MTHP 4-Methyltetrahydropyran

A novel cyclic ether solvent

2019 Nov

Contents

General information

Property and safety data

Stability

Solubility

Dehydration

Reaction examples

Process improvement examples

Appendix

Characteristics & Benefits

1. Separation from water

- Simplifies your manufacturing process.

- Reduces wastewater and emissions.

2. High Solvency Power

- Similar solubility to THF for organic compounds,

inorganic salts, resins, polar materials.

3. High boiling point

- Reaction at higher temperature than other ethers.

4. Stability

- Stable to acids, bases and Lewis acids.

5. Stable to oxidation

- Easy to store and recycle

THF/water MTHP/water

MTHP has many properties: similar solubility to THF, higher boiling point,

hydrophobicity, and stability against acid conditions or air.

Reaction Solvent

Extraction

Polymerization Coating

Applications

Product Information

Basic information

• Chemical Name : 4-Methyltetrahydropyran

• Molecular Weight : 100.16 (C6H12O)

• CAS No. : 4717-96-8

• EINECS No. : 225-207-5

• Package : Drum (160kg), Iso container

Specifications

• Purity (%GC) : > 99.0

• Water (ppm) : < 200

• Additive : BHT 20ppm

Physical Properties

bp

[℃]

mp

[℃]

Specific

Gravity

(20℃)

Viscosity

[cP]

Flash

Point

[℃]

Solubility

in water

[wt%]

Water

solubility

[wt%]

Azeotropic

Point [℃]

(H2O ratio)

SP value*

[(cal/cm3)^

0.5]

MTHP 105 - 92 0.86 0.78 6.5 1.5 1.4 84.5

(19.0wt%) 9.0

THF 65 -109 0.89 0.55 -15 ∞ ∞ 64

(6.0wt%) 9.5

2MeTHF 80 -136 0.85 0.60 -11 14 4.4 71

(11wt%) 8.9

Et2O 34.6 0.70 0.71 -45 6.5 1.2 34.2

(1.3wt%) 7.6

CPME 106 -140 0.86 0.55 -1 1.1 0.3 83

(16%) 8.4

1,4-

Dioxane 101 12 1.04 1.30 11 ∞ ∞

87.8

(18.4wt%) 10.0

*Calculated according to “Hansen solubility parameters a user’s handbook 2nd edition, CRC Press, ISBN: 0-8493-7248-8”

Safety Data (1/2)

MTHP THF 1) 2MTHF 1)

LD50

(Oral) 1000-2000 mg/kg 1650 mg/kg 300-2000 mg/kg

Serious eye

damage/irritation Irritation Damage Damage

Skin corrosion /

irritation Irritation Mild irritation Mild irritation

Ames test Negative Negative Negative

Chromosome

aberration test

(in vitro)

Negative 2) Negative 3) Negative 4)

Mutation No data Negative Negative

Repeated-dose

toxicity

NOEL

=120 mg/kg/day 5)

NOAEL

=111.3 mg/kg/day 5)

NOAEL

=26 mg/kg/day 6)

1) Cited by ECHA’s homepage

2) Species : Chinese Hamster Lung cells

3) Species : Chinese Hamster Ovary cells

4) Species : lymphocytes; peripheral human

5) 28 days oral toxicity study in rats

6) three-month oral toxicity study in rats

Safety Data (2/2)

MTHP THF 2MTHF

Biodegradability Not readily

Degradable Degradable

Not readily

Degradable

Acute toxicity

to fish

LC50 (96hr)

> 110 mg/L

LC50 (96hr)

= 2160 mg/L

EC50 (96hr)

>100 mg/L

Acute toxicity

to daphnia

EC50 (48hr)

> 100 mg/L 3485 mg/L > 139 mg/L

Freshwater alga and

cyanobacteria,

growth inhibition test

EC50 (72hr)

> 100 mg/L

EC0 (8day)

= 225 mg/L

EC50 (72hr)

> 104 mg/L

Stability to Acid / Base

Acidic condition

20%HCl aq./Solvent = 1/1(wt), 50oC Basic condition

20%NaOH aq./Solvent = 1/1(wt), 50oC

MTHP can be used under severe conditions.

e.g.) Esterification, Acetalization, Cationic polymerization,

LAH reduction, Esterification with acid chloride etc…

100%

98%

96%

94%

92%

90% 20h 40h 60h 80h 100h

Puri

ty (

%)

100%

99.8%

99.6%

99.4%

99.2%

99.0% 20h 40h 60h 80h 100h

Puri

ty (

%)

Time(hr) Time(hr)

Stability to Lewis Acid (AlCl3)

AlCl3/Solvent=2/10 (wt), 60℃

Stability of Alkyl Lithium

Residual rate of n-butyl lithium in each solvent.

