Synthesis of phosphine ligands

Abstract

A process of manufacturing a compound of Formula (I) includes: reacting an aryl bromide of Formula (III) with an aryl tert-butyl ether of Formula (IV) in the presence of an organolithium agent to provide a biaryllithium compound of Formula (II); and reacting the biaryllithium compound with chlorodicyclohexylphosphine, (I) (III) (IV) (II), wherein R1 is hydrogen or a C1-5 alkyl; R2 is isopropyl (iPr); R3 is hydrogen or a C1-5 alkoxy; and Cy is cyclohexyl.

Description

SYNTHESIS OF PHOSPHINE LIGANDSCROSS REFERENCE TO RELATED APPLICATIONThis application claims priority to U.S. Provisional Application Serial No. 63 / 623,514, filed on January 22, 2024, in the United States and Trademark Office, and all the benefits accruing therefrom under 35 U.S.C. § 119, the content of which is incorporated herein by reference in its entirety.TECHNICAL FIELD

[0001] The application generally relates to a process of producing phosphine ligands, and more specifically, to an efficient and cost effective process for the manufacture of phosphine ligands.BACKGROUND

[0002] Recently, phosphines such as 3-( / / 7-butoxy)-2',6'-diisopropyl-6-methoxy-[ l , l biphenyl]-2-yl)dicyclohexylphosphane (“GPhos”) were discovered as useful ligands that support palladium catalysts. For example, GPhos-supported palladium catalyst was found to be effective in promoting carbon-nitrogen cross-coupling reactions between a variety of amines and aryl halides, both under ambient conditions and at elevated temperatures. (J Am. Chem. Soc. 2020, 142, 35, 15027-15037)

[0003] The existing published route to GPhos, however, is lengthy, low yielding, and challenging to scale up. In some manufacturing processes that require the use of GPhos, the combined cost of the catalyst and the ligand may be a significant portion (e.g., 40%) of the cost of goods (“COG”). Therefore, there remains a need for a cost-effective process to manufacture phosphine ligands. It would be a further advantage if the ligands can be efficiently manufactured in large scales.SUMMARY

[0004] A novel process of manufacturing a compound of Formula (I) is disclosed:The process includes: reacting an aryl bromide of Formula (III)aryl tert- butyl ether of Formulathe presence of an organolithium agent to provide a biaryllithium compound of Formula (II)reacting the biaryllithium compound with chlorodicyclohexylphosphine, wherein Ri is hydrogen or a C1-5 alkyl; R2 is isopropyl (iPr); R3 is hydrogen or a C1-5 alkoxy; and Cy is cyclohexyl.

[0005] Also disclosed is a process of manufacturing a compound of Formula (1-1)wherein iPr is isopropyl, and Cy is cyclohexyl.The process includes:(a) reacting an aryl halide of Formula (VI- 1) with magnesium metal to generate a Grignard agent of Formula (V-l)(VI-1) (V-l) ;(b) reacting the Grignard agent with a peroxide being a tert-butyl ether of a peroxy acid to generate an aryl tert-butyl ether of Formula (IV-1)(IV-1) ;(c) reacting the aryl tert-butyl ether with an aryl bromide of Formula (III-l ) in the presence of an organolithium agent to generate a biaryllithium compound of Formula (II- 1)(d) reacting the biaryllithium compound with chlorodicyclohexylphosphine to manufacture the compound of Formula (1-1).BRIEF DESCRIPTION OF THE DRAWINGS

[0006] These and / or other aspects will become apparent and more readily appreciated from the following description of the embodiments, taken in conjunction with the accompanying drawings that should not be considered limiting in any way, in which:

[0007] FIG. 1 is a graph of temperature (°C) versus reaction time (minute, min) and compares the reaction temperature with the set temperature during a batch Grignard formation reaction;

[0008] FIG. 2 is a continuous stirred tank reactor (CSTR) setup for a continuous Grignard formation reaction;

[0009] FIG. 3 is a graph of temperature (°C) versus reaction time (min) and compares thereaction temperature with the set temperature for a continuous Grignard formation reaction;

[0010] FIG. 4 is a CSTR setup for continuous formation of an aryl / c / 7-butyl ether;

[0011] FIG. 5 is a graph of normalized peak area (percent, %) versus reaction time (second, s) and shows the ReactIR trends for a starting material (ArH) and lithiated species (ArLi and / or benzyne) during the lithiation of an aryl / crz-butyl ether;

[0012] FIG. 6 is a plug flow reactor (PFR) setup for continuous formation of a biaryl compound; and

[0013] FIG. 7 is a PFR setup for continuous formation of GPhos.DETAILED DESCRIPTION

[0014] The existing sequence for the synthesis of GPhos is shown in Scheme 1. (J Am. Chem. Soc. 2020, 142, 35, 15027-15037). This reaction sequence requires many steps that can be challenging to scale up in a batch.Scheme 1

[0015] The inventors hereof have discovered a new process that has substantial improvement over the published approach to make phosphine ligands. The new process has fewer steps, uses low cost commercially available building blocks, allows for simple work-up, and is readily scalable. In addition, the phosphine ligands can be continuously made in a timely manner. Thus, the new process can provide significant cost savings when performed on a large scale.

