1

Novel Oxidant NaOCl·5H2O

for Organic Reactions

CPhI worldwide 2017 at Frankfurt

Contents1. Chemical Business of NLM

2. Introduction of NaOCl·5H2O (SHC5)

3. Application for Organic Reactions

4. Introduction of SPI corporation

NaOCl·5H2O（SHC5）Sodium Hypochlorite Pentahydrate

Stand No: 80C40

2

Nippon Light Metal Holdings Co., LTD

(In millions of JPY)

- Establishment : October 1, 2012(First Phase : Nippon Light Metal Co.LTD.,1939)

- Capital : JPY 46,525 (as of January 31, 2017)

- Consolidated Sales : JPY 448,381

- Employees : 13,126 persons(as of March 31, 2017)

- Business :

3

H2

Al

ProductsBauxite

Al

metalAl2O3

Firing Processing

Soda &

Inorganics

Electrolysis

Bayer

processHall-Héroult

process

NaOH

Al(OH)3

NaCl

Hydropower

Cl2

NaOCl

We provide a variety chemicals using hydroelectric power.

NLM’s Chemical Business

AlCl3

HCl

Organochlorine

compounds

4

NLM’s Chemical Business

Soda &

Inorganics

R-CO2H

R-CH3

R-OHR-Cl

Specialty

Chemicals

R-CH2OH

R1-CO-R2

R1-CH(OH)-R2

R-SO2Cl

R-SH

R1-CO2R2

R-CH2Cl

Cl2

NaOH

R-CHCl2

R-CCl3

R-COCl

R-CHO

Hydropower

NaCl

HClH2

Electrolysis

R1-SO-R2

R1-S-R2

R1-SO2-R2

NaOCl

Al(OH)3Al2O3

Multipurpose plant

5

Contents

1. Chemical Business of NLM

2. Introduction of NaOCl·5H2O (SHC5)

3. Application for Organic Reactions

4. Introduction of SPI corporation

Stand No: 80C40

6

Introduction of sodium hypochlorite pentahydrate

NaOCl・5H2O

Crystalline

CAS: 10022-70-5

MITI : (1)-0237

UN 3212, Class5.1

Eco-friendly oxidizing agentThe World’s first industrial production !

7

2NaOH + Cl2 → NaOCｌ + NaCl + H2O

Application ：Oxidizing agent, Disinfectant, Bleach

Sodium Hypochlorite

Bleach

Not stable ⇒ Not user-friendly

Low concentration (～10％) ⇒ Poor volumetric efficiency

Alcohols oxidation Cyanation

Haloform reactionEpoxidation

8

2012 Start research on application to organic synthesis.

2013 NaOCl・5H2O was launched as name of SHC5

Development of SHC5

Succeeded in

industrial scale preparation

（Patent number: JP 4211130）

9

3 merits of SHC5

I. High Concentration (3.5 times higher)

⇒ High volumetric efficiency

Waste water reduction

II. High Stability (1 year below 7℃)

⇒ User-friendly

III. High Purity (Less NaOH (pH 11) )

⇒ Strong oxidizability

10

I. High Concentration

水

NaOCｌ

水

NaOCｌ

水

NaOCｌ

水

NaOCｌ

水

NaOCｌ

水

NaOCｌ

水

NaOCｌ

水

NaOCｌ

SHC5 (Crystalline)

○ High volumetric efficiency○ Waste water reduction

⇒ Higher productivity

Available Chlorine = 12%

Available Chlorine = 42%

H2O

+

impurities

H2O

Conventional

NaOCl Soln.

11

II. High Stability

Stability of SHC5 and conventional aq. NaOCl

aq. NaOCl SHC5

Remaining rate(7℃, 1 year) 83% 99%

User-friendly

12

III. High Purity

aq. NaOCl SHC5

Available Chlorine [%]

12 42

NaOH [%](pH as the aq. solution)

0.8（pH 13）

0.05(pH 11)

Other impurities High ⤴ Low ⤵

Strong oxidizability

13

Comparison among oxidizing agents

Oxidizing agents Disadvantage

Ozone (O3 )Difficult to use

Toxicity

Peroxide, (H2O2, , ) Explosive

Manganates (MnO2, KMnO4) Highly toxic

Swern Oxidation (DMSO + Oxalyl chloride) Bad odor

Hypervalent Iodine ( ) Explosive, Expensive

SHC5 could be a solution

for the problem

14

Contents

1. Chemical Business of NLM

2. Introduction of NaOCl·5H2O (SHC5)

3. Application for Organic Reactions

4. Introduction of SPI corporation

Stand No: 80C40

15

Application for Organic Reactions

All reactions are carried outwithout metal catalysts

SHC5

16

Comparison of SHC5 and aq. NaOClfor alcohols

Strong Oxidizability！

・N

O

17

Ketone or Aldehyde Synthesis

Tetrahedron 2016, 72, 2818.

