Manufacture of the PI3K Î²-Sparing Inhibitor Taselisib. Part 1: Early

Subscriber access provided by LUNDS UNIV

Full Paper

Manufacture of the PI3K #-Sparing Inhibitor Taselisib. Part 1: EarlyStage Development Routes to the Bromobenzoxazepine Core Travis Remarchuk, Remy Angelaud, David Askin, Archana Kumar, Andrew S. Thompson, Hua Cheng, John Reichwein, Yanping Chen, and Frédéric St-Jean Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.9b00049 • Publication Date (Web): 06 Mar 2019 Downloaded from http://pubs.acs.org on March 7, 2019

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 30 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

Organic Process Research & Development

Manufacture of the PI3K -Sparing Inhibitor Taselisib. Part 1: Early-Stage Development Routes to the Bromobenzoxazepine Core Travis Remarchuk,† Rémy Angelaud,† David Askin,† Archana Kumar,† Andrew S. Thompson,‡ Hua Cheng,‡ John F. Reichwein,‡ Yanping Chen‡ and Frédéric St-Jean*† †

Department of Small Molecule Process Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA

‡

J-Star Research, Inc., 3001 Hadley Road, Suites 1−4, South Plainfield, New Jersey 07080, USA

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

Page 2 of 30

TOC


2

Page 3 of 30 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


Abstract: Two convergent regioselective routes for the synthesis of the tetracyclic imidazobenzoxazepine triazole 1, a key intermediate towards the synthesis of taselisib, are described. In the first-generation route, a chemoselective Negishi cross-coupling reaction was developed between iodoimidazole 3 and triazole 7, which enabled the delivery of initial kilogram quantities of 1. Due to the inefficiencies in the preparation of the imidazole 3, a secondgeneration route via a highly regioselective imidazole ring formation between -chloroketone 11 and aryl amidine 12 was developed. The resulting imidazole 14 provided the handle to efficiently install the seven-membered benzoxazepine ring system in a one-pot, two-step N-alkylation and SNAr tandem reactions.

Keywords: benzoxazepine, 1,2,4-triazole, Negishi coupling, alpha-chloro ketone, amidine


3


Page 4 of 30

Introduction

Figure 1. Retrosynthesis of taselisib

Taselisib (GDC-0032) is a potent small molecule PI3k -isoform sparing inhibitor in clinical development for the treatment of various types of cancer. The synthesis of taselisib was first reported by the Discovery chemistry group at Genentech, and involved a late-stage Suzuki cross-coupling reaction between the bromobenzoxazepine tetracyclic core 1 and the borylated pyrazole 2 (Figure 1).1 Herein, we describe two alternative synthetic approaches developed that enabled kilogram-scale synthesis of tetracycle 1 to support early drug substance deliveries. In the Discovery synthesis of 1, the 1,2,4-triazole ring system was installed in the last step and involved a chemoselective palladium-catalyzed aminocarbonylation reaction with the iodoimidazole 32 to produce the corresponding amide 4 (Scheme 1).3 This reaction required a large excess of bis(trimethylsilyl)amine (HMDS), otherwise a competing reaction occurred with the DMF solvent leading to the dimethylamide by product 5.4 Conversion of the primary amide 4 to tetracycle 1 was achieved with high regioselective control by a two-step reaction, converting 4 first to the N,N-dimethylacetimidamide 6, which then reacted with isopropylhydrazine to give the desired product 1.5 Although the aminocarbonylation route (Scheme 1) enabled the initial gram-


4

Page 5 of 30 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


scale quantities of 1, the use of carbon monoxide gas, large excess of HMDS and DMA dimethylacetal6 made it difficult for larger scale production without the need for specialized equipment to handle pressurized reactions. Since the palladium-catalyzed amino carbonylation reaction was highly chemoselective, focus was then turned on developing a Negishi crosscoupling reaction directly between triazole 7 and iodoimidazole 3.7

Scheme 1. Aminocarbonylation route to form the 1,2,4-triazole ring system of 1.

