The present invention provides a novel method for the controlled stereoisomerization (comprising the stereo-conversion of chiral compounds to racemates, non-racemic mixtures and mixtures of epimers). The method of the invention provides the fully controlled generation of mixtures of different ratios of (S) and (R) stereoisomers, both enantiomers and diastereomers, of a given compound or a mixture of compounds. Such mixtures and isotopically labeled variants of said mixtures provided by the present invention are useful as an authenticity or external or internal standards in various biochemical and medical applications. Further, with the method of the invention it is possible to generate specific stereoisomers from some amino acids as well as degradation and oxidation products thereof which were previously not available. Thence, the invention provides in additional aspects the generation of a group of previously unavailable stereoisomers (enantiomers, epimers, and mixtures thereof such as a racemate) with amino acid type structures.

The present invention provides a process of producing a trifluoromcthoxylated aryl or trifluoromothoxylated heteroaryl having the structure: ##STR00001##
wherein
A is an aryl or heteroaryl, each with or without substitution; and
R.sub.1 is —H, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), -(alkylaryl), -(alkylheteroaryl), —NH-(alkyl), —N(alkyl).sub.2, —NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl), or —S-(heteroaryl), comprising:
(a) reacting a compound having the structure: ##STR00002##
with a trifluoromethylating agent in the presence of a base in a first suitable solvent under conditions to produce a compound having the structure: ##STR00003##
and
(b) maintaining the compound produced in step (a) in a second suitable solvent under conditions sufficient to produce the trifluoromethoxylated aryl or trifluormethoxylated heteroaryl having the structure: ##STR00004##

The present invention provides a process of producing a trifluoromcthoxylated aryl or trifluoromothoxylated heteroaryl having the structure: ##STR00001##
wherein
A is an aryl or heteroaryl, each with or without substitution; and
R.sub.1 is —H, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), -(alkylaryl), -(alkylheteroaryl), —NH-(alkyl), —N(alkyl).sub.2, —NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl), or —S-(heteroaryl), comprising:
(a) reacting a compound having the structure: ##STR00002##
with a trifluoromethylating agent in the presence of a base in a first suitable solvent under conditions to produce a compound having the structure: ##STR00003##
and
(b) maintaining the compound produced in step (a) in a second suitable solvent under conditions sufficient to produce the trifluoromethoxylated aryl or trifluormethoxylated heteroaryl having the structure: ##STR00004##

Disclosed herein is a continuous manufacturing process for lomustine that has a short residence time and 63 percent yield. Major advantages of this process are that the total production cost for lomustine is lower, the product is higher quality, and the manufacturing operation is safer for production personnel.

Disclosed herein is a continuous manufacturing process for lomustine that has a short residence time and 63 percent yield. Major advantages of this process are that the total production cost for lomustine is lower, the product is higher quality, and the manufacturing operation is safer for production personnel.

The present invention relates to a process to prepare ethylene amines of the formula NH.sub.2(C.sub.2H.sub.4NH).sub.pH wherein p is at least 3 or derivatives thereof wherein one or more units NHC.sub.2H.sub.4NH may be present as a cyclic ethylene urea unit or between two units NHC.sub.2H.sub.4NH a carbonyl moiety is present, by reacting an ethanolamine-functional compound, an amine-functional compound in the presence of a carbon oxide delivering agent, wherein the molar ratio of carbon oxide delivering agent to amine-functional compound is at least 0.6 to 1.

The present invention relates to a process to prepare ethylene amines of the formula NH.sub.2(C.sub.2H.sub.4NH).sub.pH wherein p is at least 3 or derivatives thereof wherein one or more units NHC.sub.2H.sub.4NH may be present as a cyclic ethylene urea unit or between two units NHC.sub.2H.sub.4NH a carbonyl moiety is present, by reacting an ethanolamine-functional compound, an amine-functional compound in the presence of a carbon oxide delivering agent, wherein the molar ratio of carbon oxide delivering agent to amine-functional compound is at least 0.6 to 1.

The present invention provides a process of producing a trifluoromcthoxylated aryl or trifluoromothoxylated heteroaryl having the structure:

##STR00001## wherein A is an aryl or heteroaryl, each with or without substitution; and R.sub.1 is H, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), -(alkylaryl), -(alkylheteroaryl), NH-(alkyl), N(alkyl).sub.2, NH-(alkenyl), NH-(alkynyl) NH-(aryl), NH-(heteroaryl), O-(alkyl), O-(alkenyl), O-(alkynyl), O-(aryl), O-(heteroaryl), S-(alkyl), S-(alkenyl), S-(alkynyl), S-(aryl), or S-(heteroaryl), comprising: (a) reacting a compound having the structure:

##STR00002## with a trifluoromethylating agent in the presence of a base in a first suitable solvent under conditions to produce a compound having the structure:

##STR00003##

and (b) maintaining the compound produced in step (a) in a second suitable solvent under conditions sufficient to produce the trifluoromethoxylated aryl or trifluormethoxylated heteroaryl having the structure:

##STR00004##

The present invention provides a process of producing a trifluoromcthoxylated aryl or trifluoromothoxylated heteroaryl having the structure:

##STR00001## wherein A is an aryl or heteroaryl, each with or without substitution; and R.sub.1 is H, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), -(alkylaryl), -(alkylheteroaryl), NH-(alkyl), N(alkyl).sub.2, NH-(alkenyl), NH-(alkynyl) NH-(aryl), NH-(heteroaryl), O-(alkyl), O-(alkenyl), O-(alkynyl), O-(aryl), O-(heteroaryl), S-(alkyl), S-(alkenyl), S-(alkynyl), S-(aryl), or S-(heteroaryl), comprising: (a) reacting a compound having the structure:

##STR00002## with a trifluoromethylating agent in the presence of a base in a first suitable solvent under conditions to produce a compound having the structure:

##STR00003##

and (b) maintaining the compound produced in step (a) in a second suitable solvent under conditions sufficient to produce the trifluoromethoxylated aryl or trifluormethoxylated heteroaryl having the structure:

##STR00004##

The present invention provides a process of producing a trifluoromethoxylated aryl or trifluoromethoxylated heteroaryl having the structure: ##STR00001##
wherein
A is an aryl or heteroaryl, each with or without substitution; and
R.sub.1 is H, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), -(alkylaryl), -(alkylheteroaryl), NH-(alkyl), N(alkyl).sub.2, NH-(alkenyl), NH-(alkynyl) NH-(aryl), NH-(heteroaryl), O-(alkyl), O-(alkenyl), O-(alkynyl), O-(aryl), O-(heteroaryl); S-(alkyl), S-(alkenyl), S-(alkynyl), S-(aryl), or S-(heteroaryl), comprising:
(a) reacting a compound having the structure: ##STR00002##
with a trifluoromethylating agent in the presence of a base in a first suitable solvent under conditions to produce a compound having the structure: ##STR00003##
and
(b) maintaining the compound produced in step (a) in a second suitable solvent under conditions sufficient to produce the trifluoromethoxylated aryl or trifluormethoxylated heteroaryl having the structure: ##STR00004##