Final Report (eng) NEU 1076p4.storage.canalblog.com/49/12/1309572/103874827.pdf18±2 C. 5. Add 4...

CONFIDENTIEL

FLOW CHART

PROJECT NEU 1076

CUSTOMER NEUROPTIS

DATE 2012 July 20th

WRITTEN BY Claude Monteils

APPROVED BY Babak Sayah

PROJET NEU 1076 CONFIDENTIEL PROVENCE TECHNOLOGIES FLOW CHART

Version 4 / 13 Date: 20/07/2012

PROVENCE TECHNOLOGIES SAS

Hôtel Technologique – Technopôle de Château Gombert 45 rue Frédéric Joliot-Curie – BP 100 – 13382 Marseille Cedex – France

Phone +33 (0)4 91 11 88 10 – Fax +33(0)4 91 11 88 10

Context and aim of the project: Following NEU1057 project, Neuroptis entrusted Provence Technologies to study the improvement feasibility of the synthetic process of compound 1057-01 with the objectives to limit each impurity level at 0.15%. The project was split in two phases:

a. Phase 1: development of a purification method of ML7 to avoid any impurity at a higher level than 0.15% (if possible not higher than 0.1%). This work includes a report describing the purification method and the results found on impurities.

b. Phase 2: depending on phase 1 output, evaluation of the cost for the preparation, purification and characterization of each impurity which % ranges from 0.1 and 0.15%.

At the end of phase 1, a purification method by successive crystallizations was developed and described below. After discussions with Axyntis Company which has been contacted for the development of a possible larger scale and GMP production, some chemists’ comments have been considered and applied during the feasibility study.


Version 4 / 13 Date: 20/07/2012



Phone +33 (0)4 91 11 88 10 – Fax +33(0)4 91 11 88 10

Synthesis Scheme :

I

SO3H

NH2

SO3H

I

SO2Cl

I

SO2N

HN

I

SO2N

HNHCl

NaNO2, 1.1eq.KI, 3eq.HCl 6N, 15v5°C>>>RT, 20h

Step A

Overall Yield 43%

1057-SM 1057-A 1057-B

1057-C1057-01

SOCl2, 2eq.DMF, 0.1eq.Toluene, 15vReflux, 2h

Homopiperazine, 4eq.Toluene, 15v10°C>>>RT, 3h

HCl 6N, 1eq.iPrOH, 4v70°C>>>RT

Step B

Step CYield 79%

Step DYield 76%

Yield 80% Yield 90%


Version 4 / 13 Date: 20/07/2012



Phone +33 (0)4 91 11 88 10 – Fax +33(0)4 91 11 88 10

Flow Chart: The table below summarizes the second version of the process that has been developed.

Process description Step and reactants IPC Synthesis scale : 50g

1. Charge SM in 15 volume of 6N HCl at 5±2°C.

2. Add 1.1eq of NaNO2 dissolved in 1 volume of water (reddish vapor emanates). Stir for 1h while the temperature raises 18±2°C. (IPC1)

3. Add 3eq of KI dissolved in 1.6 volume of water. Stir 16h at 23±2°C. Note: Not exothermic. High degassing during addition of NaNO2. Formation of a foam at the mixture surface which increases if the temperature exceeds 30°C (IPC 2)

4. Add 1eq of ammonium sulfamate dissolved in 0.3 volume of water 18±2°C.

5. Add 4 volumes of saturated Na2S2O3 solution.

6. Cool at 5±2°C, stir for 1h and filtrate. Wash with 1 volume of 6N HCl cooled at 5±2°C.

7. Put the solid in 10 volumes of toluene.

8. Use a Dean-Stark apparatus to eliminate water.

9. Cool to 20±2°C. 10. Filtrate the resulting solid,

triturate with 2 volumes of toluene and wash with 2 volumes of toluene.

11. Take and dry a sample to estimate the real dry weight (IPC 3)

NH2

SO3H

C10H9NO3SExact Mass: 223,03

I

SO3H

C10H7IO3SExact Mass: 333,92

Reactants/Solvents:

NaNO2

HCl

H2O

KI

Ammonium Sulfamate

Na2S2O3

Toluene

IPC1 : LCMS Diazo formation TT% +95% IPC 2 : LCMS Iodo formation. TT% +95% IPC3 : LCMS CQ iodo compound


Version 4 / 13 Date: 20/07/2012



Phone +33 (0)4 91 11 88 10 – Fax +33(0)4 91 11 88 10

1. Charge the previously prepared compound in 15 volumes of toluene.

2. Add catalytic amount of DMF (0.1eq).

3. Reflux the mixture. 4. Add 2eq of SOCl2. 5. Reflux the mixture for 2h.

(IPC4) 6. Eliminate SOCl2 (about 7.5

volumes eliminated) with a Dean-Stark apparatus.

