1. A method for making Gatifloxacin containing not more than about 0.1 area- % impurities comprising the steps of:
(a) heating a reaction mixture comprising 2-methylpiperazine and 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinoline carboxylic acid in a dipolar aprotic solvent to a reaction temperature from about 40\xb0C. to about 70\xb0C. for a reaction time in an atmosphere of inert gas;
(b) maintaining the reaction mixture at a holding temperature of about 40\xb0 C. or less for a holding time, to form a slurry, wherein the holding time is sufficiently long so that there is no further increase in the percent suspended solids for a period of about one-half hour;
(c) isolating gatifloxacin from the slurry formed in step (b);
(d) slurrying the isolated gatifloxacin with water or a mixture of water and acetonitrile to form a water slurry; and
(e) isolating gatifloxacin having about 0.07 area- % or less desmethyl gatifloxacin and about 0.06 area- % or less 2\u2032-methyl gatifloxacin from the water slurry.
2. The method of claim 1 wherein the reaction mixture is formed by portionwise addition of the 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-meth-oxy-4-oxo-3-quinoline carboxylic acid to a mixture of dipolar aprotic solvent and 2-methylpiperazine.
3. The method of claim 1 further comprising the step of, prior to the maintaining step, concentrating the reaction mixture to a volume that is from about 40% to about 60% of its initial volume by distilling-off dipolar aprotic solvent.
4. A pharmaceutical composition comprising gatifloxacin that contains about 0.07% or less desmethyl gatifloxacin and about 0.06% or less 2\u2032-methytl gatifloxacin.
5. The method according to claim 1, wherein the reaction temperature in step (a) is from about 53\xb0 C. to about 57\xb0 C.
6. The method according to claim 1, wherein the dipolar aprotic solvent is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, N-methylpyrolidone, and mixtures thereof.
7. The method according to claim 6, wherein the dipolar aprotic solvent is dimethylsulfoxide.
8. The method according to claim 1, wherein the inert gas is selected from the group consisting of nitrogen and argon.
9. The process according to claim 1, wherein the holding time in step (b) is from about 12 hours to about 24 hours.
10. The method according to claim 1, wherein the holding temperature in step (b) is less than about 25\xb0 C.
11. The method according to claim 1, wherein the holding temperature in step (b) is less than about 5\xb0 C.
12. The process according to claim 1, wherein the slurrying in step (d) is carried out for a slurry time that is from about thirty minutes to about three hours.
13. The method according to claim 1, wherein slurrying with water or a mixture of water and acetonitrile in step (d) is performed at a temperature of from about 20\xb0C. to about 30\xb0 C.
14. Gatifloxacin containing not more than about 0.1 area-% impurities made according to the method of claim 1.
15. The method of claim 11, further comprising prior to or simultaneous with the maintaining step, the step of adding to the reaction mixture co-solvent selected from the group consisting of benzene, toluene, dimethylcarbonate, and water.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A method for the treatment of prostate cancer in a human subject comprising administering to a subject in need of such treatment an anti-prostate cancer effective amount of a rice wine extract of fresh citrus fruit peels.
2. The method of claim 1 wherein the extract is administered orally.
3. The method of claim 1 wherein the extract is administered orally in a dosage amount of from about 5 to 120 ml from 1 to 5 times a day.
4. The method of claim 1 wherein the extract is administered orally in a total daily dosage amount of from 10 to 60 ml.
5. The method of claim 1 wherein the extract is administered orally for a period of time sufficient to cause remission of prostate cancer in the subject.
6. The method of claim 1 wherein the extract is obtained by peeling fresh citrus fruit, mixing the peels thus obtained with rice wine and allowing the mixture to stand for a period of time and at temperature and pressure conditions sufficient to extract substantially all of any rice wine-soluble compounds in the citrus peels into the rice wine.
7. The method of claim 6 wherein the temperature is ambient temperature.
8. The method of claim 6 wherein the temperature is room temperature.
9. The method of claim 6 wherein the temperature is from about 4\xb0 C. to 120\xb0 C. and the pressure is from atmospheric to 100 bar.
10. The method of claim 6 wherein more than one species of fresh citrus fruit are mixed with the rice wine.
11. The method of claim 10 wherein the fresh citrus peels are selected from the group consisting of citrus fruit grown and harvested in Japan.
12. The method of claim 6 wherein the citrus fruit is washed with water prior to peeling.
13. The method of claim 1 wherein the fresh citrus fruit is peeled by hand.
14. The method of claim 11 wherein the fresh citrus fruit is selected from the group consisting of navel oranges, C. hassaku hort., lemon. C. aurantium, C. Miyauchi iyo Hort., C. unshiu, fortunella (kumquatCumquat), Mikan unsyu (tangerine) and mixtures thereof.
15. The method of claim 11 wherein the extract further contains aloe arborescens.
16. The method claim 6 wherein the extract is aged at ambient temperature.
17. A method for the therapeutic treatment of a human having prostate cancer comprising administering to the human an anti-prostate cancer effective amount of a rice wine extract of peels from fresh citrus fruit selected from the group consisting of navel oranges. C. hassaku hort., lemons. C. aurantium, C. Miyauchi iyo Hort., C. unshiu, and mixtures thereof.
18. The method of claim 17 wherein the treatment is continued for a period of time sufficient to cause remission of the prostate cancer.
19. The method of claim 17 wherein the treatment is carried by oral administration of the rice wine extract at a dosage amount of 10 ml, two to three times per day.