Organic compounds -- part of the class 532-570 series – Organic compounds – Silicon containing
Reexamination Certificate
2001-02-28
2002-06-11
Kumar, Shailendra (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Silicon containing
C556S417000, C556S463000, C556S466000, C556S470000, C558S414000, C544S064000, C549S210000
Reexamination Certificate
active
06403818
ABSTRACT:
BACKGROUNDS OF INVENTION
The invention relates to a process for producing an &agr;-hydroxy-carbonyl compound or an (&agr;-protected hydroxy-carbonyl compound. From three starting compounds by one stepped reaction. The obtained compounds are useful to derive pharmacologically useful compounds. In the process of the invention, an &agr;-hydroxycarbonyl compound, for example an &agr;-hydroxyamide and an &agr;-hydroxyester can be simply obtained. In the process, the amide moiety can be introduced from the corresponding amine moiety and the ester, from the corresponding alcohol.
The &agr;-hydroxycarbonyl compound is observed in many physiological activity. For example, EP-A 900566 published on Mar. 10, 1999, JP-A 98-182601 published on Jul. 07, 1998 and EP-A 498680 published on Aug. 12, 1992 disclose an HIV-1 Protease Inhibitor. WO 98/57932 published on Dec. 23, 1998 and WO 96/32110 published on Oct. 17, 1996 disclose an anticoagulant (thrombin inhibitor). WO 99/05104 published on Feb. 4, 1999 discloses a cyclooxygenase-2 Inhibitor. EP-A 823423 published on Feb. 11, 1998 discloses a muscarinic M Antagonist. WO 98/05641 published on Feb. 12, 1998 discloses a bronchodilator. WO 97/29077 published on Aug. 14, 1997 discloses an antineoplastic. WO 97/21725 published on Jun. 19, 1997 discloses a gpIIb/IIIa Receptor Antagonist. JP-A 96-259558 published on Oct. 8, 1998 and EP-A 552631 published on Jul. 28, 1993 discloses an antidiabetic. WO 95/11244 published on Apr. 27, 1995 discloses an NMDA Receptor Antagonist. WO 95/05386 published on Feb. 23, 1995 discloses a phosphodiesterase IV Inhibitor.
It is evident that there are many physiologically active compounds having the &agr;-hydroxycarbonyl in the structure. This is the reason efficient synthesis of the &agr;-hydroxycarbonyl will be useful to production of a physiologically active compound such as medicines. It will be useful in particular to production of a statine compound.
PRIOR ARTS
In general, the &agr;-hydroxycarbonyl compound, especially an &agr;-hydroxyester and an &agr;-hydroxyamide including many physiologically active compounds, can be obtained by synthesizing the corresponding &agr;-hydroxycarboxylic acid and esterifying or amidating it. The key intermediate compound, the &agr;-hydroxycarboxylic acid, is synthesizd at two stages, a reaction of a nucleophilic agent principally to an aldehyde or ketone and conversion of the residue of the nucleophilic agent to a carbonyl group. Typical examples thereof include production of cyanohydrin by adding cyano to carbonyl and then acid hydrolysis (for example J. J. Chen et al., Bioorg. Med. Chem. Lett., 1996, 6, 435-438, B. E. Maryanoff et al. and .J. Am. Chem. Soc., 1995, 117, 1225-1239), addition of an alkenyl anion or an equivalent thereto to a carbonyl compound and then an oxidative cleavage (H. H. Wasserman et al., Tetrahedron Lett., 1990, 40, 6163-6166 and T. Satoh et al. J. Org. Chem., 1991, 56, 4129-4134), addition of an orthoester anion to a carbonyl compound and then acid hydrolysis (M. Hagihara et al., J. Am. Chem. Soc., 1992, 114, 6570-6571), and addition to 2-thiazolygroup to a carbonyl compound and then hydrolysis (A. Dondoni et al., Synthesis, 1995, 181-186).
In order to be converted to &agr;-hydroxyamide and &agr;-hydroxyester, condensaton of the produced carbonyl group with an amine or alcohol will be necessary. Among &agr;-hydroxycarbonyl compounds, &agr;-hydroxyamide and &agr;-hydroxyester were conventionally obtained at three stages of reaction. It is known in FRG Patent 1988, 3643461 (DE-3643461), 88-183834 to produce an &agr;-hydroxyester by addition of methyl isoccyanide to a carbonyl compound in the presence of titanium tetrachloride and in C—H. Zhou et al. Synthetic Commun., 1994, 24, 43-46 to produce &agr;-hydroxyacid by reacting an aromatic aldehyde with chloroform in the presence of &agr;-cyclodextrinand triethylbenzylammonium chloride.
