1,3-Dihydroxypropan-2-one (DHA) synthesis from Glycerol for pharmaceutical applications

Ph.D. Chemical EngineeringA.A. 2014 - III year

TorinoDecember 16th, 2014

Simone Ripandelli

Tutor: Prof. Guido Saracco

Politecnico di Torino - DISAT - Dipartimento di Scienza Applicata e Tecnologia 1

In Bracco is employed in the Iopamidol synthesis:

HO OHNH2

ICl

COClOCOCH3

Acetoluro

CONHCH(CH2OH)2

CONHCH(CH2OH)2COHN

II

IOHIopamidolo

COCl

COClCOHN

II

IOCOCH3Lactoftaluro

IodoftalAminoftal

COOH

COOHH2N

COOH

COOHO2N

COOH

COOHH2NI

I I

Iodoftaluro

COCl

COClH2NI

I I

Iopamidol synthesis

Politecnico di Torino - DISAT - Dipartimento di Scienza Applicata e Tecnologia

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2[2] X-Ray computeed Tomography Contrast Agents; Hrvoje Lusic and Mark W. Grinstaff; Chemical Reviews; 2011

Serinol is used as building block in the

synthesis of:• non-ionic iodinated X-ray contrast agents

• anti-inflammatory and analgesic drugs• cosmetics

HO OHNH2

Serinol

[1] Serinol: small molecule – big impact ; Bjorn Andreeben, Alexander Steinbuchel; AMB express, a Springer Open Journal; 2011


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Serinol: Bracco Imaging process

Serinol process became not cost-effective because of the high cost of the DHA as starting material!

DHA as starting material


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HO OHNH2

HO OHO 1) NH3

2) H2 / Cat

Usually the DHA is produced at an industrial scale by microbial fermentation of glycerol over Gluconobacter Oxydans with high selectivity.

Low productivity and high production cost are remarkable drawbacks.

[3] Production of Gluconobacter oxydans Cells from Low‐cost Culture Medium for Conversion of Glycerol to Dihydroxyacetone; Shenghua Wei, Qingxun Song and Dongzhi Wei; Preparative Biochemistry and Biotechnology; 2007

[4] Production of 1,3-dihydroxyacetone from glycerol by Gluconobacter oxydans; Hu Z.C., Liu Z.Q., Zheng Y.G., Shen Y.C.; 2010

Glycerol Simone Ripandelli

5Politecnico di Torino - DISAT - Dipartimento di Scienza Applicata e Tecnologia

Glycerol is a by-product of biodiesel fuel production (transesterification of seed oils with MeOH). The rapid expansion of the global production of biodiesel has created a major surplus of glycerol. Consumption of this extra glycerol is a necessary requisite for the commercial viability of biodiesel production.

Glycerol has become a low-cost starting material!

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[5] S. Demirel-Gulen, M. Lucas and P. Claus, Catal. Today, 2005, 102–103, 166–172[6] Oxidation of glycerol to biobased chemicals using supported mono- and bi-metallic noble metal catalysts; Ph.D. Thesis; University of Groningen

6Politecnico di Torino - DISAT - Dipartimento di Scienza Applicata e Tecnologia

General reaction pathways from glycerol

• Glycerol: low-cost starting material with high availability

• Oxygen: terminal oxydant with only water as by-product

• Catalyst: showing selectivity for the secondary carbon

Project aim: DHA from glycerol

OOH OH

OHOH OH 1/2 O2 H2O

cat.

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Catalysts Mono-metallic catalysts Au-NPs based on carbon supports

Bi-metallic catalysts Pt-Bi coupled NPs based on carbon supports

Tri-metallic catalyst Au0,6Pt0,4Bi1,0/C (metal nanoparticles)

Organometallic Palladium based catalyst (homogeneous catalyst)


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N

N

H3C

H3C

PdN

N

CH3

CH3

PdO

O

CH

CH

O

O

CH3

CH3

2

2 OTf[7] Elodie Rodrigues, Manuel F.R. Pereira, Juan J. Delgado, Xiaowei Chen, José J.M. Orfao; Cat.

Comm. 2011[8] Selective Oxidation of Glycerol to Dihydroxyacetone over Pt-Bi/C Catalyst: Optimization of

