laxmi genchem chemistry presentation
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Welcome To
Laxmi GenChem
-Solution for Healthier Life
1
-
2e-mail: vijayreddy@laxmigenchem.com www.Laxmigenchem.com
ManagementManagement
Laxmi GenChem -
Solution for Healthier Life
Mr. Vijaya Madhava Reddy.V is Business Director of Laxmi
GenChem Pharma Ltd completed M.Sc in Organic Chemistry from
Osmania University and had 13 years Industrial Experience in
Synthetic Chemistry and Project Management in CRO & API area in
various MNC’s in Hyderabad. Mr. Reddy was also a former Research
Student from Masaryk University, Czech Republic, Europe.
Mr. Jagan Mohan.G is Managing Director of Laxmi GenChem Phama
Ltd completed M.Sc in Organic Chemistry and had 12 years Industrial
Experience in Synthetic Chemistry , CRAMS, Medicinal Chemistry &
API area in various MNC’s in Hyderabad. Mr. Jagan led Laxmi
GenChem through the initial phases of evolution with remarkable
success. He is responsible for putting the right scientific talent,
leadership, processes and infrastructure in place to ensure
continuous growth.
Over ViewOver View Laxmi GenChem is a dynamic custom synthesis and contract research organization to support globally located pharmaceutical / biotech companies.
We combine Science, Innovation and People to help our clients address their drug development challenges.
New frontiers require new ways of working and we believe that to deliver the true promise of science, innovation is necessary.
Our customers benefit not just from lower costs and boosted efficiencies, but also from the infusion of fresh ideas and thinking.
3e-mail: vijayreddy@laxmgenchem.com www.Laxmi GenChem.com
Laxmi GenChem -
Solution for Healthier Life
Vision & MissionVision & Mission Laxmi GenChem would be a global leader in pharma services. Deliver value-added scientific services with speed and quality. Customer Focus - Change expected to exceptional. Customer once client forever. Strive to exceed expectations through innovative solutions. Committed to business and scientific integrity. Open, Fair, Honest and Transparent behavior. Give to get, give before you expect. Respect for individuals, property and timelines. Commit to Excel - In every act and deed Best always. Relentlessly and continuously improve ourselves and our solutions. Teamwork and Leadership Work Together…Win Together. A collective effort to be the leader in the chosen field
4e-mail: vijayreddy@laxmgenchem.com www.Laxmi GenChem.com
Laxmi GenChem -
Solution for Healthier Life
Why Laxmi GenChem?Why Laxmi GenChem?
Product Design & Development. Highly professional and experienced research team. Outstanding skills on difficult chemistry. Cost-effective services. On -time delivery Projects. Timely Communicative (Weekly Reports & Tele Conference). Data Base Management & Project Management Flexible for customer: we operate as your own chemistry department.
5e-mail: vijayreddy@laxmgenchem.com www.Laxmi GenChem.com
Laxmi GenChem -
Solution for Healthier Life
Research & Development CapabilitiesResearch & Development Capabilities
Synthesis of Medicinal chemistry Analogs, Libraries & Scaffolds. Custom synthesis of target compound/processes. R &D Process Optimization. Collaborative research. Intermediate scale (milligram scale to Multi Kilogram Scale). Special building block collections in house. Skilled at making constrained, complex analogs. Skilled at creating new synthetic routes. Project Management and Documentation.
6e-mail: vijayreddy@laxmgenchem.com www.Laxmi GenChem.com
Laxmi GenChem -
Solution for Healthier Life
ExpertiseExpertise
Alkylation, Acylation, Halogenations, Amidation, Condensation, Cyanation, Cyclo-condensation, and Formylations etc. Organo-Metallics- Alkyl Lithium (Metallation – MeLi / n-BuLi / LDA), Grignard reaction, Organoborane and Silylation reaction etc.. Palladium Chemistry: Suzuki, Sonogashira, Heck, kumada, Stille, Carbonylation and Buchwald couplings etc.. Hydrogenation using Pd/C, Pt/C, Rh/C and Rani-Ni etc.. Synthesis of Protected N-Terminal & C- Terminal Amino Acids Scaffolds & Di-peptides, Cyclic Peptides. Nucleoside chemistry: Modification of Nucleoside bases , Metal Mediating Reactions on Nucleosides, Modification of Sugar Moieties, Alkylation, Fluorination Reaction at Nucleosides Based and Sugar Moieties etc.. Asymmetric syntheses, Chiral alkylation, Chiral Amines syntheis, Enantio selective catalysis ,Chiral auxiliaries and Chiral resolution of racemates etc.. Wittig Reaction, Mitsunobu Reaction and Vilsmeier-Hack reaction etc.. Oxidation – Jones, Swern, Dess-Martin Oxidation, KMnO4, NaIO4, OsO4 and K2CrO4 etc. Reductions – Catalytic, Metal hydrides, High pressure,Birch reductions, Diborane, LAH, DIBAL-H and NaCNBH3 etc. . Beta-Lactam Antibiotices, Macrolides, Steroids and Prostaglandins. Special building blocks, API reference standards and Impurity standards. Milligram to Kilogram synthesis of complex organic molecules. Low to high temperature chemistry.
7
Laxmi GenChem -
Solution for Healthier Life
Collaboration ModelsCollaboration Models
Full time equivalent (FTE)
Fee for service (FFS) per library
Single price per compound
8e-mail: vijayreddy@laxmgenchem.com www.Laxmi GenChem.com
Laxmi GenChem -
Solution for Healthier Life
ServiceService Contract Research Organization (CRO)
Medicinal Chemistry/Synthetic Organic Chemistry. Library Synthesis/ Parallel Synthetic Chemistry. Nucleoside/Sugar Chemistry. Amino Acid/ Peptide Chemistry. Asymmetric/ Chiral Chemistry. Material Chemistry.
Custom Research & Manufacturing Services (CRAMS)
API Intermediates and Impurities ( Non-GMP)
9e-mail: vijayreddy@laxmigenchem.com www.LaxmiGenChem.com
Laxmi GenChem -
Solution for Healthier Life
Medicinal Chemistry/Synthetic Organic Medicinal Chemistry/Synthetic Organic ChemistryChemistry
Laxmi GenChem have extensive experience in synthesizing compounds designed by medicinal chemists at our clients’ site. Our major focus is given on productivity (milligram to kilogram scale) and cycle time management in these efforts with real time problem solving in synthesis.
Medicinal Important compound. Biologically active Compounds. Metabolites, Antibiotics and Macrolides. Steroids and Prostaglandins. API reference standards and Impurity standards
After completion of the project all the experimental reports would captured into Word format (doc or docx) or Structural Database (SD) according Client defined format.
10e-mail: vijayreddy@laxmgenchem.com www.Laxmi GenChem.com
Laxmi GenChem -
Solution for Healthier Life
Library Synthesis/ Parallel Synthetic ChemistryLibrary Synthesis/ Parallel Synthetic Chemistry
Laxmi GenChem have extensive experience in synthesis of a variety of libraries ranging between focused libraries 10-30 members to large 2000 member libraries, scaffolds/building blocks including complex structure involving multi-step synthesis in milligram to kilogram scale with complete characterization, lead generation, lead optimization and SAR libraries generated in 5-50 mg scale with > 90% purity of LCMS. After synthesis of the library compounds, Laxmi GenChem would capture all the synthetic procedure into SAR tables and Structural Database (SD) format in Client defined format.
