An Improved Convergent Synthesis of AZD7762: A One-Pot

Feb 15, 2017 - Boc deprotection delivered the final API, but further purification was ... It was clear that an alternative synthetic approach would be...
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An Improved Convergent Synthesis of AZD7762: A One-Pot Construction of a Highly Substituted Thiophene at the Multikilogram Scale Matthew Ball,* Martin F. Jones, Fiona Kenley, and J. David Pittam Pharmaceutical Technology and Development, AstraZeneca, Silk Road Business Park, Macclesfield, Cheshire, SK10 2NA, United Kingdom S Supporting Information *

ABSTRACT: A multikilogram synthesis of AZD7762 has been achieved using a highly convergent route employing two efficient telescoped sequences to generate the key intermediates. Aminothiophene 11 is formed in a four-step, one-pot addition− elimination−cyclization sequence from cinnamonitrile 9, constructing the trisubstituted thiophene ring with the desired API substitution pattern in place. Cinnamonitrile 9 is derived by elaboration of 3-fluoroacetophenone. Generation of the urea function, followed by deprotection, affords AZD7762 in 49% yield over 5 isolated stages from chiral piperidine 5, a 5-fold increase in yield versus the first generation route, reducing the starting material burden and eliminating the previous requirement for metal-mediated couplings and chromatography. KEYWORDS: thiophene, substituted, one-pot, convergent, synthesis, kilogram

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INTRODUCTION

would be required for the subsequent manufacturing campaign with a delivery target of 5 kg API.

AZD7762 was designed as a checkpoint kinase (CHK1) inhibitor to prevent DNA repair at key checkpoints (or “rest points”) in the cell cycle. The planned mode of action was to increase the sensitivity of cancer cells to DNA damaging treatments, and the candidate drug underwent evaluation in Phase II clinical trials as a combination therapy against various solid tumors. The first generation manufacturing route (Scheme 1) 1 started from the commercially available substituted thiophene 1. This was a modification of the early discovery route, and although this approach successfully produced 1.6 kg of API, a number of drawbacks were noted following the first kilo-lab scale manufacturing campaign. Bromination of thiophene ester 2 required 5 equiv of bromine to consume the starting material, yet also led to contamination of 3 with overbrominated products which were difficult to remove. Formation of the amide bond of 6 proceeded in only modest yield and required significant excesses of both the expensive chiral amino piperidine 5 (2.5 equiv), and trimethylaluminum (2.6 equiv). Further operational difficulties were also encountered during the extractive workup involving treatment with Rochelle’s salt to remove aluminum salts, whereby gel formation and problematic phase separation were encountered. The aryl−aryl bond was introduced using a Suzuki coupling to afford 8, which required chromatography to remove homocoupled impurities. The level of these impurities was found to be agitation rate dependent, thus displaying a lack of robustness and predictability causing concern for future scale-up. Boc deprotection delivered the final API, but further purification was necessary which involved screening of the solution through a cartridge of Quadrapure TU thiourea resin to remove residual palladium prior to crystallization of the drug substance. It was clear that an alternative synthetic approach © XXXX American Chemical Society

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RESULTS AND DISCUSSION Strategic Approach. The problematic areas of the existing route were clearly those concerned with the construction of the fully functionalized thiophene ring, specifically the installation of the aryl and amide moieties. As an alternative approach, we sought instead to investigate strategies to generate the thiophene ring in a cyclization reaction which would lead unambiguously to the desired 2,3,5-substitution pattern. If this was successful, the complexity and cost associated with the route could be significantly reduced. Our attentions turned to reported methodology which involves reaction of βchlorocinnamonitriles with α-mercaptoacetic esters in the presence of base at high temperatures, generating 2-substituted thiophene esters.2 Our aim, however, was to extend this methodology to develop a mild, scalable process which encompassed secondary amides,3 allowing direct access to thiophene 11 with the desired substitution in place (Scheme 2). This would also eliminate the need for the inefficient late-stage amidation of the ester function. This strategy required safe, efficient generation of both the cinnamonitrile 9 and αmercaptoacetic amide 10, the latter of which was not expected to be crystalline. For this reason, further investigation was required into a protected surrogate for 10. Synthesis of Cinnamonitrile 9 (Telescope 1). The new route began with the synthesis of the required cinnamonitrile 9, using Arnold homologation chemistry (Scheme 3).4 Preliminary attempts involved preforming the Vilsmeier reagent by the addition of phosphoryl chloride to DMF, followed by addition Received: November 2, 2016

