Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2001-08-24
2004-07-13
Geist, Gary (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C562S469000
Reexamination Certificate
active
06762315
ABSTRACT:
This application is a 371 of PCT/EP00/00834 filed Feb. 2, 2000.
BACKGROUND OF THE INVENTION
The present invention relates to a method for producing [1,1′:4′,1″]-terphenyl compounds substituted in the 4″ position.
4″-Alkoxyterphenyl-4-carboxylic acids whose alkoxy group contains an alkyl radical of medium chain length are used in conjunction with the echinocandin B macrocycle as building blocks for producing active ingredients with antibiotic, in particular antifungal, properties.
These active ingredients display a novel principle of action and are therefore of particular interest (WO 94/25050 and EP 0 561 639).
The 4″-substituted p-terphenyl to be emphasized from the group thereof is 4″-n-pentoxy-[1,1′:4′,1″]-terphenyl-4-carboxylic acid, which leads, after coupling with the echinocandin B macrocycle, to a product with excellent properties.
WO 94/25050 describes a multistage method for producing 4″-n-pentoxy-[1,1′:4′,1″]-terphenyl-4-carboxylic acid (cf. pages 28 and 29 part A, part B and part C).
In a first step, 4′-bromo-4-hydroxybiphenyl is reacted with an n-pentyl halide to give the corresponding 4′-bromo-4-n-pentoxybiphenyl. The 4′-bromo-4-n-pentoxybiphenyl is reacted in a second step with n-butyllithium at −78° C. to form, by transmetallation, 4′-lithium-4-n-pentoxybiphenyl which, in another step likewise at −78° C., is reacted with triisopropyl borate. Hydrolysis and work-up result in 4′-n-pentoxybiphenyl-4-boronic acid which is reacted in further steps with 4-iodobenzoic acid in a standard Suzuki coupling. The 4″-n-pentoxy[1,1′:4′,1″]-terphenyl-4-carboxylic acid is obtained as crude product which is purified by chromatography on silica gel.
The mode of synthesis is depicted diagrammatically in simplified form below
WO 94/25050 states yields only for the stages (part A and part B) up to formation of 4-(4-n-pentyloxyphenyl)phenylboronic acid. There is no statement of yield in part C, which relates to the production of 4″-n-pentoxy-[1,1′:4′,1″]-terphenyl-4-carboxylic acid.
EP 0 561 639 discloses the production of methyl 4″-n-pentoxy-[1,1′:4′,1″]-terphenyl-4 carboxylate using the aforementioned reaction steps 2, 3 and 4, employing methyl 4-iodobenzoate in place of 4-iodobenzoic acid in step 4. The yield of 4′-n-pentoxybiphenyl-4-boronic acid is 44% and in the reaction thereof with methyl 4-iodobenzoate is 64% (cf. statements on page 26, table 15 and 16, in each case second line across), which means that the overall yield is only 28.2% based on 4′-bromo-4-n-pentoxybiphenyl.
The method described above has several disadvantages. On the one hand, it is necessary to start from a very pure 4′-bromo-4-hydroxybiphenyl, which ought to contain the minimum amount of Br positional isomers in order to comply with the required isomer quality in the final product. On the other hand, the transmetallation in step 2 is rather complicated because it must be carried out at very low temperatures. If this reaction is not maintained in a particular temperature range and/or if the reaction times are too long, the corresponding 4,4″-di-n-pentoxy-[1,1′:1″,4″,1″′]-quaterphenyl is produced as a result of dimerization. This compound can, however, be removed from the desired final product only in a very complicated way. The reaction in step 3 is also carried out at very low temperature. A further disadvantage is that 4″-pentoxy-[1,1′:4′,1″]-terphenyl-4-carboxylic acid is evidently obtained as very impure crude product which must be purified by chromatography on silica gel.
SUMMARY OF THE INVENTION
In view of this, the object is to provide a method which avoids the disadvantages described above and can be carried out with acceptable effort.
