Pilot Scale Process Development of SL65.0102-10, an N-Diazabicyclo

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Pilot Scale Process Development of SL65.0102-10, an N-Diazabicyclo[2.2.2]-octyl-methyl benzamide Philippe J LIENARD, Philippe Gradoz, Hélène Greciet, Samir Jegham, and Didier Legroux Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00262 • Publication Date (Web): 14 Dec 2016 Downloaded from http://pubs.acs.org on December 15, 2016

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Organic Process Research & Development

Pilot Scale Process Development of SL65.0102-10, an N-Diazabicyclo[2.2.2]-octylmethyl benzamide. Philippe Lienard*⊥, Philippe GradozI, Hélène Greciet§, Samir Jegham# and Didier Legroux+ Sanofi-Aventis, Recherche & Développement, 13 Quai Jules Guesde, 94400 Vitry-surSeine, France *

Author to whom correspondences should be sent via email: [email protected] Pharmaceutical Science Development, Sanofi R&D, Vitry-Sur-Seine, France. I E-mail: [email protected] § E-mail: [email protected] # E-mail: [email protected] + E-mail: [email protected] ⊥

ACS Paragon Plus Environment

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Toc Graphic Cl HO

OH

Chemical process development route 10 chemical steps (5 isolated)

Medicinal chemitry route 12 chemical steps (8 isolated) O

HO O

O

H2N

N O

N N

O

O O

OH

H2N Cl O

O O

N H

N N

H2N Cl

SL65.0102-10


O

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Abstract The process development and improvements for route selection, adapted to large scale for the pilot-scale preparation of SL65.0102-10, an N-diazabicyclo[2.2.2]-octylmethyl benzamide, a 5-HT3 and 5-HT4 receptor active ligand for the treatment of neurological disorders such as cognition impairment are described in this article. Notable steps and enhancements are compared to the original route including the improvement of a chiral epoxide synthesis by shortening the number of chemical steps, the deprotection of a quaternary ammonium salt, and the redesign of the final amidification coupling to avoid chromatography.

Keywords Chiral epoxide, 1,2-diol, potassium phthalimide, Gabriel synthesis, amidification coupling.


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Introduction 5-HT4 receptor is a G-protein coupled receptor (GPCR) which belongs to serotonin receptor family. The role of 5-HT4 receptor in the modulation of many diseases is well described in the literature. 1 During the last decades, an impressive body of evidence suggested that selective stimulation of neuronal 5-HT4 receptor subtypes could be beneficial in the symptomatic treatment of memory disorders including many antidepressants, antipsychotics, anorectics, anti-emetics, gastroprokinetic agents, antimigraine agents, hallucinogens, and antactogens. 2 Within our effort to the discovery of memory dysfunction treatment, the SL65.0102-10, a selective 5-HT4 partial agonist (Ki 6.6 µM), was discovered as promising agent for the treatment of cognition impairment. Serotonin receptors are the target of a variety of pharmaceutical drugs; SL65.0102-10 1 emerged as a promising 5-HT3 and 5-HT4 inhibitor that was potentially useful for the treatment of neurological disorders. 3 Scheme 1 illustrates the medicinal chemistry research approach to 1 that involves two advanced starting materials, chiral phthalimido epoxide 2 and acid 9. N-benzylpiperazine was alkylated with epoxide 2 to afford the chiral alcohol 4 which was transformed into its corresponding mesylate derivative 5. Mesylate 5 was heated to obtain quaternary ammonium salt 6 followed by hydrogenolysis to obtain protected amine 7. The next step involved the treatment of 7 with hydrazine hydrate to deprotect the phthalimido moiety. Amide coupling of chiral amine 8 with acid 9 resulted in SL65.0102-10 1.

