ZINC HALIDE MEDIATED CYCLIZATION PROCESS LEADING TO TRICYCLIC INDOLES
CYCLIZATION
Technical Field of the Invention
The present invention relates to a chemical method and in particular to a chemical
method to obtain a tricyclic indole compound. The method of the invention can be
applied in the synthesis of tricyclic indole compounds that find use as pharmaceuticals
and as radiopharmaceuticals.
Description of Related Art
Tricyclic indole compounds are known in the art and have been reported to have activity
as melatonin antagonists (Davies 1998 J Med Chem; 41: 451-467), secretory
phospholipase A2 inhibitors (Anderson et al EP 0952149 Al), treatment for Alzheimer's
disease (Wantanabe WO 99/25340), treatment of inflammatory diseases such as septic
shock (Kinnick et al WO 03/014082 and WO 03/016277) and high binding affinity to
translocator protein (TSPO, formerly known as peripheral benzodiazepine receptor;
Wadsworth et al (WO 2010/109007).
One reported method for the synthesis of these tricyclic indole compounds broadly
comprises a condensation reaction between an analine and a bromo
oxocycloalkanecarboxylate, followed by cyclization in the presence of zinc chloride.
Davies et al (J Med Chem 1998; 4 1: 45 1-467) describe melatonin agonists and
antagonists derived from tetrahydrocyclopent[¾]indoles, tetrahydrocarbazoles and
hexahydrocyclohept[¾]indoles. The general mechanism presented in this paper for the
synthesis of these compounds comprises treating the appropriate N-methylaniline with
the appropriate 3-bromo-2-oxocycloalkanecarboxylate as shown below followed by
reaction with zinc chloride and heating for 16 hours:
In the above scheme, Me is methyl and the variables R, R1 and n are as defined by
Davies et al, supra. Following the cyclization reaction, the product was extracted three
times with a mixture of hydrochloric acid and ethyl acetate, washed with water and
Na2C0 3, dried with MgS0 4 followed by evaporation of the solvent to obtain the ester in
sufficient purity to be used in subsequent reactions.
Kinnick et al (WO 2003/014082) describe tricyclic indole compounds and a synthesis
method for their preparation comprising condensation of 2-carbomethoxy-5-
bromocyclopentanone and N-benzyl-2-chloro-5-methoxyaniline, followed by heating
with zinc chloride at reflux temperature over a period of 10-60 hours:
In the above scheme Me is methyl and Bzl is benzyl. Following the cyclization the
reaction mixture was cooled, concentrated in vacuo and purified by chromatography.
This reaction was adapted by the same group to obtain the heptane derivative,
substituting the 2-carbomethoxy-5-bromocyclopentanone of the scheme above with 2-
carbomethoxy-5-bromocycloheptanone (Kinnick et al WO 2003/016277), followed by
cooling, filtration, washing, drying and concentration in vacuo. More specifically for
this heptane derivative, Kinnick et al made 2 separate additions of ZnC^: 1M ZnCl2 in
diethyl ether added to the intermediate dissolved in toluene, and then another 1M ZnCl2
in diethyl ether added after 1 hour along with further toluene.
Anderson et al (EP0952149 Bl) describe substituted carbazoles wherein the preparation
of certain of these compounds comprises condensation of 2-carbethoxy-6-
bromocyclohexanone with an aniline followed by addition of zinc chloride and refluxing
in benzene. Following the cyclization step, the residue worked up before being taken to
the subsequent step, e.g. in one example the residue was taken up in ethyl acetate,
washed with hydrochloric acid, washed with water, dried over sodium sulfate,
evaporated in vacuo and then purified by silica gel chromatography.
Wadsworth et al (WO 2010/109007) describe the synthesis of 1 F-labelled tricyclic
compounds using similar methods according to the following scheme:
In the above Et is ethyl and PG is a protecting group and the variables Y1 1, Y12 Rlla and
R12 are defined therein. In the experimental examples, following the cyclization step, the
reaction was dissolved in ethyl acetate, washed with hydrochloric acid and potassium
carbonate (and in some cases also water), dried over magnesium sulphate, concentrated
in vacuo and in some cases also purified by silica gel chromatography.
The present inventors have found that the above-described methods present difficulties
during the cyclization reaction and/or require re-work of the cyclized product before any
subsequent reactions to be carried out, which can be time-consuming and labourintensive.