11e-mail: vijayreddy@laxmgenchem.com www.Laxmi GenChem.com
Laxmi GenChem -
Solution for Healthier Life
Nucleoside/Sugar ChemistryNucleoside/Sugar Chemistry Development of novel methodologies for the synthesis of modified nucleobases and nucleosides Medicinal chemistry of analogues of nucleobases and nucleosides. Design and synthesis of novel C-nucleosides for chemical biology. Synthesis of modified nucleoside triphosphates Novel fluorescent nucleoside labeling for bioanalytical applications. Chemical biology of base-modified nucleic acids. Click Reaction Applications in Nucelobases. Metal Mediating Reactions on Nucleosides (Suzuki, Sonogashira, Heck, Kumada, Stille, Carbonylation and Buchwald couplings) Modification of Sugar Moieties
12e-mail: vijayreddy@laxmgenchem.com www.Laxmi GenChem.com
Laxmi GenChem -
Solution for Healthier Life
Amino Acid/Peptide Chemistry Amino Acid/Peptide Chemistry Protected N-Terminal & C- Terminal Amino Acids Scaffolds & Di-peptides, Cyclic Peptides. Asymmetric/ Chiral Chemistry Chiral alkylation, Chiral Amines syntheis, Enantio selective catalysis, Chiral auxiliaries and Chiral resolution of racemates. Material Chemistry/Polymer Chemistry Photoactive conducting polymers, charge transporting polymers External stimulii small molecules. Organic Light-Emitting Diode (OLED) Materials Solar Cells: Dye-Sensitized Solar cells and Organic photovoltaic, cells, Conducting Polymers, Organic Dyes.
13e-mail: vijayreddy@laxmgenchem.com www.Laxmi GenChem.com
Laxmi GenChem -
Solution for Healthier Life
Custom Research & Manufacturing Services Custom Research & Manufacturing Services (CRAMS)(CRAMS)
At Laxmi GenChem ’ facilities, highly skilled chemists routinely carry out syntheses of complex intermediates and final products With/without technology transfer; starts with process development/optimization and approval of lab sample, followed by commercial validation campaign, regulatory filing and approval and then the long-term commercial supply.
Process Development. Route Optimization. Manufacturing. Validations. Impurities – identification, characterization and synthesis. 14e-mail: vijayreddy@laxmgenchem.com www.Laxmi GenChem.com
Laxmi GenChem -
Solution for Healthier Life
API Intermediates and ImpuritiesAPI Intermediates and Impurities
Laxmi GenChem process development chemists are specializing in the design and optimization of synthetic routes for gram to multi-kilo quantities of compounds suitable for the transfer of laboratory procedures into the pilot plant. We aim to develop scalable, safe and economical solutions.
Route of synthesis- optimization and validation Custom research and manufacturing process Scale-up & optimization intermediates and related chemicals Scale up from lab to pilot and pilot to commercialization (mg level to 1000kg level) Impurity profiling.
15e-mail: vijayreddy@laxmgenchem.com www.Laxmi GenChem.com
Laxmi GenChem -
Solution for Healthier Life
Laxmi GenChem Project Managment Request for Proposal (RFP) EvaluationRequest for Proposal (RFP) Evaluation
Laxmi GenChem quotes best cost effective pricing model that includes “Synthesis of Target Compound, Purification and Analysis, Literature Support, Chemical sourcing and shipping and Project management tools between Laxmi GenChem and the client” or between Laxmi GenChem and the client’s CRO. Laxmi GenChem CRO scientific team is capable of provides a best Route of Synthesis (ROS) and alternative of ROS for target compounds based on literature.
Execution of ProjectExecution of Project
Laxmi GenChem CRO scientific team consists of experienced Ph.D and Master Students, who have ability to synthesis the target molecule in stipulated timelines. Laxmi GenChem always keeps 20% buffer back up team for project. Our pioneer Group leader will prepare weekly reports and arranges a tele-Conference with Client on weekly basis. All the intermediates and final Compounds are analyzed characterized by NMR and LCMS purity. After completion of Project, Laxmi GenChem project Management team will provides Final reports in Word format (Doc & Docx) and Structural data format (SDF & Excel) documentation in Client defined format.
16e-mail: vijayreddy@laxmgenchem.com www.Laxmi GenChem.com
Laxmi GenChem -
Solution for Healthier Life
Time LinesTime LinesTime lines For QuoteTech Pack is Available : 24- 48 hrTech Pack is Not Available : 48- 72 hr
*Based on Chemical Sourcing information time lines may vary.
Time lines For Target CompoundsTime lines For Target Compounds Laxmi GenChem Chemistry team can deliver target compounds
Single target : 3-4 weeks Scaffold : 4-6 weeksLibrary : 6-8 weeks
*Based on complexcity of compoud time lines may vary. 17e-mail: vijayreddy@laxmgenchem.com www.Laxmi GenChem.com
Laxmi GenChem -
Solution for Healthier Life
Quality PolicyQuality Policy
Being on time every time to meet our client's needs. Consistently meeting or exceeding our client's quality requirements. Continuous improvement of our systems and processes. Ensuring proper training of our people so as to better serve our
clients. Recognizing that quality is not just another goal, but a basic strategy
for survival and growth.
18e-mail: vijayreddy@laxmgenchem.com www.Laxmi GenChem.com
Laxmi GenChem -
Solution for Healthier Life
19
Quatations for Med.Chem; API & CRAMS
Trackers ( i.e Project; Reagent; Dispatched & SAR).
Final ReportsFinal Reports
Intermediate Inventory
NMR- FID CollectionNMR- FID Collection
Monthly Evaluation tracker
MOM
Project Management- ToolsProject Management- Tools
e-mail: vijayreddy@laxmigenchem.com www.LaxmiGenChem.com
Laxmi GenChem -
Solution for Healthier Life
20
Tracker are historical record for a particular program.It shows status of all the Ongoing, Holed and Completed targets status in a structured format.It is also act as demonstrative tool at Scientific end, BD end and Client end.
Why Do we need tracker?Why Do we need tracker?
e-mail: vijayreddy@laxmgenchem.com www.Laxmi GenChem.com
Laxmi GenChem -
Solution for Healthier Life
21
What Kind of Information we do find in What Kind of Information we do find in TRACKER?TRACKER?
e-mail: vijayreddy@laxmgenchem.com www.Laxmi GenChem.com
Laxmi GenChem -
Solution for Healthier Life
22
Project Management- Final Project Management- Final ReportReportPreparation standard Template for Final report. ( Preparation standard Template for Final report. ( i. i.
ee JOC format) JOC format)Preparation of finalPreparation of final reports for all dispatched reports for all dispatched
targets.targets.Once compound has been dispatched, time final Once compound has been dispatched, time final
report has to prepare including Analytical reports report has to prepare including Analytical reports
with in the 2 weeks.with in the 2 weeks.All Final report will be send to Corresponding group All Final report will be send to Corresponding group
leaders for final proof reading then will be updated in leaders for final proof reading then will be updated in
Client e-room. Client e-room. Dispatched details in SDF format
Laxmi GenChem -
Solution for Healthier Life
e-mail: vijayreddy@laxmgenchem.com www.Laxmi GenChem.com 23
Intermediate InventoryIntermediate Inventory Identify the all key SM and intermediates and Reagents for every finished target. Record the information about all key intermediates, key SM and Reagents all finished target. This Process is very much use for Scaffold and Library Synthesis.
Minutes Of Meetings (MOM )Minutes Of Meetings (MOM ) Organize Tele-Conference with Scientific Team, BD & Client.Identification of the keys inputs and constraines from Both Sides. Record the MOM and updated to Scientific Team, BD & Client.
