Process and antiparasitic intermediates for doramectin
AssigneePfizer Inc.
InventorsConstantine Sklavounos, Thomas Charles Crawford, Neil Demers, Stephen Paul Gibson, Charles William Murtiashaw, deceased
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Abstract
Intermediates and a process for preparing doramectin, the compound of formula (I), semisynthetically from by-product in the fermentation procedure which also yields the compound of formula (I). The intermediates prepared by the process of this invention also have utility as antiparasitic agents. The process of this invention utilizes continuous reaction inert gas sparging during the pyrolysis step, resulting in a significant improvement in the overall yield of this conversion. ##STR1##
Claims23
A compound according to formula (III):
- ##STR8## wherein:
- R.sup.1 is (C.sub.2 -C.sub.5)alkanoyl or aryloxyacetyl;
- and
- R.sup.2 is hydrogen or aryloxythiocarbonyl.
A compound according to formula (IV):
- ##STR9## wherein R.sup.1 is (C.sub.2 -C.sub.5)alkanoyl or aryloxyacetyl.
A process for preparing a compound of the formula (I) ##STR10## comprising the consecutive steps of (a) reacting a compound of the formula (II) ##STR11## with an acylating agent of the formula (R.sup.4 CO).sub.2 O or R.sup.4 COX wherein R.sup.4 is aryloxymethyl and X is Cl or Br to form a compound according to formula (III) ##STR12## wherein R.sup.1 is aryloxyacetyl and R.sup.2 is hydrogen;
- (b) reacting said compound of formula (III) wherein R.sup.1 is aryloxyacetyl and R.sup.2 is hydrogen with a compound of the formula R.sup.3 OC(.dbd.S)X wherein R.sup.3 is aryl and X is Cl or Br to form a compound according to formula (III) wherein R.sup.1 is aryloxyacetyl and R.sup.2 is aryloxythiocarbonyl;
- (c) reacting said compound of formula (III) wherein R.sup.1 is aryloxyacetyl and R.sup.2 is aryloxythiocarbonyl in a reaction inert solvent at from about 150.degree. C. to about 200.degree. C. for about 2 hours to about 48 hours in the presence of calcium carbonate under continuous reaction inert gas sparging to form a compound according to formula (IV) ##STR13## wherein R.sup.1 is aryloxyacetyl;
- and (d) reacting said compound of formula (IV) wherein R.sup.1 is aryloxyacetyl with a base in an alcohol solvent to form the compound according to formula (I).
A process for preparing a compound of formula (I) ##STR14## comprising the consecutive steps of (a) reacting a compound of the formula (II) ##STR15## with an acylating agent of the formula (R.sup.4 CO).sub.2 O or R.sup.4 COX wherein R.sup.4 is (C.sub.1 -C.sub.4)alkyl and X is Cl or Br to form a compound according to formula (III) ##STR16## wherein R.sup.1 is (C.sub.1 -C.sub.4)alkanoyl and R.sup.2 is hydrogen;
- (b) reacting said compound of formula (III) wherein R.sup.1 is (C.sub.1 -C.sub.4)alkanoyl and R.sup.2 is hydrogen with a compound of the formula R.sup.3 OC(.dbd.S)X wherein R.sup.3 is aryl and X is Cl or Br to form a compound according to formula (III) wherein R.sup.1 is (C.sub.1 -C.sub.4)alkanoyl and R.sup.2 is aryloxythiocarbonyl;
- (c) reacting said compound of formula (III) wherein R.sup.1 is (C.sub.1 -C.sub.4)alkanoyl and R.sup.2 is aryloxythiocarbonyl in a reaction inert solvent at from about 150.degree. C. to about 200.degree. C. for about 2 hours to about 48 hours in the presence of calcium carbonate under continuous reaction inert gas sparging to form a compound according to formula (IV) ##STR17## wherein R.sup.1 is (C.sub.1 -C.sub.4)alkanoyl;
- and (d) reacting said compound of formula (IV) wherein R.sup.1 is (C.sub.1 -C.sub.4)alkanoyl with a lithium aluminum hydride, sodium cyanoborohydride or lithium triethylborohydride in a reaction inert solvent to form the compound according to formula (I).
A process for preparing a compound of formula (IV) ##STR18## wherein R.sup.1 is (C.sub.2 -C.sub.5)alkanoyl or aryloxyacetyl comprising reacting a compound of formula (III) ##STR19## wherein R.sup.1 is (C.sub.2 -C.sub.5)alkanoyl or aryloxyacetyl and R.sup.2 is aryloxythiocarbonyl in a reaction inert solvent at from about 150.degree. C. to about 200.degree. C. for about 2 hours to about 48 hours in the presence of calcium carbonate under continuous reaction inert gas sparging.
Dependencies are inferred from the claim text.