Scalable Process for the Production of a Highly Energetic

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Scalable Process for the Production of a Highly Energetic Bromoacetylene Building Block Philipp Kohler, Mischa Schwaninger, Alfred Stutz, Reinhard Karge, and Stefan Abele Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00223 • Publication Date (Web): 13 Sep 2018 Downloaded from http://pubs.acs.org on September 13, 2018

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Organic Process Research & Development

Scalable Process for the Production of a Highly Energetic Bromoacetylene Building Block

Philipp Kohler,*,† Mischa Schwaninger,‡ Alfred Stutz,§ Reinhard Karge,† and Stefan Abele†

†

Chemical Development, Idorsia Pharmaceuticals Ltd, Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland ‡

§

TÜV SÜD Schweiz AG, Process Safety, Mattenstrasse 24, CH-4002 Basel, Switzerland

Route Finding, Dottikon Exclusive Synthesis AG, Hembrunnstrasse 17, CH-5605 Dottikon, Switzerland

ACS Paragon Plus Environment

1

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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TOC Graphic


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Abstract

3-(Bromoethynyl)azetidine is a highly energetic building block (decomposition energy up to 1800 J g-1) that was required in multi-kg quantities for the production of an API. The development of a four-step, fully telescoped, scalable sequence for its synthesis is described, along with a detailed safety study of the corresponding hydrochloride salt in order to determine the potential explosive properties and transport classification. A screen of counterions identified the (+)-camphorsulfonic acid salt as the most suitable form for mitigation of the energetic properties, as judged by differential scanning calorimetry (onset 182 °C, energy -876 J g-1). This case study demonstrates how a daunting chemical structure can be "tamed" by chemical process development, tuning of molecular properties, and thorough safety investigations.

Keywords: Antiinfectives, bromoacetylene, azetidine, thermal safety, transport classification


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Introduction 3-(Bromoethynyl)azetidine hydrochloride (1a; Scheme 1) is a building block used for the synthesis of novel inhibitors of LpxC, which are part of an anti-infectives program at Idorsia Pharmaceuticals Ltd.1 For a production campaign aimed at material supply for the first clinical trial, it was essential to secure multi-kg quantities of this low molecular-weight, high-energy compound in good purity. The

discovery

route1

to

1a

started

by

Parikh-Doering

oxidation

of

N-Boc-3-

(hydroxymethyl)azetidine (2) to aldehyde 3,2 followed by reaction with the Ohira-Bestmann reagent to give primary acetylene 4 (Scheme 1).3,4 Terminal bromination was achieved with NBS in the presence of silver(I) nitrate.5 The Boc group of intermediate 5 was cleaved using HCl in dioxane, affording 1a in solid form as the hydrochloride. This sequence was not deemed suitable for the production of large quantities because of unfavorable reagents, such as the expensive and safety-critical Ohira-Bestmann reagent, and the light-sensitive silver(I) nitrate, as well as two chromatographic purifications.

Scheme 1. Discovery route to 3-(bromoethynyl)azetidine hydrochloride (1a).


4

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In a more general sense, it was clear from the outset that many intermediates as well as the product would be highly energetic, hence detailed safety investigations would be necessary to assess the thermal potential and define safe temperature ranges. Bromoacetylenes are known as potential explosives that are sensitive to thermal stress.6–9 We hoped to identify another salt form of the product 1 to mitigate this risk. In a further developed process, a fully telescoped reaction sequence would be desirable, since all intermediates to 1 were expected to be non-crystalline oils.

Results and Discussion First kg-Scale Process. Our first goal was to identify a method of introducing the acetylene without using potentially hazardous and costly diazo reagents. Close precedents by Hu10 and Cossy11 rely on the coupling of alkynyl-Grignard reagents with 3-haloazetidines in the presence of a simple Fe(II) or Co(II) catalyst. It is noteworthy that alkynylmagnesium or alkynyllithium reagents do not undergo uncatalyzed SN2 coupling to 3-haloazetidines.10,11 In our adaptation of this alkynylation procedure (Scheme 2), ethynyltrimethylsilane12 was deprotonated with ethylmagnesium bromide at 50 °C to generate the corresponding Grignard reagent in THF. Since this solution had a tendency to crystallize at temperatures < 35 °C, it had to be kept warm and used immediately. We intended to dose the Grignard solution into a mixture of iodoazetidine 6 and 10 mol% FeBr2 in NMP that was kept at room temperature. By using two temperaturecontrolled reaction vessels and a peristaltic pump for the transfer, slow addition was realized technically while maintaining the Grignard solution above 35 °C. Aqueous work-up (EtOAc, 0.5M HCl, brine) and concentration to dryness afforded 7 as a brown oil in nearly quantitative


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yield. The trimethylsilyl protecting group was subsequently cleaved using K2CO3 in MeOH,13 followed by aqueous work-up (EtOAc, water) to provide the primary acetylene 4.

Scheme 2. First kg-scale route to 3-(bromoethynyl)azetidine hydrochloride (1a).

Since we wanted to avoid silver(I) nitrate for the bromination, we considered using a hypobromite solution, which can be generated from elemental bromine and aqueous KOH.14–17 Due to the aqueous nature of the reagent, conversion problems were anticipated for the biphasic reaction mixtures. Therefore our initial attempts used co-solvents such as tBuOH or THF,15 however these conditions were still biphasic and suffered from slow conversion speed or completely stalled reactions on scales > 10 g. Phase transfer catalysts such as Me3BuNCl, Bu4NBr, sodium lauryl sulfate or cetyltrimethylammonium bromide only gave a modest improvement and were difficult to remove from the product. Eventually, we identified the biphasic reaction of neat, liquid 4 in warm (50 °C) KOBr solution as a scalable alternative. The reaction was fully dose-controlled when the starting material was added over the course of 1 h, using a mechanical stirrer for sufficient mixing of the two phases. Aqueous quench and work-up (2-MeTHF, 40% NaHSO3, brine) provided the Boc-protected bromoacetylene 5 as a brown oil.