Catalyst and Reaction Conditions Wenbin Hu, Daniel Knight Ind.Eng.Chem.Rev. 2010[9] Aerobic Alcohol oxydation with cationic Palladium Complexes: insights into catalyst design and

decomposition; Nicholas J. Conley, Liezel A. Labios, David M. Pearson, Charles C.L. McCrory and Robert M. Waymouth, May 2007


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Heterogeneous catalyst PtBi (I)Literature : z 70% y 42 % ; 3 wt% Pt – 0,6 wt% Bi

Method : Impregnation and subsequent chemical reduction with NaBH4

Support : Carbon Black, Graphite and Graphite Oxide (Hummers 1958 and its modifications)

Characterization : XRD, XPS, STEM, ICP


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Heterogeneous catalyst PtBi (II)Deposition + Characterization : XPS

PtBiCoupled :157.10 eV &159.00 eV [7-8]

[10] NIST X-Ray Photoelectron Spectroscopy Database

[11] The chemistry of Graphene Oxide; Daniel R.Dreyer, Sungjin Park, Christoper W. Bielawski and Rodney S. Ruoff; The Royal Society of chemistry; 2010


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Heterogeneous catalyst PtBi (III)

[8] Selective Oxidation Of Glycerol to Dihydroxyacetone over Pt-Bi/C catalyst: optimisation of catalyst and reaction conditions; Wenbin Hu, Daniel Knight, Brian Lowry, Arvind Varma; Ind. Eng.Chem.Res. 2010

Glycerol oxydation


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[12] S. Demirel-Gulen, M. Lucas and P. Claus, Catal. Today, 2005, 102–103, 166–172

GC-FID

GC-MS

HPLC-UV

The sample analysis (I) : GC-FID


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- Derivatization with TFAA- Capillary Column: DB 624 – 30m x 0,32

mm x 1,8 m- Constant pressure (11 psig)- Detector FID 240°C

DHA Glycerol

Glyceraldehyde B-hydroxypiruvic Glyceric Acid Tartronic acid

The sample analysis (II) : GC-MS


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Glycerol

DHA

TFAA CF3

GlycerolDHA

Reaction Mixture

References

The sample analysis (III) : HPLC- Derivatization with PFBHA- Column: 250 mm x 4,6 mm Zorbax Eclipse XDB-C8 column- UV detection 263 and 215 nm

DHA Pyruvic Acid Glyceraldehyde


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Oxidations in the laboratory batch reactor


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The oxidation experiments were performed in a 500 ml laboratory batch reactor sited at the Politecnico of

Turin.The O2 is provided by an external

cylinder at 200 bar.

An external digital and an analogic

barometer allow the pressure control

inside the reactor.

The temperature is tuned by an

external jacket and a cooling loop is

used to keep it constant.

A particular caved impeller is used for

the O2 recirculation.


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Heterogeneous catalyst PtBi results (I)

Catalyst Solution Conditions zmax[%]

y DHA[%]

PtBi on GO III

Pt 0,5, Bi 0,65 wt%

T = 60 °CP = 30 bar

pHin-pHfin = 5.5 – 5.0

Reaction Time = 240 min

Water solution 110 ml

Glycerol 0.1 M

Molar Ratio (Gly/cat) = 46.5

33.25 0

Pt on GO V

Pt 7 wt%

T = 60 °CP = 30 bar




Glycerol 0.1 M


21.07 0

[8] Selective Oxidation of Glycerol to Dihydroxiacetone over Pt-Bi/C catalyst: Optimisation of Catalyst and Reaction Conditions; Wenbin Hu, Daniel Knight, Brian Lowry and Arvind Varma; ; Ind. Eng.Chem.Res. 2010


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Heterogeneous catalyst PtBi results (II)

Catalyst Solution Conditions zmax[%]

y DHA[%]

PtBi on Graphite

Pt 0,75, Bi 11,8 wt%

T = 60 °CP = 30 bar




Glycerol 0.1 M


0 0

Pt on GO VI

Pt 3,8 wt%

T = 60 °CP = 30 bar




Glycerol 0.1 M


1.6 0


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Heterogeneous catalyst AuPtBi resultsTri-metallic catalyst Au0,4Pt0,6Bi1,0/C ; glycerol 1 M

