U.S. patent application number 09/811950 was filed with the patent office on 2001-08-09 for sulphonyl compounds for use as linkers in solid phase and combinatorial synthesis.
This patent application is currently assigned to Fujisawa Pharmaceutical Co. Ltd.. Invention is credited to Tanaka, Akito, Tsutsumi, Hideo.
Application Number | 20010012901 09/811950 |
Document ID | / |
Family ID | 3798713 |
Filed Date | 2001-08-09 |
United States Patent
Application |
20010012901 |
Kind Code |
A1 |
Tanaka, Akito ; et
al. |
August 9, 2001 |
Sulphonyl compounds for use as linkers in solid phase and
combinatorial synthesis
Abstract
The present invention relates to a linker shown by the following
formula (I): X--S0.sub.2--R.sup.1--(A).sub.m--R.sup.2 (I) wherein
R.sup.1 is a group of the formula (A): 1 [wherein R.sup.3, R.sup.4
and R.sup.5 are the same or different hydrogen, etc], etc, R.sup.2
is a group which can form a chemical bond to a resin which may be
protected by a conventional protective group, A is lower alkylene,
etc, X is a leaving group, and m is an integer of 0 or 1, with
proviso that A is (C.sub.2-C.sub.6)alkylene, and m is an integer of
1, when R.sup.1 is a group of the formula (A).
Inventors: |
Tanaka, Akito; (Tsukuba-shi,
JP) ; Tsutsumi, Hideo; (Toyonaka-shi, JP) |
Correspondence
Address: |
OBLON SPIVAK MCCLELLAND MAIER & NEUSTADT PC
FOURTH FLOOR
1755 JEFFERSON DAVIS HIGHWAY
ARLINGTON
VA
22202
US
|
Assignee: |
Fujisawa Pharmaceutical Co.
Ltd.
4-7, Doshomachi 3-chome
Osaka
JP
541-8514
|
Family ID: |
3798713 |
Appl. No.: |
09/811950 |
Filed: |
March 21, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09811950 |
Mar 21, 2001 |
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09331580 |
Jun 30, 1999 |
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6225480 |
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09331580 |
Jun 30, 1999 |
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PCT/JP97/04647 |
Dec 17, 1997 |
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Current U.S.
Class: |
549/388 ;
549/396; 558/56 |
Current CPC
Class: |
C07D 311/70 20130101;
Y02P 20/55 20151101; C40B 40/04 20130101; C40B 80/00 20130101; C07D
311/92 20130101; C40B 50/14 20130101; C07C 309/87 20130101 |
Class at
Publication: |
549/388 ;
549/396; 558/56 |
International
Class: |
C07D 37/78; C07D
311/92 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 30, 1996 |
AU |
PO4405 |
Claims
1. A linker of the following formula (I):
X--SO.sub.2--R.sup.1--(A).sub.m-- -R.sup.2 (I) wherein R.sup.1 is a
group of the formula (A), (B), (C), (D) and (E): 18[wherein
R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9,
R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15,
R.sup.16, R.sup.17 and R.sup.18 are the same or different hydrogen,
lower alkyl or lower alkoxy, and n is an integer of 1 to 3],
R.sup.2 is a group which can form a chemical bond to a resin which
may be protected by a conventional protective group, A is lower
alkylene or a group of the formula: --A.sup.1--O--A.sup.2--
(wherein A.sup.1 and A.sup.2 are each lower alkylene), X is a
leaving group, and m is an integer of 0 or 1, with proviso that A
is (C.sub.2-C.sub.6)alkylene, and m is an integer of 1, when
R.sup.1 is a group of the formula (A), or a salt thereof.
2. A linker of claim 1, wherein R.sup.1 is a group of the formula
(A) wherein R.sup.3, R.sup.4 and R.sup.5 are each lower alkyl,
R.sup.2 is a group which can form a chemical bond to a resin which
may be protected by a conventional protective group, A is
(C.sub.2-C.sub.4)alkylene or a group of the formula:
--A.sup.1--O--A.sup.2-- [wherein A.sup.1 and A.sup.2 are each
(C.sub.1-C.sub.4)alkylene], X is halogen, m is an integer of 1.
3. A linker of claim 2, wherein R.sup.1 is a group of the formula:
19R.sup.2 is a group which can form a chemical bond to a resin
which may be protected by a conventional protective group, A is
trimethylene, X is chloro, and m is an integer of 1.
4. A linker of claim 1, wherein R.sup.1 is a group of the formula
(B) wherein R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are each lower
alkyl, R.sup.10 is hydrogen, and n is an integer of 3, R.sup.2 is a
group which can form a chemical bond to a resin which may be
protected by a conventional protective group, A is
(C.sub.1-C.sub.4)alkylene or a group of the formula:
--A.sup.1--O--A.sup.2-- [wherein A.sup.1 and A.sup.2 are each
(C.sub.1-C.sub.4)alkylene], X is halogen, and m is an integer of 0
or 1.
5. A linker of claim 4, wherein R.sup.1 is a group of the formula:
20R.sup.2 is a group which can form a chemical bond to a resin
which may be protected by a conventional protective group, A is
methylene or --(CH.sub.2).sub.2--O--CH.sub.2--, X is chloro, and m
is an integer of 1.
6. A linker of claim 1, wherein R.sup.1 is a group of the formula
(B) wherein R.sup.6, R.sup.7, R.sup.8, R.sup.9 and R.sup.10 are
each lower alkyl, and n is an integer of 3, R.sup.2 is a group
which can form a chemical bond to a resin which may be protected by
a conventional protective group, A is (C.sub.1-C.sub.4)alkylene or
a group of the formula: --A.sup.1--O--A.sup.2-- [wherein A.sup.1
and A.sup.2 are each (C.sub.1-C.sub.4)alkylene], X is halogen, and
m is an integer of 0 or 1.
7. A linker of claim 6, wherein R.sup.1 is a group of the formula:
21R.sup.2 is a group which can form a chemical bond to a resin
which may be protected by a conventional protective group, X is
chloro, and m is an integer of 0, or R.sup.1 is a group of the
formula: 22R.sup.2 is a group which can form a chemical bond to a
resin which may be protected by a conventional protective group, A
is methylene or --(CH.sub.2).sub.2--O--C- H.sub.2--, X is chloro,
and m is an integer of 1.
8. A linker of claim 1, wherein R.sup.1 is a group of the formula
(C) wherein R.sup.11, R.sup.12, R.sup.13, R.sup.14 are each lower
alkyl, and R.sup.15 is hydrogen, R.sup.2 is a group which can form
a chemical bond to a resin which may be protected by a conventional
protective group, A is (C.sub.1-C.sub.4)alkylene or a group of the
formula: --A.sup.1--A.sup.2-- [wherein A.sup.1 and A.sup.2 are each
(C.sub.1-C.sub.4)alkylene], X is halogen, m is an integer of 1.
9. A linker of claim 8, wherein R.sup.1 is a group of the formula:
23R.sup.2 is a group which can form a chemical bond to a resin
which may be protected by a conventional protective group, A is
methylene, X is chloro, and m is an integer of 1.
10. A linker of claim 1, wherein R.sup.1 is a group of the formula
(D) wherein R.sup.16 is lower alkyl, R.sup.2 is a group which can
form a chemical bond to a resin which may be protected by a
conventional protective group, A is (C.sub.1-C.sub.4)alkylene or a
group of the formula: --A.sup.1--O--A.sup.2-- [wherein A.sup.1 and
A.sup.2 are each (C.sub.1-C.sub.4)alkylene], X is halogen, m is an
integer of 1.
11. A linker of claim 10, wherein R.sup.1 is a group of the
formula: 24R.sup.2 is a group which can form a chemical bond to a
resin which may be protected by a conventional protective group, A
is trimethylene, X is chloro, and m is an integer of 1.
12. A linker of claim 1, wherein R.sup.1 is a group of the formula
(E) wherein R.sup.17 and R.sup.18 are each lower alkyl, R.sup.2 is
a group which can form a chemical bond to a resin which may be
protected by a conventional protective group, A is
(C.sub.1-C.sub.4)alkylene or a group of the formula:
--A.sup.1--O--A.sup.2-- [wherein A.sup.1 and A.sup.2 are each
(C.sub.1-C.sub.4)alkylene], X is halogen, m is an integer of 1.
13. A linker of claim 12, wherein R.sup.1 is a group of the
formula: 25R.sup.2 is a group which can form a chemical bond to a
resin which may be protected by a conventional protective group, A
is methylene, X is chloro, and m is an integer of 1.