7. Cool to RT. 8. Purify on a pad of silica (2 parts). 9. Elute with 15 volumes of toluene. 10. Concentrate the filtrate

(evaporate about 10 volumes). 11. Estimate the obtained weight.

I

SO3H

C10H7IO3SExact Mass: 333,92

I

SO2Cl

C10H6ClIO2SExact Mass: 351,88

Reactants/Solvents:

Toluene

SOCl2

DMF

IPC 4: LCMS Acyl chlorideformation. TT% +95% Preparation of the sample in the presence of MeOH.


Version 4 / 13 Date: 20/07/2012



Phone +33 (0)4 91 11 88 10 – Fax +33(0)4 91 11 88 10

1. Add at 10±2°C the solution of the

acyl chloride prepared in the last step to a solution of Homopiperazine in 15 volumes of toluene ( 4eq calculated in comparison to the estimated weight of acyl).

2. Stir for 3h at 20±2°C (IPC5)

3. Filtrate the solid and wash with 1 volume of toluene.

4. Wash the toluene phase with water (6x10 volumes) to reach pH 7.

5. Filtrate the organic phase to get rid of remaining solid.

6. Concentrate to dryness (IPC6 + IPC 7)

I

SO2Cl

C10H6ClIO2SExact Mass: 351,88

I

O2SN

NH

C15H16IN2O2SExact Mass: 415

Reactants/Solvents:

Toluene

Homopiperazine

Water

IPC 5 : LCMS. Sulfonamide formation. TT% +95% IPC 6 : TLC IPC 7 : LCMS QC of the sulfonamide


Version 4 / 13 Date: 20/07/2012



Phone +33 (0)4 91 11 88 10 – Fax +33(0)4 91 11 88 10

1. Charge the product in iPrOH (4 volumes).

2. Reflux the solution (turns homogeneous).

3. Stop heating and cool slowly to 20±2°C.

4. Cool to 5±2°C, filtrate and wash the solid with 1 volume of iPrOH at 5±2°C.

5. Take a sample of the solid and dry it. Estimate the quantity obtained.

6. Put the solid with 10 volumes of iPrOH and reflux the mixture.

7. Add 1eq of 6N HCl in the solution. 8. Reflux for 15 minutes. 9. Come back slowly to 20±2°C and

cool to 5±2°C. 10. Filtrate and wash the solid with 1

volume of iPrOH at 5±2°C. 11. Mix the solid with 2 volumes of

water and reflux. 12. Come back slowly to 20±2°C and

cool to 5°±2°C. 13. Filtrate and wash the solid with 3

volume of acetone at 20±2°C 14. Mix the solid with 10 volumes of

iPrOH and 0.5 volume of water. 15. Reflux for 30 minutes. 16. Come back slowly to 20±2°C. 17. Filtrate and wash the solid with 1

volume of iPrOH. 18. Mix the solid with 10 volumes of

iPrOH and 0.5 volume of water. 19. Reflux for 30 minutes. 20. Let cool to 20±2°C. 21. Filtrate and wash the solid with 1

volume of iPrOH 22. Mix the solid with 10 volumes of

iPrOH and 0.5 volume of water. 23. Reflux for 30 minutes. 24. Come back slowly to 20±2°C. 25. Filtrate and wash the solid with 1

volume of iPrOH and 3 volumes of acetone

Final QC

I

O2SN

NH

I

O2SN

NH

Reactants/Solvents:

isoPropanol

HCl

Water

Acetone

HCl

C15H18ClIN2O2SExact Mass: 451,98

C15H17IN2O2SExact Mass: 416,01

Final QC:

• HPLC • MS • NMR

….


