CPhI 2009

HAMARI CHEMICALS, LTD

Cost performance, high quality, and environmentally friendly services.

More than 55 years of experience in custom manufacturing.

More than 60 reactions on commercial scale (500 – 5000 L).

cGMP Manufacturing facilities.

Process development, Method validation and Stability testing.

FTE-Full Time Equivalent study.

API Development Service for IND and NDA.

Hamari Chemicals can offer your company…

CPhI 2009

API Development Service

Inquiry

PreClinicalPreClinical

Pre-INDPre-IND INDIND PhⅠ- PhⅢPhⅠ- PhⅢ NDANDA PAIPAI FDAApprovalFDAApproval

5 days5 days

Evolution

1-4 weeks1-4 weeks

Phase 1Phase 1

ProcessDevelopment

ValidationLot

Pilot GLP Lot

ProcessOptimization

Manufacturing GMP Lot

Phase 2Phase 2 Phase 3Phase 3 Phase 4Phase 4 Phase 5Phase 5 Phase 6Phase 6

Commercial

Phase 7Phase 7

AnalyticalDevelopment

Stability Testing

Method Validation

Fastest case：Hamari is able to start GLP pilot production within 3 monthsFastest case：Hamari is able to start GLP pilot production within 3 months

1-6 months1-6 months 2 months2 months

API is providedAPI is provided API is providedAPI is provided API is providedAPI is provided

API Development Service from IND to NDA

CPhI 2009

Timeline of IND Project

0 1 2 3 4 5 6 7 8 9 10 11 12

months

Technical feasibility study, Raw material availability and Price idea

Process development and Firm quotation for pilot quantities GLP Production and Reports

Process optimization andEstablishing specification GMP Production and Reports

Analytical method Validation

Kg-Lab production

Small samples for determining specification

1

IND Project (total steps 5)GLP-API 2 Lot, GMP-API 1 Lot

Kg-Lab1kg

GLP-API1st

20Kg

GMP-API20Kg

20g×3

GLP-API2nd

20Kg

Customer GMP audits

Actual Example

Analytical development

Analytical study

CPhI 2009

Project 1 Domestic Major Pharmaceutical CompanyOne year contract with 5 employeesProcess development for API Manufacturing of GLP Batch

Project 2 Domestic Major Pharmaceutical CompanyOne year contract with 2 employeesProcess development for intermediates Manufacturing of non-GMP Batch

FTE

(Full Time Equivalent) Study Examples

FTE Study & Custom synthesis

Custom

Synthesis

Contracts for all themesProcess development and manufacturing of API and intermediates

CPhI 2009

Master Plan and Protocol

Weekly Report

Monthly Report

End of Synthesis Process Development Report

End of Campaign Manufacturing Report

Telephone Conferences

Meetings and Reports

Upon Request Hamari Can Provide:

CPhI 2009

PeptidesReductionChiral TechnologyAlkylationHeterocyclicsOxidationHalogenationEtherificationGlycosylationNucleic Acid

Using SPPS and Solution phase synthesis.

Hamari’s Technology

Reductive amination using metal catalysts.

Swern, OXONE,TEMPO, RuCl3 and Sharpless

Negishi and Suzuki reaction

Indoles and Quinolines using Nitration

Chlorination (POCl3 ), Bromination (NBS, Br2 )

Phase transfer catalyst such as TBAB

Using trichloroacetimidate as the glycosyl donor

Asymmetric transfer Hydrogenation

API for antiviral agents

CPhI 2009

Ala-His-Lys

More than More than 30 years of experience 30 years of experience in peptide synthesisin peptide synthesis..

H2NN

CO2H

NH Tfa

O

HN

N CO2H

HN NH2

O

Tfa-Lys-ProL-Carnosine

H2 n

N

ZnO

N

N

O

O

N

H

Capacity (maximum per year)di-peptide : 50 tonstri-peptide : 20 tonstetra-peptide : 10 tonspenta-peptide : 10 tonshexa-peptide : 5 tons

Capacity / kg to ton scale

Zinc Carnosine / Polaprezinc- API in Japan- Dietary supplement in USA

Peptide Manufacturing

N

NH

HN

H2N

Me HN NH2

CO2H

O

O

CPhI 2009

Peptide Manufacturing

Expertise in small to medium length molecular peptides.

