Process for preparing 4-mercaptopyrrolidine intermediate compounds and a process for their use in preparing carbapenem -2-em-3 carboxylic acids
AssigneeTanabe Seiyaku Co., Ltd.
InventorsHiroshi Ohmizu, Masahiko Seki, Takeshi Yamanaka
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Abstract
An improved process for preparing a 4-mercaptopyrrolidine compound [I]: ##STR1## wherein R is H, lower alkyl or lower alkanoyl, R.sup.1 is H or SH-protecting group, and X is O or S, which comprises reacting halogenobutyric acid compound [VI], or a salt thereof, with amine compound [VII], or a salt thereof, and if necessary, followed by thiocarbonylating the product and/or removing the protecting group, said 4-mercaptopyrrolidine compound [I] being useful as intermediate for carbapenem antibacterial agents.
Claims8
A process for preparing a 4-mercaptopyrrolidine compound of the formula [1]:
- ##STR12## wherein R is a hydrogen atom, a lower alkyl group or a lower alkanoyl group, R.sup.1 is a hydrogen atom or a protecting group for thiol group, and X is an oxygen atom or a sulfur atom, which comprises reacting a halogenobutyric acid compound of the formula [VI]:
- ##STR13## wherein R.sup.11 is a protecting group for thiol group, R.sup.2 is a hydrogen atom or a protecting group for carboxyl group, and R.sup.3 is a halogen atom, or a salt thereof, with an amine compound of the formula [VII]:
- RNH.sub.2 [VII]
- wherein R is the same as defined above, or a salt thereof to obtain a compound of the formula:
- ##STR14## wherein R.sup.11 and R are the same as defined above, and if necessary, followed by thiocarbonylating the product and/or removing the protecting group for thiol group from the product.
A halogenobutyric acid compound of the formula [VI]:
- ##STR15## wherein R.sup.11 is a protecting group for thiol group, R.sup.2 is a hydrogen atom or a protecting group for carboxyl group, and R.sup.3 is a halogen atom, or a salt thereof.
A process for preparing a 4-mercaptopyrrolidine compound of the formula [1]:
- ##STR16## wherein R is a hydrogen atom, a lower alkyl group or a lower alkanoyl group, R.sup.1 is a hydrogen atom or a protecting group for thiol group, and X is an oxygen atom or a sulfur atom, which comprises
- (i) reacting a halogenosuccinic acid compound of the formula [III]:
- ##STR17## wherein R.sup.2 is a hydrogen atom or a protecting group for carboxyl group, and R.sup.4 is a halogen atom, or a salt thereof, with a thiol compound of the formula [III]:
- R.sup.11 SH [III]
- wherein R.sup.11 is a protecting group for thiol group, or a salt thereof, to give a mercaptosuccinic acid compound of the formula [IV]:
- ##STR18## wherein R.sup.11 and R.sup.2 are the same as defined above, (ii) subjecting the compound [IV] or a salt thereof to reduction to give a hydroxybutyric acid compound of the formula [V]:
- ##STR19## wherein R.sup.11 and R.sup.2 are the same as defined above, (iii) halogenating the compound [V] or a salt thereof to give a halogenobutyric acid compound of the formula [VI]:
- ##STR20## wherein R.sup.3 is a halogen atom, and R.sup.11 and R.sup.2 are the same as defined above,
- (iv) reacting the compound [VI] or a salt thereof with an amine compound of the formula [VII]:
- RNH.sub.2 [VIII]
- wherein R is the same as defined above, or a salt thereof, to obtain a compound of the formula:
- ##STR21## wherein R.sup.11 and R are the same as defined above, and if necessary, (v) followed by thiocarbonylating the product and/or removing the protecting group for the thiol group from the product.
A process for preparing a 2-(pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxy lic acid derivative of the formula [VIII]:
- ##STR22## wherein R.sup.5 is a hydrogen atom or a protecting group for hydroxy group, R.sup.6 is a hydrogen atom or an ester residue, R is a hydrogen atom, a lower alkyl group or a lower alkanoyl group and X is an oxygen atom or a sulfur atom, or a salt thereof, which comprises reacting a halogenobutryric acid compound of the formula [VI]:
- ##STR23## wherein R.sup.11 is a protecting group for thiol group, R.sup.2 is a hydrogen atom or a protecting group for carboxyl group, and R.sup.3 is a halogen atom, or a salt thereof, with an amine compound of the formula [VII]:
- RNH.sub.2 [VII]
- wherein R is the same as defined above, or a salt thereof, to obtain a compound of the formula ##STR24## wherein R.sup.11 and R are the same as defined above, and if necessary, thiocarbonylating the product and/or removing the protecting group for thiol group from the product, to give a 4-mercaptopyrrolidine compound of the formula [I]:
- ##STR25## wherein R.sup.1 is a hydrogen atom or a protecting group for thiol group, R and X are the same as defined above, followed by converting the compound [I] by a conventional method into the 1-methylcarbapenem derivative of the formula [VIII].
Dependencies are inferred from the claim text.