Catalyst Solution Conditions zmax y DHA

[mg] [-] [-] [%] [%]

102MR = 7000 H2O

pH = 7P =30 barT = 60°C

29,4 0

100MR = 7000 H2O

pH = 91 eq NaOH

P =30 barT = 60°C

40,7 0

102MR = 7000 H2O

pH = 11 eq HCl

P =30 barT = 60°C

4,2 0

N° Solvent MR Ox. Time z s y

[-] [-] [Gly/cat.] [-] [h] [%] [%] [%]

1 CH3CN:H2O(10:1)

10 O2 4 95 / 69

5 CH3CN:H2O(10:1)

10 air 18 / / 73

2 DMSO 20 air 24 47 80 /

3 CH3CN 20 benzoquinone 24 97 99 /

4 CH3CN:H2O(7:1)

20 benzoquinone 3 97 99 /

Legend :

z: conversions: selctivity Y: yieldMR : Molar Ratio

[13] Selective Catalytic Oxidation of Glycerol to Dihydroxyacetone; Ron M. Painter, David M. Pearson, and Robert M. Waymouth; 2010

Conditionsroom temperature1 atm air [13]

The results in the literature (I) Homogeneous catalyst


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N

N

H3C

H3C

PdN

N

CH3

CH3

PdO

O

CH

CH

O

O

CH3

CH3

2

2 OTf

The results in the literature (II)

[13] Aerobic Alcohol Oxydation with Cationic Palladium Complexes: Insights into Catalyst Design and Decomposition; Nicholas R. Conley, Liezel A. Labios, David M. Pearson, Charles C.L. McCrory and M. Waymouth; American Chemical Society 2007


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Research aims:N° Solven

tMR Ox. Tim

ez s y

[-] [-] [Gly/cat.] [-] [h] [%] [%] [%]

1 CH3CN:H2O

(10:1)

10 O2 4 95 / 69

5 CH3CN:H2O(10:1)

10 air 18 / / 73

2 DMSO 20 air 24 47 80 /3 CH3CN 20 benzoquinon

e24 97 99 /

4 CH3CN:H2O(7:1)

20 benzoquinone

3 97 99 /

Solvent:Avoid solvents as DMSO and ACN

Molar Ratio:Increase the MR of 1 or 2 order of magnitude

Terminal Oxidant:Avoid not environmental friendly ones

(BQ) Time:Reduce the reaction timeYield and selectivity:Maximize DHA yield

The results in the literature (III)



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II

III

IV OTf2

2

N NCH3 CH3

PdN N

C CCH3 CH3

N NCH3 CH3

PdO OO

CH3

OCH3

OTf2

2

N

N

H3C

H3C

PdN

N

CH3

CH3

PdO

O

CH

CH

O

O

CH3

CH3

+ 2 CH3CN

NH2CCH3

OSCF3

OO

N NCH3 CH3

PdO OO

CH3

OCH3

N NCH3 CH3

PdN N

C CCH3 CH3

2

2 OTf2

F CF

FSO

OOH C

CH3

OSCF3

OO

NH2CH3CN

N NCH3 CH3

Pd2+CO

-O CH3 2N N

CH3 CH3Pd

O OO

CH3

OCH3

MW = 208.26 MW = 224.51

MW = 432.76

I PdNc_C

PdNc_A

PdNc_D

A synthetic description for the dimer synthesis

[14 ]


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[14] Interaction of acetonitrile with trifluoromethanesulfonic acid: unexpected formation of a wide variety of structures; George E. Salnikov, Alexander M. Genaev, Vladimir G. Vasiliev and Vyacheslav G. Shubin 2012

The synthesis of PdNc_C (II)

N NCH3 CH3

Pd2+CO

-O CH3 2N N

CH3 CH3Pd

O OO

CH3

OCH3

MW = 208.26 MW = 224.51

MW = 432.76

Molar ratio Neoc./Pd(OAc)2 = 1

Reaction solventsToluene-Dicloromethane

Product isolationPetroleum EtherFiltrationDry under vacuum

YIELD = 87.54 %Politecnico di Torino - DISAT - Dipartimento di Scienza Applicata e Tecnologia

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The synthesis of PdNc_C (III)

Sample Weight Pd amount

Average s

[-] [mg] [%w/w] [-] [-]