Laxmi GenChem -
Solution for Healthier Life
24e-mail: vijayreddy@laxmgenchem.com www.Laxmi GenChem.com
Thiazole- Sulfonamide Derivatives Thiazole- Sulfonamide Derivatives BrEtO
O
O
H2N NH2
S
N
S
OEt
O NH2 N
S
OEt
O NH2
Br
N
S
OEt
O
Br
N
S
OEt
OHO INT-A
NS
OEtO
S NO
O
F F
Cl
NS
OH
S NO
O
F F
Cl
NS
O
S NO
O
F F
Cl
Dess-Martin Oxidation
NSS N
O
O
F F
Cl
EtO O
wittig Reaction
Mitsunobu
NSS N
O
O
F F
Cl
EtO O
NSS N
O
O
F F
Cl
HO O
1 2 3 4 5
6 7
8 9
Et-2-Br-Pyruvate
IO
OAcAcOOAc
O
INT-A
SNH O
OF
F
ClNH2
FFS Cl
O
O
Cl
Py
BrominationDe-Amination Grignard
Reduction Hydrolysis
Diazatization
NS
NH
S NO
O
F F
Cl
R
R-NH2/Na(OAc)3BHDIBAL/THF
NBS/ACNNaNO2/H2SO4
7
iPrMgBr/CH3CHO
THF/ -70oC to - 40oC DEAD/TPP/Toulene
Reductive AminationCH2Cl2
THF
Pd/C/EtOAc LiOH/H2O/THF
H3PO2Heat
NSS N
O
O
F F
Cl
HN OR
EDC/HOBt/DMF
R-NH2
Coupling Reactioin
10
-70oC to RT
1.LiOH/H2O/THF2.EDC/HOBt/DMF
NS
NH
O
S NO
O
F F
Cl
R
R-NH2
25e-mail: vijayreddy@laxmgenchem.com www.Laxmi GenChem.com
A A Potent Janus Kinase 2/Fms-Like Tyrosine Kinase-3 Potent Janus Kinase 2/Fms-Like Tyrosine Kinase-3 (JAK2/FLT3) Inhibitor(JAK2/FLT3) Inhibitor
N,O,O-Hetero Macro cyclic compounds
N,N,O-Hetero Macro cyclic compound
N
NO
N
O
O
NH
N
N
O
ON
O
O
NH
N
N
N
NH
O
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N,O,O-Macro Cyclic Compounds-N,O,O-Macro Cyclic Compounds-Retro SynthesisRetro SynthesisDisconnection Approach- RCM Route
Disconnection Approach- Non-RCM Route
N
NO
N
O
O
NH
1
2
3
4
5
3
6
N
N
O
ON
O
O
NH
1
2
4
53
3
6
N
NO
N
O
O
NH
1
2
3
4
5
N
N
O
ON
O
O
NH
1
2
3 5
6
4
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N,O,O-Macro Cyclic CompoundsN,O,O-Macro Cyclic CompoundsN,O,O-Macro Cyclic-RCM Route
28
CHOOH
O2N
Cl Cl CHOO
O2N
ClO
O2N
Cl
HOBr O
O2N
Cl
O
5-Nitro Salicylaldehyde
O
O2N
N
ONH
O
H2N
N
O
N
N
Cl
OH
INT-B
N
N O N
O
O
NH
1 2 3 4
5 6 Target
INT-A
N
N
Cl
Cl
2,4-Dichloropyrimidine
N
N
Cl
B OHHO
O O
INT-C
N
N O N
O
O
NHMetathesis
Suzuku Rection N
N
Cl
O
INT-C
Br
O-Alkylation
Reduction N-Alkylation
Reduction
Reduction Bezylic O-Allylation
4N HCl
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N,O,O-Macro Cyclic CompoundsN,O,O-Macro Cyclic CompoundsN,O,O-Macro Cyclic-Non-RCM Route
CHOOH
O2N
Cl Cl
CHOO
O2N
Cl O
O2N
Cl
HOBr Br O
O2N
Cl
OBr
N
N
Cl
O
NO2
Cl
O
O
NH
5-Nitro Salicylaldehyde
pyrrolidine
N
N O Cl
O
O
NH
N
N
Cl
OH
N
N O N
O
O
NH
INT-B
1 2 3
4 5 Target
Reduction O-Allylation
O-AllylationCoupling Reaction
INT-A
N
N
Cl
Cl
2,4-Dichloropyrimidine N
N
Cl
B OHHO
OO
Suzuku Rection Reduction
INT-B
N-Alkylation
Reduction
29e-mail: vijayreddy@laxmgenchem.com www.Laxmi GenChem.com
A Potent Inhibitor of Cyclin Dependant Kinases (CDKs), Janus A Potent Inhibitor of Cyclin Dependant Kinases (CDKs), Janus Kinase 2 (JAK2) and Fms-LikeTyrosine Kinase-3 (FLT3) Kinase 2 (JAK2) and Fms-LikeTyrosine Kinase-3 (FLT3)
N,N,O- Macro Cyclic RCM Route
30
CHO
O2NO2N
N
5-Nitro-Benzaldehyde
N
N
Cl
Cl
2,4DichloropyrimidineN
N
Cl
BOHHO
OH OH
N
N
Cl
Br
1 2
O
NH
H2N
N
3
INT-A
INT-B
N
N
N
NH
O
N
N
N
NH
O
INT-B
Metathesis
Suzuku Rection coupling ReactionO-Alkylation
NO2- Reduction
Reductive amination
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1,2,3,4 tetra hydro quinoline Derivativies1,2,3,4 tetra hydro quinoline Derivativies
N NH
(Z)
N
(Z)
Quinoline BocNBoc
OHBr
NBoc
O
NBoc
OHHN
R1
R1NH2R2X
NBoc
OHN
R1
Dry HClR2
NH
OHN
R1
R2
N
OHN
R1
R2R3 OH
O
R3O
MitsunobuCenter Inversion
NBoc
HNR1
OH R2X
NBoc
OHN
R1
Dry HClR2
NH
OHN
R1
R2
N
OHN
R1
R2R3 OH
O
R3O
Anti
Syn
1 2 3 4
5 6 7
8 9 10
Reduction N-Boc Bromo-Hydrine Epoxidatioin
Opeing of Epoxide O-Alkylation De-Boc Amidation
O-Alkylation De-Boc Amidation
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Asymmetric Aldol Products -Chiral Oxazolidinone AuxiliaryAsymmetric Aldol Products -Chiral Oxazolidinone Auxiliary
EXAMPLES
Tetrahedron. 1992, 48, 2132- 2142 J.Org.Chem. 1990, 55, 6260- 6268
32
ChiralNHO
O
NO
O1. BuLi
2.n-BuCOCl
O1. n-Bu2BOTf/ TEA
2.R-CHONO
O O
R
OH
HO
O
R
OHLiOH/ H2O2
THF/ H2O
1 2
TARGET
Aldol Reaction
David A. Evans(S)-4-benzyloxazolidin-2-one
Evans- SYN
O
BO
n-Bu
n-Bu
n-Bu
R
HN
OO
SYN
HO
O OHHO
O OH
HO
O OH
HO
O OH
NHO
O OH
N
BrBr
Br
HO
O OH
N
HO
O OHHO
O OHHO
O OH
HO
O OH
HO
O OH
HO
O OHHO
O OH
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Pyrrolidine Derivativies- Azamethine Ylide
33
NH
MeO2CGlycine
Para-HCHO
PhMe/ RefluxBn-Br/ 0 oCCO2Me
O
O
OOBn
O
O
O
2.Pd/C/ EtOAc
1.Boc2O/ TEA DPPA/TEA
BnOH/C6H6 N
Ph
N
MeO2C NHCbz
NPh O
NPh
N
NHCbz
1. LiOH/THF
2. SOCl2/Pyrrolidine
ON
MeOHPd(OH)2
NPh
N
NH2O
N
1 2 3
4 5 6
7
TARGET
NaOMe, DMFO
O
OMeOBn
I2, xylene
Reflux
Maleic anhydride Azomethine-ylide