6

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Cleavage of the Boc group was done under essentially unchanged conditions compared to the original synthesis. Reaction with HCl in dioxane led to direct crystallization of the hydrochloride 1a, which was filtered and washed with heptane. Drying in a stream of nitrogen (no heating due to safety considerations) afforded the desired product as a brown solid in 85–90% w/w NMR purity and 73% overall yield over the four steps. This fit-for-purpose sequence was successfully implemented on batch sizes up to 12.5 kg at a CRO, but not before we had studied the thermal safety of all intermediates and the product (see below).

Salt Screening. The thermal stability of bromoacetylenes is notoriously poor, and many of them are shock-sensitive,

6–8

a problem which was exacerbated in our case by the additional

presence of a strained four-membered ring and low molecular weight. The non-brominated acetylenes 7 and 4 had high thermal decomposition energies of -699 to -1203 J g-1 (derived from the DSC thermograms), but the corresponding onset temperatures were relatively high, indicating low probability of decomposition (Table 1, Entries 1–2). In contrast, the bromoacetylene 5 had a low thermal onset of 133 °C (Entry 3). The hydrochloride 1a obtained from the first kg-scale process showed an even lower onset temperature of 106 °C or 93 °C (results from two different batches arbitrarily named "Batch One" and "Batch Two"; Entries 4– 5). When material of higher purity was generated by charcoal treatment and crystallization, the onset temperature was as low as 82 °C (Entry 6). A typical DSC thermogram (Batch Two) is given in Figure 1; the steep slope of the first exothermic event is indicative of autocatalytic decomposition. The corresponding free base 1 (Entry 7) was unstable even at room temperature and decomposed spontaneously to a black solid after concentration on gram scale (exothermic polymerization, no explosion observed). We concluded that handling of the neat


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bromoacetylenes 5 and 1a was potentially highly hazardous, and only admissible on scale after more detailed investigations (see below). In any case, operations such as unloading, drying or shipping of neat 1a would require a thorough risk assessment and additional safety measures, such as strict temperature control and/or limited batch size.

Table 1. Decomposition onset temperature (left limit) and energy of various derivatives of 1a as determined by DSC. See Supporting Information for DSC thermograms. All samples were prepared using the first kg-scale process followed by basic extraction and addition of the corresponding acid to the solution of the free base as appropriate. DSC measurements are single determinations unless stated otherwise.

Entry

Compound

Structure

limit Energy

Left

[J g-1]

[°C] 117

1

7

(first -41

exothermic

exothermic

event)

event)

195 (second -1203 exothermic event)

a

event) a

4

232

-699

3

5

133

-976

106

-1197

1a, Batch Oneb

(second

exothermic

2

4

(first


8

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Entry

5

Compound

1a, Batch Twob

Structure

Left

limit Energy

[°C]

[J g-1]

93

-1306

6

1a c

82

-1789

7

1

–d

–d

8

1b

64

-935

9

1c

118

-639

10

1d

81

-940

11

1e

163

-1206

12

1f

98

-480


9


Entry

Compound

13

Structure

Left

Page 10 of 35

limit Energy

[°C]

[J g-1]

1g

144

-791

14

1h

146

-723

15

1i

182

-876

a

Two exothermic events for this compound (compare thermogram in SI). b As obtained from the

reaction (brown solid). Values for two separate batches (arbitrarily named "Batch One" and "Batch Two") are given. c After treatment of the crude brown solid with charcoal and evaporative crystallization from H2O, giving colorless crystals (small scale).

d

Decomposition during

isolation.


10

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Figure 1. DSC thermogram of 1a, Batch Two from the first kg-scale process (brown solid). Left limit 93 °C, energy -1306 J g-1 for first exothermic event.

In order to mitigate these risks, we hoped to find a salt with a higher onset temperature. The added molecular weight of the counterion might additionally lower the decomposition energy through a "dilution effect". For screening purposes, we generated small quantities of the desired salts by basic extraction of 1a, followed by treatment with the corresponding acid and crystallization. While carboxylates showed no pronounced, positive effect as counterions (1b– 1d, Entries 8–10), tetrafluoroborate increased the onset to 163 °C (1e, Entry 11), and tetraphenylborate showed a lowered decomposition energy (1f, Entry 12). The most favorable options investigated were sulfonic acid salts (1g–1i, Entries 13–15), the best of which seemed to


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be the salt of (+)-camphor-10-sulfonic acid (CSA) with a well manageable thermal onset of 182 °C and a somewhat reduced decomposition energy of -876 J g-1 as compared to the hydrochloride (1i, Entry 15). This salt was selected as target compound for the development of an improved, telescoped process (see below).

Further Safety Investigations of 1a. Since the hydrochloride 1a showed a high decomposition energy of -1197 to -1789 J g-1 and a low onset of 82–106 °C by DSC (Table 1, Entries 4–6), it was further characterized by additional safety investigations as a prerequisite for our R&D activities on 100 g scale and the outsourced kg-scale production. A falling hammer test (Table 2, Entry 1) was negative, hence the substance was not impact sensitive. As a consequence of this negative result, we concluded that the substance was also not friction sensitive. However, a decomposition test in a mini-autoclave (Entry 2) showed a rapid pressure increase of +9 bar within 4 s, starting at a temperature of 107 °C. An additional time pressure test (Entry 3) also showed a rapid pressure increase from 690 to 2070 kPa within 30 ms, indicating the substance ability to deflagrate rapidly according to the Orange Book criteria.18 Later on, still limited in sample availability, a closed pressure vessel test (CPVT, Entry 4) was performed.19,20 Based on this test an explosivity ranking in correspondence to the UN transport classification criteria was made: rank B.21 This test confirmed the rapid deflagration behavior. In fact, the rating based on this test, in correspondence to the UN transport classification, was close to the boundary limit for detonative decomposition (rank A), which means that 1a is a potential dangerous goods class 1 substance (explosive substance) but not detonative, although mechanical stress (impact, friction) was not sufficient to trigger an explosion. In practice, standard production equipment was considered adequate for the production of 1a on pilot scale, provided that a thorough risk


12

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assessment had taken place. However, the routine production process should then be designed for an alternative salt (refer to Salt Screening above) to avoid any risks related to potential explosives handling.