14. A derivative of the linker (I) of the present invention of the
following formula: AM--SO.sub.2--R.sup.1--(A).sub.m--R.sup.2
wherein AM is a residue of "amine compound", and R.sup.1, R.sup.2,
A and m are each as defined in claim 1.
Description
TECHNICAL FIELD
[0001] The present invention relates to the field of the solid
phase chemistry. More particularly, the present invention provides
a linker for solid phase and combinatorial synthesis of an organic
compound containing --NH-- group in its molecule (e.g. amidino
group).
BACKGROUND ART
[0002] Chemical methods have been developed recently for the
synthesis of combinatorial libraries of various organic compounds
such as peptides, benzodiazepines, oligosaccharides, etc. Solid
phase methods are often employed to synthesize the combinatorial
libraries because it offers advantages over traditional
solution-based methods, for examples, a) excess reagents and
soluble by-products can be simply removed by resin washing; b) the
technique is readily amenable to automation, enabling many
compounds to be prepared simultaneously; c) resin bound toxic or
hazardous compounds can be handled safely without risk to users or
the environment. In combinatorial synthesis using the solid phase
synthesis, it is very important to choose a "suitable linker" in
accordance with the object compound to be synthesized.
[0003] Up to now, however, a linker efficiently available for
amidino group in the solid phase synthesis has not been known.
Therefore, such linker is desired.
DISCLOSURE OF INVENTION
[0004] The linker of the present invention can be shown by the
following formula (I):
X--SO.sub.2--R.sup.1--R(A).sub.m--R.sup.2 (I)
[0005] wherein
[0006] R.sup.1 is a group of the formula (A), (B), (C), (D) and
(E): 2
[0007] [wherein
[0008] R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8,
R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14,
R.sup.15, R.sup.16, R.sup.17 and R.sup.18 are the same or different
hydrogen, lower alkyl or lower alkoxy, and
[0009] n is an integer of 1 to 3],
[0010] R.sup.2 is a group which can form a chemical bond to a resin
which may be protected by a conventional protective group,
[0011] A is lower alkylene or a group of the formula:
--A.sup.1--O--A.sup.2--
[0012] (wherein A.sup.1 and A.sup.2 are each lower alkylene),
[0013] X is a leaving group, and
[0014] m is an integer of 0 or 1,
[0015] with proviso that A is (C.sub.2-C.sub.6)alkylene, and
[0016] m is an integer of 1,
[0017] when R.sup.1 is a group of the formula (A).
[0018] The linker of the present invention can be prepared by the
following reaction scheme. 3
[0019] wherein R.sup.1, R.sup.2, A, X and m are each as defined
above.
[0020] The sulfonation reaction can be carried out, for example, in
accordance with the methods described in Examples in this
specification, but not limited thereto, the reaction can be carried
out according to the methods known in this field of the art.
[0021] The starting compound (II) or a salt thereof can be prepared
according to Preparations in this specification or similar manners
thereto, for instance. Further, one can prepare the compound (II)
or a salt thereof from a known compound in accordance with the
known methods in this field of the art.
[0022] In the above and following description of the present
specification, suitable examples and illustrations of the various
definitions which the present invention includes within the scope
thereof are explained in detail as follows.
[0023] Suitable "salt" may be the conventional ones and include a
metal salt such as an alkali metal salt (e.g. sodium salt,
potassium salt, etc) and an alkaline earth metal salt (e.g. calcium
salt, magnesium salt, etc), an ammonium salt, an organic base salt
(e.g. trimethylamine salt, triethylamine salt, pyridine salt,
picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine
salt, etc), an organic acid salt (e.g. acetate, trifluoroacetate,
maleate, tartrate, fumarate, methanesulfonate, benzenesulfonate,
formate, toluenesulfonate, etc), an inorganic acid salt (e.g.
hydrochloride, hydrobromide, hydriodide, sulfate, phosphate, etc),
a salt with an amino acid (e.g. arginine, aspartic acid, glutamic
acid, etc), and the like.
[0024] Suitable "lower alkyl" may include straight or branched ones
having 1 to 6 carbon atom(s) such as methyl, ethyl, propyl,
isopropyl, butyl, t-butyl, pentyl, hexyl, or the like.
[0025] Suitable "lower alkylene" may include straight or branched
ones having 1 to 6 carbon atom(s) such as methylene, ethylene,
trimethylene, 1-methylethylene, tetramethylene, pentamethylene,
hexamethylene, or the like.
[0026] Suitable "lower alkoxy" may include straight or branched
ones having 1 to 6 carbon atom(s) such as methoxy, ethoxy, prosoxy,
isopropoxy, butoxy, t-butoxy, pentyloxy, hexyloxy, or the like.
[0027] Suitable "a group which can form a chemical bond to a resin"
may be selected in accordance with the kind of resin (e.g.
amino-resin, etc) and the concrete examples thereof can be
exemplified as follows (the corresponding resin type is also
indicated; <P> means "resin").
[0028] 1) --COOH (H.sub.2N--<P>)
[0029] 2) --NH.sub.2 (HOOC--<P>)(Z--SO.sub.2--<P>; Z
means a leaving group)
[0030] 3) a leaving group (H.sub.2N--<P>)
[0031] 4) --C.dbd.P.phi..sub.3; .phi. means "phenyl"
(OHC--<P>)
[0032] 5) --C.dbd.CH.sub.2 (Z--.phi.--<P>)
[0033] 6) --C.dbd.CH--X ((HO).sub.2B-.phi.--<P>)
[0034] 7) --CHO
(.phi..sub.3P.dbd.CH--<P>)(H.sub.2N--<P>)
(HO--CH.sub.2CH(OH)CH.sub.2--<P>)
[0035] 8) --OH (Z--CH.sub.2--<P>)
[0036] 9) --SH (Z--CH.sub.2--<P>)
[0037] 10) --Si(CH.sub.3).sub.2H (H.sub.2C.dbd.CH--<P>)
[0038] 11) --SO.sub.2Z (H.sub.2N--<P>)
[0039] Suitable "protected carboxy" may be the conventionally
protected carboxy and may include esterified carboxy such as lower
alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl,
propoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl,
pentyloxycarbonyl, hexyloxycarbonyl, etc),
halo(lower)alkoxycarbonyl (e.g. trichloroethoxycarbonyl, etc) and
the like.
[0040] Suitable "a leaving group" may include halogen (e.g. fluoro,
chloro, bromo, iodo), lower alkoxy as mentioned above, aryloxy
(e.g. phenoxy, etc), and the like.
[0041] Preferred embodiment of the linker (I) may be as
follows.
[0042] 1. the linker (I) wherein
[0043] R.sup.1 is a group of the formula (A) wherein
[0044] R.sup.3, R.sup.4 and R.sup.5 are each lower alkyl,
[0045] R.sup.2 is a group which can form a chemical bond to a resin
which may be protected by a conventional protective group,
[0046] A is (C.sub.2-C.sub.4)alkylene or a group of the
formula:
--A.sup.1--O--A.sup.2--
[0047] [wherein A.sup.1 and A.sup.2 are each
(C.sub.1-C.sub.4)alkylene],
[0048] X is halogen,
[0049] m is an integer of 1,
[0050] in which the more preferred one may be the linker (I)
wherein
[0051] R.sup.1 is a group of the formula: 4
[0052] R.sup.2 is carboxy or protected carboxy,
[0053] A is trimethylene,
[0054] X is chloro, and
[0055] m is an integer of 1.
[0056] 2. the linker (I) wherein
[0057] R.sup.1 is a group of the formula (B) wherein
[0058] R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are each lower
alkyl,
[0059] R.sup.10 is hydrogen, and n is an interger of 3,
[0060] R.sup.2 is a group which can form a chemical bond to a resin
which may be protected by a conventional protective group,
[0061] A is (C.sub.1-C.sub.4)alkylene or a group of the
formula:
--A.sup.1--O--A.sup.2--
[0062] [wherein A.sup.1 and A.sup.2 are each
(C.sub.1-C.sub.4)alkylene],
[0063] X is halogen, and
[0064] m is an integer of 0 or 1,
[0065] in which the more preferred one may be the linker (I)
[0066] wherein
[0067] R.sup.1 is a group of the formula: 5
[0068] R.sup.2 is carboxy or protected carboxy,
[0069] A is methylene or --(CH.sub.2).sub.2--O--CH.sub.2--,
[0070] X is chloro, and
[0071] m is an integer of 1.