A 8.95 20.932 21.7

± 0.6B 8.62 22.082

C 9.44 21.960

Sample Weight Water Amount

Average

[-] [mg] [wt%] [wt%]A 109.2 8.70

7.86B 103.1 7.69C 101.9 7.20

ICP assay = 95.52 %

ICP analysis:Karl-Fischer analysis


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The synthesis of PdNc_A (I)

I F CF

FSO

OOH C

CH3

OSCF3

OO

NH2CH3CNN N

CH3 CH3Pd

O OO

CH3

OCH3

N NCH3 CH3

PdN N

2

2 OTf

CH3C

CCH3


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Molar ratio TfOH/PdNc_C1 = 2,5

Reaction solventsCH3CN anhydrous

Product isolationDiethyl Ether + FiltrationDry under vacuumYIELD = 84.15 %

The synthesis of PdNc_A (II)


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Karl-Fischer analysisSample Weight Water

AmountAverage

[-] [mg] [wt%] [wt%]A 100.6 2.32

2.39B 96.5 2.04C 102.0 2.63

Sample Weight Pd amount

Average s

[-] [mg] [%w/w] [-] [-]

A 17.73 14.334 14.2

± 0.2B 17.60 14.173

C 11.39 13.969

ICP analysis:

1

54 3

2 ICP assay = 96.9 %

The synthesis of PdNc_D (I)


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OTf2

2

N NCH3 CH3

PdN N

C CCH3 CH3

N NCH3 CH3

PdO OO

CH3

OCH3

OTf2

2

N

N

H3C

H3C

PdN

N

CH3

CH3

PdO

O

CH

CH

O

O

CH3

CH3

+ 2 CH3CN

Karl-Fischer analysis Sample Weight Pd amount

Average s

[-] [mg] [%w/w] [-] [-]

A 5.29 17.013 17.3

± 0.8B 4.02 16.729

C 5.48 18.248

ICP analysis: Sample Weight Water

AmountAverage

[-] [mg] [wt%] [wt%]A 44.4 1.87

1.825B 44.1 1.78

NMR

Reagents molar ratio PdNc-A : PdNc-C: 1:1

Reaction Solvent: CH3CN anhydrous

Product Isolation: Diethyl Ether + filtration

The synthesis of PdNc_D (II)


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Yield = 77.5 %

ICP assay = 89.1 %

Matrix-Assisted Laser Desorption/Ionization (MALDI):-High Molecular Weight (> 400-500 g/mol)-Mild Ionization

[15] Chemoselective Pd-Catalyzed Oxidation of Polyols: Synthetic Scope and Mechanistic Studies Kevin Chung, Steven M. Banik, Antonio G. De Crisci, David M. Pearson, Timothy R. Blake, Johan V. Olsson, Andrew J. Ingram, Richard N. Zare, and Robert M. Waymouth

Experimental Strategy


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Catalysts under screening:

To be Investigated:

Nature of the solvent : pure Water, CH3CN:Water (10:1; 1:1)

Molar Ratio between substrate and catalyst (MR= 16,160,1600)

Oxygen pressures: 3, 10 and 30 bar Reaction temperatures: 23°C, 40°C and 60°C

2

2OTfN

N

CH3

CH3

PdO

OPd

N

H3C

N

H3C

O

O

CH

CH

CH3

CH3

N NCH3 CH3

PdN O O

CH3C

30

Monomer active catalyst

Oxygen solubility

A briefly consideration on the glycerol and DHA solubility (90 mg/mL = 1 M) at room temperature

Solution (H2O:CH3CN

)

DHA Glycerol

100:0 Yes Yes75:25 Yes Yes50:50 Yes Yes25:75 Yes (slow) Incomplete1:10 Yes (slow) Incomplete

• Glycerol uncomplete solubility in CH3CN• Sampling in CH3CN:Water (10:1) is not

representative for glycerol during the reaction

No specific study about mass-transfer was made.Anyway the different solubility of O2 into the two solvents (CH3CN and H2O) was evaluated.

