WO2001027087A2 - Process for making boc-protected 3-aminohydantoins/thiohydantoins and 3-aminodihydrouracils/dihydrothiouracils - Google Patents

Process for making boc-protected 3-aminohydantoins/thiohydantoins and 3-aminodihydrouracils/dihydrothiouracils Download PDF

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WO2001027087A2
WO2001027087A2 PCT/US2000/027503 US0027503W WO0127087A2 WO 2001027087 A2 WO2001027087 A2 WO 2001027087A2 US 0027503 W US0027503 W US 0027503W WO 0127087 A2 WO0127087 A2 WO 0127087A2
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ring
carbamic acid
mmol
resin
dimethylethyl ester
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PCT/US2000/027503
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French (fr)
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WO2001027087A3 (en
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Shengde Wu
John Michael Janusz
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The Procter & Gamble Company
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Priority to US10/089,329 priority patent/US6784293B1/en
Publication of WO2001027087A2 publication Critical patent/WO2001027087A2/en
Publication of WO2001027087A3 publication Critical patent/WO2001027087A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/72—Two oxygen atoms, e.g. hydantoin
    • C07D233/80—Two oxygen atoms, e.g. hydantoin with hetero atoms or acyl radicals directly attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/86—Oxygen and sulfur atoms, e.g. thiohydantoin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • 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.
  • 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.
  • compounds containing the 3-aminohydantoin or 3-aminodihydrouracil nucleus are useful as anticonvulsant agents, antibacterial agents, metalloprotease inhibitors, diuretic agents, and pesticides.
  • the present invention provides a process for the efficient assembly of Boc- protected 3-aminohydantoins/fhiohydantoins and 3- aminodihydrouracils/dihydrothiouracils via a one-pot solution phase or solid phase synthesis from readily available starting materials.
  • 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.
  • 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:
  • X is O or S.
  • n is 0 or 1.
  • Rj 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.
  • R 2 is H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, or heteroaromatic ring.
  • preferred substituents include: halo, hydroxy, alkoxy, aryloxy, acyloxy, carboxy, alkoxycarbonyl, mercapto, alkylthio, arylthio, acylthio, amino, carbamoyl, carbamoyloxy, amido, alkoxylamido, ureido, guanidino, aryl, heteroaryl, cycloalkyl or heterocyclyl.
  • Ri and R 2 may instead together form a ring system; said ring system being carbocyclic ring, heterocyclic ring, or heteroaromatic ring.
  • Rj and the member carbon atom adjacent to the carbon atom containing R 2 may instead together form a ring system; said ring system being carbocyclic ring, heterocyclic ring, or heteroaromatic ring.
  • the Boc-protected 3-aminohydantoins/thiohydantoins and 3- aminodihydrouracils/dihydrothiouracils of the present invention may be further modified into substituted 3 -aminohydantoins/thiohy dantoins and 3- aminodihydrouracils/dihydrothiouracils using methods known to one of ordinary skill in the art.
  • Carbamic acid (tetrahydro-2,6-dioxo-3-(phenylmethyl)-l(2H)-pyrimidinyl)-, 1,1- dimethylethyl ester.
  • Carbamic acid (tetrahydro-6-oxo-3-(phenylmethyl)-2-thioxo-l(2H)-pyrimidinyl)-, 1,1- dimethylethyl ester.
  • Carbamic acid (tetrahydro-6-oxo-3-(4-methoxyphenyl)-2-thioxo- 1 (2H)-pyrimidinyl)- 1,1 -dimethylethyl ester.
  • Carbamic acid (hexahydro-l,6,8-trioxo-2H-pyrazinol[l,2-c]pyrimidin-7(6H)- yl)-, 1,1- dimethylethyl ester.
  • the present invention provides a one-pot solution-phase process for preparing compounds according to Formula I above depicted below as Scheme I.
  • Ri and R 2 are as defined above for Formula I, and R is alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, or heteroaromatic ring.
  • R is methyl, ethyl, and benzyl.
  • the resulting intermediates according to Sia need not be isolated, but rather undergo intramolecular cyclization to the desired products of Formula I on warming.
  • the next step in the process is heating the reaction mixture.
  • Commonly used organic solvents are used. Preferred organic solvents include THF, DMF, dioxane, and methylene chloride. The most preferred organic solvent is dioxane.
  • Solid-Phase Process for Making Compounds According to Formula I in another embodiment, provides a solid-phase process for preparing compounds according to Formula la below.
  • Formula la is a subset of Formula I compounds.
  • Ri a is H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, or heteroaromatic ring
  • R 2a is H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, or heteroaromatic ring
  • R ⁇ a and R 2a are as defined above for Formula I, and Q is a Merrifield resin, hydroxymethyl resin, Wang resin, or PEG resin, preferably a Merrifield resin.
  • These resin-bound or amino acid esters are made from commercially available starting materials from methods known to one of ordinary skill in the art.
  • a preferred method for the preparation of Merrifield resin-bound or amino acid esters resins is to esterify the Merrifield resin with ⁇ -bromoacetic acid or acrylic acid.
  • Relevant references include: Wilson, L. J.; Li, M.; Portlock, D. E. Tetrahedron Lett. 1998, 39 5135-5138. Morphy, J. R.; Rankovic, Z.; Rees, D. C. Tetrahedron Lett. 1996, 37 3209-3212. Kolodziej, S.; Hamper, B. C. . Tetrahedron Lett. 1996, 37 5277-5280.
  • This method allows for the ready preparation of 3-aminohydantoins/ thiohydantoins and 3-aminodihydrouracils/dihydrothiouracils which contain a wide variety of substituents at N-1, including basic groups which can be difficult to purify when made by solution methods.
  • 1 ,4-dioxane is added dropwise 660 mg (5 mmol) of tert-butyl carbazate in 25 mL of 1 ,4- dioxane.
  • the solution is stirred for 3 hours at room temperature, followed by the addition of N-2-furanylmethyl- -alanine ethyl ester 985 mg (5 mmol).
  • the resulting mixture is refluxed for 24 hours.
  • the dioxane is removed under reduced pressure.
  • 1 ,4-dioxane is added dropwise 0.66 g (5 mmol) of tert-butyl carbazate in 25 mL of 1 ,4- dioxane.
  • the solution is stirred for 3 hours at room temperature, followed by the addition of N-(4-methoxyphenyl)- -alanine ethyl ester 1.12 g (5 mmol).
  • the resulting mixture is refluxed for 48 hours.
  • the dioxane is removed under reduced pressure.
  • the Merrifield resin-bound -bromoacetate ester (3 g, loading 0.67 mmol/g) is treated with DMSO (60 mL) and 2-(2-aminoethyl)-l-methylpyrrolidine (1.42 g, 10 mmol) and allowed to shake for 24 hours at room temperature. Washing two times each with DMF, MeO ⁇ , DCM affords the resin.
  • Example 25 Preparation of carbamic acid, [tetrahydro-2,6-dioxo-3-[l-(phenylmethyl)-4- piperidinyl]-l(2/7)-pyrimidinyl]-, 1,1-dimethylethyl ester: Merrifield resin-bound acrylate ester (2 g, loading, 8.0 mmol/g) is treated with DMSO (50 mL) and 4-amino-l-benzyl-piperidine (1.52 g, 8 mmol) and allowed to shake for 24 hours at room temperature. Washing two times each with DMF, MeOH, DCM affords the resin.