[0072] 3. the linker (I) wherein
[0073] R.sup.1 is a group of the formula (B) wherein
[0074] R.sup.6, R.sup.7, R.sup.8, R.sup.9 and R.sup.10 are each
lower alkyl, and
[0075] n is an integer of 3,
[0076] R.sup.2 is a group which can form a chemical bond to a resin
which may be protected by a conventional protective group,
[0077] A is (C.sub.1-C.sub.4)alkylene or a group of the
formula:
--A.sup.1--O--A.sup.2--
[0078] [wherein A.sup.1 and A.sup.2 are each
(C.sub.1-C.sub.4)alkylene],
[0079] X is halogen, and
[0080] m is an integer of 0 or 1,
[0081] in which the more preferred one may be the linker (I)
wherein
[0082] R.sup.1 is a group of the formula: 6
[0083] R.sup.1 is carboxy or protected carboxy,
[0084] X is chloro, and
[0085] m is an integer of 0, or
[0086] R.sup.1 is a group of the formula: 7
[0087] R.sup.2 is carboxy or protected carboxy,
[0088] A is methylene,
[0089] X is chloro, and
[0090] m is an integer of 1.
[0091] 4. the linker (I) wherein
[0092] R.sup.1 is a group of the formula (C) wherein
[0093] R.sup.11, R.sup.12, R.sup.13, R.sup.14 are each lower alkyl,
and
[0094] R.sup.15 is hydrogen,
[0095] R.sup.2 is a group which can form a chemical bond to a resin
which may be protected by a conventional protective group,
[0096] A is (C.sub.1-C.sub.4)alkylene or a group of the
formula:
--A.sup.1--O--A.sup.2--
[0097] [wherein A.sup.1 and A.sup.2 are each
(C.sub.1-C.sub.4)alkylene],
[0098] X is halogen,
[0099] m is an integer of 1,
[0100] in which the more preferred one may be the linker (I)
wherein
[0101] R.sup.1 is a group of the formula: 8
[0102] R.sup.2 is carboxy or protected carboxy,
[0103] A is methylene,
[0104] X is chloro, and
[0105] m is an integer of 1.
[0106] 5. the linker (I) wherein
[0107] R.sup.1 is a group of the formula (D) wherein
[0108] R.sup.16 is lower alkyl,
[0109] R.sup.2 is a group which can form a chemical bond to a resin
which may be protected by a conventional protective group,
[0110] A is (C.sub.1-C.sub.4)alkylene or a group of the
formula:
--A.sup.1--O--A.sup.2--
[0111] [wherein A.sup.1 and A.sup.2 are each
(C.sub.1-C.sub.4)alkylene],
[0112] X is halogen,
[0113] m is an integer of 1,
[0114] in which the more preferred one may be the linker (I)
wherein
[0115] R.sup.1 is a group of the formula: 9
[0116] R.sup.2 is carboxy or protected carboxy,
[0117] A is trimethylene,
[0118] X is chloro, and
[0119] m is an integer of 1.
[0120] 6. the linker (I) wherein
[0121] R.sup.1 is a group of the formula (E) wherein
[0122] R.sup.17 and R.sup.18 are each lower alkyl,
[0123] R.sup.2 is a group which can form a chemical bond to a resin
which may be protected by a conventional protective group,
[0124] A is (C.sub.1-C.sub.4)alkylene or a group of the
formula:
--A.sup.1--O--A.sup.2--
[0125] [wherein A.sup.1 and A.sup.2 are each
(C.sub.1-C.sub.4)alkylene],
[0126] X is halogen,
[0127] m is an integer of 1,
[0128] in which the more preferred one may be the linker (I)
wherein
[0129] R.sup.1 is a group of the formula: 10
[0130] R.sup.2 is carboxy or protected carboxy,
[0131] A is methylene,
[0132] X is chloro, and
[0133] m is an integer of 1.
[0134] The linker which the present invention provides is the
efficient one for the solid phase synthesis of the compound
containing --NH-- group such as "amidino" group in its molecule
(hereinafter referred to as "amine compound" in this
specification). Since there are various therapeutically active
"amine compound" and so the present invention is very useful in the
solid phase synthesis.
[0135] Since the compound (I) of the present invention is "linker",
the "amine compound" to be used is not limited and the present
invention can be applied to any "amine compound" which is useful as
the key intermediate in the solid phase synthesis and can form a
bond to the linker of the present invention during the solid phase
reaction, then can be cleaved after the reaction.
[0136] As for said "amine compound", the following compounds can be
exemplified, but it is not limited thereto.
[0137] 1) the compound of the formula:
R.sup.a--NH.sub.2 or R.sup.b--NH--R.sup.c
[0138] [wherein R.sup.a, R.sup.b and R.sup.c are each a residue of
an organic group such as lower alkyl, aryl (e.g. phenyl, naphthyl,
anthryl, etc)];
[0139] 2) the compound of the formula: 11
[0140] [wherein R.sup.d and R.sup.e are each a residue of an
organic group such as lower alkyl, aryl (e.g phenyl, naphthyl,
anthryl, etc)];
[0141] 3) heterocyclic compound containing --NH-- moiety such as
imidazole or its derivative, indole or its derivative, or the
like.
[0142] Said "amine compound" can be reacted with the linker of the
present invention in a conventional manner to form the compound of
the formula:
AM--SO.sub.2--R.sup.1--(A).sub.m--R.sup.2
[0143] wherein AM is a residue of "amine compound", and
[0144] R.sup.1, R.sup.2, A and m are each as defined above.
[0145] As for this compound, the preferred
"--SO.sub.2--R.sup.1--(A).sub.m- --R.sup.2" moiety can be referred
to the ones as exemplified for the linker (I) before.
[0146] If "a group which can form a chemical bond to a resin" can
also react with said "amine compound", this group can be protected
by a conventional protective group in this field of the art. The
protective group can be selected depending on the kind of "a group
which can form a chemical bond to a resin".
[0147] During the solid phase synthesis, the linker of the present
invention, "amine compound" and "resin" form the following
structure.
AM--SO.sub.2--R.sup.1--(A).sub.m--R.sup.2.sub.b--<P>
[0148] wherein R.sup.2.sub.b is a chemical bond, <P> is
resin, and
[0149] AM, R.sup.1, R.sup.2, A and m are each as defined above.
[0150] In order to show said usefulness, we describe later in this
specification the concrete examples (References) which show how the
linker of the present invention contributes to the solid phase
synthesis of the derivatives of "amine compound" using
"benzamidine", etc as the representative compound.
[0151] The following Preparations, Examples and References are
given only for the purpose of illustrating the present invention in
more detail.
[0152] Preparation 1
[0153] A mixture of 2,3,5-trimethylphenol (10.0 g), ethyl
4-bromobutyrate (12.6 ml), potassium carbonate (12.2 g), and
dimethylformamide (DMF, 100 ml) was stirred at room temperature
overnight. The reaction mixture was poured into a mixture of ethyl
acetate (AcOEt) and water. The separated organic phase was washed
with a saturated aqueous solution of sodium hydrocarbonate (sat.
NaHCO.sub.3aq.), water, and brine, and was dried over magnesium
sulfate (MaSO.sub.4). After evaporation, the resulting residue was
purified by chromatography over silica gel (CHCl.sub.3 as eluent)
to give ethyl 4-(2,3,5-trimethylphenoxy)butyrate (16.35 g) as an
oil compound.
[0154] IR (Neat): 2937, 2870, 1736, 1614, 1583 cm.sup.-1
[0155] .sup.1H-NMR (200 MHz, CDCl.sub.3, .delta.): 1.27 (3H, t,
J=7.1 Hz), 2.0-2.4 (2H, m), 2.04 (3H, s), 2.22 (3H, s), 2.27 (3H,
s) , 2.50 (2H, t, J=7.4 Hz) , 3.97 (2H, t, J=7.4 Hz), 4.14 (2H, q,
J=7.1 Hz), 6.51 (1H, s), 6.60 (1H, s)
[0156] MASS spectrum m/e: 251 (M+H.sup.+)
EXAMPLE 1
[0157] A mixture of chlorosulfonic acid (4.78 ml) and
CH.sub.2Cl.sub.2 (25 ml) was added dropwise into a mixture of ethyl
4-(2,3,5-trimethylphenoxy)- butyrate (6.00 g) and dichloromethane
(CH.sub.2Cl.sub.2, 500 ml) under ice-water cooling over 10 minutes,
and was stirred at room temperature for 2.5 hours. The reaction
mixture was poured into a mixture of ice and sat. NaHCO.sub.3ac.