Although the aminocarbonylation route (Scheme 1) enabled the initial gram-scale quantities of 1, the use of carbon monoxide gas, large excess of HMDS and DMA dimethylacetal8 made it difficult for larger scale production without the need for specialized equipment to handle pressurized reactions. Since the palladium-catalyzed aminocarbonylation reaction was highly chemoselective, focus was then turned on developing a Negishi crosscoupling reaction directly between triazole 7 and iodoimidazole 3 (Figure 2). 9


5


Page 6 of 30

Figure 2. Negishi approach to 1

Results and Discussion The first approach to synthesize triazole 7 involved N-alkylation of 3-methyl-1H-1,2,4triazole 8 with 2-iodopropane (approach A, Scheme 2).10,11 In the presence of DBU at 60 °C, the alkylation proceeded to give a 60:40 intractable mixture of 3-methyl-triazole 7 and 5-methyltriazole 7’ in 53% yield.12 When the alkylation was performed at 25 °C instead of 60 °C, both alkylation isomer products were observed in a similar ratio, albeit with lower reaction conversion. Alternatively, starting with 1-isopropyl-1,2,4-triazole 9 (approach B, Scheme 2) and performing a lithiation with 1.1 equivalent of n-BuLi, followed by a MeI quench resulted in only the undesired regioisomer 7’ being formed. Nevertheless, the 60:40 mixture of 7/7’ from approach A (Scheme 2) was used directly in a Negishi cross-coupling reaction (Scheme 3) to establish whether isomer 7’ would participate in the reaction.

Scheme 2. First generation approaches to synthesize triazole 7.


6

Page 7 of 30 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


The Negishi cross-coupling reaction was initially performed at three different temperatures (–60 °C, –40 °C and –20 °C) after organozinc formation with stoichiometric amounts of n-BuLi and ZnCl2 (relative to 7). Following the addition of iodoimidazole 3 and catalytic Pd(PPh3)4 to the triazole organozinc, every experiment was warmed to 60 °C for 18 h. After work-up, only the cross-coupled product 1 was isolated, arising from the exclusive reaction of triazole isomer 7. Isomer 7’ appeared to remain unreacted (as determined by HPLC analysis), which can be rationalized when looking at the difference in energy of the lithiated intermediates from 7 and 7’, where the former might be the only species that accumulated to react downstream and form organozinc [Zn]-7, followed by 1.13,14 After subsequent optimization, the reaction was demonstrated on 0.66 kg scale of the 7/7’ mixture (60:40),15 and afforded 1 in 73% isolated yield (corrected relative to the amount of 7) with high purity (>99 A% by HPLC). With this promising result for the Negishi approach, focus was then turned towards a more efficient and regioselective synthesis of triazole 7.

Scheme 3. Negishi cross-coupling reaction of 3 and triazole mixture 7/7’.

Based on literature precedent, N’-isopropyl acetamidrazone (IPAA) 10 from was made from addition of isopropylhydrazine hydrochloride (IPH•HCl) to acetamidine hydrochloride in


7


Page 8 of 30

the presence of Et3N (Scheme 4).16 Then, treatment of IPAA 10 with triethylorthoformate afforded the desired triazole 7 regiospecifically. This sequence was successfully demonstrated on scale; in a two-step one-pot process 21 kg of 7 was synthesized in 52% yield with 98 A% purity by GC.

Prior to the scale-up of the Negishi reaction, further experiments were performed to examine the effect of catalyst loading and equivalents of ZnCl2 on the conversion to product 1. Complete conversions (>99 A% by HPLC) were obtained at ≥4 mol% Pd(PPh3)4, whereas lowering the loading to 3.5 mol% catalyst resulted in incomplete conversions (90–95 A% by HPLC). The amount of ZnCl2 in THF17 was also evaluated and in two experiments, using either 1.2 equiv or 0.6 equiv of ZnCl2 relative to triazole 7, and showed no impact on the yield or purity of the product 1. For the scale-up, the ZnCl2 charge was set in between the two values at 0.9 equivalents relative to triazole 7 to ensure complete formation of the organozinc intermediate. With the optimized conditions, tetracycle 1 was produced in 77% yield and 99.4 A% purity by HPLC (Scheme 4).