Extensive technology using Solution Phase Synthesis.

Experience in cGMP synthesis for clinical studies.

NEW-Acquired resources and equipment for Solid Phase Synthesis.

Peptide projects

di -peptide : 9 tri -peptide : 9

tetra -peptide : 7penta -peptide : 6hexa -peptide : 1 hepta -peptide : 1deca -peptide : 1 Peptide mimic : 1Total projects (2006-2008) 35

Manufacturing Experience

Intermediates forIntermediates for-- ACE inhibitors ACE inhibitors -- AntiAnti--cancer drugscancer drugs-- HIV protease inhibitorsHIV protease inhibitors

Cosmetic substancesCosmetic substancesDietary supplementsDietary supplements

Custom Manufacturing

CPhI 2009

ACE InhibitorsACE Inhibitors

Lisinopril Ester/FARGA-3 (Europe)

Di-peptide Derivative (Japan)

Di-peptide Derivative (Japan)

Peptides - Custom Manufacturing

NH

O

N

CO2H

N CF3

O

H

O OC2H5

Commercial (Yonezawa)Capacity : 30 tons 30 tons / year/ yearPurity： >99%，RSS: <0.5%In accordance with In accordance with cGMP cGMP

Manufacturing

Commercial (Yonezawa)Capacity : 1.5 tons 1.5 tons / year/ yearIn accordance with In accordance with cGMPcGMP

Manufacturing

Commercial (Yonezawa)Capacity : 500kg 500kg / year/ yearIn accordance with In accordance with cGMP cGMP

Manufacturing

CPhI 2009

Anti-Cancer DrugsAnti-Cancer Drugs

Peptides - Custom Manufacturing

Commercial：Currently ongoing

Hexa-peptide 150 kg / year (25 kg / Lot) His, Trp, Ser, etc…Tri-peptide 30 kg / year (15 kg / Lot) Arg, etc…

IND Products ：2006-2008

TriTri--peptidepeptide 11 ProjectsProjects 30 kg 30 kg (2008) (2008) PentaPenta--peptidepeptide 4 Projects 4 Projects 10 kg, 15 kg, 10 kg 10 kg, 15 kg, 10 kg (2008)(2008)DecaDeca--peptidepeptide 1 Project 1 Project 50 g 50 g (2008) (2008) Peptide mimic Peptide mimic 2 Projects 2 Projects 10 kg 10 kg (2006) (2006)

2 kg, 8 kg 2 kg, 8 kg (2007) (2007)

CPhI 2009

Peptides - Custom Manufacturing

Intermediates and API for LH-RH analoguesIntermediates and API for LH-RH analogues

APO(Ac-D-2-Nal-D-4-ClPhe-D-3-Pal)Registry Number:129225-22-5

HPLC purity : NLT 99%

Peptide-L-Arg(nitro)-Pro-D-Ala-NH2 Peptide-Lys(Ipropyl.X)-Pro-D-Ala- NH2

We are able to provide our process development for intermediates and API of LH-RH analogs such as Degarelix and Abarelix etc…

NH

Cl

O

HN

O

OH

N

OHN

O NH

O

N

O NH

O

NH2

NH

N NHO2N

peptide NH

O

N

O NH

O

NH2

NX

X:Cbz-, BOC-, Fmoc-

peptide

CPhI 2009

Reduction Reactions

Osaka

500L Hastelloy 1.0 MPa500L SUS 0.5 MPa100L SUS 0.2 MPa

Autoclaves

Catalysts ＆ Reagents

Pd-C

SBHRed-AlLAH

Rh-Alumina

Pt-C RaneyNi

DIBAH

Extensive experience in safely handlingMetal catalysts.