The separated organic phase was washed with sat. NaHCO.sub.3aq.,
water, and brine, and was dried over MgSO.sub.4. After filtration,
the filtrate was evaporated to give 4-(3-ethoxycarbonylpropox-
y)-2,3,6-trimethylbenzenesulfonyl chloride (16.35 g) as an oil
compound.
[0158] IR (Neat): 1983, 2940, 1733, 1581, 1558, 1465 cm.sup.-1
[0159] .sup.1H-NMR (200 MHz, CDCl.sub.3, .delta.): 1.27 (3, t,
J=7.2 Hz), 2.0-2.4 (2H, m), 2.04 (3H, s), 2.55 (2H, t, J=7.1 Hz),
2.67 (3H, s), 2.71 (3H, s), 4.0-4.2 (4H, m), 6.65 (1H, s)
[0160] Reference 1
[0161] 1N NaOH (6.43 ml) was added into a mixture of benzamidine
hydrochloride (1.00 g) and acetone (25 ml) under ice-water cooling,
and then a mixture of
4-(3-ethoxycarbonylpropoxy)-2,3,6-trimethylbenzenesulfo- nyl
chloride (3.36 g) and acetone (5 ml) was added dropwise thereto
over 10 minutes. The reaction mixture was stirred at room
temperature for 2 hours. The reaction mixture was concentrated by
N.sub.2 flow to remove the excess of solvents, and was poured into
a mixture of water and AcOEt. The separated organic phase was
washed with sat. NaHCO.sub.3aq., water, and brine, and was dried
over MgSO.sub.4. After evaporation, the resulting residue was
purified by chromatography over silica gel (CHCl.sub.3-methanol
(MeOH) as eluent) to give N-[4-(3-ethoxycarbonylprop-
oxy)-2,3,6-trimethylbenzenesulfonyl]-benzamidine (1.39 g) as an oil
compound.
[0162] IR (Neat): 3425, 3328, 1729, 1633, 1585, 1537 cm.sup.-1
[0163] .sup.1H-NMR (200 MHz, CDCl.sub.3, .delta.): 1.29 (3H, t,
J=7.1 Hz), 2.0-2.4 (2H, m), 2.10 (3H, s), 2.52 (2H, t, J=7.1 Hz),
2.66 (3H, s), 2.73 (3H, s), 4.03 (2H, t, J=6.0 Hz), 4.14 (2H, q,
J=7.1 Hz), 6.55 (1H, s), 7.3-7.6 (3H, m), 7.77 (2H, d, J=6.9
Hz)
[0164] MASS spectrum m/e: 433 (M+H.sup.+)
[0165] Reference 2
[0166] A mixture of
N-[4-(3-ethoxycarbonylpropoxy)-2,3,6-trimethylbenzenes- ulfonyl]
benzamidine (0.39 g), 1N NaOH (1.80 ml), and ethanol (EtOH, 1 ml)
was stirred at room temperature overnight. The reaction mixture was
poured into a mixture of ethyl acetate (AcOEt) and dil. HCl. The
separated organic phase was washed with water and brine, and was
dried over magnesium sulfate (MgSO.sub.4). After evaporation, the
resulting residue was dissolved with AcOEt. Dicyclohexylamine (0.18
ml) was added thereto, and was evaporated in vacuo. The resulting
precipitate was washed with diethyl ether (Et.sub.2O) to give
N-[4-(3-carboxypropoxy)-2,3-
,6-trimethylbenzenesulfonyl]-benzamidine dicyclohexylamine salt
(16.35 g).
[0167] mp: 157-160.degree. C.
[0168] IR (KBr): 3371, 2939, 2859, 1618, 1552, 1446 cm.sup.-1
[0169] .sup.1H-NMR (200 MHz, CDCl.sub.3, .delta.): 1.0-3.0 (26H,
m), 2.14 (3H, s), 2.38 (2H, t, J=7.1 Hz), 2.65 (3H, s), 2.71 (3H,
s), 4.03 (2H, t, J=6.3 Hz), 6.55 (1H, s), 6.59 (1H, brs), 7.2-7.6
(6H, m), 7.78 (2H, d, J=7.1 Hz)
[0170] MASS spectrum m/e: 405 (M+H.sup.+ of free)
[0171] Anal. Calcd. for C.sub.32H.sub.47N.sub.3O.sub.5S: C, 65.61;
H, 8.09; N, 7.17 Found: C, 65.65; H, 8.44; N, 6.71
[0172] Reference 3
[0173]
N-[4-(3-Carboxypropoxy)-2,3,6-trimethylbenzenesulfonyl]-benzamidine
dicyclohexylamine salt (586 mg) was dissolved with a mixture of
dil. HCl and CH.sub.2Cl.sub.2. The separated organic layer was
washed with water and brine, and dried over MgSO.sub.4. After
filtration, 1-(3-dimethylamino-propyl)ethylcarbodiimide
hydrochloride (211 mg) and 1-hydroxybenzotriazole (149 mg) were
added to the filtrate. The reaction mixture was mixed with
aminomethylated polystyrene resin (0.78 mmol/g, 586 mg), was shook
by N.sub.2 bubbling at room temperature for 2.5 hours. The
Ninhydrin test on the reaction resin was negative at the end of the
reaction. The resin was washed 5 times with CH.sub.2Cl.sub.2. After
dried by N.sub.2 flow, 20% acetic anhydride in CH.sub.2Cl.sub.2 (50
ml) was added thereto to complete capping of the resin. The resin
was washed with CH.sub.2Cl.sub.2 5 times, and dried by N.sub.2 flow
and in vacuo to give "compound 1" (771 mg). 12
[0174] Reference 4
[0175] The "resin 1" (187 mg) was mixed with a mixture of m-cresol
(0.04 ml), thioanisole (0.24 ml), 1,2-ethanedithiol (0.12 ml),
trimethylsilylbromide ( 0.27 ml), and trifluoroacetic acid (TFA,
1.3 ml). The reaction mixture was heated at 80.degree. C. for 13
hours. After filtration, the resin was washed with TFA 3 times. The
combined filtrate was concentrated by N.sub.2 flow, and was poured
into Et.sub.2O (6 ml), which resulted in white precipitation. The
mixture was cooled by dry-ice for 1 hour, and was centrifuged at
3000 rpm for 3 minutes. This washing operation was repeated twice.
The resulting precipitate was dried to give benzamidine
trifluoroacetate (13.2 mg).
[0176] mp: 214.degree. C. (decomp.)
[0177] Anal. Calcd. for
C.sub.7H.sub.8N.sub.2.CF.sub.3COOH.0.6H.sub.2O: C, 44.13; H, 4.20;
N, 11.43 Found: C, 44.30; H, 3.99; N, 11.05
[0178] The retention time of HPLC under the following conditions of
the product was consistent with an authentic sample.
[0179] HPLC conditions:
[0180] Column; YMC-PACK R-ODS-15 S-15 120A ODS (YMC Co., Ltd.),
[0181] 4.6.phi..times.250 mm;
[0182] Flow, 1 ml/min;
[0183] Detection, 254 nm;
[0184] Retention time, 6.74 min;
[0185] Elution program was shown in Table 1.
1TABLE 1 Time program for the HPLC study 0 6.00 6.01 8.00 8.01
minute 5 5 80 80 5 % CH.sub.3CN in 0.1% TEA aq.
[0186] Preparation 2
[0187] A mixture of 4-(2,3,5-trimethylphenoxy)butyrate (9.09 g), 1N
NaOH (58 ml), and EtOH (80 ml) was stirred at room temperature
overnight. The reaction mixture was poured into mixture of
Et.sub.2O and water. The separated water phase was washed with
Et.sub.2O, and was acidified by 6N HCl. After extraction by AcOEt,
the AcOEt was washed with water and brine, and dried over
MgSO.sub.4, and then evaporated. The resulting precipitate was
collected by filtration, and dried to give
4-(2,3,5-trimethylphenoxy)butyric acid (4.91 g).
[0188] mp: 90-93.degree. C.
[0189] IR (KBr): 2913, 1712, 1581 cm.sup.-1
[0190] .sup.1H-NMR (200 MHz, CDCl.sub.3, .delta.): 1.94 (2H, tt,
J=7.1 and 6.3 Hz), 2.01 (3H, s), 2.15 (3H, s), 2.01 (3H, s), 3.40
(2H, t, J=7.1 Hz;, 3.91 (2H, t, J=6.3 Hz), 6.56 (1H, s), 6.57 (1H,
s), 12.12 (1H, br s)
[0191] MASS spectrum m/e: 223 (M+H.sup.+)
[0192] Preparation 3
[0193] A mixture of 4-(2,3,5-trimethylphenoxy)butyric acid (4.82
mg) dimethylaminopyridine (DMAP, 0.26 g), 2,2,2-trichloroethanol
(2.50 ml), 1-(3-dimethylaminopropyl)-ethylcarbodiimide
hydrochloride (4.57 g) and CH.sub.2Cl.sub.2 was stirred at room
temperature overnight. The reaction mixture was poured into a
mixture of AcOEt and water. The separated AcOEt was washed with
dil. HCl, sat. NaHCO.sub.3, water, and brine, and dried over
MgSO.sub.4, and then evaporated to give 2,2,2-trichloroethyl
4-(2,3,5-trimethylphenoxy)butyrate (8.11 g) as an oil compound.
