Company Presentation 2019 - CPhI Online Technical Presentation Jan...•In-house Halex conversion of chlorinated intermediate to fluorinated intermediate. Case study: Back integration

Company Presentation 2019

NAVIN FLUORINE INTERNATIONAL LIMITED

Refrigerant Gases Inorganic Fluorides Specialty Chemicals CRAMS

NFIL At A Glance

R 22,R 134 etc

HF, HF AdductsKF, ABF, NaF

etc

Fluro-containing Pharma and AgriIntermediates

BF3 and its adducts

Custom Services from mg to multi

ton-level.

From chemical structure to process

Technology transferSafety assessment

Equipment engineering

Impurity identificationImpurity profiling

Evaluation of bulk costRaw material availability

Feasibility assessmentScalability assessment

Process streamliningSpecification setting

R&D and manufacturing: Runcorn, UK

• 45 Fume hoods across 6 laboratories.

• High pressure chemistry facility includingfluorination, carbonylation, and hydrogenation.

• Vessel size up to 20 L (glass & stainless steel).

• Analytical capabilities include NMR (300 MHz), FT-IR, HPLC, GC, and titrimetry (including KF).

• Production of quantities from grams up to several kilograms.

• Various synthetic laboratories with 2,500 m2 laboratory space.

• Dedicated area with 2 x 5 L and 2 x 25 L autoclaves.

• In-house calorimetry capabilities (HEL Phi-Tec I calorimeter).

• Analytical development laboratory including NMR, FT-IR, UV-VIS, GC, GC-MS, HS-GC, HPLC, HPLC-MS, UPLC, titrimetry, and coulometric KF.

• R&D facilities on same site and in proximity to manufacturing plants.

R&D operations: Dewas, India

• Pilot plant with reactors from 50 L to 500 L.

• Glass-lined, stainless steel 316, Hastelloy C-276, and Inconel reactors.

• Total reactor capacity of 10 kL.

• Stainless steel 316 fluorination and hydrogenation autoclaves from 100 L to 650 L - pressures up to 40 bar - with work-up capacity up to 2,000 L.

• Total autoclave capacity of 1,150 L.

• Multiple solids isolation and drying capabilities.

• Distillation section and separate liquids packaging.

GMP pilot plant: Dewas, India

• Manufacturing plant with reactors from 500 L to 7,000 L.

• Glass-lined, stainless steel 316 L, and Hastelloy C-276 reactors.

• Total capacity is 50 kL.

• Stainless steel fluorination and hydrogenation autoclaves from 1,000 L to 2,000 L - pressures up to 40 bar - with work-up capacity up to 3,000 L.

• Total autoclave capacity of 4,000 L.

• Multiple solids isolation and drying capabilities.

GMP production plant: Dewas, India

• Board approval for significant expansion of current GMP facility in Dewas given February 2018.

• Multi-tonne, multi-purpose plant, cGMP and statutory requirement compliant, scheduled for completion in 2019.

• Reactor capacity up to 10,000 L with maximum operating pressure of 100 bar.

• New plant will have total working capacity of approximately 100 KL.

• Bank of 6 to 8 1,000-1,500 L fluorination reactors –pressure up to 40 bar.

• Set up of safety laboratory for evaluation of process safety and powder properties.

• Introduction of kilogram laboratory.

Expansion plans: Dewas, India

• Chromatographic capabilities include GC, GC-MS, HS-GC, HPLC-MS, and UPLC.

• Spectrometric techniques comprise NMR (300 MHz), UV-VIS, FT-IR.

• Wet chemistry capabilities.

• Coulometric KF capabilities

• Muffle furnace.

• Microbiology laboratory.