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Abstract

The present invention provides a process for the efficient assembly of Boc-protected 3-aminohydantoins/thiohydantoins and 3-aminodihydrouracils/dihydrothiouracils having the following structure: (I) wherein X is O or S; N is 0 or 1; R1 is H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, or heteroaromatic ring; R2 is H, alkyl, carboxyclic ring, heterocyclic ring, aromatic ring, or heteroaromatic ring; and when n is 0, R1 and R2 may instead together form a ring system; said ring system being carbocyclic ring, heterocyclic ring, or heteroaromatic ring; or when n is 1, R1 and the member carbon atom adjacent to the carbon atom containing R2 may instead together form a ring system; said ring system being carboxyclic ring, heterocyclic ring, or heteroaromatic ring, via a one-pot solution phase or solid phase synthesis from readily available starting materials.

Description

PROCESS FOR MAKING BOC-PROTECTED 3-
AMINOHYDANTOINS/THIOHYDANTOINS AND 3-
AMINODIHYDROURACILS/DIHYDROTHIOURACILS
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 Bl, April 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, January 24, 1969. Kobayashi, N. et al. Japanese Patent, 09176131 A2, July 8, 1997. Taub, W. U.S. Patent 2767193, 1956. Chem. Abstr., 1957, 51, 5811. Szczepanski, H.; Kristinsson, H.; Maienfish, P.; Ehrenfreund, J. WO 95/18123, 1995. Lindemann, A.; Khan, N. H.; Hofmann, K. J. Am. Chem. Soc., 1952, 74, 476-479. Gante, I; 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-l, 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.; Ann, 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- aminohy dantoins, 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/fhiohydantoins 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:
Figure imgf000005_0001
In Formula I above, X is O or S. In Formula I above, n is 0 or 1.
In Formula I above,
Figure imgf000005_0002
is H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, or heteroaromatic ring. When Rj 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, R2 is H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, or heteroaromatic ring. When R2 is substituted alkyl, preferred substituents include: halo, hydroxy, alkoxy, aryloxy, acyloxy, carboxy, alkoxycarbonyl, mercapto, alkylthio, arylthio, acylthio, amino, carbamoyl, carbamoyloxy, amido, alkoxylamido, ureido, guanidino, aryl, heteroaryl, cycloalkyl or heterocyclyl.
In Formula I above, when n is 0, Ri and R2 may instead together form a ring system; said ring system being carbocyclic ring, heterocyclic ring, or heteroaromatic ring.
When n is 1, Rj and the member carbon atom adjacent to the carbon atom containing R2 may instead together form a ring system; said ring system being carbocyclic ring, heterocyclic ring, or heteroaromatic ring.
The Boc-protected 3-aminohydantoins/thiohydantoins and 3- aminodihydrouracils/dihydrothiouracils of the present invention may be further modified into substituted 3 -aminohydantoins/thiohy dantoins and 3- aminodihydrouracils/dihydrothiouracils using methods known to one of ordinary skill in the art.
Compounds which may be prepared using the present invention include, but are not limited to the following:
Carbamic acid, [2,5-dioxo-3-(phenylmethyl)-l-imidazolidinyl]-, 1,1-dimethylethyl ester. o
O Carbamic acid, [5-oxo-3-(phenylmethyl)-2-thioxo-l-imidazolidinyl]-, 1,1-dimethylethyl ester.
BCΛΛ Q
Carbamic acid, [4-methyl-2,5-dioxo-3-(phenylmethyl)-l-imidazolidinyl]-, 1,1- dimethylethyl ester.
Figure imgf000006_0001
Carbamic acid, [4-methyl-5-oxo-3-(phenylmethyl)-2-thioxo-l-imidazolidinyl]-, 1,1- dimethylethyl ester.
Figure imgf000006_0002
Carbamic acid, ((7aS)-tetrahydro-l,3-dioxo-lH-pyrrolo[l,2-c]imidazol-2(3H)-yl-, 1,1- dimethylethyl ester.
Figure imgf000006_0003
Carbamic acid, ((7aS)-tetrahydro- 1 -oxo-3-thioxo- lH-pyrrolo[ 1 ,2-c]imidazol-2(3H)-yl-, 1,1 -dimethylethyl ester.
Figure imgf000006_0004
Carbamic acid, (Ηexahydro-l,3-dioxoimidazol[l,5-a]pyridin-2(3H)-yl)-, 1,1- dimethylethyl ester.
Figure imgf000006_0005
Carbamic acid, (Hexahydro-l-oxo-3-thioxoimidazol[l,5-a]pyridin-2(3H)-yl)-, 1,1- dimethylethyl ester.
Figure imgf000007_0001
Carbamic acid, (( 1 OaS)- 1,5,10,1 Oa-tetrahydro- 1 ,3-dioxoimidazol [ 1 ,5-b]isoquinolin- 2(3H)-yl)-, 1,1-dimethylethyl ester.
Figure imgf000007_0002
Carbamic acid, ((10aS)-l,5,10,10a-tetrahydro-l-oxo-3-thioxoimidazol[l,5-b]isoquinolin- 2(3H)-yl)-, 1,1-dimethylethyl ester.
Figure imgf000007_0003
Carbamic acid, (Tetrahydro-5,7-dioxoimidazol[5,l-b]thiazol-6(5H)-yl)-, 1,1- dimethylethyl ester.
Figure imgf000007_0004
Carbamic acid, (Tetrahydro-7-oxo-7-thioxoimidazol[5,l-b]thiazol-6(5H)-yl)-, 1,1- dimethylethyl ester.
Figure imgf000007_0005
Carbamic acid, ((6i?,7aS)-tetrahydro-6-hydroxy- 1 ,3-dioxo- lH-pyrrolo[ 1 ,2-c]imidazol- 2(3H)-yl-, 1 , 1 -dimethylethyl ester.
Figure imgf000007_0006
Carbamic acid, (2,5-dioxo-3-phenyl-l-imidazolidinyl)-, 1,1-dimethylethyl ester.
Figure imgf000007_0007
Carbamic acid, (5-oxo-3-phenyl-2-thioxo-l-imidazolidinyl)-, 1,1-dimethylethyl ester.
Figure imgf000008_0001
Carbamic acid, (tetrahydro-2,6-dioxo-3-(phenylmethyl)-l(2H)-pyrimidinyl)-, 1,1- dimethylethyl ester.
Figure imgf000008_0002
Carbamic acid, (tetrahydro-6-oxo-3-(phenylmethyl)-2-thioxo-l(2H)-pyrimidinyl)-, 1,1- dimethylethyl ester.
Figure imgf000008_0003
Carbamic acid, (3-(2-furanylmethyl)tetrahydro-2,6-dioxo-l(2H)-pyrimidinyl)-, 1,1- dimethylethyl ester.
Figure imgf000008_0004
Carbamic acid, (3-(2-furanylmethyl)tetrahydro-6-oxo-2-thioxo-l(2H)-pyrimidinyl)-, 1,1- dimethylethyl ester.
Figure imgf000008_0005
Carbamic acid, (3-butyltetrahydro-2,6-dioxo-l(2H)-pyrimidinyl)-, 1,1-dimethylethyl ester.