Version 4 / 13 Date: 20/07/2012



Phone +33 (0)4 91 11 88 10 – Fax +33(0)4 91 11 88 10

Synthetic Methodology : The synthesis scheme (page 3) describes the preparation of 1-(5-iodonaphtalene-1-sulfonyl)-1,4-diazepane hydrochloride (1076-01) in 4 steps. In the first step, 5-amino-1-naphtalene sulfonic acid (1076-SM) reacts with 6N HCl*, NaNO2* and KI* at 23±2°C to give 5-iodo-1-naphtalene sulfonic acid (1076-A). In the second step, 5-iodo-1-naphtalene sulfonyl chloride (1076-B) is prepared in Toluene* from 5-iodo-1-naphtalene sulfonic acid (1076-A) in presence of SOCl2* and catalytic amount of DMF*. In the third step, 5-iodo-1-naphtalene sulfonyl chloride (1076-B) and Homopiperazine* react in Toluene* to give1-(5-iodonaphtalene-1-sulfonyl)-1,4-diazepane (1076-C). In the fourth step, 1-(5-iodonaphtalene-1-sulfonyl)-1,4-diazepane (1076-C) is acidified with 6N HCl* in iPrOH* to prepare 1-(5-iodonaphtalene-1-sulfonyl)-1,4-diazepane hydrochloride (1076-01). *Commercial compound


Version 4 / 13 Date: 20/07/2012



Phone +33 (0)4 91 11 88 10 – Fax +33(0)4 91 11 88 10

STEP A 5-iodo-1-naphtalene sulfonic acid (1076-A)

I

SO3H

NH2

SO3H NaNO2, 1.1eq.KI, 3eq.HCl 6N, 15v5°C>>>RT, 16h

Step A(Yield= 80%)

1076-SM 1076-A

In a 2 liters 3 necks round-bottomed flask equipped with a mechanic stirrer, 5-amino-1-naphtalene sulfonic acid* (50g, 224 mmol) is charged with 6N aqueous HCl* (750mL, 15 volumes). The suspension is cooled at 5±2°C and a solution of NaNO2* (17 g, 246 mmol) in Water* (50mL, 1 volume) is added dropwise at 5±2°C over 10 minutes (no exothermic reaction is observed). The suspension is stirred for 1 hour while the temperature has reached to 18±2°C (at this time LC/MS analysis showed no starting material). A solution of KI* (111.5g, 672 mmol) in Water* (80mL, 1.6 volume) is added dropwise at 18±2°C over 30 minutes, (no exothermic reaction is observed but a high degassing is observed at the beginning of the addition). The reaction mixture is stirred at 23±2°C for 20 hours and then cooled at 18±2°C. A solution of ammonium sulfamate* (25.6g, 224 mmol) in Water* (15mL, 0.3 volume) was added and the reaction mixture is stirred at 18±2°C for 15 minutes. A saturated aqueous Na2S2O3* solution (200mL, 4 volumes) is added (endothermic reaction was observed, the temperature decreases to 2°C). The reaction mixture is cooled at 5±2°C and then stirred for 1 hour. The precipitate is filtered (on sintered glass (Ø=10 cm; porosity=3; height solid=3.5 cm) and rinsed with 6N HCl* (50mL, 1 volume) cooled at (5±2°C) (height of the solid after rising=1.5 cm). The resulting solid is added to 500ml (10 volumes) of toluene under stirring. The suspension is refluxing with a Dean-Stark apparatus to remove water. The mixture is then cooled to 18±2°C and filtered under vacuum on sintered glass (Ø=10 cm, porosity=3). The cake (thickness 2cm) is triturated twice with 100ml of toluene (2 volumes) and washed twice with 100ml of toluene (2 volumes). The resulting brown solid is used in the next step without purification. Humid weight : 130.2 g Estimated weight (by sample estimation): 60 g Yield: 80% Analysis: HPLC, MS


Version 4 / 13 Date: 20/07/2012



Phone +33 (0)4 91 11 88 10 – Fax +33(0)4 91 11 88 10

STEP B 5-iodo-1-naphtalene sulfonyl chloride (1076-B)

I

SO3H

I

SO2Cl

Step B(Yield =90%)

1076-A 1076-B

SOCl2, 2eq.DMF, 0.1eq.Toluene, 15vReflux, 2h

In a 1 liter 3 necks round-bottomed flask is charged 5-iodo-1-naphtalene sulfonic acid (1076-A) (20g, 59.9 mmol) in 300ml of Toluene* (15 volumes/expected dry weight). The suspension is stirred at 18±2°C before (463µL, 6 mmol) of DMF is added. The mixture is refluxed before SOCl2* (8.7mL, 119.7 mmol) is added dropwise in 5 minutes. The mixture is refluxed for 2h. SOCl2* is removed with a Dean-Stark apparatus (about 7.5 volumes are removed). The mixture is cooled to room temperature and filtered on a pad of silica* (2parts) and the solid with 15 volumes of toluene*. The filtrate is evaporated under vacuum to remove 10 volumes of the solvent. The resulting solution is used without purification in the next step and the weight is estimated by sample. Estimated weight (by sample estimation): 19 g Yield: 90% Analysis: HPLC, MS (methyl ester form)


