N-protected/N-substituted-beta-amino hydroxy sulfonates

Details N-protected/N-substituted-beta-amino hydroxy sulfonates N-protected/N-substituted-beta-amino hydroxy sulfonates

2002-03-20

2003-07-01

Gerstl, Robert (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

Reexamination Certificate

active

06586627

ABSTRACT:

BACKGROUND OF THE INVENTION
Synthesis of many pharmaceuticals, such as aspattyl protease inhibitors, involve the preparation of beta-amino alcohol intermediates from N-protected/N-substituted alpha-amino aldehydes in one or more steps. In particular, pharmaceuticals containing at least one chiral center can be prepared from chiral N-protected/N-substituted alpha-amino aldehydes. Examples of the preparation of chiral N-protected/N-substituted alpha-amino aldehydes and their use as pharmaceutical intermediates in the preparation of aspartyl protease inhibitors, such as renin and HIV protease inhibitors, dietetic sweeteners, bestatin derivatives can be found in Chem. Pharm. Bull. 30:1921-1924, 1982; J. Org. Chem. 43:2480-2482, 1978; J. Org. Chem. 47:3016-3018, 1982; Tet. Let. 27:2337-2340, 1986; PCT/US94/12201; WO 93/23388; WO 94/04491; WO 94/04492; WO 94/04493; U.S. Pat. No. 4,990,669; Tet. Let. 30:5421-5424, 1989; Philos. Trans. R. Soc. London, A, 326:573-578, 1988; Chem. Rev. 89:149-164, 1989; and J. Org. Chem. 52:2361-2364, 1987. In addition, N-substituted alpha-amino aldehydes are known to have cysteine proteinase inhibition activity, such as papin, calpain and cathepsin inhibition (see for example EP 393457).
A drawback to the use of N-protected/N-substituted alpha-amino aldehydes is their instability to storage, particularly long term storage, (see U.S. Pat. No. 4,990,669; Chem. Rev. 89:149-164, 1989; J. Org. Chem. 47:3016-3018, 1982; and J. Am. Chem. Soc. 109:236-239, 1987). This is particularly true for use of N-protected/N-substituted alpha-amino aldehydes in manufacturing processes, where it is sometimes advantageous to store and ship large quantities of intermediates, such as the N-protected/N-substituted alpha-amino aldehydes, to other locations for processing. Generally, N-protected/N-substituted alpha-amino aldehydes are used promptly following preparation and are not shipped or stored for long periods. Some efforts have been made to form configurationally stable derivatives of N-protected/N-substituted alpha-amino aldehydes (see J. Org. Chem. 52:2361-2364, 1987; and J. Am. Chem. Soc. 109:236-239, 1987), but such derivatives are not always applicable and the aldehyde group may still be unstable to long term storage, for example, due to air oxidation to the corresponding carboxylic acid, trimerization to the corresponding 1,3,5-trioxanes, and the like.
SUMMARY OF THE INVENTION
The present invention relates to a stabilized form of N-protected/N-substituted alpha-amino aldehydes, in particular, N-protected/N-substituted-beta-amino hydroxy sulfonates, and their preparation and use. An N-protected/N-substituted alpha-amino aldehyde can be stored for extended periods in the form of a N-protected/N-substituted-beta-amino hydroxy sulfonate which can be readily prepared and converted back into the N-protected/N-substituted alpha-amino aldehyde under mild conditions.
DETAILED DESCRIPTION OF THE INVENTION
This invention relates to the preparation and use of N-protected/N-substituted-beta-amino hydroxy sulfonates, a stabilized form of N-protected/N-substituted alpha-amino aldehydes, having the formula
wherein W represents a cation which is capable of forming a sulfate salt; preferably, W represents a metal cation or a quaternary amine cation; more preferably, W represents a mono- or divalent metal cation; even more preferably, W represents a cation of lithium, sodium, potassium, calcium, manganese, magnesium, barium, chromium, iron, nickel, cobalt, copper, zinc, cadmium, tin or silver; even more preferably, W represents a cation of lithium, sodium, potassium, calcium, magnesium, barium, iron, nickel, copper or zinc; most preferably, W represents a cation of lithium, sodium or potassium;
R
1
represents alkyl, alkenyl, alkyl substituted with one or more aryl radicals, cycloalkenylalkyl, alkanoyl, haloalkanoyl, aroyl, alkoxycarbonyl, aralkoxycarbonyl, heteroaralkoxycarbonyl or 9-phenylfluoren-9-yl radicals; preferably, R
1