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Scheme 1. First-Generation Manufacturing Route to AZD7762

Scheme 2. Second Generation Retrosynthetic Strategy for AZD7762, Trisubstituted Thiophene Synthesis

Scheme 3. Telescoped Synthesis of Cinnamonitrile 9

reducing the possibility for thermal runaway. Once these changes were in place, the process was inherently safe at the proposed scales in the required kilolab equipment. In situ conversion of the intermediate iminium species 13 to cinnamonitrile 9 [single geometrical isomer; (Z) by 1H NMR/ NOESY] was performed by the addition of solid hydroxylamine hydrochloride to generate the oxime 14, followed by spontaneous dehydration in the reaction medium. Unfortunately, a second potentially uncontrollable exotherm was encountered when hydroxylamine hydrochloride was dosed as a solid, presumably exacerbated by its notably slow dissolution.

of 3-fluoroacetophenone (final concentration 0.50 kg/L) to initially generate iminium 13. Detailed process safety studies indicated that this procedure would be unacceptably exothermic for the required scale of manufacture. In order to remedy this, a greater quantity of DMF was implemented (final concentration 0.14 kg/L). Crucially, the order of addition was also altered by beginning with a warm solution of 3fluoroacetophenone in DMF (40 °C), prior to the slow addition of phosphoryl chloride. Performing the addition at this higher temperature facilitated the rapid consumption of the Vilsmeier reagent, preventing accumulation and therefore B

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Scheme 4. Key Telescoped Synthesis of Thiophene 11, Describing Each Operational Stage

The use of a solution of hydroxylamine hydrochloride in DMF (14.4 M) allowed more controlled addition, although hydroxylamine hydrochloride was shown to be unstable in neat DMF at temperatures >30 °C. Care was therefore taken to constitute the solution at 20 °C immediately prior to use.5 An additional delayed exotherm was also noted at the end of the addition. In a similar vein to the Vilsmeier formation, this was rendered safe by the slow addition of the hydroxylamine solution to the 40 °C reaction mixture, a temperature common to the first stage. In this manner, the prevention of accumulation of hydroxylamine hydrochloride and intermediates resulted again in a basis of control for the exotherm. At this point the synthesis of cinnamonitrile 9 had been accomplished with a high degree of control in an easily operable, one-pot sequence. At the end of reaction, simply cooling and treating with water facilitated direct crystallization of 9 in high purity and 65% yield;6 a total of 10 kg of 9 was generated using this process. Should future demand for this building block increase significantly, we would also envisage implementation of the recent continuous-flow based approach to chlorocinnamonitriles, reported by Buchwald and Pellegatti.7 Synthesis and Delivery of Aminothiophene 11 (Telescope 2). With cinnamonitrile 9 in hand, we began developing the key cyclization chemistry to generate the thiophene ring (Scheme 4). As outlined previously, in an extension to the existing methodology, we opted to build the required thiol amide as opposed to the thiol ester. This required stepwise construction of the amide 15 followed by introduction of a stable, crystalline source of sulfur masked with a suitable protecting group. In this regard we first selected thiobenzoic acid; however, the volatility and associated odor were deemed unfavorable for use at scale. The sodium or potassium salt of thiobenzoic acid was also sought as a potentially less volatile alternative, but when it was found that this material was not widely available, this approach was not pursued further. Potassium thioacetate was then examined; as well as being easily handled, this would have the benefit of carrying an acetate as a protecting group which might be easily unmasked prior to cyclization. Unfortunately, attempts at isolation of chloroacetamide 15 or thioacetate 16 as crystalline solids were unsuccessful, leading to oils in each case.

