HAMUR MAYASI KULLANARAK ORGANIK SOLVENT DE -KETO ESTER REDUKSİYONU VE ESTER HİDROLİZİ

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1 PRJE EDİR? Proje belli bir amacı olan ve bu amacı gerçekleştirmek için çeşitli bilimsel deney ve faaliyetlerin bir bütçe dahilinde belli bir süre içerisinde sonuçlandırılmasıdır. Eğer proje başarı ile sonuçlanmış ise ya bir makale olarak yayınlanır yada patent ile korunma altına alınır. PRJEİ ÖEMİ -Yaratıcılığı geliştirir -Kişinin filozofisini değiştirir -Problem çözme, mantıksal düşünme, iletişim gibi yetenekleri geliştirir

bütçe dahilinde belli bir süre içerisinde sonuçlandırılmasıdır.

2 HAMUR MAYASI KULLAARAK RGAIK SLVET DE -KET ESTER REDUKSİYU VE ESTER HİDRLİZİ H Hamur Mayasi H Isopropilpalmitat H Preparative -Ketoesters Reductions and Ester Hydrolyses by Yeast. Using Free Cells in rganic Media T. Haag, T. Arslan and D. Seebach. Chimia 1989, 43, 851.

-Ketoesters Reductions and Ester Hydrolyses by Yeast.

3 ATİSES ÜKLESİD AALGLARI SULF PRJESİ DA DA H B B B P - B CH 2 S CH 2 B H B DA DA ormal DA Sulfon Analog Peptide Analog Redesigning ucleic Acids. S. A. Benner, T. R. Battersby, B. Eschgfaeller, D. Hutter, J.T Kodra, S. Lutz, T. Arslan, D. Baeschlin, M. Blaettler, C. Y. Switzer, S. E. Moroney, J. Voegel, L. MacPherson, U. von Krosigk, C. Hammer, C. Richert, Z. Huang, J. Horlacher, M. Koenig, B. Hyrup, M. Egli, E. Mueller, J. Schmidt, J. Piccirilli, A. Roughton, H. Held, S. Jurczyk, S. Lutz,, K. P. ambiar K. C. Schneider, J Stackhouse. Pure Appl. Chem. 1998, 70, 263.

Voegel, L. MacPherson, U. von Krosigk, C. Hammer, C. Richert, Z. Huang, J. Horlacher, M. Koenig, B. Hyrup, M. Egli, E. Mueller, J. Schmidt, J.

4 ATİSES UKLESİDLERİ YAPI TAŞLARII SETEZİ H Hamur Mayasi Su H H H H R Reduction of 2 -Substituted 3-xoglutarates Mediated by Baker's Yeast. Variation in Enantioselectivity without Corresponding Variation in Diastereoselectivity. T. Arslan and S. A. Benner. J. rg. Chem. 1993, 58, Determination of the Absolute Configuration of Dimethyl (2S,3S) 2-allyl-3- hydroxyglutarate: A Chiral Building Block for Preparing Branched-chain ucleoside Analogs. T. Arslan, B. Herradon, W. B. Schweizer and S. A. Benner. Helv. Chim. Acta. 1993, 76, 2969.

5 DA-TPISMERASE PRJESİ Structurally Modified Substrates for DA Topoisomerase I. Effect of Inclusion of a Single 3' - Deoxynucleotide within the Scissile Strand. T. Arslan, A. T. Abraham and S. M. Hecht. ucleosides and ucleotides 1998, 17, 515. Effect of 3' - Deoxynucleotides on DA Topoisomerase I Binding and Activity. T. Arslan, T. Abraham and S. M. Hecht. J. Biol. Chem. 1998, 273,

M. Hecht. ucleosides and ucleotides 1998, 17, 515.

6 ATEŞBÖCEĞİ LUCİFERASE A DĞAL LMAYA AMİASİTLERİ SPESİFİK LARAK YERLEŞTİRİLMESİ Misacylated Transfer RAs as a Source of Synthetic Enzymes. V Karginov; S Mamaev, H An, A Laikhter, T Arslan, C Crasto, G Short, S M.Hecht,. Book of Abstracts, 212th ACS ational Meeting, rlando, FL, August (1996)

V Karginov; S Mamaev, H An, A Laikhter, T Arslan, C Crasto, G Short, S M.

