Development of an Efficient Synthesis of an Agonist of Acetylcholine

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Development of an efficient synthesis of an agonist of acetylcholine nicotinic receptor Christophe HARDOUIN, Aurélie Poixblanc, François Barière, Rodolphe Tamion, Thierry Dubuffet, Yvon Hervouet, and Patrick Mouchet Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00220 • Publication Date (Web): 28 Aug 2018 Downloaded from http://pubs.acs.org on August 29, 2018

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Organic Process Research & Development

Development of an efficient synthesis of an agonist of acetylcholine nicotinic receptor Christophe Hardouin,* Aurélie Poixblanc, François Barière, Rodolphe Tamion, Thierry Dubuffet, Yvon Hervouet, Patrick Mouchet Industrial Research Centre, Oril Industrie, 13 rue Desgenétais, 76210 Bolbec, France. [email protected]

ACS Paragon Plus Environment

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Organic Process Research & Development 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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Table of Contents Graphic


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ABSTRACT:

A

new

manufacturing

process

for

N-[[1-

(methylamino)cyclopropyl]methyl]pyridine-3-amine hemigalactarate (1) has been developed. Herein we wish to report the development and optimization of the route using alternative reaction conditions for a reduction / oxidation / reductive amination / protecting group cleavage sequence. Improvement of the crystallization process enabled the production of multikilogram amounts of agonist 1 under cGMP control with a purity of > 99.5%. A telescoped process involving 5 steps is also described.

KEYWORDS: telescoped process, TEMPO oxidation on scale, reductive amination, environmental footprint


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INTRODUCTION For the past decades, finding a treatment or even a cure to Alzheimer’s disease (AD) has been extensively studied. Recent figures published by the Alzheimer’s Association showed that more than 5 million Americans are living with AD and 47 millions estimated worldwide.1 It is expected to reach more than 130 million in 2050. Age-related cognitive disorders are due to a lower efficacy of neurons to both synthesize and release specific neurotransmitters. Among them, central cholinergic pathways via acetylcholine nicotinic receptors play a major role in memory processes.2 In order to oppose the cholinergic hypoactivity seen in normal or pathologic ageing, central acetylcholine nicotinic receptors have now been identified as potentially novel therapeutic targets.3 In this context, pyridinylamino-cyclopropanamine hemigalactarate 1 (Figure 1) was selected as a novel, potent and selective agonist of α4β2 and α3β2 acetylcholine nicotinic receptor subtypes. Figure 1. Chemical structure of 1

0.5

1

RESULTS AND DISCUSSION As part of a drug discovery program in our laboratories, an efficient, scalable and safe route to kilogram quantities of 1 was required for clinical trials. The original nine step synthesis is


4

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depicted in Scheme 1.4 Commercially available dimethyl cyclopropane-1,1-dicarboxylate 2 was chosen as starting material and was converted following a two-step sequence into the tert-butyl carbamate protected amine 4 via saponification followed by a Curtius rearrangement in a mixture of toluene and tert-butanol at -20 °C. N-Methylation in DMF followed by reduction of the ester with LiBH4 in THF provided alcohol 5. Swern oxidation to give the corresponding aldehyde followed by reductive amination with 3-aminopyridine and sodium cyanoborohydride afforded intermediate 6. The hydrochloride salt 7 was isolated with a good purity after acidic cleavage of the Boc-protected amine. Because of hygroscopic properties, hydrochloride salt 7 was replaced by hemigalactarate 1 after a salt selection. Treating the hydrochloride salt with sodium hydroxide followed by addition of galactaric acid in a mixture of ethanol and water provided desired compound 1. Scheme 1. Original synthesis of 1a

a

2

c,d

b

3

e,f

4

g 6

5

h,i 7

2 HCl

0.5 1

a

Reagents and conditions: (a) NaOH, MeOH,85-90 %; (b) Et3N, toluene, 70 °C then DPPA, t-BuOH, 45-55 %; (c) t-BuOK, MeI, DMF, 88 %; (d) LiBH4, THF reflux, 3 h, 75-95 %; (e) (COCl)2, DCM, -20 °C, DMSO then Et3N, 95 %; (f) 3-aminopyridine, MeOH, AcOH, NaBH3CN, 0 °C; (g) EtOH HCl, 60-70 % over two steps; (h) 30 % aqueous NaOH, DCM; (i) galactaric acid, EtOH, water, 100 °C, 57% over two steps.


5


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However this route possesses some major drawbacks: (i) the use of hazardous reagents such as diphenyl phosphoryl azide DPPA (concerns about its availability in bulk at this time), MeI, LiBH4, NaBH3CN and undesirable solvent such as DMF;5 (ii) each intermediate was evaporated to dryness to give either a solid (acid 3, alcohol 5) or an oil that could not be suitable for scale up; (iii) crystallization of the final product provided small particles that slowed down the filtration; (iv) few crops were needed to isolate the API with a moderate yield of 65 %. We therefore envisioned a second-generation synthesis.