Attention then turned to developing a telescoped sequence, to avoid the isolation of any intermediates en route to 11. We required a suitable solvent to use throughout; the formation of α-chloroacetamide 15 was found to be a facile process in 2methyl THF, and in the absence of a chromophore, reaction progress could be followed by gas chromatography. An excess of chloroacetyl chloride (1.15 equiv) was required to give complete reaction to 15 in 2 h, and this initially led to overacylated impurities downstream. This was remedied by simply agitating with aqueous sodium chloride at the end of the reaction to hydrolyze excess chloroacetyl chloride, facilitating a subsequent phase separation leaving 15 within the upper organic phase. The use of N,N-diisopropylethylamine (DIPEA) as a base during this stage was found to generate highly colored reaction mixtures, which persisted through the sequence and resulted in 11 as a discolored brown solid. After an organic base screen, pyridine was found to be a superior alternative, completely eliminating unwanted coloration in the reaction medium and subsequent solid product. It is postulated that the higher basicity of DIPEA had facilitated deprotonation of chloroacetyl chloride at the α-position, generating chloroketene which can polymerize or react further to give low levels of colored impurities. With further investigation, this may prove to be a general consideration when choosing the optimum base for this type of acylation reaction. Direct treatment of the resulting 2-MeTHF solution of 15 with potassium thioacetate initially led to sticky deposits of potassium chloride around the vessel walls, poor mixing, and trapping of starting materials. Since the solubility of potassium chloride in 2-MeTHF is poor, we switched to a biphasic system, dissolving the potassium thioacetate in water prior to addition to the solution of 15 in 2-MeTHF. This led to solubilization of the resulting potassium chloride and a clear biphasic mixture. Again, this has the benefit of a simple phase separation at the end of reaction; the removal of the aqueous phase resulted in a 2-MeTHF solution of thioacetate 16 which can be used directly in the subsequent cyclization without isolation. Since the published cyclization chemistry used sodium methoxide as a base,2 we envisaged an additional role for this reagent in the concomitant deprotection (deacylation) of 16 to give the free thiolate which could take part in reaction with 9 C

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Scheme 5. Proposed Mechanism for the Addition−Elimination and Base-Catalyzed Cyclization to 11

(Scheme 5). It became apparent that the order of addition is not critical;8 it is possible to deacylate 16 in solution with sodium methoxide and then add cinnamonitrile 9 to initiate addition−elimination, followed by cyclization. Similarly, it is possible to add solid 9 to the solution of thioacetate 16 first at which point no reaction occursfollowed by dropwise addition of sodium methoxide. It was the latter approach that was chosen as a basis of safety for exotherm generation and operational simplicity. Mechanistically, it is postulated that initial methanolysis of the thioacetate group leads to a thiolate anion which takes part in an addition−elimination (Scheme 5). In initial investigations, a large excess of sodium methoxide (3.5 equiv) was used to complete the cyclization. This was accompanied by significant byproduct formation (ca. 1% by area), identified by mass spectrometry as methoxy impurity 17, later confirmed by synthesis. We reasoned that a smaller sodium methoxide charge may minimize the formation of this byproduct, and indeed, in laboratory studies the reaction proceeded to 11 in >97% conversion, with as little as 1.25 equiv of sodium methoxide (wrt 5)significantly lower than the theoretical requirement of 2.0 equiv of base. To improve the conversion rate and robustness, we finally selected 1.5 equiv of sodium methoxide (wrt 5) and utilized a slight undercharge of cinnamonitrile 9 (0.9 equiv wrt 5) to minimize the impurity 17. Gratifyingly, the result was clean conversion to 11 within 1 h at ambient temperature with no detectable 17. As can be seen from the proposed mechanism (Scheme 5), after the initial stoichiometric deacylation the anionic cyclization itself is potentially