Yonezawa

2500L SUS 1.0 MPa1800L SUS 1.0 MPa1700L SUS 1.0 MPa1000L SUS 0.2 MPa500L SUS 6.8 MPa

Our capability to use chemical reagents

CPhI 2009

R1

CO2R2

O

NH2N

O

NH

CF3

O

CO2H

DIBAH

Raney Ni＋

-50 to -60 ℃

H2

NNH

R1

O

NH

CF3

O

CO2H

CO2R2

Reduction with DIBAH on commercial scale

Asymmetric Schiff base reduction (H2 / Raney Ni , 30 tons / year)

Horner-Emmons reaction(EtO)2POCH2CO2Me

Reductive aminationNaBH(OAc)3N

R CO2MeN

R CHO

Reduction Experience

Pd-CH

CO2EtEtO2C

ClH2

H

CO2EtEtO2C

Cl

Selective hydrogenation by using Pd-C（without dehalogenation）

N

RCO2Me

N

RHN R

CPhI 2009

Please note！- Asymmetric synthesis Instead of optical resolution.- When it is not appropriate to use other catalysts.

Hamari is able to provideFull Time Equivalent study needed for your custom synthesisUsing our Asymmetric Transfer Hydrogenation technology.

Please note！- Asymmetric synthesis Instead of optical resolution.- When it is not appropriate to use other catalysts.

Hamari is able to provideFull Time Equivalent study needed for your custom synthesisUsing our Asymmetric Transfer Hydrogenation technology.

Asymmetric Transfer Hydrogenation using Chiral Ru- and Ir - catalysts

O

Me

R[H]

Hamari catalyst(Chiral Ru-, Ir-catalyst)

N

Me

R

H2N

Me

RHN

*

NX

N

Cl

ArHet

O

H

H

Rn

40-80%ee

RO

N Me Hamari catalyst(Chiral Ir-catalyst)

RO

HN Me

[H]

X=Ru , Ir

Hamari Chiral Technology

70-90%ee

Chiral Ru-complex ee(%) .arene-Ru(Ⅱ)-TsDPENca.20%eeHamari catalyst Ru 40%eeHamari catalyst Ir 80%ee

Chiral Ru-complex ee(%) .arene-Ru(Ⅱ)-TsDPENca.20%eeHamari catalyst Ru 40%eeHamari catalyst Ir 80%ee

CPhI 2009

Alkyllithium

Olefination -Horner-Emmons and Wittig reactions

Horner-Emmons

Alkylation

Etherification

PTC-catalyzed (e.g. TBAB)Mild condition (<80℃)High yield (>90%)

～ - 90℃ max. 1000L～ - 50℃ max. 3000L

Alkyllithium (n-BuLi), LDA, NaH, tert-BuOK, tert-BuONa, MeONa, Li, etc.

Base

NH

OR

Quinoline & Quinazoline Derivatives

Carbazole Derivatives

Grignard ReactionO

Cl R Cl

OH

R CO2H

OHR-MgBr

CuI

CN

H

O

Ph3 PCH2 R2 Br＋ －

tert-BuOKNaOMe

(EtO)2 POCH2 CN

R2

Cryogenic reactionsCryogenic reactions

Y

X

OAr

R1

R2

Mitsunobu reaction using DIAD

R

OH

R

ORR-OH

DIAD*, PPh3

＊DIAD : Diisopropyl azodicarboxylate

Wittig

CPhI 2009

Negishi and Suzuki

Negishi Cross Coupling

Pilot plant (Hamari Osaka)Capacity : 50kg 50kg / Batch/ BatchResidual Pd :Residual Pd : NMT NMT 1 ppm 1 ppm levellevelIn accordance with In accordance with cGMPcGMP