Figure imgf000008_0006
Carbamic acid, (3 -butyltetrahydro-6-oxo-2-thioxo- 1 (2H)-pyrimidinyl)-, 1 , 1 -dimethylethyl ester.
Η s Boc-N - ΛN^^
Carbamic acid, (tetrahydro-6-oxo-3-phenyl-2-thioxo-l(2H)-pyrimidinyl)-, 1,1- dimethylethyl ester.
Figure imgf000009_0001
Carbamic acid, (tetrahydro-6-oxo-3-(4-methoxyphenyl)-2-thioxo- 1 (2H)-pyrimidinyl)- 1,1 -dimethylethyl ester.
Figure imgf000009_0002
Carbamic acid, (hexahydro-l,6,8-trioxo-2H-pyrazinol[l,2-c]pyrimidin-7(6H)- yl)-, 1,1- dimethylethyl ester.
Figure imgf000009_0003
Carbamic acid, [3-[(4-methoxyphenyl)methyl)-2,5-dioxo-l-imidazolidinyl]-, 1,1- dimethylethyl ester.
Figure imgf000009_0004
Carbamic acid, [3-(l,3-benzodioxol-5-ylmethyl)-2,5-dioxo-l-imidazolidinyl]-, 1,1- dimethylethyl ester.
Figure imgf000009_0005
Carbamic acid, [2,5-dioxo-3-[2-(2-pyridinyl)ethyl]-l-imidazolidinyl]-, 1,1-dimethylethyl ester.
Figure imgf000009_0006
Carbamic acid, [3-[2-(5-methoxy-lH-indol-3-yl)ethyl]-2,5-dioxo-l-imidazolidinyl]- 1,1- dimethylethyl ester.
Figure imgf000009_0007
Carbamic acid, [3-[2-(lH-imidazol-4-yl)-ethyl]-2,5-dioxo-l-imidazolidinyl]-, 1,1- dimethylethyl ester.
Figure imgf000010_0001
Carbamic acid, [3-[2-(lH-imidazol-l-yl)-ethyl]-2,5-dioxo-l-imidazolidinyl]-, 1,1- dimethylethyl ester.
Figure imgf000010_0002
Carbamic acid, [3-[2-[[5-nitro-2-pyridinyl]amino]ethyl]-2,5-dioxo- 1 -imidazolidinyl]-, 1 , 1 -dimethylethyl ester.
Figure imgf000010_0003
Carbamic acid, [2,5-dioxo-3-[2-(l-piperidinyl)ethyl]-l -imidazolidinyl]-, 1,1- dimethylethyl ester.
Figure imgf000010_0004
Carbamic acid, [5-oxo-3-[2-(l- piperidinyl)ethyl]-2-thioxo-l -imidazolidinyl]-, 1,1- dimethylethyl ester.
Figure imgf000010_0005
Carbamic acid, [3-[2-(l-methyl-2-pyrrolidinyl)ethyl]-2,5-dioxo-l -imidazolidinyl]-, 1,1- dimethylethyl ester.
Figure imgf000010_0006
Carbamic acid, [3-[2-(2-methyl-l-piperidinyl)propyl]-2,5-dioxo-l -imidazolidinyl]-, 1,1- dimethylethyl ester.
Figure imgf000011_0001
Carbamic acid, [2,5-dioxo-3-[3-(l-piperidinyl)propyl]-l -imidazolidinyl]-, 1,1- dimethylethyl ester.
Figure imgf000011_0002
Carbamic acid, [3-[3-(4-morpholinyl)propyl]-2,5-dioxo-l -imidazolidinyl]-, 1,1- dimethylethyl ester.
Figure imgf000011_0003
Carbamic acid, [2,5-dioxo-3-[3-(2-oxo-l-pyrrolidinyl)propyl]-l -imidazolidinyl]-, 1,1- dimethylethyl ester.
Figure imgf000011_0004
Carbamic acid, [3-[(6,6-dimethylbicyclo[3.1.1 ]hept-3-yl)methyl]-2,5-dioxo- 1 - imidazolidinyl]-, 1,1-dimethylethyl ester.
Figure imgf000011_0005
Carbamic acid, [2,5-dioxo-3-[l-(phenylmethyl)-4-piperidinyl]-l -imidazolidinyl]-, 1,1- dimethylethyl ester.
Figure imgf000011_0006
Carbamic acid, [3-[(4-methoxyphenyl)methyl)-5-oxo-2-thioxo-l -imidazolidinyl]-, 1,1- dimethylethyl ester.
Figure imgf000011_0007
Carbamic acid, [tetrahydro-3-[(5-nitro-2-pyridinyl)amino]ethyl]-2,6-dioxo-l(2H)- pyrimidinyl]-, 1,1-dimethylethyl ester.
Figure imgf000012_0001
Carbamic acid, [tetrahydro-3-[2-(4-morpholinyl)ethyl]-2,6-dioxo- 1 (2H)-pyrimidinyl]- 1 , 1 -dimethylethyl ester.
Figure imgf000012_0002
Carbamic acid, [tetrahydro-2,6-dioxo-3-[l-(phenylmethyl)-4-piperidinyl]-l(2H)- pyrimidinyl]-, 1,1-dimethylethyl ester.
Figure imgf000012_0003
Solution-Phase Process for Making Compounds According to Formula I
In one embodiment, the present invention provides a one-pot solution-phase process for preparing compounds according to Formula I above depicted below as Scheme I. The process depicted below in Scheme I requires no chromatographies (for n = 0) and a simple liquid/liquid extraction and crystallization/filtration at the end.
Scheme 1
Figure imgf000012_0004
Sia Formula I
The process depicted above in Scheme I begins with providing a compound according to Formula II. In Formula II, X is as defined above for Formula I. Compounds according to Formula II can be made from known starting materials and methods known to one of ordinary skill in the art. One particularly preferred method for the preparation of compounds according to Formula II involves slow addition of commercially available t-butoxycarbonyl (Boc) hydrazine to carbonyldiimidazole (X = O) or fhiocarbonyldiimidazole (X = S). Once made, compounds according to Formula II need not be isolated, but rather can be reacted in situ for the next step.
Compounds according to Formula II are first reacted with or amino acid esters having the following general structure:
Figure imgf000013_0001
wherein Ri and R2 are as defined above for Formula I, and R is alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, or heteroaromatic ring. Preferred R is methyl, ethyl, and benzyl. These or amino acid esters are commercially available or are made from commercially available starting materials from methods known to one of ordinary skill in the art.
The resulting intermediates according to Sia need not be isolated, but rather undergo intramolecular cyclization to the desired products of Formula I on warming. Thus, the next step in the process is heating the reaction mixture. The preferred reaction time is 8 hours and the reaction temperature is preferably kept between 60-70°C for 3- aminohydantoin derivatives (Formula I wherein n = 0). The preferred reaction time is >24 hours and the reaction temperature is preferably kept between 100-110°C for 3- aminodihydrouracil derivatives (Formula I wherein n = 1). Commonly used organic solvents are used. Preferred organic solvents include THF, DMF, dioxane, and methylene chloride. The most preferred organic solvent is dioxane.
Solid-Phase Process for Making Compounds According to Formula I In another embodiment, the present invention provides a solid-phase process for preparing compounds according to Formula la below. Formula la is a subset of Formula I compounds.