[0194] IR (KBr): 2925, 1754, 1612, 1581 cm.sup.-1
[0195] .sup.1H-NMR (200 MHz, CDCl.sub.3, .delta.): 2.01 (3H, s),
2.04 (2H, m), 2.15 (3H, s) , 2.04 (3H, s), 2.67 (2H, t, J=7.1 Hz),
3.97 (2H, t, J=6.3 Hz), 6.81 (2H, br s)
[0196] MASS spectrum m/e: 353 (M.sup.+)
EXAMPLE 2
[0197] The following compound was obtained according to a similar
manner to that of Example 1.
[0198]
4-[3-(2,2,2-Trichloroethoxy)carbonylpropoxy]-2,3,6-trimethylbenzene-
sulfonyl chloride (6.40 g) as an oil compound.
[0199] IR (Neat): 2939, 1756, 1681, 1606, 1583, 1556 cm.sup.-1
[0200] .sup.1H-NMR (200 MHz, CDCl.sub.3, .delta.): 2.01 (3H, s),
2.04 (2H, m), 2.15 (3H, s), 2.04 (3H, s), 2.67 (2H, t, J=7.1 Hz),
3.97 (2H, t, J=6.3 Hz), 6.84 (1H, s)
[0201] MASS spectrum m/e: 451 (M-H.sup.+)
[0202] Reference 5
[0203] The following compound was obtained according to a similar
manner to that of Reference 1.
[0204]
4-Ethoxycarbonylpropoxy-N-{4-[3-(2,2,2-trichloroethoxy-carbonyl(pro-
poxy]-2,3,6-trimethylbenzenesulfonyl}benzamidine (3.28 g) as an oil
compound.
[0205] .sup.1H-NMR (200 MHz, CDCl.sub.3, .delta.): 1.17 (3H, t,
J=7.1 Hz), 1.8-2.1 (4H, m), 2.22 (3H, s), 2.4-2.8 (10H, m), 4.0-4.2
(6H, m), 4.90 (2H, s), 6.75 (1H, s), 6.99 (2H, d, J=8.9 Hz), 7.82
(2H, d, J=8.9 Hz), 7.83 (1H, br s), 8.76 (1H, s)
[0206] MASS spectrum m/e: 667 (M+H.sup.+)
[0207] Reference 6
[0208] Zn powder (0.32 g) was added to a mixture of
4-ethoxycarbonylpropoxy-N-{4-[3-(2,2,2-trichloroethoxy-carbonyl)propoxy]--
2,3,6-trimethylbenzenesulfonyl}benzamidine (0.65 g), water (2 ml),
and AcOH (18 ml) under ice-water cooling. The reaction mixture was
stirred at room temperature for 3.25 hours, and then evaporated.
The resulting precipitate was removed by filtration, and was washed
with AcOEt and isopropyl ether (IPE). The filtrate, AcOEt, and IPE
were combined, and then washed with water. The organic phase was
dried over MgSO.sub.4, and evaporated. The resulting residue was
purified by chromatography over silica gel (CHCl.sub.3--MeOH as
eluent) to give 4-ethoxycarbonylpropoxy-N- -[
4-(3-carboxypropoxy)-2,3,6-trimethylbenzenesulfonyl]-benzamidine
(0.17 g) as an oil compound.
[0209] IR (Neat): 3424, 3330, 3243, 2973, 1725, 1720, 1635
cm.sup.-1
[0210] .sup.1H-NMR (200 MHz, CDCl.sub.3, .delta.): 1.17 (3H, t,
J=7.1 Hz), 1.8-2.1 (4H, m), 2.22 (3H, s), 2.4-2.8 (10H, m), 4.0-4.2
(6H, m) , 4.90 (2H, s), 6.75 (1H, s), 6.99 (2H, d, J=8.9 Hz), 7.82
(2H, d, J=8.9 Hz), 7.83 (1H, br s), 8.76 (1H, s)
[0211] MASS spectrum m/e: 535 (M+H.sup.+)
[0212] Anal. Calcd. for
C.sub.26H.sub.34N.sub.2O.sub.8S.1/4H.sub.2O: C, 57.92, H; 6.45; N;
5.20 Found: C, 57.93; H, 6.45; N; 5.06
[0213] Reference 7
[0214] A mixture of
4-ethoxycarbonylpropoxy-N-[4-(3-carboxypropoxy)-2,3,6--
trimethylbenzenesulfonyl]benzamidine (1.00 g),
1-(3-dimethylaminopropyl)et- hylcarbodiimide hydrochloride (0.39
g), aminomethylated polystyrene resin (ArgoGel.sup.R 0.41 mmol/g,
1.14 g), 1-hydroxybenzotriazole (149 mg), CH.sub.2Cl.sub.2 (5 ml),
and DMF (5 ml) was shocked by N.sub.2 bubbling at room temperature
for 2 hours. The Keiser test on the reaction resin was negative at
the end of the reaction. The resin was washed 5 times with
CH.sub.2C.sub.2 and DMF, and dried by N.sub.2 flow to give the
following "compound 2", which was used in the next reaction without
further treatment. 13
[0215] Reference 8
[0216] A mixture of the above resin (2, assumed 0.47 mmol according
to Reference 7), 1N NaOH (1.56 ml), and EtOH (10 ml) was shook by
N.sub.2 bubbling room temperature overnight. The end of the
reaction was determined by solid phase .sup.1H-NMR on the resin
using nanoprobe (Varian Unity plus 300). The resin was washed with
EtOH, water, 0.5N HCl, CH.sub.2Cl.sub.2, and DMF, and dried by
N.sub.2 flow to give the following "compound 3", which was used in
the next reaction without further treatment. 14
[0217] Reference 9
[0218] A mixture of the above resin (3, assumed 0.47 mmol according
to Reference 7), H-Asp(OtBu)ValOtBu (0.53 g),
1-(3-dimethylaminopropyl)ethyl- carbodiimide hydrochloride (0.30
g), 1-hydroxybenzotriazole (0.21 g), and CH.sub.2Cl.sub.2 (15 ml)
was shocked by N.sub.2 bubbling at room temperature for 9 hours.
The end of the reaction was determined by solid phase .sup.1H-NMR
on the resin using nanoprobe (Varian Unity plus 300). The resin was
washed with CH.sub.2Cl.sub.2, and DMF, and dried by N.sub.2 flow to
give the following "compound 4", which was used in the next
reaction without further treatment. 15
[0219] Reference 10
[0220] The resin 4 (assumed 0.47 mmol according to Reference 7),
was mixed with a mixture of trifluoromethanesulfonic acid (TfOH,
0.8 ml), thioanisole (TA, 0.8 ml), and TFA (7.2 ml). The reaction
mixture was stirred under water cooling for 2.5 hours. After
filtration, the resin was washed with TFA 3 times. The combined
filtrate was concentrated by N.sub.2 flow, and was poured into a
mixture of water (40 ml) and Et.sub.2O (40 ml). The mixture was
adjusted to pH 2.08 by addition of 1N NaOH. The separated water
phase was subjected to preparative HPLC under the below conditions
to give the following compound 5 (57.0 mg, 56.3% from Reference
7).
[0221] mp: 155-158.degree. C.
[0222] IR (KBr): 3332, 3118, 1718, 1668, 1614 cm.sup.-1
[0223] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 0.84 (6H, d, J=6.7 Hz),
1.8-2.2 (3H, m), 2.30 (2H, t, J=7.3 Hz), 2.3-2.8 (2H, m), 4.0-4.2
(3H, m), 4.65 (1H, m), 7.14 (2H, d, J=8.9 Hz) , 7.79 (1H, d, J=8.5
Hz) , 7.82 (2H, d, J=8.9 Hz), 8.30 (1H, d, J=7.7 Hz), 9.03 and 9.14
(4H, each s)
[0224] MASS spectrum m/e: 437 (M+H.sup.+)
[0225] Preparative HPLC conditions: Column, YMC-PACK R-ODS-15 S-15
120A ODS (YMC Co., Ltd.), 50 .phi..times.250 mm; Elution, 16%
CH.sub.3CN in 0.1% TFAaq., Flow, 118 ml/min; Detection, 254 nm;
Retention time, 6.5 min.
