Note: Descriptions are shown in the official language in which they were submitted.
lZZ0~78~
This invention relates to new 1,1,2-triphenyl-but-1-ene
derivatives which possess valuable therapeutically-
applicable properties.
British Patent Specification 1 013 907 discloses that
1,1,2-triphenyl-alkene derivatives possess anti-
oestrogenic properties and therefore they arP being
considered for treatment of hormone-dependent tumors.
One of them, (Z)-1-[4'-(2-dimethylaminoethoxy)phenyl]
-1,2-diphenyl-but-1-ene (Tamoxifen, INN rec.) has already
proven to have anti-oestrogenic properties in the therapy
of hormone-dependent mammary tumors.
In German Offenlegungsschrift (DE-OS) 2 807 599 it has
been established that a metabolite of Tamoxifen, (Z)-l-
[4'-dimethylaminoethoxy)phenyl]-1-(4'-hydroxyphenyl)-
2-phenyl-but-1-ene displays similar strong anti-
oestrogenic activity. This holds true also for a number
of (Z)-1-[4'-2-dimethylaminoethoxy)-phenyl]-1-(4'-
hydroxyphenyl)-2-phenyl-but-1-ene derivatives as described
in European Application 0 002 097. From German
Offenlegunsschrif~ (DE-OS)3 046 719 it emerges that
(E)-1-[4'-(2'alkylaminoethoxy)phenyl]-1-(3'hydroxyphenyl)-
2-phenyl-but-1-enes also possesses marked anti-oestrogenic
properties.
In a highly specific test procedure it has been
ascertained that a number of new l,1,2-triphenyl-but-1-
ene derivatives are clearly superior to Tamoxifen in their
anti-oestxogenic effect. As shown below, compounds of the
general formula (1) inhibit the growth of mammary tumor
cells much more strongly than Tamoxifen. This is in
keeping with their stronger binding affinity to estrogen
receptors.
--1--
1220787
The invention concerns 1,1,2-triphenyl-but-1-ene
derivatives of the general formula (1), whose
configuration corresponds to the E-form:
0-CH2CH2N(R )2 0-CH2CH2N(Rl)2
' 3 ~ ~
HO HO
E-Form 7.-Form
in which R in position 3' or 4' represents a methyl group,
methoxy group, hydroxy group or a halogen atom and R
represents a lower alkyl group. The lower alkyl group can
contain 1-4 C-atoms, preferably 1-3 C-atoms.
In this specification, the terms E-form and Z-form (E =
"entgegen" meaning "across"), (Z = "zusammen" meaning
"together") refer to the position of the 3'-hydroxyphenyl
group (priority 1 on the C-atom 1) relative to the
position of the substituted phenyl group (priority 1 on
C-atom 2) on the double bond in the butene chain
[Nomenclature rule: R.T. Morrison, R.N. Boyd, Lehrbuch
der Organischen Chemie, Verlag Chemie, page 167 (1974)].
The E- and Z-forms are clearly distinguished in their
proton resonance signals of the dialkylamino group and the
O-CH2 group in the -O-CH2CH2N(CH3)2 side chain. The
resonance signals of the E-form in the claimed compounds
are shifted to higher values compared to the Z-form.
[D.J. Collins, J.J. Hobbs and C.W. Emmers, J. Med. Chem.
14, 952 (1971)].
The invention also concerns a process for production of
compounds of general formula (1) characterised in that
carbinols of the general formula (2).
~Z20'787
O-CH 2CH2N ( R ) 2
~ ~ R (2)
R2_~
in which R in position 3' or 4' can be a methyl group,
methoxy group, acetoxy group, a halogen atom, or -OR'
where R' is an easily hydrolysable protective group, Rl
can be a lower alkyl group, and R represents an easily-
hydrolysable protective group, are dehydrated in a manner
known per se by the action of mineral acid, elimination of
the protective group, the E-form is isolated from the
resulting pair of isomers and optionally it is converted
to a therapeutically acceptable salt.
The easily hydrolysable protective group for R' and R2 is
preferably the tetrahydropyranyl residue. The elimination
of the protective group and the dehydration is achieved
successfully with mineral acid in an alcoholic medium,
preferably in ethanolic hydrochloric acid solution. The
separation of the pair of isomers can be carried out by
crystallisation or by chromotographic methods. According
to solubility, the free bases of acid-addition salts are
used for separation.