Figure imgf000013_0002
wherein X is O or S; n is 0 or 1;
Ria is H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, or heteroaromatic ring; R2a is H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, or heteroaromatic ring;
The solid phase process is depicted below as Scheme II.
Scheme II
Figure imgf000014_0001
Siia Formula I
The process depicted above in Scheme II begins with providing a compound according to Formula II. Compounds according to Formula II are first reacted with resin-bound or amino acid esters having the following general structure:
Figure imgf000014_0002
wherein Rιa and R2a are as defined above for Formula I, and Q is a Merrifield resin, hydroxymethyl resin, Wang resin, or PEG resin, preferably a Merrifield resin. These resin-bound or amino acid esters are made from commercially available starting materials from methods known to one of ordinary skill in the art. A preferred method for the preparation of Merrifield resin-bound or amino acid esters resins is to esterify the Merrifield resin with α-bromoacetic acid or acrylic acid. Relevant references include: Wilson, L. J.; Li, M.; Portlock, D. E. Tetrahedron Lett. 1998, 39 5135-5138. Morphy, J. R.; Rankovic, Z.; Rees, D. C. Tetrahedron Lett. 1996, 37 3209-3212. Kolodziej, S.; Hamper, B. C. . Tetrahedron Lett. 1996, 37 5277-5280.
Compounds according to Formula II are preferably reacted with these resin- bound or amino acid esters at room temperature. Intermediates according to Siia are then thoroughly washed to remove impurities and excess reagents. In this reaction step, common organic solvents are used. Preferred organic solvents include THF, DMF, dioxane, acetonitrile and methylene chloride. The most preferred solvent is anhydrous DMF. Warming compounds according to Siia induces intramolecular cyclization and release from the resin to provide the desired products according to Formula I. Thus, the next step in the process is heating the reaction mixture. The temperature of the cyclization reaction is preferably kept between about 60-70°C and the reaction time is preferably about 8-10 hours for the formation of 3-aminohydantoin derivatives (Formula I, wherein n = 0). The temperature of the cyclization reaction is preferably kept between about 90-95°C and the reaction time is preferably 24 hours for the formation of 3- aminodihydrouracil derivatives (Formula I, wherein n = 1 ).
This method allows for the ready preparation of 3-aminohydantoins/ thiohydantoins and 3-aminodihydrouracils/dihydrothiouracils which contain a wide variety of substituents at N-1, including basic groups which can be difficult to purify when made by solution methods.
The following non-limiting examples illustrate the present invention:
Example 1 Preparation of carbamic acid, [5-oxo-3-(phenylmethyl)-2-thioxo-l-imidazolidinyl]-, 1,1-dimethylethyl ester:
To a solution of 990 mg (90%, 5.0 mmol) of thiocarbonyldiimidazole in 25 mL of 1,4-dioxane is added dropwise 0.66 g (5 mmol) of tert-buryl carbazate in 25 mL of 1,4- dioxane. The solution is stirred for 3 hours at room temperature, followed by the addition of N-benzylglycine ethyl ester 996 mg (5 mmol). The resulting mixture is heated to 60 °C for 4 hours. The dioxane is removed under reduced pressure. The residue is dissolved in EtOAc (150 mL) and washed with water (2 x 50 mL), 0.1Ν aqueous HC1 (2 x 50 mL), dried with MgSO4 and concentrated in vacuo to afford carbamic acid, [5-oxo-3- (phenylmethyl)-2-thioxo-l -imidazolidinyl]-, 1,1-dimethylethyl ester (1.52 g, 95%).
Example 2 Preparation of carbamic acid, [4-methyI-5-oxo-3-(phenylmethyl)-2-thioxo-l- imidazolidinyl]-, 1,1-dimethylethyl ester:
To a solution of 593 mg (90%, 3.0 mmol) of thiocarbonyldiimidazole in 15 mL of 1,4-dioxane is added dropwise 0.66 g (5 mmol) of tert-buryl carbazate in 25 mL of 1,4- dioxane. The solution is stirred for 3 hours at room temperature, followed by the addition of N-benzylalanine ethyl ester 621 mg (3 mmol). The resulting mixture is heated to 60 °C for 4 hours. The dioxane is removed under reduced pressure. The residue is dissolved in EtOAc (100 mL) and washed with water (50 mL), 0.1Ν aqueous HCl (2 x 25 mL), dried with MgSO4 and concentrated in vacuo to afford carbamic acid, [4-methyl-5-oxo-3- (phenylmethyl)-2-thioxo-l -imidazolidinyl]-, 1,1-dimethylethyl ester (887 mg, 80%).
Example 3 Preparation of carbamic acid, (Tetrahydro-5,7-dioxoimidazol[5,l-b]thiazo- 6(5H)- yl)-, 1,1-dimethylethyl ester:
To a solution of 1.03 g (6.4 mmol) of carbonyldiimidazole in 30 mL of THF is added dropwise 0.66 g (5 mmol) of tert-butyl carbazate in 10 mL of THF. The solution is stirred for 4 hours at room temperature, followed by the addition of methyl thiozolidine- 2-carboxlate HCl salt 920 mg (5.0 mmol). The resulting mixture is heated to reflux for 4 hours. The THF is removed under reduced pressure. The residue is dissolved in EtOAc (100 mL) and washed with water (100 mL), 0.1Ν aqueous HCl (100 mL), water (100 mL), dried with Νa2SO4 and concentrated in vacuo to afford carbamic acid, ((7aS)- tetrahydro-5,7-dioxoimidazol[5,l-b]thiazo- 6(5H)-yl)-, 1,1-dimethylethyl ester (1.0 g, 74%).
Example 4 Preparation of carbamic acid, ((10aS)-l,5,10,10a-tetrahydro-l,3-dioxoimidazol[l,5- b]isoquinolin-2(3//)-yl)-, 1,1-dimethylethyl ester:
To a solution of 1.06 g (6.5 mmol) of carbonyldiimidazole in 25 mL of 1,4- dioxane is added dropwise 0.66 g (5 mmol) of tert-butyl carbazate in 25 mL of 1,4- dioxane. The solution is stirred for 3 hours at room temperature, followed by the addition of benzyl (S)-(-) l,2,3,4-tetrahydro-3-isoquinoline carboxylate p-toluenesulfonic acid salt 2.19 g (5 mmol) and triethylamine (0.5 mL). The resulting mixture is heated to 60 °C for 4 hours. The dioxane is removed under reduced pressure. The residue is dissolved in EtOAc (150 mL) and washed with water (2 x 50 mL), 0.1N aqueous ΗC1 (2 x 50 mL), dried with MgSO4 and concentrated to 20mL in vacuo to give a white precipitate. The solid is filtered off and dried in vacuo to afford carbamic acid, ((1 OaS)- 1,5, 10,1 Oa- tetrahydro- l,3-dioxoimidazol[l,5-b]isoquinolin-2(3H)-yl)-, 1,1-dimethylethyl ester (1.38 g, 87%).
