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Redesign of the Synthesis and Manufacture of an Azetidine-Bearing Pyrazine David R. J. Hose, Phillip Hopes, Alan Steven, and Christian Herber Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00384 • Publication Date (Web): 18 Jan 2018 Downloaded from http://pubs.acs.org on January 18, 2018

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Organic Process Research & Development

Redesign of the Synthesis and Manufacture of an Azetidine-Bearing Pyrazine David R. J. Hose†, Phillip Hopes‡, Alan Steven*,† and Christian Herber§ †

Pharmaceutical Technology & Development, AstraZeneca, Charter Way, Macclesfield, SK10 2NA, United Kingdom

‡

Cyton Biosciences Ltd, 68 Macrae Road, Bristol, BS20 0DD, United Kingdom

§

DOTTIKON Exclusive Synthesis AG, P.O. Box CH – 5605 Dottikon, Switzerland [email protected]

ACS Paragon Plus Environment

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

Table of Contents graphic


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ABSTRACT Commercial route definition for a glucokinase activator called for a re-evaluation of the synthesis and processes used to access multikilogram quantities of a pyrazine building block. The processes developed allowed a literature route to sodium 6-oxo-1H-pyrazine-3carboxylate to be leveraged.

One of these processes consisted of a highly selective

decarboxylation that allowed the target building block to be accessed with complete regioselectivity in standard batch processing equipment. The presence of an azetidine ring in the target required the mitigation of impurity liabilities arising from the use of the hydrochloride salt of azetidine as an input material.

KEY WORDS azetidine, decarboxylation, glucokinase activator, pyrazine, sulfolane



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INTRODUCTION AZD1656 (1), a compound containing two pyrazine units, has been developed by AstraZeneca as a glucokinase activator for the treatment of type 2 diabetes.1-3 This article will discuss the development of the manufacturing processes used to obtain chloropyrazine 2, (Scheme 1) one of the key building blocks of AZD1656 (1).

Scheme 1. Principal disconnections of AZD1656 (1)

AZD1656 (1)

2

ArOH =

TACTICAL CHANGES TO MEDICINAL CHEMISTRY APPROACH The chemistry utilised by medicinal chemistry colleagues is outlined in Scheme 2. Ester 3 was first converted to acid 4 using lithium chloride in DMF. The conversion of acid 4 to acid chloride 5 used oxalyl chloride and was catalysed by DMF that tracked through from the first stage. When AZD1656 progressed into development, potassium carbonate in THF was successfully introduced for the conversion of ester 3 to acid 4.

Dichloromethane was

developed out of the acid chloride formation as part of a switch to the use of thionyl chloride and catalytic tetrabutylammonium chloride in toluene. Acid chloride 5 was then coupled with an aqueous solution of azetidine whose alkalinity was maintained above pH 9 using


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potassium carbonate. With these changes in place, 130 kg of chloropyrazine 2 were delivered as part of initial development deliveries.

Scheme 2. Medicinal chemistry approach to chloropyrazine 2 a 91 % 3

4

b

c

5

77 % over 2 steps 2

(a) LiCl, DMF; (b) (COCl)2, CH2Cl2; (c) (i) (CH2)3N•HCl, Et 3N, (ii) chromatography

DEVELOPMENT OF AZETIDINE ACYLATION As development progressed, the use of externally sourced acid 4 proved to be more attractive on cost grounds versus the continued use of ester 3 as the starting material. Development efforts focused at this stage on the amidation of acid chloride 5 with azetidine (6). Sourcing azetidine free base was ruled out due to its tendency to oligomerize,4 necessitating the sourcing and use of the hydrochloride salt.5 Accelerating rate calorimetry of this salt indicated an onset of exothermic activity from ~71 °C, and 29 °C was evaluated as the temperature at which it would take 24 h for the decomposition to reach its maximum rate under adiabatic conditions.6 It was shipped and stored in 100 kg lots kept at 5 °C.7 Compounds 7 and 8, two of the impurities repeatedly present in amide 2 that had been manufactured to date, implied the opening of the azetidine ring at some stage. Adding the acid chloride 5 solution to a basic solution of azetidine was found to be important in limiting the ring-opening of the azetidine ring of chloropyrazine 2 by chloride, though at the expense of the formation of impurity 9. 3-Chloropropylamine (10) in the azetidine hydrochloride