Scheme 1. Medicinal chemistry synthetic route to SL65.0102-10 1 O

O

O O

a

N O

b

N

c

N

N O HN

O HO

N

2

N

OMsO N

4

O N

5 bn

3

O e

N

N

N

H2N

f

O

N

O 7

8

N

O N H

H2N

N , 3HCl

6 bn

O d

N

N

O O

O

H2N

N Cl

OH

N

1

, 2HCl

SL65.0102-10

9 Cl

Reagents and conditions: a) toluene, 80 to 120oC, 95%; b) CH3SO2Cl, TEA, DCM, no purification. c) toluene, reflux, 87%; d) H2/Pd/C, MeOH, 50oC, 68%; e) NH2NH2/EtOH/reflux, then 4N HCl, 0°C, 77%; f) DCC, NaOH, pyridine/water, RT, purification on SiO2/chromatography then HCl/EtOH, 44%.


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+, CH3SO3-

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The medicinal chemistry route, however, could not support the multi-kilogram quantities of the drug substance required to support the preclinical and clinical activities. As the target molecule progressed to clinical development and increasing quantities of drug substance were required several alternate synthetic routes and iterations were successfully demonstrated on kilolab and pilot plant scale. The ultimate goal was to establish an economical and industrializable synthesis of SL65.0102-10 1. This paper summarizes the process development of SL65.0102-10 1.

Results and discussion Chiral phthalimido epoxide 2 was chosen as a starting material by the medicinal chemistry group for the preparation of small quantity batches. However no reliable large scale quantity manufacturer was available for this compound in the late 1990’s. The available reactors were not equipped to handle epichlorohydrin safely, so two alternate syntheses of this compound were evaluated for the first batches at pilot scale. Scheme 2 shows the first approach to 2 that starts from (S)-(+)-1,2-isopropylideneglycerol or (S)-(+)solketal 10, a widely commercially available substrate for early development. These compounds had been successfully used to prove the compound 1 synthesis on small scale and were readily available in multi-kilogram quantities. The objectives for the first pilot plant campaigns were to demonstrate a scaleable synthesis of 1 and to deliver drug substance rapidly. Scheme 2. Early development synthesis of chiral phthalimido epoxide 2 HO

MsO

S O

a O

O

c

O

N

N O

10

O

O

b

O

O HO

O

12

11

OH

13 d

2

e

f

N

N

N O

O

O

O

O

O O 15

O

Br O

Ph

14

O

O

Ph

Reagents and conditions: a) CH3SO2Cl, TEA, toluene, 93.5%; b) potassium phthalimide, DMF, TEBAC, 71.1%; c) HCl, water, 86.2%; d) PhCHO, toluene, PPTS, 81.6%; e) NBS, dichloroethane, 87.6%; f) MeONa, toluene, 80.8%.


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The first step in the synthesis of 11 involved selective mesylation of the hydroxyl group of (S)-(+)-solketal 10 using mesyl chloride in toluene in the presence of triethylamine. After aqueous work-up and appropriate organic phase washes, the crude compound 11 was engaged in the following step after a solvent exchange with DMF using vacuum distillation. The standard reaction protocol commonly employed in the literature 4 was found to be satisfactory for the reaction with potassium phthalimide. An isolation process was chosen that minimized labor: addition of water and filtration. There were very few impurities. The high purity product allows the crude to be used directly in the next reaction without recrystallization. The next step involved the hydrolysis of the dioxolane protecting group of 12 with diluted HCl. 5 The resulting diol 13 was reacted with benzaldehyde to form acetal 14 . Further reaction with N-bromosuccinimide allowed easy opening of the acetal ring to afford bromo ester intermediate 15. The formation of epoxide 2 was realized with sodium methoxide in toluene solution. 6 This sequence, without formal intermediate isolation, was terminated with a recrystallization in ethanol to guarantee the quality for engaging epoxide 2. During this early development, the seven-step process was utilized to supply a total of 12.4 kg of epoxide 2 with 27% overall yield and no undesired enantiomer detectable by chiral HPLC. 7 However, the long-term goal was to establish an industrializable synthesis of 1. This implied:

minimum number of chemical steps;

technical scalability and good robustness of the processes;

good overall yield and process productivity (space-time-yield);

acceptable process safety and industrial hygiene;

tolerable waste generation (minimal environmental impact). Using these criteria, the overall process to synthesize 2 via (S)-(+)-solketal 10 was

challenged with another approach depicted in scheme 3.