autocatalytic in base. This would be made possible due to the fact that the proposed nitrile anion 21 is basic enough to deprotonate the uncyclized compound 19, thus propagating the catalytic cycle.9 The main impurity which resulted under a variety of conditions was ∼2−3% of the uncyclized congener 19, as identified by LCMS. This impurity is adequately removed during the efficient isolation protocol utilizing a highly convenient, seeded, cooled antisolvent-based crystallization directly from the reaction mixture. In summary, this operationally simple sequence of transformations constitutes an ambient temperature, one-pot, fourstage telescope in which chiral amine 5 is transformed into highly elaborate thiophene intermediate 11 in 71% overall yield. This approach resulted in the manufacture of 15 kg of aminothiophene 11 in excellent purity (>97% w/w), with a significantly reduced cycle time and environmental burden when compared to the first-generation route. Synthesis and Delivery of AZD7762. Completion of the synthetic sequence involved the elaboration to urea 8 in a twostage protocol using trichloroacetyl isocyanate (TCANCO), followed by methanolysis of the trichloroacetyl function. An alternative direct approach to the synthesis of 8 using potassium cyanate proved moderately successful but led to a poorer impurity profile and was therefore discounted. Finally, the removal of the BOC group with HCl and basification with triethylamine followed by a controlled water addition resulted in AZD7762 in good physical form. It should be noted, however, that during manufacture, prior to crystallization of the product, it was necessary to install a Harborlite filtration to D

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Scheme 6. Final Synthesis of AZD7762 (Including Yields at Kilolab Scale)

temperature at 39 to 41 °C during the addition. The resulting reaction mixture was stirred at 40 °C for 1 h before analysis for conversion to iminium 13 by HPLC. To the resulting reaction mixture was added a solution of hydroxylamine hydrochloride (45.17 g, 0.637 mol) in N,Ndimethylformamide (240 mL) dropwise, maintaining the temperature at 39−45 °C during the addition, followed by a line-wash of N,N-dimethylformamide (40 mL). After stirring at 40 °C for 15 min, the reaction mixture was sampled for conversion to 9 before cooling to 15−20 °C and addition of water (800 mL) dropwise, maintaining the temperature between 17 and 21 °C. The reaction mixture was then cooled to 5 °C and stirred at this temperature for a further 20 min before filtration of the solid, displacement washing with two separate portions of water (2 × 240 mL), and drying at 40 °C to afford the title compound as a pale yellow solid (72.16 g, 69% yield). This process was operated in 4 batches of up to 3.3 kg input 3-fluoroacetophenone each, generating a total of 10.1 kg of 9. The average yield was 65%. 1 H NMR (400 MHz, DMSO-d6, 300 K): 7.72−7.65 (m, 2H), 7.63−7.56 (m, 1H), 7.49−7.42 (m, 1H), 7.03 (s, 1H). 13C NMR (100 MHz, DMSO-d6, 300 K): 162.0 (d, J = 245 Hz), 149.3 (d, J = 3 Hz), 135.6 (d, J = 8 Hz), 131.1 (d, J = 9 Hz), 123.3 (d, J = 3 Hz), 118.8 (d, J = 21 Hz), 115.8 (s), 113.8 (d, J = 24 Hz), 99.3 (s). GC-HRMS Calcd for [M] C9H5NFCl: 181.0095; found [M]+: 181.0090. (S)-3-{[3′-Amino-5′-(3″-fluorophenyl)thiophene-2′carbonyl]amino}-piperidine-1-carboxylic Acid tert-Butyl Ester (11). Piperidine 5 (120.0 g, 0.599 mol) was dissolved in 2-methyltetrahydrofuran (540 mL). Pyridine (58.14 mL, 0.719 mol) was added, followed by a line-wash of 2-methyltetrahydrofuran (60 mL). Chloroacetyl chloride (55.32 mL, 0.689 mol) was added dropwise, maintaining the temperature at 21− 25 °C, followed by a line wash of 2-methyltetrahydrofuran (60 mL). After 2.5 h at ambient temperature, the reaction mixture was sampled for conversion to 15 by GC before the addition of a 16% (w/w) aqueous solution of sodium chloride (360 mL). The mixture was stirred for 30 min before separating off the aqueous phase.

remove traces of a hazy residue. The resulting physical losses reduced the yield to 78% from the expected >90%. Pleasingly, investigations confirmed that this residue was not related to the desired chemistry, but derived from a contaminant in commercial supplies of TCANCO.10 Its level can therefore be controlled on specification for future manufacture, removing the need for harborlite filtration. After the subsequent planned recrystallization from aqueous methanol, 7 kg of AZD7762 was produced in good yield and excellent purity (Scheme 6).