Example 5 Preparation of carbamic acid, ((10aS)-l,5,10,10a-tetrahydro-l-oxo-3- thioxoimidazol[l,5-b]isoquinolin-2(3//)-yl)-, 1,1-dimethylethyl ester:
To a solution of 972 mg (6 mmol) of carbonyldiimidazole in 25 mL of 1,4- dioxane is added dropwise 0.66 g (5 mmol) of tert-butyl carbazate in 25 mL of 1,4- dioxane. The solution is stirred for 3 hours at room temperature, followed by the addition of benzyl (S)-(-) l,2,3,4-tetrahydro-3-isoquinoline carboxylate p-toluenesulfonic acid salt 2.19 g (5 mmol) and triethylamine (0.5 mL). The resulting mixture is heated to 60 °C for 4 hours. The dioxane is removed under reduced pressure. The residue is dissolved in EtOAc (150 mL) and washed with water (2 x 50 mL), 0.1N aqueous HCl (2 x 50 mL), dried with MgSO4 and concentrated to 20mL in vacuo to give a white precipitate. The solid is filtered off and dried in vacuo to afford carbamic acid, ((10aS)-l,5, 10,10a- tetrahydro- 1 -oxo-3-thioxoimidazol[ 1 ,5-b]isoquinolin-2(3H)-yl)-, 1 , 1 -dimethylethyl ester (1.56 g, 94%).
Example 6
Preparation of carbamic acid, (2,5-dioxo-3-phenyl-l-imidazolidinyl)-, 1,1- dimethylethyl ester:
To a solution of 915 mg (5.6 mmol) of carbonyldiimidazole in 15 mL of 1,4- dioxane is added dropwise 528 g (4.8 mmol) of tert-butyl carbazate in 15 mL of 1,4- dioxane. The solution is stirred for 2 hours at room temperature, followed by the addition of N-phenyl glycinate ethyl ester 716 mg (4.0 mmol). The resulting mixture is heated to 70 °C for 7 hours. The dioxane is removed under reduced pressure. The residue is dissolved in EtOAc (100 mL) and washed with water (50 mL), 0.1N aqueous ΗC1 (2 x 50 mL), dried with MgSO4 and concentrated to 20mL in vacuo to give a white precipitate. The solid is filtered off and dried in vacuo to afford Preparation of carbamic acid, (2,5- dioxo-3-phenyl-l -imidazolidinyl)-, 1,1-dimethylethyl ester (858 mg, 76%).
Example 7 Preparation of carbamic acid, (5-oxo-3-phenyl-2-thioxo-l-imidazolidinyl)-, 1,1- dimethylethyl ester:
To a solution of 593 mg (3.0 mmol) of thiocarbonyldiimidazole in 15 mL of 1,4- dioxane is added dropwise 396 g (3.0 mmol) of tert-butyl carbazate in 15 mL of 1,4- dioxane. The solution is stirred for 3 hours at room temperature, followed by the addition of N-phenyl glycinate ethyl ester 495 mg (3.0 mmol). The resulting mixture is heated to 70 °C for 7 hours. The dioxane is removed under reduced pressure. The residue is dissolved in EtOAc (100 mL) and washed with water (50 mL), 0.1N aqueous ΗC1 (2 x 50 mL), dried with MgSO4 and concentrated to afford crude product which is further purified by Biotage column (eluent: EtOAc/Hexane, 3/7). The pure product, carbamic acid, (5-dioxo-3-phenyl-2-thioxo-l -imidazolidinyl)-, 1,1-dimethylethyl ester, is obtained as semisolid material (820 mg, 81%).
Example 8 Preparation of carbamic acid, (hexahydro-l,3-dioxoimidazol[l,5-a]pyridin-2(3H)- yl)-, 1,1-dimethylethyl ester:
To a solution of 972 mg (6 mmol) of carbonyldiimidazole in 25 mL of 1,4- dioxane is added dropwise 792 g (6 mmol) of tert-butyl carbazate in 25 mL of 1,4- dioxane. The solution is stirred for 2 hours at room temperature, followed by the addition of ethyl pipercolinate 785 mg (5 mmol). The resulting mixture is heated to 60-70 °C for 4 hours. The dioxane is removed under reduced pressure. The residue is dissolved in EtOAc (150 mL) and washed with water (50 mL), 0.1N aqueous HCl (2 x 50 mL), dried with MgSO4 and concentrated to afford carbamic acid, (hexahydro-1,3- dioxoimidazol[l,5-a]pyridin-2(3H)-yl)-, 1,1-dimethylethyl ester (1.21 g, 90%).
Example 9 Preparation of carbamic acid, (3-(phenylmethyl)tetrahydro-2,6-dioxo-l(2H)- pyrimidinyl)-, 1,1-dimethylethyl ester:
To a solution of 1.14 g (7 mmol) of carbonyldiimidazole in 50 mL of 1,4-dioxane is added dropwise 793 mg (6 mmol) of tert-butyl carbazate in 10 mL of 1,4-dioxane. The solution is stirred for 4 hours at room temperature, followed by the addition of N-benzyl- -alanine ethyl ester 1.04 g (5 mmol). The resulting mixture is refluxed for 72 hours. The dioxane is removed under reduced pressure. The residue is dissolved in EtOAc, washed with H2O, 0.1 Ν HCl, H2O respectively and dried over Νa2SO4 and concentrated in vacuo to afford carbamic acid, (3-(phenylmethyl)tetrahydro-2,6-dioxo-l(2H)- pyrimidinyl)-, 1,1-dimethylethyl ester (1.02 g, 64%).
Example 10
Preparation of carbamic acid, (3-(2-furanylmethyl)tetrahydro-2-oxo-6-thioxo-l(2//)- pyrimidinyl)-, 1,1-dimethylethyl ester:
To a solution of 988 mg (90%, 5.5 mmol) of thiocarbonyldiimidazole in 15 mL of
1 ,4-dioxane is added dropwise 660 mg (5 mmol) of tert-butyl carbazate in 25 mL of 1 ,4- dioxane. The solution is stirred for 3 hours at room temperature, followed by the addition of N-2-furanylmethyl- -alanine ethyl ester 985 mg (5 mmol). The resulting mixture is refluxed for 24 hours. The dioxane is removed under reduced pressure. The residue is purified by Biotage column (eluent: EtOAc/Hexane, 6/4) to afford carbamic acid, (3-(2- furanylmethyl)tetrahydro-2-oxo-6-thioxo- 1 (2H)-pyrimidinyl)-, 1 , 1 -dimethylethyl ester (1.25 g, 77%).
Example 11 Preparation of carbamic acid, (3-(2-furanylmethyl)tetrahydro-2,6-dioxo-l(2Z/)- pyrimidinyl)-, 1,1-dimethylethyl ester:
To a solution of 810 mg (90%, 5.0 mmol) of carbonyldiimidazole in 25 mL of 1,4- dioxane is added dropwise 660 mg (5 mmol) of tert-butyl carbazate in 25 mL of 1 ,4- dioxane. The solution is stirred for 3 hours at room temperature, followed by the addition of N-2-furanylmefhyl -alanine ethyl ester 985 mg (5 mmol). The resulting mixture is refluxed for 24 hours. The dioxane is removed under reduced pressure. The residue is purified by Biotage column (eluent: EtOAc/Hexane, 6/4) to afford carbamic acid, (3-(2- furanylmethyl)tetrahydro-2,6-dioxo-l(2H)-pyrimidinyl)-, 1,1-dimethylethyl ester (1.01 g, 65%).