Version 4 / 13 Date: 20/07/2012



Phone +33 (0)4 91 11 88 10 – Fax +33(0)4 91 11 88 10

STEP C 1-(5-iodonaphtalene-1-sulfonyl)-1,4-diazepane (1076-C)

I

SO2Cl

1076-B

I

SO2N

HN

1076-C

Homopiperazine, 4eq.Toluene, 15v10°C>>>RT, 3h

Step C(Yield=79%)

In a 3 liters 3 necks round-bottomed flask is stirred Homopiperazine* (21.6 g, 215.6 mmol, 4eq) in Toluene* (285ml, 15 volumes). The mixture is cooled to 10±2°C with an ice-bath and the solution of 5-iodo-1-naphtalene sulfonyl chloride (1076-B) (19 g, 53.9 mmol) is added in 30 minutes (T0=7°C, Tfinal=14°C). Then, the reaction is stirred at 20±2°C for 3 hours. Salts are filtered under vacuum on sintered glass (Ø=10 cm, porosity=3, cake thickness=1cm) and the solid is washed with 20 ml (1 volume) of toluene. The filtrate is washed 6 times with 200ml of water (10 volumes) to reach pH 7. The organic phase is filtered on cotton to removed particles. The filtrate is evaporated under vacuum to give 17.8g of 1-(5-iodonaphtalene-1-sulfonyl)-1,4-diazepane (1076-C) as a beige solid. Yield: 79% Analysis: HPLC, MS, CCM


Version 4 / 13 Date: 20/07/2012



Phone +33 (0)4 91 11 88 10 – Fax +33(0)4 91 11 88 10

STEP D 1-(5-iodonaphtalene-1-sulfonyl)-1,4-diazepane hydrochloride (1076-01)

I

SO2N

HN

I

SO2N

HNHCl

Step D(Yield=76%)

1076-C 1076-01

HCl 6N, 1eq.iPrOH, 4v70°C>>>RT, 1h

In a 250ml 3 necks round-bottomed flask is stirred 1-(5-iodonaphtalene-1-sulfonyl)-1,4-diazepane (1076-C) (17.8g, 42.8 mmol) in 230ml (4 volumes) of iPrOH*. The suspension is refluxed until the mixture turns homogeneous and cooled slowly to 20±2°C. Then, the solution is cooled to 5±2°C, filtrated and the precipitate wash with 1 volume of iPrOH*cooled at 5±2°C. (A sample of the filtrated solid is dry to estimate the quantity of dry compound prepared). Then:

• Put the solid in 10 volumes of iPrOH* and reflux the solution. Add 1eq of 6N HCl* and reflux for 15 minutes. Cool back slowly to room temperature and cool to 5±2°C. Filtrate and wash with 1 volume of iPrOH*.

• Put the solid in 2 volumes of water and reflux the solution. Cool slowly to room temperature and cool to 5±2°C. Filtrate and wash with 3 volumes of acetone* at 20±2°C.

• Put the solid in in 10 volumes of iPrOH* and 0.5 volume of water and stir the solution for 30 minutes. Cool slowly to room temperature. Filtrate and wash with 1 volume of iPrOH*.

• Put the solid in in 10 volumes of iPrOH* and 0.5 volume of water and stir the solution for 30 minutes. Cool slowly to room temperature. Filtrate and wash with 1 volume of iPrOH*.

• Put the solid in in 10 volumes of iPrOH* and 0.5 volume of water and reflux the solution for 30 minutes. Cool slowly to room temperature. Filtrate and wash with 1 volume of iPrOH* and 3 volumes of acetone*.

14.8 g of 1-(5-iodonaphtalene-1-sulfonyl)-1,4-diazepane hydrochloride (1076-01) are obtained as a white solid. Yield: 76% Analysis: NMR 1H, 13C, HPLC, MS, TLC


Version 4 / 13 Date: 20/07/2012



Phone +33 (0)4 91 11 88 10 – Fax +33(0)4 91 11 88 10

ANNEXE

CERTIFICATE OF ANALYSIS

NEU 1076-01

Final Report (eng) NEU 1076p4.storage.canalblog.com/49/12/1309572/103874827.pdf18±2 C. 5. Add 4...

Documents

Transcript of Final Report (eng) NEU 1076p4.storage.canalblog.com/49/12/1309572/103874827.pdf18±2 C. 5. Add 4...