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Scheme 3. Pilot plant synthesis of chiral phthalimido epoxide 2 O Cl

O

R a HO

N O HO

16

N

b

S

OH

O

OH

O

2

13

Reagents and conditions: a) potassium phthalimide, DMF, TEBAC, 94.5%; b) CH3C(OCH3)3, toluene, PPTS, 50°C, then TMSCl, at room temperature, and MeONa, 30°C, 66.5%.

The development of a more efficient route to epoxide 2 was a critical step in implementing a fast and shorter synthesis for pilot scale and we relied on two main contributions: the commercial availability of chiral (R)-(-)-3-chloro-1,2-propanediol 16 and the ability to scale up the Sharpless procedure to convert phthalimide diol 13 into epoxide 2 in a one pot procedure. 8 The alkylation of potassium phthalimide with R-3-chloro-(1,2)-propanediol 16 led to 2-[(2S)-2,3-dihydroxypropyl]-1,3-isoindolinedione 13. The optimization laboratory showed that a slow addition of R-3-chloro-(1,2)-propanediol 16 to the potassium phthalimide as a hot suspension in DMF, in the presence of a phase transfer agent, gave better yields of the expected intermediate 13. The extrapolation of this process to the pilot scale by extending the addition time and contact time at 100°C was very easily validated. The recrystallization in ethyl acetate, performed in pilot run 1, was avoided for runs 2 and 3, thanks to the quality of the crude product, which did not require purification, as the remaining phthalimide did not impact the next step.

Table 1. Scale-up of N-alkylation of potassium phthalimide using R-3-chloro-(1,2)propanediol 16. Run

Solvent

Reaction time 100°C

Laboratory Pilot 1 Pilot 2 Pilot 3

DMF DMF DMF DMF

3h 4h20 6h 6h

Eq. (potassium phthalimide)

Scale (mole)

Yield (%)

1.06 1.06 1.07 1.07

0.1 90.6 720.4 1117.2

54 50.3 59.4 94.5

Purity (assay of phthalimide ) (%) 0.5 0.6 4 3.5

In lab-scale campaigns, epoxidation of diol 13 was performed after drying in a vacuum dryer. Prior to pilot plant scale, an effort was made to replace this vacuum drying by an azeotropic removal of the residual water in the diol 13 in the next step solvent, i.e. toluene.


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Epoxide 2 was prepared by reacting trimethyl orthoacetate and chlorotrimethylsilane, which led to an acetyl chlorohydrin intermediate which was cyclized to epoxide 2 using sodium methoxide. The detailed mechanism is provided in the literature 9

and is represented in scheme 4.

Scheme 4. Un-isolated intermediates 17 and 18 of one-pot reaction of epoxide 2 O N O HO

O a

S

b

N

OH

13

O

O 17

O

N O

O

Cl O

O

OMe 18 c

O N O

O

2

Reagents and conditions: a) CH3C(OCH3)3, toluene, PPTS, 50°C; b) TMSCl, room temperature; c) MeONa, 30°C, 66.5%.