Quality control: Dewas, India

Scalability of nucleophilic fluorination methods

Fluorination type MethodScale-up at

NavinMain concern

Deoxofluorination Sulfur tetrafluoride Yes

Deoxofluorination XtalFluor(-E or –M) Yes

Deoxofluorination DAST or Deoxo-Fluor No Thermal stability

Deoxofluorination Phenofluor NoAvailability and

price

Halex KF Yes

Halex CsF Possible Price

Halex Bu4F (anhydrous) Possible Price

Balz-Schiemann NaNO2, HBF4 Possible Safety

Balz-Schiemann tert-butylONO, HF-pyridine Yes

Fluorination type MethodScale-up at

NavinMain concern

Fluorination Fluorine No Safety

Fluorination Trifluoromethyl hypofluorite No Safety

Fluorination Acetyl hypofluorite No Safety

Fluorination Perchloryl fluoride No Safety

Fluorination Xenon difluoride PossiblePrice and

availability

Fluorination NFSI Yes

Fluorination Selectfluor Yes

Fluorination N-Fluoropyridinium sulfate Yes

Scalability of electrophilic fluorination methods

Scalability of trifluoromethylation methods and building block approach

Fluorination type MethodScale-up

at NavinMain concern

Trifluoromethylation Trifluoroacetic acid derivatives Yes

Trifluoromethylation MFDA Yes

Trifluoromethylation TMSCF3/TESCF3 Yes

Trifluoromethylation Umemoto reagents No Availability and price

Trifluoromethylation Togni reagents No Safety

Trifluoromethylation Shibata reagents No Availability and price

Trifluoromethylation Trifluoromethylator™ No Availability and price

TrifluoromethylationPotassium trimethoxy-(trifluoromethyl)borate

No Availability and price

Difluoromethylation TFDA/MFDA Yes

Difluoromethylation (Difluoromethyl)trimethylsilane Yes

Difluoromethylation Difluoromethyl triflate Yes

Building block Various Yes

Non-fluorination chemistry

Case study: Back integration of fluorinated building block

Development of a process from cheap commodity was desired to strengthen supply chain for key starting material, reduce exposure to China, and bring fluorination in house.

Seven different routes using starting materials available in bulk were identified

5 steps

KF, sulfolane

PTC,

• One route was identified as the most cost-effective option.

• Process optimisation was performed in-house.

• Technology transfer of process to established partner for toll

manufacturing of chlorinated intermediate.

• In-house Halex conversion of chlorinated intermediate to fluorinated

intermediate.

Case study: Back integration of fluorinated building block

End 2015September

2016Second

half 2016December

2016January

2018

Process technology transfer from customer.

Delivery of 150 kg TMD from purchased TFB.

Delivery of 3 MT TMD from purchased TFB.

Six month programme for route scouting, optimisation, PR&D,and piloting for TFB.

Delivery of 8 MT TMD from split supply: 2.5 MT TFB purchased from China and 3.8 MT locally produced. Toll manufacturer converted 7 MT 1,3,5-trichlorobenzene to 7 MT 2,4,6-trichlorobenzonitrile, which was converted in-house to 3.8 MT TFB.

Case study: Back integration of fluorinated building block

• TCC is a Navin in-house product.

• Fluorination step involves deoxofluorination with SF4.

• Downstream chemistry involves non-fluorination chemistry (reduction, FGI, Mitsunobu coupling, and deprotection)

• Heterocyclic building block not available on bulk and (two-step) process developed from scratch with approx. 1 MT production in 2017.

3 steps

SF4, HF, CH2Cl2

8 steps

Case study: Deoxofluorination downstream chemistry

Mid 2015

Early 2017

First half 2017

First half 2017

2018

Downstream chemistry

transferred to manufacturing

site with development

work, 1 kg demonstration batch, and 5 kg

piloting campaign completed in 4

months.

Three-step fluorinated

building block already

transferred to manufacturing site for large-

scale production

(>100 kg batches).

First bulk campaign

furnishing 64 kg final material

completed in 4 months with

maximum 24 kg batch size for

TPA.

Follow-up campaign of 225 kg final

material with 75 kg batch size for TPA.

Manufacturing campaign of

1.2 MT TPA in progress.

Case study: Deoxofluorination downstream chemistry

Delivery of 55 kg late-stage intermediate

Existing process comprised six separate stages

Chemistry involved non-fluorination chemistry

Dilute bottleneck step

Diificult separation of regioisomeric mixture

Case study: We also do non-fluorinated chemistry!

Case study: We also do non-fluorinated chemistry!

tert-Butyl chloroacetateKO-tert-Bu, DMF

Process improvements

• Simplified work-up procedure.