input material was identified as the principal source of impurity 7. It was also shown that 3chloropropylamine reacts faster with acid chloride 5 than azetidine so any increase in the charge of azetidine relative to acid chloride 5, would increase levels of alkyl chloride 7. Whilst a typical level of 3-chloropropylamine in azetidine hydrochloride was of the order of 0.5–1.0% wt/wt, 10% wt/wt was detected in one batch that had been destined for a kilogram lab manufacture. Fortuitously, it proved possible to control levels of 3-chloropropylamine by washing the aqueous azetidine solution with toluene prior to use in the coupling with acid chloride 5.

7

9

8

10

Figure 1. Impurities in chloropyrazine 2

REVISED SYNTHESIS OF CHLOROPYRAZINE 2 Whilst a further 430 kg of chloropyrazine 2 were delivered starting from acid 4, the latter occasionally required drying on receipt before it could be successfully engaged in the transformation to acid chloride 5 and it was proposed that it would be cheaper to manufacture it inhouse.8 Ideas for its synthesis, some of which use validated literature precedent,9-13 are shown in Scheme 3. The route disclosed by Mano et al. was selected for development based


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on its use of inexpensive and readily available diaminomaleonitrile (11) and glyoxylic acid (12) as starting materials.

Scheme 3. Possible means of synthesizing acid 4

reference 11

references 9-10

4 reference 13

12

11

reference 12

Scheme 4. Revised synthesis of chloropyrazine 2

a

c

b

Na • 16

14

11

•OH2 Na • 13

e

d

f

5

13

4

g

5

2

Na • 17

15

a) glyoxylic acid, sulfuric acid, water, 30 °C; b) i) NaOH (aq), 10 °C, ii) 100 °C, iii) 10 °C, H2SO4 (aq); c) sulfolane, toluene, Aliquat 336, 150 °C; d) i) NaOH (aq), ii) HCl (aq); e) i) PCl5, toluene, 80 °C, ii) water; f) i) nBu4NCl, toluene, 73 °C, ii) SOCl2; g) i) (CH2)3NH2Cl, K 2CO3, toluene, water, ii) acid chloride 5


16


The studies of Mano et al., which ultimately take us as far as the sodium salt Na•13, start with the condensation of equimolar amounts of diaminomaleonitrile and glyoxylic acid monohydrate.9,14 Whilst their condensation to form bisnitrile 14 proceeds without the need for exogeneous acid, the use of a catalytic amount of sulfuric acid was found to accelerate the reaction. It also avoided the initial formation of a voluminous suspension with poor mixing properties when no acid was used. The decision not to isolate bisnitrile 14 was made after initial lab-scale isolations provided a low-melting solid (mp 180 °C), that were beyond the capability of standard reactor vessels. Catalytic amounts of Brønsted acid were initially used in sulfolane in an attempt to partially solubilise sodium salt Na•16 and to lower the temperature required for the decarboxylation to one that could be achieved using standard plant equipment. Whilst successful, this approach formed sodium salt Na•13 that was dark in colour and of low strength. The replacement of the Brønsted acid by phase-transfer catalysts Aliquat HTA-1 or Aliquat 336 allowed the decarboxylation to proceed without excessive darkening of the reaction mixture. The latter was used for cost reasons, despite its tendency to degrade under the reaction conditions. Controlling the water content of the reaction mixture prior to the addition of the catalyst helped to control the colour of the sodium salt Na•13 produced during the decarboxylation, and was achieved through azeotropic distillation with toluene. None of the regioisomeric 2,6-disubstituted product Na•17 arising from decarboxylation at the 3-position of the pyrazine ring was detected during the conversion of

Na•16 to Na•13. A possible explanation for the regioselectivity of the reaction is the loss of carbon dioxide to initially form a carbanion 18 that is in the plane of the σ-framework of the pyrazine ring. If such a species were to form at the 3-position, as in carbanion 19, then it would be destabilised by a lone pair-lone pair repulsion (Scheme 5). Consistent with this possible explanation, limited calculations performed using dimethyl sulfoxide as a surrogate solvent for sulfolane, showed the free energy change was more unfavourable when the decarboxylation took place at the 3-position, rather than the 2-position (Scheme 5). Whilst the decarboxylation is an irreversible process, application of the Bell-Evans-Polanyi principle



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might reasonably lead to an expectation that the respective activation energy barriers reflect this difference in free energy.