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CONCLUSION In summary a new, highly convergent multikilo synthesis of AZD7762 has been achieved. This involved two telescoped sequences, including the key cyclization which uses newly developed chemistry to generate the thiophene skeleton with the desired 2,3,5-substitution unambiguously installed. This has led to 5-fold reduction in the required quantity of chiral piperidine 5 and an improved overall yield of 49% (versus first generation route, 9%). In addition, the synthesis is now free of toxic metals, has simple solid isolations directly from the reaction mixtures, and requires no chromatography, producing an API of high purity for clinical development.

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EXPERIMENTAL SECTION General. Starting materials, reagents, and solvents were obtained from commercial suppliers and used without further purification. HPLC analyses were performed with an Agilent 1100 instrument. Intermediate purities were measured by quantitative NMR analysis using an internal standard of known purity, typically maleic acid or 2,3,5,6-tetrachloronitrobenzene. Accurate mass GC-MS or LC-MS methods were used to confirm elemental formulas. Yields quoted (mass and percentage) are corrected for purity. The processes described below are taken from the laboratory process descriptions used as for kilolab manufacture. A description of the scale on which these processes were operated is given for each stage. (Z)-3-Chloro-3-(3′-fluorophenyl)-acrylonitrile (9). To a solution of 3-fluoroacetophenone (80.0 g, 0.579 mol) in N,Ndimethylformamide (560 mL) at 40 °C was added phosphoryl chloride (92.50 mL, 0.990 mol) dropwise, maintaining the E