Table 2. Additional safety tests performed on 1a. Entry

Test

1

BAM

Result

Explosive behavior

Fallhammer Hammer weight 10 kg, falling height 40 Substance not impact

(EC/440/2008; REACH

cm: no detonation in 6 repetitions

sensitive

Test

method regulation) 2

3

Decomposition

test Heating rate 2.40 K min-1, exotherm at Explosive

(mini-autoclave;

107–184 °C, pressure increase of +9 bar cannot be excluded

ESCIS)

within 4 s; repeated determination

Time pressure test Pressure increase from 690 to 2070 kPa Substance (UN C.1)

within 30 ms; final pressure 2430 kPa; propagate single determination

4

behavior

Closed

can a

deflagration

pressure Heating rate 2.50 K min-1, exotherm at Substance deflagrates

vessel test (CPVT)

117–148

°C,

maximum

pressure rapidly and/or gives

-1

increase rate 2298 bar s , maximum violent pressure 60 bar; repeated determination

effect

heating

upon under

confinement

For reasons of transport risk assessment, it was necessary to determine the self-accelerating decomposition temperature (SADT)22 of 1a. Three isothermal DSC measurements were done at 90, 100, and 110 °C (Table 3).


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Table 3. Isothermal DSC measurements on 1a. Entry

Temperature [°C]

Time

at

peak Maximum heat flow Decomposition

maximum [min]

[mW g-1]

energy [J g-1]

1

90

171

41

-576

2

100

55

115

-582

3

110

19

385

-674

A plot of the natural logarithm of the thermal power (maximum heat flow) against the reciprocal of the absolute temperature gave a linear plot (Arrhenius diagram, Figure 2). The slope of the fitted line corresponded to the activation energy divided by the ideal gas constant. Thus, an activation energy for the decomposition of 1a of 129 kJ mol-1 was calculated. From this value, the time-to-maximum rate (TMRad), i.e. the time until a thermal runaway occurs under adiabatic conditions, can be approximately calculated assuming 0th order kinetics according to Stoessel.23–25 By applying a process temperature of 25 °C, a heat release rate of 41 W kg-1 at 90 °C (Table 3, Entry 1), and the new activation energy of 129 kJ mol-1, a TMRad of 30 days is calculated.


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7 6.5 6 ln(heat flow)

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


5.5 5

y = -15554x + 46.524 R² = 0.9963

4.5 4 3.5 3 0.00255

0.0026

0.00265

0.0027

0.00275

0.0028

1/T [1/K]

Figure 2. Arrhenius diagram of the natural logarithm of the thermal power (maximum heat flow) against the reciprocal of the absolute temperature derived from the isothermal DSC measurements of 1a. From the slope (–15554 K), an activation energy of EA = –R · slope = 129 kJ mol-1 is calculated (R = 8.31 J mol-1 K-1: ideal gas constant).

A Semenov plot was constructed indicating the heat flow as a function of the temperature (Figure 3).26 The cooling curve (linear relationship) of a 50 L transport package (UN 1G package according to Ref18) was plotted in such a way that there was only one intersection point with the heat production curve. According to Ref18 such a package has a typical heat loss of 29 mW kg-1 K-1. The intersection of this line with the temperature axis gave a critical temperature of 36.1 °C; rounding to the next higher multiple of 5 gave the SADT of 40 °C.


15


500 450

heat flow [mW/g]

400

385

350 y = '0.00167082e'0.11198356x R² = '0.99792358

300 250 200 150

115

100 50

41

0 0

20

40

60

80

100

120

T [°C]

0.5 0.4 0.3 heat flow [mW/g]

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

Page 16 of 35

0.2 0.1 0 30

32

34

36

38

40

42

44

46

48

50

-0.1 -0.2

T [°C]

Figure 3. Above: Semenov plot showing the heat flow during the decomposition of 1a as a function of the temperature T (black) and the cooling curve (linear relationship) of a 50 L transport package (red). Below: expanded view near the tangent point and the intersection with the T axis (marked as red squares).


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Transport classification. Under the assumptions that the substance 1a is not explosive (test sequence of the classification procedure for dangerous goods class 1 according to Ref27 could not be completed), it should at least be classified into Division 4.1 (self-reactive for transportation). Due to the SADT of 40 °C, 1a shall be subjected to temperature control during carriage.27 The control temperature is 30 °C and the emergency temperature is 35 °C.

Reaction Calorimetry of Bromination. The bromination (Scheme 2, Step 3) was identified as the most safety critical step because of its exothermic nature and the high thermal potential of the product 5 (onset 133 °C, decomposition energy -976 J g-1; Table 1, Entry 3). The thermal profile of the reaction was investigated by a reaction calorimetric measurement (Systag FlexyCUBE, see Figure 4 and Supporting Information). Addition of the neat starting material to the KOBr solution at 50 °C over 30 min gave the results presented in Table 4. For the purpose of these calculations, we used an estimated heat capacity (Cp) of 3.0 kJ kg-1K-1.28


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Figure 4. Reaction calorimetric measurement of the bromination reaction. Above: raw data of the measurement. TR: temperature of reaction mixture (dark blue); TJ: temperature of reactor


18

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jacket (orange). The system was calibrated by heating with 5 W (light blue). After equilibration, the starting material 4 was added at a constant rate over 30 min (yellow). Then the final mixture was calibrated again by heating with 5 W (light blue). Throughout the experiment, TR was kept constant at 50 °C. The exothermicity was determined from the temperature difference TR – TJ (grey). Below: calorimetric data. Reaction heat (dark blue), reaction heat after end of addition (yellow), heat flow (orange), adiabatic temperature increase (grey), adiabatic temperature increase after end of addition (light blue). The extracted calorimetric values are given in Table 4.