Those arts are involved in problems that reaction conditions are severe, agents are limited and conversion is impossible directly to &agr;-hydroxyamide.
Then Passerini Reaction can produce &agr;-acyloxyamide at a single stage. It is disclosed in I. Ugi et al. Comprehensive Organic Synthesis; Pergamon, N.Y., Vol. 2, pp 1083-1109 and H. Bienayme Tetrahedron Lett., 1998, 39, 4255-4258. Passerini Reaction, however, limits the nucleophilic agent to isocyanide and produces many products with a low yield, this way having a difficulty in application. A few of isocyanides are availale in the commercial market and therefore many isocyanides have to be synthesized to obtain necessary amides.
An example of multi-component reaction, that is, one pot reaction, supporting usefulness of the invention, is disclosed in R. B. Armstrong et al. Acc. Chem. Res., 1996, 29, 123-131.
DISCLOSURE OF INVENTION
The invention provides a process for producing an &agr;-hydroxy-carbonyl compound or an &agr;-protected hydroxy-carbonyl compound by reacting a carbonyl compound (I) with a compound (II) and a compound (III). The compounds (I), (II) and (III) are defined below.
R
1
, R
2
, R
3
and R
4
are an organic group, being different from or the same as one another. They, in particular R
1
and R
2
, may be any organic group that will not disturb the reaction. They may be protected by a protective group or have at least one substituent.
PG is a protective group for hydroxy group. Y is R
4
N, S or O.
R
1
, R
2
, R
3
and R
4
may have at least one substituent such as an aliphatic group, an alicyclic group or an aromatic hydrocarbon group which may have at least one substituent. R
1
, R
2
, R
3
and R
4
may have at least one substituent, for example, that shown by Z
1
, Z
2
or Z
3
. Z
1
, Z
2
and Z
3
are defined below and are different from or the same as one another.
In the above shown reaction, an aldehyde or ketone compound (I), an amine or alcohol compound (II) and a compound of H-MAC-TBS (III) may be reacted with one another in one pot. The reaction may be conducted in the presence of a base, which is useful when the amine compound (II) is weakly basic. Then it may be conducted with an agent to eliminate a hydrogen cation of the compound (III) or an agent to activate the compound (III). Then the reaction may be effected with the compound (III) activated.
The protective group may include TBDMS, TMS, TBDPS, an acyl group such as acetate, an organic metal or heteroatom group such as R
2
B, R
3
Ge and R
3
Sn, which can be connected with oxygen atom and then phosphoric acid or sulfonic acid.
The organic group for R
1
, R
2
, R
3
and R
4
may include typically an alkyl such as methyl, ethyl, propyl and butyl, an alkenyl such as ethylene and propylene, an alkynyl such as ethynyl and an aryl such as phenyl.
The reaction of the invention can produce an &agr;-hydroxy-carbonyl compound, including statine compounds such as cyclohexylnorstatine and statines having the following formulae. These are useful as HIV inhibitor.
The organic group is not limited, as far as it does not disturbe the invention, and for example includes: hydrogen atom, hydroxy group, a C
1-8
alkyl group, a C
3-8
cycloalkyl group, a C
4-8
bicycloalkyl group, a C
1-8
alkyl C
3-8
cycloalkyl group, a C
1-8
alkoxy C
1-8
alkyl group, a hydroxy C
1-8
alkyl group, a mercapto C
1-8
alkyl group, a C
1-8
alkylthio C
1-8
alkyl group, a C
1-8
alkylsulfonyl C
1-8
alkyl group, a C
1-8
alkylsulfinyl C
1-8
alkyl group, a halogeno C
1-8
alkyl group, a nitro C
1-8
alkyl group, a cyano C
1-8
alkyl group, a C
1-8
alkoxycarbonyl C
1-8
alkyl group, C
1-8
alkylthiocarbonyl C
1-8
alkyl group, a C
1-8
alkylaminocarbonyl C
1-8
alkyl group, di C
1-8
alkylaminocarbonyl C
1-8
alkyl group, a C
2-9
alkanoyl C
1-8
alkyl group, a C
2-9
alkanoyloxy C
1-8
alkyl group, a C
2-8
alkenyl group, a C
3-8
cycloalkenyl group, a C
1-8
alkyl C
3-8
cycloalkenyl group, a C
1-8
alkoxyl C
1-8
alkenyl group, a hydroxy C
1-8
alkenyl group, a mercapto C
1-8
alkenyl group, a C
1-8
alkylthio C
1-8
alkenyl group, a C
1-8
alkylsulfonyl C
1-8
alkenyl group, a C
1-8
alkylsulfinyl C
1-8
alkenyl group, a
Birch & Stewart Kolasch & Birch, LLP
Eisai Co. Ltd.
Kumar Shailendra
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