• Elimination of inefficient slurry procedure.

• Introduction of more efficient slurry procedure in next stage.

Overall yield improvement from 6% to 11%

Piloting batch (1 kg) delivered after development work

Delivery of agreed amount with 10% overage

A total of 29 batches were completed in 3½ months

Delivery within originally agreed timelines

Case study: We also do non-fluorinated chemistry!

Fluorination strategies

Nucleophilic deoxofluorination

Sulfur tetrafluoride

Gas

1962

Requires autoclave, high p and T

Very toxic

Hazardous

DAST

Liquid

1975

Thermally unstable

Reacts violently with water, releasing HF

Deoxo-Fluor®

Liquid

1999

Slightly more thermally stable

than DAST

Shares the disad-vantages of DAST

XtalFluor-M™

Crystalline

2010

More thermally stable than DAST or Deoxo-

Fluor

Does NOT react with water or release HF

Phenofluor™

Crystalline

2010

Thermally stable

Air stable, but moisture sensitive

BF4-

XtalFluor-E™

Crystalline

2009

More thermally stable than DAST or Deoxo-

Fluor

Does NOT react with water or release HF

BF4-

Nucleophilic deoxofluorination

Nucleophilic deoxofluorination

Deoxofluorination: trifluoromethyl derivatives

HF, SF4, 140°C, 12 h

HF, SF4, 80°C, 10 h

93%

25%

HF, SF4, 80°C, 10 h

85%

Deoxofluorination: difluoromethyl(ene) compounds

HF (cat), SF4, DCM

90°C, 12 h

73%

HF (cat), SF4, DCM

60°C, 36 h

HF (cat), SF4, DCM

75°C, 16 h

86%

77%

Deoxofluorination: monofluoro compounds

DAST, CH2Cl2

-60°C to rt, 16 h,

NaOH, then HCl

66%

66% overall

HF (cat), SF4, CH2Cl2

40°C, 20 h

HF, SF4, -55°C, 10 h

69%

XtalFluor: increased selectivity

XtalFluor-EEt3N.2HF, CH2Cl2

-40 °C to rt, 16 h

91%

62:125:1 with Deoxo-Fluor

XtalFluor-EEt3N.3HF, CH2Cl2

-50°C to rt, 16 h

81%

12:12.3:1 with DAST

Nucleophilic substitution

Tetrabutyl ammonium fluoride

Prepared in-situ as amhydrous reagent in

solution

Requires anhydrous reagent

Requires anhydrous polar, aprotic solvents

Does not require high temperatures

Potassium fluoride

Crystalline

Requires phase-transfer catalyst

Requires anhydrous polar, aprotic solvents

Requires high temperatures

Cesium fluoride

Crystalline

Does not requires phase-transfer catalyst

Requires anhydrous polar, aprotic solvents

Requires high temperatures

KF, sulfolane100°C, 24 h

KF, 18-crown-6tetraglyme150°C, 6 h

88%

59%

63%

KF, sulfolane185°C, 24 h

Nucleophilic substitution

L.J. Allen et al., J. Org. Chem., 2014, 79, 5827–5833.

CsF, DMSO100°C, 24 h

90%

63%

92%

Bu4NF, DMSO

25°C, 24 h

Bu4NF, DMSO

25°C, 24 h

Nucleophilic substitution

Nucleophilic substitution: trifluoromethylation

R. Murray et al., Ind. Eng. Chem., 1947, 39, 302–305.

E.T. McBee et al., J. Am. Chem. Soc., 1947, 69, 947–950.

HF, SbF5 (cat)

rt, 1-2 h

85%

HF, SbF5 (cat)

rt, 1-2 h

91%

HF110-120°C, 1-2 h

Cl2, h

90-110°C, 91 h

96% 45-59%

Balz-Schiemann fluorination

1) NaNO2, HCl, H2O

2) HBF4,

78%

tBuONO, HF-pyridine-50 to -20°C

43%

G. Schiemann & W. Winkelmüller, Org. Synth., 1933, 13, 52-55.

H.S. Kim et al., J. Med. Chem., 2003, 46, 4974-4987.