The solution calculations additionally indicated that the

carboxylate virtually exclusively resides at the 2-position, rather than the 3-position, further biasing the outcome of the decarboxylation.

Scheme 5

− CO2 2 −

∆Grxn = +57.6 kJ/mol

18

Calculations performed at IEFPCM//B3LYP/6-31+G(d,p) level of theory

3 2

Na • 16

∆G = −27.2 kJ/mol − CO2 3 2

− 3

∆Grxn = +90.0 kJ/mol 19

Initial attempts at isolating sodium salt Na•13 involved adding ethyl acetate to the sulfolane (mp 27.5 °C) solution to allow the slurry to be manipulated at ambient temperatures. This led to sodium salt Na•13 displaying a very small particle size, to the detriment of the filtration time. Washing the cake with ethyl acetate failed to completely displace all of the sulfolane, and was implicated in the formation of further fines which reduced the filtration performance still further. These issues were overcome by filtering the slurry produced at the end of the reaction at 70 °C, in order to avoid the freezing of the sulfolane solvent, and then washing the cake with toluene. The presence of residual sulfolane in sodium salt Na•13 on scaling up was implicated in balling observed when in a dryer, as well as significantly lowering the yield as part of its subsequent conversion to acid 4. The development of a process that would completely rid isolated sodium salt Na•13 of sulfolane was mindful of the lack of recrystallization options afforded by its insolubility in organic solvents.

The discovery that the yield for the


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conversion to acid 4 could be increased from 60–68% to 85–90% by switching from (sulfolane-free) sodium salt Na•13 to the corresponding free acid as the starting material, guided the decision to target the isolation of acid 13 itself. This was conveniently done by dissolving sodium salt Na•13 off the filter with an alkaline solution, washing with toluene, to remove any residual Aliquat 336 and the products of its decomposition, before acidifying with hydrochloric acid to precipitate the free acid in a form that filtered easily.

This

delivered 831 kg of high strength (98% wt/wt) acid 13 in an average yield of 77% from sodium salt Na•16. It was recognised that the long-term use of hydrochloric acid for the acidification ran the risk of corroding parts of the plant, though its use was retained for development manufacture, as the use of sulfuric acid led to the contamination of the sodium salt Na•13 isolated with sodium sulfate. The double chlorination of acid 13 to acid chloride 5 using just thionyl chloride did not proceed to completion.

The finding that it could be accelerated using phosphorus

pentachloride as an additive led to the use of phosphorus pentachloride in toluene. In the optimised procedure, the reaction was initially run at 50 °C to selectively complete the formation of the acid chloride 5 before it was heated to 85 °C in order to chlorinate the pyrazinone ring. Acid chloride 5 formed from acid 4 in this manner was not deemed to be of sufficient quality for use in the manufacture of chloropyrazine 2. To circumvent this, the phosphorus oxychloride by-product of the chlorination was distilled off and the initially formed acid chloride 5 was hydrolysed to acid 4, a material that crystallised out of aqueous solution. This initially produced a reddish brown solid, though the treatment of the acid chloride 5 solution with charcoal, prior to the hydrolysis, allowed material that was a lighter brown and displayed a strength of >99.5% wt/wt to be reproducibly isolated. The procedure was used to deliver 698 kg of acid 4 in an average yield of 86% from acid 13 as part of a manufacturing campaign. The acid 4 so isolated was elaborated to chloropyrazine 2 using the



previously established procedure which involved reforming acid chloride 5 and then coupling with azetidine.