Curtius Rearrangement & Insitu Cbz Protection
N
MeO2CO
OH
BocN
MeO2C NHCbz
Boc
1.De-Boc
Reductive amination
NPh OBr
HN OPd(TPP)4
Buchwald Coupling
De-Bn lation
Cbz- De Protection
Regio Specific addition
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Biological Active cyclopetanone-3-amine Derivatives
Bn-Br/ 0 oC OOBn
O
O
O
Pd/C/ EtOAc
2.NaN3/H2O/Bu4NBr
1. LiOH/THF
2. SOCl2/PyrrolidineMeOH
Pd(OH)2
1 2 3
4 5
6
NaOMe, DMFO
O
OMeOBn
KMnO4/H2O
Curtius Rearrangement
O
O
OMeOBn
HO2CHO2C O
Ac2O/NaOAc
130 oC/ 5h
OO
NH
O
O
O1.(COCl)2/DMF
BnOH
Cbz
OOH
O
OO
NH
O
ON
Cbz
NH2
O
ON
ON3
O
OO
N CO
OO
O
BnO
Claisen condensation
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N
O
N
NHO
BocN
NHO
Boc
BrBr
N
NHO
Boc
N3
N
NHO
Boc
H2N
N
NHO
Boc
NSO
O
Cl
MeO2C
HN
NHO
NSO
O
Cl
MeO2C
HCl
N
NHO
Boc
HNS
OO
Cl
NH2OH.HCl/NaHCO3
N
NHO
Boc
Br
BocN
N
Boc
OH
EtOHPTS-Cl
NaOH/Acetone
BeckmannOxime
Br2/PCl5 H2, Pd/C
NaN3/DMF H2, Pd/C
SO
OClCl
TEA/DCM
MeO2C
Br
KOtBu/DMF
HCl/ Et2O
1,4-diazepane-Derivativies
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Indanone Derivatives
36
R1
CHO
R2
R1
R2
OEt
O R1
R2
OEt
O
O
R1
R2
Cinnamate
OH
R1
R2
R1
R2
R1
R2 O
R1
R2O
Indane-1-one
Ph3POEt
O
Wittig Reaction
H2, Pd/C
EtOH
1.LiOH/THF:H2O
2. SOCl2/CS2/AlCl3Friedel–Crafts
NaBH4
THF/MeOH
cat. CSAC6H6/ reflux
mCPBA/DCMNaHCO3
InCl3/THF
R1 = Cl, Br & FR2 = H, Cl, Br & F
THF
CHOOEt
O
OEt
O
O
Cinnamate Indane-1-one
Ph3POEt
O
Wittig Reaction
H2, Pd/C
EtOH
1.LiOH/THF:H2O
2. SOCl2/CS2/AlCl3Friedel–Crafts
R1 = Cl, Br & FR2 = Cl, Cl & F
THF
R2
R1
R2
R1 R1
R2
R1
R2
R1
R2
R1
R2
O
H2N O
O
iPrOH/ reflux
S+
I- NaH HNO
O
OHR2
R1
HNOH
O
OHLiOH/THF:H2O
Indane-2-one
2,4- Sub
3,5- Sub
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Subs of (4-Nitro-1H-imidazol-1-yl)pyrrolidin-2-oneSubs of (4-Nitro-1H-imidazol-1-yl)pyrrolidin-2-one
EXAMPLES
N
O
N
N
O2N
N
O
N
N
O2N
N
O
N
N
O2N
O
N
O
N
N
O2N
OH
N
O
N
N
O2N
N
O
N
N
O2N
N
O
N
N
O2N
N
O
N
N
O2N
Cl F
FF
F
Cl
Cl
Cl
J. Med. Chem. 2002, 45, 1184- 1194 J.Org.Chem. 1989, 54, 6069- 6100
37
O OBr
BrBr
ORed PBr2
RNH2 Br
BrNHR
O
TEA/THF
NaH/THF
NR
O
Br
N
NH
O2N
K2CO3 / DMF NR
O
NN
NO2
1 2 3 TARGET
Br
BrOMe
O
MeOH
K2CO3/Toluene
n-Bu4NHSO4 Br
MeOO
N
NH
O2N
K2CO3 / DMFEt3NBnBr
OMe
O
N
N
NO2
e-mail: vijayreddy@laxmgenchem.com www.Laxmi GenChem.com
N
N N
Cl
H2N
NO
R
X N
N N
NCl
H2N
R
N
N N
Cl
H2N
R
N
N N
Cl
H2N
R
OHN
N N
Cl
H2N
R
OH
N
N N
Cl
H2N
NO
F
N
O
N
N N
N
H2N
Cl
N
NN
N
N NH2N
Cl
N
O
N
N N
Cl
H2N O
NHNN
OH
N
N NH2N
Cl
N
O
OH
Heat Shock Protein-90 Inhibitors
e-mail: vijayreddy@laxmgenchem.com www.Laxmi GenChem.com 38
Heat Shock Protein InhibitorHeat Shock Protein Inhibitor
39
DiBAL-H
SOCl2 scaffold NN N
OTBDMSCl
OO
H2N
Br2
Br
DMF
1 23 4
NN N
OHCl
OO
H2NBr
TBAF/THF
NaH
5
O
O
O
HO n-BuLi
MeI / THF
6
SOCl2MeOH THFAcOH
Target
O
O
O
HO O
O
O
O O
O
O
O
Br
O
OHO
Br
O
OCl
BrCHCl3
N
N N
Cl
H2NPMB
OH
N
N NH
Cl
H2N
OH
NN N
Cl
H2NPMB
OMeO
N
N N
Cl
H2N
I
PMB
N
N NH
Cl
H2N
I
1 2 3
TFA / H2SO4
80 0C/ 2h
Pd(PPh3)4
Binap TEA
100 Psi
L-selectride
K2CO3 / DMF MeOH
PMB-Cl
N
N NH
Cl
H2N
OTBDMSTBDMS-Cl
IMD
80 0C
scaffold4
Carbonylaation
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Heat Shock Protein InhibitorHeat Shock Protein Inhibitor
40
O
O
O
O
HO H+
MeOH
O
AcOH
HNO3 Pd / C
NaNO2
HCl
1
O
O
O NO2
O
OO
NH2
O
OO NH
NO2
O
O
O NH2NO2 Pd/C
EtOAcO
O
ONH
NN
O
OHNH
NN
DiBAL-H
2 3 4
56 7 8 9
N
N N
Cl
H2N
O
NH
NN
OH
OMe
O
O NHO
TFAKNO3
Ac-Cl
Et3NEtOAc
O
O
OO
NH2NH2
Con.-HCl
11
O
ClNH
NNN
N NH
Cl
H2N
OTBDMS
N
N N
Cl
H2N
O
NH
NN
OTBDMS
TBAF
THFNaH
SOCl2CHCl3
10 Target
e-mail: vijayreddy@laxmgenchem.com www.Laxmi GenChem.com
41
Heat Shock Protein InhibitorHeat Shock Protein InhibitorPd(dppf)Cl2bis(pinacolato)diboronKOAc, dioxane/ 800CK2CO3 N
N NH2N
Cl
N
O
FF
BocN
O
HN
NBoc
N
N NH2N
Cl
N
O
FF
ONH
HO HOTEA DCM / TEA
BocN
MsOK2CO3, DMF
F
F
OHBr
TFA
(Boc)2O Ms-Cl
N
N NH2N
Cl
N
O
I
N
N NHH2N
Cl I
K2CO3, DMF
N
O
Br
F FO
Br
NBoc
F FO
Br
NH
F FO
Br
NAcOH/ CH2ONaBH(OAc)3 TFA
SuzukiINT-A
INT-B
INT-B
N
N NH2N
Cl
N
O
FF
ON
Pd(dppf)Cl2bis(pinacolato)diboronKOAc, dioxane/ 600CK2CO3
F FO
Br
N
SuzukiINT-A
N
N NH2N
Cl
N
O
I
N-Methylation
Reductive Aminaation
e-mail: vijayreddy@laxmgenchem.com www.Laxmi GenChem.com
Biological Active Hetero Cyclic Ring CompoundsBiological Active Hetero Cyclic Ring Compounds
42
NS
HN
F3CO
OEt
5M KOH, MeOH, Reflux NS
HN
F3CO
OH
NMeO
H.HCl
EDCI/DIPEA/DMF
NS
HN
F3CO
N OMe
CH3MgBrN
S
HN
F3CO
NH2OH.HCl, Py, MeOH
NS
HN
F3CH2N
NCS
F3C
NH4OH
Dioxane
HN
F3C
NH2
S
O
Cl+
O
H
OEt
NS
HN
F3CNOH
Zn-AcOH
EtOH/ Reflux
THF/ 0 oC to RT
weinreb amide Ketone OximeGrignard Scafold
N
S
HN
HN
NN
N
O
O
EDCI / HOBT/ DMF
OH
N
S
HN
HN
NN
N
O
HN
O
N
S NH
K2CO3/ DMF80 oC/ 1h.