7 Firefly Luciferase: Alteration of the Color of Emitted Light. S. V. Mamaev, A. L. Laikhter, T. Arslan and S. M. Hecht. J. Am. Chem. Soc. 1996, 118, 7243.

8 ATEŞBÖCEĞİ LUCIFERASE I KİMYASAL EERJİYİ IŞIĞA ÇEVİRME MEKAİZMASI Structurally Modified Firefly Luciferases Effect of Amino Acid. Substitution at Position 286. T. Arslan, S. V. Mamaev,. V. Mamaeva and S. M. Hecht. J. Am. Chem. Soc. 1997, 119,

Amino Acid. Substitution at Position 286. T. Arslan, S. V.

9 SILDEAFIL CITRATE EP Temel patent Pfizer Ethoxy benzoic acid H SCl 2 Toluene Cl 2-Ethoxybenzoyl chloride + 2 H H 2 4-Amino-1-methyl -3-n-propyl pyrazole -5-carboxyamide CH 2 Cl 2 Et 3 2 H H 4-(2-Ethoxybenzamido-1-methyl 3-n-propylpyrazole-5-carboxyamide(I) 2 H H EtH, H 2 2 ah CH 2 Cl 2, ac 3 ac 3, acl Ether H Chlorsulfonic acid CH 2 Cl 2, H 2, MeH S Cl H (I) 5-(2-Ethoxyphenyl)-1-methyl 3-n-propyl-1,6-dihydro-7Hpyrazole[4,3,d]pyrimidin-7-one 5-(5-Chlorosulphonyl 2-Ethoxyphenyl)-1-methyl 3-n-propyl-1,6-dihydro-7Hpyrazole[4,3,d]pyrimidin-7-one(II)

3-n-propylpyrazole-5-carboxyamide(I) 2 H H EtH, H 2 2 ah CH 2 Cl 2, ac 3 ac 3, acl Ether H Chlorsulfonic acid CH 2 Cl 2, H 2, MeH S Cl H (I)

10 (II) -methylpiperazine EtH CH 2 Cl 2, MeH, ac 3 S H Citric acid MeH Sildenafil base S H. CH H CH CH Sildenafil Citrate

11 SDIUM ALEDRATE TRIHYDRATE US Temel patent Merck H H 1) P 3 H, PCl 3 Sunflower oil 2) ah, MeH H P 3 H 2 H P 3 a.3h % 4-Aminobutanoic acid Sodium Alendronate Trihydrate Preparation of 4-Amino-1-hydroxybutylidene-1,1-bisphosphonic acid. EP B1, eidem US

3h 2 50-60% 4-Aminobutanoic acid Sodium Alendronate Trihydrate

12 Antihypertensive Drugs

13 LISIPRIL + AlCl 3 96% Maleic anhydride -Benzoylacrylic acid H HCl(g) EtH 94% Cl Ethyl-2-chloro-4-oxo-4- phenylbutyrate (I) Et (I) + (II) Et3/LiH ai Dioxane 53% H 2.HCl CF 3 C (CH 2 ) 4 CH CH * Trifluoroacetyl -L-Lysine l hydrochloride Et H Et CBn Benzyl alcohol SCl 2 (CH 2 ) 4 HCCF 3 Pd/C EtH, HCl ah ph 3 65% (CH 2 ) 4 HCCF 3 H 2.HCl CF 3 C (CH 2 ) 4 CH CBn * 6 -Trifluoroacetyl -L-lysine benzyl ester hydrochloride(ii) Im 2 C CH 2 Cl 2 Et H (CH 2 ) 4 HCCF 3 CH 2 -(1-(S)-Ethoxycarbonyl-3- phenylpropyl)- 6 -trifluoroacetyl -L-lysine (S)-1-[ 2 -(Ethoxycarbonyl-3- phenylpropyl)- 6 -trifluoroacetyl -L-lysyl] 2 -carboxyl anhydride(iii)

HCl CF 3 C (CH 2 ) 4 CH CH * Trifluoroacetyl -L-Lysine l hydrochloride Et H Et CBn Benzyl alcohol SCl 2 (CH 2 ) 4 HCCF 3 Pd/C EtH, HCl ah ph 3 65% (CH 2 ) 4