<Test conditions>

- 1.6M, n-BuLi in hexane 30ml

- Ether 30ml

- Temperature 50oC

Rate constant and half life period

k1

Half life

period

MTHP 0.27 2.4 hr

THF 4.91 0.1 hr

2MTHF 0.69 0.8 hr

CPME 0.13 5.6 hr

Stability to Autoxidation

Peroxide formation of ether solvents

<Test conditions>

- Under air at 25oC, without stabilizer.

- POV is measured by Iodometry method.

Stable to oxidation

Saturated concentration：23 wt % (20oC)

HCl gas can be solved at high concentration. The stability of the solution is good.

Stability test

<Method>

Each of 5wt% HCl solution

was prepared and stored

under N2. The residual

rate and new generated

products were analyzed

by GC.

Solvent Temp. Residual

rate （3days）

New generated product

Number Main product GC%

MTHP 20℃ 99.98% 4 － －

60℃ 99.99% 11 － －

EtOH 20℃ 96.28% 18

Diethyl acetal 3.35

EtCl 0.05

Diethyl ether 0.01

AcOEt 20℃ 99.88% 8

EtOH 0.05

AcOH 0.04

EtCl 0.00

Dioxane 20℃ 99.99% 11 － －

Solubility and stability of HCl gas in MTHP

<Method>

HCl gas was blown into MTHP for 1h,

and measured by titration.

Solubility of Inorganic Salts

<Test Condition>

- 10 mL of Solvents

- 22℃

- Tested in house

0

10

20

30

40

tBuOK LiBr ZnCl2 ZnBr2

MTHP

THF

2MeTHF

Toluene

2.3% 2.2%

<0.1%

26%

>40%

21%

15% 15%

26%

<0.1%

>40% >40%

<0.1% <0.1%

>40%

Solu

bilit

y (

wt%

, 22℃

)

Solubility of Resins

Resin MTHP THF 2MTHF

ABS ○ ○ ○

Acrylic resin ○ ○ ○

Polystyrene ○ ○ ○

Vinyl chloride (PVC) ○ △ ○

Polycarbonate (PC) △ △ ○

Fluoro rubber △ △ △

SBR △ △ △

Polyurethane (PU) △ △ △

Butyl rubber △ × ×

Nylon-6 × × ×

Phenol resin × × ×

Polypropylene (PP) × × ×

HDPE × × ×

LDPE × × ×

Teflon × × ×

Test panel of resin was dipped into each solvent at 50℃ for 7days.

After being dipped, size was measured and increasing rate was calculated.

○：dissolved more than 100%, △：from 30% to 100%, ×：less than 30%

391

162

96

65 34 25 38

0

100

200

300

400

500

0% 20% 40% 60% 80% 100%

Mois

ture

conte

nt

(ppm

)

Accumulated distillate rate*

Moisture content in distillation fraction

<Method>

MTHP 2350g (water 1,49%), 20 plates, reflux ratio 5, at normal pressure

Total distillate weight

Starting weight

×100 *

Dehydration by distillation

Drying with Molecular Sieves

200

22 14 0

50

100

150

200

250

0 10 20 30 40 50

Mois

ture

conte

nt

(ppm

)

Time (hr)

Moisture content

<Method>

Molecular sieve 4A (MS4A) was heated (microwave) for 1min and vacuumed for 30 min.

MS4A was added (10 wt%), and the solution was stirred and stored.

Grignard reaction

Organometallic reaction

Dehydration condensation：esterification, acetalization

Wittig reaction

Reduction reaction

Oxidation reaction

Suzuki-Miyaura coupling

Olefin metathesis

Halogenation, Dehalogenation

Michael addition

Protecting group

Reaction Examples

Grignard reagent Products

X Solvent Initiate

(℃)

Temp. for RX

drop (℃)

Yield

(%)

Adduct

(%)

Homo coupling

(%)

Reductant

(%)

Br MTHP 50 50 54 35 3.1 23

0 72 66 15.8 16

Cl MTHP 90

60 94 91 0.5 6

0 N.R. － － －

THF 66 － N.R. － － －

Homo coupling and reductant were restrained by using alkyl chloride.

