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3. Recent Progress of Selective Monohydrolysis of Symmetric Diesters Satomi Niwayama Graduate School of Engineering Muroran Institute of Technology

4. half-ester Synthesis of Pharmaceuticals with the use of half-esters

5. C 6 H 5 COOC 2 H 5 H 3 CCOOC 2 H 5 C 6 H 5 COOC 2 H 5 H 3 CCOOH C6H5C6H5 COOC 2 H 5 COOH Pr COOC 2 H 5 Pr KOH EtOH r.t.100hrs (yield unknown) COOC 2 H 5 C 6 H 5 KOH EtOH r.t.1.5 hrs 98.5 % (as a crude product) KOH EtOH r.t.20 hrs COOC 2 H 5 COOH 74.6 % Corey, E. J. J. Am. Chem. Soc. 1952, 74, 5897 Vecchi, A.; Melone, G. J. Org. Chem. 1959, 24, 109 Corey, E. J. J. Am. Chem. Soc. 1952, 74, 5897 Previous examples of monosaponification

6. 0oC0oC +H3O+H3O CO2RCO2R CO2HCO2H CO2RCO2R CO 2 R R=Me, Et New Selective Monohydrolysis aqueous NaOH or KOH THF or other co-solvent

7. Comparison to Classical Conditions CO 2 Me THF/aqueous NaOH (2eq.) 0 o C, 30-60 min. CO 2 H CO 2 Me ~quant. white cryst. m.p. 106-107 o C(lit. 108-109 o C) CO 2 Me CO 2 H CO 2 Me NaOH/MeOH (1eq.) 10% yellowish r.t.r.t. + diester + dicarboxylic acid

8. Monohydrolysis of Symmetric Diesters MeO2CMeO2C CO 2 Me MeO2CMeO2C CO 2 H CO 2 Me CO 2 Me O CO H 2 CO 2 Me O >99% 95% b 1a 5 CO 2 Me HO 2 C CO 2 Me 1b HO2CHO2C CO 2 Me 79% 2b entry 1 2 MeO 2 C 3 5a 70% 2a 4 diester productyield (%) a 4b HO 2 CCO 2 Me 3b 3a 5b 4a >99% entry diester productyield (%) a CO Me 2 CO 2 Me O O CO 2 H CO 2 Me O >99% 6 6a6b Ph 7 CO 2 CH 2 CH 3 7a CO 2 H CO 2 CH 2 CH 3 7b CO 2 H CO 2 CH 2 CH 3 8 CO 2 CH 2 CH 3 8a 8b >99% 96% O 2 CO H CO2CH2CH3CO2CH2CH3 CO 2 CH 2 CH 3 O CO 2 CH 2 CH 3 9 9a 9b >99% a. Yields are isolated yields from silica gel column chromatography based on the amounts of the diesters submitted to the reaction. b. The yield was diminished due to the slight volatility of 3b.

9. -O2C-O2C CO2CO2 - 2 CO - - O2CO2C CO 2 R RO 2 C RO 2 C CO 2 R RO 2 C RO 2 C CO2CO2 - CO2RCO2R - O2CO2C CO2RCO2R -CO2-CO2 Potential Mechanism H2OH2O H2OH2O 2 H OH O H2OH2O - CO 2 H 2 O Soap-like aggregates prohibit further hydrolysis

11. Solvent Effects

12. Effects of Kinds of Co-Solvent

13. O H R H H OMe R H H Me H H SnBu 3 O O ++ O O a) high pressure H MeCO 2 Me + MeCHO H or OMe  + Me  OO Nu - H +H + O  ++ OO O R R MeO anti-Cram 82-90 Cram 18-10 : A B  + OMe OO  + O Me Nu-Nu-. heating or BF 3 OEt 2. b) i) BF 3 OEt 2 ii) H 2, Pd/C + Yamamoto, Y. ; Nemoto, H.; Kikuchi, R.; Komatsu, H.; Suzuki, I. J. Am. Chem. Soc. 1990, 112, 8598 RR R or  + OMe OO ++ OO Conformational Preference of the Starting Diesters

14. The Conformer of Dimethyl Maleate with the Lowest Energy (MP2/6-31G(d)//B3LYP/6-31G(d)) dihedral angles 7.4 o 111.2 o 72.6 o 2.850Å 8.3 o n->  * interaction

15. Experimental Support for the Predominant Conformation by Theoretical Studies

17. 6.586.58 2.922.232.122.922.232.12 4.624.62 2.11 1.82 1.08 1010 15 20 25 86.886.8 74.569.067.974.569.067.9 13.213.2 25.5 31.0 32.1 82.282.2 67.8 64.6 51.9 17.817.8 32.2 35.4 48.1 Reaction time/min. Reaction time/min. a (%)b (%) ratio a:b CO 2 CH 3 o 1) aqueous MOH THF/H 2 O, 0 C M=Li, Na, K, Cs 2) H 3 O + LiOH + CO 2 H CO 2 CH 3 a CO 2 H b NaOH a (%)b (%) ratio a:b a (%) b (%) ratio a:b b (%) a (%) diester 2066.233.81.961.96 67.832.22.112.11 consumed 2561.138.91.571.57 67.432.62.072.07 3059.240.81.451.45 61.438.61.591.59 3555.944.11.271.27 60.939.11.561.56 KOH CsOH diester consumed Selectivity: K>Cs>Na≥Li Electropositive character: Cs≥K>Na≥Li

18. New Conditions for Monohydrolysis of Linear Diesters More hydrophobic 100g $306 ~96% purity ~100% purity

21. Recognition of Steric Environment 0 oC0 oC 0 oC0 oC

22. Summary co-solvent aqueous base 0oC0oC H3O+H3O+ CO2RCO2R CO R CO2HCO2H CO2RCO2R 2 R=Me, Et A highly efficient, mild, straightforward reaction using co-solvent-aqueous base at 0 o Cwas found to produce pure half-esters from symmetric diesters in high yields. This reaction has been licensed by Kishida Chemical Co.Ltd., Japan www.kishida.co.jp

23. Organic Chemistry : Current ResearchOrganic Chemistry : Current Research Pharmaceutica Analytica ActaPharmaceutica Analytica Acta Clinical Pharmacology &Clinical Pharmacology & Biopharmaceutics

24.  4th International Conference on 4th International Conference on Medicinal Chemistry & Computer Aided Drug Designing

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