There is therefore a need for improved methods for carrying out this
cyclization reaction.
Summary of the Invention
The present invention relates to a method for the production of tricyclic indole
compounds comprising a cyclization step wherein this step is improved over known
methods. The present inventors have observed that the zinc halide reagent used for the
cyclization appears to deactivate itself over time. The inventive method proposes to add
the zinc halide using multiple additions at defined timepoints. With the method of the
invention it is not required to separate the two phases formed during the cyclization
reaction and carry out a re-work of one of the phases in order to result in an acceptable
yield. The lot-wise addition of zinc halide during cyclization has been observed to
facilitate better conversion, thereby improving yield and avoiding significant rework of
the cyclized product.
Detailed Description of the Preferred Embodiments
In one aspect the present invention provides a method for the production of a compound
of Formula Z :
wherein:
Z is an R group selected from halo or Ci_3 alkyl;
Z2 is an R2 group selected from hydrogen, hydroxyl, halo, cyano, Ci_3 alkyl, Ci_3
alkoxy, Ci_3 fluoroalkyl, or Ci_3 fluoroalkoxy;
is an R3 group selected from Ci_6 alkyl or -O-R 7 wherein R is Ci_6 alkyl;
is an R4 group selected from O, S, SO, SO2 or CH2;
Z5 is an R5 group selected from CH2, CH2-CH 2, CH(CH 3)-CH 2 or CH2-CH 2-CH 2;
Z6 is an R6 group selected from Ci_i0 alkyl or an amine protecting group, or R6 is the
group -O-R 8 wherein R8 is Ci_i0 alkyl, C3_i 2 aryl, C7-14 arylalkyl or a hydroxyl
protecting group;
wherein said method comprises cyclizing of a compound of Formula Y:
wherein each of Y1 6 are the same as each of Z1 6 ;
wherein said cyclizing is carried out by introduction of a zinc halide in a suitable solvent
to a solution of said compound of Formula Y wherein said introduction comprises a first
addition and a second addition carried out at least 6 hours after said first addition.
The term "halo" or "halogen" is taken to mean any one of chloro, fluoro, bromo or iodo.
The term "alkyl" used either alone or as part of another group is defined as any straight
- CnH2n+i group, branched - CnH2n+i group wherein n is >3, or cyclic - CnH2n-i group
where n is >2. Non-limiting examples of alkyl groups include methyl, ethyl, propyl,
isobutyl, cyclopropyl and cyclobutyl.
The term "hydroxy1" refers to the group -OH.
The term "cyano" refers to the group -CN.
The term "alkoxy" refers to an alkyl group as defined above comprising an ether linkage,
and the term "ether linkage" refers to the group -C-0-C-. Non-limiting examples of
alkoxy groups include, methoxy, ethoxy, and propoxy.
The terms "fluoroalkyl" and ''fluoroalkoxy''refer respectively to an alkyl group and an
alkoxy group as defined above wherein a hydrogen is replaced with a fluoro.
The term "aryl" refers to any molecular fragment or group which is derived from a
monocyclic or polycyclic aromatic hydrocarbon, or a monocyclic or polycyclic
heteroaromatic hydrocarbon.
The term "arylalkyl" refers to an aryl-substituted alkylene group wherein aryl and
alkylene are as defined above.
The term "protecting group" is meant a group which inhibits or suppresses undesirable
chemical reactions, but which is designed to be sufficiently reactive that it may be
cleaved from the functional group in question to obtain the desired product under mild
enough conditions that do not modify the rest of the molecule. Protecting groups are
well-known in the art and are discussed in detail in 'Protective Groups in Organic
Synthesis', by Greene and Wuts (Fourth Edition, John Wiley & Sons, 2007).
Non-limiting examples of suitable protecting groups for hydroxyl include methyl, ethyl,
isopropyl, allyl, t-butanyl, benzyl (-CH 2C6H ), benzoyl (-COC 6H ), and for ester groups
include t-butyl, ester benzyl ester, isopropyl, and methyl and ethyl esters.
The term "cyclizing" refers to the formation of a cyclic compound from an open-chain
compound.
A "zinc halide" is suitably selected from zinc chloride and zinc bromide and is preferably
zinc chloride.