[0016] The new process can efficiently manufacture a compound of Formula (I):

[0017] In Formula (I) as well as in the formulas of the intermediates that are used to prepare the compound of Formula (I), Ri is hydrogen or a C1-5 alkyl such as isopropyl; R2 is isopropyl (iPr);R3 is hydrogen or a C1-5 alkoxy such as methoxy; and Cy is cyclohexyl. In an embodiment, Ri is hydrogen or isopropyl; and R3 is hydrogen or methoxy. In other examples, Ri is isopropyl andR3 is hydrogen; both Ri and R3 are hydrogen; Ri is isopropyl and R3 methoxy; or Ri is hydrogen and R3 is methoxy. In yet another example, Ri is hydrogen and R3 is methoxy, and the compound of Formula (I) is GPhos having Formula (1-1):

[0018] The process for manufacturing a compound of Formula (I) includes: providing a biaryllithium compound of Formula (II), and reacting the biaryllithium compound with chlorodi cyclohexylphosphine (wherein Ri, R2, and R3 are the same as the corresponding groups in Formula (I).

[0019] The reaction between the biaryllithium compound and chlorodicyclohexylphosphine (also referred to as “ligand forming reaction”) can be carried out at a temperature of -78 °C to 10 °C, for example between -20 °C and 10 °C, between -15 °C and 5 °C, or between -10 °C and 5°C.The reaction can be conducted in tetrahydrofuran (THF), toluene, cyclohexane or a combinationthereof as a solvent. Other solvents may also be suitable. The molar ratio between ClPCy2 and the biaryllithium compound may be 0.9: 1 to 1.5:1, or 1:1 to 1.5:1, or 1.2: 1 to 1.4:1. The reaction conditions for the ligand forming reaction are not limited thereto, and a person of ordinary skilled in the art would be able to modify these conditions depending on the scale of the reaction to achieve the desired results.

[0020] The ligand forming reaction can be carried out in a flow reactor to allow for a continuous production of the compound of Formula (I), with minimal reaction time, and in a large scale. In a continuous process, the biaryllithium compound and ClPCy2 may be passed through a ligand synthesis flow reactor at a temperature ranging from -78 °C to 10 °C, -20 °C to 10 °C, -15 °C to 5 °C, or -10 °C to 5°C to generate the compound of Formula (I) in the reactor. The flow rate may be adjusted appropriately to obtain the desired retention time. In an embodiment, the biaryllithium compound is fed to the ligand synthesis flow reactor as a solution of the biaryllithium compound in a solvent such as THF, for example in an amount of 10 percent by weight (weight%) to 30 weight% in THF. ClPCy2 can be fed to the ligand synthesis flow reactor as a solution of ClPCy2 in a solvent such as toluene, for example in an amount of 10 weight% to 30 weight% in toluene. Both the biaryllithium compound solution and the ClPCy2 solution can be pre-cooled before introduced into the flow reactor. A person of ordinary skill in the art would be able to modify these conditions depending on the scale of the reaction to achieve the desired results.

[0021] The biaryllithium compound used in the ligand forming reaction can be prepared by reacting an aryl bromide of Formula (III) with an aryl tert-butyl ether of Formula (IV) in the presence of an organolithium agent:(III) (IV) wherein Ri, R2, and R3 are the same as the corresponding groups in Formula (I). For convenience, the reaction is referred to as a biaryl forming reaction.

[0022] In an embodiment, the organolithium agent is sec-butyllithium. Surprisingly, the use of sec-butyllithium can allow for purer reaction product, minimal work-up, improved yield, or acombination thereof. The prepared biaryllithium compound can be used directly in the subsequent ligand forming reaction without purification.

[0023] The biaryl forming reaction can be carried out at a temperature of -78 °C to -60 °C, for example between -78 °C and -65 °C. The solvent used can include THF, toluene, cyclohexane, or a combination thereof. Other solvents may also be suitable. The organolithium agent and the aryl tert-butyl ether can have a molar ratio of 2: 1 to 3 : 1 , for example 2.1: 1 to 2.8: 1 , or 2.2: 1 to 2.6: 1. The aryl bromide and the aryl tert- butyl ether can have a molar ratio of 0.9: 1 to 1 : 5, for example 1 : 1 to 1.4, or 1 :2 to 1 :4. The reaction conditions for the biaryl forming reaction are not limited thereto, and a person of ordinary skilled in the art would be able to modify these conditions depending on the scale of the reaction to achieve the desired results.

