This invention provides for a flow synthesis process for producing Oseltamivir and pharmaceutically acceptable salts thereof from shikimic acid in particular but not exclusively to a flow synthesis process for producing Oseltamivir phosphate from shikimic acid in a nine-step flow synthesis that provides for superior reaction times and product yields compared to known methods.

Provided are an intermediate for synthesizing a camptothecin derivative, a preparation method therefor, and the use thereof. An intermediate A can be obtained from 3-fluoro-4-methylaniline by means of acylation, bromination, and cross-coupling reactions. The intermediate A can be used for preparing an intermediate B to further prepare exatecan mesylate. The intermediate compound B can be obtained from the intermediate A by means of a rearrangement reaction, and exatecan mesylate can be obtained from the intermediate compound B by means of deprotection for acetamido and amino at the a site, a condensation reaction, and a hydrolysis reaction. The reaction starting materials have a low price, the reaction conditions of each step are moderate, the operation is simple, and the yield is high, such that the intermediate is suitable for industrial production.

Provided are an intermediate for synthesizing a camptothecin derivative, a preparation method therefor, and the use thereof. An intermediate A can be obtained from 3-fluoro-4-methylaniline by means of acylation, bromination, and cross-coupling reactions. The intermediate A can be used for preparing an intermediate B to further prepare exatecan mesylate. The intermediate compound B can be obtained from the intermediate A by means of a rearrangement reaction, and exatecan mesylate can be obtained from the intermediate compound B by means of deprotection for acetamido and amino at the a site, a condensation reaction, and a hydrolysis reaction. The reaction starting materials have a low price, the reaction conditions of each step are moderate, the operation is simple, and the yield is high, such that the intermediate is suitable for industrial production.

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 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 application provides processes for synthesizing targeting molecules of Formula (I) comprising a retinoid moiety useful in the synthesis of fat-soluble compounds for targeting and enhancing activity of therapeutic molecules, including siRNA.

##STR00001##

The present application provides processes for synthesizing targeting molecules of Formula (I) comprising a retinoid moiety useful in the synthesis of fat-soluble compounds for targeting and enhancing activity of therapeutic molecules, including siRNA.

##STR00001##

There is provided an α-carbonyl alkenyl ester and a preparation method therefor, and the α-carbonyl alkenyl ester is further used to react with a primary or secondary amine to prepare an amide. The two reactions are combined to develop an amide bond and peptide bond formation method that directly use carboxylic acids and amines as starting materials and allenones as a condensing reagent. The α-carbonyl alkenyl ester corresponding to an α-amino acid serves as a peptide synthesis building block and is used in solid phase peptide synthesis. The method is carried out under mild reaction conditions, simple to operate, and has a high yield. Compared with existing amide bond condensation reagents, the allenones have the advantages of being simple to prepare, having good stability, a low molecular weight, not racemizing when activating α-chiral carboxylic acids, and is a novel amide bond and peptide bond condensing reagent.

There is provided an α-carbonyl alkenyl ester and a preparation method therefor, and the α-carbonyl alkenyl ester is further used to react with a primary or secondary amine to prepare an amide. The two reactions are combined to develop an amide bond and peptide bond formation method that directly use carboxylic acids and amines as starting materials and allenones as a condensing reagent. The α-carbonyl alkenyl ester corresponding to an α-amino acid serves as a peptide synthesis building block and is used in solid phase peptide synthesis. The method is carried out under mild reaction conditions, simple to operate, and has a high yield. Compared with existing amide bond condensation reagents, the allenones have the advantages of being simple to prepare, having good stability, a low molecular weight, not racemizing when activating α-chiral carboxylic acids, and is a novel amide bond and peptide bond condensing reagent.