CONCLUSIONS A means of manufacturing chloropyrazine 2 on a large scale has been developed. One of the challenges that had to be overcome involved handling azetidine, a material that poses process safety concerns either as its free base or hydrochloride salt, and whose facile ring-opening by chloride had to be addressed. Due to concerns over the handling and transport of azetidine hydrochloride, the inhouse hydrogenolysis of N-benzhydrylazetidine was envisaged as a more appropriate means of accessing azetidine over the long-term. Issues associated with using sulfolane as solvent for a high temperature decarboxylation also had to be overcome as part of the development of an economically viable, regioselective and scalable means of accessing acid 13. Whilst the number of chemical transformations (excluding salt breaks) in the route to chloropyrazine 2 is high (7), it is replete with control points. It was used to deliver 647 kg of chloropyrazine 2 in a single manufacturing campaign, with an overall yield of 44.3% yield from diaminomaleonitrile (11). With further development, there may well be the opportunity to access chloropyrazine 2 directly from acid 13 without the need to isolate acid 4.

EXPERIMENTAL SECTION General. NMR spectra were recorded on a Bruker instrument with tetramethylsilane (TMS) as internal reference, unless otherwise stated. Chemical shifts are expressed in ppm (δ) relative to TMS, whilst coupling constants (J) are in Hz. Infrared spectra were recorded with diamond ATR sampling on an FTIR spectrometer using powdered samples. Melting points were recorded using a Q2000 differential scanning calorimeter from TA Instruments. High


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resolution mass spectra were recorded on a Waters Synapt UPLC-MS instrument. Unless stated otherwise, commercial grade materials were used.

Sodium

3-carboxy-6-oxo-1H-pyrazine-2-carboxylate

monohydrate

(Na•16).

Aqueous glyoxylic acid solution (244 kg of 50% wt/wt, 1.65 kmol)15 was added over at least 30 min. to a solution of diaminomaleonitrile (178 kg, 1.65 kmol) and sulfuric acid (35.6 kg of 50% wt/wt, 181 mol) in water (1041 L). The batch held for a further 30 min. at 30 °C before it was polish filtered, washing through with more water (89 L).16 1H NMR (referenced to water peak at δH = 4.79, 500 MHz, 27 °C) 8.24 (1H, s).

13

C NMR (unreferenced in water,

125.7 MHz, 27 °C) 160.6, 144.5, 129.8, 120.6, 114.3, 112.6. Sodium hydroxide solution (660 kg of 50% wt/wt, 8.25 kmol) was then added to the filtrate with cooling such that the temperature did not rise above 10 °C during the addition of the first 60% of the charge.17 The batch was then aged for 6 h at 100 °C before being cooled to 60 °C and diluted with water (712 L).18 After cooling to 10 °C,19 the pH was adjusted to 2 using sulfuric acid solution (ca. 712 kg of 50% wt/wt, 3.63 kmol),20 resulting in the crystallisation of monosodium salt Na•16. The batch was allowed to desupersaturate for a further 30 min., before it was filtered and the cake sequentially washed with water (823 L) and isopropanol-water (826 L of 67%v/v). Vacuum drying at 45 °C gave monosodium salt monohydrate Na•16 as a tan solid (339 kg at 99.1% wt/wt, 90.8%). Mp 144.0 °C. IR 3158, 1669, 1594, 1524, 1464, 1441, 1345, 1096, 964, 835, 814, 781, 759, 710, 643 cm-1. 1H NMR (DMSO-d6, 500 MHz, 27 °C) δ 11.21 (1H, br s), 8.12 (1H, s), 3.34 (2H, br s). H

13

C NMR

(DMSO-d6, 125.7 MHz, 27 °C) δ 163.4, 161.3, 154.7, 150.1, 134.8, 125.4. HRMS C

elemental calculated for C6H3N2O5 (M–H+ where M is diacid 16): 183.0042; found: 183.0039.