Example 12 Preparation of carbamic acid, (3-butyltetrahydro-6-oxo-2-thioxo-l(2.H)- pyrimidinyl)-, 1,1-dimethylethyl ester:
To a solution of 984 mg (90%, 5.5mmol) of thiocarbonyldiimidazole in 25 mL of 1,4-dioxane is added dropwise 0.66 g (5 mmol) of tert-butyl carbazate in 25 mL of 1,4- dioxane. The solution is stirred for 3 hours at room temperature, followed by the addition of N-n-butyl- -alanine methyl ester 795 mg (5 mmol). The resulting mixture is refluxed for 24 hours. The dioxane is removed under reduced pressure. The residue is dissolved in EtOAc (100 mL) and washed with water (50 mL), 0.1Ν aqueous HCl (2 x 25 mL), dried with MgSO4 and concentrated in vacuo to afford carbamic acid, (3- butyltetrahydro-6-oxo-2-thioxo-l(2H)-pyrimidinyl)-, 1,1-dimethylethyl ester (1.23 g, 81%).
Example 13 Preparation of carbamic acid, (3-butyltetrahydro-2,6-dioxo -l(2//)-pyrimidinyl)-, 1,1-dimethylethyl ester:
To a solution of 1.14 g (7.0 mmol) of carbonyldiimidazole in 30 mL of 1,4- dioxane is added dropwise 0.79 g (6 mmol) of tert-butyl carbazate in 20 mL of 1 ,4- dioxane. The solution is stirred for 4 hours at room temperature, followed by the addition of N-n-butyl- -alanine methyl ester 795 mg (5 mmol). The resulting mixture is refluxed for 40 hours. The dioxane is removed under reduced pressure. The residue is dissolved in EtOAc, washed with H2O, 0.1 Ν HCl, H2O respectively and dried over Νa2SO4 and concentrated in vacuo to afford carbamic acid, (3-butyltetrahydro-2,6-dioxo- l(2H)-pyrimidinyl)-, 1,1-dimethylethyl ester (1.28 g, 84%).
Example 14 Preparation of carbamic acid, (tetrahydro-6-oxo-3-(4-methoxyphenyl)-2-thioxo- l(2H)-pyrimidinyl)-, 1,1-dimethylethyl ester: To a solution of 988 mg (90%, 5.5 mmol) of thiocarbonyldiimidazole in 25 mL of
1 ,4-dioxane is added dropwise 0.66 g (5 mmol) of tert-butyl carbazate in 25 mL of 1 ,4- dioxane. The solution is stirred for 3 hours at room temperature, followed by the addition of N-(4-methoxyphenyl)- -alanine ethyl ester 1.12 g (5 mmol). The resulting mixture is refluxed for 48 hours. The dioxane is removed under reduced pressure. The residue is dissolved in EtOAc (100 mL) and washed with water (50 mL), 0.1Ν aqueous ΗC1 (2 x 25 mL), dried with MgSO4 and concentrated in vacuo to afford carbamic acid, (tetrahydro-6- oxo-3-(4-methoxyphenyl)-2-thioxo-l(2H)-pyrimidinyl)-, 1,1-dimethylethyl ester (0.59 g, 33%).
Example 15
Preparation of Merrifield resin-bound -bromoacetate ester :
To a solution of DIC (diisopropylcarbodiimide) (31g, 253 mmol), -bromoacetic acid (35g, 246 mmol) and Merrifield resin (50 g, 33.5 mmol, loading level: 0.67 mmol/g) in methylene chloride (600 mL) is added DMAP (lg, 8.1 mmol). The resulting mixture is shaken at room temperature for 24 hours. Resin is collected on a glass filter and washed two times each with DMF, MeOΗ, DCM. The resin is dried to give the Merrifield resin- bound -bromoacetate ester (53.1 g, yield 98%).
Example 16 Preparation of carbamic acid, [2,5-dioxo-3-[2-(2-pyridinyl)ethyl]-l-imidazolidinyl]-, 1,1-dimethylethyl ester:
Merrifield resin-bound -bromoacetate ester (2 g, loading 0.67 mmol/g) is treated with DMF (40 mL) and 2-(2-aminoethyl)pyridine (810 mg, 6.6 mmol) and allowed to shake for 24 hours at room temperature. Washing two times each with DMF, MeOΗ, DCM afforded resin. This is then treated with Boc-hydrazinecarbonylimidazole (6.6 mmol) in 40 mL of DMF (prepared in situ according to the process of solution-phase chemistry which is described above in Scheme 1) at room temperature for 10 hours and washed two times each with DMF, MeOH, DCM to afford a resin according to Siia (where n = 0, X = O, \ = 2-(2-pyridinyl)ethyl). The resin is then placed in a flask with 40 mL of DMF and heated to 65-70°C for 8 hours. After cooling, the resin is filtered, washed with small amount of DMF, DCM and MeOH and the combined filtrates concentrated. The residue is dissolved in 30 mL of MeOH and filtered, concentrated in vacuo to give desired product, carbamic acid, [2,5 dioxo-3-[2-(2-pyridinyl)ethyl]-l- imidazolidinyl]-, 1,1-dimethylethyl ester (183 mg, 63%).
Example 17 Preparation of carbamic acid, [3-[2-(5-methoxy-l//-indoI-3-yl)ethyl]-2,5-dioxo-l- imidazolidinyl]-, 1,1-dimethylethyl ester:
Merrifield resin-bound -bromoacetate ester (2 g, loading 0.67 mmol/g) is treated with DMSO (60 mL) and 5-methoxytryptamine (1.0 g, 5.26 mmol) and allowed to shake for 24 hours at room temperature. Washing two times each with DMF, MeOH, DCM affords the resin. This is then treated with Boc-hydrazinecarbonylimidazole (5.2 mmol) in 60 mL of DMF (prepared in situ according to the process of solution-phase chemistry which is described above in Scheme 1) at room temperature for 10 hours and washed two times each with DMF, MeOH, DCM to afford a resin according to Siia (where n = 0, X =
O, Ri = 2-(5-methoxy-lH-indol-3-yl)efhyl). The resin is then placed in a flask with 50 mL of DMF and heated to 60-70°C for 8 hours. After cooling, the resin is filtered, washed two times each with DMF, DCM and MeOΗ and the combined filtrates concentrated. The residue is dissolved in 30 mL of MeOΗ and filtered, concentrated in vacuo to give desired product, carbamic acid, [3-[2-(5-methoxy-lH-indol-3-yl)ethyl]-2,5- dioxo-1 -imidazolidinyl]-, 1,1-dimethylethyl ester (310 mg, 61%).
Example 18 Preparation of carbamic acid, [3-[2-(lH-imidazol-4-yl)-ethyl]-2,5-dioxo-l- imidazolidinyl]-, 1,1-dimethylethyl ester:
Merrifield resin-bound -bromoacetate ester (2 g, loading 0.67 mmol/g) is treated with DMSO (60 mL) and histamine (733 mg, 6.6 mmol) and allowed to shake for 24 hours at room temperature. Washing two times each with DMF, MeOΗ, DCM afford the resin. This is then treated with Boc-hydrazinecarbonylimidazole (6.6 mmol) in 60 mL of DMF (prepared in situ according to the process of solution-phase chemistry which is described above in Scheme 1) at room temperature for 10 hours and washed two times each with DMF, MeOH, DCM to afford a resin according to Siia (where n = 0, X = O, Ri = 2-(lH-imidazol-4-yl)-ethyl). The resin is then placed in a flask with 50 mL of DMF and heated to 60-70°C for 8 hours. After cooling, the resin is filtered, washed with small amount of DMF, DCM and MeOΗ and the combined filtrates concentrated. The residue is dissolved in 30 mL of MeOΗ and filtered, concentrated in vacuo to give desired product, carbamic acid, [3-[2-(lH-imidazol-4-yl)-ethyl]-2,5-dioxo-l-imidazolidinyl]-, 1,1-dimethylethyl ester (202 mg, 50%).