[0226] The purity of the product was confirmed by RP-HPLC under the
following conditions, and the retention time was consistent with an
authentic sample.
[0227] Analytical HPLC conditions: Column, YMC-PACK R-ODS-15 S-15
120A ODS (YMC Co., Ltd), 4.6.phi..times.250 mm; Flow, 1 ml/min;
Detection, 254 nm; Retention time, 6.7 min; Elution 18% CH.sub.3CN
in 0.1% TFA ac. 16
[0228] Preparation 4
[0229] According to the method of G. Manecke and G. Bourweig (Chem.
Ber., 1959, 92, 2958-61), 2-hydroxy-3,4,6-trimethyl-benzaldehyde
was synthesized from 2,3,5-trimethylphenol.
[0230] Preparation 5
[0231] A suspension of 2-hydroxy-3,4,6-trimethylbenzaldehyde (16.45
g), diethyl isopropylidenemalonate (20.05 g), and anhydrous
potassium carbonate (40.10 g) in dimethylformamide (DMF) (11) was
heated at 130-135.degree. C. for 8 hours. After removing the
solvent under reduced pressure, the mixture was diluted with water,
and extracted with ethyl acetate (AcOEt). The organic phase was
washed with water and brine, dried over magnesium sulfate
(MgSO.sub.4), and evaporated to give a residue. The residue was
purified by chromatography over silica gel (AcOEt-hexane 3:97 as
eluent) to give ethyl (2,5,7,8-tetramethyl-2H-chromen-2-yl)acetat-
e as an oil (22.45 g).
[0232] bp: 152-153.degree. C. (2 mm)
[0233] IR (Neat): 1735, 1608 cm.sup.-1
[0234] .sup.1H-NMR (200 MHz, CDCl.sub.3, .delta.): 1.23 (3H, t,
J=7.1 Hz), 1.57 (3H, s), 2.07 (3H, s), 2.19 (3H, s), 2.23 (3H, s),
2.67 and 2.71 (2H, ABq, J=14.0 Hz), 4.11 (2H, q, J=7.1 Hz), 5.72
(1H, d, J=9.9 Hz), 6.54 (1H, s), 6.55 (1H, d, J=9.9 Hz)
[0235] MASS spectrum m/e: 275 (M+H.sup.+), 187
(M.sup.+--CH.sub.2CO.sub.2E- t)
[0236] Preparation 6
[0237] A solution of ethyl
(2,5,7,8-tetramethyl-2H-chromen-2-yl)acetate (20.00 g) in methanol
(MeOH) (300 ml) was hydrogenated in the presence of 10% palladium
on carbon (50% wet, 4.0 g) in one atmosphere of hydrogen at room
temperature for 16 hours. The catalyst was filtered off and MeOH
was removed under reduced pressure to give a residue. The residue
was purified by chromatography over silica gel (AcOEt-hexane 3:97
as eluent) to give ethyl (2,5,7,8-tetramethylchroman-2-yl)acetaze
as an oil (18.72 g).
[0238] bp: 157-159.degree. C. (2 mm)
[0239] IR (Neat): 1732, 1575 cm.sup.-1
[0240] .sup.1H-NMR (200 MHz, CDCl.sub.3, .delta.): 1.26 (3H, t,
J=7.1 Hz), 1.43 (3H, s), 1.8-2.1 (2H, m), 2.05 (3H, s), 2.16 (3H,
s), 2.19 (3H, s), 2.55-2.75 (4H, m), 4.15 (2H, q, J=7.1 Hz), 6.57
(1H, s)
[0241] MASS spectrum m/e: 277 (M+H.sup.+), 189
(M.sup.---CH.sub.2CO.sub.2E- t)
[0242] Anal. Calcd. for C.sub.17H.sub.24O.sub.3: C, 73.88; H, 8.75
Found: C, 73.99; H, 8.95
EXAMPLE 3
[0243] A solution of chlorosulfonic acid (2.79 ml) in
dichloromethane (CH.sub.2Cl.sub.2) (15 ml) was added dropwise to a
solution of ethyl (2,5,7,8-tetramethylchroman-2-yl)acetate (2.90 g)
in CH.sub.2Cl.sub.2 (100 ml) at 0-10.degree. C. over an hour. After
stirring at room temperature for 5 hours, the reaction mixture was
poured into chilled saturated aqueous sodium hydrogen carbonate
(sat. as. NaHCO.sub.3). The separated organic phase was washed with
sat. aq. NaHCO.sub.3, water, and brine, and dried over MgSO.sub.4.
After filtration, the filtrate was concentrated under reduced
pressure to give 2-ethoxycarbonylmethyl-2,5,7,-
8-tetramethylchroman-6-sulfonyl chloride as a syrup (3.29 g).
[0244] IR (Neat): 1720, 1550 cm.sup.-1
[0245] Reference 11
[0246] To a suspension of benzamidine hydrochloride (2.72 g) in
acetone (70 ml) was added EN aqueous sodium hydroxide (1N
N.sub.aOH) (17.3 ml) under ice-cooling. To the mixture of a
solution of
2-ethoxycarbonylmethyl-2,5,7,8-tetramethyl-chroman-6-sulfonyl
chloride (3.25 g) in acetone (15 ml) was added dropwise over 15
minutes under ice-cooling, and stirred at room temperature for 20
hours. Acetone was removed under reduced pressure to give a
residue. To the residue was added a mixture of water and AcOEt and
the mixture was acidified with 1N HCl. The separated organic phase
was washed with water and brine, and dried over MgSO.sub.4. After
filtration, the filtrate was evaporated and purified by
chromatography over silica gel (AcOEt-hexane 50:50 as eluent) to
give
N-(2-ethoxycarbonylmethyl-2,5,7,8-tetramethylchroman-6-sulfonyl)b-
enzamidine as a glass (1.60 g).
[0247] IR (CHCl.sub.3): 3450, 3350, 1730, 1630, 1532 cm.sup.-1
[0248] .sup.1H-NMR (200 MHz, CDCl.sub.3, .delta.): 1.26 (3H, t,
J=7.1 Hz,, 1.43 (3H, s), 1.8-2.15 (2H, m), 2.11 (3H, s), 2.6-2.75
(10H, m), 4.15 (2H, q, J=7.1 Hz), 6.23 (1H, br s), 7.35-7.6 (3H,
m), 7.75-7.85 (2H, m), 8.14 (1H, br s)
[0249] MASS spectrum m/e: 459 (M+H.sup.+)
[0250] Anal. Calcd. for C.sub.24H.sub.30N.sub.2O.sub.5S: C, 62.86;
H, 6.59; N, 6.11 Found C, 62.78; H, 6.60; N, 6.00
[0251] Reference 12
[0252] A solution of
N-(2-ethoxycarbonylmethyl-2,5,7,8-tetramethylchroman--
6-sulfonyl)benzamidine (1.54 g) in a mixture of ethanol (EtOH) (30
ml) and 1N NaOH (7.05 ml) was stirred at room temperature for 30
hours. EtOH was evaporated under reduced pressure to give a
residue. A mixture of AcOEt and 1N HCl was added to the residue.
The organic phase was washed with water and brine, and dried over
MgSO.sub.4. After filtration, the filtrate was concentrated under
reduced pressure to give
N-(2-carboxymethyl-2,5,7,8-tetramethylchroman-6-sulfonyl)benzamidine
as a glass (1.49 g).
[0253] IR (CHCl.sub.3): 3450, 3350, 1710, 1630, 1535 cm.sup.-1
[0254] .sup.1H-NMR (200 MHz, CDCl.sub.3, .delta.): 1.45 (3H, s),
1.75-2.1 (5H, m), 2.5-2.7 (10H, m), 6.40 (1H, br s), 7.3-7.55 (3H,
m), 7.75-7.8 (2H, m), 8.12 (1H, br s)
[0255] MASS spectrum m/e: 431 (M+H.sup.+), 373
[0256] Reference 13
[0257] A solution of dicyclohexylamine (0.54 g) in AcOEt (1 ml) was
added to a solution of
N-(2-carboxymethyl-2,5,7,8-tetramethylchroman-6-sulfonyl-
)benzamidine (1.27 g) in AcOEt (11 ml) at room temperature.
