AMINO-SUBSTITUTED TETRACYCLIC COMPOUNDS

COMPOSES TETRACYCLIQUES AMINES

English Abstract

ABSTRACT OF THE DISCLOSURE
This invention relates to a process for the preparation of a compound
of the general formula:
<IMG> XII
or a salt ester thereof, wherein
X stands for oxygen, sulphur, the group <IMG>
or the group -CH2-;
R7 stands for hydrogen or C1-4 alkyl; and
n is one or two, which comprises either:-
(a) hydrolysing or alcoholysing a compound of the formula:
<IMG> XIII
or a corresponding amide, wherein rings A and B, n and X are as previously
defined; or

(b) reacting an organometallic compound of the formula:
<IMG>
M Hal
wherein M is a metal atom and Hal is a halogen atom, with carbon dioxide and
decomposing the organometallic complex so obtained or
(c) hydrogenating a corresponding 3,4-dihydro compound,
and when a free acid of formula I is required hydrolysing a corresponding ester.
The compounds so produced are useful as intermediates in the synthesis of
compounds having useful pharmacological properties.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Process for the preparation of a compound of the general formula
XII
<IMG>
or a salt or ester thereof, wherein
X stands for oxygen, sulphur, the group <IMG> or the group -CH2-;
ring A is either unsubstituted or substituted in the 6- or 7- position by a
halogen having an atomic number not greater than 53, an alkoxy group of l to
4 carbon atoms, an alkyl group of 1 to 4 carbon atoms or a hydroxy group,
ring B is either unsubstituted or substituted in either or both of the 11-
and 12- positions by a halogen having an atomic number not greater than 53,
an alkoxy group of 1 to 4 carbon atoms, an alkyl group of l to 4 carbon
atoms, a hydroxy group or a trifluoromethyl group,
R7 represents hydrogen or methyl, and
n is one or two, which comprises either:
(a) hydrolysing or alcoholysing a compound of the formula
XIII
<IMG>
or a corresponding amide, wherein ring A, ring B, n and X are as
previously defined; or
11

(b) reacting a corresponding organometallic compound of the formula
<IMG>
M Hal
wherein M is a metal atom and Hal is a halogen atom, with carbon dioxide and
decomposing the organometallic complex so obtained, or
(c) hydrogenating a corresponding 3,4-dihydro compound; and when a
free acid of formula I is required hydrolysing a corresponding ester.
2. A process according to claim 1 in which a free acid of formula I
is esterified to produce a corresponding ester.
3. A process according to claim 2 in which the ester is a methyl, butyl
benzyl or phenethyl ester.
4. A process according to claim 1(a) in which the hydrolysis is
effected by reaction with alkali.
5. A process according to claim 1 in which ring A and ring B are
unsubstituted or are substituted by chlorine, methoxy or methyl, and
X stands for oxygen, sulphur, the group <IMG> or the group <IMG> .
6. A process according to claim 1 in which ring A and ring B are
unsubstituted, X stands for the group <IMG> and n is one.
7. A process for the preparation of 2-carboxy-1,2,3,4-tetrahydro-
9H-tribenzo-(b,d,f) cycloheptatriene which comprises hydrolysing 2-cyano-
1, 2, 3, 4-tetrahydro-9H-tribenzo-(b,d,f)-cycloheptatriene.
12

8. A process according to claim 7 in which the free acid obtained is
converted into the corresponding methyl, butyl, benzyl or phenethyl ester.
9. A process according to claim 1 in which ring A and ring B are un-
substituted, X is the group <IMG> and n is two.
10. A process for the preparation of 2-ethoxycarbonylmethyl-1,2,3,4-
tetrahydro-9H-tribenzo-(b,d,f)-cycloheptatriene which comprises hydrogenating
the corresponding 3,4-dihydro compound.
11. A process according to claim 10 in which the starting material is
prepared by reacting 2-keto-1,2,3,4-tetrahydro-9H-tribenzo-(b,d,f)-cyclohepta-
triene with triethylphosphoroacetate and sodium hydride.
12. A process according to claim 10 in which the ester obtained is
hydrolysed to produce 2-carboxymethyl-1,2,3,4-tetrahydro-9H-tribenzo-(b,d,f)-
cycloheptatriene.
13. A compound of the general formula XII as defined in claim 1 whenever
prepared by the process of claim 1 or by an obvious chemical equivalent thereof.
14. A compound of the general formula XII given in claim 1 in which ring
A, ring B, X and n are as defined in claim 5, whenever prepared by the process
of claim 5 or by an obvious chemical equivalent thereof.
15. 2-carboxy-1,2,3,4-tetrahydro-9H-tribenzo-(b,d,f)-cycloheptatriene,
whenever prepared by the process of claim 7 or by an obvious chemical equivalent
thereof.
16. The methyl, butyl, benzyl or phenethyl ester of 2-carboxy-1,2,3,4-
tetrahydro-9H-tribenzo-(b,d,f)-cycloheptatriene, whenever prepared by the process
of claim 8 or by an obvious chemical equivalent thereof.
13