Example 19 Preparation of carbamic acid, [3-[2-(l-methyl-2-pyrrolidinyl)ethyl]-2,5-dioxo-l- imidazolidinyl]-, 1,1-dimethylethyl ester:
The Merrifield resin-bound -bromoacetate ester (3 g, loading 0.67 mmol/g) is treated with DMSO (60 mL) and 2-(2-aminoethyl)-l-methylpyrrolidine (1.42 g, 10 mmol) and allowed to shake for 24 hours at room temperature. Washing two times each with DMF, MeOΗ, DCM affords the resin. This is then treated with Boc- hydrazinecarbonylimidazole (10 mmol) in 60 mL of DMF (prepared in situ according to the process of solution-phase chemistry which is described above in Scheme 1) at room temperature for 10 hours and washed two times each with DMF, MeOΗ, DCM to afford a resin according to Siia (where n = 0, X = O, Ri = 2-(l-methyl-2-pyrrolidinyl)ethyl). The resin is then placed in a flask with 50 mL of DMF and heated to 60-70°C for 8 hours. After cooling, the resin is filtered, washed with small amount of DMF, DCM and MeOΗ and the combined filtrates concentrated. The residue is dissolved in 30 mL of MeOΗ and filtered, concentrated in vacuo to give desired product (445 mg, 69%).
Example 20
Preparation of carbamic acid, [3-[2-[[5-nitro-2-pyridinyl]amino]ethyl]-2,5-dioxo-l- imidazolidinyl]-, 1,1-dimethylethyl ester:
Merrifield resin-bound -bromoacetate ester (3 g, loading 0.67 mmol/g) is treated with DMSO (60 mL) and 2-(2-aminoethylamino)-5-nitropyridine (1.82 g, 10 mmol) and allowed to shake for 24 hours at room temperature. Washing two times each with DMF, MeOΗ, DCM affords the resin. This is then treated with Boc-hydrazinecarbonylimidazole (10 mmol) in 60 mL of DMF (prepared in situ according to the process of solution-phase chemistry which is described above in Scheme 1) at room temperature for 10 hours and washed two times each with DMF, MeOΗ, DCM to afford a resin according to Siia (where n = 0, X = O, R] = 2-[[5-nitro-2-pyridinyl]amino]ethyl). The resin is then placed in a flask with 50 mL of DMF and heated to 60-70°C for 8 hours. After cooling, the resin is filtered, washed two times each with DMF, DCM and MeOH and the combined filtrates concentrated. The residue is dissolved in 30 mL of MeOH and filtered, concentrated in vacuo to give desired product, carbamic acid, [3-[2-[[5-nitro-2- pyridinyl]amino]ethyl]-2,5-dioxo-l -imidazolidinyl]-, 1,1-dimethylethyl ester (440 mg, 58.5%).
Example 21 Preparation of carbamic acid, [2,5-dioxo-3-[2-(l-piperidinyl)ethyl]-l- imidazolidinyl]-, 1,1-dimethylethyl ester: Merrifield resin-bound -bromoacetate ester (2 g, loading 0.67 mmol/g) is treated with DMSO (60 mL) and l-(2-aminoethyl)piperidine ( 0.88 g, 6.7 mmol) and allowed to shake for 24 hours at room temperature. Washing two times each with DMF, MeOH, DCM affords the resin. This is then treated with Boc-hydrazinecarbonylimidazole (6.5 mmol) in 50 mL of DMF (prepared in situ according to the process of solution-phase chemistry which is described above in Scheme 1) at room temperature for 10 hours and washed two times each with DMF, MeOH, DCM to afford a resin according to Siia (where n = 0, X = O, Ri = 2-(l-piperidinyl)ethyl). The resin is then placed in a flask with 30 mL of DMF and heated to 60-70°C for 8 hours. After cooling, the resin is filtered, washed two times each with DMF, DCM and MeOH and the combined filtrates concentrated. The residue is dissolved in 30 mL of MeOH and filtered, concentrated in vacuo to give desired product, carbamic acid, [2,5-dioxo-3-[2-(l-piperidinyl)ethyl]-l- imidazolidinyl]-, 1,1-dimethylethyl ester (262 mg, 59%).
Example 22 Preparation of Merrifield resin-bound acrylate ester:
To a solution of DIC (15g, 119 mmol), acrylic acid (17g, 208 mmol) and Merrifield resin (25 g, 200 mmol, loading level: 0.80 mmol/g) in methylene chloride (300 mL) is added DMAP (0.5g, 4 mmol). The resulting mixture is shaken at room temperature for 24 hours. Resin is collected on a glass filter and washed two times each with DMF, MeOH, DCM. The resin is dried to give the Merrifield resin-bound acrylate ester (37 g, yield 94%).
Example 23 Preparation of carbamic acid, [tetrahydro-3-[(5-nitro-2-pyridinyl)amino]ethyl]-2,6- dioxo-l(2 7)-pyrimidinyl]-, 1,1-dimethylethyl ester: Merrifield resin-bound acrylate ester (2 g, loading 0.8 mmol/g) is treated with DMSO (50 mL) and 2-(2-aminoethylamino)-5-nitropyridine (1.46 g, 8.0 mmol) and allowed to shake for 24 hours at room temperature. Washing two times each with DMF, MeOH, DCM affords the resin. This is then treated with Boc- hydrazinecarbonylimidazole (8 mmol) in 40 mL of DMF (prepared in situ according to the process of solution-phase chemistry which is described above in Scheme 1) at room temperature for 24 hours and washed two times each with DMF, MeOH, DCM to afford a resin according to Siia (where n = 1, X = O, Rj = (5-nitro-2-pyridinyl)aminoethyl). The resin is then placed in a flask with 40 mL of DMF and heated to 95°C for 24 hours. After cooling, the resin is filtered, washed two times each with DMF, DCM and MeOH and the combined filtrates concentrated. The residue is dissolved in 40 mL of EtOAc and filtered, concentrated in vacuo to give desired product carbamic acid, [tetrahydro-3-[(5- nitro-2-pyridinyl)amino]ethyl]-2,6-dioxo- 1 (2H)-pyrimidinyl]-, 1 , 1 -dimethylethyl ester (289 mg, 46%).