O
NN
N
O
1
O
N
S
HN
HN
NN
N
O
O
O
6
BrO
OO
OH
NN
N
O
O
OLiOH
THF/H2O
MeNH2
EDCI / HOBT/ DMF
HClFFF
F FF
F FF
F FFNH2
N
NH
OH
NH2
O
CH2O,HCl
H2O NHN
NH
OH
OSOCl2,MeOH
NHN
NH
OMe
OSeO2,PPSE
NN
NH
OMe
O
NEt3, CCl4
Base Hydrolysis
t-Butyl ester is intact
Acid Hydrolysis
2 3 4
7
5
isothiocyanate Thio Urea thiazole
Scafold
e-mail: vijayreddy@laxmgenchem.com www.Laxmi GenChem.com
Biological Active Hetero Cyclic Ring CompoundsBiological Active Hetero Cyclic Ring Compounds
43
N NO2
BrBr THF NO2N
HN Br Fe, AcOH CH(OEt)3, HCl
DMF/H2O
CO, Pd(BINAP)Cl2
Hunig's base, n-BuOH
LiOH
THF/H2O
NH2N
HN BrNN
N Br
NN
N CO2Bu
NN
N CO2H
NS
HN
CF3HN
NN
N
O
1.TFA/DCM
EDCI/HOBT
6
1 2 3 4
5
NBoc
NH2
N N N N
NNBoc
Boc Boc Boc Boc
Boc NS
HN
CF3HN
NN
N
O
N
2. NaCNBH3
AcOH/CH3CHO
Scafold
Carbonylation
Reductive amination
e-mail: vijayreddy@laxmgenchem.com www.Laxmi GenChem.com
44
OHH2N
R1
O
OH2N
R1
O
(S)-Alanine
OHN
R1
O
Boc NH
HN
R1
ONH2Boc
R2 O
NHNN
NH
HN
R1
R2Boc
NN
N
HN
R1
R2Boc
NN
NNH2
R1
R2
1 2 3
4 5 TARGET
Esterification N-Boc Hydrazide
N-Methylation De-BocCyclization
Acid Hydrazide
R1= H, CH3Ph, CH (CH3)2
R2= Me, PhR2 O
NHDry HClMeOHR-CN
Pinner reaction
MeI Dry HCl
4-ME, 3, 5-DI Substitutes- 4H-1, 2, 4-triazols
e-mail: vijayreddy@laxmgenchem.com www.Laxmi GenChem.com
API Projects
45e-mail: vijayreddy@laxmgenchem.com www.Laxmi GenChem.com
ZudovidineZudovidine Chemical Name is Chemical Name is 3 azido-3 -deoxythymidin(AZ′ ′3 azido-3 -deoxythymidin(AZ′ ′ T).T). DNA intercalating drug type.DNA intercalating drug type. Retrovir activityRetrovir activity..
HN
NO
HO
O
OHN
NO
TrtO
O
OHN
NO
TrtO
O
O
OH OH OMes
HN
NO
TrtO
O
O
HN
NO
TrtO
O
O
N3
HN
NO
HO
O
O
N3
AZT4
1 2 3THYMIDINE
NaN3/Li2CO3
t-BuOk
DMF
DMSO
46e-mail: vijayreddy@laxmgenchem.com www.Laxmi GenChem.com
StavudineStavudine Chemical Name is Chemical Name is 2',3'-didehydro-3'-2',3'-didehydro-3'-
deoxythymidinedeoxythymidine.BRAND Name is .BRAND Name is ZeritZerit StavudineStavudine is converted within the body to its active is converted within the body to its active formform
((stavudine triphosphatestavudine triphosphate). This active form is similar to ). This active form is similar to thymidine triphosphatethymidine triphosphate, a chemical that is required by the , a chemical that is required by the HIV virus to make new DNA.HIV virus to make new DNA.HN
NO
HO
O
O
OH
HN
NO
MesO
O
O
OMes
HN
NO
HO
O
O
HN
NO
HO
O
O
THYMIDINE 1
STAVUDINE
HN
NO
O
O
O
Oxtane INT
Crude STAVUDINE
Mes-Cl/NMM
O
Aq-NaOH
75 oC/ 3h30 oC/ 1h
Alcholic KOH NMPO / Acetone
60 oC/ 3hIPA 75 oC/ 3h
47e-mail: vijayreddy@laxmgenchem.com www.Laxmi GenChem.com
48
OHOHO
HO OH
OOHO
O O
CH3OOTsO
O O
CH3
OH3C O
O O
CH3OHH3C O
HO OH
OAcH3C O
AcO OAc
N
NFNH2
O
H3C O
AcO OAc
NH
NF
NH2
O
Acetone/MeOH
H2SO4/CH2Cl2/TEA
CH2Cl2/PTS-ClPy/DMAP
NaBH4/DMSO H2SO4/H2O
CH2Cl2/Py/AC2O 1.HMDS/MeSO2Cl/TOLUENE
2.SnCl4/CH2Cl2
H3C O
AcO O
O
anchimeric assistance
N
NF
NH
O
TMS
TMS
Up side attack
Capiceitabine
N
NFNH
O
H3C O
AcO OAc
O
O
n-amyl chloroformate
Py/DCM N
NFNH
O
H3C O
HO OH
O
O
DCM TOLUENE
NaOH/H2O/MeOH
D-ribose
Cytosine
Capiceitabine (Anti-Tumor drug/ Xeloda Trade Name)
e-mail: vijayreddy@laxmgenchem.com www.Laxmi GenChem.com
49
NH
(R)O
O
O
Boc
NH
(R)OH
O
HO
BocH2N (R)OH
O
HO
NH
(R)OH
O
O
Boc
H2N
Isobutyl chloroformate
NMM/DCMBoc2O/NaOH
H2O
DMS
NH
(R)HN
O
O
Boc
O
O
OCl
Mixed anhydride
O
H2N (R)HN
O
O
HN (R)HN
O
O
O
AcOH/Ac2OHCl/H2O
L-Serine
Lacosamide
NaOH/H2O
Lacosamide (Anticonvulsant / Vimpat Trade Name)
e-mail: vijayreddy@laxmgenchem.com www.Laxmi GenChem.com
50
NCl
CHOOHCAc2O
NClCHO
NCl
OHMgBr
I
O
O
Pd(OAc)2
NCl
O
O
O
NCl
OH
O
O
(-)-B-Chlorodiispopinocamphenyl borane
.H2O
NCl
OH
OHMeMgCl/CeCl3 NCl
OH
OMes
THF
Mes-Cl/DIPEA
ACN/Toulene
NCl
HO
S
O OH
NCl
HO
S
O ONa
HS
O OH
NaOMe/DMSO
TBA salt
1.AcOH/Toulene
2.NaOH/MeOH
H2N
NH2
DIPEA/DCM
Montelukast Sodium
Montelukast Na (leukotriene receptor antagonist / Singulair Trade Name)
e-mail: vijayreddy@laxmgenchem.com www.Laxmi GenChem.com
51e-mail: vijayreddy@laxmgenchem.com www.Laxmi GenChem.com
Vardenafil-INT
Vardenafil is a PDE5 inhibitor used for treating erectile dysfunctionVardenafil is a PDE5 inhibitor used for treating erectile dysfunctionO
NH2
O OCN
O
NH2
NH O
NH
NHNH2N2H4.H2O
IPA
O
N
HNN
NH
OO
O
N
HNN
N
O
O
NH
O
O
O
Verdanafil-Int
O
NH
O
O
OOH
O
NH
O
OH
O
NH2
O
Cl
INT-3
INT-3
O
N
HNN
N
O
SN
OO
N
Vardenafil
52e-mail: vijayreddy@laxmgenchem.com www.Laxmi GenChem.com
NH2
OO
NH2
OO
HCl HClN
OO
OON
OO
OO
NH2
OO
NH2
OHO
NH2
OO
HCl
Pt-C/MeOHIPA/tBuOKToluene/TEA
CAS No.: 61367-07-5Ref : Organic Process Research & Development 2009, 13, 1141–1144