17. 2-Ethoxycarbonylmethyl-1,2,3,4-tetrahydro-9H-tribenzo-(b,d,f)-
cycloheptatriene whenever prepared by the process of claim 10 or by an obvious
chemical equivalent thereof.
18. 2-Carboxymethyl-1,2,3,4-tetrahydro-9H-tribenzo-(b,d,f)-cyclo-
heptatriene whenever prepared by the process of claim 12 or by an obvious
chemical equivalent thereof.
19. Process for the preparation of a compound of the general formula
<IMG>
or a salt or ester thereof, wherein
X stands for oxygen or the group -CH2-;
ring A is either unsubstituted or substituted in the 6- or 7-position by a
halogen having an atomic number not greater than 53, an alkoxy group of 1 to
4 carbon atoms, an alkyl group of 1 to 4 carbon atoms or a hydroxy group,
ring B is either unsubstituted or substituted in either or both of the 11-
and 12- positions by a halogen having an atomic number not greater than 53,
an alkoxy group of 1 to 4 carbon atoms, an alkyl group of 1 to 4 carbon atoms,
a hydroxy group or a trifluoromethyl group,
n is one or two, which comprises either:
(a) hydrolysing or alcoholysing a compound of the formula
14

XIII
<IMG>
or a corresponding amide, wherein ring A, ring B, n and X are as previously
defined; or
(b) reacting a corresponding organometallic compound of the formula
<IMG>
M Hal
wherein M is a metal atom and Hal is a halogen atom, with carbon dioxide and
decomposing the organometallic complex so obtained, or
(c) hydrogenating a corresponding 3,4-dihydro compound; and when a
free acid of formula I is required hydrolysing a corresponding ester.
20. A compound of the general formula as defined in claim 19 whenever
prepared by the process of claim 19 or by an obvious chemical equivalent thereof.
21. A process according to claim 19, in which a free acid of formula I
is esterified to produce a corresponding ester.
22. A process according to claim 21, in which the ester is a methyl,
butyl, benzyl or phenethyl ester.
23. A process according to claim 19(a), in which the hydrolysis is
effected by reaction with alkali.

24. A process according to claim 19, in which in the starting materials
ring A and ring B are unsubstituted or are substituted by chlorine, methoxy or
methyl.
25. A process according to claim 19, in which in the starting materials
ring A and ring B are unsubstituted, X stands for the group <IMG> and n is one.
26. A process according to claim 19, in which in the starting materials
ring A and ring B are unsubstituted, X stands for the group <IMG> and n is two.
27. A process according to claim 7, in which the starting material
2-cyano-1,2,3,4-tetrahydro-9H-tribenzo-(b,d,f)-cycloheptatriene is prepared by
reacting 2-iodo-1,2,3,4-tetrahydro-9H-tribenzo-(b,d,f)-cycloheptatriene with
sodium cyanide.
28. A process according to claim 1(c) or 19(c), in which the corresponding
3,4-dihydro compound is prepared by reacting a compound of the general formula Il:
<IMG>
(II)
in which X, ring A and ring B are as defined in claim 1 or 19, with a compound
represented by the formula Ph3P=CH-B or (EtO)2-P(?O)-CH2-COR' in NaH and a
suitable solvent or with a compound represented by the formula BrZn-CH2-COR',
wherein Ph stands for an aryl group, B represents a carboxyl group, an
esterified carboxyl group, an amide group, a cyano group or hydroxy group and R'
stands for an alkoxy group, and if necessary converting the moiety of the product
into a carboxyl group or a salt or ester thereof.
16