Table 4. Reaction calorimetric data for the bromination (addition of neat 4 into the KOBr solution at 50 °C during 30 min). Reaction heat

QR

45 kJ kg-1

Reaction enthalpy

∆HR

105 kJ mol-1

Specific heat capacity of the reaction mixture28

Cp

3.0 kJ kg-1K-1

Adiabatic temperature increase

∆Tad = QR / Cp

15 °C

Maximum Temperature of Synthesis Reaction MTSR (considering full-batch reaction -> worst case)

(full- 65 °C

batch)

Thermal conversion at end of addition (semi-

85%

batch reaction) Maximum Temperature of Synthesis Reaction MTSR (considering semi-batch reaction)

batch)

Maximum heat release (semi-batch reaction)

qmax

(semi- 52 °C

28 W kg-1


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In a full-batch scenario, the Maximum Temperature of Synthesis Reaction (MTSR) indicates the temperature reached if the whole reaction heat of the desired reaction is accumulated adiabatically. In the present case, the MTSR was determined at 65 °C. An additional DSC measurement of the final reaction mixture (Supporting Information) showed a decomposition reaction beginning at about 119 °C (left limit of the peak). According to the calculation method by Stoessel (see above) a TD24 of 59 °C was estimated for this decomposition.25,29 The measured decomposition heat of 203 J g-1, which corresponds to an adiabatic temperature increase of ∆Tad(decomp.) = 68 °C, had heated the reaction mixture to a final temperature of 133 °C; a boiling point barrier was present at 100 °C (boiling of water). Therefore the full-batch reaction fell into Stoessel criticality class 5 (Table 5) and had to be redesigned for improved safety.23–25,30 In the case of a semi-batch reaction, the starting material was dosed slowly into the aqueous reaction mixture. The calorimetric measurement indicated 85% thermal conversion at the end of addition over 30 min, corresponding to a manageable 15% thermal accumulation. The corresponding temperature increase of 2 °C gave a new MTSR of 52 °C and led thus to a process of criticality class 2 (Table 5), which was deemed sufficiently safe to run in a pilot plant setting if additional safety measures were in place (e.g. interruption of the dosing in case of a temperature deviation). According to the planned process, addition was done over the course of 1 h, which further reduced the heat accumulation potential.31

Table 5. Characteristic temperatures for the bromination in full-batch and semi-batch mode, and related Stoessel diagram.


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Mode

TP

MTT32

TD24

MTSR

criticality class

Full-batch

50 °C

100 °C

59 °C

65 °C

5

Semi-batch

50 °C

100 °C

59 °C

52 °C

2

Improved Process. Downsides of the first kg-scale process included the low purity (85–90% w/w by NMR) and undesirable brown color of the product, which was problematic in the subsequent synthetic steps. For reasons of safety and efficiency, we wanted to introduce a fully telescoped sequence, all three intermediates being oils. Additionally, we implemented a direct crystallization of the more thermally stable (+)-camphor-10-sulfonic acid salt 1i rather than the HCl salt 1a (see above). Further laboratory investigations led us to the improved process shown in Scheme 3. In practice, the following changes were introduced: Step 1: iPrMgCl instead of EtMgBr, 25 °C instead of 50 °C, DMF instead of NMP, work-up with ammonium citrate/cyclohexane instead of 1M HCl/EtOAc; Step 2: catalytic NaOMe instead of stoichiometric K2CO3, 45 °C instead of rt; Step 3: NaOCl + NaBr instead of NaOH + Br2 for the generation of hypobromite, 0.2 eq NaOH instead of 7 eq KOH, starting material as solution in cyclohexane rather than neat, dosing of NaOCl rather than the starting material; Step 4: (+)-CSA


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instead of HCl, 70 °C instead of rt, direct crystallization of the product by constant-volume solvent exchange to MeCN.

Scheme 3. Improved, fully telescoped process to (+)-camphor-10-sulfonic acid salt 1i.

In the first step, deprotonation of ethynyltrimethylsilane using iPrMgCl offered the advantage that the resulting alkynylmagnesium chloride was more soluble than the corresponding bromide, hence no special temperature control of the Grignard solution was necessary anymore. We found that even a small excess of iPrMgCl as compared to ethynyltrimethylsilane (such as 1.3 eq iPrMgCl to 1.1 eq ethynyltrimethylsilane) led to a complete quench of the desired reaction due to reduction of iodide 6, resulting in formation of the organomagnesium species, which was protonated to the corresponding des-iodinated side product upon work-up. The coupling reaction was performed in DMF, which gave ca. 10% higher yield compared to NMP and other screened solvents (N,N-dimethylacetamide, DMF, THF, MeCN). After quenching onto aqueous ammonium citrate, the product was obtained as a solution in cyclohexane (rather than EtOAc), which was telescoped through all the following steps.