It was determined that to obtain good quality epoxide 2 without the presence of the intermediate acetyl chlorohydrin, it was necessary to use equimolar quantities of sodium methoxide and chlorotrimethylsilane, i.e. 1.5 equivalents. In addition, we showed that the epoxide 2 partially degraded during the recrystallization in ethanol. However, at the pilot scale (30 to 60 kg), this one-pot transformation sequence was reproduced several times with 65.3% to 74.0% yield range and quality greater than 98% as well as enantiomeric excess superior to 99% were reproducibly achieved. The process to prepare epoxide 2 was shown to be reliable and reasonably robust; a total of 180 kg was prepared in the early pilot plant campaigns, most of which was used to prepare batches of SL65.0102-10 1. This route using R-3-chloro-(1,2)-propanediol 16 as starting material was considered significantly more efficient than the first route using (S)(+)-solketal 10, particularly due to the reduction of the number of steps and intermediate isolations. The N-benzylpiperazine alkylation with epoxide 2 was performed using the same procedure used by medicinal chemistry and the mesylation of the intermediate 4 was


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conducted using standard conditions as well. The remaining challenge was isolation of quaternary ammonium salt 6 from the rather complex reaction mixture, taking into account its high water solubility and hygroscopicity. Extensive studies were performed to find a robust isolation process to overcome the propensity of the product to oil out of solution and to limit yield of isolation of quaternary ammonium salt 6. Thus, this quarternization step was submitted to a laboratory optimization, which allowed demonstrating the α,α,α-trifluorotoluene as the only solvent to make both the final reaction and the product isolation by crystallization. Indeed, the quaternary ammonium 6 was obtained by a sequence of three operations without isolation. The alkylation was conducted in toluene and intermediate 4 was obtained by removal of the toluene by solvent stripping. Intermediate 4 was converted to the mesylate 5 in dichloromethane and after washing, the solution of dichloromethane was added to the α,α,α-trifluorotoluene at 90°C to achieve the cyclization. The dichloromethane was distilled off as the addition progressed; the reaction was continued for several hours after the previous addition (10 hours). The filtration of the quaternary ammonium 6 was very slow, probably due to partial crystallization. However, compound 6 was obtained with 74% yield average (on 60 kg scale) and adequate quality to be processed to the next steps without additional purification. Our attention shifted to minimizing the number of steps to produce intermediate 8. It occurred to us that the two-step deprotection of quaternary ammonium 6 was a viable way to produce intermediate 8, and for the first batches we used the medicinal chemistry methods based on catalytic hydrogenolysis and reaction with hydrazine hydrate as depicted in scheme 1. Our strategy for simplifying this into a one-pot reaction was to use hydrochloric acid as a single reagent. Additionally, the elimination of hydrazine hydrate by replacement with less hazardous conditions was considered beneficial with regards to safety and hygiene. Preliminary laboratory experiments demonstrated that the use of 20% HCl was suitable to generate the desired intermediate 8.


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Scheme 5. One-pot deprotection of quaternary ammonium 6 O O

O

a

N

N O

O

b

c

N

N

N

O HN

N

2

O HO 4

3

N

OMsO N

5 bn

N

O

N

6

N

+, CH3SO3-

bn

d

N

H2N 8

N , 2HCl, CH SO H 3 3

Reagents and conditions: a) toluene, reflux, no purification; b) CH3SO2Cl, TEA, DCM, 0°C, no purification. c) α,α,αtrifluorotoluene, 90°C, 73.8%; d) HCl 20%, reflux, 48.5%.

However, debenzylation and removal of the 1,2-benzenedicarboxylic acid byproduct after removal of protecting moiety with hydrochloric acid were sluggish, even at elevated temperatures, and required preliminary solvent stripping. It appeared that the solvent stripping was necessary to remove the benzyl chloride or the benzyl alcohol formed during the reaction to push the reaction toward intermediate 8. At large scale, the captured of benzyl chloride was performed with alcoholic aqueous sodium hydroxide at the reactor event to avoid its release in atmosphere. Even though this step needed further optimization, the compound 8 (weight of free amine based on HPLC assay), was obtained with 48.5% yield on 35 kg average scale and in adequate quality to be processed to the next steps without additional purification. A final treatment in methanol allowed intermediate 8 to be obtained with satisfactory quality to be engaged in the final coupling with acid 9. As the only published procedure to synthetize 8-amino-7-chloro-2,3-dihydro-1,4benzodioxin-5-carboxylic acid 9 required special safety equipment compatible with chlorine gas manipulation, 10 this route was deemed impractical in our facility. Considering our intention was to externalize this intermediate 9, no in-depth optimization work was undertaken, thus the medicinal chemistry procedure was used according to scheme 6.