29. A process according to claim 1(a) or 19(a), in which the compound of
the formula XIII is prepared by (1) reducing a compound of the formula II:
(II)
<IMG>
in which X, ring A and ring B are as defined in claim 1 or 19, to the
corresponding hydroxy compound, (2) converting the hydroxy compound produced
of step (1) into a corresponding halide, and (3) reacting the halide thus
obtained with an alkali metal cyanide.
30. A process according to claim 1(b) or 19(b), in which the metal is
magnesium and the halogen is iodine.
31. A process for the preparation of 2-carboxy-1,2,3,4-tetrahydro-
tribenzo(b,d,f)-oxepine which comprises hydrolysing 2-cyano-1,2,3,4-
tetrahydro-tribenzo(b,d,f)-oxepine.
32. 2-Carboxy-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine, whenever
prepared by the process of claim 31 or by an obvious chemical equivalent thereof.
33. A process according to claim 31, in which the starting material is
prepared by (1) reducing 2-keto-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine by
lithium aluminum hydride to obtain 2-hydroxy-1,2,3,4-tetrahydro-tribenzo(b,d,f)-
oxepine, (2) reacting the 2-hydroxy compound obtained in step (1) with
phosphorous triiodide to obtain 2-iodo-1,2,3,4-tetrahydrotribenzo(b,d,f)-
oxepine, (3) reacting the 2-iodo compound obtained in step (2) with sodium
cyanide.
17

34. A process for the preparation of 2-carboxy-7-methoxy-1,2,3,4-
tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene which comprises hydrolysing
2-cyano-7-methoxy-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene.
35. 2-Carboxy-7-methoxy-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cyclo-
heptatriene whenever prepared by the process of claim 34 or by an obvious
chemical equivalent thereof.
36. A process for the preparation of 2-carboxy-7-methoxy-10-chloro-1,2,3,4-
tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene which comprises hydrolysing
2-cyano-7-methoxy-10-chloro-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cyclohepta-
triene.
37. 2-Carboxy-7-methoxy-10-chloro-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-
cycloheptatriene whenever prepared by the process of claim 36 or by an obvious
chemical equivalent thereof.
38. A process for the preparation of 2-carboxy-9-methyl-1,2,3,4-
tetrahydro-9H-tribenzo(b,d,f)-azepine which comprises hydrolysing 2-cyano-9-
methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-azepine.
39. 2-Carboxy-9-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-azepine
whenever prepared by the process of claim 38 or by an obvious chemical
equivalent thereof.
40. A process for the preparation of 2-carboxy-7-methoxy-9-methyl-
1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-azepine which comprises hydrolysing
2-cyano-7-methoxy-9-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-azepine.
41. 2-Carboxy-7-methoxy-9-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-
azepine whenever prepared by the process of claim 40 or by an obvious chemical
equivalent thereof.
18

42. A process for the preparation of 2-carboxy-1,2,3,4-tetrahydro-
tribenzo(b,d,f)-thiepine which comprises hydrolysing 2-cyano-1,2,3,4-
tetrahydro-tribenzo(b,d,f)-thiepine.
43. 2-Carboxy-1,2,3,4-tetrahydro-tribenzo(b,d,f)-thiepine whenever
prepared by the process of claim 42 or by an obvious chemical equivalent thereof.
44. A process for the preparation of 2-carboxy-12-methyl-1,2,3,4-
tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene which comprises hydrolysing
2-cyano-12-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene.
45. 2-Carboxy-12-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-
cycloheptatriene whenever prepared by the process of claim 44 or by an obvious
chemical equivalent thereof.
46. A process for the preparation of 2-ethoxycarbonylmethyl-9-methyl-
1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-cycloheptatriene which comprises
hydrogenating the corresponding 3,4-dihydro compound.
47. 2-Ethoxycarbonylmethyl-9-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-
cycloheptatriene whenever prepared by the process of claim 46 or by an obvious
chemical equivalent thereof.
48. A process according to claim 44 in which the ester obtained is
hydrolysed to produce 2-carboxymethyl-9-methyl-1,2,3,4-tetrahydro-9H-
tribenzo(b,d,f)-cycloheptatriene.
49. 2-Carboxymethyl-9-methyl-1,2,3,4-tetrahydro-9H-tribenzo(b,d,f)-
cycloheptatriene whenever prepared by the process of claim 48 or by an
obvious chemical equivalent thereof.
19

