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New Prostacyclin Analogues.

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According to preliminary kinetic measurements the rate of
hydrogenation is nearly proportional to the concentration of
chromium or titanium catalyst and corresponds to a reaction
of first order referred to magnesium[']. In the case of the
chromium catalyst (0.086 mol Cr/l) the rate of hydrogenation increases only slightly with increasing hydrogen pressure between 5 and 80 bar.
The following experimentally verified reactions may be regarded as possible steps of the homogeneously catalyzed hydrogenation of magnesium: (i) metallic magnesium reacts
with anthracene in THF at 20°C or above in the molar ratio
1 : 1 to give orange, sparingly soluble anthracenemagnesium
(2) [eq. (a)]; (ii) in the reaction of (2) with CrC& or TiC1, in
THF, which leads to formation of the catalytically active
species, free anthracene (1) is formed leq. (b)]; (iii) in presence of the dissolved chromium or titanium catalyst, (2) is
hydrogenated by hydrogen (at 30-60 "C/80 bar) to magnesium hydride [eq. (c)], with liberation of anthracene (1) (only
small amounts of 9,lO-dihydroanthracene were detected).
O(Ti)-cat.
A
CAS Registry numbers:
(11, 120-12-7; MgH2, 7693-27-8: CrCII, 10025-73-7; TiCI,, 7550-45-0
[I] a) E. Wiberg, H. Goeltzer, R. Bauer, Z. Naturforsch. B 6. 394 (1951): b) T N.
Dymowa. Z . K . Sterlyadkina, V. C Safronov. Zh. Neorg. Khim. 6. 763 (1961);
Chem. Abstr. 55, 23 144 (1961): c) J. Bousquet, J:M. Blanchard. B. Bonneror,
P. Claudy, Bull. SOC.Chim. Fr. 1969, 1841; d) C. M. Slander, J . Inorg. Nucl.
Chem. 39, 221 (1977); e) M. H. Minrz, 2. Gavra, 2. Hadari, ibid. 40, 765
(1978).
121 a) J. J. Reilly, R. H. Wiswall. Inorg. Chem. 6. 2220 (1967); b) ibid. 7. 2254
(1968); c) R. H. Wiswall, Top. Appl. Phys 29, 201 (1978); d ) J. J Reilly in:
Hydrides for Energy Storage. Pergamon Press. Oxford 1978, p. 301
[3] a) J. J. Reilly, R. H. Wiswall, Proc. 7th IECEC Conf. (Am. Chem. SOC.)1972.
1342: b) D L. Douglass. Metall. Trans. 6 A , 2179 (1975); c) see ref. [Zd], therein p. 151: d ) B. Tanguy, J:L. Soubeyroux. M Pezat, J. Porrier. P. Hagenmuller, Mater. Res. Bull 1 1 , 1441 (1976); e) B. Darrier. M . Pezar. A. Hbika.
P. Hagenmuller. ibid. 14, 377 (1979): f) M . H. Minrz. S. Malkielv. Z . Gavra.
Z . Hadari. J. Inorg. Nucl. Chem. 40. 1949 (1978).
141 a) J. C. Sn-vder, US-Pat. 3485585 (1969); Chem. Abstr. 72.45603 (1970); b)
the hydrogenation of Mg at 20"C/I bar in T H F with a VCI,/Mg catalyst in
T H F has been reported: B. Jezowska-Trzebiarowska,P. Sobora, J. Utko, Bull.
Acad. Pol. Sci. Ser. Sci. Chim 24. 331 (1976): this catalyst system. however.
rapidly becomes inactive.
[ S ] H. E. Ramsden, US-Pat. 3354190 (1967).
[6] B. Bogdanovic. DOS 2 804445 (1979), Studiengesellschaft Kohle: Chem
Abstr. 91, 159787 (1979).
[7] The kinetic measurements were carried out in a 2 I autoclave fitted wtth stirrer.
[8] The filtration IS laborious; a much quicker filtration, particularly in experiments on a larger scale (up to 0.7 kg Mg), is possible with a pressure filter
(Polypropylene cloth 2832, Verseidag).
[9] The procedure for the production of MgHz with TiCI, or FeCI2 is analogous;
the product is somewhat coarser and more easily filterable
MgHz + ( I )
THF
New Prostacyclin Analogues
The reaction sequence eq. (a) and eq. (c) represents a catalytic cycle of magnesium hydrogenation via anthracenemagnesium (2) as intermediate. This assumption is supported by
the experimental finding that the hydrogenation of (2) [eq.
(c)] according to our method is considerably faster than the
hydrogenation of elemental magnesium.
Thus, in this method a magnesium hydride/magnesium
system is obtained which, because of the high dehydrogenation/hydrogenation rate (at 200-350 "C/1-50
bar) and
high content of reversibly bound hydrogen in the magnesium
hydride so produced (ca. 7 wt-W), is particularly suitable as a
hydrogen storage system.