The starting materials needed for synthesis of the
compounds according to the invention can be produced by
the following process, for example:
--3--
~220787
By reaction of potassium phenylate with 2-chlorethyl-N,N-
dialkyl-ammonium chloride at elevated temperature in
ethanolic caustic potash solution and conversion of the
reaction product into the hydrochloride, compound (3) is
obtained.
(R )2NCH2CH20 ~ X HCl (3)
in which R has the same meaning as in Formula (2).
-3a-
~2207~7
In a Friedel-Crafts Reaction of compound (3) with
substituted phenylacetyl chlorides of the general formula
(4)
R
Cl-C0CH2 ~ (4)
in which R in position 3' or 4' can be a methyl group,
methoxy group, acetoxy group, a halogen atom, or -OR'
where R' is an easily hydrolysable protective group,
ethanones of general formula (S) are obtained
(R )2NCH2CH2o ~ C ~ CH2 ~ (5)
in which R has the same meaning as in formula (4) and
has the same meaning as in formula (2).
Compounds of the general formula (5) are converted with
ethyl bromide in dimethyl formamide in the presence of
sodium hydride to substituted butanones of the general
formula (6)
(Rl)2NCH2CH2o ~ & ~ CH ~ R
0 ICH2 (6)
CH3
in which R has the same meaning as in formula (4) and
has the same meaning as in formula (2).
Compounds of general formula (6) react in anhydrous
tetrahydrofuran with 3'-(2-tetrahydropyralyloxy)-phenyl
magnesium bromide to diatereomeric carbinols of the
general formula (7)
~2:~0~87
(R )2NC~2CH20 ~ ~ H)- CH ~ (7)
in wh;ch R has the same meaning as in formula (4) and Rl has the same
meaning as in formula (2).
Compounds of general formula (7) cleave off the tetrahydropyranyl
residue in the presence of mineral acid even at room temperature in
alcoholic solution and are converted by heat, with dehydration and -
optionally with elimination of a further protective group, to a pair
of isomers, from which the E-isomer in its salt form or its base form
can be isolated, so that compounds of general formula (1) in accord-
ance with claim 1 can be obtained.
The following compounds support the claims:
Table 1
o-CH2CH2N(R )2
OH
Compound R' R Melting Point
No. C (1)
.
1 -CH3 3~-CH3 169 (a)
2 -CH3 4~-CH3 168 (a)
3 -CH3 4'-OCH3133 to 134 (a)
4 -CH3 3'-OH 186 (b)
-CH3 4'-C1 161 to 162 (a)
6 -CH3 4'-Br 169 to 170 (a)
7 -C2H5 4'-OCH31-28 to 130 (c)
-
(1) Crystallised from : (a) acetone (b) ether/petroleum ether (c) acetonitrile
- 5 -
1220'787
The superiority of the claimed compounds is substantiated clearly in
highly specific test procedures.
a) Binding affinity to oestradiol receptors
The measurement of binding affinity to oestradiol receptors is carried
out according to the method of N. Devleeschouwer, G. Leclercq, A. Danguy
and J.C. Heuson ~Europ. J. Cancer, 14, 821 - 723 (1978)].
The uterus cytosol of female prepubertal white 2 kg heavy rabbits (New
Zealand type) was incubated for 18 hours at 4C with 2.5 x 10 9 M ~3H~-
oestradiol as well as with addition of unlabelled oestradiol (control)
or test substances at various concentrations. The binding affinity to
the oestradiol receptor is expressed as the concentration of unlabelled
oestradiol (control) or test substance added to the uterus cytosol which
achieved a 50 percent displacement of the L3H} oestradiol bound to
the oestradiol receptor.
Table 2
Binding affinity of the test substances
O-CH2CH2N(CH3)2
~J '~ 3
,
- 6 -
1220787
__ _
Compound R2 R ED50% ~M~
.
Oestradiol 1.8 x lO 9
(Control)
Tamoxifen H H 2.5 x lO 7
_
l OH 3~-CH3 3.5 x 10-8
2 OH 4~-CH3 7.3 x lO 8
3 OH 4'-OCH3 2.8 x lO 8
OH 4'-Cl 8.5 x lO 8
* Mola~ concentration of the substance which displaces 50% ~3H
oestradiol from the oestradiol receptor.