Grignard reagent was not obtained in the THF case.

Alkyl Grignard (aromatic aldehyde)

Grignard reagent Products

X Solvent Initiate

(℃)

Temp. for RX

drop (℃)

Yield

(%)

Adduct

(%)

Homo coupling

(%)

H abstraction

(%) *

Br MTHP 50 0 72 43(60) 16.1 20.6(28.6)

Cl MTHP 90 60 94 60 (64) 0.4 20.7 (22.0)

THF 66 － N.R. － － －

Homo coupling was restrained by using alkyl chloride.

Grignard reagent was not obtained in the THF case.

＊ Yield in () is based on Grignard reagent.

Alkyl Grignard (aromatic ketone)

Grignard reagent Products

X Solvent Initiate

(℃)

Temp. for RX

drop (℃)

Yield

(%)

Adduct

(%)

Homo coupling

(%)

Br

MTHP 30 0 66 66 13

THF 30 0 61 42 34

Cl MTHP 30 30 68 59 3

Homo coupling was restrained by using MTHP.

Benzylic Grignard

Homo coupling was restrained by using MTHP & THF.

Grignard reagent Products

X Solvent Initiate

(℃)

Temp. for RX

drop (℃)

Yield

(%)

Adduct

(%)

Homo coupling

(%)

Br

MTHP 90 60 93 91 0.9

CPME 80 60 79 78 5.0

THF 60 60 >95 95* N.D.

Cl MTHP 105 － N.R. － －

* After extraction with AcOEt

Phenyl Grignard

Grignard reaction

Kobayashi, S. et al;

Chem. Asian J. 2019, 14 (21), 3921–3937.

Grignard reaction

Kobayashi, S. et al;

Chem. Asian J. 2019, 14 (21), 3921–3937.

< Sonogashira-hagiwara cross coupling >

< Radical addition >

<Michael addition (organocopper reagent)>

Organometallic reaction

Kobayashi, S. et al;

Chem. Asian J. 2019, 14 (21), 3921–3937.

<Esterification>

Impurities by hydrolysis was not detected, and could be recovered high purity of MTHP.

<Acetalization>

Yield (%) Impurities by hydrolysis Purity of recovery MTHP

97 Not detected ＞99.9%

Dehydration condensation azeotrope

oC composition

MTHP 85 81/19(H2O)

Toluene 85 80/20(H2O)

Yield (%) Impurities by hydrolysis Purity of recovery MTHP

99 Not detected ＞99.9%

<trans-type Wittig reaction with triethylamine and MgBr2>

<trans-type Wittig reaction in solid-liquid phase>

<cis-type Wittig reaction with unstable ylide>

Wittig reaction

Solvent Yield (%) trans/cis remark

MTHP 91 100/0 －

MeOH 88 100/0 R:Et/Me=3/97

Solvent Yield (%) trans/cis remark

MTHP 60 100/0 －

THF 63 100/0 Extracting solvent needed

CPME 24 100/0 Low solvency power to MgBr2

In the case of MTHP, good yield and no possibility of ester exchange

Wittig reaction (trans-type)

Solvent Yield (%) trans/cis

MTHP 83 3.4/96.6

THF 85 3.2/96.8

CPME 86 3.5/96.5

Wittig reaction (cis-type)

MTHP THF

30 min. after 1N-HCl added

Solvent Yield (%) remark

MTHP 95 －

THF 88 Yield check after extraction

with AcOEt

Reduction reaction

separable

High oxidation rate

Solvent carboxylic (%) aldehyde (%) alcohol (%) remark

MTHP 89 8.5 0.9 －

CPME 64 15.0 13.0 Low conversion

CH2Cl2 75 0.9 0.6 Low selectivity

Oxidation reaction

08.11.2019

Suzuki-Miyaura coupling

R MTHP CPME THF

Me reaction time 5h 7h 11h

Yield 93% 89% 91%

OMe reaction time 3h 5h 12h

Yield 99% 68% 96%

CO2Me reaction time 3h 5h 15h

Yield 92% 83% 88%

Solvent comparison at each substituent

In the case of MTHP, the reaction time was shorter and the yield was higher.

