Claims
- 1. A process for preparing the 10-deazaminopterin and its 10-alkyl derivatives, which comprises
- (1) reacting 3-chloro-1-methoxy-propene with the reaction product of alkyl lithium with a p-alkyl-benzoic acid in which the alkyl group has the structure: ##STR6## corresponding to the 10-carbon group of the desired 10-deazaminopterin, wherein R.sub.1 and R.sub.2 are each selected from the group consisting of hydrogen and alkyl having from one to eight carbon atoms, in the presence of an acid acceptor at a temperature below 0.degree. C. at which the reaction proceeds in the presence of an inert solvent under anhydrous conditions, thereby substituting a methoxy-propylene group at the p-alkyl group of the acid;
- (2) converting the methoxy-propylene group to a bromo-acetaldehyde group by reaction with bromine while maintaining the pH within the range from about 7 to about 8, with addition of a buffer if necessary to maintain the pH below 8;
- (3) reacting this reaction product with 2,4,5,6-tetraaminopyrimidine at an acid pH within the range from about 3 to about 5 and an elevated temperature within the range from about 35 to about 75.degree. C., cyclizing the 5,6-amino groups thereof with the aldehyde and bromine groups of this reaction product, and forming a dihydro-pteridine ring containing the 5,6-nitrogen atoms in the ring;
- (4) dehydrogenating the pteridine ring by reaction with potassium iodide/iodine KI.sub.3, thereby forming the corresponding 4-amino-4-desoxy-10-deazapteroic acid;
- (5) reacting the 4-amino-4-desoxy-10 deazapteroic acid with isobutyl chloroformate in the presence of an acid acceptor at a temperature within the range from 0.degree. to -5.degree. C.; adding diethyl-L-glutamate hydrochloride to the reaction mixture, and continuing the reaction at a temperature within the range from 0.degree. to -5.degree. C., thereby converting the pteroic acid group to the corresponding glutamide diethyl ester; and then
- (6) hydrolyzing off the esterifying ethyl groups by reacting the ester with dilute aqueous alkali, forming the free diacid of the glutamide group and completing the 10-deazaminopterin compound.
- 2. A process according to claim 1, which comprises rearranging methyl propargyl ether to the corresponding 1-methoxy-allene under anhydrous conditions in the presence of alkali, at an elevated temperature under an inert atmosphere, and then adding hydrogen chloride across the allenic double bonds of 1-methoxy-allene under anhydrous conditions at a temperature below about -25.degree. C. under an inert atmosphere, with the 1-methoxy-allene in solution in an inert solvent; and using the resulting 3-chloro-1-methoxy-propene-containing reaction mixture directly in Step (1).
- 3. A process according to claim 2 in which the alkali is an alkali metal alkoxide.
- 4. A process according to claim 1 in which the acid acceptor in Step (1) is a tertiary amine.
- 5. A process according to claim 1 in which the reaction of the p-alkyl-benzoic acid with the alkyl lithium is carried out at a temperature of from 0.degree. to 5.degree. C., and the 3-chloro-1-methoxy-propene in solution in an inert solvent is added slowly to the reagent reaction mixture and reaction continued until the reaction mixture is colorless.
- 6. A process according to claim 1 in which the Step (1) bromo-acetaldehyde reaction product is washed and carbonated in aqueous solution with gaseous carbon dioxide, to reduce the pH to within the range from about 8 to about 9.
- 7. A process according to claim 1 in which in Step (2) solid sodium bicarbonate is added to maintain the pH below 8 and the reaction mixture is then acidified by addition of aqueous hydrochloric acid to a pH of about 2.
- 8. A process according to claim 1 in which Step (3) is carried out in an organic acid solvent at a temperature within the range from 35.degree. to 75.degree. C.
- 9. A process according to claim 1 in which in Step (5) the acid acceptor is triethylamine, and 4-amino-4-desoxy-10-deazapteroic acid is in solution in an inert solvent, the isobutyl chloroformate is added slowly to the reaction mixture, and upon completion of the reaction, diethyl-L-glutamate hydrochloride, organic amine and more solvent are added, and reaction continued at the same temperature until complete; dimethylformamide which is liberated is removed, and the residue mixed with alkaline aqueous buffer solution in which the diester is insoluble.
- 10. A process according to claim 1 in which the p-alkyl-benzoic acid has the formula: ##STR7## the Step (1) reaction product has the formula: ##STR8## the Step (2) reaction product has the formula: ##STR9## the Step (3) reaction product has the formula: ##STR10## the Step (4) reaction product has the formula: ##STR11## the Step (5) reaction product has the formula: ##STR12## and the 10-deazaminopterin product has the formula: ##STR13## wherein: R.sub.1 and R.sub.2 are hydrogen or alkyl having from one to about eight carbon atoms.
Parent Case Info
This is a division of application Ser. No. 233,280, filed Feb. 10, 1981, now U.S. Pat. No. 4,369,319, which in turn is a division of Ser. No. 75,913, filed Sept. 17, 1979, now U.S. Pat. No. 4,393,064, which in turn is a continuation-in-part of Ser. No. 883,627, filed Mar. 6, 1978, which in turn is a continuation-in-part of Ser. No. 761,152, filed Jan. 21, 1977, which is a continuation-in-part of Ser. No. 664,213, filed Mar. 5, 1976, the last three mentioned being now abandoned.
Non-Patent Literature Citations (2)
Entry |
De Graw et al., J. Med. Chem., 1974, vol. 17, No. 5, pp. 552-553. |
DeGraw et al., J. Med. Chem., 1971, vol. 14, No. 9, pp. 866-867. |
Divisions (2)
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Number |
Date |
Country |
Parent |
233280 |
Feb 1981 |
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Parent |
75913 |
Sep 1979 |
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Continuation in Parts (3)
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Number |
Date |
Country |
Parent |
883627 |
Mar 1978 |
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Parent |
761152 |
Jan 1977 |
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Parent |
664213 |
Mar 1976 |
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