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The TMS cleavage was done in a mixture of cyclohexane and MeOH using 0.25 eq of NaOMe. It was important to remove all residual MeOH from the organic solution by both an aqueous wash and concentration of the solution to ca. 30% w/w, because already small amounts of MeOH had a negative influence on conversion in the subsequent bromination. We speculate that residual MeOH may consume part of the hypobromite to form MeOBr, which may not be sufficiently reactive or decay too quickly at the reaction temperature to brominate the terminal alkyne.33 With the described two aqueous washes, the residual MeOH level was typically < 0.1% a/a by GC. The NaOBr required for the bromination was generated using NaBr and NaOCl solution, which were less hazardous in handling than elemental bromine with comparable reaction profile and yield. The amount of NaOH was reduced from the original 7 eq to 0.2 eq, resulting in faster conversion due to improved mass transfer between the organic and the aqueous phase. Under these conditions, the reaction showed 10% accumulation of reagent for 2 h dosage of NaOCl, which was deemed acceptable. The Boc cleavage using (+)-camphor-10-sulfonic acid necessitated an increased reaction temperature due to the lower reactivity (acid strength) compared to HCl. Based on solubility data, potential crystallization solvents were anisole, iPrOAc and MeCN, the latter of which was preferred since it forms a low-boiling azeotropic mixture with cyclohexane (MeCN:cHex 60:40, 62 °C).34 During slow addition of the starting material solution, simultaneous constant-volume solvent exchange from cyclohexane to MeCN with seeding, followed by slow cooling, resulted in complete crystallization of the desired product 1i as a white to off-white solid. The overall yield of the whole sequence was 77% with no isolated intermediates. The product was better in purity (99.3% a/a by GC, 96% w/w by NMR) and color (off-white, Figure 5) compared to the


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first process, which can be explained by cleaner reaction profiles, the use of the non-polar cyclohexane as the extraction solvent, and a purging effect of the final crystallization, which was more controlled than the original crystallization, including seeding.

Figure 5. Comparison of the typical product color from the first process (1a, left) and the improved process (1i, right).

Conclusion We have developed a four-step route to a highly energetic bromoacetylene building block 1a suitable for kilogram-scale production. Extensive safety assessments of the hydrochloride 1a and the bromination reaction are presented. Additionally, we have further improved the process to a fully telescoped sequence delivering the more thermally stable (+)-CSA salt 1i in excellent


24

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purity. Cyclohexane is beneficially used as solvent through all steps, facilitating, in addition, the phase splits and extraction. This process is deemed suitable for production on pilot-plant scale.

Experimental Section General remarks. 1 vol or 1 wt means 1 L of solvent or 1 kg of reagent, respectively, with respect to the reference starting material. Compounds are characterized by 1H NMR (400 MHz, Bruker) or

13

C NMR (100 MHz, Bruker); internal standard for quantitative NMR was 1,4-

dimethoxybenzene. For quantitative analysis by GC, dodecane was used as internal standard. As tentative assay standards, a sample of each intermediate was purified by column chromatography and the assay determined by 1H NMR. Further details for the GC−MS and DSC methods are listed in the Supporting Information. All temperatures are internal temperatures, and yields are presented as is, unless otherwise stated. Experimental data are given for the telescoped process (Scheme 3). tert-Butyl 3-((trimethylsilyl)ethynyl)azetidine-1-carboxylate (7). iPrMgCl (18.1% w/w, freshly titrated; 331.14 g, 0.583 mol, 1.10 eq) and THF (75 mL, 0.5 vol) were charged at rt. Ethynyltrimethylsilane (58.54 g, 0.596 mol, 1.125 eq) was added at 20–30 °C over 1 h [exothermic, gas evolution]. After stirring the reaction mixture (grey solution) at 20–30 °C for 15 min, the Grignard solution was ready for the use in the coupling reaction. In a second flask, NBoc-3-iodoazetidine 6 (150 g, 0.530 mol, 1.00 eq) and FeCl2 (2.02 g, 0.016 mol, 3 mol%) were dissolved in dry DMF (600 mL, 4 vol) to give a yellow to orange solution. Then, 10/11 of the Grignard solution (1.00 eq) was added dropwise at 15 °C over 2 h [exothermic]. After the addition, the reaction mixture was stirred for another 30 min and the conversion checked by GC. The remaining 1/11 of the Grignard solution (0.10 eq) was added based on the IPC result (target


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conversion: starting material ≤ 1% a/a). The reaction mixture was quenched on a biphasic mixture of citric acid (20.68 g, 0.108 mol, 0.2 eq), aqueous ammonia (25%; 7.22 g, 0.106 mol, 0.2 eq), water (600 mL, 4 vol), and cyclohexane (600 mL, 4 vol) [exothermic]. The aqueous layer was drained at 30–40 °C and the organic layer concentrated to 500–600 mL at 40–55 °C under reduced pressure. The product solution was filtered and the concentration adjusted to 25% w/w with cyclohexane. Yield based on assay: 90%. Purity (GC−MS): 91.4% a/a, Rt 8.6 min, [M – tBu]+ = 197; 1H NMR (concentrated sample, CDCl3): δ 4.12 (t, J = 8.5 Hz, 2H), 3.93 (dd, J = 7.9, 6.5 Hz, 2H), 3.34 (tt, J = 8.7, 6.4 Hz, 1H), 1.45 (s, 9H), 0.17 (s, 9H). tert-Butyl 3-ethynylazetidine-1-carboxylate (4). Methanol (96 mL, 0.8 vol), cyclohexane (96 mL, 0.8 vol), and NaOMe in MeOH (30% w/w; 21.32 g, 0.118 mol, 0.25 eq) were charged and the temperature adjusted to 45 °C. At this temperature, the solution of 7 (25% w/w in cyclohexane, 480 g, 0.474 mol, 1.00 eq) was added dropwise over 1 h, and the reaction mixture was stirred for 20 min. The conversion was checked by GC (starting material < 0.25% a/a). Water (12.97 g, 0.720 mol, 1.5 eq) was added and the reaction mixture stirred additionally for 1 h at 45 °C. The reaction mixture was diluted with water (400 mL, 3.33 vol), stirred for at least 5 min, and the layers were separated. The organic layer was washed with water (200 mL, 1.67 vol) and concentrated to about 30% w/w by distillation at 40–55 °C under reduced pressure. The content of MeOH and MeOTMS was checked by GC (MeOH < 0.5% a/a, MeOTMS < 4.0% a/a). If the limits for MeOH or MeOTMS were not reached, distillation was resumed while keeping the volume constant by feeding cyclohexane. This solution was used directly in the next step (bromination). Yield based on assay: 94%. Purity (GC−MS): 84.6% a/a, Rt 7.0 min, [M – tBu]+ = 125; 1H NMR (concentrated sample, CDCl3): δ 4.16 (t, J = 8.6 Hz, 2H), 3.96 (dd, J = 8.3, 6.3 Hz, 2H), 3.33 (ttd, J = 8.7, 6.4, 2.4 Hz, 1H), 2.30 (d, J = 2.5 Hz, 1H), 1.46 (s, 9H).