Description

114853~
This application is a divisional of our copending Canadian Patent
Application No. 199,996 filed May 15, 1974.
In our copending Canadian application number 199,996, certain
compounds were disclosed which possess valuable C.N.S. activities, but
at the same time exhibited exceedingly low toxicity. These compounds
are of the general formula I:
/ R~
(CH2)n N
R6 ~
as well as the pharmaceutically acceptable salts thereof, in which
X stands for oxygen, sulphur, the group NR7 or the group -CH2-;
ring A is either unsubstituted or substituted in the 6- or 7- position by
a halogen having an atomic number not greater than 53, an alkoxy group of
1 to 4 carbon atoms, an alkyl group of 1 to 4 carbon atoms or a hydroxy
group, ring B is either unsubstituted or substituted in either or both
of the 11- and 12- positions by a halogen having an atomic number not
greater than 53, an alkoxy group of 1 to 4 carbon atoms, an alkyl group
of 1 to 4 carbon atoms, a hydroxy group or a trifluoromethyl group,
R5 and R6 represent hydrogen, alkyl (1-4) which are either unsubstituted
or substituted by a phenyl group, or the group -NR5R6 together represents
a morpholino, piperidino or pyrrolidino group;
R7 stands for hydrogen or methyl;
n is the number 0, 1 or 2 and the dotted line means an
optional C-C bond when n is zero.
D

1148539
The present invention relates to intermediates useful in the
synthesis of compounds of formula I. Such intermediates are compounds
of the general formula XII:
XII
(CH2)n-1 - COOH
or a salt or ester thereof; wherein
X stands for oxygen, sulphur, the group NR7 or the group-CH2-;
ring A is either unsubstituted or substituted in the 6- or 7- position by
a halogen having an atomic number not greater than 53, an alkoxy group
of 1 to 4 carbon atoms, an alkyl group of 1 to 4 carbon atoms or a hydroxy
group, ring B is either unsubstituted or substituted in either or both
of the 11- and 12- positions by a halogen having an atomic number not
greater than 53, an alkoxy group of 1 to 4 carbon atoms, an alkyl group
of 1 to 4 carbon atoms, a hydroxy group or a trifluoromethyl group,
R7 stands for hydrogen or ~ethyl; and
n is one or two.
The invention also relates to a process for the preparation
of a compound of formula XII, which comprises either:-
(a) hydrolysing or alcoholysing a compound of the formula:
XIII
(CH2)n-1 CN
or a corresponding amide, wherein ring A, ring B, n and X are as previously
i ~ - 2 -

11~8539
defined; or
(b) reacting an organometallic compound of the formula:
M Hal
wherein M is a metal atom and Hal is a halogen atom, with carbon
dioxide and decomposing the organometallic complex so obtained or;
(c) hydrogenating a corresponding 3,4-dihydro compound;
and when a free acid of formula XII is required hydrolysing a corresponding
ester.
Thus as indicated above the compounds of formula XII can be
prepared by various methods, a number of which are described below.
In one method, the starting material is of general formula II:
II
1 >
in which ring A, ring B and X have the meanings mentioned above,
and which is described and claimed in our copending Canadian application
318,926 filed concurrently (26227-34D).
The compounds of formula II are conveniently prepared by
condensing a compound of general formula III:
~ III
D _ 3

1148539
with methyl vinyl ketone.
The keto group of compound II is reduced to a hydroxyl
group, preferably with metal hydrides such as LiAlH4, diborane or
in particular NaBH4. This hydroxyl group is then converted into
the cyano group in a conventional manner, for instance by reaction
with SOC12, PC15, PBr3, followed by reaction with a metal cyanide
etc., resulting in a compound of the general formula IV.
~3
(CH2)n-1 ~ CN
in which ring A, ring B and X have the meanings specified before, and
n is one.
The conversion to a compound of formula XIII can be performed
in the usual way, for instance by treating a corresponding halide with
a cyanide such as potassium- or sodium cyanide. The cyano group in
the compound thus obtained can then be hydrolysed to the corresponding
carboxyl group. An extension of the alkyl chain can be performed
by reducing the carboxyl compound to afford the hydroxy-methyl compound.
The hydroxy-methyl compound thus obtained is converted into a compound
in which the hydroxyl group is replaced by a leaving group, and repeating
the above-mentioned cyanide reaction.
Compounds of formula XII can also be prepared by a Wittig reaction,
a Wittig-Horner reaction or a Reformatski reaction. The starting material
is a keto compound of formula II. Reagents necessary in these reactions
are well-known and described in any chemical handbook, for example:

