Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
2002-06-25
2004-08-31
Rao, Deepak (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
C544S310000, C544S311000, C544S312000, C546S084000, C546S121000, C546S210000, C546S274400, C548S154000, C548S302700, C548S312100, C548S312700, C548S313700, C548S314700, C548S318100
Reexamination Certificate
active
06784293
ABSTRACT:
TECHNICAL FIELD
The present invention is directed to a process for the efficient solution and solid-phase synthesis of Boc-protected 3-aminohydantoins/thiohydantoins and 3-aminodihydrouracils/dihydrothiouracils.
BACKGROUND OF THE INVENTION
The present invention is directed to a novel process for synthesizing Boc-protected 3-aminohydantoins, 3-aminodihydrouracils, and their thio-substituted counterparts using a one-pot solution-phase or solid-phase process. 3-aminohydantoin and 3-aminodihydrouracil derivatives are useful in both the pharmaceutical and agrochemical industries. For example, compounds containing the 3-aminohydantoin or 3-aminodihydrouracil nucleus are useful as anticonvulsant agents, antibacterial agents, metalloprotease inhibitors, diuretic agents, and pesticides.
Synthetic routes for the preparation of 3-aminohydantoin derivatives are disclosed in the following references: Kiec-Kononowicz, K.; Zejc, A.; Byrtus, H.
Pol. J. Chem
. 1984, 58, 585. Lange, J. et al. Polish Patent, PL 123138 B1, Apr. 30, 1984. Wright, G. C.; Michels, J. G.; Spencer, C. F.
J. Med. Chem
. 1969, 12, 379-381. Bernard, L. et al. French Patent, 2000801, Jan. 24, 1969. Kobayashi, N. et al. Japanese Patent, 09176131 A2, Jul. 8, 1997. Taub, W. U.S. Pat. No. 2,767,193, 1956
. Chem. Abstr
., 1957, 51, 5811. Szczepanski, H.; Kristinsson, H.; Maienfish, P.; Ehrenfreund, J. WO 95/18123, 1995. Lindemann, A.; Khan, N. H.; Hoffmann, K.
J. Am. Chem. Soc
., 1952, 74, 476-479. Gante, J.; Lautsch, W.
Chem. Ber
., 1964, 97, 994. Schlogl, K.; Derkosch, J.; Korger, G. C.
Monatsh. Chem
. 1954, 85, 607. Schlogl, K.; Korger, G.
Monatsh. Chem
. 1951, 82, 799. Davidson, J. S.
J. Chem. Soc
. 1964, 4646-4647. Gillis, B. T.; Dain, J. G.
J. Heterocyclic Chem
. 1971, 8, 339-339. Wildonger, R. A; Winstead, M. B.
J. Heterocyclic Chem
. 1967, 4, 981-982. Lalezari, I.
J. Heterocyclic Chem
. 1985, 22, 741-743. Saegusa, Y.; Harada, S.; Nakamura, S.
J. Heterocyclic Chem
. 1990, 27, 739-742. Milcent, R.; Akhnazarian, A.; Lensen, N.
J. Heterocyclic Chem
. 1996, 33, 1829-1833. Ragab, F. A.; Eid, N. M.; El-Tawab, H. A.
Pharmazie
1997, 52 (12), 926-929. Yoon, J; Cho, C-W; Han; H; Janda, K. D.
Chem. Comm
. 1998, 2703-2704. However, in general the synthetic routes disclosed above involve multiple steps, require harsh reaction conditions, and/or produce relatively low yields.
Additionally, there has been growing interest in the development of solid-phase synthetic approaches to hydantoin and dihydrouracil derivatives, particularly those substituted at the N-1, N-3, and C-5 positions. Syntheses of 1-aminohydantoins and 3-aminohydantoins by solid-phase synthetic approaches are disclosed in the following references: Dewitt, S. H.; Kiely, J. S.; Stankovic, C. J.; Schroder, M. C.; Reynolds Cody, D. M.; Pavia, M. R.
Proc. Natl. Acad. Sci
. 1993, 90, 6909-6913. Dressman, B. A.; Spangle, L. A.; Kaldor, S. W.
Tetrahedron Lett
. 1996, 37, 937-940. Hanessisan, S.; Yany, R.-Y.
Tetrahedron Lett
. 1996, 37, 5835-5838. Kim, S. W.; Ahn, S. Y.; Koh, J. S.; Lee, J. H.; Ro, S.; Cho, H. Y.
Tetrahedron Lett
. 1997, 38, 4603-4606. Matthews, J.; Rivero, R. A.
J. Org. Chem
. 1997, 62, 6090-6092. Gong, Y-D.; Najdi, S.; Olmstead, M. M.; Kurth, M. J.
J. Org. Chem
. 1998, 63, 3081-3086. Xiao, X.; Ngu, K.; Chao, C.; Patel, D. V.
J. Org. Chem
. 1997, 62, 6968-6973. Smith, J.; Liras, J. L.; Schneider, S. E.; Anslyn, E. V. J.
J. Org. Chem
. 1996, 61, 8811-8813. Sim, M. M.; Ganesan, A.