Diisopropyl ether (10 ml) was added and the mixture was stirred at
room temperature to give
N-(2-carboxymethyl-2,5,7,8-tetramethylchroman-6-sulfonyl)-benzami-
dine dicyclohexylamine salt as a solid (1.59 g).
[0258] mp: 201-204.degree. C.
[0259] IR (Nujol): 3350, 1620, 1550, 1530 cm.sup.-1
[0260] .sup.1H-NMR (200 MHz, CDCl.sub.3, .delta.): 1.1-2.9 (28H,
m), 1.45 (3H, s), 2.11 (3H, s), 2.60 (3H, s), 2.62 (3H, s), 5.40
(2H, br s), 6.36 (1H, br s), 7.35-7.55 (3H, m), 7.75-7.85 (2H, m),
8.10 (1H, br s)
[0261] MASS spectrum m/e: 431 (M+H.sup.+ of free)
[0262] Anal. Calcd. for C.sub.34H.sub.49N.sub.3O.sub.5S: C, 66.74;
H, 8.07; N, 6.87 Found: C, 66.36; H, 8.29; N, 6.70
[0263] Preparation 7
[0264] A solution of ethyl
(2,5,7,8-tetramethylchroman-2-yl)-acetate (8.00 g) in
tetrahydrofuran (THF) (16 ml) was added dropwise to the suspension
of lithium aluminum hydride (1.10 g) in THF (40 ml) under reflux.
After refluxing for 2 hours, a solution of water (1 ml) in THF (5
ml) was added to the reaction mixture. The insoluble material was
filtered off and the filtrate was concentrated under reduced
pressure to give a residue. The residue was purified by
chromatography over silica gel (AcOEt-hexane 10:90) to give
2-(2,5,7,8-tetramethylchroman-2-yl)ethanol as a solid (5.00 g).
[0265] mp: 67-69.degree. C.
[0266] IR (Nujol): 3400, 1460 cm.sup.-1
[0267] .sup.1H-NMR (200 MHz, CDCl.sub.3, .delta.): 1.30 (3H, s),
1.7-2.0 (4H, m), 2.05 (3H, s), 2.16 (3H, s), 2.20 (3H, s), 2.26
(1H, s), 2.63 (2H, t, J=6.8 Hz), 3.8-4.0 (2H, m), 6.58 (1H, s)
[0268] MASS spectrum m/e: 235 (M+H.sup.+), 189, 149
[0269] Anal. Calcd. for C.sub.15H.sub.22O.sub.2: C, 76.88; H, 9.46
Found: C, 76.92; H, 9.61
[0270] Preparation 8
[0271] A solution of potassium tert-butoxide (1.92 g) in THF (10
ml) was added dropwise to a solution of
2-(2,5,7,8-tetramethylchroman-2-yl)ethano- l (4.00 g) and ethyl
bromoacetate (2.00 ml) in THF (20 ml) at 0-10.degree. C. and the
mixture was stirred for 30 minutes under same condition. After
addition of ethyl bromoacetate (1.90 ml), a solution of potassium
tert-butoxide (1.92 g) in THF (10 ml) was added dropwise and the
mixture was stirred at 0-10.degree. C. for 30 minutes. This
procedure was repeated 3 times. A solution of NaOH (5.0 g) in water
(10 ml) was added and heated at 50-55.degree. C. for 5 hours. The
mixture was adjusted to pH 3 with 6N hydrochloric acid (6N HCl) and
extracted with AcOEt. The organic phase was dried over MgSO.sub.4
and concentrated under reduced pressure to give a syrup. A mixture
of the syrup and a cation-exchange resin, Amberlyst.RTM. 15 (1 g)
in MeOH (100 ml) was heated under reflux for 30 hours. After
removal of catalyst, the solution was concentrated under reduced
pressure to give a syrup. The syrup was purified by chromatography
over silica gel (AcOEt-hexane 5:95) to give methyl
[2-(2,5,7,8-tetramethylchroman-2-yl)ethoxy]acetate as an oil (3.37
g).
[0272] IR (Neat): 1755, 1575 cm.sup.-1
[0273] .sup.1H-NMR (200 MHz, CDCl.sub.3, .delta.): 1.30 (3H, s),
1.75-2.1 (4H, m), 2.10 (3H, s), 2.15 (3H, s), 2.19 (3H, s), 2.60
(2H, t, J=6.5 Hz), 3.6-3.85 (2H, m), 3.74 (3H, s), 4.08 (2H, s),
6.55 (1H, s)
[0274] MASS spectrum m/e: 307 (M+H.sup.+), 279, 217, 149
[0275] Anal. Calcd. for C.sub.18H.sub.26O.sub.4: C, 70.56; H, 8.55
Found: C, 70.60; H, 8.70
EXAMPLE 4
[0276]
2-[2-(Methoxycarbonylmethoxy)ethyl]-2,5,7,8-tetramethylchroman-6-su-
lfonyl chloride was obtained according to a similar manner to that
of Example 3.
[0277] IR (Neat): 1752, 1549 cm.sup.-1
[0278] .sup.1H-NMR (200 MHz, CDCl.sub.3, .delta.): 1.35 (3H, s),
1.8-2.05 (4H, m), 2.14 (3H, s), 2.60 (3H, s), 2.63 (3H, s),
2.65-2.75 (2H, m), 3.55-3.85 (2H, m), 3.76 (3H, s), 4.09 (2H,
s)
[0279] Reference 14
[0280]
N-{2-[2-(Methoxycarbonylmethoxy)ethyl]-2,5,7,8-tetramethylchroman-6-
-sulfonyl}benzamidine was obtained according to a similar manner to
that of Reference 11.
[0281] IR (CHCl.sub.3): 3420, 3320, 1740, 1625, 1530 cm.sup.-1
[0282] .sup.1H-NMR (200 MHz, CDCl.sub.3, .delta.): 1.30 (3H, s),
1.8-2.05 (4H, m), 2.11 (3H, s), 2.61 (3H, s), 2.63 (3H, s, 2.6-2.7
(2H, m), 3.55-3.85 (2H, m), 3.75 (3H, s), 4.08 (2H, s), 6.18 (1H,
br s), 7.35-7.6 (3H, m), 7.75-7.85 (2H, m), 8.13 (1H, br s)
[0283] MASS spectrum m/e: 489 (M+H.sup.+)
[0284] Anal. Calcd. for C.sub.25H.sub.32N.sub.2O.sub.6S: C, 61.46;
H, 6.60; N, 5.73 Found: C, 61.15; H, 6.72; N, 5.61
[0285] Reference 15
[0286]
N-{2-[2-(Carboxymethoxy)ethyl]-2,5,7,8-tetramethyl-chroman-6-sulfon-
yl}benzamidine was obtained according to a similar manner to that
of Reference 12.
[0287] IR (CHCl.sub.3): 3420, 3330, 3230, 1720, 1623, 1528
cm.sup.-1
[0288] .sup.1H-NMR (200 MHz, CDCl.sub.3, .delta.) : 1.30 (3H, s),
1.8-2.05 (4H, m), 2.10 (3H, s), 2.5-2.7 (2H, m), 2.60 (3H, s), 2.61
(3H, s), 3.6-3.85 (2H, m), 4.10 (2H, m), 6.32 (1H, br s), 7.35-7.55
(3H, m), 7.75-7.8 (2H, m), 8.12 (1H, br s)
[0289] Reference 16
[0290]
N-{2-[2-(Carboxymethoxy)ethyl]-2,5,7,8-tetramethyl-chroman-6-sulfon-
yl}benzamidine dicvclohexylamine salt was obtained according to a
similar manner to that of Reference 13.
[0291] mp: 184-186.degree. C.
[0292] IR (Nujol): 3380, 1622 cm.sup.-1
[0293] .sup.1H-NMR (200 MHz, CDCl.sub.3, .delta.): 1.28 (3H, s),
2.09 (3H, s), 2.59 (3H, s), 2.61 (3K, s), 3.84 (2H, s), 7.11 (1H,
br s), 7.25-7.55 (3H, m) , 7.75-7.85 (2H, m) 8.01 (1H, br s)
[0294] MASS spectrum m/e: 475 (M+H.sup.+ of free)
[0295] Anal. Calcd. for C.sub.36H.sub.53N.sub.3O.sub.6S: C, 65.92;
H, 8.14; N, 6.41 Found: C, 65.65; H, 8.39; N, 6.29
[0296] Preparation 9
[0297] According to the method of D. Murali and G. S. Krishna Rao
(Synthesis, 1987, 254-56), 5,6,7,8-tetrahydro-3-methyl-1-naphthyl
acetate was synthesized from cyclohexanone and triethyl
3-methyl-4-phosphonocroto- nate.