The affinity of the claimed compounds for the oestradio1 receptor is 3 to 9
times higher than with Tamoxifen.
b) Inhibition of RNA synthesis in isolated human breast tumor cells
Some years ago, it became possible to isolate oestrogen receptor positive
rER +J breast tumor cells from patients and to grow them continuously
in vitro. These so-called Cell Lines contain almost all the morpho-
logical characteristics and metabolic actiYities obserYed in vivo. There-
fore they represent an ideal model for testing anti-oestrogens, as direct
statements can be made about the influence on the cell types to be treated
in vivo.
1220787
To test anti-oestrogenic properties of the claimed compounds, oestrogenic
receptor positive human breast tumor cells of the cell line ZR-75-1 were
used, as described by Engel, L.W. et al C Linda W. Engel et al, Cancer Re-
search 38, 3352 - 3364 (1978)~. The influence of the claimed compounds on
the growth of these cells was monitored by the incorporation of labelled
uridine or thymidine according to the method of Lippmann, M. et al. ~Marc
Lippmann et al, Cancer Research 36, 4595 - 4601 (1976)~.
ZR-75-1 cells were incubated with Tamoxifen or with one of the claimed com-
pounds for 48 hours in concentrations of 4 x 10 6rMJto 1 x 10 7LM~, then
mixed with labelled uridine or thymidine and after one hour the incorpor-
oration rate of the labelled material into the cells was determined.
Table 3 shows the percentage inhibition of the cellular RNA-synthesis by
the claimed compounds in comparison to Tamoxifen.
To imitate conditions ~n vivo the potency of the anti-oestrogenic effect
of the claimed compounds was tested in the presence of an oestrogen.
ZR-75-1 cells were mixed simultaneously with one of the claimed compounds
in a concentration of 1 x 10 6 t M~ and with 17-g-oestradiol (1 x 10 8~M7),
after incubation for 48 hours labelled uridine or thymidine was added
and after one hour the rate of incorporation of the labelled material
into the cells was determined (Table 4).
8 .
~2207~7
Table 3
Percentage inhibition of RNA-synthesis in ZR-75-1 cells, in com arison
P
with Tamoxifen.
Concentrations of Substance
4 x 10 6 ~M7 1 1 x 10 6 ~M~ ~ 1 x 10 7 ~M~
Compound No. P e r c e n t a g e I n h i b i t i o n
1 100 74 47
Tamoxifen 100 44 29
2 100 62 42
Tamoxifen 100 39 16
3 100 68 36
Tamoxifen 99 43 13
100 73 33
Tamoxifen 100 44 29
.
100 61 41
Tamoxifen 100 39 16
6 .100 70 47
Tamoxifen 100 59 . 43
7 91 37 4
Tamoxifen 93 46 2
As appears from Table 3, the claimed compounds inhibit RNA-synthesis in
ZR-75-1 cells much more stron~ly from a dilution of 1 x 10 6 ~M~ than
Tamoxifen which has been taken as the comparative substance in each of the
tests concerned.
. .
_ 9 _
122078'7
Table 4
Percentage inhibition of RNA-synthesis in ZR-75-1 cells
-
Conce ~ntrations of Substance
Compound Compound + 17-~-oestradiol
1 x 10 6 CM~ 1 X 10 6 CM] 1 X 10 8~M~
_ _
Compound No. P e r c e n t a g e I n h i b i t i o n
_ _
1 74 74
_
2 62 58
3 68 65
4 73 . 79
6 70 74
7 37 41
As appears from Table 4, the claimed compounds inhibit the RNA -synthesis in
ZR-75-1 cells unhindered also in the presence of a relatively high concen-
tration of 17-~-oestradiol.
The compounds according to the invention therefore represent a valuableenrichment of the stock of medicines and can be used for treatment of malign
breast tumors.
- 10 -
1220787
The invention also concerns medicines wh;ch contain a compound of
general formula (1) as active ingredient as well as conventional
phanmaceutical carriers and adjuvants.
The cla;med compounds are preferably administered orally. Usually the
oral dose amounts to 0.01 to 0.2 9, preferably ~.02 to 0.1 9. Never-
theless it can under certain circumstances be necessary to deviate
from the above doses, dependins upon the individual behaviour with
respect to the medicament or the kind of fonmùlation and the point of
time or the interval at which the administration takes place. Thus it
can be sufficient in some cases to manage with less than the above
minimum amount, while in other cases the above-mentioned upper limit
must be exceeded. In the case of application of larger amounts, it
can be advisable to divide these into several individual doses through
the day. The active ingredient can be made up in conventional form for
oral administration e.g. in capsules, as tablets or as dragees. The
release of the claimed compounds can be accelerated or delayed according
to pharmaceutical adaptation.