1148539
Ph3P=CH-B ~Wittig), (Eto)2-P~-3~ 0)-CH2-COR' in NaH and a suitable
solvent (Wittig-Horner) and, BrZn-CH2-COR' (Reformatski), whereby
Ph stands for an aryl group, in particular a phenyl group, B
represents a carboxyl group, an esterified carboxyl group, an
amide group, a cyano group or a hydroxyl group, and R' stands
for an alkoxy group. An additional reaction may then be necessary to
convert these moieties into a carboxyl group. It may also be necessary
to reduce the double bond (/\1,2) formed pursuant to these reactions
by means of a catalytic hydrogenation in order to obtain a compound
of formula XII.
Compounds of formula XII when n = 1 can further be prepared
by treating an organometallic compound of the following formula,
M Hal
fD 5 _

1148539
when ring A, ring B, and X have the meanings specified before,
Hal represents a halogen atom, in particular iodine, and
M represents a metal atom, in particuliarmagnesiUm, with C02,
and subsequently decomposing the organometallic complex so obtained.
Esters of the compound XII are derived from aliphatic,
cycloaliphatic, aromatic or araliphatic alcohols with 1-18 carbon
atoms, which may be substituted by hydroxy or halogen groups, especially
lower aliphatic alcohols with 1-6 carbon atoms, or phenylaliphatic
alcohols with 7-10 C-atoms, such as methanol, ethanol, isopropanol,
butanol, hexanol, phenethylalcohol, benzylalcohol, phenylpropylalcohol,
p-chlorobenzylalcohol, p-hydroxyphenethylalcohol, etc.
The novel compounds of the formula XII may be isolated from
the reaction mixture in the form of a pharmaceutically acceptable acid
addition salt when X is the group / NR7, dependent upon the conditions
in which the reaction is carried out. The acid addition salts may also
be obtained by treating the free base with a pharmaceutically acceptable
organic or inorganic acid. Acids that can be used in this connection
are: hydrochloric acid, hydrobromic acid or hydroiodic acid, phosphoric
acid, acetic acid, propionic acid, glycollic acid, maleic acid, malonic
acid, succinic acid, tartaric acid, citric acid, ascorbic acid, salicyclic
acid or benzoic acid.
The compounds according to this invention contain an asymmetric
carbon at position 2 of the tetracyclic molecule. By resolving these
compounds or a starting product in their synthesis, the optical isomers
can also be obtained in a direct way.
iD

1~48539
In the Examples the following nomenclature and numbering has been
used:
~ C ~ 11 1, 2, 3, 4-tetrahydro-9H-
6 ~ 2 tribenzo (b,d,f)-cyclohepta-
~ ~ I triene
8 9 10
7 ~ X ~ 11 X = O or S
6 ~ 12 1, 2, 3, 4-tetrahydro-tribenzo
~ ~ I (b,d,f)-oxepine or -thiepine
8 9 10
7 ~ N ~ 11
6 ~ 12 1, 2, 3, 4-tetrahydro-9H-
tribenzo (b,d,f)-azepine
g~
By way of example the preparation of various starting products is
disclosed. The preparation of analogous starting products proceeds in
exactly the same way.
Example 1
6.2 g of 2-keto-1,2,3,4-tetrahydro-tribenzo (b,d,f)-oxepine are added to
a suspension of 3.7 g of lithium aluminium hydride in 300 ml of dry ether.
After refluxing for 2 hours 14.8 ml of water are added carefully. The
suspension obtained is filtered off and after
-- 7