Second-generation synthesis Our first leverage was to identify a starting material containing already the 1-amino-1cyclopropane carboxylic moiety that was commercially available on large scale. Boc-1-amino-1cyclopropane carboxylic acid 8 was selected as shown in Scheme 2. Methylation step was explored using bases such as sodium hydride (NaH), sodium hydroxide (NaOH), potassium hydroxide (KOH) or potassium tert-butoxide (t-BuOK) in tetrahydrofuran (THF) with Bu4NHSO4 as phase transfer catalyst. Dimethyl sulfate (DMS) was selected as methylating agent instead of methylene iodide thanks to higher boiling point and a better environmental footprint. KOH and t-BuOK gave the best results in terms of conversion and selectivity but the reaction mixture was thicker with KOH and this could be an issue when scaling up. Heating at 35 °C with t-BuOK and slowly adding 3 equivalents of DMS in 3.5 hours was beneficial for an easy stirring and a good mass transfer. Calorimetric studies showed 2 stages during the reaction. From 0 to 37 % of loading, heat release was about 17 w / kg of reaction mixture. From 37 to 77 % of loading, heat release dropped to 10 w / kg. This matched with GC profile where monomethylated species is formed first before being converted to the desired product.6 From 77 to 100 % of loading, no


6

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more heat was released suggesting that less DMS could be used (not explored). Scale up on 10 kg proceeded well in the Pilot Plant and provided N-methyl ester 9 with 95 % yield as fluid oil after evaporation to dryness. Remaining DMS was quantified < 12 ppm. Because lithium borohydride (LiBH4) was not easy to handle on large scale, we decided to use sodium borohydride (NaBH4) which we considered as safer reducing agent. A preliminary screening showed a moderate conversion in a mixture of THF and MeOH whereas no conversion was observed in both solvents alone.7 Compound 10 was the major impurity identified by NMR and mass spectrometry arising from intramolecular cyclisation between the alcohol moiety and the Boc group (up to 25 % in the crude mixture when prolonged reaction time). Extended studies were required to optimize the rate of conversion and to improve the selectivity working on the amount of NaBH4, MeOH and order of addition. For safety reasons, we decided to load NaBH4 first before adding THF. The best conditions were identified by adding a solution of ester in THF on a suspension of 3.5 eq of NaBH4 (incomplete conversion if less). Dropwise addition of MeOH (sluggish conversion if less than 11 eq) on the mixture heated at 55 °C allowed the reduction to start while controlling both gas evolution and foaming. Almost no accumulation was observed since only traces of ester remained at the end of the addition. Following those conditions, the level of major impurity was lowered to 1.8 % in the reaction mixture. On large scale, the rate of MeOH addition was adjusted to stabilize the temperature of the reaction mixture at 55 °C. To avoid mixing issues, the reaction was quenched by adding water first at 55 °C followed by an aqueous citric acid solution. Alcohol 5 was isolated with 95 % yield and 93.8 % purity on 7.8 kg scale. Scheme 2. Methylation reduction sequence starting from N-protected aminoacid 8a


7


a

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b

8

9

5

10

a

Reagents and conditions: (a) t-BuOK, Me2SO4, Bu4NHSO4 cat., THF, 10 °C, 95 %; (b) NaBH4, MeOH, THF, 55 °C, 95 %.

Large scale oxidation in the pharmaceutical industry is well documented.8 To avoid the generation of large amount of carbon monoxide and carbon dioxide associated to the Swern oxidation and also nasty smell, we decided to investigate a TEMPO-mediated process using inexpensive bleach (NaOCl) as co-oxidant.9 Reacting alcohol 5 with 1 mol % of TEMPO, catalytic KBr, 6 eq of NaHCO3 and bleach in a mixture of dichloromethane (DCM) and water provided the desired aldehyde without any trace of over-oxidation. In order to improve the environmental footprint of this reaction, DCM was successfully replaced with EtOAc. Aldehyde 11 was isolated as an oil in 95 % yield with a satisfactory purity and was engaged in the next step without any purification (Scheme 3). In the original synthesis, aldehyde 11 was treated with 3-aminopyridine and NaBH3CN. Many impurities were generated during this step associated with large amounts of aqueous waste to destroy. Alternate conditions were evaluated such as a mixture of titanium isopropoxide and polymethylhydrosiloxane (PMHS),10 triacetoxy borohydride (NaBH(OAc)3) with TFA or AcOH.11 However desired amine 6 was obtained with a moderate yield. Reductive amination was also investigated using hydrogen and Pd/C in solvents such as MeOH, EtOH, THF, DCM, toluene, AcOEt with or without acidic treatment (acetic acid, HCl 37 %, conc. H2SO4). Best results were obtained in EtOH with a catalytic amount of H2SO4. After one night at 60 °C and 20 bar of hydrogen, 92 % of desired Boc-protected amine 6 was obtained in the reaction mixture without any trace of corresponding alcohol or starting material (HPLC analysis). However a