J. Org. Chem
. 1997, 62, 3230-3233. Wilson, L. J.; Li, M.; Portlock, D. E.
Tetrahedron Lett
. 1998, 39, 5135-5138. Hamuro, Y.; Marshall, W. J.; Scialdone, M. A.
J. Comb. Chem
. 1999, 1, 163-167.
There is a continuing need for improved processes for producing 3-aminohydantoins, 3-aminodihydrouracils, and their thio-substituted counterparts.
SUMMARY OF THE INVENTION
The present invention provides a process for the efficient assembly of Boc-protected 3-aminohydantoins/thiohydantoins and 3-aminodihydrouracils/dihydrothiouracils via a one-pot solution phase or solid phase synthesis from readily available starting materials.
DETAILED DESCRIPTION OF THE INVENTION
Definitions and Usage of Terms
“Alkyl” is a saturated or unsaturated hydrocarbon chain having 1 to 18 carbon atoms, preferably 1 to 12, more preferably 1 to 6, more preferably still 1 to 4 carbon atoms. Alkyl chains may be straight or branched. Preferred branched alkyl have one or two branches. Unsaturated alkyl have one or more double bonds and/or one or more triple bonds. Alkyl chains may be unsubstituted or substituted with from 1 to about 4 substituents unless otherwise specified.
“Aromatic ring” is a benzene ring or a naphthlene ring.
“Carbocyclic ring” is a saturated or unsaturated hydrocarbon ring. Carbocyclic rings are not aromatic. Carbocyclic rings are monocyclic, or are fused, spiro, or bridged bicyclic ring systems. Monocyclic carbocyclic rings contain from about 4 to about 10 carbon atoms, preferably from 4 to 7 carbon atoms, and most preferably from 5 to 6 carbon atoms in the ring. Bicyclic carbocyclic rings contain from 8 to 12 carbon atoms, preferably from 9 to 10 carbon atoms in the ring. Carbocyclic rings may be unsubstituted or substituted with from 1 to about 4 substituents on the ring.
“Heteroatom” is a nitrogen, sulfur, or oxygen atom. Groups containing more than one heteroatom may contain different heteroatoms. As used herein, halogens are not heteroatoms.
“Heterocyclic ring” is a saturated or unsaturated ring containing carbon and from 1 to about 4 heteroatoms in the ring. Heterocyclic rings are not aromatic. Heterocyclic rings are monocyclic, or are fused or bridged bicyclic ring systems. Monocyclic heterocyclic rings contain from about 4 to about 10 member atoms (carbon and heteroatoms), preferably from 4 to 7, and most preferably from 5 to 6 member atoms in the ring. Bicyclic heterocyclic rings contain from 8 to 12 member atoms, preferably 9 or 10 member atoms in the ring. Heterocyclic rings may be unsubstituted or substituted with from 1 to about 4 substituents on the ring.
“Heteroaromatic ring” is an aromatic ring system containing carbon and from 1 to about 4 heteroatoms in the ring. Heteroaromatic rings are monocyclic or fused bicyclic ring systems. Monocyclic heteroaromatic rings contain from about 5 to about 10 member atoms (carbon and heteroatoms), preferably from 5 to 7, and most preferably from 5 to 6 in the ring. Bicyclic heteroaromatic rings contain from 8 to 12 member atoms, preferably 9 or 10 member atoms in the ring. Bicyclic heteroaromatic rings are ring systems wherein at least one of the two rings is a heteroaromatic ring and the other ring is a heteroaromatic ring, an aromatic ring, a carbocyclic ring, or a heterocyclic ring. Heteroaromatic rings may be unsubstituted or substituted with from 1 to about 4 substituents on the ring.
“Member atom” refers to a polyvalent atom (C, O, N, or S atom) in a chain or ring system that continues the chain or ring system. For example, in benzene the six carbon atoms are member atoms and the six hydrogen atoms are not member atoms.
Compounds Prepared Using the Present Process
The present invention is directed to a one-pot, solution-phase process for making Boc-protected 3-aminohydantoins/thiohydantoins and 3-aminodihydrouracils/dihydrothiouracils according to Formula I below:
In Formula I above, X is O or S.
In Formula I above, n is 0 or 1.
In Formula I above, R
1
is H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, or heteroaromatic ring. When R
1
is substituted alkyl, preferred substituents include: halo, hydroxy, alkoxy, aryloxy, acyloxy, carboxy, mercapto, alkylthio, arylthio, acylthio, carbamoyl, amido, aromatic ring, heteroaromatic ring, carbocyclic ring, and heterocyclic ring.
In Formula I above, R
2
is H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, or heteroaromatic ring. When R
2
is substituted alkyl, preferred substituents include: halo, hydroxy, alkoxy, aryloxy, acyloxy, carboxy, alkoxycarbonyl, mercapto, alkylthio, arylthio, acylthio, amino, carbamoyl, carbamoyloxy, amido, alkoxylamid
Janusz John Michael
Wu Shengde
Echler Sr. Richard S.
Kellerman James C.
Rao Deepak
The Procter & Gamble & Company
Upite David V.
LandOfFree
Process for making Boc-protected... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Process for making Boc-protected..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for making Boc-protected... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3320783