By Wilhelm Bartmann, Gerhard Beck, Jochen Knolle, and
R. Helmut Rupp'']
Dedicated to Professor Rorf Huisgen on the occasion of
his 60th birthday
Prostacyclin (PGI,) (1)I'l has been found in animal and
human experiments to lower the blood pressure and to hinder platelet aggregation after intravenous administrationl2I.
Since it is less rapidly biologically deactivated than the "classical" prostaglandins E2 and FzUit has been considered as a
circulating hormone affecting the cir~ulation~~!
Aqueous solutions of pure (1) have a halflife of only 3 min
at pH 7.5 and 37"CL41;(1) is hydrolyzed to 6-0x0-PGF,,,
Procedure
(4.
All reactions carried out under argon. A suspension of
magnesium powder (73.2 g, 3.0 mol) (Riedel-de Haen) in anhydrous THF (350 ml) is treated with ethyl bromide (0.3 ml)
and, after 30 minutes' stirring, with 5.35 g (30.0 mmol) of (1).
After three hours' stirring (during which time (2) is formed)
anhydrous CrCl, (4.75 g, 30.0 mmol) is added and stirring
continued for a further 15-30 min until cessation of the
weakly exothermic reaction. The olive-green suspension is
transferred to a I 1 autoclave fitted with glass insert and magnetic stirrer and hydrogenated at 60-65 "C external temperature and a H,-pressure of 80 bar; the rate of hydrogenation
(Fig. 1) is measured via the drop in pressure in a hydrogen
storage vessel. On completion of reaction the light-gray suspension is filtered through a glass frit (D4, diameter 9 crn)['I,
and the MgH, washed twice with THF and pentane and
dried in a high vacuum at 20 " C .One obtains 76.0 g of a pyrophoric magnesium hydride which is free from elemental
magnesium; according to the elemental analysis and the
amount of hydrogen liberated by hydrolysis the MgHz is ca.
94% pure (rest: THF, MgCl,, catalyst['].
Received: May 14. 1980 [Z 581 b I€]
German version: Angew. Chem. 92, 845 (1980)
Angew Chem In1 Ed. Engl 19 (iYX0) No 10
f
OH
OH
(1)
'
OH
(2)
OH
It has been a preparative goal of various laboratories to
synthesize chemically more stable analogues of (l)f5].As far
as can be seen, the biological action of (1) is closely connected with the electronic and steric parameters of the enol
ether structure. Prostacyclin analogues differing considerably from the natural product in this partial structure are biologically less active@].
[*] Dr. W Bartmann. Dr. G. Beck, Dr. J. Knolle. Dr. R. H. Rupp [
'1
Hoechst AG
Postfach 800320, 6230 Frankfurt/M. 80 (Germany)
[ '1 To whom correspondence should be addressed
0 Verlag Chemie. GmbH, 6940 Weinherm, 1980
0S70-0833/X0/lO10-0R19
S 02 50/0
819
A
,,
M
(4hj, X * S
(4ej, x = NH
We now wish to describe the synthesis of prostacyclin analogues (22), (24), and (26) in which the enol ether structure
(3) has been replaced by a P-hetero-imino group (4).
Replacement of the C - C double bond by a C-X single
bond should permit adoption of conformations resembling
the Z-configuration of the natural product. It was expected
that compounds having the partial structures (4b) and (4c)
would be more resistant to acids than (1).The starting material for the synthesis should be industrially available.
x
0
:
&OTHP
-
H?
--CONH2
L O T H P
OR'
+
C-CONH,
O'$V
OC H2Ph
OTHP
OC H2Ph
(8)
7)
R' = H
16j, R' = C Hz P h
(5j,
Ub A c R
OAc
i l X j , R4 = A c
1
1
<
foZH
$
C O ~ R ~
C O ~ R ~
i4
S
'Y
q$
6 6R4 R
(211. R4 = A c ,
R5 = CzH5
(2-7). R4 = H,
R5
(ZO), R4 = A c
i l Y ) , R4 = A c
i
=
b R4
OR4
123/, R4 = A c ,
R S = C2H5
( 2 4 ) , R4 = H,
CH,
R5
=
(.?.5j>
R4 = A c
(261, R4 = H
CH,
CH3
R =
OR4
Scheme 1.
820
Scheme 1 shows the transformation of the known synthon
into the analogues (22), (24), and (26).