[0298] Preparation 10
[0299] A solution of 5,6,7,8-tetranydro-3-methyl-1-naphthyl acetate
(11.00 g) and NaOH (6.50 g) in a mixture of water (50 ml) and MeOH
(150 ml) was refluxed for 5 hours. MeOH was removed under reduced
pressure to give a residue. AcOEt was added to the residue and
c-HCl was added dropwise under ice-cooling. The organic phase was
washed with brine and dried over MgSO.sub.4. After filtration, the
filtrate was concentrated under reduced pressure to give
5,6,7,8-tetrahydro-3-methyl-1-naphthol as a solid (8.19 g).
[0300] mp: 94-95.degree. C. (hexane)
[0301] IR (Nujol): 3450-3350, 1623, 1582 cm.sup.-1
[0302] .sup.1H-NMR (200 MHz, CDCl.sub.3, .delta.): 1.65-1.9 (4H,
m), 2.23 (3h, s), 2.58 (2H, t, J=6.0 Hz), 2.70 (2H, t, J=5.8 Hz),
4.61 (1H, s), 6.44 (1H, s), 6.51 (1H, s)
[0303] MASS spectrum m/e: 163 (M+H.sup.+)
[0304] Preparation 11
[0305] A suspension of boric acid (5.88 g) in glycerol (20 ml) was
heated at 170.degree. C. for 30 minutes. Temperature of the
reaction mixture was lowered at 155.degree. C. and
5,6,7,8-tetrahydro-3-methyl-1-naphthol (5.00 g) was added dropwise
over 10 minutes. After 15 minutes, hexamethylenetetramine (4.35 g)
was added dropwise below 180.degree. C. and stirred at 170.degree.
C. for 30 minutes. The mixture was cooled to 110.degree. C. and 24%
aqueous sulfuric acid (20 ml) was added. The mixture was steam
distilled and AcOEt was added to the distillate. The organic phase
was washed with brine and dried over MgSO.sub.4. After filtration,
the filtrate was concentrated under reduced pressure to give
5,6,7,8-tetrahydro-1-hydroxy-3-methylnaphthalene-2-carbaldehyde as
a solid (2.15 g). A pure sample was obtained by recrystallization
from EtOH--H.sub.2O.
[0306] mp: 74-75.degree. C. (EtOH--H.sub.2O)
[0307] IR (Nujol): 1625 cm.sup.-1
[0308] .sup.1H-NMR (200 MHz, CDCl.sub.3, .delta.) 1.7-1.85 (4H, m),
2.52 (3H, s), 2.6-2.75 (4H, m), 6.44 (1H, s), 10.20 (1H, s), 12.35
(1H, s)
[0309] MASS spectrum m/e: 191 (M+H.sup.+), 175
[0310] Anal. Calcd. for C.sub.12H.sub.14O.sub.2: C, 75.76; H 7.42
Found: C, 75.96; H 7.55
[0311] Preparation 12
[0312] Ethyl (7,8,9,10-tetrahydro-2,5-dimethyl-2H-naphtho-[
2,1-e]pyran-2-yl)acetate was obtained according to a similar manner
to that of Preparation 5. 17
[0313] IR (Neat): 1735, 1605 cm.sup.-1
[0314] .sup.1H-NMR (200 MHz, CDCl.sub.3, .delta.) 1.23 (3H, t,
J=7.1 Hz), 1.56 (3H, s), 1.65-1.8 (4H, m,, 2.23 (3H, s), 2.55-2.8
(6H, m), 4.11 (2H, q, J=7.1 Hz), 5.69 (1H, d, J=10.0 Hz), 6.46 (1H,
s), 6.53 (1H, d, J=10.0 Hz)
[0315] MASS spectrum m/e: 301 (M+H.sup.+), 213
(M.sup.+--CH.sub.2CO.sub.2E- t)
[0316] Anal. Calcd. for C.sub.19H.sub.24O.sub.3: C, 75.97; H, 8.05
Found: C, 75.54; H, 8.13
[0317] Preparation 13
[0318] Ethyl (3,4,7,8,9,10-hexahydro-2,5-dimethyl-2H-naphtho-[
2,1-e]pyran-2-yl)acetate was obtained according to a similar manner
to that of Preparation 6.
[0319] IR (Neat): 1730, 1578 cm.sup.-1
[0320] .sup.1H-NMR (200 MHz, CDCl.sub.3, .delta.) 1.26 (3H, t,
J=7.1 Hz), 1.42 (3H, s), 1.7-1.75 (4H, m), 1.8-2.15 (2H, m), 2.16
(3H, s), 2.5-2.65 (8H, m), 4.14 (2H, q, J=7.1 Hz), 6.50 (1H, s)
[0321] MASS spectrum m/e: 303 (M+H.sup.+), 215
(M.sup.+--CH.sub.2CO.sub.2E- t)
[0322] Anal. Calcd. for C.sub.19H.sub.26O.sub.3: C, 75.46; H, 8.67
Found: C, 75.32; H, 8.82
EXAMPLE 5
[0323]
2-Ethoxycarbonylmethyl-3,4,7,8,9,10-hexahydro-2,5-dimethyl-2H-napht-
ho[2,1-e]pyran-6-sulfonyl chloride was obtained according to a
similar manner to that of Example 3.
[0324] IR (Neat): 1730, 1705 cm.sup.-1
[0325] Reference 17
[0326]
N-(2-Ethoxycarbonylmethyl-3,4,7,8,9,10-hexahydro-2,5-dimethyl-2H-na-
phtho[2,1-e]pyran-6-sulfonyl)benzamidine was obtained according to
a similar manner to that of Reference 11.
[0327] IR (CHCl.sub.3): 3450, 3350, 1725, 1630, 1533 cm.sup.-1
[0328] .sup.1H-NMR (200 MHz, CDCl.sub.3, .delta.): 1.26 (3H, t,
J=7.1 Hz), 1.43 (3H, s), 1.6-1.75 (4H, m), 1.8-2.3 (2H, m), 2.6-2.7
(9H, m), 3.27 (2H, br s), 4.14 (2H, q, J=7.1 Hz), 6.22 (1H, br s),
7.35-7.6 (3H, m), 7.75-7.8 (2H, m) , 8.16 (1H, br s)
[0329] MASS spectrum m/e: 485 (M+H.sup.+), 397
[0330] Anal. Calcd. for C.sub.26H.sub.32N.sub.2O.sub.5S: C, 64.44;
H, 6.65; N, 5.78 Found: C, 64.27; H, 6.64; N, 5.57
[0331] Reference 18
[0332]
N-(2-Carboxymethyl-3,4,7,8,9,10-hexahydro-2,5-dimethyl-2H-naphtho[2-
,1-e]pyran-6-sulfonyl)benzamidine was obtained according to a
similar manner to that of Reference 12.
[0333] IR (CHCl.sub.3): 3420, 3320, 1710, 1632, 1530 cm.sup.-1
[0334] .sup.1H-NMR (200 MHz, CDCl.sub.3, .delta.): 1.45 (3H, s),
1.68 (4H, br s), 1.85-2.2 (2H, m), 2.6-2.75 (2H, m), 2.61 (3H, s),
2.67 (2H, s), 6.27 (1H, br s), 7.3-7.6 (3H, m), 7.75-7.8 (2H, m),
8.15 (1H, br s)
[0335] MASS spectrum m/e: 457 (M+H.sup.+), 391
[0336] Reference 19
[0337] A solution of dicyclohexylamine (0.22 g) in AcOEt (1 ml) was
added to a solution of
N-(2-carboxymethyl-3,4,7,8,9,10-hexahydro-2,5-dimethyl-2-
H-naphtho[2,1-e]pyran-6-sulfonyl)-benzamidine (0.55 g) in AcOEt (4
ml) and the mixture was stirred at room temperature to give
N-(2-carboxymethyl-3,4,7,8,9,10-hexahydro-2,5-dimethyl-2H-naphtho[2,1-e]p-
yran-6-sulfonyl)benzamidine dicyclohexylamine salt as a solid (0.66
g).
[0338] mp: 188-190.degree. C.
[0339] IR (Nujol): 3370, 1620, 1530 cm.sup.-1
[0340] MASS spectrum m/e: 457 (M+H.sup.+ of free)
[0341] Anal. Calcd. for C.sub.36H.sub.51N.sub.3O.sub.5S: C, 67.78;
H, 8.06; N, 6.59 Found: C, 67.37; H, 8.26; N, 6.36
* * * * *