The "suitable solvent" for said zinc halide is selected from diethyl ether, propan-2-ol,
toluene, tetrahydrofuran (THF), 2-methyl-THF (MTHF) and cyclopentylmethylether
(CPME).
Said R1 group is preferably at the bottom position (i.e. the 8 position of either Formula Y or
Z) of the aryl ring to which it is attached.
Said R2 group is preferably at the top position (i.e. the 5 position of either Formula Y or Z)
of the aryl ring to which it is attached.
Said R1 group is preferably halo and is most preferably chloro.
Said R2 group is preferably Ci_3 alkoxy, Ci_3 or Ci_3 fluoroalkoxy, most preferably Ci_3
alkoxy and most especially preferably methoxy.
Said R3 group is preferably -O-R 7 wherein R7 is Ci_6 alkyl, preferably wherein R7 is C 1-
alkyl and most preferably wherein R7 is ethyl.
Said R4 group is preferably S, SO, S0 2 or CH2 and is most preferably CH2.
Said R5 group is preferably CH2, CH2-CH 2, or CH2-CH 2-CH 2 and is most preferably CH2-
CH .
Said R6 group is preferably Ci_io alkyl or an amine protecting group. Alternatively
preferably said R6 group is the group -O-R 8 wherein R8 is Ci_i0 alkyl, C3- i2 aryl, C7-14
arylalkyl or a hydroxyl protecting group. In this alternative preferred embodiment R8 is
preferably a hydroxyl protecting group and most preferably is benzyl.
For a preferred compound of either Formula Y or Formula Z:
Said R1 group is halo;
Said R2 group is Ci-3 alkoxy, Ci_3 or Ci_3 fluoroalkoxy;
Said R3 group is-O-R 7 wherein R7 is Ci_6 alkyl;
Said R4 group is S, SO, S0 2 or CH2;
Said R5 group is CH2, CH2-CH 2, or CH2-CH 2-CH 2; and,
Said R6 group is Ci_i0 alkyl or an amine protecting group.
For an alternative preferred compound of either Formula Y or Formula Z:
Said R1 group is halo;
Said R2 group is Ci-3 alkoxy, Ci_3 or Ci_3 fluoroalkoxy;
Said R3 group is-O-R 7 wherein R7 is Ci_6 alkyl;
Said R4 group is S, SO, S0 2 or CH2;
Said R5 group is CH2, CH2-CH2, or CH2-CH2-CH2; and,
Said R6 group is the group -O-R 8 wherein R8 is Ci_i0 alkyl, C3-i2 aryl, C7-14 arylalkyl or a
hydroxyl protecting group.
For a most preferred compound of either Formula Y or Formula Z:
Said R1 group is at the bottom position of the aryl ring to which it is attached and is halo;
Said R2 group is at the top position of the aryl ring to which it is attached and is Ci_3 alkoxy,
Ci_3 or Ci_3 fluoroalkoxy;
Said R3 group is-O-R 7 wherein R7 is Ci_3 alkyl;
Said R4 group is CH2;
Said R5 group is CH2-CH2; and,
Said R6 group is the group -O-R 8 wherein R8 is a hydroxyl protecting group.
For an especially preferred compound of either Formula Y or Formula Z:
Said R1 group is at the bottom position of the aryl ring to which it is attached and is chloro;
Said R2 group is at the top position of the aryl ring to which it is attached and is Ci_3 alkoxy;
Said R3 group is-O-R 7 wherein R7 is ethyl;
Said R4 group is CH2;
Said R5 group is CH2-CH2; and,
Said R6 group is the group -O-R 8 wherein R8 is benzyl.
For a most especially preferred compound of either Formula Y or Formula Z:
Said R1 group is at the bottom position of the aryl ring to which it is attached and is chloro;
Said R2 group is at the top position of the aryl ring to which it is attached and is methoxy;
Said R3 group is-O-R 7 wherein R7 is ethyl;
Said R4 group is CH2;
Said R5 group is CH2-CH2; and,
Said R6 group is the group -O-R 8 wherein R8 is benzyl.