Scheme 4. Second generation synthesis of triazole 7 and Negishi cross-coupling.


8

Page 9 of 30 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


The Negishi cross coupling route was phase-appropriate for early-stage development, however for larger scale production of 1, there were several bottleneck steps to address. The use of ZnCl2 and a palladium catalyst required a scavenging step later in the process and the preparation of iodoimidazole 3 was low-yielding, but also poorly atom economical. [3+2] Imidazole Ring Formation Approach for the Synthesis of Benzoxazepine 1. An alternative synthetic approach to 1 was developed to use triazole 7 by further functionalization at the C-5 position to afford -chloroketone 11. This substrate can be used in a formal [3+2] alkylation/condensation with aryl amidine 12 to prepare the imidazole ring system of 1 (Figure 3).18

Figure 3. The [3+2] imidazole ring formation approach to 1. To first examine the functionalization of triazole 7, the lithiated triazole was quenched with several chlorocarbonyl reagents (I–IV) (Scheme 5). From the screening study, only the 2chloroacetyl chloride reagent I failed to give the desired product. The other three reagents gave comparable yields (60–64%) of -chloroketone 11 after isolation. The Weinreb amide reagent IV afforded the cleanest reaction profile and highest isolated yield (64%) of product 11 on gram scale, and was thus chosen for further optimization.19


9


Page 10 of 30

Scheme 5. Synthesis of chloroketone 11 from triazole 7.

The effect of temperature on the stability of the tetrahedral intermediate derived from Weinreb amide IV was examined at two temperatures (–20 °C and 0 °C). After lithiation of triazole 7 with n-BuLi at –20 °C and addition of IV, the reaction mixture was maintained at either –20 °C or warmed to 0 °C, and then held for an additional 20 h. The reaction mixture at 0 °C darkened over time, and resulted in significant lower assay yield of the product 11 relative to the reaction performed at –20 °C. The mode of addition was also found to be a critical process parameter. When the lithiated triazole was added to a THF solution of Weinreb amide IV at –20 °C, there was a 10–15% increase in assay yield relative to the inverse mode of addition.20 The –20 °C temperature was also essential to maintain for the quench in order to prevent degradation of 11. Propionic acid (neat) was found to be an effective quenching reagent since it allowed good agitation at –20 °C and good product stability. To assess the practicality of isolating chloroketone 11, an aqueous work-up was performed to remove the N-methyl-N-methoxy amine byproduct, and then solvent exchange into 2-propanol afforded solids that were filtered off.21 Upon drying of the solids under vacuum (40 °C/150 mm Hg), sublimation of the product was observed. The product was also determined to be a lachrymator. Subsequently, this resulted in the development of a telescoped procedure in which -chloroketone 11 intermediate could


10

Page 11 of 30 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


directly be used in the reaction with aryl amidine 12. To implement the telescoped process, amidine 12∙HCl had to be freebased first.22 Several bases were examined and organic bases such as Et3N, i-Pr2NEt, and DBU were found to be inefficient. Aqueous K3PO4 and K2HPO4 led to significant hydrolysis of amidine 12 to the corresponding amide (up to 10 A% by HPLC). Only the use of aqueous KHCO3 in THF at reflux was found to be effective to freebase 12∙HCl while minimizing the hydrolysis by-product (Scheme 6).

Scheme 6. Scale-up of the telescoped synthesis of 14.

For the multi-kilogram scale manufacturing of imidazole 14 (Scheme 6), the Weinreb amide IV was prepared from the reaction of acyl chloride I and N,O-dimethylhydroxylamine hydrochloride, which was then delivered as a solution after workup and solvent swap to THF.23 Lithiation of triazole 7 between –40 °C and –20 °C and subsequent acylation with the Weinreb amide THF solution (21 wt% by assay), resulted in 72% assay yield of -chloroketone 11 after aqueous work-up. This solution was then added to a suspension of previously freebased amidine 12 in THF and aqueous KHCO3 to form crude imidazole 14. Crystallization of the crude product from MIBK provided 49.5 kg of imidazole 14 in 66% yield and high purity (99.5 A% by HPLC).