( CPME: low catalyst solubility, THF: low reflux temperature)

08.11.2019

Olefin metathesis

Raw material containing ester group

Raw material containing silylether group

Solv. Temp(℃） Time(h) Yield(%) Conv.(%) Sel(%)

CH2Cl2 40 24 97 100 97

MTHP 40 48 61 63 97

70 42 96 97 99

100 24 75 100 75

Solv. Temp(℃） Time(h) Yield(%) Conv.(%) Sel(%)

CH2Cl2 40 24 99 100 99

MTHP 40 48 80 87 92

70 24 87 91 96

70 48 95 100 95

The reaction proceeded efficiently under 70oC

08.11.2019

Halogenation

Solv. Temp(℃) Time(h) Yield(%) Conv.(%) Sel(%)

CH2Cl2 40 6 48.7 49.7 98.0

↑ 24 92.6 93.6 98.0

MTHP

40 6 80.1 80.7 99.3

↑ 12 96.8 100 96.8

70 2 95.5 100 95.5

①Chlorination

The reactivity was improved compared with ethylene chloride.

Solv. Temp(℃) Time(h) Yield(%) Conv.(%) Sel(%)

CH2Cl2 25 3 87.7 90.6 96.8

MTHP 25 1 94.6 98.6 95.9

②Bromination

08.11.2019

Dehalogenation

Solv. Temp(℃) Time(h) Conv.(%) Sel(%) Yield(%) OH ether

tBuOH 83 2 86.8 30.8 26.7 24.3 17.7

DMF 100 2 100 87.9 87.9 0 12.3

MTHP 100 2 100 90.0 90.0 0 9.9

CPME 100 2 83.3 82.8 69.0 0 10.5

Solv. Temp(℃) Time(h) Conv.(%) Sel(%) Yield(%) OH ether

tBuOH 83 7 31.4 44.9 14.1 0 14.7

DMF 100 7 100 85.3 87.9 0 9.5

MTHP 100 7 96 85.1 81.8 0 11.4

CPME 100 7 32.4 86.1 27.9 0 3.5

①Debromination

②Dechlorination

08.11.2019

Michael addition

Solv. Temp(℃) Time(h) Yield(%) Conv.(%) Sel(%)

Toluene

25 22 59.4 60.2 98.7

70 3 60.9 69.6 87.5

THF

25 3 24.1 28.7 84.0

↑ 22 84.3 86.3 97.7

MTHP

25 3 - 56.8 -

↑ 22 93.6 95.5 98.0

70 3 90.0 94.3 95.4

Reactivity and selectivity were improved compared with Toluene and THF.

08.11.2019

Protecting group

Hydroxyl group（benzyl group）

Hydroxyl group （silyl group）

BnX Temp(℃) Time(h) Yield(%)

BnCl 100 24 95.8

BnBr 100 2 95.5

Amino group（tert-butoxycarbonyl group）

Higher yield and solvent recovery due to less loss in the aqueous layer

Solvent Loss to aqua

layer-1

Loss to aqua

layer-2 Yield

Solvent

recovery

MTHP product 2%

solvent 2%

product 5%

solvent 2% 82% MTHP 85%

THF product 15%

solvent 35%

product 5%

solvent 3% 68%

THF 60%

AcOEt 87%

No solvent

substitution

Process improvement (eg: LAH reduction)

1) Grignard reaction 2) Oxidation 3) Cyclization (azeotropic hydration)

Grignard reaction Oxidation Cyclization TTL

Reaction

Solvent

Extracting

Solvent

Yield

(%)

Reaction/

Extracting

Yield

(%)

Reaction/

Extracting

Yield

(%)

Yield

(%)

MTHP MTHP 99 MTHP 85 Lactone only

MTHP 93 92

Process improvement (Solvent rationalization)

08.11.2019

Apply to the process for the intermediate of existing drug

1) Acid chlorination 2) Esterification 3) Amination 4) Reduction

１） ２） ３） ４） total

Yield(%) Yield(%) Yield(%) Yield(%) Yield(%)

Literature* 99 97 92 76 66.3

MTHP 100 93 85 85 67.2

* J. Med. Chem. 2017, 60 (15), 6480

(Antifungal)

MTHP

✔ Separation from water

✔ High boiling point

✔ High solvency power

✔ High stability

MTHP contributes to various reactions, improvement of your manufacturing

processes, and reduces environmental impacts.