It is an essential feature of the present invention that the zinc halide is introduced using
more than one addition. The present inventors have found in addition that second and
subsequent additions of zinc halide are suitably carried out at least 6 hours after the
previous addition. If subsequent additions of zinc halide are made too early, the present
inventors have faced significant problems stirring the reaction, which is assumed to be
due to precipitation of zinc halide. Addition of zinc halide can in another embodiment
further comprise a third addition wherein said third addition is carried out at least 6
hours after said second addition. Preferably, the time between each addition is from 6-
36 hours, most preferably from 12-24 hours. The quantity of zinc halide added at each
addition is also important. Preferably, a significant surplus is used in the first addition
with half the amount of the first addition for each subsequent addition, e.g. around a
gram of zinc halide per gram of uncyclized intermediate (i.e. compound of Formula Y)
for the first addition and around half a gram per gram of uncyclized intermediate for
each subsequent addition. In one embodiment, >3 molar equivalents can be used with
the first addition.
Compounds of Formula Y can be obtained from commercial starting materials using or
adapting methods described in the prior art. Reference is made in this regard to the
teachings of Julia & Lenzi (Bulletin de la Societe de France 1962: 2262-2263), Davies et
al (J Med Chem 1998; 41: 451-467), Kinnick et al (WO 2003/014082 and WO
2003/016277), Anderson et al (EP0952149 Bl) and Wadsworth et al (WO
2010/109007). In each of these publications compounds of Formula Y are obtained by
condensation reaction between an analine and a bromo oxocycloalkanecarboxylate as
illustrated in Scheme 1below:
Scheme 1
In the above scheme R' is an R7 group as defined herein, R" is an R1 and/or an R2 group
as defined herein, R " is an R6 group as defined herein and n' is an integer of 1-3.
The compounds of Formula Z obtained by the above-described method of the invention
may be further converted by means well-known to those of skill in the art to obtain
additional compounds. Therefore, in another embodiment, the method of the present
invention further comprises conversion of the group -C(=0)-Z of Formula Z to the
group -C(=0)-Z 1 wherein Z1 is hydroxyl or NR R1 wherein R9 and R1 are
independently Ci_3 alkyl, C7- io arylalkyl, or R9 and R1 , together with the nitrogen to
which they are attached, form a nitrogen-containing C4 6 aliphatic ring optionally
comprising 1 further heteroatom selected from nitrogen, oxygen and sulphur.
A "nitrogen-containing C aliphatic ring " is a saturated C4 _6 alkyl ring comprising a
nitrogen heteroatom. Examples include pyrolidinyl, piperidinyl and morpholinyl rings.
This further step can be easily achieved using well-known synthetic chemistry
techniques. For example, where Z3 in the group -C(=0)-Z 3 is -O-R 7 it can be converted
to -C(=0)-Z 13 wherein Z13 is hydroxyl by straightforward removal of the R7 group by
hydrolysis using an acid or a base, preferably by using a base such as NaOH.
In another embodiment, the method of the present invention further comprises
conversion of the group -N-Z 6 to the group —N-Z16 wherein Z16 is hydrogen, Ci_io
alkylene-OH or Ci_io alkylene-LG wherein LG is a leaving group.
The term "alkylene " refers to a divalent linear -CnH2n- group.
The term "leaving group " refers to a molecular fragment that departs with a pair of
electrons in heterolytic bond cleavage. Non-limiting examples of suitable leaving groups
include halo groups selected from chloro, iodo, or bromo, aryl or alkyl sulfonates such
as tosylate, triflate, nosylate or mesylate.
Z16 is preferably Ci_io alkylene-LG and most preferably Ci_6 alkylene-LG.
LG is preferably halo, or an aryl or alkyl sulfonate, and is most preferably an aryl or alkyl
sulfonate. Preferred aryl or alkyl sulfonates are selected from tosylate, triflate, nosylate and
mesylate.
Conversion of the group -N-Z 6 to the group -N-Z can be carried out in a
straightforward manner, e.g. by simply removing a protecting group in order to obtain -
NH2 or -N-alkylene-OH, and by further reacting with a suitable source of a leaving
group to obtain -N-alkylene-LG. Suitable sources of leaving groups are commercially
available and well-known to those skilled in the art, e.g. sulfonyl chloride reagents such
as p-toluenesulfonyl chloride (TsCl) and methanesulfonyl chloride (MsCl).
In a yet further embodiment, the method of the invention further comprises conversion of
the group -N-Z 16 to the group -N-Z 26 wherein Z26 is Ci_i0 alkylene- 1 F.
