Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2001-08-17
2003-12-30
Wilson, James O. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C549S283000, C549S306000
Reexamination Certificate
active
06670458
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a process for effectively preparing L-ribose from a 1,4-lactone compound.
BACKGROUND ART
L-ribose is widely used as raw materials for food, cosmetics or medicines. Recently, as physiological functions of L-nucleosides have been gradually discovered with the support of genetic engineering, new medicines containing L-nucleoside as active ingredient are newly developed and thus, the demand for L-nucleosides are on the increase. Particularly, demand for L-ribose is highly increased as it is the key intermediate for BW1263w94(Glaxo Wellcome) as antiherpes and L-FMAU (Bukwang & Triangle) as antihepatitis B. Thus, many researchers in this field are interested in the development of an industrially applicable process for preparing the same (see: Nucleic acid & Nucleotide 18(2), 187(1999); JP 11/12294; WO 98/39347). In this regard, recently, there has been developed a process for preparing L-ribose and rare sugars using an enzyme controlling the chirality (see: WO 99/61648).
However, since the existing processes for the preparation of L-ribose had the problems of low production yield and productivity, a new effective process was strongly required. Complying with such a requirement, more effective chemical processes have been filed and patented. The researches were much more activated recently, and as a result thereof, even a biological method using an enzyme has come.
Hitherto, L-ribose of the following formula (1) was conventionally prepared from L-arabinose of the following formula (2). That is, the hydroxy group at C
2
position of L-arabinose was stereoselectively converted to give L-ribose.
One of the methods for providing L-ribose from L-arabinose proceeds via L-arabinal intermediate as depicted in the following Scheme 1 (see: J. Am. Chem. Soc., 56, 1152 (1934)). However, this method has some problems in economy due to the low yield:
Further, as depicted in the following Scheme 2, the C
2
position of L-arabinose may be oxidized by pyridine dichromate and then reduced by sodium borohydride (NaBH
4
) to provide L-ribose in a considerably high yield. However, since it is difficult to handle pyridine dichromate, said method can hardly be applied to an industrial production (see: Nucleosides & Nucleotides, 18(2), 187(1999)).
Recently, a method wherein C
2
position is stereoselectively converted in a direct manner using molybdenium trioxide (MoO
3
) as a catalyst has been developed. However, the yield of this method is low, and it is not easy to isolate and purify the resulting L-ribose from the reactants (see: JP 11-12,294). Further, an American researcher has developed a new type of process for preparing L-ribose from D-ribose (Formula III), that is, a process wherein C
1
aldehyde group of D-ribose is reduced and C
5
hydroxy group is oxidized to give L-ribose (see: the following Scheme 3). But, the problems thereof such as extremely low reaction temperature of −78° C., the nasty smell of sulfides, etc. should be solved first for the process to be industrially applied (see: WO 98/39,347).
For the purpose of overcoming the problems encountered in the synthetic methods as explained above, a Japanese researcher has designed a process for preparing L-ribose using a specific enzyme (L-ribose isomerase). This process proceeds considerably smoothly due to the use of an enzyme. However, it also has the problems to be solved for its industrial application. That is, economical and stable supply of the starting material ribitol has to be secured (see: WO 99/61,648).
DISCLOSURE OF INVENTION
Thus, the present inventors, who were keenly aware of the problems, have extensively studied to develop an economical and convenient process for obtaining L-ribose under the recognition of the absolute need thereof. As a result, we have identified that such a purpose can be achieved by a process as explained below, and then completed the present invention.
Therefore, an object of the present invention is to provide a process for effectively preparing L-ribose.
BEST MODE FOR CARRYING OUT THE INVENTION
The present invention relates to a process for preparing L-ribose of formula (1) characterized in that
(a) a compound of the following formula (3):
wherein R
1
, R
2
, R
3
and R
4
independently of one another represent C
2
-C
6
-carbonyl, benzoyl or benzyl, or R
1
and R
2
, or R
3
and R
4
may combine with each other to form isopropylidene or cyclohexylidene, is reacted with a secondary amine of the following formula (4):
wherein R′ and R″ are identical with or different from each other and independently of one another represent straight-chain or branched C
1
-C
6
-alkyl, or may combine together with the nitrogen atom to which they are attached to form 4- to 7-membered saturated heterocycle, and then reacted with a sulfonyl group-containing compound of the following formula (5):
wherein R″′ represents straight-chain or branched C
1
-C
6
-alkyl, phenyl or tolyl, and L represents reactive leaving group, preferably halogen or
to give a compound of the following formula (6):
wherein R
1
, R
2
, R
3
and R
4
are defined as above, which has a converted chirality at 4-position carbon as compared with the compound of formula (3);
(b) the compound of formula (6) is reduced by DIBAL-H and then reacted with a compound of the following formula (7):
RX (7)
wherein R represents benzyl, benzoyl, C
1
-C
4
-alkanoyl or C
1
-C
4
-alkyl, and X represents halogen, to give a compound of the following formula (8):
wherein R
1
, R
2
, R
3
, R
4
and R are defined as above;
(c) the compounds of formulae (6) and (8) are reacted with periodic acid and then reduced by DIBAL-H or NaBH
4
to give compounds of the following formulae (9) and (10), respectively:
wherein R
1
, R
2
and R are defined as above; and
(d) the compound of formula (9) or (10) thus obtained is subjected to a hydrolysis reaction in a solvent.
The process for preparing L-ribose according to the present invention can be summarized as the following Scheme 4.
Hereafter, the process of the present invention will be more specifically explained step by step.
First, in Step (a), the 1,4-lactone compound of formula (3) is reacted with the secondary amine of formula (4) and then reacted with the sulfonyl group-containing compound of formula (5) to convert the chirality of 4-position carbon. As the similar chirality conversion process known in the art, there can be mentioned a process wherein a 1,5-lactone compound is reacted with benzyloxyamine (a primary amine) and then subjected to Mitsunobu reaction to convert the chirality of 5-position carbon in a comparatively high yield, as depicted in the following Scheme 5 (see: J. Am. Chem. Soc., 122, 2995(2000)):
This method provides a comparatively high reaction yield. However, the starting materials such as benzyloxyamine or DEAD are expensive and thus, uneconomic; the reactant triphenylphosphine is not suitable for being used industrially; and work-up process is not easy due to some side reactions such as the formation of lactam compound by N-cyclization reaction instead of the formation of lactone compound by O-cyclization. Therefore, this method is not appropriate for being utilized in an industrial production.
Therefore, the present inventors have tried to develop a new process effectively converting the chirality of 4- or 5-position carbon in 1,4- or 1,5-lactone compound and as a result thereof, come to the conclusion that such a purpose can be achieved using a secondary amine and a sulfonyl group-containing compound.
The process of Step (a) is preferably carried out in a solvent. Any typical organic solvent which does not adversely affect the reaction may be used, but ethyl acetate, methylene chloride, tetrahydrofuran, pyridine, etc. are preferable. However, alcohol solvents are not appropriate. The reactant secondary amine of formula (4) itself can function as a solvent. Therefore, in such a case, the reaction can proceed smoothly without any need to use a separate solvent. The react
Hong Hyun Woung
Jeong Nak Cheol
Kim Gun Cheol
Kim Sul A
Lee Sang Jo
Hanchem Co., Ltd.
Owens, Jr. Howard V.
Wilson James O.
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