Appendix

Physiochemical properties 1/2

Physical State Liquid

Color Colorless, Clear

Melting Point - 92 oC

Boiling Point 105 oC

Flash Point 6.5 oC

Relative Density 0.857 g/cm3

Vapor Pressure 60 torr /39 oC

Solubility Water : 1.5g/100g THF : >= 500g/L

Acetone : >= 500g/L DMSO : >= 500g/L

Partition coefficient Log Pow = 1.9 (N-Octanol / water)

Auto-ignition Temperature 222 oC

Viscosity 0.78 mPa･s (20 oC

Physiochemical properties 2/2

Calorific capacity 1820 J kg-1 K-1（25 oC）

Vapor density 3.01 kg m-3 （105 oC）

Explosibility range 1.1% ~ 9.9% (50 oC)

Relative dielectric constant 4.8 (23 oC)

Surface tension 28.2 ×10-3 N/m (20oC)

Dipole moment 1.864 debye (Calculated Value (MOPAC MM2-PM5))

Hildebrand parameter 18.33 (MPa)1/2

Hansen parameters δ (dispersion) 16.87 (MPa)1/2

δ (polarity) 4.02 (MPa)1/2

δ (hydrogen bonding) 5.94 (MPa)1/2

bp

[℃]

mp

[℃]

Specific

Gravity

(20℃)

Viscosity

[cP]

Flash

Point

[℃]

Solubility

in water

[wt%]

Water

solubility

[wt%]

Azeotropic

Point [℃]

(H2O ratio)

SP value*

[(cal/cm3)^

0.5]

MTHP 105 - 92 0.86 0.78 6.5 1.5 1.4 85

(19wt%) 9.0

Toluene 111 - 95 0.87 0.59 4.0 0.1 85

(20wt%)

CH2Cl2 40 - 97 1.33 0.43 - 0.0 38

(2wt%)

Acetone 56 - 94 0.79 0.32 - 21 ∞ ∞ -

AcOEt 77 - 84 0.90 0.43 - 4 8.3 70

(8wt%)

Physical Properties

Regulation Status

Government Inventory list Status No.

Existing and New Chemical Substances (ENCS) Present -

Industrial Safety and Health Law Substances

(ISHL)

Present

8-(4)-1740

Government Inventory list Status No.

European Inventory of Existing Commercial

Chemical Substances (EINECS)

Present 225-207-5

Regulation (EC) No 1907/2006 (REACH) Registered -

Japan

Europe

Registrant : Kuraray Europe GmbH (Importer)

Tonnage Band : 10-100 MT

Regulation Status

Government Inventory list Status

United States - Section 8(b) Inventory (TSCA) Not listed

China - Inventory of Existing Chemical Substances (IECSC) Applying

Canada - Domestic Substances List (DSL) Not listed

Korea - Existing Chemicals Inventory (KECI/KECL) Not listed

Taiwan - Taiwan Chemical Substance Inventory (TCSI) Not listed

New Zealand - Inventory of Chemicals (NZIoC) Not listed

Philippines - Inventory of Chemicals and Chemical

Substances (PICCS)

Not listed

Australia - Inventory of Chemical Substances (AICS) Not listed

Thailand – Existing chemicals Inventory Applying

Other Countries

Toxicity Study

Test Name Results GLP

Acute toxicity(oral) LD50=1000-2000mg/kg/day (rat)

Acute toxicity(dermal) No data available

Skin corrosion/irritation (in vivo) No data available

Skin corrosion/iirritation (in vitro) In progress ○

Eye damage/irritation (in vivo) No data available

Eye damage/irritation (in vitro) In progress ○

Skin sensitization No data available

A bacterial reverse mutation test Negative ○

Chromosome aberration test in

Chinese Hamster Cells (in vitro)

Negative

○

Repeated dose oral toxicity 28day NOEL =120mg/kg/day (Rats) ○

Reproductive screening test 28day No data available

Eco-toxicity study

Test Name Results GLP

Acute toxicity (fish) LC50 (96h) > 110 mg/l ○

Acute Immobilisation Test (Daphnia sp.) EC50 (48h) > 100 mg/l ○

Growth Inhibition Test (Green Algae) EC50 (72h )> 100 mg/l ○

Biodegradation study Not biodegraded

(Biodegradation by BOD :

2%)

○

Activated sludge respiration inhibition

test

No data available