8

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moderate yield of 13 isolated in the next step (only 50 %) prompted us to check by TLC the purity of crude 6. Since it was not as pure as expected, we decided to proceed stepwise by generating imine 12 first before adding the hydride. Aldehyde-imine equilibrium was displaced in refluxing toluene using a Dean-Stark apparatus to eliminate water.12 After extended optimization, complete reduction of imine 12 was achieved with 0.6 eq of NaBH4. Addition of ethanol at 65 °C was necessary to start the reaction by solubilizing NaBH4. Gas evolution and heat release were controlled by the rate of EtOH addition. To avoid gum formation, the reaction mixture was carefully quenched by adding water first followed by a 15 % aqueous citric acid solution. To obtain a good yield, monitoring pH was required before distilling EtOH, phase separation and concentration of the toluenic phase.13 Scheme 3. New conditions to synthesize 1a

a

5

b

12 in toluene

11

c

d

7

e

6

f

1

13

a

Reagents and conditions: (a) KBr cat., NaHCO3, TEMPO cat., NaOCl, EtOAc, water 20 °C, 95 %; (b) 3aminopyridine, toluene reflux, quant.; (c) NaBH4, EtOH, 65 °C, 90 %; (d) HCl, EtOH, reflux, 79 %; (e) NaOH, water, 96 %; (f) galactaric acid, iPrOH, water, 100 °C, 73 %.

In order to shorten the synthesis, Boc cleavage with galactaric acid was attempted but failed to give a decent conversion. Instead, the solution of crude Boc-protected amine was treated with a 3.5 M hydrochloride solution in anhydrous EtOH to provide after filtration hydrochloride salt 7


9


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with excellent chemical purity (> 99 %) and 71 % yield over 3 steps (imine formation, reduction, Boc cleavage and salt formation). Hemigalactarate salt 1 was identified as a suitable crystal form for development. However we had concerns about its manufacture since filtration of the slurry was slow with too much material lost in the liquors. Basic treatment of hydrochloride 7 with NaOH provided free base 13 as an oil after concentration of the organic phase. In the original synthesis, crystallization was run in a mixture of EtOH and water to provide desired compound 1 with a satisfactory purity. In order to improve both process and yield, we explored various combinations of water and alcohol such as MeOH and isopropanol (iPrOH). MeOH was quickly excluded because its amount in the final product was determined to be higher than the ICH accepted specification (> 3000 ppm by GC/MS). A first screening with iPrOH showed encouraging results (Table 1). In order to include a polish filtration in the process for clinical batch manufacturing, we also checked if the mixture was soluble at reflux. Conditions leading to a suspension were rejected (see entry 2, 7 and 8). Based on the best yield and an acceptable dilution, a 70:30 mixture of iPrOH/water, 10 mL/g was selected (entry 9).14 A second screening, focused on seeding to improve the process by avoiding spontaneous nucleation (Table 2). As shown on Figure 2, metastable zone was determined with a Crystal 16 apparatus and gave us an insight into the window for the addition of seed.15 In order to improve the productivity, starting dilutions with a 70:30 mixture of iPrOH/water at 8 mL/g (or 125 g/L, entry 1, 2, 3 and 4) and at 6 mL/g (entry 5 and 6) were evaluated. Based on Figure 2, 48 °C was considered as the ideal temperature for seeding at 8 mL/g and 58 °C for seeding at 6 mL/g. Finally, extra iPrOH was added (except entry 1) at 0 °C and aging was extended. It was beneficial and we were pleased to isolate 1 with 92 % yield on lab-scale (Table 2, entry 4). This


10

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optimized process provided clinical batches of 1 with satisfactory rate of filtration, 73 % yield and an excellent chemical purity of 99.88 %. Table 1. Effect of ratio and dilution of the iPrOH/water mixture

a

Entry

iPrOH/water

Dilution (mL/g)

Solubilization at reflux

Yield (%)a

1

80:20

32

yes

41

2

90:10

16

no

˗b

3

80:20

16

yes

0c

4

70:30

16

yes

45

5

60:40

16

yes

0c

6

50:50

16

yes

0c

7

80:20

10

no

˗b

8

75:25

10

no

˗b

9

70:30

10

yes

53

10

60:40

10

yes

51

Isolated yield after filtration at 5 °C; b Not isolated; c No crystallization.