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6-Oxo-1H-pyrazine-3-carboxylic acid (13). A slurry of monosodium salt Na•16 (95.0 kg at 99.1% wt/wt, 420 mol) in sulfolane (420 kg) and toluene (40 L) was prepared and vacuum distilled at ca. 60 °C to remove some of the toluene (10 L). Aliquat 336 in toluene (28 kg of 50% wt/wt, 34.6 mol) was added, washing through with more toluene (5 L). The batch was vacuum distilled at 60 °C, using a Dean-Stark arrangement with a toluene-filled receiver, until the water content was ≤ 0.3% wt/wt (ca. 2 L water removed). The batch was then aged for 2.5 h at 150 °C before being cooled to 70 °C, and filtered hot.21 The cake was washed with toluene (137 L), before being dissolved off the filter with sodium hydroxide solution (825 kg of 2.36% wt/wt, 487 mol). The small organic phase was separated off, before the aqueous phase was washed with more toluene (58 L). The aqueous phase was adjusted to pH 1.0 using hydrochloric acid (ca. 90 kg of 33% wt/wt, 815 mol).

The

temperature was kept below 45 °C during the addition, until the pH was 6.5 whereupon the temperature was adjusted to 75 °C for the remainder of the addition. Activated charcoal (3.5 kg Chemviron PWA) was stirred with the batch for 90 min whilst it was at 75 °C. It was then warmed to 90 °C and filtered, washing through with hydrochloric acid solution (32 kg of 2.1% wt/wt, 18 mol). The temperature of the filtrate was then lowered to 5 °C over at least 90 min. and the slurry filtered. The cake was washed with water (3 x 67 L), before it was vacuum dried below 55 °C using a paddle dryer. This afforded acid 13 as a light brown solid (45.4 kg, 77.1%). Mp 269.2 °C. IR 2889, 1724, 1614, 1389, 1301, 1249, 1200, 1135, 877, 790, 785, 729, 633 cm-1. 1H NMR (DMSO-d6, 500 MHz, 27 °C) δ 8.05 (1H, d, J=1.1 Hz), H

7.98 (1H, d, J=1.1 Hz). 133.1, 124.0.

13

C NMR (DMSO-d6, 125.7 MHz, 27 °C) δ 164.6, 155.9, 147.8, C

HRMS elemental calculated for C5H3N2O3 (M–H+): 139.0144; found:

139.0143.

5-Chloropyrazine-2-carboxylic acid (4). A slurry of acid 13 (48.0 kg, 343 mol) in toluene (195 L) was added to a solution of phosphorus pentachloride (150 kg, 720 mol) in


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toluene (200 L) that was being stirred at 0 °C. The addition was washed through with more toluene (85 L). After being heated for 2 h at 80 °C, a put (480 L) and take (ca. 530 L) vacuum distillation was performed at 70 °C. Activated charcoal (1.2 kg Chemviron PWA) was stirred with the batch for 30 min at the same temperature, before the batch was cooled to 20 °C and filtered into a receiver containing water (240 L), washing through with more toluene (48 L). The mixture was stirred at 20 °C for 10 h, and at least 60 min at 0 °C before it was filtered. The cake was sequentially washed with water (48 L) and toluene (48 L), and dried below 45 °C to give acid 4 as a white solid (46.5 kg, 85.6%). Mp 157.5 °C. IR 1730, 1319, 1310, 1264, 1158, 1120, 1029, 911, 844, 826, 799, 728, 720 cm-1. 1H NMR (DMSOd6, 500 MHz, 27 °C) δ 9.01 (1H, s, J=1.3 Hz), 8.92 (1H, s, J=1.3 Hz). H

13

C NMR (DMSO-d6,

125.7 MHz, 27 °C) δ 164.4, 151.1, 145.5, 144.4, 142.5. HRMS elemental calculated for C

C5H2ClN2O2 (M–H+): 156.9805; found: 156.9801.

5-Chloropyrazine-2-carbonyl chloride (5). A slurry of acid 4 (320 kg, 2.02 kmol) and tetrabutylammonium chloride (6.4 kg, 23 mol) was slurried in toluene (1220 L) and heated to 73 °C. Thionyl chloride (341 kg, 2.87 kmol) was dosed in over at least 60 min and rinsed through with more toluene (230 L). After stirring for a further 4 h, a put (1530 L) and take (ca. 1700 L) vacuum distillation was performed at 50 °C. The put (1700 L) and take (ca. 1700 L) vacuum distillation was then repeated, before more toluene (2856 L) was added. This solution of acid chloride 5 (ca. 9.0% wt/wt) could be stored at 20 °C. A sample was analysed by 1H NMR after solvent swapping from toluene to CDCl3. 1H NMR (CDCl3, 400 MHz, 27 °C) δ 9.11 (1H, d, J=1.3 Hz), 8.82 (1H, d, J=1.3 Hz). H

Azetidin-1-yl(5-chloropyrazin-2-yl)methanone (2).