By mixing with solid powdery-carriers such as micronised cellulose,
potato starch or maize starch, with additives such as sodium citrate
or calcium carbonate and binders such as polyvinyl pyrrolidone, gela-
tine or celtulose derivatives, optionally with addition of lubricants
such as magnesium stearate, sodium lauryl sulphate or polyethylene
glycols, they can be worked up into tablets or to dragee cores. Ob-
viously with the oral administration forms, flavour adjusting agents
can be added.
Two-part capsules, e.g. of hard gelatine, as well as closed soft
gelatine capsules with a softener such as e.g. glycerine are suitable
as other forms of administration. The push-together capsules contain
the active ingredient preferably as a granulate e.g. mixed with fillers
such as lactose, saccharose, mannite, starches such as e.g. potato
starch or amylopectin, celluose derivatives or highly dispersed sili-
cates. In soft gelatine capsules the active ingredient is dissolved
or suspended in suitable fluids, e.g. in plant oils or in fluid poly-
ethylene glycols.
1220~87
The production of the starting materials is carried out according to
known processes, such as described in part in German Patent Specifi-
cation (DE - PS) 3 046 719.
Production of the starting materials.
a) N,N-dimethyl-2-phenoxyethyl ammonium chloride.
117 9 (1.8 Mol) potassium hydroxide and 94.1 9 (1.0 Mol) phenol were
dissolved in 500 ml ethanol, mixed with a suspension of 144 9 (1.0 Mol)
2-chloroethyl-N,N-dimethyl ammonium chloride in 500 ml ethanol and heated
with vigorous stirring for 1 hour under reflux. After cooling the product
is drawn off from the precipitated potassium chloride, post-washed with
ethanol and the filtrate is concentrated under vacuum to dryness. The
residue is taken up with ether, washed several times with 10 percent
caustic soda solution, and then with water, and dried oYer sodium sul-
phate. By introduction of dry hydrogen chloride N,N-dimethyl-2-
phenoxyethyl ammon;um chloride is obtained, which can be recrystallised
from isopropanol. Colourless crystals of melting point 163C.
Yield 104.7 9.
b) 1- ~ 4'-2-dimethylaminoethoxy) phenyl~ -2-(subst. phenyl)-ethan-l-one.
20.1 9 (0.1 Mol) N,N-dimethyl-2-phenoxyethyl ammonium chloride
and 0.12 Mol of a corresponding substituted phenyl acetyl chloride in
1 1 dichloromethane are mixed in portions with 24.7 9 (0.18 Mol) anhy-
drous aluminium chloride at room temperature with vigorous stirring,
then warmed slowly and heated for 2 hours under reflux. After cooling
the mixture is poured onto ice, 100 ml concentrated hydrochloric acid
is added thereto, separation is effected and the organic phase is agi-
tated twice more with 10 percent hydrochloric acid. The united aqueous
solutions are made alkaline and extracted three times with 200 ml ethyl
acetate each time. After washing with water and drying over sodium
sulphate the solvent is distilled off under vacuum and the resulting
1- L4'-(2-dimethylaminoethoxy) phenyl~ -2-(subst. phenyl)-ethan-l-one
is re-crystallised out of petroleum ether.
12207~7
c) 1- r4'-(2-dimethylam-noethoxy~henyl~ -2-(subst.phenyl)-butan-1-one
The preparation is carried out by reaction of a corresponding 1- r4'-
2-dimethylaminoethoxy)phenyl~ -2-(subst. phenyl)~than-l-one with ethyl
brom;de and sodium hydride in anhydrous dimethyl formamide as described
in detail ;n Ger~an Patent Specification (DE-PS) 3 046 719 (Example~
d) 1- ~4'-(2-dimethylaminoethoxy)phenyl] -2-(subst. phenyl-
1- C3'-(2-tetrahydropyranyloxy)phenyl~-butan-1-ol (Diastereomers)
The preparation is carried out by reaction of the 1- ~4'-(2-dimethylamino-
ethoxy)phenyl~ -2-(subst. phenyl)butan-l-one with 3'-(2-tetrahydro-
pyranyloxy)phenyl magnesium bromide in anyhydrous tetrahydrofuran, as
described in detail in German Patent Specification (DE-PS) 3 046 719
(Example le).
