Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2002-06-13
2003-11-11
Davis, Brian (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C560S115000, C560S148000, C560S160000, C564S413000, C564S487000, C564S503000
Reexamination Certificate
active
06646150
ABSTRACT:
This application is a 371 of PCT/JP00/01021 filed Feb. 23, 2000.
TECHNICAL FIELD
The present invention relates to a novel process for industrially producing (aminomethyl)trifluoromethylcarbinol derivatives, in particular, optically active compounds thereof, which are useful as a starting compound for producing drugs.
PRIOR ART
(Aminomethyl)trifluoromethylcarbinol derivatives, in particular, optical active compounds thereof are important starting compounds for producing drugs such as protease inhibitors, etc., and some processes for producing the same have been reported.
For instance, JP-A-10-513173 (WO 96/23812) (hereinafter, occasionally referred to as Ref. 1) and J. Med. Chem., 40, 3173-3181 (1997) (hereinafter, occasionally referred to as Ref. 2) disclose the process as indicated in the Reaction Scheme (1) shown in
FIG. 1
for producing (2R,3S)-3-amino-1,1,1-trifluoro-4-methyl-2-pentanol.
However, this process consists of many steps and further contains optical resolution steps, by which the total yield of the desired compound is low, and hence, this process is not suitable for industrial production.
The reaction conditions for each step:
(1) NaNO
2
, DMF;
(2) CF
3
CH(OH)OEt, K
2
CO
3
, t-BuOMe, fractional crystallization, distillation under reduced pressure;
(3) LiAlH
4
, Et
2
O;
(4) Triphosgen, NaOH;
(5) {circle around (1)} BuLi/THF, (−)-menthyl chloroformate;
{circle around (2)} Fractional crystallization;
(6) KOH
In addition, J. Med. Chem., 35, 641-662 (1992) (hereinafter, occasionally referred to as Ref. 3) discloses a process for producing (3S,2RS)-3-amino-4-phenyl-1,1,1-trifluoromethyl-2-butanol, which comprises obtaining N-t-butoxycarbonyl-L-phenylalaninal (aldehyde compound) from N-t-butoxycarbonyl-L-phenylalanine, followed by reacting the resultant with trimethyl(trifluoromethyl)silane (Ruppert reagent), as shown in the Reaction Scheme (2) shown in FIG.
2
. However, it may be difficult to synthesize the intermediate for this process, i.e., an aldehyde compound, depending on the kinds of the amino acid, and when an amino acid having a large steric hindrance such as valine is used, the reaction with trimethyl(trifluoromethyl)silane cannot proceed. Therefore, this process cannot be a generally applicable process for producing (aminomethyl)trifluoromethylcarbinol derivatives.
As shown in the Reaction Scheme (3) shown in
FIG. 3
, J. Org. Chem., 63, 5179-5192 (1998) (hereinafter, occasionally referred to as Ref. 4) discloses that the 5-OH compound was synthesized starting from an optically active amino acid wherein the amino group is protected via the compound 1-8, and that said 5-OH compound could not be converted into a trifluoromethyl ketone compound by acid decomposition. In addition, there is no description as to the reduction of the 5-OH compound.
Further, WO 97/19681 (hereinafter, occasionally referred to as Ref. 5) illustrates in formula the synthesis of trifluoromethyl ketone compound starting from the compound 1-8 as shown in the Reaction Scheme (3). However, this literature does not disclose the conversion of the 5-OH compound into trifluoromethyl ketone compound. This literature merely indicates the synthesis of trifluoromethyl ketone compound by treating the 5-OH compound wherein the 2-position is substituted by 4-methylphenyl group or t-butyl group by ion-exchange resin.
DISCLOSURE OF INVENTION
The present inventors have intensively studied to find a process for industrially producing optically active (aminomethyl)trifluoromethyl-carbinol derivatives, and found that optically active (aminomethyl)-trifluoromethylcarbinol derivatives can surprisingly be obtained in high yield by reducing the 5-OH compound such as Compound 1b or 4b as shown the above Reaction Scheme (3), and further found that (aminomethyl)trifluoromethyl carbinol derivatives can be obtained easily in high yield by carrying out the reaction of each step of the above Reaction Scheme (3) starting from Compound 1-8 stepwise or in one-pot reaction, and have accomplished the present invention.