14 H CH SCl 2 HCl H CMe L-Proline MeH 87% L-Proline methyl ester Hydrochloride (IV) Et (C H 2 ) 4 HCCF 3 (III) + (IV) CH 2 Cl 2 97% Full p rotected Lisinopril H CMe H H 2 MeH ah 53% H CH 2H 2 Lisinopril Process for the Production of Lisinopril. EP B1 Supported by Tübitak-Teydeb

Full p rotected Lisinopril H CMe H H 2 MeH ah 53% H CH 2H 2 Lisinopril

15 Temel patent EP , SmithKline 1988

16 DCC DMAP DMF H 2H H Protected Valacyclovir H 2 /Pd(5%) MeH, 0.5 HCl 2H H H 2.HCl.H 2 Valacyclovir Hydrochloride Monohydrate Preparation ovel Polymorphs of Valacyclovir US Supported by Tübitak-Teydeb

24 LSARTA PTASSIUM Temel patent EP Du Pont 1988 C C MgCl + Cl Mn THF 4-Tolylmagnesium Chloride(I) 2-Chloro benzonitrile(ii) 4-Methyl-2'-cyanobiphenyl(III) C 4-Methyl-2'-cyanobiphenyl(III) a 3 Et 3 HCl Toluene H 5(4-Methyl-1,1-biphenyl2-yl) 1H-tetrazole(IV)

25 H TrCl Tr CH 2 Cl 2 5(4-Methyl-1,1-biphenyl2-yl) 1H-tetrazole(IV) Et 3 AcEt 5(4-Methyl-1,1-biphenyl 2-yl)-1-triphenylmethyl- 1H-tetrazole(V) Tr Br 2 AIB CH 2 Cl 2 Toluene a 2 S 4 Br Tr 5(4-Methyl-1,1-biphenyl 2-yl)-1-triphenylmethyl- 1H-tetrazole(V) 5(4'-Bromomethyl-1,1- biphenyl2-yl) 1H-tetrazole(VI)

26 Br Tr + H Cl 5(4'-Bromomethyl-1,1- biphenyl2-yl) 1H-tetrazole(VI) DMF, K 2 C 3 MeH, abh 4 H 2, EtAc 2-Butyl-2-chloro 1H-Imidazole-5- carboxaldehyde (VII) H Cl Tr Trityl Losartan (VIII)

27 Cl H Cl H HH 2.HCl Methanol Acetone Water Ethyl acetate H Trityl Losartan Losartan Acid Cl H Cl H H KH, IPA t-butylmethylether - + K Losartan Acid Losartan Potassium METHD FR PRDUCIG METAL SALTS F LSARTA W 2007 / A1

28 Methoxytriphenylmethane safsızlığının oluşması Cl Cl H H H 3 + MeH HH 2.HCl Methanol Acetone Water - + Cl H H + Me PRCESS FR PRDUCIG BIPHEYL-TETRAZLE CMPUDS EP

29 Hydroxylamine nin Türevlendirilmesi H 2 H + MeH H Hydroxylamine 1-p-Tolyl-ethanone 1-p-Tolyl-acetoxime Supported by Tübitak-Teydeb

30 Methoxy safsızlığının retro-michael Mechanisması Üzerinden luşması Cl Cl H H + H -H 2 + MeH H retro-micheal product Losartan Acid -H + Cl Me H Methoxy impurity PRCESS FR PRDUCIG USEFUL SALTS FRM F BIPHEYL-TETRAZLE CMPUDS PCT/TR2006/000036

31 IRBESARTA Basic Patent EP Sanofi 1990 HH 2.HCl Methanol Acetone Water Ethyl acetate H Crude Irbesartan H Ethanol Water Irbesartan H METHD FR PRDUCIG PURE CRYSTALLIE FRMS F 2-n-BUTYL-3-((2- (1H-TETRAZLE-5-YL) (1,1 -BIPHEYL)-4-METHYL)-1,3-DIAZAPSPIR (4,4 ) -1- E-4-E PCT/TR2006/000046