Figure 2. Determination of the metastable zone with Crystal 16


11


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Table 2. Addition of iPrOH at 0 °C after crystallization Entry

Starting dilutiona (mL/g)

Ending dilution (mL/g)

iPrOH/water after dilution

Yield (%)b

1c

8

8

70:30

77

2c

8

13

80:20

78

3c

8

16

85:15

89

4c

8

25

90:10

92

5d

6

12

85:15

87

6d

6

18

90:10

84

a

iPrOH/water 70:30 mixture on 3 g scale; Seeding at 48 °C; d Seeding at 58 °C.

b

Isolated yield after filtration at 0 °C;

c

Telescoped process Starting from ester 9, we investigated the way to improve the global process: our goal was to circumvent handling oils. After completion of the reduction step, solvent switch to EtOAc provided alcohol 5 as solution in EtOAc that was oxidized with bleach and a catalytic amount of


12

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TEMPO. After productivity optimization of this process, we found out that NaHCO3 was not necessary. The amount of water was consequently highly reduced (0.1 mL/g instead of 15) and was only used to solubilize catalytic KBr. Solvent switch to toluene followed by condensation with 3-aminopyridine led to imine 12 which was reduced to give the Boc protected amine 6 in toluene after EtOH distillation. Boc cleavage under acidic conditions provided hydrochloride salt 7 with a global yield of 82 % and a > 99 % chemical purity (see Scheme 4). To validate this approach, free base formation with NaOH in DCM, solvent switch from DCM to iPrOH and treatment with galactaric acid provided final product 1 with 76 % yield and 99.89 % purity. Scheme 4. Telescoped process to produce the hydrochloride salt 7a

a

b

9

5 in EtOAc

c

11 in toluene

d

12 in toluene

e

7

6 in toluene

a

Reagents and conditions: (a) NaBH4, MeOH, THF, 55 °C; hydrolysis then solvent switch to EtOAc; (b) KBr cat., TEMPO cat., NaOCl, EtOAc, water, 20 °C; solvent switch to toluene; (c) 3-aminopyridine, toluene reflux; (d) NaBH4, EtOH, 65 °C; hydrolysis then EtOH distillation (e) HCl, EtOH, reflux, 82 % over 5 steps.

SUMMARY A scalable process was developed to manufacture compound 1 with an excellent chemical purity. The main issues encountered in the original synthesis were circumvented by changing the starting material and by developing suitable conditions for the Pilot Plant. Crystallization of 1 was improved to give the desired active pharmaceutical ingredient (API) with a quality that met


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clinical specifications. A telescoped procedure starting from ester 9 was also developed to generate hydrochloride salt 7 with 82 % over 5 chemical steps.

EXPERIMENTAL SECTION General. All reagents and solvents were purchased from commercial suppliers and used without further purification. Nuclear magnetic resonance (NMR) spectra were obtained using a Bruker 400 MHz spectrometer in the indicated solvents. Chemical shifts are expressed in parts per million (ppm) and coupling constants are reported in Hertz (Hz). Splitting patterns are indicated as follows: s, singlet; d, doublet; t, triplet; m, multiplet; br, broad. High Performance liquid chromatography (HPLC) data were obtained using the following methods: Compounds 6, 13, 7 and 1: Column: Uptisphere HDO 3 µm, 25 cm x 4 mm; flow rate 1 mL/min; temperature 40 °C; UV detection 210 nm; solvent system: 0.02 M of aqueous sodium heptane sulfonate adjusted to pH 2.5 with H3PO4 (A) and acetonitrile (B). Gradient: t=0 80A/20B; t=30 20A/80B. Solution of 10 mg of 6 in 20 mL of a 1:1 mixture of (A) and acetonitrile. Amount injected: 5 µL. Gas chromatography (GC) data were obtained using the following methods: Compounds 9, 5 and 11: Column: CPSIL 5CB 5 µm 25 m x 0.32 mm; flow rate 1 mL/min; temperature 40 °C to 250 °C (+ 6 °C/min); gas: H2; pressure 0.6 bar at 4.5 mL/min; injection mode: split; split rate: 60 mL/min; injector temperature: 250 °C; FID detection; detector temperature: 250 °C. Solution of 3.5 mg/mL of acetonitrile; 1 mL injected. Methyl

1-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]cyclopropane-1-carboxylate

(9).