11


Page 12 of 30

Optimized synthesis of bromobenzoxazepine 1 from imidazole 14. Installation of the sevenmembered benzoxazepine ring of 1 was achieved in two steps using ethylene carbonate, which afforded a highly regioselective alkylation of 14, followed by an intramolecular SNAr reaction (Scheme 7) on the aryl fluoride.24 Early experiments, using 7.5 equiv of ethylene carbonate in toluene at reflux over 13 hours, showed complete consumption of starting imidazole 14, and conversion to hydroxylethyl 15 up to ~80 A% by HPLC.25 After an additional 18 h at reflux in toluene, the cyclized product 1 reached a maximum conversion to ~75 A% by HPLC. Two major impurities, that accounted for the remainder of the A%, were tentatively identified as polyether derivative(s) of the type 16 and regioisomer 18.26 Both impurities were present in up to 20 A% and 3 A% by HPLC respectively in the crude reaction mixture. Furthermore, it was found that the conversion to 1 was poorly reproducible. In some instances, 15 completely converted to the cyclized product 1, whereas in other cases, under identical reaction conditions, only trace product 1 was observed.27 Scheme 7. Two-step alkylation/SNAr reactions from 14 to 1.


12

Page 13 of 30 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


Various solvents were screened for the direct conversion of 14 to benzoxazepine 1, which include: MIBK, 1,4-dioxane, DMA, water, n-BuOAc, t-AmOH, AcOH, DMSO and 1methylimidazole.28 From these solvents, only 1-methylimidazole resulted in significant product 1 formation (35 A% by HPLC), along with intermediate 15 (50 A% by HPLC) and complete consumption of starting material 14. Other solvents (DMF, NMP, DMA, 1-butanol, MIBK, dibutyl ether) and bases (CsOH, K3PO4, NaOH, DABCO & DIPEA) were also screened in combination under similar reaction conditions, however, none of these conditions proved to be superior to neat 1-methylimidazole. To help prevent the formation of polyether 16, the amount of ethylene carbonate was lowered to 6 equiv. Complete conversion of 15 to 1 could not be accomplished in 1-methylimidazole alone, and an additional base was required. The use of a second base to further promote the SNAr reaction was then examined. Starting with isolated 15, NaH initially gave a clean conversion to benzoxazepine 1 in 93 A% by HPLC, but was not considered for scale up (Table 1, entry 1) due to the hazardous nature of that mixture.29 In contrast, NaHMDS was less effective, and gave 52 A% of 1 (Table 1, entry 2), but also a substantial amount of one major impurity, identified as the N-vinyl impurity 17 (38 A%).30 Higher conversion to 1 (78 A%) with no major impurity forming was achieved with KOtBu in MeOH, but required extensive reaction time (>120 h) to reach high conversion (Table 1, entry 3). Switching to a biphasic reaction mixture of 50% aqueous NaOH/2-MeTHF, with n-Bu3NMeCl as a phase transfer catalyst (PTC), 85 A% conversion to 1 was observed after 24h, alongside 15 A% of impurity 17 which continued to increase with prolonged reaction time (Table 1, entry 4). Lowering the concentration of the NaOH solution to 15% helped prevent the formation of 17 (5 A%), albeit lower starting material consumption (Table 1, entry 5). Ultimately, controlling the reaction time led to the optimized conditions, using 2-MeTHF, 50% aqueous NaOH and 3.5


13


Page 14 of 30

mol% of n-Bu3NMeCl, which gave 90 A% conversion to 1 after only 3.5 h with 5 A% of impurity 17 (Table 1, entry 6). Table 1. Base and solvent screen for conversion of hydroxylethyl 15 to benzoxazepine 1. Entrya