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Scheme 6. Synthesis route of acid 6 COOH O O

a

Br

COOH O

Br

19

O

b

Br

COOH O

Br

20

c

CO2H O

O

O

NO2

NH2

21

22

CO2H O Cl

O NH2

9

e

d

COOH O O NHAc

23

Reagents and conditions: a) Br2, AcOH, AcONa, 40°C, 94.1%; b) HNO3, H2SO4, AcOH, room temperature, 84%; c) H2, Pd/C, MeOH, TEA, 60-75°C / 4.5 bars of hydrogen, not isolated; d) Ac2O, AcOH, room temperature, overnight, 70.6% over two steps; e) NCS, AcOH, 50 to 85°C, 67.7%.

The 1,4-benzodioxan-5-carboxylic acid 19 was treated with bromine in acetic acid, then the di-bromo intermediate 20 was submitted to nitration in sulfuric acid to afford intermediate 21. The next step involved hydrogenation of 21 under moderate hydrogen pressure in methanol to remove bromo substituents and reduce the nitro moiety to obtain intermediate 22, without solid isolation. Intermediate 22 was acetylated with acetic anhydride in acetic acid. The final operation was a chlorination of intermediate 23 using Nchlorosuccinimide to supply acid 9. This process, starting with the inexpensive compound 19, represents an improvement in terms of safety compared to the procedure previously reported with the use of free gas chlorine. Overall, the scale up of these five steps was successful and the reaction and isolation processes proved to be robust: a total of 43.7 kg of acid 9 was manufactured in consistent fashion in our facility, avoiding chlorine gas handling. At the final coupling stage, for scaling-up purpose it was reasoned that this straightforward transformation could be realized without the DCC coupling agent. This reagent presented an important disadvantage due to the generation of by-products that required removal by chromatography. Thus, as shown in scheme 7, we found that coupling between this triamine 8 and the acid 9 was better performed by a mixed anhydride derived from pivaloyl chloride in the presence of triethylamine at 0°C.


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Scheme 7. Final coupling of triamine 8 and acid 6 O N

H2N

a

O

N

N H

H2N

, 3HCl 8

O

O O

O

H2N

N Cl

OH

N

1

, 2HCl, H2O

SL65.0102-10

9 Cl

Reagents and conditions: a) pivaloyl chloride, trimethylamine, acetone, 0°C, 67.4%, and then clarification in hot ethanol and final crystallization in ethanol after HCl addition, 76.7%.

After the reaction, the crude mixture was filtered after 1 hour of stirring and then, the active compound 1, as its free base, was isolated by adjusting the pH of the liquid phase to basic with sodium hydroxide. The crude base 1 was submitted to a filtration in hot ethanol through a 2 µm filter for clarification before HCl was added. The hot filtrate was partially concentrated and cooled to crystallize the product hydrochloride salt. Filtration of the suspension at low temperature allowed the isolation of the active compound 1. Overall a total of 21.56 kg of 1 was manufactured in 70% yield (as free base of active compound 1) and 67.5 % for the final crystallization including salt formation with hydrochloric acid.