[0024] The biaryl forming reaction can also be carried out in a flow reactor. In a continuous process, the aryl bromide, the aryl tert-butyl ether, and the organolithium agent are passed through a biaryl synthesis flow reactor at a temperature of -78 °C to -60 °C or -78 °C to -65 °C to form the biaryllithium compound.

[0025] In an embodiment, the aryl bromide is fed to the biaryl synthesis flow reactor as a solution of the aryl bromide in a solvent such as THF, for example in an amount of 10 weight% to 30 weight% in THF. The aryl tert-butyl ether can be fed to the biaryl synthesis flow reactor as a solution of the aryl tert-butyl ether in a solvent such as THF, for example in an amount of 10 weight% to 30 weight% in THF. The organolithium agent can be fed to the biaryl synthesis flow reactor as a solution of the organolithium agent (e.g., .sec-butyl lithium) in cyclohexane / toluene, for example at a concentration of 0.1 to 5 M. All of the aryl bromide solution, the aryl tert-butyl ether solution, and the organolithium agent solution can be pre-cooled before being introduced into the biaryl synthesis flow reactor. The flow rate may be adjusted appropriately to obtain the desired retention time.

[0026] In an embodiment, the aryl bromide is premixed with the aryl tert-butyl ether before contacting the organolithium agent in the flow reactor. For example, the aryl bromide and the aryl tert-butyl ether can pass through a mixer to form a mixture; and the mixture and the organolithium agent are passed through the biaryl synthesis flow reactor at a temperature of -78 °C to -60 °C to form the biaryllithium compound.

[0027] Advantageously, the output from the biaryl synthesis flow reactor, which include the biaryllithium compound, can be used as a feed stream for the ligand synthesis flow reactor. Inother words, the biaryl synthesis flow reactor can be coupled to the subsequent ligand synthesis flow reactor to generate a continuous process to the compound of Formula (I). Accordingly, the process can include passing the aryl bromide, the aryl tert-butyl ether, and the organolithium agent through a biaryl synthesis flow reactor at a temperature of -78 °C to -60 °C to generate the biaryllithium compound; and passing the biaryllithium compound and ClPCy2 through a ligand synthesis flow reactor at a temperature of -78 °C to 10 °C to manufacture the compound of Formula (I). When the biaryl forming reaction and the ligand forming reaction have different reaction temperatures, the temperature of the output from the biaryl synthesis flow reactor can be adjusted, for example, at a mixer, before it is introduced to the ligand synthesis flow reactor as a feed stream.

[0028] The aryl tert-butyl ether used in the biaryl forming reaction, in turn, can be prepared by reacting a Grignard agent of Formula (V) with a peroxide:wherein R3 is the same corresponding group in Formula (I). For convenience, the reaction is referred to as a tert-butyl ether installation reaction.

[0029] The peroxide is a tert-butyl ether of a peroxy acid. An example of the peroxide is tertbutyl peroxybenzoate.

[0030] The peroxide and the Grignard agent can have a molar ratio of 0.9: 1 to 2: 1, 1: 1 to 1.5, or 1.1: 1 to 1.4. The tert-butyl ether installation reaction can be conducted at a temperature of - 10 °C to 10 °C or -10 °C to 5 °C in a solvent such as THF. The reaction sequence allows for a more direct installation of tert-butyl ether as compared to the published route. In addition, the product can be purified by distillation instead of using tedious and costly silica gel chromatography purifications, which can further improve the efficiency of the new process disclosed herein. The reaction conditions for the tert-butyl ether installation reaction are not limited thereto, and a person of ordinary skilled in the art would be able to modify these conditions depending on the scale of the reaction to achieve the desired results.

[0031] The tert-butyl ether installation reaction can be carried out in a flow reactor. In a flow process, the Grignard agent of Formula (V) and the peroxide can be passed through a peroxide addition flow reactor at a temperature of -40 °C to 20 °C, -20 °C to 10 °C, or -10 °C to 5 °C toform the aryl tert-butyl ether. In an embodiment, Grignard agent of Formula (V) is fed to the peroxide addition flow reactor as a solution of the Grignard agent in a solvent such as THF, for example in an amount of 10 weight% to 20 weight% in THF. The peroxide can be fed to the peroxide addition flow reactor as a solution of the peroxide in a solvent such as THF or toluene, for example in an amount of 20 weight% to 30 weight% in THF or toluene. Other solvents may also be suitable. The flow rate may be adjusted appropriately to obtain the desired retention time.