The claimed process is described in more detail below by way of pro-
duction Examples.
Example 1
Production according to the invention of
(E)-l- [4'-(2-dimethylaminoethoxy)phenyl~ -1-(3'hydroxyphenyl)-2-
(4'-methoxyphenyl)-but-1-ene (Compound No. 3).
51.9 9 (0.1 Mol) of the diastereomer mixture of l-t4'-(2-dimethylamino-
ethoxy)phenyl~ -2-(4'-methoxyphenyl)-1- ~ 3'-(2-tetrahydropyranyloxy)
phenyl~ -butan-l-ol in 1.5 1 ethanol are mixed with 60 ml concentrated
hydrochloric acid and heated for 2 hours under reflux. Then the solvent
is removed under vacuum, and the residue is suspended in 200 ml dilute
ammonia solution and agitated twice with 250 ml ethyl acetate each timè.
The organic phase is washed to a neutral state with water and after drying
over sodium sulphate the solvent is removed under vacuum. The residue is
crystallised out of acetone. Colourless crystals of melting point 133 -
134C; Rf 0.35 CHC13/CH30H (7/3); yield 8.34 9 (20%).
- 13 _
1220'78~
C27H31N3 (417-5) Calculated C 77.66 H 7.48 N 3.36
Found C 77.45 H 7.52 N 3.31
Molecular Weight 417 (determined by mass spectrometry)
IR-Spectrum (KBr) r(0-H) 3650 to 2600 om 1
H-NMR-Spectrum *
(CDC13) : 0.90 t (3) CH3 C J=7.0
2.33 s (6) (C-3)2N
2.43 to 2.87 m (4) CH2 and CH2N
3.63 to 4.10 t (5) CH20 and CH30
and 3.80 s
5.23 wide s (1) OH Cinterchangeable with D20
6.33 to 7.47 m (12) Aromatics-H
* Taken at 60 MHz; the chemical shifts are given in ppm against TMS (=0.0),
the relative intensities are enclosed-in brackets. s = singlet; d = doublet;
t = triplet; m = multiplet; J = coupling constant in Hz. ~ = 0Ø
Example 2
Production according to the invention of
~ 1- L4'-(2-dimethylaminoethoxy)phenyl~ -1,2-bis-(3'-hydroxy-phenyl)-
but-l-ene (Compound No. 4)
58.9 g (0.1 Mol) of the diastereomer mixture of l-L 4'-(2-dimethylamino-
ethoxy)phenyl~ -1,2-bis- ~ 3'-2(tetrahydropyranyloxy)-phenyl~ -butan-l-ol
in 1 ~.95 percent ethanol is mixed with 30 ml concentrated hydrochloric
acid, then heated for 2 hours under reflux and worked up as in Example 1.
Colourless light-sensitive crystals of melting point 186C ~ ether/
petroleum ether 1/1)] ; Rf 0.20 ~ CHC13/CH30H (7/3)1 ; yield 24.2 g (60~).
- 14-
12207~7
C26H29N03 (403.5) Calculated C 77.39 H 7.24 N 3.47
Found C 77.53 H 7.39 N 3.44
Molecular Weight 403 (detenmined by mass spectrometry)
IR-Spectrum (KBr) y(OH) 3600 to 2300 cm 1
H-NMR-spectrum
(d6-DMSO) 0.83 t (3) CH3 ~ J=7.0
2.17 s (6) (CH3)2N
2.33 to 2.73 m (4) CH2 and C~ N
3.90 t (2) CH20 rJ=6.0
6.40 to 7.43 m (12) Aromatics-H
9.33 wide s (2) OH [interchangeable with D20
Example 3
Production according to the invention of
(E)-2-(4'-bromophenyl)-1-~ 4'-(2-dimethylaminoethoxy)phenyl~ -1-
(3'-hydroxyphenyl)-but-1-ene (Compound No. 6).
56.8 9 (0.1 Mol) of the diastereomer mixture of 2-(4'-bromophenyl)-1-
~ 4'-(2-dimethylaminoethoxy)phenyl~ 3'-(2-tetrahydropyranyloxy)-
phenyl~ -butan-l-ol in 500 ml ethanol are mixed with 25 ml concentrated
hydrochloric acid, then heated for 2 hours under reflux and worked up
as in Example 1. Colourless crystals of melting point 169 to 170C
~ acetone~ ; Rf 0.30 ~CHC13/CH30H (7/3)] ; yield 30.3 9 (65%).