Base/Catalyst

Solvent (vol)

1

NaH (60 % dispersion)

DMF

2

NaHMDSb (1M in THF)

DMF

3

KOtBud

MeOH

4

50% NaOH/ n-Bu3NMeCle,h

5

15% NaOH/ n-Bu3NMeCle,h

6

50% NaOH/ n-Bu3NMeClf,h

Temperature Time (°C) (h) 1(A%)g 17(A%)g 15(A%)g

23

16

93

NDc

ND

23

16

52

38

ND

50

24

22

ND

78

48

40

ND

58

120

78

ND

16

24

85

15

ND

48

76

23

ND

2MeTHF

65

2MeTHF

65

16

85

5

6

2MeTHF

65

3.5

90

5

3

a

Reactions were carried out on 1g (2.5 mmol) of 15 with 20V of solvent, unless noted otherwise;

b

10V of base solution (10.0 mmol, 400 mol%) and 10V of solvent used; cND = Not Detected;

d

300 mol% base; e10 mol% catalyst; f3.5 mol% catalyst; gDetermined by HPLC analysis of the

crude reaction. h6.5V of base solution and 13.5V of solvent used.


14

Page 15 of 30 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


The optimized conditions for both the imidazole alkylation to 15, and intramolecular SNAr to 1 as isolated steps were then combined into a telescoped one-pot, two-step reaction. Two modifications in the second step were required in order for the two reactions to be compatible. The first was to replace 2-MeTHF with toluene since this did not allow good phase separation with the aqueous phase when charged to with the 1-methylimidazole from the first step. The second was to use dilute (25–35%) aqueous KOH, instead of NaOH to facilitate phase separation and avoid emulsions during workup. On scale, the first step alkylation to 15 resulted in 95 A% conversion to 1 by HPLC after 6 h at 65 °C, with ~5 A% of impurity 17 and < 0.1 A% of impurity 18. After development and implementation of a crystallization procedure using IPA and water, 39.9 kg of the benzoxazepine 1 in 78% yield and 99.5 A% purity by HPLC was obtained (Scheme 8). Although very low amounts of regioisomer 18 were detected in the isolated product (99.9A%, 99.1 wt% assay). Scheme 8. One-pot telescoped alkylation and SNAr reactions to 1.


15


Page 16 of 30

Conclusion Two convergent routes to benzoxazepine 1 have been described. In the first-generation process route, a Negishi cross-coupling reaction was developed between iodoimidazole 3 and triazole 7 to give benzoxazepine 1 in 77% yield on 5 kg scale. Later, a regioselective synthesis of 7 was discovered that involved reaction of isopropylhydrazine and acetamidine to form intermediate IPAA 10, followed by condensation with triethyl orthoformate to yield exclusively isomer 7. Although the Negishi route to 1 provided a synthesis that enabled early API manufacturing, the preparation of iodoimidazole 3 was not efficient enough to enable large–scale synthesis. Thus, an alternative synthetic strategy to benzoxazepine 1 via a [3+2] imidazole synthesis was developed. This second-generation process involved condensation of aryl amidine 12 with -chloroketone 11, to provide imidazole 14 in 66% overall yield. In another two-step one-pot reaction, 14 was converted the benzoxazepine 1 using an efficient and highly regioselective alkylation/SNAr tandem reaction with ethylene carbonate and afforded, after crystallization, 35 kg of 1 in 69% overall yield and >99.9 A% purity.