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tert-Butyl 3-(bromoethynyl)azetidine-1-carboxylate (5). (Stoichiometry calculated assuming 100% yield; 1.00 eq corresponds to 85.9 g, 0.474 mol 4.) A solution of crude 4 (33.4% w/w in cyclohexane; 242.3 g, 0.447 mol, 0.94 eq) was charged together with water (150 mL, 1.7 vol), sodium hydroxide (30% w/w, 12.6 g, 0.095 mol, 0.2 eq), and NaBr (68.21 g, 0.663 mol, 1.4 eq), and the biphasic mixture heated to 45 °C. At this temperature, a solution of NaOCl (freshly titrated, 11.2%-w/w; 440.6 g, 0.663 mol, 1.4 eq) was added dropwise over 2 h [exothermic] and the mixture was stirred for another 2 h. After complete conversion, the excess NaOCl was quenched by addition of aqueous NaHSO3 (38% w/w; 51.9 g, 0.190 mol, 0.4 eq) [exothermic]. The aqueous layer was drained and the organic layer washed with water (150 ml, 1.7 vol). The resulting solution (256 g) was used directly in the next step (Boc cleavage). Yield based on assay: 93%. Purity (GC−MS): 92.0% a/a, Rt 8.7 min, [M – tBu]+ = 203; 1H NMR (concentrated sample, CDCl3): δ 4.13 (t, J = 8.6 Hz, 2H), 3.96 (dd, J = 8.4, 6.3 Hz, 2H), 3.34 (tt, J = 8.7, 6.3 Hz, 1H), 1.46 (s, 9H). 3-(Bromoethynyl)azetidin-1-ium (+)-camphor-10-sulfonate (1i). (Stoichiometry calculated assuming 100% yield; 1.00 eq corresponds to 123.3 g, 0.474 mol 5.) (+)-Camphor-10-sulfonic acid (132.0 g, 0.568 mol, 1.2 eq) was charged in MeCN (616 mL, 5 vol) and the mixture heated to 70 °C. Subsequently, a solution of crude 5 (42.3% w/w in cyclohexane; 256.0 g, 0.416 mol, 0.88 eq) was added dropwise over 1 h while keeping the temperature at 65–75 °C by distillation of the cyclohexane/MeCN/water mixture. After 65% of the addition, the mixture was seeded to induce crystallization. At the end of the addition, distillation was continued until the internal temperature reached 77 °C, then the mixture was stirred for 1 h at this temperature. The slurry was cooled to rt over at least 1 h and aged at least 1 h. The suspension was filtered and the cake washed with MeCN (2 x 100 mL, 2 x 0.8 vol). The wet product was dried in the cabinet at 50 °C


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until constant weight to afford 1i (160.35 g, 98% yield) as a white to off-white solid. Purity (GC−MS, after derivatization with BuOCOCl): 99.3% a/a, Rt 9.3 min, [M – H + CO2Bu]+ = 259; assay (quantitative 1H NMR): 96.0% w/w; residual MeCN (quantitative 1H NMR): 2% w/w; residual water (volumetric Karl Fischer titration): 0.10% w/w; 1H NMR (DMSO-d6): δ 8.79 (br. s, 2H), 4.16–4.10 (m, 2H), 3.98–3.91 (m, 2H), 3.75 (tt, J = 9.0, 7.6 Hz, 1H), 2.88 (d, J = 14.7 Hz, 1H), 2.71–2.63 (m, 1H), 2.38 (d, J = 14.7 Hz, 1H), 2.24 (ddd, J = 18.0, 4.4, 2.9 Hz, 1H), 1.94 (t, J = 4.5 Hz, 1H), 1.88–1.83 (m, 1H), 1.81 (d, J = 18.1 Hz, 1H), 1.32–1.25 (m, 1H), 1.05 (s, 3H), 0.75 (s, 3H); 13C NMR (DMSO-d6): δ 216.8, 78.8, 58.7, 51.0, 47.6, 47.2, 47.1, 42.8, 42.6, 26.9, 24.6, 23.2, 20.6, 20.0.

Supporting Information NMR characterization data of all intermediates, GC–MS method, DSC traces, and reaction calorimetric data (Systag FlexyCUBE) for the bromination. This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]. Telephone: +41 58 844 0675. ORCID Philipp Kohler: 0000-0002-2424-9527 Mischa Schwaninger: 0000-0003-4045-5408


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Stefan Abele: 0000-0002-5034-4579

Present Addresses †Chemical Development, Idorsia Pharmaceuticals Ltd, Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

ACKNOWLEDGMENT P.K. and S.A. would like to thank Dr. Jean-Philippe Surivet, Dr. Philippe Panchaud, Dr. Stefan Diethelm and Dr. Georg Rüedi for the fruitful collaboration with medicinal chemistry; Synphabase AG for scale-up; and Stéphanie Combes and Ivan Schindelholz for their experimental work. We thank Dr. Thomas Weller for continuous support.