Manufacturing

ZnBrR1 Br R2

R1 R2

＋

Pd(dba)2

PPh3

SuzukiSuzuki--Miyaura Cross CouplingMiyaura Cross Coupling

I

R1R1

R2(HO)2B

R2

Pd(OAc)2

ligand, base＋

Manufacturing

Commercial (Yonezawa)Capacity : 100kg100kg / Batch/ BatchResidual Pd :Residual Pd : NMT NMT 1 ppm 1 ppm levellevelIn accordance with In accordance with cGMPcGMP

CPhI 2009

R

N

R

N

NR

N

Quinolines Isoquinolines Quinazolines

Aminothiazoles

NH

OR

Carbazoles

NH

R

CO2H

NO2

Indoles

Heterocyclic Derivatives

S

N CO2R2

H2N

N OR1

S

R1 R2

R3

Thiophenes

N

N

CH3

NH

R

O

Imidazoles

O

N

Me

OH

Oxazoles

CPhI 2009

NitrationReduction

Oxazole DerivativesLiAlH4

L-Asp(OMe)-OH

Heterocyclic Derivatives

H2N

O

OH

OMe

O

Leimgruber - Batcho indole synthesis

Oxazole synthesis and the following LiAlH4 - reduction

O

N

OMe

OMe

O

N

Me

OH

R

Me

R

Me

NO2

R

NO2

N

R

NH2

N

NH

R

Indole Derivatives

ROMe

O

NitrationR

OMe

O

NO2Reduction

ROMe

O

NH2

Quinazolins synthesis

Quinazolines

NH

N

O

R

CPhI 2009

Oxidation

CAN : (NH4)2Ce(NO3)6

CAN,NaBrMe CH2Br

TEMPO

OHR H

R

O

TEMPO (1mol%)

NaBr, NaClO aq.

Oxone®

；Potassium Peroxymonosulfate

S

O

S

Oxone®

Safely handling reagents such as CAN, TEMPO,Oxone®

MnO2 and Sulfonium salts (Swern oxid.)

N

CH3

CH3

CH3

CH3

O

OHR HR

OMnO2

MnO2

:

activated type

Swern and related oxidations

DMSO / WSC

ROH

MeMe

RH

O

MeMe

R1

R2

Me

OH

R1

R2

Me

O

(COCl)2

/ DMSO -60℃

CPhI 2009

Glycosylation

Using Trichloroacetimidate as the Glycosylation donor

O

AcO OCCCl3

OAc

OAc

OAc

NH

O

AcO OH

OAc

OAc

OAc

O

AcO OAc

OAc

OAc

OAc

D-Glucose

Cl3

CCNCl3

CCN

AcNHNH2

AcNHNH2Ac2

O, pyridineAc2

O, pyridine

1) BF3

･Et2

O1) BF3

･Et2

O

2) NaOMe2) NaOMe

β-Glucopyranosideβ-Glucopyranoside

Actual ExampleActual Example

AglyconO

O

HOH

HO

OH

OH

CPhI 2009

API and Intermediates for antiviral agents API and Intermediates for antiviral agents

Nucleic Acid Derivatives

IND Products IND Products ：：20072007--20082008Anti HIV project ; nonAnti HIV project ; non--GMP 2Lot(1kg, 15kg)GMP 2Lot(1kg, 15kg)，，GMP 1Lot 1(3kg)GMP 1Lot 1(3kg)

ON

HO

HN

O

OMe

HO OHHO

ON

HO

HN

O

OMe

HOHO

ON

HO

HN

O

OMe

R

ON

HO

HN

O

OMe

HO OHR

ON

HO

HN

O

OMe

HOR

ON

PvO

HN

O

OMe

HO OHOHC

CPhI 2009

High temperature reactions (200-300℃)Precise Distillations for PurificationPhosgene ChemistryFluorinationReductions using DiboraneOxidations using OzonePhoto-reactive Chemistry

Types of reactions that Hamari is unable to perform

CPhI 2009

Thank you very much for your time and attention“Your Partner for the Future”

Hamari Chemicals, Ltd.http://www.hamarichemicals.com

Hall 4, Booth No. 4G01