16

Page 17 of 30 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


Experimental Section General Information. Unless noted otherwise, NMR measurements were carried out on either a Bruker Avance 3 500 MHz, a Varian Mercury 300 MHz, or a Bruker Ultrashield 400 MHz instrument at ambient temperature. All 1H NMR spectra are reported in parts per million (ppm) relative to residual CHCl3 signal (δ 7.26 ppm) or DMSO (δ 2.50 ppm) in the deuterated solvent unless otherwise stated. Data for 1H NMR are recorded as follows: chemical shift (ppm), multiplicity (s, singlet; bs, broad singlet; d, doublet; t, triplet; q, quartet; sept, septet; h, heptet; dd, doublet of doublet; m, multiplet), coupling constant (Hz) and integration. All

13

C NMR

spectra are reported in ppm relative to CDCl3 (δ 77.06ppm) or DMSO-d6 (δ 39.53 ppm) and were obtained with complete 1H decoupling unless otherwise stated. HRMS data was collected on an Agilent 6530C qTOF equipped with an ESI source in positive ionization mode. The samples were introduced into the mass spectrometer using an Agilent 1290 UPLC with an Agilent Extended-C18 (2.1-50mm, 1.8µm) column and a gradient from 5% to 95% acetonitrile in water with 0.1% formic acid in both channels at a flow rate of 0.6 mL/min. Melting points were measured by differential scanning calorimetry (DSC) on a Shimadzu DSC-50 or on a Buchi Melting Point B-540. Reagents and solvents were purchased from Sigma-Aldrich, Alfa Aesar or Acros and used without further purification. Regioselective synthesis of triazole 7 from isopropylhydrazine. To a 500 L reactor was charged methanol (288 L), isopropylhydrazine hydrochloride (36.0 kg, 326 mol, 1.0 equiv) and acetamidine hydrochloride (30.8 kg, 326 mol, 1.0 equiv), followed by triethylamine (34.3 kg, 339 mol, 1.04 equiv). The reaction mixture was stirred for 12 h while maintaining the temperature at 45–50 °C. The solvent was removed completely under vacuum and ethanol (288


17


Page 18 of 30

L) was charged to the residue. Triethyl orthoformate (50.7 kg, 342 mol, 1.1 equiv) was charged and the suspension was heated under reflux for 3 h. The reaction mixture was concentrated under vacuum, diluted with THF (175 L) and cooled to ~5 °C. Then triethylamine (34.3 kg, 339 mol, 1.0 equiv) was added dropwise to the above solution. A filtration was performed and the cake was washed with THF (25 L). The combined filtrates were concentrated to give crude product as a brown oil. The crude product was purified further by distillation (1 mmHg / 65–70 °C) to give 1-isopropyl-3-methyl-1H-1,2,4-triazole 7 (21.6 kg, 97.9 A% by GC) in 52% yield. 1H NMR (300 MHz, CDCl3) δ 7.97 (s, 1H), 4.47 (m, 1H), 2.41 (s, 3H), 1.53 (d, J = 6.0 Hz, 6H).

13

C NMR

(75.5 MHz, CDCl3) δ 160.1, 140.8, 51.7, 22.2, 22.4, 13.9.

Scale-up of Negishi cross-coupling reaction to bromobenzoxazepine core 1. To a 100-L reactor was charged under nitrogen, THF (36 L) and triazole 7 (3.0 kg, 24 mol, 1.43 equiv) and cooled to –25 °C. A solution of n-BuLi (1.6M in hexanes, 24 mol, 1.43 equiv) was slowly charged to the reaction mixture while maintaining the internal temperature between –20 °C to – 25 °C (2 h) and then maintained for 1 h. Zinc chloride (ZnCl2) (1.96 kg, 14.4 mol, 0.86 equiv) and THF (5.76 L) were charged to the reaction mixture while maintaining the internal temperature between –20 °C to –25 °C and then warmed to 20 °C and aged for 1 h. The reaction mixture was charged with iodoimidazole 3 (6.5 kg, 16.8 mol, 1.0 equiv) then evacuated under vacuum and purged with N2 (3 x) followed by addition of Pd(PPh3)4 (0.97 kg, 0.84 mol, 0.05 equiv). The reaction mixture was agitated for 0.5 h at ~20 °C then warmed to 65 °C and held overnight (total time ~12 h). Analysis by HPLC indicated the reaction was complete (5

Manufacture of the PI3K Î²-Sparing Inhibitor Taselisib. Part 1: Early

Recommend Documents