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To the resulting organic phase was added a filtered solution of potassium thioacetate (102.65 g, 0.899 mol) in water (204 mL), followed by a line-wash of water (36 mL), maintaining the temperature at 19−26 °C throughout. After stirring overnight at ambient temperature, the organic phase was sampled for conversion to 16 by HPLC before separating off the aqueous phase. To the organic phase was added solid 9 (97.93 g, 0.539 mol) before dropwise addition of a solution of sodium methoxide in methanol (202 mL @ 25% w/w, 0.899 mol), maintaining the temperature at 21−24 °C. This was followed by a line wash of methanol (36 mL). After stirring for 1 h 50 min at ambient temperature, the reaction mixture was sampled by HPLC for conversion to 11 before heating to 33 °C, followed by dropwise addition of water (600 mL). After stirring for 10 min, the aqueous phase was separated off. To the organic phase was added isohexane (960 mL) dropwise before removing a small sample of the reaction mixture, allowing it to cool and crystallize before returning it to the bulk mixture to seed crystallization. Dropwise addition of a second portion of isohexane (480 mL), followed by cooling to 3 °C over 1 h, and stirring at this temperature overnight caused crystallization of the product. Filtration, displacement washing the solid with icecold tert-butyl acetate (240 mL), and 2 × ice-cold mixed solvent system of tert-butyl acetate and isohexane (1:1, 2 × 240 mL) and drying at 40 °C over 3 days afforded 11 as a pale yellow solid (176.70 g, 70% yield based on 5). This process was operated in 3 batches of up to 4.8 kg input of 5 each, generating a total of 15.3 kg of 11. The average yield was 71%. 1 H NMR (400 MHz, DMSO-d6, 353 K): 7.49−7.32 (m, 3H), 7.19−7.12 (m, 1H), 7.01 (s, 1H), 6.91 (d, 1H), 6.29 (br.s, 2H), 3.91−3.64 (m, 3H), 2.96−2.77 (m, 2H), 1.92−1.77 (m, 1H), 1.74−1.30 (m, 12H). 13C NMR (100 MHz, DMSO, 353 K): 164.3 (s), 163.1 (d, J = 245), 154.6 (s), 153.9 (s), 142.2 (d, J = 3 Hz), 136.1 (d, J = 8 Hz), 131.6 (d, J = 9 Hz), 121.9 (d, J = 3 Hz), 118.7 (s), 115.6 (d, J = 21 Hz), 112.4 (d, J = 23 Hz), 102.5 (s), 79.2 (s), 48.6 (s), 46.1 (s), 44.1 (s), 30.3 (s), 28.6 (s), 24.1 (s); LC-HRMS calcd for [M + H] C21H27FN3O3S: 420.1752; found [M + H]+: 420.1748. ( S ) - 3 - ( { 5′ - ( 3 ″- F l u o r o p h e n y l ) - 3 ′- [ 3 ‴ - ( 2 ⁗ , 2 ⁗ , 2 ⁗ trichloroacetyl)ureido]thiophene-2′-carbonyl}-amino)-piperidine-1-carboxylic Acid tert-Butyl Ester (22). To a solution of 11 (73.12 g, 0.174 mol) in tetrahydrofuran (800 mL) was added trichloroacetyl isocyanate (23.23 mL, 0.196 mol), maintaining the temperature at 20−30 °C during the addition. After 2.5 h at ambient temperature, the mixture was sampled by HPLC for conversion to 22 before the addition of isohexane (1120 mL) dropwise over 1 h. After stirring for a further 1 h, the reaction mixture was filtered; the solid was washed with isohexane (160 mL) and dried at 40 °C to afford 22 as a pale peach solid (101.88 g, 96% yield). This process was operated in 5 batches of up to 3.8 kg input of 11 each, generating a total of 19.7 kg of 22. The average yield was 95%. 1 H NMR (400 MHz, DMSO-d6, 353 K): 11.70 (s, 1H), 11.49 (br. s, 1H), 8.24 (s, 1H), 7.80 (d, 1H), 7.57−7.40 (m, 3H), 7.26−7.18 (m, 1H), 3.97−3.67 (m, 3H), 2.95−2.78 (m, 2H), 1.97−1.84 (m, 1H), 1.78−1.53 (m, 2H), 1.51−1.33 (m, 10H). 13C NMR (100 MHz, DMSO-d6, 343 K): 162.3 (d, J = 245 Hz), 161.7 (s), 160.3 (s), 153.7 (s), 148.5 (s), 141.9 (d, J = 3 Hz), 140.5 (s), 134.6 (d, J = 8 Hz), 131.1 (d, J = 9), 121.4 (d, J = 3 Hz), 119.5 (s), 115.3 (d, J = 21 Hz), 114.7 (s), 112.0 (d, J = 23 Hz), 91.8 (s), 78.4 (s), 47.4 (s), 45.7 (s), 43.2 (s), 29.2