ABBREVIATIONS API, active pharmaceutical ingredient; LpxC, 2,3-diacylglucosamine 1-phosphate (lipid X) biosynthesis, step C catalyzing enzyme; NMP, N-methylpyrrolidin-2-one; CRO, contract research organization; DSC, differential scanning calorimetry; CSA, camphor-10-sulfonic acid; BAM, Bundesanstalt für Materialforschung und –prüfung, Germany; ESCIS, Expert Commission for Safety in the Swiss Chemical Industry, Switzerland; ASTM International,


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formerly American Society for Testing and Materials; SADT, self-accelerating decomposition temperature; TMRad, time-to-maximum rate under adiabatic conditions; MTSR, maximum temperature of synthesis reaction; MTT, maximum temperature for technical reasons.

REFERENCES 1. (a) Gauvin, J.-C.; Mirre, A.; Ochala, E.; Surivet, J.-P. Antibacterial 2H-Indazole Derivatives. WO 2015036964, 2015. (b) Hubschwerlen, C.; Ochala, E.; Specklin, J.-L.; Surivet, J.-P. Antibacterial 1H-Indazole and 1H-Indole Derivatives. WO 2015091741, 2015. (c) Chapoux, G.; Gauvin, J.-C.; Panchaud, P.; Specklin, J.-L.; Surivet, J.-P.; Schmitt, C. 1,2-Dihydro-3H-pyrrolo[1,2-c]imidazol-3-one Derivatives and Their Use as Antibacterial Agents. WO 2015132228, 2015. (d) Schmitt, C.; Surivet, J.-P.; Chapoux, G.; Mirre, A.; Specklin, J.-L. Antibacterial Benzothiazole Derivatives. WO 2016079688, 2016. (e) Panchaud, P.; Schmitt, C.; Surivet, J.-P. Antibacterial Annulated Pyrrolidin-2one Derivatives. WO 2017036968, 2017. (f) Chapoux, G.; Diethelm, S.; Gauvin, J.-C.; Panchaud, P.; Surivet, J.-P. Antibacterial Heterocyclic Derivatives. WO 2017037039, 2017. (g) Blumstein, A.-C.; Chapoux, G.; Jacob, L.; Masse, F.; Mirre, A.; Panchaud, P.; Schmitt, C. Substituted 1,2-Dihydro-3H-pyrrolo[1,2-c]imidazole-3-one Antibacterial Compounds. WO 2017037221, 2017. 2. Parikh, J. R.; Doering, W. v. E. Sulfur Trioxide in the Oxidation of Alcohols by Dimethyl Sulfoxide. J. Am. Chem. Soc. 1967, 89, 5505–5507.


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3. Ohira, S. Methanolysis of Dimethyl (1-Diazo-2-oxopropyl) Phosphonate: Generation of Dimethyl (Diazomethyl) Phosphonate and Reaction with Carbonyl Compounds. Synth. Commun. 1989, 19, 561–564. 4. Müller, S.; Liepold, B.; Roth, G. J.; Bestmann, H. J. An Improved One-pot Procedure for the Synthesis of Alkynes from Aldehydes. Synlett 1996, 521–522. 5. Hofmeister, H.; Annen, K.; Laurent, H.; Wiechert, H. A Novel Entry to 17α-Bromo- and 17α-Iodoethynyl Steroids. Angew. Chem. Int. Ed. 1984, 23, 727–729. 6. Urben, P. G. (Ed.) Bretherick's Handbook of Reactive Chemical Hazards; 7th edition, Academic Press: Oxford, Burlington, 2007. 7. Whiting, M. C. Handling Acetylenic Compounds. Chem. Eng. News 1972, 50(23), 86. 8. Kloster-Jensen, E.; Heilbronner, E. Unstable Acetylenes. Chem. Eng. News 1978, 56(19), 38. 9. Witulski, B.; Alayrac, C. Product Subclass 1: 1-Haloalk-1-ynes and Alk-1-yn-1-ols. In Science of Synthesis; de Meijere, A. (Ed.); Georg Thieme Verlag: Stuttgart, New York, 2006; Vol. 24, pp 905–932. 10. Cheung, C. W.; Ren, P.; Hu, X. Mild and Phosphine-Free Iron-Catalyzed Cross-Coupling of Nonactivated Secondary Alkyl Halides with Alkynyl Grignard Reagents. Org. Lett. 2014, 16, 2566–2569.


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11. Barré, B.; Gonnard, L.; Campagne, R.; Reymond, S.; Marin, J.; Ciapetti, P.; Brellier, M.; Guérinot, A.; Cossy, J. Iron- and Cobalt-Catalyzed Arylation of Azetidines, Pyrrolidines, and Piperidines with Grignard Reagents. Org. Lett. 2014, 16, 6160–6163. 12. For use of acetylene, ethynyltrimethylsilane, and 2-methyl-3-butyn-2-ol for scale-up, see: (a) Königsberger, K.; Chen, G.-P.; Wu, R. R.; Girgis, M. J.; Prasad, K.; Repič, O.; Blacklock, T. J. A Practical Synthesis of 6-[2-(2,5-Dimethoxyphenyl)ethyl]-4ethylquinazoline and the Art of Removing Palladium from the Products of Pd-Catalyzed Reactions. Org. Process Res. Dev. 2003, 7, 733–742; (b) Andresen, B. M.; Couturier, M.; Cronin, B.; D'Occhio, M.; Ewing, M. D.; Guinn, M.; Hawkins, J. M.; Jasys, V. J.; LaGreca, S. D.; Lyssikatos, J. P.; Moraski, G.; Ng, K.; Raggon, J. W.; Stewart, A. M.; Tickner, D. L.; Tucker, J. L.; Urban, F. J.; Vazquez, E.; Wei, L. Streamlined Processes for the Synthesis of a Farnesyl Transferase Inhibitor Drug Candidate. Org. Process Res. Dev. 2004, 8, 643–650; (c) Chung, J. Y. L.; Steinhuebel, D.; Krska, S. W.; Hartner, F. W.; Cai, C.; Rosen, J.; Mancheno, D. E.; Pei, T.; DiMichele, L.; Ball, R. G.; Chen, C.-y.; Tan, L.; Alorati, A. D.; Brewer, S. E.; Scott, J. P. Asymmetric Synthesis of a Glucagon Receptor Antagonist via Friedel−Crafts Alkylation of Indole with Chiral α‑Phenyl Benzyl Cation. Org. Process Res. Dev. 2012, 16, 1832–1845. 13. Cai, C.; Vasella, A. Oligosaccharide Analogues of Polysaccharides. Part 3. A New Protecting Group for Alkynes: Orthogonally Protected Dialkynes. Helv. Chim. Acta 1995, 78, 732–757. 14. Straus, F.; Kollek, L.; Heyn, W. Über den Ersatz positiven Wasserstoffs durch Halogen. Ber. Chem. Ges. B 1930, 63, 1868–1885.