32 SafsızlıkA IRBESARTA IMPURITIES - H H ah Water H H H H H

33 Safsızlık B H -

34 CADESARTA CILEXETIL Temel patent EP Takeda, 1990 C Ethyl 1-(2'-cyano-biphenyl -4-ylmethyl)- 2-ethoxybenzimidazole -7-carboxylate(III) 1. trimethyltin azide, toluene 2. ah, C 2 H 5 H 3. trityl chloride, (C 2 H 5 ) 3,CH 2 Cl 2 H Trityl Candesartan(IV) Trt

35 Tr IV + I cyclohexyl 1-iodoethyl carbonate K 2 C 3, DMF Tr Trityl Candesartan Cilexetil H H 2 S 4 Aceton MeH Water Trityl Candesartan Cilexetil Crude Candesartan Cilexetil

36 H H EtH Crude Candesartan Cilexetil Candesartan Cilexetil

37 CADESARTA SAFSIZLIKLARI H R1 R H 3 + H Desethyl Candesartan R R1 + H H 2

38 Candesartan Cilexetil için yeni bir Proses Tr H H 2 S 4 EtAc Water Toluen Trityl Candesartan Cilexetil Crude Candesartan Cilexetil A Process for Preparing Candesartan Cilexetil in High Purity TR2009/07894 Supported by Tübitak-Teydeb

43 ZLEDRIC ACID MHYDRATE EP B1 Basic patent Ciba 1987 Basamak 1:Ham Zoledronic Acid Monohydrate Üretimi H.HCl 1H-imidazol-1-yl-acetic acid hydrochloride H 3 P 3 PCl 3 Sunflower oil EtAc EtH MeH H P H H H P H Crude zoledronic acid monohydrate.h 2

44 Step-2: Zoledronic Acid Monohydrate Kristalizasyonu H P H H H P H.H 2 Water ah HCl H P H H H P H.H 2 Crude zoledronic acid monohydrate Zoledronic acid monohydrate A General Process For The Preparation of Bisphosphonic Acids and Salt Thereof TR 2009/08880

45 X-Ray Diffractogram of Zoledronic acid monohydrate (Batch o: 8M0001)

46 X-Ray Diffractogram of Form I (US B2)

47 SDIUM IBADRATE MHYDRATE US Basic patent Boehringer 1987 Sodium Ibandronate Monohydrate Step 1 HCl C 9 H 20 Cl Methylpentyl propionic acid Hydrochloride H H 3 P 3, PCl 3 Sunflower oil Ethyl acetate H 2, ah MeH.H 2 H P P H H H a C 9 H 22 a 7 P 2.H Crude Sodium Ibandronate Monohydrate Supported by Tübitak-Teydeb

48 Sodium Ibandronate Monohydrate Step 2.H 2 H H P H P H a Ethanol H 2.H 2 H H P H P H a C 9 H 22 a 7 P H 2 C 9 H 22 a 7 P H 2 Processes For The Preparation f Sodium Ibandronate Monohydrate Polymorphs and Polymophs Mixture TR 2009/08885

49 X-Ray Diffractogram of Ibandronate Sodium monohydrate A+B (TA.01.34)

50 X-Ray Diffractogram of Form A which is taken from literature

51 X-Ray Diffractogram of Form B which is taken from literature

52 Teşekkür: Arkadaşlarıma: eslihan Çakar, Bedriye Koç, Filiz Sahpaz, Evren Özarslan, Ayçil Yurdakul,Emre Burmaoğlu, urten Rıdvanoğlu, Sait Uluözyurt, ihat Arslan, Hasan kaya, Selda Turhan, Melek Köroğlu, Tuba Biçer, Yıldız Gülkok, Mustafa Tekgezer, Ender Ermiş, Meral Çolak, Yasemin şahin, Serkan Karaman and Müge Dedeoğlu Mentors of Pharmaceutical Industry: Sn. Ender Koçak ve Sn. Hasan Ulusoy Tubitak-Teydeb e: Sanayi Ar-Ge si Destekleri için Çanakkale Universitesine: Bu Konuşmayı lanak Sağladığı için

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. DR. TUNCER ASLAN Özgeçmiş E-posta: tuncerarslan2009@hotmail.com

. DR. TUNCER ASLAN Özgeçmiş E-posta: tuncerarslan2009@hotmail.com Eğitim: -Lisans, Kimya, Orta Doğu Teknik Üniversitesi, Ankara, Türkiye, 1986. -Denklik çalışmaları, İsviçre Federal Teknoloji Enstitüsü,