(s), 27.7 (s), 23.2 (s). LC-HRMS Calcd for [M + Na] C24H26Cl3FN4NaO5S: 629.0566; found [M + Na]: 629.0561. (S)-3-{[5′-(3″-Fluorophenyl)-3′-ureido-thiophene-2′-carbonyl]-amino}-piperidine-1-carboxylic Acid tert-Butyl Ester (8). To a suspension of 22 (101.45 g, 0.169 mol) in methanol (516 mL) was added triethylamine (58.15 mL, 0.417 mol). After 2.5 h at ambient temperature, the mixture was sampled by HPLC for conversion to 8 before the addition of water (206 mL) over 10 min. After stirring overnight at ambient temperature, the reaction mixture was heated to 45 °C for 15 min before addition of a second portion of water (1083 mL) over 2 h. After a further 1 h at 45 °C, the reaction mixture was allowed to cool to 20 °C and stirred at this temperature for 1 h. The reaction mixture was filtered, and the solid was washed with water (206 mL) before drying at 40 °C to afford 8 as a white solid (75.79 g, 98% yield). This process was operated in 5 batches of up to 4.8 kg input of 22 each, generating a total of 14.2 kg of 8 in quantitative yield. 1 H NMR (400 MHz, DMSO-d6, 353 K): 9.86 (s, 1H), 8.24 (s, 1H), 7.60−7.41 (m, 3H), 7.41−7.33 (m, 1H), 7.22−7.15 (m, 1H), 6.36 (br. s, 2H), 3.94−3.68 (m, 3H), 2.97−2.79 (m, 2H), 1.94−1.84 (m, 1H), 1.76−1.55 (m, 2H), 1.47−1.34 (m, 10H). 13C NMR (100 MHz, DMSO-d6, 353 K): 163.6 (s), 163.1 (d, J = 244), 155.4 (s), 154.6 (s), 145.5 (s), 142.3 (d, J = 2 Hz), 136.0 (d, J = 8 Hz), 131.8 (d, J = 9 Hz), 122.2 (d, J = 3 Hz), 120.0 (s), 115.9 (d, J = 22 Hz), 112.6 (d, J = 23 Hz), 110.5 (s), 79.2 (s), 48.3 (s), 46.5 (s), 44.1 (s), 30.1 (s), 28.6 (s), 24.1 (s). LC-HRMS Calcd for [M + H] C22H28FN4O4S: 463.1810; found [M + H]+: 463.1815. 5-(3′-Fluorophenyl)-3-ureidothiophene-2-carboxylic Acid (S)-Piperidin-3″-ylamide (AZD7762). To a suspension of 8 (75.3 g, 0.163 mol) in methanol (383 mL) was added an aqueous solution of hydrochloric acid (40.78 mL @ 37% w/w in water, 0.488 mol) dropwise, maintaining the temperature at 20 to 30 °C. The resulting reaction mixture was heated at 50 °C for 4 h before analysis by HPLC for conversion to AZD7762. Triethylamine (85.10 mL, 0.610 mol) was added dropwise before addition of water (345 mL). A small sample of the reaction mixture was then removed, allowing it to cool and crystallize before returning to the bulk mixture in order to seed crystallization. After stirring for 30 min, water (613 mL) was added over 1.5 h before stirring at 50 °C for a further 30 min and allowing to cool to 20 °C with stirring overnight. The reaction mixture was filtered and the solid washed with water (153 mL) before drying at 40 °C to afford AZD7762 as a white solid (56.6 g, 96% yield). This process was operated in 4 batches of up to 4.3 kg input of 8 each, generating a total of 8.2 kg of AZD7762; the average yield was 78%. [Note: The yield was lower than expected due to the Harborlite treatment which was introduced to remove a haze generated from a contaminant in TCANCO, a material introduced in the previous stage.10 The Harborlite treatment successfully removed the impurity and afforded a typical quality product.] Spectroscopic data are reported af ter the f inal recrystallization. Recrystallization of AZD7762. AZD7762 (50.0 g, 0.138 mol) in methanol (650 mL) was heated to 30 °C for 30 min before filtering through a 1.6 μm glass microfiber filter paper into a second vessel, followed by a line-wash with methanol (100 mL). The resulting solution was cooled to 10 °C before the addition of water (250 mL) over 20 min, maintaining the temperature at 10−15 °C. The reaction was then seeded with AZD7762 (150 mg, 0.3% w/w), and the contents of the vessel were allowed to stir at 10 °C for 30 min. The addition of a F

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However, this impurity is completely purged in the crystallization liquors and did not pose any issue on scale-up.

second portion of water (500 mL) over 1 h 30 min, maintaining the temperature 10−13 °C, followed by stirring for 20 h at 10 °C, completed the crystallization. Filtration, washing with water (2 × 100 mL), and pulling dry on the filter for 30 min before drying under vacuum at 40 °C afforded AZD7762 as a white solid (46.16 g, 92% yield). This process was operated in 3 batches of up to 2.6 kg of AZD7762 each, generating a total of 6.9 kg of pure AZD7762. The average yield was 93%. 1 H NMR (400 MHz, DMSO-d6, 353 K): 9.88 (br. s, 1H), 8.22 (s, 1H), 7.52−7.36 (m, 4H), 7.19 (m, 1H), 6.35 (br. s, 2H), 3.81 (m, 1H), 2.95 (m, 1H), 2.76 (m, 1H), 2.44−2.56 (m, 2H), 1.82 (m, 1H), 1.67−1.34 (m, 3H). 13C NMR (100 MHz, DMSO-d6, 353 K): 163.3 (s), 163.1 (d, J = 243 Hz), 155.5 (s), 145.2 (s), 142.0 (d, J = 3 Hz), 136.0 (d, J = 3 Hz), 131.8 (d, J = 9), 122.2 (d, J = 3 Hz), 120.1 (s), 115.8 (d, J = 21 Hz), 112.6 (d, J = 23 Hz), 111.0 (s), 51.6 (s), 47.4 (s), 46.3 (s), 30.9 (s), 25.5 (s). LC-HRMS Calcd for [M + H] C17H20FN4O2S: 363.1286; found [M + H]+: 363.1277.