Trans-4-Amino-1-cyclohexanecarboxylic Acid HClTrans-4-Amino-1-cyclohexanecarboxylic Acid HCl
53e-mail: vijayreddy@laxmgenchem.com www.Laxmi GenChem.com
Methyl trans-3-amino-cyclobutane HCl
HO2CCO2H
SO2Cl2
HO2CCO2H
ClPy/
CO2H
ClSO2Cl2/MeOH
CO2Me
Cl
NaN3
CO2Me
N3
CO2Me
N3
CO2Me
H2N
CO2Me
H2N
Pd-C/H2
Pd-C/H2
76%64%
81%
32%
29%
67%
71%
CAS 74316-29-3
Ref:Synthetic Communications1, 41: 1644–1649, 2011
54e-mail: vijayreddy@laxmgenchem.com www.Laxmi GenChem.com
(Toluene-4-sulfonylmethyl)-phosphonic acid diethyl ester
SCH3
CH3
NCS
S
CH3
ClP(OEt)3
S
CH3
PO OEt
OEt
H2O2 / Na2WO4
CH3
PO OEt
OEt
OSO
1-Methyl-4-methylsulfanyl-benzene 1 2 3Mol. Wt.: 306.32
55e-mail: vijayreddy@laxmgenchem.com www.Laxmi GenChem.com
1,1-difluoroethanesulfinate (Hu'S Reagent) Derivatives
N SH
EtO P CF2BrO
OEt
KOH/ H2O/MeCNN S CF2H
NaIO4/RuCl3.H2O (cat)N S
CF2H
O O
2-(Difluoromethylsulfonyl)pyridineHu'S Reagent
2-Mercaptopyridine
ClN SO
OF F
ClI
ClSO
F FNaO
Br
Br
N SO
OF F
Br
SO
F FNaO
Br
BrN S
O
OF F
SO
F FNaO
Br
BrBr
N SO
OF F
SO
F FNaO
Br
78%
Br
Br Br
70%
N SCF2H
O O
56e-mail: vijayreddy@laxmgenchem.com www.Laxmi GenChem.com
Perampanel –INT (1-Phenyl-5-(pyridin-2-yl)-2(1H)-pyridone)
N
O
(HO)2BN
O
N
NH
O
N
Suzuki Coupling
N BrN
O
BrN
Br
Br
De-Methylation
Methylation
N
O
N
B(OH)2
Exact Mass: 122.05
INT-1 INT-2INT-3
INT-4 CAS No: 381725-50-4
N
O
N
CN
Perampanel
57e-mail: vijayreddy@laxmgenchem.com www.Laxmi GenChem.com
HO O
O
NH2
HO O
O
NHBocHO OH
O
NH2
H2SO4/MeOH NaHCO3/(BOC)2
1,4-DiOxaneTBDPSO O
O
NHBoc
TBDPS-Cl
Imidazole/DMF
TBDPSO
O
NHBoc
DIBAL-H
DCM; - 78 oCTBDPSO
NHBoc
HN
OH
NH
PhHO
DCM/MgSO4~ 65 oC for 3 steps
N PhHO
OH
OBn
OBn
TBDPSONHBoc
N PhHO
OBn
TBDPSONHBoc
HN PhZn, Cu(OAc)2
AcOH; 60 oC92%
OBn
TBDPSONH
N NHBocBn1) TFA/DCM
2) HgO
NHBoc
NHBocS
BocHN
NBoc
NBoc
OBn
iPrMgCl / THF; - 78 oC86%
HN N O
NBocN
OBocN
NBoc
TBDPSO
Bn
OBn
1 2 3 4
5 6 7
8 9 10
13 14
12
14
CHO
11
Tetrahedron: Asymmetry 9 (1998) 629–646
J. Am. Chem. Soc. 2011, 133, 20172–20174- Comp-2Tetrahedron: Asymmetry 1997, 8, 2381–2401Tetrahedron: Asymmetry 9 (1998) 629–646.
J.CHEM. SOC. CHEM.COMMUN., 1989
J. Am. Chem. Soc. 2011, 133, 20172–20174- Comp-2
N PhHOShiff's Base Reductive Amination
NaH/BnBr
THF; 0 oC93%
Site One Ref erence
NH2OH. HCl/MeOH86%
NaBH4/MeOH87%
AgOACThen I2;AgOAc
Then AcOH,AgOAC
3 Step One Pot Cyclization
Saxitoxin-Natural Product. ( Total 19 Steps)
58e-mail: vijayreddy@laxmgenchem.com www.Laxmi GenChem.com
O
HO
HO O
F
O
BzO
BzO N
F
NHPO
OO
O
O
NMI, DCM, 0 oC to rt 1h, 52%
CHOO
O
Ph3PC(Me)CO2Et, DCM, -40 oC, 79% E\Z 97:3
O
OCO2Et
O
OOHHO
HCO2Et
O
OCO2Et
ROH
F
O
BzO
BzO O
F
O
BzO
BzO
F
OAc N
O
NHBz
O
BzO
BzO N
F
NH
O
O
O
HO
HO N
F
NH
O
O
O
OO
OH
CO2Et
SO
O
KMnO4, acetone0 oC, 87%
1.SOCl2, TEA, DCM, -0 oC,2.aq. NaOCl, TEMPO, NaHCO3, MeCN, 0 oC,
1.TEAF, dioxane 100 oC, 87%2. (MeO)2CMe2, Con.HCl,dioxane, rt, 87%
R=SO3HR=H
Con.HCl, EtOH, rt
BzCl, pyridine,rt
1.Li(O-tBu)3AlH, THF -20 oC2.AC2O, DMAP ,-20 oC
SnCl4,PhCl ,65C70% Aq. AcOH,100 oC
25% methanolic ammonia, 0-15 oC O
F
OPN
H
OO
O N NH
O
O
OPh
NN
NHBz
OTMS
D(+)-Glyceraldehyde CAS : 453-17-8
CAS :5736-03-8
F
FF
FF
Sofosbuvir Synthesis
59e-mail: vijayreddy@laxmgenchem.com www.Laxmi GenChem.com
CytidineCAS:65-46-3
O
O
O NN
O
NHBz
OH
SPDIT
O
HO
HO NN
O
NH2
OH
O
O
O NN
O
NHBz
O
O
O
O NN
O
NHBz
SPDIT OHO
BzO
BzO NN
O
NHBz
OH
O
BzO
BzO NN
O
NHBz
OH
O
BzO
BzO NN
O
NHBz
F
O
BzO
BzO NN
O
NHBz
O
BzO
BzO NNH
O
F
O
O
HO
HO NNH
O
F
O
NH
P OOO
O
ClO
HO
O NNH
O
F
O
PNH
OO
O
1.Bz2O,DMF, rt2.TIDPSCl2, DMF
1.DMSO, TFAA, TEA, -15 oC
1.TBAF, AcOH,rt, 61%2.BzCl, pyridine, rt, 67%
DAST, toluene, -20 oC-rtMeLi, -78 oC
80% AcOH, reflux, 91%
NH3, MeOH, rt, 60%
NMI, THF, 0 oC-rt,1h, 15% SOFOSBUVIR
SPDIT
19%14% 15%
OPh
12 3
4 5
6a 6b 6c7
8
9
Sofosbuvir Alternative ROS
60e-mail: vijayreddy@laxmgenchem.com www.Laxmi GenChem.com
O
HO
HOO
NH
HN
O
O
F O
HO
HO NNH
O
O
F
O
HO
OP
O
HN
O
OO
NNH
O
O
F
OP
O
HN
O
OO
F
F z
F
F
t-BuMgCl/THF
PL-102
PL- 102 ( IsoSteric Structure to Sofosbuvir)
61e-mail: vijayreddy@laxmgenchem.com www.Laxmi GenChem.com
N
HN NH
N
N
N FF H
O
HN O
O
ONHO
O
N
HN N
H
O
HN O
OB
O
O
N
HN N
H
OOBO
O
HN
N
N FF
O O
Br
NH2
NH2
BrN
H
OO
O
O
NH2
O
OO
OH
O
O
N
FFO O Br
O
ON
O O
OK O
FF
Br
Cl
LDP-IMP-4
ONHO
O
HO Br
Ledipasvir-IMP-4 Synthesis ( Total 24 Steps)
62e-mail: vijayreddy@laxmgenchem.com www.Laxmi GenChem.com
ADU-S100 Synthesis ( Total 21 Steps)
OHHO
HOO
N
NNH2
N
N
OBzBzO
BzOO
N
NNHBz
N
NPyridinePhCOCl
2N NaOH
OHHO
HOO
N
NNHBz
N
N
DMTr-Cl
Pyridine
ODMTrHO
HOO
N
NNHBz
N
N
1 2 3 4
ClP
N
O
N
ODMTrHO
TBDMSOO
N
NNHBz
N
N
ODMTrTBDMSO
HOO
N
NNHBz
N
NTBDMS-ClPyridine
5 5a