This object is achieved by a method for producing [1,1′:4′,1″]-terphenyl compounds with the formula
in which R is hydrogen or a straight-chain or branched C
1
-C
4
-alkyl radical, in particular hydrogen, a C
1
-C
2
-alkyl radical or C(CH
3
)
3
, R
1
is hydrogen, a straight-chain or branched C
1
-C
4
-alkyl radical or a straight-chain or branched C
1
-C
4
-alkoxy radical, in particular hydrogen, a C
1
-C
2
-alkyl radical or C
1
-C
2
-alkoxy radical, preferably hydrogen, and R
2
is hydrogen, a straight-chain C
1
-C
12
-alkyl radical, an unsubstituted phenyl radical, a phenyl radical which is substituted by one or two C
1
-C
4
-alkyl groups or C
1
-C
4
-alkoxy groups, or a radical —(CH
2
)
x
OR
3
in which x is an integer from 1 to 4 and R
3
is a straight-chain or branched C
1
-C
4
-alkyl radical, in particular a straight-chain C
1
-C
8
-alkyl radical, an unsubstituted phenyl radical or a radical —(CH
2
)
x
OR
3
, in which x is an integer from 1 to 4 and R
3
is a straight-chain or branched C
1
-C
4
-alkyl radical, preferably a straight-chain C
1
-C
6
-alkyl radical or a radical —(CH
2
)
x
OR
3
in which x is an integer from 1 to 2 and R
3
is a straight-chain or branched C
1
-C
4
-alkyl radical.
It comprises reacting a metal aryl of the formula
in which A is a monovalent metal or MeX, where Me is a divalent metal and X is Cl, Br or I, and R
2
is A or a trisubstituted silyl radical, or has the meaning indicated in formula (1), excepting hydrogen, with a boric ester at −80 to 40° C. in the presence of an inert solvent, converting the reaction product by hydrolysis into a boronic acid of the formula
reacting the boronic acid, a boronic anhydride obtainable from boronic acid by elimination of water, or a mixture of boronic acid and boronic anhydride, with an alcohol, and reacting the boronic ester formed thereby with a biphenyl compound of the formula
in which R and R
1
have the meaning indicated in formula (1), and D is Cl, Br, I, O
3
S—C
n
F
2n+1
, where n is an integer from 1 to 4, or N
2
+
Y
−
where Y
−
is ClO
4
−
, BR
4
−
or HSO
4
−
, at 40 to 180° C. in the presence of a catalyst and of a polar solvent.
The method of the invention is depicted diagrammatically below in simplified form
The metal aryl of the formula (2) can be prepared be reacting a benzene derivative appropriately halogenated in the p position for example with Mg or an Li alkyl. There is no formation of a quaterphenyl compound which can be separated from the desired final product only with difficulty. The reaction of the metal aryl with boric ester does not in any case require the low temperatures indicated in WO 94/25050. Grignard compounds allow a reaction at distinctly higher temperatures than indicated in WO 94/25050.
A metal aryl of the formula (2) in which A is Li, Na, K, MgX or ZnX, in particular Li, MgX or ZnX and X is Cl, Br or I, in particular Cl or Br, is normally employed.
The method is particularly simple when a metal aryl of the formula (2) in which A is MgCl, MgBr or MgI, in particular MgCl or MgBr, preferably MgCl, is employed.
As already mentioned above, a metal aryl of the formula (2) in which R
2
is A or a trisubstituted silyl radical, or has the meaning indicated in the compound of the formula (1), but in this case cannot be hydrogen, is employed.
If it is intended to produce a terphenyl compound of the formula (1) in which R
2
is hydrogen, it is possible to start from a metal aryl (2) in which R
2
is A or the trisubstituted silyl radical, and to obtain the appropriate phenolic terphenyl compound by the subsequent work-up of the reaction product.
The trisubstituted silyl radical in the metal aryl is a radical SiR
4
R
5
R
6
in which the radicals R
4
, R
5
and R
6
are identical or different and are a phenyl radical or a C
1
-C
4
-alkyl radical, in particular are the same and are a C
1
-C
4
-alkyl radical. The silyl radical acts as protective group which can easily be eliminated after the reaction to form the appropriate phenolic group. A partic
Haber Steffen
Scherer Stefan
Bisulca Anthony A.
Clariant GmbH
Geist Gary
Hanf Scott E.
Zucker Paul A.
LandOfFree
Method for producing (1,1′,4, 11″)-terphenyl... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Method for producing (1,1′,4, 11″)-terphenyl..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Method for producing (1,1′,4, 11″)-terphenyl... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3225706