Labelling with 1 F can be achieved by nucleophilic displacement of LG in one step by
reaction with a suitable source of [1 F]-fluoride ion (1 Fo), which is normally obtained as
an aqueous solution from the nuclear reaction 1 0(p,n) 1 F and is made reactive by the
addition of a cationic counterion and the subsequent removal of water. 1 F can also be
introduced by O-alkylation of hydroxyl groups with 1 F(CH 2 ) 3-LG wherein LG is as
defined above.
[1 F]-radiotracers are now often conveniently prepared on an automated radiosynthesis
apparatus. There are several commercially-available examples of such apparatus,
including Tracerlab™ and Fastlab™ (GE Healthcare Ltd). Such apparatus commonly
comprises a "cassette " , often disposable, in which the radiochemistry is performed,
which is fitted to the apparatus in order to perform a radiosynthesis. The cassette
normally includes fluid pathways, a reaction vessel, and ports for receiving reagent vials
as well as any solid-phase extraction cartridges used in post-radiosynthetic clean up
steps. In a preferred embodiment therefore the further step of conversion of the group -
N-Z 16 to the group -N-Z 26 wherein Z26 is Ci_i0 alkylene- 1 F is automated.
The following non-limiting examples serve to illustrate the invention in more detail.
Brief Description of the Examples
Example 1 describes how the method of the present invention can be carried out to
obtain a compound of Formula Z by cyclizing a compound of Formula Y.
List of Abbreviations used in the Examples
EtOAc: ethyl acetate
HPLC: high performance liquid chromatography
TLC: thin- layer chromatography
Examples
Example 1: Synthesis of ethyl 9-(2-(benzyloxy)ethyl)-8-chloro-5-methoxy-2,3,4,9-
tetrahydro-lH-carbazole-4-carboxylate
Step 1: Synthesis of ethyl 3-bromo-2-oxocyclohexanecarboxylate
1 2
Step 2: Synthesis ofN-(2-(benzyloxy)ethyl)-2-chloro-5-methoxyaniline
Step 3: Synthesis of ethyl 3-((2-(benzyloxy)ethyl)(2-chloro-5-methoxyphenyl)amino)-2-
hvdroxycvclohex-l-enecarboxylate
Step 4: Synthesis of ethyl 9-(2-(benzyloxy)ethyl)-8-chloro-5-methoxy-2,3,4,9-
tetrahydro-lH-carbazole-4-carboxylate
7
Each of steps 1-3 was carried out as described by Wadsworth et al (WO 2010/109007
Example 1).
For step 4 the general procedure used was firstly to charge compound 6 (x g, 1 mole
equivalent) and diethyl ether (20 ml/g compound 6) under a nitrogen atmosphere. Zinc
chloride was then added at ~lg per gram of compound 6 and the reaction mixture
heated to a good reflux and maintained at reflux for ~ 1 day. Then additional zinc
chloride was added at -0.5 g per gram of compound 6 and refluxed for a further ~ 1 day.
A third addition of zinc chloride at 0.4-0.6g per gram of compound 6 was carried out
with reflux maintained with monitoring of the reaction with TLC (eluent 25% EtOAc in
heptane, UV 254nm), with the normal reaction time being approximately 5 days. Work
up comprised evaporation of the reaction mixture (25-40°C) under vacuum to obtain an
oily mass. The crude was weighed and then dissolved in ethyl acetate (1-10 ml/g crude)
and washed with HC1 ( 1 part concentrated HC1 and 5 parts water (approximately 2M), 2
x 1-lOml/g crude). The ethyl acetate phase was then concentrated under vacuum at 25-
50°C and a sample withdrawn for TLC (eluent 25% EtOAc in heptane, UV 254 nm).
Storage at room temperature or below.
Table 1: shows the results of carrying out the cyclization step according to an
embodiment of the present invention comprising multiple additions of zinc chloride
wherein -19-25 hours elapsed between each addition.

