Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-04-23
2002-09-03
Chang, Ceila (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06444827
ABSTRACT:
TECHNICAL FILED
The present invention relates to a novel method for producing a compound of the formula [11]
wherein R is an optionally substituted aromatic hydrocarbon group, an optionally substituted alicyclic hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted condensed heterocyclic group, which is useful as a therapeutic agent for diabetes, and a method for producing an intermediate for producing this compound [11].
BACKGROUND ART
The above-mentioned compound [11] useful as a therapeutic agent for diabetes, an intermediate and a method for producing them have been already disclosed in the specification of WO95/18125, and an intermediate compound [6′]
and a method for producing same have been specifically disclosed in Journal of Medicinal Chemistry, 1992, Vol. 35, No. 14, 2625.
However, these conventional production methods require many steps and the yields of the final product and intermediates therefor are not sufficiently satisfactory. In addition, solvent, base, catalyst and the like to be used in each step suffice for use at laboratory levels but many of them are problematically impractical and cannot be used in industrial production.
DISCLOSURE OF THE INVENTION
Therefore, many attempts have been made in each step to solve such problems. To be specific, Steps 1-4 of the method (hereinafter to be referred to as A method) disclosed in Journal of Medicinal Chemistry, 1992, Vol. 35, No. 14, 2625, which is the production method most similar to the inventive method, were considered.
In A method, for example, compound [6′] wherein R is phenyl, which is one of the intermediates in the present invention, is produced by the following Steps 1 to 4.
Step 1
According to A method, compound [1] is reacted with compound [2′] in dichloromethane in the presence of triethylamine to give compound [3′]. Dichloromethane used here as a solvent is impractical for industrial production because a large amount thereof after use cannot be drained out by regulation. The present inventors have found that a safe and economical aqueous solvent (particularly water) can be also used for this reaction and solved this problem. Surprisingly, the use of an inorganic base, such as potassium carbonate, sodium carbonate and the like, as a base here was also found to increase the yield to 92-97%. Consequently, the yield could be increased by 10% as compared to conventional methods.
Step 2 and Step 3
According to A method, compound [3′] is reacted in 10 equivalents of acetic anhydride in the presence of 6-7 equivalents of triethylamine using dimethylaminopyridine to give compound [4′]. However, an aftertreatment step is necessary for obtaining compound [4′], which comprises adding water to the solvent, acetic anhydride, to convert same to acetic acid, followed by isolation and purification. This aftertreatment step requires a long time, during which time the obtained compound [4′] becomes partially decomposed. The present inventors conducted intensive studies to solve this problem associated with the aftertreatment step, as well as to improve yield. As a result, it has been found that, by adding acetic anhydride in advance in an amount (about 4 equivalents) necessary in the next step and by using dimethylaminopyridine in a toluene solvent in the presence of 0.25 equivalent of N-methylmorpholine, compound [4′] can be obtained. The obtained compound [4′] can be used in the next step without isolation or purification, and cyclization of compound [4′] using p-toluenesulfonic acid monohydrate resulted in the production of compound [5′] at a high yield (95-97%/o). Consequently, the yield of compound [5′] could be increased by about 40% as compared to A method.
Phosphorus oxychloride (POCl
3
) used in Step 3 of A method is a toxic substance having high corrosiveness, so that the use thereof is under considerable restriction, which is greatly problematic for industrial use. The present inventors have found that p-toluenesulfonic acid monohydrate could afford safety and facilitated use, whereby an industrially utilizable production method was found.
Step 4
According to A method, compound [5′] is reacted with lithium aluminum hydride (LiAlH
4
) in diethyl ether to give compound [6′]. Both LilH
4
and diethyl ether used here are highly inflammable, posing problems of safety when they are used industrially. The present inventors have solved this problem by using sodium borohydride (NaBH
4
) and tetrahydrofuran, as well as methanol as a reduction accelerator (activator), whereby a method for obtaining compound [6′] free of industrial problems has been established.
Surprisingly, the use of this method was also found to not only solve the problems of safety but also increase the yield to 85-95%. Consequently, the yield could be improved as compared to A method.
As the method to obtain the final compound [11′] from compound [6′], a method disclosed in WO95/18125 (hereinafter this method is to be referred to as B method) is most similar to the method of the present invention. The present inventors concretely considered B method.
wherein R
1
is a lower alkyl.
Step 5
According to B method, compound [6′] is reacted with p-toluenesulfonyl chloride (TsCl) in dichloromethane in the presence of pyridine to give compound [7′].
Dichloromethane used as a solvent here is subject to great restriction of waste discharge when used in large amounts, as mentioned in Step 1 of A method, so that it is impractical in industrial production. The present inventors have found that the compound can be also efficiently reacted in toluene, which is safe, whereby this problem was solved.
As regards yield, B method accompanies, besides the objective compound [7′], compound [15]
as a byproduct that reduces the yield of the objective compound [7′]. To solve this problem, the method generally exemplified in the specification of WO95/18125, but not concretely disclosed as an example, was employed. To be specific, mesyl group was used as a leaving group instead of tosyl group. Namely, methanesulfonyl chloride (MsCl) instead of TsCl was reacted with compound [6′] to surprisingly afford the objective compound [7″]
at a yield of 99-100%.
Step 6 and Step 7
In B method, compound [7′] is reacted with 4-hydroxybenzaldehyde [12] to give compound [13], and compound [13] is further reacted with malonic acid derivative [14] to give compound [9′]. In this step, compound [13] is rather unstable and the yield of compound [9′] from compound [7′] was 65%, which is not at all satisfactory. The present inventors previously synthesized compound [8] from compound [12] and compound [14]
wherein R
1
is as defined above, to improve the yield, and reacted the resulting compound and compound [7″] to find that compound [9′] could be obtained at a high yield (80-85%).
Step 8 and Step 9
In B method, compound [9′] is reduced under hydrogen atmosphere using a catalyst to give compound [10′], and compound [10′] is reacted with hydroxylamine in anhydrous alcohol to give the final objective compound [11′]. According to this step, the yield (about 40%) of the final compound is not satisfactory. To increase the yield, the present inventors did not isolate compound [10′] but reacted the compound with hydroxylamine in a mixed solvent of tetrahydrofuran, water and alcohol, in the presence of a base (e.g., potassium carbonate, sodium carbonate or sodium methoxide) to give the
Ando Koji
Suzuki Masanobu
Chang Ceila
Foley & Lardner
Japan Tobacco Inc.
Wright Sonya
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