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US 9,139,514 B2Granted
Process for producing oseltamivir phosphate and intermediate compound
AssigneeSumitomo Chemical Company, Limited
InventorsYujiro Hayashi, Hayato Ishikawa
Life of this patent
Estimating the term…
Abstract
Disclosed are a process suited to large scale synthesis with high yield for producing oseltamivir phosphate, in which a preparation of oseltamivir phosphate which is highly safe as a pharmaceutical product can be produced, and an intermediate compound for producing oseltamivir phosphate. In this production process, an intermediate compound represented by general formula (V) is synthesized by employing Michael reaction/Michael reaction/Horner-Wadsworth-Emmons reaction, and oseltamivir phosphate is produced by converting the substituent groups in this intermediate compound.
Claims2
A process for producing oseltamivir phosphate comprising the following steps (1-1) to (1-8):
- (1-1) subjecting a compound represented by the following general formula (I) and a compound represented by the following general formula (II) to a Michael reaction, and subjecting thus obtained compound and a compound represented by the following general formula (III) or the general formula (IV) to a Michael reaction and a Horner-Wadsworth-Emmons reaction to obtain a compound represented by the following general formula (V):
- wherein, R1 represents a protecting group of a carboxyl group;
- R2 represents an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group which may have a substituent;
- R3 each independently represents an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl, group, or a heterocycloalkyl group which may have a substituent, and may form a ring structure by linking with each other;
- and
- A represents an arylene group, a heteroarylene group, a cycloalkylene group, or a heterocycloalkylene group which may have a substituent;
- (1-2) subjecting the compound represented by the above general formula (V) and a thiol compound to a Michael reaction to obtain a compound represented by the following general formula (VI):
- wherein, R1 and R2 are as defined above;
- and R4 represents an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, a cycloalkenyl group, a heterocycloalkenyl group, an alkyl group, an alkenyl group, or an alkynyl group which may have a substituent;
- (1-3) reducing the compound represented by the above general formula (VI), and subjecting to a reverse Michael reaction to obtain a compound represented by the following general formula (VII):
- wherein, R1 and R2 are as defined above;
- (1-4) protecting an amino group of the compound represented by the above general formula (VII) and deprotecting a carboxyl group to obtain a compound represented by the following general formula (VIII):
- wherein, R2 is as defined above;
- and R5 represents a group in which a protecting group is bound to an amino group;
- (1-5) halogenating a carboxyl group of the compound represented by the above general formula (VIII) to obtain a compound represented by the following general formula (IX):
- wherein, R2 and R5 are as defined above;
- and R6 represents a halogen atom;
- (1-6) allowing the compound represented by the above general formula (IX) to react with an azide to obtain a compound represented by the following general formula (X):
- wherein, R2 and R5 are as defined above;
- (1-7) subjecting the compound represented by the above general formula (X) to a Curtius rearrangement reaction to obtain a compound represented by the following general formula (XI):
- wherein, R2 and R5 are as defined above;
- and
- (1-8) deacetylating the compound represented by the above general formula (XI) and deprotecting an amino group to obtain a compound represented by the following general formula (XII):
- wherein, R2 is as defined above.
21 more elements
A process for producing oseltamivir phosphate comprising the following steps (2-1) to (2-9):
- (2-1) subjecting a compound represented by the following general formula (I) and a compound represented by the following general formula (II) to a Michael reaction, and subjecting thus obtained compound and a compound represented by the following general formula (III) or the general formula (IV) to a Michael reaction and a Horner-Wadsworth-Emmons reaction to obtain a compound represented by the following general formula (V):
- wherein, R1 represents a protecting group of a carboxyl group;
- R2 represents an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group which may have a substituent;
- R3 each independently represents an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group which may have a substituent, and may form a ring structure by linking with each other;
- and
- A represents an arylene group, a heteroarylene group, a cycloalkylene group, or a heterocycloalkylene group which may have a substituent;
- (2-2) subjecting the compound represented by the above general formula (V) and a thiol compound to a Michael reaction to obtain a compound represented by the following general formula (VI):
- wherein, R1 and R2 are as defined above;
- and R4 represents an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, a cycloalkenyl group, a heterocycloalkenyl group, an alkyl group, an alkenyl group, or an alkynyl group which may have a substituent;
- (2-3) deprotecting a carboxyl group of the compound represented by the above general formula (VI) to obtain a compound represented by the following general formula (XIII):
- wherein, R2 and R4 are as defined above;
- (2-4) halogenating a carboxyl group of the compound represented by the above general formula (XIII) to obtain a compound represented by the following general formula (XIV):
- wherein, R2 and R4 are as defined above;
- and R6 represents a halogen atom:
- (2-5) allowing the compound represented by the above general formula (XIV) to react with an azide to obtain a compound represented by the following general formula (XV):
- wherein, R2 and R4 are as defined above;
- (2-6) subjecting the compound represented by the above general formula (XV) to a Curtius rearrangement reaction to obtain a compound represented by the following general formula (XVI):
- wherein, R2 and R4 are as defined above;
- (2-7) deacetylating the compound represented by the above general formula (XVI) to obtain a compound represented by the following general formula (XVII):
- wherein, R2 and R4 are as defined above;
- (2-8) reducing the compound represented by the above general formula (XVII) to obtain a compound represented by the following general formula (XVIII):
- wherein, R2 and R4 are as defined above;
- and
- (2-9) subjecting the compound represented by the above general formula (XVIII) to a reverse Michael reaction to obtain a compound represented by the following general formula (XII):
- wherein, R2 is as defined above.
22 more elements
Dependencies are inferred from the claim text.