11~8539
that the filtrate is dried and e~aporated to dryness to obtain 2-
hydroxy-l, , 3, 4-tetrahydro-tribenzo (b,d,f)-oxepine.
2.62 g of the 2-hydroxy compound obtained above is dissolved in 50
ml of benzene whereupon 5 g of phosphorus triiodide is added. The
mixture is refluxed for 2 hours. After cooling this mixture ice-
water is cautiously added. The organic layer is separated, washed
with water and dried. The solvent (benzene) is then evaporated yielding
3.6 g of the oily 2-iodo-compound. This residue is immediately dissolved
in 300 ml dimethyl formamide, after which 4 g sodium cyanide is added.
The mixture obtained is heated at 90C for one hour stirring all
the time. The reaction-mixture is then poured into 600 ml water
and extracted with ether to obtain 2-cyano-1, 2, 3, 4-tetrahydro-
tribenzo (b,d,f)-oxepine. The crude nitrile is obtained after evaporation
of the ether and immediately used for further reactions.
Example II
1.5 g of 2-cyano-1, 2, 3, 4-tetrahydro-tribenzo ~b,d,f)-
oxepine (as prepared in Example I) is suspended in 80 ml diethyleneglycol
and 65 ml of an aqueous KOH solution (40%). The mixture is reflu~ed
for 5 hours. After cooling the mixture to ambient temperature, it
is poured into 450 ml water. The aqueous mixture is extracted with
ether to remove non-acidic material. The water-phase is acidified
to about pH 3, whereupon the mixture is extracted with ether. The
ether extracts are washed, dried and then evaporated, yielding 0.80
g of the crude 2-carboxy-1, 2, 3, 4-tetrahydro-tribenzo (b,d,f)-
oxepine.
Example III
l In the manner described in Example II, 2.3 g 2-cyano-1,
2, 3, 4- tetrahydro-9H-tribenzo (b,d,f)-cycloheptatriene is hydrolysed

~ 148539
into the corresponding 2-carboxy-compound. Recrystallization from
benzene gives 1.2 9 of the pure carboxy-compound, melting point 196-
202C, which is then converted into the methyl-, butyl-, benzyl- and
phenethyl-ester.
In the same way are prepared:
2-carboxy-7-methoxy-1, 2, 3, 4-tetrahydro-9H-tribenzo (b,d,f)-cyclohepta-
triene.
2-carboxy-7-methoxy-10-chloro-1, 2, 3, 4-tetrahydro-9H-tribenzo (b,d,f)-
cycloheptatriene.
2-carboxy-9-methyl-1, 2, 3, 4-tetrahydro-9H-tribenzo (b,d,f)-azepine
and the corresponding 7-methoxy compound.
2-carboxy-1, 2, 3, 4-tetrahydro-tribenzo (b,d,f)-thiepine.
2-carboxy-12-methyl-1,~2, 3, 4-tetrahydro-9H-tribenzo (b,d,f)-cyclo-
heptatriene.
Example IV
22.50 9 of triethylphosphonoacetate (prepared by means of the
Michaelis-Arbuzow reaction) is added dropwise at 20C to a slurry of
50% sodium hydride (4.9 9) in 200 ml of dry 1,2-dimethoxyethane.
After addition the reaction mixture is stirred for 1 hour at room temperature
until gas evolution ceased. Then 26 9 of 2-keto-1, 2, 3 , 4-tetrahydro-
9H-tribenzo (b,d,f)-cycloheptatriene is added slowly at such a rate that
the temperature is maintained below 40C. After an additional quarter
of an hour the mixture is poured into a large excess of water and the
aqueous solution extracted with ether. The ether layer after being dried
over sodiumsulphate and evaporated gives 26.0 9 of 2-ethoxycarbonylmethyl
-3,4-dihydro-9H-tribenzo (b,d,f)-cycloheptatriene.
Catalytic hydrogenation of 15 9 of this productin methanol
~D g

~1~8539
and palladium~charcoal-catalyst gives the 1, 2, 3, 4-tetrahydro-compound.
In the same manner is prepared 2-ethoxycarbonylmethyl-9-methyl-1,
2, 3, 4-tetrahydro-9H-tribenzo-Cb,d,f) cycloheptatriene.
Example V
10 g of the ethoxycarbonylmethyl-compound obtained in
the Example IV is heated in a mixture of 15 g of potassium hydroxide,
10 ml of water and 200 ml of ethanol for 2 hours at boiling temperature.
The mixture is concentrated in vacuo to about 50 ml, diluted with
water and acidified to pH 3 with hydrochloric acid. Extraction with
benzene and evaporation of the solvent gives 9.5 g of 2-carboxymethyl-
1, 2, 3, 4-tetrahydro-9H-tribenzo (b,t,f)-cycloheptatriene.
In the same manner is prepared:
2-carboxymethyl-9-methyl-1, 2, 3, 4-tetrahydro_H-tribenzo ~b,d,f)-
cycloheptatriene.
- 10 -