The O2 results from 8 to 9 times more soluble in CH3CN than in Water

The gas volume above the liquid works as a O2 provision storage

Considerations


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Activity results: effect of the MR


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Legend :z: conversionMR : Molar Ratio

The conversion level was valuable only at the end of the reactionThe conversion is comparable between MR = 16 and Mr = 1600An higher amount of catalyst guarantees an higher DHA yield (up to 35-40%)

Activity results: effect of the water


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Legend :z: conversionMR : Molar Ratio

The trend of the conversion level was valuable using only water as solventAn higher amount of catalyst guarantees an higher conversionAn higher amount of catalyst guarantees an higher DHA yieldThe maximum yield is no higher than 18 % (MR 16)

Activity results: effect of the solvent


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Legend :RED line : WaterBLUE line : CH3CN:Water

A comparison between the glycerol conversion into different mixturesPure Water and CH3CN:water (10:1)Conversion is comparableThe maximum yield is higher with CH3CN:Water (10:1)

Considerations (I)Summarizing 60 °C - 30 bar

Using CH3CN:Water (10:1 v/v) as solvent

z is independent from the MRy depends on the MR; higher is MR lower is the DHA yield

Using Water as solvent

z and y depend on the MR

Dy between CH3CN:Water and Water ≈ 20%

Similar results were obtained from the experimental campaign at 40°C and 10 bar

Low conversions and yields were obtained at mild conditions (23-65°C; 3 bar)Politecnico di Torino - DISAT - Dipartimento di Scienza Applicata e Tecnologia

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Experimental Results from batch reactor (IV)


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Regeneration Factor:

Ratio between the moles of glycerol

(at zmax) converted and the moles of

catalyst at t = 0

The mechanism proposed



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Dimer results (I)


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2

2OTfN

N

CH3

CH3

PdO

OPd

N

H3C

N

H3C

O

O

CH

CH

CH3

CH3

Monomer Dimer

Conditions Catalystzmax [%]

Monomer Dimer60°C 30 bar; MR=

16CH3CN:Water (10:1)

85,0 91,9

60°C 30 bar; MR= 16

Water

85,2Plateu =170 min

95,91Plateu = 90 min

60°C 30 bar; MR= 160

CH3CN:Water (10:1)

65,9 70,5

Compare Dimer and Monomer

Different behavior Dimer vs. MonomerDependence from the solvent: with CH3CN the yield is higherThe yield with Dimer (MR = 16) is comparable with data from literature.

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Considerations (II)

The results obtained with Dimer z Results obtained were quite similar comparing monomer with dimer in

water as in acetonitrile water mixture 10:1. Y Higher DHA yields were obtained using dimer as catalyst. With the dimer the DHA max. yield reached was around 70% in a mixture acetonitrile water 10:1 which is in accordance with literature results.

Dy between CH3CN:Water and Water ≈ 5 -10% (with monomer was ≈ 20%)

Reaction time was reduced to 2 h at 60°C and 30 bar.Politecnico di Torino - DISAT - Dipartimento di Scienza Applicata e Tecnologia

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2

2OTfN

N

CH3

CH3

PdO

OPd

N

H3C

N

H3C

O

O

CH

CH

CH3

CH3

Summarizing


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Heterogeneous catalysts

Au/C no selectivity to DHA, low conversion

Pt-Bi/GO no selectivity to DHA, conversion comparable with literature

Au-Pt-Bi/C no selectivity to DHA, conversion higher with basic pH

Homogeneous catalysts• Reliable way of synthesis for the monomeric and the dimeric form of the

catalyst with a complete characterization

• The screening on the catalyst activity showed a fundamental role played by

Solvent mixture and Molar ratio to the maximum DHA yield.

Ongoing and future activities


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Homogeneous catalysts

• To develop a kinetic model(s) considering the de-composition of the catalyst

• To support the best catalyst.

• To study the catalyst aging.

• Pt-Bi on GO as Heterogeneous catalysts have found another interesting

catalytic application: the selective oxydation of glucose to D-Saccharic Acid,

used as starting material for the adipic acid synthesis.


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Thank yout for your kind attention …

…and I would like to thank

Dott. Armando Mortillaro (Bracco Imaging)Ph.D. Diego Rozzi (C4T) &My colleagues from DISAT and Chemistry Department of Bracco Imaging

Science

1,3-Dihydroxypropan-2-one (DHA) synthesis from Glycerol for pharmaceutical applications