14

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1-[(tert-Butoxycarbonyl)amino]cyclopropanecarboxylic acid 8 (10.0 kg, 49.7 mol, 1 eq) in THF (61 kg) was added in 1 hour on a suspension of potassium tert-butoxide (12.3 kg, 109.6 mol, 2.2 eq) in THF (35.5 kg). The feed line was rinsed with THF (5 kg) and the reaction mixture was stirred at 20 °C for 1 hour. The milky suspension was heated to 30 °C and DMS (19.0 kg, 150.0 mol, 3 eq) was added in 4.5 hours followed by addition of THF (5 kg) to rinse the feed line. GC analysis confirmed complete consumption of 8 at the end of the addition. 27 wt % aqueous ammonia solution (45.0 kg) was carefully added at 20 °C in 35 minutes and the reaction mixture was stirred 1 hour. After standing still for 30 minutes, the organic phase was separated. The aqueous phase was treated with water (20 L) and NaCl (4 kg) then extracted with EtOAc (26 kg). The organic layer was separated and the aqueous phase was extracted with EtOAc (26 kg). Organic layers were combined, washed with water (70 L) and concentrated to dryness to give 9 as an oil (10.8 kg, 95 % yield, 97.1 % purity). 1H NMR (400 MHz, CDCl3): δ 3.65 (s, 3 H), 2.82 (s, 3 H), 1.41 (s, 2 H), 1.37 (s, 9 H), 1.14 (br s, 2 H).

13

C NMR (100 MHz, CDCl3): δ 173.6,

156.6, 79.9, 52.2, 41.5, 34.4, 28.3 (3 C), 17.5 (2C).

Carbamic acid, N-[1-(hydroxymethyl)cyclopropyl]-N-methyl-, 1,1-dimethylethyl ester (5). Sodium borohydride (7.8 kg, 206.3 mol, 3.5 eq) was charged in a nitrogen flushed vessel followed by THF (36.2 kg) and stirred for 10 minutes at 20 °C. A solution of methyl 1-[methyl[(2-methylpropan-2-yl)oxycarbonyl]amino]cyclopropane-1-carboxylate 9 (13.52 kg, 59.0 mol, 1 eq) in THF (21.7 kg) was added in 3 minutes. The feed line was rinsed with THF (12 kg) and the reaction mixture was heated to 60 °C. Methanol (21.4 kg, 668.8 mol, 11.3 eq) was carefully added in 2.5 hours to control foam formation and gas evolution. The reaction mixture was stirred 2 hours and then cooled to 50 °C. Water (50 L) was added in 90 minutes followed by careful


15


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addition of 18 wt % aqueous citric acid solution (12.4 kg of acid in 67.6 L of water). Volatiles were removed by vacuum distillation before adding water (60 L) and EtOAc (60 kg). The aqueous layer was separated and extracted twice with EtOAc (60 kg). Organic layers were combined and concentrated until reaching Kf = 1 % then volume of solution was adjusted to 100 L. Crude alcohol 5 in EtOAc was obtained in 95 % yield and 93.8 % purity. 1H NMR (400 MHz, DMSO-d6): δ 4.65 (br s, 1 H), 3.39 (d, J = 8 Hz, 2 H), 2.75 (br s, 3 H), 1.36 (s, 9 H), 0.71 (m, 4 H). 13C NMR (100 MHz, DMSO-d6): δ 155.4, 78.2, 64.6, 41.1, 34.6, 28.1 (3 C), 12.6, 11.9. MSESI (m/z): [M + NH4]+ calcd for C10H19N03, 201.1365; found, 201.8.

Carbamic acid, N-(1-formylcyclopropyl)-N-methyl-, 1,1-dimethylethyl ester (11). TEMPO (123 g, 0.78 mol, 0.01 eq), potassium bromide (961 g, 8.1 mol, 0.1 eq) and NaHCO3 (39.19 kg, 466 mol, 6.2 eq) were charged in a nitrogen flushed vessel. A solution of carbamic acid, N-[1-(hydroxymethyl)cyclopropyl]-N-methyl-, 1,1-dimethylethyl ester 5 in EtOAc (15.36 kg, 74.4 mol, 1 eq, 124.67 kg of solution) was then added followed by water (223 kg). The biphasic mixture was stirred 30 minutes at 20 °C before adding bleach (60 kg, 1.2 eq, 1.52 mol/kg) in 100 minutes. After aging 20 minutes, TLC showed complete conversion. The reaction mixture was filtered and the cake was washed with EtOAc (14 kg). The organic layer was separated and the aqueous phase was extracted twice with EtOAc (33 kg). Organic layers were combined, washed twice with water (38.5 kg) and concentrated to dryness. Aldehyde 11 was isolated with 95 % yield and 97.6 % purity as an oil that solidifies on storage. 1H NMR (400 MHz, DMSO-d6): δ 8.73 (s, 1 H), 2.73 (s, 3 H), 1.50 (br s, 2 H), 1.38 (s, 2 H), 1.32 (s, 9 H). 13C NMR (100 MHz, DMSO-d6): δ 199.3, 155.6, 78.8, 49.2, 34.2, 27.9 (3 C), 16.2 (2 C).