An aqueous potassium carbonate

solution (508 kg of 12% wt/wt, 0.44 kmol) was added to a slurry of azetidine hydrochloride (83 kg, 0.89 kmol)22 in toluene (777 L) such that the temperature remained below 20 °C.



After washing through with water (327 L), the biphasic mixture was stirred for 30 min at 20

°C before being optionally filtered. The phases were cut and the aqueous phase washed with toluene (2 x 777 L). Potassium carbonate (229 kg, 1.66 kmol) was added to the aqueous phase after the first toluene wash. A known fraction of acid chloride 5 solution in toluene (1598 kg at 9.0% wt/wt, 0.81 kmol) prepared above was then added over 60 min., before being washed through with toluene (159 L). After a further 30 min, the reaction mixture was filtered and the filter cake rinsed with toluene (230 L). The phases were cut and the organic phase sequentially washed with water (767 L), hydrochloric acid solution (140 kg of 33% wt/wt diluted with 767 L water), and then sodium chloride solution (896 kg of 25% wt/wt). A vacuum distillation at about 50 °C was then used to remove some of the toluene (2270 L). Heptanes (1635 L) were then added and the batch treated with activated charcoal (16 kg) for 60 min at 95 °C. The batch was filtered hot, washing through with hot heptane (166 L). The temperature was then adjusted to 55 °C, prior to seeding with chloropyrazine 2 (0.1 kg) slurried in heptane (7 L).

Desupersaturation to a thick slurry was allowed to proceed

whereupon the jacket temperature was linearly ramped over at least 3 h so that the final batch temperature was below −5 °C. Desupersaturation was allowed to proceed for a further 3 h, before the slurry was isolated and the cake washed with petroleum ether (2 x 184 L of fraction 140–155 °C). The wet cake was vacuum dried at 45 °C to give chloropyrazine 2 as a white solid (117 kg, 73.4% from acid 4, based on the use of 40.0% of the acid chloride 5 solution). Mp 104.2 °C. IR 1624, 1434, 1297, 1140, 1122, 1024, 991, 920, 791, 707, 610 cm-1. 1H NMR (DMSO-d6, 500 MHz, 27 °C) δ 8.91 (1H, d, J=1.3 Hz), 8.83 (1H, d, J=1.3 H

Hz), 4.53 (2H, dd, J=7.7, 7.7 Hz), 4.10 (2H, dd, J=8.1, 7.6 Hz), 2.29 (2H, dddd, J=8.1, 7.7, 7.7, 7.6 Hz).

13

C NMR (DMSO-d6, 125.7 MHz, 27 °C) δ 162.1, 149.7, 145.0, 144.4, 142.8, C

54.1, 48.9, 16.1. HRMS elemental calculated for C8H9N3OCl (M+H+): 198.0434; found: 198.0440.


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ASSOCIATED CONTENT Supporting information available: 1H NMR spectra,

13

C NMR spectra, infrared spectra and

DSC traces for sodium salt Na•16, acid 13, acid 4 and chloropyrazine 2.

AUTHOR INFORMATION Corresponding Author E-mail: [email protected] ORCID Alan Steven: 0000-0002-0134-0918 ORCID David R. J. Hose: 0000-0003-3872-7996

Notes The authors declare no competing financial interest.

References 1.

McKerrecher, D.; Waring, M. J., Chapter One - Property-Based Design in the

Optimisation of Benzamide Glucokinase Activators: From Hit to Clinic. In Progress in Medicinal Chemistry, Lawton, G.; Witty, D. R., Eds. Elsevier: 2013, 52, 1. 2.