Claims
A method for the production of a compound of Formula Z
wherein:
Z1 is an R1 group selected from halo or Ci_3 alkyl;
Z2 is an R2 group selected from hydrogen, hydroxyl, halo, cyano, Ci_3 alkyl, Ci_3
alkoxy, Ci_3 fluoroalkyl, or Ci_3 fluoroalkoxy;
is an R3 group selected from Ci_6 alkyl or -O-R 7 wherein R is Ci_6 alkyl;
Z is an R4 group selected from O, S, SO, SO2 or CH2;
Z5 is an R5 group selected from CH2, CH2-CH 2, CH(CH 3)-CH 2 or CH2-CH 2-CH 2;
Z6 is an R6 group selected from Ci_i0 alkyl or an amine protecting group, or R6 is the
group -O-R 8 wherein R8 is Ci_i0 alkyl, C3_i 2 aryl, C7-14 arylalkyl or a hydroxyl
protecting group;
wherein said method comprises cyclizing of a compound of Formula Y:
wherein each of Y1 6 are the same as each of Z1 6 ;
wherein said cyclizing is carried out by introduction of a zinc halide in a suitable
solvent to a solution of said compound of Formula Y wherein said introduction
comprises a first addition and a second addition carried out at least 6 hours after
said first addition.
(2) The method as defined in Claim 1 wherein said R1 group is at the bottom position of
the aryl ring to which it is attached.
(3) The method as defined in either Claim 1 or Claim 2 wherein said R2 group is at the
top position of the aryl ring to which it is attached.
(4) The method as defined in any one of Claims 1-3 wherein said R1 group is halo.
(5) The method as defined in Claim 4 wherein said R1 is group chloro.
(6) The method as defined in any one of Claims 1-5 wherein said R2 group is Ci_3
alkoxy, Ci_3 or Ci_3 fluoroalkoxy.
(7) The method as defined in Claim 6 wherein said R2 group is Ci-3 alkoxy.
(8) The method as defined in Claim 7 wherein said R2 group is methoxy.
(9) The method as defined in any one of Claims 1-8 wherein said R group is -O-R 7
wherein R7 is Ci_6 alkyl.
(10) The method as defined in Claim 9 wherein R7 is C 1-3 alkyl.
( 11) The method as defined in Claim 10 wherein R7 is ethyl.
(12) The method as defined in any one of Claims 1-1 1 wherein said R4 group is S, SO,
S0 2 or CH2.
(13) The method as defined in Claim 13 wherein said R4 group is CH2.
(14) The method as defined in any one of Claims 1-13 wherein said R5 group is CH2,
CH2-CH2, or CH2-CH2-CH2.
(15) The method as defined in Claim 14 wherein said R5 group is CH2-CH2.
(16) The method as defined in any one of Claims 1-15 wherein said R6 group is selected
from Ci-io alkyl or an amine protecting group.
(17) The method as defined in any one of Claims 1-15 wherein said R6 group is the group
-O-R 8 wherein R8 is Ci_i0 alkyl, C3- i2 aryl, C7 - i4 arylalkyl or a hydroxyl protecting
group.
(18) The method as defined in Claim 1 wherein R8 is a hydroxyl protecting group.
(19) The method as defined in Claim 18 wherein R8 is benzyl.
(20) The method as defined in any one of Claims 1-19 wherein said zinc halide is zinc
chloride.
(21) The method as defined in any one of Claims 1-20 which further comprises
conversion of the group -C(=0)-Z of Formula Z to the group -C(=0)-Z 1 wherein
Z1 is hydroxyl or NR R1 wherein R9 and R1 are independently Ci_3 alkyl, C7_io
arylalkyl, or R9 and R1 , together with the nitrogen to which they are attached, form
a nitrogen-containing C4 6 aliphatic ring optionally comprising 1 further heteroatom
selected from nitrogen, oxygen and sulphur.
(22) The method as defined in any one of Claims 1-21 which further comprises
conversion of the group -N-Z 6 to the group -N-Z 16 wherein Z16 is hydrogen, C 1-10
alkylene-OH or Ci_io alkylene-LG wherein LG is a leaving group.
(23) The method as defined in Claim 22 wherein Z16 is Ci_io alkylene-LG.
(24) The method as defined in Claim 23 wherein Z16 is Ci_6 alkylene-LG.
(25) The method as defined in either Claim 23 or Claim 24 wherein LG is halo, or an aryl
or alkyl sulfonate.
(26) The method as defined in Claim 25 wherein LG is an aryl or alkyl sulfonate.
(27) The method as defined in Claim 26 wherein said aryl or alkyl sulfonate is selected
from tosylate, triflate, nosylate and mesylate.
(28) The method as defined in Claim 23 which further comprises conversion of the group
-Z1 to the group -N-Z 26 wherein Z26 is Ci_i0 alkylene- 1 F.