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
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.
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.
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, 2260. 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.
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, 12383.
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 25-29 (1996)
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.
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, 10877.
SILDEAFIL CITRATE EP 463756 Temel patent Pfizer 1992 2-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)
(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
SDIUM ALEDRATE TRIHYDRATE US 4922007 Temel patent Merck 1992 2 H H 1) P 3 H, PCl 3 Sunflower oil 2) ah, MeH H P 3 H 2 H P 3 a.3h 2 50-60% 4-Aminobutanoic acid Sodium Alendronate Trihydrate Preparation of 4-Amino-1-hydroxybutylidene-1,1-bisphosphonic acid. EP 1390363 B1, eidem US 7009071
Antihypertensive Drugs
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)
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 1513868 B1 Supported by Tübitak-Teydeb
Temel patent EP 308065, SmithKline 1988
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 0252776 Supported by Tübitak-Teydeb
LSARTA PTASSIUM Temel patent EP 324377Du 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)
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)
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)
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 / 062675A1
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 EP2001869
Hydroxylamine nin Türevlendirilmesi H 2 H + MeH H Hydroxylamine 1-p-Tolyl-ethanone 1-p-Tolyl-acetoxime Supported by Tübitak-Teydeb
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
IRBESARTA Basic Patent EP 454511. 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
SafsızlıkA IRBESARTA IMPURITIES - H H ah Water H H H H H
Safsızlık B H -
CADESARTA CILEXETIL Temel patent EP459136 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
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
H H EtH Crude Candesartan Cilexetil Candesartan Cilexetil
CADESARTA SAFSIZLIKLARI H R1 R H 3 + H Desethyl Candesartan R R1 + H H 2
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
ZLEDRIC ACID MHYDRATE EP 0275 821 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
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
X-Ray Diffractogram of Zoledronic acid monohydrate (Batch o: 8M0001)
X-Ray Diffractogram of Form I (US7435827B2)
SDIUM IBADRATE MHYDRATE US 4942 157 Basic patent Boehringer 1987 Sodium Ibandronate Monohydrate Step 1 HCl C 9 H 20 Cl 2 209.72 -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 2 359.21 Crude Sodium Ibandronate Monohydrate Supported by Tübitak-Teydeb
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 2 359.21.H 2 C 9 H 22 a 7 P 2 359.21.H 2 Processes For The Preparation f Sodium Ibandronate Monohydrate Polymorphs and Polymophs Mixture TR 2009/08885
X-Ray Diffractogram of Ibandronate Sodium monohydrate A+B (TA.01.34)
X-Ray Diffractogram of Form A which is taken from literature
X-Ray Diffractogram of Form B which is taken from literature
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