Waring, M. J.; Clarke, D. S.; Fenwick, M. D.; Godfrey, L.; Groombridge, S. D.;

Johnstone, C.; McKerrecher, D.; Pike, K. G.; Rayner, J. W.; Robb, G. R.; Wilson, I., Property based optimisation of glucokinase activators - discovery of the phase IIb clinical candidate AZD1656. Med. Chem. Commun. 2012, 3, 1077. 3.

Processes for making AZD1656 are covered in the following patents. a) Butters, M.

Crabb, J.; Hopes, P.; Patel, B. Process for preparation of benzoyl amino heterocyclic compounds. WO 2010092387, August 19, 2010. b) Bowden, S. A.; Hoile, D. P.; Lövqvist, K. Crystalline polymorphic form 631. WO 2010092386, August 19, 2010. c) Briggner, L.-



E.; Lindfors, L.; Smith, C. M. Pharmaceutical formulations. WO 2012007758, January 19, 2012. 4.

Goethals, E. J.; Schacht, E. H.; Bogaert, Y. E.; Ali, S. I.; Tezuka, Y. Polym. J. (Tokyo)

1980, 12, 571. 5.

Alabanza, L. M.; Dong, Y.; Wang, P.; Wright, J. A.; Zhang, Y.; Briggs, A. J. Org.

Process Res. Dev. 2013, 17, 876. 6.

Azetidine hydrochloride was found to decompose with an energy of –820 J/g, though

without the attendant gas evolution that would indicate a detonation or deflagration, and there was no sensitivity to impact in a BAM Fallhammer test. 7.

The material was classified as a solid with UN number 3238 (“self-reactive solid type,

temperature controlled”). 8.

Alternative means of accessing chloropyrazine 2 that did not route via acid 4 were

ideated but were not investigated due to the positive and established experience that existed around the conversion of acid 4 to chloropyrazine 2. A further attraction of accessing chloropyrazine 2 from acid 4 and acid chloride 5 was the stability of toluene solutions of the latter which enabled it to be stored for months at 21 °C. 9.

Mano, M.; Seo, T.; Imai, K. Chem. Pharm. Bull. 1980, 28, 3057.

10.

Hosogai, T.; Nishida, T.; Stoi, K.; Takagi, T. 2-Substituted 5,6-dicyano-3-

hydroxypyrazines. JP 50059379, May 22, 1975. 11.

Sato, N.; Arai, S. J. Heterocyclic Chem. 1982, 19, 407.

12.

Sato, N.; Fujii, M., J. Heterocyclic Chem. 1994, 31, 1177.

13.

Kiener, A.; Roduit, J. P.; Tschech, A.; Tinschert, A.; Heinzmann, K. Synlett 1994, 10,

814. 14.

The use of the conditions of Mano et al. led in our hands to sodium salt Na•13 that

filtered slowly as part of its isolation and was dark in colour. Also, whilst the HPLC purity


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was high (>95 LC area percent), the assay varied from 30−85% wt/wt. As a result of these characteristics, redesign of the literature conditions was necessary. 15.

Bisnitrile 14 shows lower purity when the amount of glyoxylic acid used is outside a

0.95–1.05 eq. window versus with respect to the amount of diaminomaleonitrile. 16.

Filtering after the reaction mixture has been left for longer or held at a higher reaction

temperature will remove insoluble intermediates arising from the hydrolysis of the nitrile functionality of bisnitrile 14 to the corresponding amides. This acts to reduce the reaction yield as these amides would otherwise be converted to the monosodium salt Na•16. 17.

Controlling the exotherm associated with the sodium hydroxide addition (T ≤ 10 °C),

prevents dark coloured sodium salt Na•16 from being isolated. 18.

Diluting the batch with water whilst its temperature is above ambient prevents the

precipitation of the trisodium salt of acid 16. 19.

The sodium sulfate was found to precipitate out, whereupon it was challenging to

remove, if the temperature was below 10 °C during the desupersaturation. 20.

No sodium sulfate was adjudged to have coprecipitated, according to a barium

chloride test to assess sulfate content. 21.

Small quantities of unreactive disodium salt meant the reaction could never be pushed

beyond 98% conversion. 22.

Azetidine hydrochloride can deliquesce, depending on its mode of manufacture.


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