Palladium catalysed fluorinations

X = Br, I, OTf

CsF, tBuBrettPhos[(cinnamyl)PdCl]2

80-130°C, 12 h

57-84%

83% 84% 57%

77%63%73%

D.A. Watson et al., Science, 2014, 325, 1661-1664.

Electrophilic fluorination

NFSI

Crystalline

1991

Thermally unstable

Stable to moisture

Selectfluor®

Crystalline

1992

Decomposes above 80°C.

Stable to moisture, virtually non-hygorscopic

N-fluoropyridiniumtriflate

Crystalline

1986

Thermally stable

Stable to moisture, non-hygroscopic

NFSI, LDA, THF-78°C to rt

NFSI, CH2Cl2

rt, 24 h

85%

46%

40%

NFSI, THF, Et2O

-78°C to rt

E. Differding & H. Ofner, Synlett, 1991, 187-189.

Electrophilic fluorination: NFSI

Selectfluor, MeCNrt, 2 h

95%

41;58

Selectfluor, MeCNreflux, 15 min

80%o:p = 62:38

R.E. Banks et al, J. Chem. Soc., Chem. Commun., 1992, 595-596.

Electrophilic fluorination: Selectfluor

MFDA

Liquid

1989

Stable at room temperature

Moisture sensitive

Trifluoroacetic acid and derivatives

Liquid/Crystalline

1981

Thermally stable

Hydroscopic, does not react with water

TMSCF3/TESCF3

Liquids

1989/1991

Thermally stable

Moisture sensitive

Trifluoromethylation

M. Chen & S.L. Buchwald, Angew. Chem. Int. Ed., 2013, 52, 11628-.

CF3CO2Na, CuI, NMP

140-160°C, 4 h

69-99%

CF3CO2K, CuI

pyridine, NMP200-210°C, 16 min

64-96%

K. Matsui et al., Chem. Lett., 1981, 1719-1720.

Trifluoromethylation: trifluoroacetates

Q.-Y. Chen & S.W. Wu, J. Chem. Soc., Chem. Commun., 1989, 705-706.

74%70%

90%

MFDA, CuI, DMF65-70°C, 2.5 h

53-92%

80% 81% 68%

Trifluoromethylation: MFDA

G.K.S. Prakash et al., J. Am. Chem. Soc., 1989, 111, 393–395.

85% 77% 80%

TMSCF3, TBAF, THF

0-25°C, 1-2 h, thenHCl, H2O

65-90%

Trifluoromethylation: TMSCF3/TESCF3

TESCF3, KF, CuI

DMF, NMP80°C, 24 h

23-94%

94% 71% 53%

H. Urata & T. Fuchikami, Tetrahedron Lett., 1991, 32, 91-94.

Trifluoromethylation: TMSCF3/TESCF3

TFDA and MFDA

Liquids

2004/2012

Stable at room temperature

Moisture sensitive

(Difluoromethyl)-trimethylsilane

Liquid

2011

Thermally stable

Moisture sensitive

Difluoromethyltriflate

Liquid

2013

Thermally stable

Moisture sensitive

Difluoromethylation

W.A. Dolbier Jr. et al., J. Fluorine Chem., 2004, 125, 459-469.

F. Eusterwiemann et al., J. Org. Chem., 2012, 77, 5461-5464.

MFDA, TMSCl, KIdiglyme, solvent

115-120°C, 2 days

TFDA, NaF, solvent95-120°C, 1-2 h

64-98%

53-92%

80%65% 71%

Difluoromethylation: TFDA and MFDA

64%

78%

POCl3,

1,4-dioxane100°C, 3 h

PPA

82%

neat50°C, 16 h

Fluorinated building blocks: cyclisations

72%

49%

1) LDA, THF2) CO2

1) LDA, THF2) CO2

-78°C, 2 h

72%

1) LDA, THF2) CO2

Fluorinated building blocks: directed lithiations

60%

87%

NH3, H2O

150°C, 50 h

NH3, H2O

55°C, 5 h

99%

NH3, H2O

55°C, 5 h

Fluorinated building blocks: selective substitution

Company Presentation 2018