Et3N, DCM
+ ODMTr
HOH
OTBDMSO
NN
N
NHBzN
PO
NNC
6
3'
3'2'
ODMTr
HO H
OTBDMSO
NN
N
NHBzN
POH
A) Pyridiium trifluoroacetate
B) tert-butylamine3'
C) dichloroacetic acid in DCMOH
HO H
OTBDMSO
NN
N
NHBzN
P OHOH
3'
7 8
5'O-DMTr Deprotection
O-CE De-Protection
Elimination
O-Bz Deprotection1'-OH- Protection
OH
N & O-Bz Protection
63e-mail: vijayreddy@laxmgenchem.com www.Laxmi GenChem.com
ADU-S100 Synthesis ( Total 21 Steps)
ODMTrTBDMSO
HOO
N
NNHBz
N
N
5a
2'
ClP
N
O
N
Et3N, DCM ODMTrOTBDMS
OO
N
NNHBz
N
N
2'PO
NNC
6a
64e-mail: vijayreddy@laxmgenchem.com www.Laxmi GenChem.com
ADU-S100 Synthesis ( Total 21 Steps)
OH
HO H
OTBDMSO
NN
N
NHBzN
P OHOH
3'
8
ODMTrOTBDMS
OO
N
NNHBz
N
N
PO
NNC
D) ACN/Py ODMTr
TBDMSO
O
O
NN
NHBzN
N
PO2'
2'
O
HO H
OTBDMSO
NN
N
BzHNN
P OHOH
NC
O3'
5' & 2'- Linking
ODMTr
TBDMSO
O
O
NN
NHBzN
N
PO
O
HO H
OTBDMSO
NN
N
BzHNN
P SHOH
NC
S3'
P-S Insertion
2'E) DDTT
OHTBDMSO
O
O
NN
NHBzN
N
PO
O
HO H
OTBDMSO
NN
N
BzHNN
P OHSH
SF) DCA/Water 3'2'
G) DMOCP
CN
O-DMTr DeprotectionH) I2 / H2O
O
OTBDMSO
O NN
NHBz
NN
POH
OH
O
TBDMSO
NN
N
BzHN N
PHS
SO
O5' & 3'- Back Linking
I) SiO2
J) NH4OH, MeOH
O
OTBDMSO
O NN
NH2
NN
POH
OH
O
TBDMSO
NN
N
H2N N
PHS
OSH
O
O-CE & N-Bz Deprotection
L)TEA-3HF,
O
OHO
O NN
NH2
NN
PO
H
OH
O
HO
NN
N
H2N N
PHS
O
SH
OO-TDDMS Deprotection
9 10
11 12
13 ADU-S100M) SepPak desalting N)Ion exchange
K) Prep.HPLC
CN
Medicinal ChemistryVijay M Reddy 65
NC
O
NNN N
N N
SMeO
OClNC
O
NH2HN
N
SMe
MeOOC
N N
SMeO
OCl
NHH2N
OO O
N N
N N
SMeO
OCl
HOOC
NC
COOMe
N N
SMeO
OCl
Cl
N
SMeO
OMeOOCN
Br
MeOOCN
Br
HOOC
ClNH2
MeOHSOCl23 h87%
THFNaSMe
reflux16 h57%
m-CPBA
DCM20 C16 h77%
AlMe390 C2 h87 %
PCl5
benzenereflux16 h
NH2NH2H2O92% Toluene
reflux3 h96%
1. Oxalyl Chloride2. PCl5, CBr4, DCM
1 2 3 4
6 7 8
9
10Et3N
HN N
SMeO
OCl
O5
NC
O
NH2HN
9
NH2.NH2.H2O;
16 h; 20 C; 80%
Synthesis of G007-LK-Tankyrase 1/2 Inhibitor
Ref: J. Med. Chem. 2013, 56, 3012−3023
Research Work
Medicinal ChemistryVijay M Reddy 66
R & NH are at - Position
R & NH are at Position
R is at - NH is at Position
- Amino acid
- Amino acid
- Amino acid
NO
HR
H OH
N
OH
RH OH
N
OH
H
R
OH
NN
NN
O
O
O
O
R
R
R
R
- PolyPeptide chaine
N N N
O O O
RRR
H
H
H
H
H HH
- PolyPeptide chaine
N N N
O O O
H HH
- PolyPeptide chaine
R R R
Types of Amino Acid & Poly Types of Amino Acid & Poly peptidepeptide
Vijay M Reddy Medicinal Chemistry 67
Peptide-based nano structuresPeptide-based nano structures
68Vijay M Reddy Medicinal Chemistry
Choice of Backbone Structure
1972 Hassel predicted that cyclic tetra peptides composed by alternative α and β- amino acids would stack through backbone- backbone H-bonding to form hollow cylindrical structure.
Later X-ray crystallographic work partially validated these prediction. Two of four expected inter subunit H-bonding was observed.
1974 De Santis and co workers recognized the possibility of forming cylindrical structure by ring –stacking of cyclic D,L- α- peptides.
Early attempts to experimentally verify this prediction met with limited success due to the extreme insolubility of peptides examined.
1993 Ghadiri and co workers complied 1st evidence of forming hollow tubular structure by self -assembly of cyclic D,L- α- peptides, by bearing suitable hydrophobic side chain.
Molecular modeling and experimental studies indicated that 8 –residue cyclic peptides possess optimum balance of low ring-strain .Ghadiri, M. R et al. Nature 1994, 369,301- 304.Ghadiri, M. R et al. J. Am. Chem. Soc. 1998, 120, 651- 656.Ghadiri, M. R et al. J. Am. Chem. Soc. 1996, 118, 43-50.
Medicinal ChemistryVijay M Reddy 69
Choice of Backbone Structure
Cyclic D,L- α- peptides with 8, 10 and 12-residue which give internal Van der waals diameters 7, 10, 13 Å respectively.
1996 Dieter Seebach reported that cyclic tetramers of β3- amino acids can adopt flat ring confirmation and stack in the solid state through back- back bone H-bonding.
Ghadiri, M. R et al. J. Am. Chem. Soc. 1998, 120, 651- 656.Seebach, et al. HelV. Chim. Acta 1997, 80, 173-182
(a) flat-ring C2 symmetrical conformation described by Seebach
(b) an alternative flat-ring C4 symmetrical conformation.central hole 2.6-2.7Å in diameter, large enough to allow passage of water and small ions
Medicinal ChemistryVijay M Reddy 70
A Model A Model CycloCyclo Peptide Nano tubes Peptide Nano tubes
NH
NHO
R
OR
HN
HNO
R
OR H H
HH
HH
HH
3- Cyclic Peptide (Tetra peptide)
HN
HN
HN NH
NH
NH
NH
HN
O
O
O
OO
O
O
O
RR
R
RR
R
R
R
- Cyclic Peptide (Octa Peptide)
D
D
D
D
L
L L
L
In β3-Tetra peptides CH2- Group α to Carbonyl group is responsible for optimum balance of Cyclo Peptides.