16

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Carbamic acid, N-methyl-N-[1-[(3-pyridinylamino)methyl]cyclopropyl]-, 1,1-dimethylethyl ester (6). Carbamic acid, N-(1-formylcyclopropyl)-N-methyl-, 1,1-dimethylethyl ester 11 (209.5 g, 1.05 mol, 1 eq), 3-aminopyridine (104 g, 1.104 mol, 1.05 eq) and toluene (230 mL) were charged in a 2 L reactor. The reaction mixture was refluxed with a Dean Stark apparatus for 5 hours to eliminate 18 g of water. Imine 12 (290 g) was obtained in toluene (868 g). 726.5 g of this solution was added on NaBH4 (14.8 g, 393 mmol, 0.6 eq) and the suspension was heated to 65 °C. After 15 minutes, EtOH (324 g, 7.04 mol, 10.8 eq) was added in 2 hours and the reaction mixture was stirred 15 minutes at 65 °C. Water (132 g) was added in 45 minutes followed by 15 wt % citric acid solution (320 g) in 45 minutes. The solution was cooled to 20 °C and pH was checked (< 7). EtOH was removed by distillation and the two phases were separated. Aqueous layer was extracted with toluene (520 mL) and organic layers were combined then washed with water (130 mL). Concentration to dryness provided 6 as brown oil (162 g, 90 % yield). 1H NMR (400 MHz, DMSO-d6): δ 7.97 (m, 1 H), 7.72 (d, J = 4 Hz, 1 H), 7.02 (dd, J = 4, 8 Hz, 1 H), 6.926.89 (m, 1 H), 3.23 (br s, 2 H), 2.72 (s, 3 H), 1.38 (s, 9 H), 0.75 (br s, 4 H). 13C NMR (100 MHz, DMSO-d6): δ 155.3, 145.2, 136.7, 135.1, 123.5, 116.9, 78.5, 45.9, 39.5, 33.9, 28.1 (3 C), 12.7 (2 C).

N-[[1-(methylamino)cyclopropyl]methyl]pyridine-3-amine hydrochloride (1:2) (7). Carbamic acid, N-methyl-N-[1-[(3-pyridinylamino)methyl]cyclopropyl]-, 1,1-dimethylethyl ester 6 (14.3 kg, 51.6 mol, 1 eq) was dissolved at 60 °C in EtOH (20.5 kg) in a nitrogen flushed reactor. The solution was heated to reflux and 3.5 mol/kg of hydrochlorhydric ethanol (45.25 kg, 158.2 mol, 3 eq) was added in 75 minutes. The feed line was rinsed with EtOH (2.5 kg) and the


17


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reaction mixture was stirred for 20 minutes. The solution was cooled to –5 °C in 3 hours and began to precipitate at 23 °C. The suspension was stirred 2 hours at –5 °C and was then filtered. The cake was washed twice with EtOH (11 kg) and was dried under reduced pressure at 50 °C to afford 7 as white solid (10.47 kg, 79 % yield and 95.7 % purity by HPLC). 1H NMR (400 MHz, DMSO-d6): δ 9.80 (br s, 2 H), 8.23 (d, J = 4 Hz, 1 H), 8.06 (d, J = 8 Hz, 1 H), 7.82 (d, J = 8 Hz, 1 H), 7.75 (dd, J = 4, 8 Hz, 1 H), 7.70 (br s, 1 H), 3.60 (d, J = 4 Hz, 2 H), 2.59 (s, 3 H), 1.17 (d, J = 4 Hz, 2 H), 0.85 (d, J = 4 Hz, 2 H).

13

C NMR (100 MHz, DMSO-d6): δ 147.8, 128.6, 127.7,

127.6, 124.7, 43.6, 40.1, 30.4, 9.0 (2 C).

N-[[1-(methylamino)cyclopropyl]methyl]pyridine-3-amine (13). N-[[1-(methylamino)cyclopropyl]methyl]pyridine-3-amine hydrochloride (1:2) 7 (10.37 kg, 41.5 mol, 1 eq) and water (31.1 kg) were charged in a nitrogen flushed reactor. A solution of 85.6 kg of NaOH (10.85 kg, 271.3 mol, 6.5 eq in 74.7 kg of water) was added in 10 minutes at 20 °C and the reaction mixture was stirred for 20 minutes. Dichloromethane (68.8 kg) was added to the reaction mixture and phases were separated. The aqueous layer was extracted with dichloromethane (68.8 kg). Organic layers were combined and concentrated to dryness to give free amine 13 as viscous oil (7.10 kg, 96 % yield and 95.8 % purity). 1H NMR (400 MHz, DMSO-d6): δ 8.00 (d, J = 4 Hz, 1 H), 7.74 (d, J = 4 Hz, 1 H), 7.08-7.04 (m, 1 H), 6.92 (dd, J = 1, 4 Hz, 1 H), 5.74 (m, 1 H), 3.04 (d, J = 4 Hz, 2 H), 2.25 (s, 3 H), 2.15 (m, 1 H), 0.53-0.49 (m, 2 H), 0.46-0.42 (m, 2 H).