That is, the present invention provides novel processes for producing (aminomethyl)trifluoromethylcarbinol derivatives by the following Process A or Process B.
Process A of the present invention is a process for producing (aminomethyl)trifluoromethylcarbinol derivatives of the formula (I):
wherein R
1
is a group corresponding to the side chain of a natural or non natural &agr;-amino acid, R
2
is a hydrogen atom or R
21
(in which R
21
is a protecting group for amino group having a carbonyl group at the binding site to the nitrogen atom), provided that when a functional group exists in R
1
, then such functional groups may optionally be protected,
or an acid addition salt thereof,
which comprises reducing a 5-hydroxy-5-trifluoromethyl-1,3-oxa-zolidine derivative of the formula (II) (hereinafter, occasionally referred to as the 5-hydroxy compound):
wherein R
1
and R
21
are as defined above,
if necessary, removing a protecting group for amino group R
21
from the product to give a compound of the formula (I) wherein R
2
is a hydrogen atom, then followed by converting the product into an acid addition salt thereof, if necessary.
In addition, Process B of the present invention is a process for producing (aminomethyl)trifluoromethylcarbinol derivatives of the formula (I):
wherein R
1
and R
2
are as defined above,
or an acid addition salt thereof,
which comprises carrying out the following Steps (a), (b) and (c) stepwise or by one-pot reaction, if necessary, removing a protecting group for amino group R
21
from the product to give a compound of the formula (I) wherein R2 is a hydrogen atom, then followed by converting the product into an acid addition salt thereof, if necessary.
Step (a): Step of obtaining 5-trialkylsilyloxy-5-trifluoromethyl-1,3-oxazolidine derivative of the formula (IV) (hereinafter, occasionally referred to as the 5-trialkylsilyloxy compound);
wherein R
1
and R
21
are as defined above,
by reacting a 1,3-oxazolidin-5-one derivative of the formula (III) (hereinafter, occasionally referred to as the 5-ketone compound):
wherein R
1
and R
21
are as defined above,
with a trialkyl(trifluoromethyl)silane;
Step (b): Step of removing a trialkylsilyl group from the compound (IV) to give a 5-hydroxy compound of the formula (II):
wherein R
1
and R
21
are as defined above; and
Step (c): Step of reducing the compound (II).
Further, the present invention provides an (aminomethyl)trifluoromethylcarbinol derivative of the formula (I):
wherein R
1
and R
2
are as defined above,
or an acid addition salt thereof, which is produced by Process A or Process B.
The terms in the present description are explained below.
The “group corresponding to the side chain of a natural or non-natural &agr;-amino acid” defined by R
1
means a group corresponding to the amino acid side chain of a naturally occurred or artificially synthesized &agr;-amino acid, i.e., a group obtained by removing a —CH(NH
2
)COOH moiety from an &agr;-amino acid, and when a functional group containing a nitrogen atom, an oxygen atom or a sulfur atom exists in said group, then said functional groups may be protected. The protecting group may be any one which does not disturb the production of the 5-hydroxy compound (II) either chemically, sterically and/or electronically.
Examples of the functional groups containing a nitrogen atom are an amino group, a mono-lower alkylamino group, a guanidino group, a 3-indolyl group, a 4-imidazolyl group, a 2-, 3- or 4-piperidyl group, a 3-morpholinyl group, a 2-piperazinyl group, etc.
Examples of the functional groups containing an oxygen atom are a hydroxy group, a carboxyl group, etc.
Examples of the functional groups containing a sulfur atom are a mercapto group, a sulfo group (—SO
3
H), etc.
For these functional groups, it is preferable to select ones being stable under conditions for removal of protecting group for amino group R
21
. Examples of the protecting groups are well known in this art, and can be easily selected by making reference to, for example, Protecting Group in Orga
Deguchi Takashi
Inoue Yasunao
Omodani Tomoki
Sato Fuminori
Shiratake Ryotaro
Dainippon Pharmaceutical Co., Ltd.
Davis Brian
Wenderoth , Lind & Ponack, L.L.P.
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