Broad range of application

18

Without Organic Solvent

Dropwise: 2-octanol

2-Octanol

SHC5 + water (slurry)

TEMPO

NaHSO4H2O

Dropwise: aq. NaOCl

30% aq. NaOCl

(from SHC5)

2-Octanol

TEMPO

NaHSO4H2O

High yield using both methodsSHC5 can be use as slurry or high concentrated solution

Yield：96% Yield：97%

Method A Method B

19

Oxidation of Sulfur compound

Need with metal catalysts

Oxidizing agents : H2O2 or mCPBA

Explosive

20

Selective Oxidation for Sulfoxide

High selectivity without catalyst

21

Selective Oxidation for Sulfone

High activity and wide applicability

22

Customer comments

Annual output: More than 10 mt

We have Positive Customer feedback comments:

>Achieved better productivity

>Easy quality control and process management

23

Summary

SHC5 is three times more volumetric efficiency than

aq. NaOCl, and reduces wastes water.

The accurate mass of SHC5 can be easily measured

by using a balance without titration.

SHC5 can be adjusted to any concentration of the

solution.

SHC5 is strong oxidant and can be applied to various

organic reactions.

SHC5 can replace explosive, expensive or toxic

oxidizing agents such as H2O2, mCPBA, and

PhI(OAc)2.

24

Kambara Chemical works

25

Contents

1. Chemical Business of NLM

2. Introduction of NaOCl·5H2O (SHC5)

3. Application for Organic Reactions

4. Introduction of SPI corporation

Stand No: 80C40

Corporate profile

Corporate Name

Date of Establishment

Summit Pharmaceuticals International Corporation

November 21st, 1949Capital

480 million (100% subsidiary of Sumitomo Corporation)President & CEO

Kenichi Nakamura

Number of Employees

147 (as of April 2017)

Sales

JPY23.8 billion (year ended March 2016)

Location

Tokyo Head officeOsaka officeYokohama Support CenterAPI Laboratory

Description of Business

Import/Export and marketing of pharmaceuticals (including animal drugs), foods, food additives, quasi-drugs, cosmetics, medical devices and the material from which these items are made, bulks and end products.

Distribution of drug discovery support tools including cells / tissues from animals, plants and microorganisms, import and marketing of analytical instruments and biology service for drug discovery.Consulting services regarding pharmaceutical development and new drug licensing.

Value chain for medical & healthcare business

Research Development Manufacturing Marketing & Sales

APIs & Intermediates

FormulationRegulatory Affair /

Quality Control

Bioresource Materials, Drug Discovery

Instruments Partnering Support

Manufacturing Support Business

Global presence

Customers Supplier /

Summit Pharmaceuticals International

Distribution /Summit Pharmaceuticals

Europe

APIs, Intermediates, Excipients

56 Drum/VAN =

8,400 kg/VAN（Reefer 20 FT)

10 kg×15

・10 kg/PE bag

・PE: Thickness 0.1mm

・150 kg/Drum（10 kg×15）

Refrigerated Transport System

150

kg/Dram

30

At Stand No: 80C40

See you

Summit Pharmaceuticals Europe Ltd.

TEL: +39-0269551.210

E-mail: massimiliano.paciolla@sumitomocorp.com

Website: http://summitpharmaeurope.com/

■For more Information

We are at our booth on 24th 15:00-16:00

All Inquiries welcome

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Supporting Information

32

Nippon Light Metal Holdings Co., LTD

33

Solubility of SHC5

20.0

25.0

30.0

35.0

40.0

45.0

0.0 5.0 10.0 15.0 20.0 25.0

溶解

度[ｇ

/100ｇ-H

2O]

有効

塩素

[wt%

]

温度 [℃]

138

176

229

307

432

670

Availa

ble

chlo

rine [%

]

Temp. [℃]