Example 24 Preparation of carbamic acid, (tetrahydro-3-[2-(4-morpholinyl)ethyl]-2,6-dioxo- l(2Z/)-pyrim'dinyl]-, 1,1-dimethylethyl ester:
Merrifield resin-bound acrylate ester (2 g, loading, 8.0 mmol/g) is treated with DMSO (50 mL) and 4-(2-aminoethyl)morpholine (1.04 g, 8 mmol) and allowed to shake for 24 hours at room temperature. Washing two times each with DMF, MeOΗ, DCM affords the resin. This is then treated with Boc-hydrazinecarbonylimidazole (8 mmol) in 40 mL of DMF (prepared in situ according to the process of solution-phase chemistry which is described above in Scheme 1) at room temperature for 24 hours and washed two times each with DMF, MeOΗ, DCM to afford a resin according to Siia (where n = 1 , X = O, Ri = 2-(4-morpholinyl)ethyl). The resin is then placed in a flask with 40 mL of DMF and heated to 95°C for 24 hours. After cooling, the resin is filtered, washed two times each with DMF, DCM and MeOΗ and the combined filtrates concentrated. The residue is dissolved in 40 mL of EtOAc and filtered, concentrated in vacuo to give desired product carbamic acid, [tetrahydro-3-[2-(4-morpholinyl)ethyl]-2,6-dioxo-l(2H)- pyrimidinyl]-, 1,1-dimethylethyl ester (229 mg, 42%).
Example 25 Preparation of carbamic acid, [tetrahydro-2,6-dioxo-3-[l-(phenylmethyl)-4- piperidinyl]-l(2/7)-pyrimidinyl]-, 1,1-dimethylethyl ester: Merrifield resin-bound acrylate ester (2 g, loading, 8.0 mmol/g) is treated with DMSO (50 mL) and 4-amino-l-benzyl-piperidine (1.52 g, 8 mmol) and allowed to shake for 24 hours at room temperature. Washing two times each with DMF, MeOH, DCM affords the resin. This is then treated with Boc-hydrazinecarbonylimidazole (8 mmol) in 40 mL of DMF (prepared in situ according to the process of solution-phase chemistry which is described above in Scheme 1) at room temperature for 24 hours and washed two times each with DMF, MeOH, DCM to afford a resin according to Siia (where n = 1 , X = O, Ri = l-(phenylmethyl)-4-piperidinyl). The resin is then placed in a flask with 40 mL of DMF and heated to 95°C for 24 hours. After cooling, the resin is filtered, washed two times each with DMF, DCM and MeOH and the combined filtrates concentrated. The residue is dissolved in 20-30 mL of MeOH and filtered, concentrated in vacuo to give desired product carbamic acid, [tetrahydro-2,6-dioxo-3-[l-(phenylmethyl)-4-piperidinyl]- l(2H)-pyrimidinyl]-, 1,1-dimethylethyl ester (289 mg, 45%).
Example 26
Preparation of carbamic acid, [tetrahydro-6-oxo-3-(phenylmethyl)-2-thioxo-l(2 /) - pyrimidinyl]-, 1,1-dimethylethyl ester:
Merrifield resin-bound acrylate ester (2 g, loading, 8.0 mmol/g) is treated with DMSO (50 mL) and benzyl amine (1.025 g, 9 mmol) and allowed to shake for 24 hours at room temperature. Washing two times each with DMF, MeOH, DCM affords the resin. This is then treated with Boc-hydrazinecarbonylimidazole (6 mmol) in 50 mL of DMF (prepared in situ according to the process of solution-phase chemistry which is described above in Scheme 1) at room temperature for 24 hours and washed two times each with DMF, MeOH, DCM to afford a resin according to Siia (where n = 1, X = S, Ri = benzyl). The resin is then placed in a flask with 50 mL of DMF and heated to 95°C for 24 hours.
After cooling, the resin is filtered, washed two times each with DMF, DCM and MeOH and the combined filtrates concentrated. The residue is dissolved in 40 mL of EtOAc and filtered, concentrated in vacuo to give desired product carbamic acid, [tetrahydro-6-oxo-
3-(phenylmethyl)-2-thioxo-l(2H) -pyrimidinyl]-, 1,1-dimethylethyl ester (117 mg, 22%).

Claims

WHAT IS CLAIMED IS:
1. A method for making a compound according having the following structure:
Figure imgf000026_0001
wherein
X is O or S; n is 0 or 1 ;
Ri is H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, or heteroaromatic ring;
R2 is H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, or heteroaromatic ring; and when n is 0, Ri and R2 may instead together form a ring system; said ring system being carbocyclic ring, heterocyclic ring, or heteroaromatic ring; or when n is 1, Ri and the member carbon atom adjacent to the carbon atom containing R2 may instead together form a ring system; said ring system being carbocyclic ring, heterocyclic ring, or heteroaromatic ring;
said method comprising the steps of: a) providing a compound having the following structure
H
Boc H r \=N wherein X is as defined above;
b) reacting the compound provided in step a above with an or amino acid ester having the structure:
Figure imgf000026_0002
wherein Ri and R2 are as defined above and R is alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, or heteroaromatic ring; and c) heating the reaction mixture.
2. A method for making a compound according having the following structure:
Figure imgf000027_0001
wherein
X is O or S; n is 0 or 1 ;
Ria is H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, or heteroaromatic ring;
R2a is H, Cι-C8 alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, or heteroaromatic ring;
said method comprising the steps of: a) providing a compound having the following structure
Figure imgf000027_0002
wherein X is as defined above;
b) reacting the compound provided in step a above with a resin-bound or amino acid ester having the structure:
Figure imgf000027_0003
wherein Ri and R2 are as defined above and is a Merrifield resin, hydroxymethyl resin, Wang resin, or PEG resin; and
c) heating the reaction mixture.
PCT/US2000/027503 1999-10-08 2000-10-05 Process for making boc-protected 3-aminohydantoins/thiohydantoins and 3-aminodihydrouracils/dihydrothiouracils WO2001027087A2 (en)

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US10/089,329 US6784293B1 (en) 1999-10-08 2000-10-05 Process for making Boc-protected 3-aminohydantoins/thiohydantoins and 3-aminodihydrouracils/dihydrothiouracils

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Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
MURPHY A M ET AL: "Automated Synthesis of Peptide C-Terminal Aldehydes" JOURNAL OF THE AMERICAN CHEMICAL SOCIETY., vol. 114, no. 8, 8 April 1992 (1992-04-08), pages 3156-3157, XP002162269 AMERICAN CHEMICAL SOCIETY, WASHINGTON, DC., US ISSN: 0002-7863 *
SAEGUSA Y ET AL: "Reaction of 1,3,4-Oxadiazolones with Free L-alpha-Amino Acids: A Facile Synthesis of Novel 3,5-Disubstituted Hydantoins " JOURNAL OF HETEROCYCLIC CHEMISTRY., vol. 27, no. 3, 1990, pages 739-742, XP000983529 HETEROCORPORATION. PROVO., US ISSN: 0022-152X cited in the application *
VEVERKA M; MARCHALIN M: "Addition-Cyclization Reaction of Ethyl Isothiocyanatoacetate with Carboxylic Acid Hydrazides" COLLECTION OF CZECHOSLOVAK CHEMICAL COMMUNICATIONS., vol. 52, no. 1, 1987, pages 113-119, XP000983448 ACADEMIC PRESS, LONDON., GB ISSN: 0010-0765 *
YOON J ET AL: "Solution and soluble polymer synthesis of 3-aminoimidazoline-2,4-diones" CHEMICAL COMMUNICATIONS., no. 24, 1998, pages 2703-2704, XP002162268 ROYAL SOCIETY OF CHEMISTRY., GB ISSN: 1359-7345 cited in the application *

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