13

C NMR (100 MHz, DMSO-d6): δ 145.8, 137.1, 135.7, 124.0, 117.7,

45.8, 40.0, 32.0, 12.4 (2 C).

N-[[1-(methylamino)cyclopropyl]methyl]pyridine-3-amine hemigalactarate (1).


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N-[[1-(methylamino)cyclopropyl]methyl]pyridine-3-amine 13 (6.67 kg, 37.7 mol, 1 eq) was dissolved in isopropanol (20 kg) and stirred for 30 minutes at 20 °C. Galactaric acid (3.95 kg, 18.8 mol, 0.5 eq) was charged in a nitrogen flushed reactor followed by the solution of 13. Water (16 L) was added followed by iPrOH (9.3 kg) and the suspension was heated to reflux. After complete solubilization, the resulting solution was filtered through a 0.5 µm in-line filter and then cooled down to 60 °C in 30 minutes. 1.35 L of solution were removed and cooled at 0 °C. The reaction mixture was cooled to 48 °C in 15 minutes and seeding was performed by adding 1.35 L of the cooled suspension. The reaction mixture was stirred at 48 °C for 1 hour, cooled to 45 °C in 100 minutes, to 30 °C in 180 minutes and then to 0 °C in 240 minutes. Isopropanol (82.7 kg) was added in 5 hours and the suspension was stirred at 0 °C for 180 minutes. After filtration, the cake was washed four times with iPrOH (16 kg) and dried at 50 °C on the filter. Compound 1 was isolated as white powder with 73 % yield and 99.88 % purity. 1H NMR (400 MHz, D2O): δ 7.91 (s, 1 H), 7.80 (dd, J = 1, 4 Hz, 1 H), 7.20-7.17 (m, 1 H), 7.13 (dd, J = 1, 4 Hz, 1 H), 4.14 (s, 1 H), 3.84 (s, 1 H), 3.33 (s, 2 H), 2.63 (s, 3 H), 1.03-0.99 (m, 2 H), 0.91-0.87 (m, 2 H).

13

C NMR (100 MHz, D2O): δ 179.4, 144.7, 137.7, 134.5, 124.7, 121.4, 71.7, 71.4,

44.4, 40.1, 30.2, 8.8 (2 C).

Telescoped procedure for compound 7 Oxidation: TEMPO (1.78 g, 11 mmol, 0.01 eq), KBr (13.9 g, 111 mmol, 0.10 eq) and carbamic acid, N-[1-(hydroxymethyl)cyclopropyl]-N-methyl-, 1,1-dimethylethyl ester 5 (222 g, 1.11 mol, 1 eq) were charged in a 4 L reactor followed by EtOAc (1.64 L) and water (22 mL). The reaction mixture was stirred at 20 °C and a solution of bleach (819 g, 1.47 mol, 1.32 eq) was added in 2 hours. At the end of the addition, GC analysis confirmed complete consumption of 9. Layers


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were separated and the aqueous phase was extracted twice with EtOAc (660 mL). Organic layers were combined and washed with water (660 mL). The solution was heated to reflux and 1.5 L of EtOAc was distilled before adding toluene (950 mL) dropwise while heating progressively to 120 °C. After removing traces of EtOAc, aldehyde 11 (210 g) was obtained in toluene (811 mL) with 98.3 % purity. Reductive amination: To this solution was added 3-aminopyridine (104 g, 1.10 mol, 1.05 eq) followed by toluene (236 mL). The reaction mixture was heated to reflux and water was removed with a Dean Stark apparatus. After stirring for 5 hours at reflux, the reaction mixture was cooled to 20 °C and was added in a 2 L reactor on NaBH4 (14.8 g, 393 mmol, 0.6 eq). The suspension was heated to 65 °C and EtOH (324 g, 10.8 eq) was added dropwise in 2 hours. HPLC control showed complete conversion and water (132 mL) was added in 45 minutes followed by a 15 wt % aqueous citric acid solution (329 g) in 45 minutes. The reaction mixture was then heated to reflux and EtOH was distilled. After cooling at 20 °C, the organic layer was removed and the aqueous phase was extracted with toluene (520 mL). Organic layers were combined, washed with water (130 mL) and concentrated to provide 444.5 g of solution of 6 (162.5 g in 325 mL of toluene) with 86.9 % purity. Boc-cleavage and hydrochloride formation: 146 g of toluenic solution of 6 (50 g, 1.78 mmol, 1 eq) was heated to 70 °C and stirred for 15 minutes. A 3.2 M hydrochlorhydric solution of EtOH (167 mL, 3.3 eq) was added dropwise in 70 minutes and the reaction mixture was stirred for 2 hours. HPLC control showed complete conversion and temperature was cooled to 0 °C in 2 hours. After 1 hour stirring, the suspension was filtered and washed twice with toluene. The cake was dried at 80 °C overnight to give hydrochloride salt 7 with 82 % yield and 99.6 % purity.