After protection of the aIcohoI function in (5) (benzyl
bromide/sodium hydride/50 "C) the lactone (6) is aminolyzed in methanol (autoclave, 36 h/130 "C/ammonia) and
the resulting hydroxyamide (7) oxidized according to Jones
to form the oxoamide (8) (Cr03/H20/H2S04/acetone/
- 20 "C). Compound (8) slowly tautomerizes to the hydroxylactam (9). Mild removal of the hydroxy group is accomplished by conversion of (9) into the phenylthio compound
(10) which is also directly accessible from (8) (C6H5SH/
C1Si(CH3)3/pyridine/CH2C12/reflux).Compound (10) can
be desulfurized at room temperature with Raney nickel in
fert-butyl alcohol to form (11) which gives the alcohol (12)
on keeping for 5 h at 50 "C or on treatment with Pd/C/hydrogen in methanol at 25 "C.
After esterification of the alcohol function of (12) to form
(13) (AczO/pyridine/5 "C) and methanolysis of the tetrahydropyranyloxy group (CH30H/p-toluenesulfonic acid/
25 "C) compound (14) is oxidized to (1.5) (dimethyl sulfoxide/oxalyl chloride/CH,Cl,/ - 60 "C) and the crude product
condensed according to Horner-Emmons-Wittig with dimethy1 (2-oxohepty1)phosphonate to produce the enone (16)
(NaH/dimethoxyethane (DME)/25 "C). Reduction to ( I 7)
and its esterification (Ac20/pyridine/5 "C) led to the diacetate (18), which affords the lactim ether (22) on reaction with
ethyl o-bromobutyrate (Ag20/xylene/120 "C) followed by
removal of the acetate groups (K2C03/CH30H/25" C ) from
the product (21).
The thiolactim ether (24) can be obtained by transformation of (18) into the thiolactam (19) (P4SIo.4pyridine/pyridine/80 "C), alkylation with ethyl o-bromobutyrate (NaH/
DME/25 "C) to form (23) and removal of the acetate groups
(KzCO3/CH30H/25 "C).
The S-methyl thiolactim ether (20) preparable from (19)
(NaH/DME/CH31/25 "C) is treated at 80 "C in methanol
with y-aminobutyric acid to form (25). Hydrolysis of the acetate groups (K2C03/CH30H/25"C) leads to the amidine
(26).
Compounds (22), (24), and (26) exhibit interesting biological properties. Thus (24), for example, inhibits platelet aggregation with an IC50191
value of 5 x lo-'' [MI and is more acidresistant than prostacyclin (I)'']. The three analogues were
characterized by 'H-NMR, IR, and mass spectra: (22)
(CDC13): 6=5.53 (2H, m, H-C-=C), 4.25 ( I H , m,
3.8 (1 H, m,
H-C-N---C),
4.1 (1 H, m, H-C-0),
H-C-0),
3.77 (3H, s, COzCH3), 3.67 (2H, m, CH2-0);
(24): (CDCl,): 6=5.58 (2H, m, H-C-C),
4.38 ( l H , m,
H-C-N-C),
4.08 ( l H , m, H-C-0),
3.81 (IH, m,
H-C-0),
3.67 (3H, s, C02CH3), 3.1 (2H, m, CH2-S);
(26): ((CD3)2SO/CF3C02D):6= 5.46 (2 H, m, H-C-- C),
4.31 ( I H , m, H-C-N-C),
3.89 (IH, m, H-C-0),
3.8
(1 H, m, H-C-0),
3.23 (2 H, m, CH2-N).
(41'1
0 Verlag Chemie, GmbH, 6940 Weinheim, 1980
Received: March 25, 1980 [Z 577 IE]
German version: Angew. Chem. 92. 850 (1980)
[I] S. Moncada, R. Gryglewski, S. Bunring, J. R. Vane, Nature 263,663 (1976).
[2] K. C. Nicolaou, G. P. Gasic. W. E. Barnerre. Angew. Chem. 90, 360 (1978).
Angew. Chem. Int. Ed. Engl. 17, 360 (1978).
131 R. J. Gryglewski, Biochem. Pharmacol. 28. 3161 (1979).
[4] G. J. Dustin,S. Moncada, J. R . Vane, Brit. J. Pharmacol. 62, 414P (1978).
[5] 0.Kiyolaka, H. Nishiyama, Tetrahedron Lett. 1979, 3003, and references
cited therein.
[6] K . C. Nicolaou, W. J Sipio, R. L. Magolda, J . Chem. SOC. Chem. Commun.
1978, 1067; E. J. Corey, L. Szekely. C. S. Shiner, Tetrahedron Lett. 1977,
3529.
[7] J. S. Bindra, A . Grodski, T A SchaaJ E. J. Corey, J. Am. Chem. SOC.95,
7522 (1973).
[8] This experiment was performed by Dr. U. Weithmann.
[9] IC5<,is that concentration at which the aggregation i s 50% inhibited.
0570-0833/80/1010-0820
$ 02.50/0
Angew. Chem. Inl. Ed. Engl. 19 (1980) No. 10
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