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(7) Buchwald, S. L.; Pellegatti, L. Org. Process Res. Dev. 2012, 16, 1442. (8) Ball, M.; Jones, M. F.; Kenley, F. R.; Pittam, D. J. PCT Int. Appl. WO2009133389, 2009. (9) A similar autocatalytic process is implicated in the synthesis of benzyl trichloroacetimidate from benzyl alcohol, trichloroacetonitrile, and catalytic sodium hydride; see: Wessel, H. P.; Iversen, T.; Bundle, D. R. J. Chem. Soc., Perkin Trans. 1 1985, 11, 2247−50. and Cramer, F.; Pawelzik, K.; Baldauf, H. J. Chem. Ber. 1958, 91, 1049. (10) The Harborlite filtration was necessary to remove small amounts of a hazy white solid from the reaction mixture and resulted in a lower yield than expected (78% vs > 90% during development) presumably due to product retention on the filter. The unexpected solid was later assigned as the oxalyl bridged dimer 24 (by LCMS), thought to be derived from residual oxalyl chloride present in commercial trichloroacetyl isocyanate (TCANCO). We would like to highlight here that residual oxalyl chloride would be a common problem for many uses of TCANCO and should be analyzed for if thought to pose a significant risk to product purity.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.oprd.6b00364. 1 H and 13C NMR spectra for compounds 9, 11, 22, 8, and AZD7762 (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Matthew Ball: 0000-0002-5519-0118 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors would like to thank Mark Harrison and Paul Davey for mass spectrometry, Karen Rome for analysis, and Lyn Powell and Andrew Philips for helpful discussions.

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REFERENCES

(1) Ashwell, S.; Gero, T.; Ioannidis, S.; Janetka, J.; Lyne, P.; Su, M.; Toader, D.; Yu, D.; Yu, Y. P. Int. Appl. WO2005066163, 2005. (2) (a) Hartmann, H.; Liebscher, J. Synthesis 1984, 1984, 275−276. (b) Andersen, H. S.; Olsen, O. H.; Iversen, L. F.; Sørensen, A. L. P.; Mortensen, S. B.; Christensen, M. S.; Branner, S.; Hansen, T. K.; Lau, J. F.; Jeppesen, L.; Moran, E. J.; Su, J.; Bakir, F.; Judge, L.; Shahbaz, M.; Collins, T.; Vo, T.; Newman, M. J.; Ripka, W. C.; Møller, N. P. H. J. Med. Chem. 2002, 45, 4443−4459. (3) During the manufacturing campaign, a complementary laboratory scale (∼1 g) synthesis of 2-(1)-amido-3-amino-5-aryl thiophenes was reported. This work uses an altered order of reactivity and requires disodium disulfidea less handlable, more toxic source of sulfurand higher temperatures than our approach; see: Lassagne, F.; Pochat, F.; Sinbandhit, S. Synth. Commun. 2007, 37 (7), 1133−1140. (4) (a) Arnold, Z.; Zemlicka, J. Collect. Czech. Chem. Commun. 1959, 24, 2385. (b) Liebscher, B.; Neumann, B.; Hartmann, H. J. Prakt. Chem. 1983, 325, 915. (5) N-Methyl pyrrolidone was also found to be a potential solvent for hydroxylamine hydrochloride, although this caused complications in the final crystallization and no further work was progressed. (6) The reaction also generates ∼25% of the enamine impurity 23, formed from double addition of the Vilsmeier reagent. This was found to be remarkably consistent, regardless of reaction conditions. G

DOI: 10.1021/acs.oprd.6b00364 Org. Process Res. Dev. XXXX, XXX, XXX−XXX