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15. Eglinton, G.; McCrae, W. Reactive Acetylenic Intermediates: the Synthesis of 1Bromoacetylenes and Mercury Acetylides. J. Chem. Soc. 1963, 2295–2299. 16. Miller, S. I.; Ziegler, G. R.; Wielenseck, R. Phenylbromoethyne. Org. Synth. 1965, 45, 86–88; Org. Synth. Coll. Vol. 1973, 5, 921–923. 17. Brandsma, L.; Verkruijsse, H. D. Practical and Safe Procedures for the Preparation of the Lower Homologues of Bromoacetylene. Synthesis 1990, 984–985. 18. Recommendations on the Transport of Dangerous Goods, Manual of Tests and Criteria, 6th revised edition, United Nations, New York and Geneva, 2015. 19. Baker, G. P.; Whitmore, M. W. Investigation of the Use of a Closed Pressure Vessel Test for Estimating Condensed Phase Explosive Properties of Organic Compounds. J. Loss Prev. Proc. Ind. 1999, 12, 207–216. 20. Knorr A.; Koseki H.; Lib X.-R.; Tamurac M.; Wehrstedt K.D.; Whitmore M.W. A Closed Pressure Vessel Test (CPVT) Screen for Explosive Properties of Energetic Organic Compounds. J. Loss Prev. Proc. Ind. 2007, 20, 1–6. 21. Rank A: detonation, i.e. potentially class 1 explosive; rank B: rapid deflagration and/or violent effect upon heating under confinement i.e. potentially class 1 explosive, but not detonable; rank C: medium and/or slow deflagration or low effect of heating under confinement, i.e. not class 1 explosive; rank D: no deflagration and no effect of heating under confinement, i.e. no explosive properties. Further details regarding the CPVT are listed in the Supporting Information.


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22. Self-accelerating decomposition temperature (SADT): the lowest temperature at which the compound in a shipping package will undergo self-accelerating decomposition, i.e. the heat evolution from the decomposition reaction is higher than the heat removal rate from the package, which consequently leads to heat accumulation and temperature increase of 6°C or more within one week, as defined in the UN Orange Book.18 23. Stoessel, F. What Is Your Thermal Risk? Chem. Eng. Prog. 1993, 89, 68–75. 24. Stoessel, F.; Fierz, H.; Lerena, P.; Killé, G. Recent Developments in the Assessment of Thermal Risks of Chemical Processes. Org. Process Res. Dev. 1997, 1, 428–434. 25. Stoessel, F., Thermal Safety of Chemical Processes, Risk Assessment and Process Design; Wiley-VCH: Weinheim, 2008. 26. Hungerbühler, K.; Ranke, J.; Mettier, T. Chemische Produkte und Prozesse, SpringerVerlag, Berlin, Heidelberg, 1999. 27. Recommendations on the Transport of Dangerous Goods, Model Regulations, 19th revised edition, United Nations, New York and Geneva, 2015. 28. Heat capacity estimated based on the following mass fraction weighted specific heat capacities of the components: water 4.2 kJ kg-1·K-1, caustic potash 1.15 kJ kg-1·K-1, bromine 0.5 kJ kg-1·K-1, 4 1.7 kJ kg-1·K-1. 29. The heat release rate q0 at the process temperature T0 is also required for the calculation. It can be estimated in the following way: a minimum heat release still giving a measurable signal in the DSC measurement of qonset = 10 W kg-1 is assumed


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(conservative, instrument-dependent value). This minimal heat release corresponds to the left limit of the decomposition event at temperature Tonset. The heat release at the process temperature is extrapolated using Arrhenius' law: q0 = qonset · exp[–EA/R · (1/T0 – 1/Tonset)]. 30. For another example of such a discussion of thermal safety, see: Abele, S.; Schwaninger, M.; Fierz, H.; Schmidt, G.; Funel, J.-A.; Stoessel, F. Safety Assessment of Diels-Alder Reactions with Highly Reactive Acrylic Monomers. Org. Process Res. Dev. 2012, 16, 2015–2020. 31. In addition to a thorough risk assessment, it is strongly recommended to complement the results of this section by additional RC1 data, which are more precise. 32. MTT: maximum temperature for technical reasons, often the boiling point. 33. Concerning the low stability of MeOBr, see: Bushong, F. W. On the Alkyl Hypobromites. R–O–Br. Trans. Kans. Acad. Sci. 1896, 15, 81–82. 34. Smallwood, I. M., Handbook of Organic Solvent Properties; Elsevier: New York, Toronto, 1996.


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Scalable Process for the Production of a Highly Energetic

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