So

lub

ility

[g

/10

0g

(H2O

)]

34

Ava

ilab

le c

hlo

rin

e [%

]A

va

ilab

le c

hlo

rin

e [%

]

Days Available chlorine

Solid state stability of SHC5

35

Solution state stability of SHC5

0

5

10

15

20

0 10 20 30

7℃

20℃

30℃

20% NaOCl溶液

経過日数 [日]

有効

塩素

濃度

[wt%

]

17

18

19

20

0 1 2

7℃

20℃

30℃

経過日数 [日]

有効

塩素

濃度

[wt%

]

0～2日の拡大図

分解<1%

0

5

10

15

20

25

30

0 10 20 30

7℃

20℃

30℃

30% NaOCl溶液

経過日数 [日]

有効

塩素

濃度

[wt%

]

27

28

29

30

0 1 2

7℃

20℃

30℃

経過日数 [日]

有効

塩素

濃度

[wt%

]

0～2日の拡大図

分解2.6%

分解5.9%

20％ solution 30％ solutionA

va

ilab

le c

hlo

rin

e [%

]

Ava

ilab

le c

hlo

rin

e [%

]

Ava

ilab

le c

hlo

rin

e [%

]

Ava

ilab

le c

hlo

rin

e [%

]

Days Days

Decomposition<1%

Decomposition

<6%

Decomposition

<3%

DaysDays

Enlarged figure of 2 days Enlarged figure of 2 days

36

Safety assessment

Explosive tests based on Japanese Industrial Standards

・Drop Hammer Test

⇒ Negative・Friction Test

⇒ Negative

DSC measurement

・SHC5 react with stainless steel

・SHC5 does not react with glass, titanium and resins

No explosive material

37

Safety assessment

DSC measurement

・ Stainless steel reacts with SHC5.

・ Titanium, glass and resins can use

equipments below ambient temperature.

38

NaOCl (1.2 eq.)

Bu4NHSO4 (0.05 eq.)CH2Cl2, 5℃

R2R1

OH

R2R1

O

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8 9

Ket

on

e(%

)

Time (h)

2-Octanone

NaOCl・5H2O crystals(42%)

13% commercial NaOClaqL-Menthone

NaOCl・5H2O crystals(42%)

13% commercial NaOClaq

Oxidation with NaOCl without TEMPO

39

Effect of hydrogen sulfate

as acid catalyst

40

Application for carboxylic acid synthesis

41

Typical examples for glycol cleavageReview: Synthesis 2014, 46, 3283.

NaIO4

Pb(OAc)4

Pb(OAc)4 is highly toxic×

× Trans-isomer is resisted

42

Glycol cleavage

43

Mechanism of cleavage

Trans-isomer

Cis-isomer

44

Sulfonyl chloride synthesis

Yield (Time)

45

Sulfonyl bromide synthesis

Yield (Time)

46

Acetonitrile/water ratio

47

The effect of pH

48

Solvent effect for sulfone synthesis

49

Bromination at aromatic ring

Entry SubstrateSHC5

X eq.

NaBr

Y eq.Time Product

1 2 2.2 25 h

2 6.5 823 h

8 min

3 1.5 219 h

55 min

4 6.5 8 23 h

5 6.5 84 h

35 min

50

Halo-lactonization

Chloro-lactonization

Iodo-lactonization

OH

CH3

O NaOCl・5H2O ( 2 eq.)

AcOH ( 2 eq. )

EtOAc : H2O = 3 : 4

70 ℃ 1 h 18 min

31 %

OCl

O

CH3H

( cis : trans = 57 :43 )

OH

ONaOCl・5H2O ( 2 eq.)

NaI ( 4 eq. )

AcOH ( 2 eq. )

EtOAc : H2O = 3 : 4

r.t, 18 h 30 min97 %

OI

O

H

51

Davis oxaziridine

F. A. Davis, A. C. Sheppard, Tetrahedron, 45, 5703 (1989).

Davis, F. A.; Vishwakarma, L. C.; Billmers, J. G.; Finn, J. J. Org. Chem. 1984, 49, 3241.

Davis’ Oxaziridine

52

Succeeded in Oxaziridine Synthesis by SHC5

Usually, oxaziridine is prepared by ｍCPBA or Oxone®

⇒There is no example using NaOCl as an oxidant

Oxaziridine Synthesis by SHC5

53