · H2O. Calculated, %: C 21.03, H
6.35, N 4.90, P 21.69.
(4-Aminobutyl)(2-phenylethyl)phosphinic acid
(Ih), hydrochloride. Yield 29%, (per ammonium
hypophosphite), mp 143–145°С (1N HCl–acetone). 1H
NMR spectrum (D2O), d, ppm: 0.8–1.10 m (6Н,
3СН2), 1.33 m (2Н, CH2), 2.05 m (2Н, CH2), 2.23 t
(2Н, CH2N), 6.25–6.45 m (5Н, Ph). 31P NMR
spectrum (D2O + DCl), δP, ppm: 60.5. Found, %: C
51.93, 52.10; H 7.51, 7.53; P 11.09, 10.91.
C12H20NO2P · HCl. Calculated, %: C 51.90; H 7.62; P
11.15.
Synthesis of ethyl [2-(diethoxyphosphinoyl)ethyl]
[3-(phthalimido)propyl]phosphinate (Vi) with vinyl
phosphonate as unsaturated component. A mixture
of 1.5 g (0.018 mol) of ammonium hypophos-phite and
8 ml (0.036 mol) of hexamethyldisilazane was stirred
under reflux for 2 h, cooled to 30–40С, and 2.8 ml
(0.018 mmol) diethyl vinylphosphonate was added
dropwise. The mixture was stirred at 80°С for 2 h
[15], cooled to room temperature, and 4.2 g (0.018 mol)
of N-(3-bromopropyl)phthalimide was then added in
one portion under a slow argon flow. The mixture was
stirred under reflux for 7 h, diluted with 20 ml of
alcohol, refluxed for 1 h, and then evaporated in a
vacuum. The residue was evaporated with benzene or
toluene (2 × 20 ml), after which 30 ml (0.33 mol) of
triethyl orthoformate was added, and the mixture was
refluxed with a Dean–Stark trap to remove the ethyl
acetate and alcohol formed. Excess triethyl ortho-
formate was removed, and the residue was chromato-
graphed on silica gel (eluent chloroform) to isolate 2.5 g
(36% per ammonium hypophosphite) of an oily
ACKNOWLEDGMENTS
The author is grateful to G.D. Shishko and L.F.
Rozhko for measuring certain physicochemical charac-
teristics and for elemental analysis of newly prepared
organophosphorus compounds, performed at the
Institute of Physiologically Active Compounds,
Russian Academy of Sciences.
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