Medicinal ChemistryVijay M Reddy 71
- Peptide Nano tube (Octa Peptide)
N
NN
N
N
NO
OO
O
O
O
R
H H
HH
H
HN
ON
O
R
H
H
N
NN
N
N
NO
OO
O
O
O
RH H
HH
H
HN
ON
O
R
H
H
N
NN
N
N
NO
OO
O
O
O
R
H H
HH
H
HN
ON
O
R
H
H
N
NN
N
N
NO
OO
O
O
O
RH H
HH
H
HN
ON
O
R
H
H
N NN N
OO OO
R R
H H H H
N NN N
OO OO
R R
H H H H
N NN N
OO OO
R R
H H H H
N NN N
OO OO
R R
H H H H
- Peptide Nano tube (Tetra peptide)
Structural attribute of Cyclic Peptide
Ghadiri, M. R et al. J. Am. Chem. Soc. 1998, 120, 651- 656.
No N
et Dipole M
oment
- Octa Peptide Nano tube
N
NN
N
N
NO
OO
O
O
O
R
H H
HH
H
HN
ON
O
R
H
H
N
NN
N
N
NO
OO
O
O
O
RH H
HH
H
HN
ON
O
R
H
H
N
NN
N
N
NO
OO
O
O
O
R
H H
HH
H
HN
ON
O
R
H
H
N
NN
N
N
NO
OO
O
O
O
RH H
HH
H
HN
ON
O
R
H
H
N NN N
OO OO
R R
H H H H
N NN N
OO OO
R R
H H H H
N NN N
OO OO
R R
H H H H
N NN N
OO OO
R R
H H H H
Medicinal ChemistryVijay M Reddy 72
Ghadiri’s α-cyclic polypeptides
Medicinal ChemistryVijay M Reddy 73
Some other cyclic polypeptide
Medicinal ChemistryVijay M Reddy 74
Jan H. van Maarseveen et al.Org. Lett., Vol. 8, No. 5, 2006, 919-922
Tyrosinase inhibitor- Click Chemistry ApproachN
O
NHN
HO
HNO
O
N
O
NN
HO
HNO
O
NN
N
O
NN
NHO
O
NN
N
O
NN
HO
N
O
NN
O
Cyclo- [Pro-Val-Pro-Tyr]
HO
NN
Triazole analogue 2
Pro
Pro Val
TyrTyr Pro
ValPro
Pro
Pro
ValVal
TyrTyr Pro
Triazole analogue 3 Triazole analogue 4
Pro
Cyclo- [Pro-Val-Pro-Tyr] is a natural product isolated from Lactobacillus helveticus.
Tyrosinase (phenol oxidase) [EC 1.14.18.11 is known to be a key enzyme for melanin biosynthesis in plants, microorganisms and mammalian cells, and also known to be as a copper-containing enzyme.
Compound Tyrosinase activity IC50/mMa
cyclo-[Pro-Tyr-Pro-Val]
1.5
Triazole analogue 2
0.5
Triazole analogue 3
0.6
Triazole analogue 4
1.6
(S) N(S)
O
NHN
(S)
HO
(S)
HNO
O
O
Cyclo- [Pro-Val-Pro-Tyr]
Pro
Pro Val
Tyr
R'
NN
N R
R'
1,3- Cyclo addition
Alkyne
Azide
1,4- Di substituted1,2,3- Triazole
RN
NN
Catalyst
123
Medicinal ChemistryVijay M Reddy 75
Reasons behind the Replacement Reasons behind the Replacement of Peptide Bond with Hetero of Peptide Bond with Hetero
CyclicCyclic
Triazole & Oxadiazoles mimics planarity of amide bond.Triazole & Oxadiazoles mimics planarity of amide bond.
Triazole and peptide bond both possess large dipole (5D, 3.7D, respectively).Triazole and peptide bond both possess large dipole (5D, 3.7D, respectively).
CC distance distance of of Peptide and Triazole Peptide and Triazole & & Cβ distance Cβ distance of of triazole and oxadiazole triazole and oxadiazole are are comparable.comparable.
Peptide bond Hetero cyclic are Peptide bond Hetero cyclic are Isoteric Structures.Isoteric Structures.
Jan H. van Maarseveen et al.Org. Lett., Vol. 8, No. 5, 2006, 919-922Kolb, H.C., Sharpless, B.K. Drug. Disc. Today. 2003, 8, 1128-1136.Kevin Burges, J. AM. CHEM. SOC. 2011, 133, 462–477
H2N
R1
NNN
OHR
O
5.1 Ao
NH2
OR1 N
H
ROH
O
3.9 Ao
Peptide Bond 1,2,3- Triazole
SP3 N N
O
H2N NH
R2
O
5.2 Ao
1,2,4- Oxadiazole
H2NNNN
OHO
5.5 Ao
1,2,3- Triazole
R1 R2
R1
C CDistance C CDistance C CDistance
Medicinal ChemistryVijay M Reddy 76
N N
O(S)
NH(S)
R2HN
O
NN
O (S)HN
(S)
R2 NH
O
R1
R1
NN
O
(S)
HNR1
(S)
R2
HN
O
NN
O(S) N
HR1
(S)R2 HN
O NN
O
(S)NH
R1
(S)
R2
NH
O
N NO
(S)
HN
R1
(S)R2
NH
O
HH
H
H
HH
HH
C2C4
N N
O(S)NH
(S)R2HN
OPg1
R1
Pg2
CC22 & C & C44 Symmetry 1,3,4- Oxadiazole Back Bone Cyclic Peptides Symmetry 1,3,4- Oxadiazole Back Bone Cyclic Peptides
Monomer consist of 2-Amino acids with 1,3,4-Oxadiazole
Medicinal ChemistryVijay M Reddy 77
Chemistry Scheme Execution
OHO
H2NR1
OO
H2NR1
OOH
NR1
Boc NH
OHN
R1
Boc NH2
SOCl2/MeOH
reflux; 6h;
(Boc)2O/TEA
DCM, RTOver night
HyrazinehydrateMeOH/ Reflux4h
OHO
Cl
N NNN
O
N NO
ClNH
OHNBoc NH2
NH
OHN
R1Boc
HN Cl
ODCM/ RT/ 6hDCM ACN/ Reflux/ 4h
PTS-Cl/ TEA N N
OR1
NHBocCl
R1= CH3, Ph, Leu & Val
N N
OR1
NHBocI
R2
H2N OO
N NOR1
NHR2HN
OOO
O TFA/DCM
N NOR1
NH2. TFAR2HN
OOTEA /ACN
KI/Acetone
Finkelstein reaction A B
R2= Leu, Cys, Trp, Typ & His
Medicinal ChemistryVijay M Reddy 78
Future Chemistry Scheme Execution
N N
ONH
R1 R2HNO
O
NNO HN
R1
R2 NH
O
BocDimarization
A X B
N N
ONH HN
O
NN
OHNNH
O
R1
R1
1) TFA/DCM
2) Coupling
N N
ONH
R1 R2HN
O
NNO NH
R1
R2 NH
O
NN
OHN
R1R2
NHO
O
N N
ONH
R1
R2HN
OBoc
NN
O
HNR1
R2
HN
O
NNO
NHR1
R2 HN
O NN
O
NHR1
R2
NH
O
N NO
HN
R1
R2NH
O
HH
HH
HH
H H
Coupling
1) TFA/DCM
2) Coupling
1) TFA/DCM2) Coupling
Medicinal ChemistryVijay M Reddy 79
Application of SA peptidesApplication of SA peptides
New Materials Sensors Molecular electronics Ions Channels Antimicrobial
Medicinal ChemistryVijay M Reddy 80
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