: - 15 -
1Z2(~7~7
C26H28BrN02 (466.4) Calculated C 66.95 H 6.05 N 3.00
Found C 66.71 H 5.88 N 3.02
Molecular Weight 465 * ~determined by mass spectrometry~
IR-Spectrum ~KBr) y(O-H) 3600 to 2400 cm 1
1 H-NMR-spectrum
(d6-DMSO) : 0.83 t (3) C ~ [J=7.
2.23 s (6) (CH3)2N
2.30 to 2.73 m (4) CH2 and CH2N
3.93 t (2) CH20 CJ=6.01
6.50 to 7.60 m (12) Aromatics-H
9.43 s (1) OH ~interchangeable with D20
* Molecular weight with Bromisotope 79.
Example 4
Medicament containing
(E)-1-~ 4'-dimethylaminoethoxy)phenyl~ 1-(3'-hydroxyphenyl)-2-
(3'-methylphenyl)-but-1-ene-hydrochloride.
21.82 9 powdered (E)-l- ~4'-t2-dimethylaminoethoxy)phenyl~ -1-(3'-
hydroxyphenyl)-2-(3'-methylphenyl)-but-1-ene- hydrochloride are blended
with 40 g lactose and 140 9 starch, then mixed with 33 9 talc and 13 9
calcium stearate, and after careful thorough mixing, the mixture is filled
into two thousand hard gelatine capsules of suitable size so that each
capsule contains 10 mg active ingredient (calculated as free base).
16 -
lZ20~7B7
Example 5
Medicament containing
(E)~ 4'(2-dimethylaminoethoxy~phenyl~ -1-(3'-hydroxyphenyl)-2-
(4'-methoxyphenyl)-but-1-ene.
20.0 9 finely powdered (E)-l- ~4'-(2-dimethylaminoethoxy)phenyl] -1-
(3'-hydroxyphenyl)-2-(4'-methoxyphenyl)-but-1-ene, after blending with
111 9 mannite, 15 9 maize starch and 6 9 alginic acid, is granulated and
the dried granulate after careful blending with 0.75 9 methyl cellulose
and 1.5 9 magnesium stearate is compressed into one thousand tablets, so
that each tablet contains 20 mg active ingredient.
Example 6
Production according to the invention of
(E)-1-~4'-(2-diethylaminoethoxy) phenyl]-1-(3'-hydroxyphenyl)-2-
(4'-methoxyphenyl)-but-1-ene (Compound No . 7)
For preparation of the N,N-diethyl-2-phenoxyethyl amnonium chloride,
117 9 (1.8 Mol) potassium hydroxide and 94.1 9 (1 Mol) phenol in 1 1
ethanol are reacted with 172 9 (1.0 Mol) 2-chloroethyl-N,N-diethylamn;onium
chloride, as described above under a). Colourless crystals with a melt-
ing point of 136 - 137C are obtained from isopropanol in a yield of 79 9.
In an analogous manner to that described in b) above or in DE-PS
30 46 719, the 1-t4'-(2-diethylaminoethoxy)phenyl]-2-(4'methoxyphenyl)-
1- C3'-(2-tetrahydropyranyloxy)phenyl~ -butan-l-ol is prepared therefrom.
54.7 9 (0.1 Mol) of the diàstereomeric mixture of 1- C4'-(2-diethylamino-
ethoxy)phenyl~ -2-(4'methoxyphenyl)-1- r3'-(2-tetrahydropyranyloxy)-phenyl]
-butan-l-ol in 1 1 ethanol are reacted with 30 ml conc. hydrochloric acid,
then heated for 2 hours under reflux and worked up as described in Example
1. Colourless light-sensitive crystals of melting point 128 - 130C
(acetonitrile); Rf 0.46rbenzene, triethylamine (94/6)~; yield 7.6 9 (20%).
12207~7
C29H35N3 (445.6)
Molecular weight 445 (determined by mass spectrometry)
H-NMR-spectrum :0.70 to 1.23 m (9~ 3CH3
(CDC13) 2.23 to 2.97 m (8) 3CH2N and C=CCH2
3.67 to 4.03 t
and 3.73 s (5) CH20 and CH30
- 6.27 to 7.30 m (12) Aromatics-H
7.8 s (1) OH Cinterchangeable with D20
- - 18 -