represents alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkyl of 1-3 carbon atoms substituted with 1-3 aryl radicals, alkyl of 1-3 carbon atoms substituted with a cycloalkenyl radical of 3-8 ring members, alkanoyl of 1-4 alkyl carbon atoms, haloalkanoyl of 1-4 alkyl carbon atoms and 1-3 halo radicals, aroyl, alkoxycarbonyl of 1-8 alkyl carbon atoms, arylmethoxycarbonyl, heteroarylmethoxycarbonyl or 9-phenylfluoren-9-yl radicals; more preferably, R
1
represents alkyl of 1-5 carbon atoms, alkenyl of 2-5 carbon atoms, alkyl of 1-2 carbon atoms substituted with 1-3 aryl radicals, alkyl of 1-2 carbon atoms substituted with a cycloalkenyl radical of 5-6 ring members, alkanoyl of 1-4 alkyl carbon atoms, haloalkanoyl of 1-2 alkyl carbon atoms and 1-3 halo radicals, aroyl, alkoxycarbonyl of 1-5 alkyl carbon atoms, arylmethoxycarbonyl, heteroarylmethoxycarbonyl or 9-phenylfluoren-9-yl radicals; even more preferably, R
1
represents methyl, ethyl, ethenyl, propenyl, benzyl, diphenylmethyl, naphthylmethyl, trityl, cyclohexenylmethyl, acetyl, butyryl, chloroacetyl, fluoroacetyl, dif luoroacetyl, trifluoroacetyl, benzoyl, 2-methylbenzoyl, 2,6-dimethylbenzoyl, 2,4,6-trimethylbenzoyl, 2,4,6-triisopropylbenzoyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, phenylmethoxycarbonyl, (2-methylphenyl)methoxycarbonyl, isobutoxycarbonyl, (4-methylphenyl)methoxycarbonyl, (4-methoxyphenyl)methoxycarbonyl, pyridylmethoxycarbonyl, or 9-phenylfluoren-9-yl radicals; most preferably, R
1
represents methyl, ethyl, benzyl, diphenylmethyl, naphthylmethyl, trityl, trifluoroacetyl, tert-butoxycarbonyl, phenylmethoxycarbonyl or (4-methoxyphenyl)methoxycarbonyl radicals;
R
2
represents hydrogen, alkyl, alkenyl, aralkyl, cycloalkyl, cycloalkenylalkyl or aryl radicals; preferably, R
2
represents hydrogen, alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkyl of 1-3 carbon atoms substituted with an-aryl radical, cycloalkyl of 3-8 ring members, alkyl of 1-3 carbon atoms substituted with a cycloalkenyl radical of 3-8 ring members, or aryl radicals; more preferably, R
2
represents hydrogen, alkyl of 1-5 carbon atoms, alkenyl of 2-5 carbon atoms, alkyl of 1-2 carbon atoms substituted with an aryl radical, cycloalkyl of 3-6 ring members, alkyl of 1-2 carbon atoms substituted with a cycloalkenyl radical of 5-6 ring members, or aryl radicals; even more preferably, R
2
represents methyl, ethyl, ethenyl, propenyl, benzyl, cyclohexenylmethyl or naphthylmethyl radicals; most preferably, R
2
represents methyl, ethyl or benzyl radicals; or —NR
1
R
2
represents heterocyclo or heteroaryl radicals; preferably, —NR
1
R
2
represents 5-6 ring membered heterocyclo, 5-6 ring membered heteroaryl, benzo fused 5-6 ring membered heterocyclo or benzo fused 5-6 ring membered heteroaryl radicals; more preferably, —NR
1
R
2
represents 5-6 ring membered heterocyclo or benzo fused 5-6 ring membered heterocyclo radicals; even more preferably, —NR
1
R
2
represents pyrrolidinyl, piperidinyl, pyrrolyl, 2-isoindolinyl, phthalimidyl, succinimidyl or maleimidyl radicals; tost preferably, —NR
1
R
2
represents 2-isoindolinyl, phthalimidyl, succinimidyl or maleimidyl radicals;
R
3
represents alkyl, alkenyl, alkynyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, alkylthioalkyl, arylthioalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl or cycloalkylalkyl radicals; preferably, R
3
represents alkyl radical of 1 to 5 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, haloalkyl radical of 1 to 5 carbon atoms, cyanoalkyl radical of 1 to 5 alkyl carbon atoms, hydroxyalkyl radical of 1 to 5 alkyl carbon atoms, alkoxyalkyl radical of 1 to 5 alkyl carbon atoms and 1-3 alkoxy carbon atoms, aryloxyalkyl radical of 1 to 5 alkyl carbon atoms, alkylthioalkyl radical of 1 to 5 alkyl carbon atoms and 1-3 alkylthio carbon atoms, arylthioalkyl radical of 1 to 5 alkyl carbon atoms, aryl radical, aralkyl radical of 1 to 5 alkyl carbon atoms, heteroaralkyl radical of 1 to 5 alkyl carbon atoms and 5-6 ring members and benzo fused 5-6 ring members, cycloalkyl radical of 3-8

Affiliated with

Also associated with

Rating

N-protected/N-substituted-beta-amino hydroxy sulfonates does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with N-protected/N-substituted-beta-amino hydroxy sulfonates, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and N-protected/N-substituted-beta-amino hydroxy sulfonates will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3021937