Conclusions Efforts towards process development synthesis of SL65.0102-10 1 were reported. The first epoxide 2 batches were prepared from (S)-(+)-solketal 10 in six chemical steps in about 27% overall yield. Although this synthesis proved to be scalable, we changed to a shorter synthesis route starting from (R)-(-)-3-chloro-1,2-propanediol in two chemical steps with a greatly improved overall yield of 62.4%. Access to the quaternary ammonium salt 6 was well-managed using optimized conditions, particularly the use of trifluorotoluene for the quaternarization step. All deprotections were managed in a one-pot reaction, avoiding hazardous hydrazine, to afford triamine 8. Acid 9 was manufactured in a consistent fashion using a medicinal chemistry route. The final amide coupling was performed with a mixed anhydride method to avoid chromatography purification. Compared with the first generation synthesis from medicinal chemistry, key achievements were:

minimizing the number of steps while maintaining a good overall yield - the medicinal chemistry route was performed in 12 chemical steps with 8 isolated steps as the


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chemical process development route was minimized to only 10 chemical steps with 5 isolated steps -.

technical scalability and good robustness improved with exclusion of purification chromatography along the route,

acceptable process safety and industrial hygiene in which the handling of toxic and hazardous reagents were avoided,

and finally the development of a new access route to epoxide 2.

The chemical process development still needs to be worked, to optimize yields of each step, and also to minimize the waste generation.

Acknowledgements This work is published 20 years after the original patent publication of the medicinal chemistry route. We are grateful to the many colleagues within Sanofi who provided analytical support. In particular, this paper is dedicated to all colleagues of the Sanofi Porcheville development center with thanks for their endeavor, professionalism and expertise. Supporting Information Supplementary materials content a detailed experimental section and 1H and 13C NMR spectra for final compound: SL65.0102-10 1. References 1

a) Hoyer, D.; Clarke, D.E.; Fozard, J.R.; Hartig, P.R.; Martin, G.R.; Mylecharane E.J.; Saxena P.R.; Humphrey P.P. Pharmacol. Rev. 1994, 46 (2), 157–203. b) Frazer, A.; Hensler, J.G Chapter 13: Serotonin Receptors". In Siegel, G.J.; Agranoff B.W.; Albers R.W.; Fisher S.K.; Uhler M.D. editors.Basic Neurochemistry: Molecular, Cellular, and Medical Aspects. Philadelphia: Lippincott-Raven. 263–292, 1999. 2 Frick, W.; Glombik, H.; Kramer, W.; Heuer, H.; Brummerhop, H.; Plettenburg, O. Novel fluoroglycoside heterocyclic derivatives, pharmaceutical products containing said compounds and the use thereof a) WO2004/052903 2004. b) WO2004/052902 2004. 3 Jegham, S.; Koenig J. J.; Lochead, A.; Nedelec, A.; Guminski, Y. N-[(1,4diazabicyclo[2.2.2]oct-2-yl)methyl] benzamide derivatives, their preparations and their application in therapeutics a) FR 2756563 06/13/1995 9506951 1995. b) US 5663173 1997, Washington, DC: U.S. Patent and Trademark Office. 4 Gibson, M.S.; Bradshaw, R.W. Angewandte Chemie International Edition in English 1968, 7(12), 919-930. 5 Hough, L.; Jones, J.K.N.; Magson, M.S. J. Chem. Soc. 1952, 1525. 6 Akhrem, A.A.; Zharkov, V.V.; Zaitseva, G.V.; Mikhailopulo, LA. Tetrahedron Lett.1973, 14(17), 1475-1478..


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7

No R isomer detected by chiral HPLC for both processes (from (S)-(+)-solketal and (R)(-)-3-chloro-1,2-propanediol. 8 Kim, B.M.; Sharpless, K.B. Tetrahedron Lett. 1989, 30, 655. 9 Kolb, H.C.; Sharpless, K.B. Tetrahedron 1992, 48(48), 10515-10530. 10 Gaster, L.M.; Jennings, A.J.; Joiner, G.F.; King, F.D.; Mulholland, K.R.; Rahman, S.K.;Wardle, K.A. Journal of medicinal chemistry 1993, 36(25), 4121-4123.


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Pilot Scale Process Development of SL65.0102-10, an N-Diazabicyclo

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