AUTHOR INFORMATION


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Corresponding Author *E-mail: [email protected] ORCID Christophe Hardouin: 0000-0002-0438-5644 Notes The authors declare no competing financial interest. ACKNOWLEDGMENT We would like to acknowledge A. Grenier and N. Pinault for hydrogenation studies, A. Pimont and S. Mathieu for safety assessment studies, D. Castagnos for NMR analysis, P. Authouart for analytical support. REFERENCES (1) For details, https://www.alz.org / (2) Drachman D. A.; Leavitt J. Human memory and the cholinergic system. A relationship to aging ?, Arch. Neurol. 1974, 30, 113–121. (3) (a) Cassels B. K.; Bermudez I.; Dajas F.; Abin-Carriquiry J. A.; Wonnacott S. From ligand design to therapeutic efficacy: the challenge for nicotinic receptor research. Drug Discovery Today 2005, 10, 1657–1665. (b) Buccafusco J. Neuronal nicotinic receptor subtypes. Molecular Interventions 2004, 4, 285–295. (c) Gatto G. J.; Bohmes G. A.; Caldwell W. S.; Letchworth S. R.; Traina V. M.; Obinu M. C.; Laville M.; Reibaud M.; Pradier L.; Dunbar G.; Bencherif M. TC-1734: An orally active neuronal icotinic acetylcholine receptor modulator with antidepressant, neuroprotective and long-lasting cognitive effects. CNS Drug Reviews, 2004, 10, 147–166. (d) Geerts H. Ispronicline (Targacept). Curr. Opin. Investig. Drugs 2006, 7, 60–69. (e)


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Holladay, M. W.; Dart, M. J.; Lynch, J. K. Neuronal nicotinic acetylcholine receptors as targets for drug discovery. J. Med. Chem. 1997, 40, 4169–4193. (f) Newhouse P.; Potter A.; Corwin J. Effects of nicotinic cholinergic agents on cognitive functioning in Alzheimer’s and Parkinson’s disease. Drug Dev. Res. 1996, 38, 278–289. (4) (a) Goldstein, S.; Guillonneau, C.; Charton, Y.; Lockhart, B.; Lestage, P. Novel Polysubstituted 1,1-Pyridinyl Aminocyclopropanamine. Derivatives, Method For Preparing Same and Pharmaceutical Compositions Containing Same. Patent WO2007012761, July 27th, 2005. (b) Charton, Y.; Guillonneau, C.; Lockhart, B.; Lestage, P.; Goldstein, S. Preparation and affinity profile of novel nicotinic ligands. Bioorg. Med. Chem. Lett. 2008, 18, 2188–2193. (5) Mariotte, D.; Fouquet, M.-H.; Le Flohic, A.; Dhulut, S.; Pin, F.; Le Blanc, A.; Rollin, A.; Picard, J. Élaboration d’un guide de choix de solvants durables. L’actualité Chimique 2018, 427428, 95–99. (6) GC and TLC showed that kinetics of N-methylation was faster than O-methylation. (7) Rawalpally, T.; Ji, Y.; Cleary, T.; Edwards, B. Scalable Non-Aqueous Process to Prepare Water Soluble 3-Amino-pentan-1,5-diol. Org. Process Res. Dev. 2009, 13, 478–482. (8) Caron, S.; Dugger, R. W.; Gut Ruggeri, S.; Ragan, J. A.; Brown Ripin, D. H. Large-Scale Oxidations in the Pharmaceutical Industry. Chem. Rev. 2006, 106 (7), 2943–2989. (9) Ciriminna, R.; Pagliaro, M. Industrial Oxidations with Organocatalyst TEMPO and Its Derivatives. Org. Process Res. Dev. 2010, 14, 245–251. (10) Chandrasekhar, S.; Raji Reddy, C.; Ahmed, M. A. Single Step Reductive Amination of Carbonyl Compounds with Polymethylhydrosiloxane-Ti(OiPr)4. Synlett 2000, 11, 1655–1657.


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(11) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah, R. D. Reductive Amination of Aldehydes and Ketones with Sodium Triacetoxyborohydride. Studies on Direct and Indirect Reductive Amination Procedures. J. Org. Chem. 1996, 61, 3849–3862. (12) Imine 12 was characterized by 1H and 13C NMR as a mixture of cis and trans isomers. (13) pH 7 was selected to avoid Boc removal and losses of 6 in the aqueous layer during phase separation. (14) Replacement of iPrOH by EtOH under the same conditions gave a lower yield (44 % instead of 53 %). (15) Beckmann, W. Seeding the Desired Polymorph: Background, Possibilities, Limitations, and Case Studies. Org. Process Res. Dev. 2000, 4, 372–383.


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Development of an Efficient Synthesis of an Agonist of Acetylcholine

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