[0032] The Grignard agent of Formula (V), in turn, can be prepared by reacting an aryl halide of Formula (VI) with magnesium metal:

[0033] Advantageously, the generated Grignard agent can be used directly in the tert-butyl ether installation reaction without purification. The Grignard forming reaction can be conducted in THF as a solvent at a temperature ranging from 20 °C to 65 °C, 25 °C to 65 °C, or 45 °C to 65 °C. The molar ratio of the aryl halide and the magnesium metal can be 1: 1 to 1: 1.5. The reaction conditions are not limited thereto, and a person of ordinary skilled in the art would be able to modify these conditions depending on the scale of the reaction to achieve the desired results.

[0034] The Grignard forming reaction can be carried out in a flow reactor as well. A continuous production of the Grignard agent as disclosed herein can improve the yield and facilitate the synthesis of the Grignard agent in a large scale with minimal temperature increase during the reaction. In a continuous process, the aryl halide can be passed through a Grignard flow reactor containing magnesium metal at a temperature of 45 °C to 65 °C to generate the Grignard agent.

[0035] Advantageously, the generated Grignard agent can be used directly in the sequent reaction with the peroxide without purification. In an embodiment, the Grignard flow reactor can be directly coupled to the subsequent peroxide addition flow reactor to generate a completely continuous process to the aryl tert-butyl ether.

[0036] As an example, a process of manufacturing a compound of Formula (1-1)wherein iPr is isopropyl, and Cy is cyclohexyl, includes:(a) reacting an aryl halide of Formula (VI- 1) with magnesium metal to generate a Grignard agent of Formula (V-l)(VI-1) (V-l) ;(b) reacting the Grignard agent with a peroxide being a tert-butyl ether of a peroxy acid to generate an aryl tert-butyl ether of Formula (IV-1)(IV-1);(c) reacting the aryl tert-butyl ether with an aryl bromide of Formula (III-l ) in the presence of an organolithium agent to generate a biaryllithium compound of Formula (II- 1)(d) reacting the biaryllithium compound with ClPCy2 to manufacture the compound of Formula (I-l).

[0037] In an embodiment, the Grignard agent from (a) is reacted with the peroxide without purification, the biaryllithium compound from (c) is reacted with ClPCy2 without purification, or a combination thereof. In various embodiments, at least one, at least two, at least three, or all of(a), (b), (c), or (d) is independently carried out in a flow reactor.

[0038] The new process allows for a more direct installation of / c / 7-butyl ether, and can convert the prepared aryl tert-butyl ether to the compound of Formula (I) without work-up or isolation of intermediates. Utilization of flow effectively manages highly exothermic and cryogenic reactions in large scales. The new process can result in significantly cost savings when performed on a large scale.

[0039] Another process to prepare the compound of Formula (I) is shown in Scheme 2.int-4Scheme 2

[0040] Compound 3 can be prepared from Compound 2 in a process as described herein in the context of prepping an aryl tert-butyl ether of Formula (IV) from an aryl halide of Formula (VI). Compound 3 can react with L in the presence of an organolithium agent such as / ?-butyllithium at a temperature of -78 °C to -60 °C in a solvent such as THF to generate Compound 4. A Grignard agent formed from l-bromo-2,6-diisopropylbenzene and magnesium metal can react with Compound 4 and L at 5 °C to 35 °C to generate Int-4. Int-4 can react with an organolithium agent (e.g., / ?-buty 1 lithium or .scc-butyl lithium) at a temperature of -78 °C to -60 °C in a solvent such as THF to generate a lithiated intermediate. The lithiated intermediate can then react with ClPCy2 at a temperature of -20 °C to 10 °C to generate GPhos.

[0041] The present invention is illustrated and further described in more detail with reference to the following non-limiting examples.EXAMPLESABBREVIATIONSMe MethylPh Phenyl w-BuLi N-butyllithium s-BuLi Sec-butyllithiumMeTHF 2-MethyltetrahydrofuranMTBE Methyl tert-butyl etherTMEDA TetramethylethylenediamineTEA TriethanolamineTHF TetrahydrofuranRxn ReactionPdt ProductTCU Temperature control unitRT Room temperatureTemp TemperatureAP Area percentLCAP Liquid Chromatography Area percentHPLC High Resolution Liquid ChromatographyNMR Nuclear Magnetic ResonanceGENERAL METHODS

[0042] All commercially available reagents and solvents were purchased and used without further purification.

[0043] Quantitative 'H NMR (qNMR) spectroscopy was performed referencing to Sigma Aldrich TraceCERT grade internal standards with 25 seconds relaxation delay.

[0044] Samples were analyzed for purity on a HPLC equipped with a Poroshell 120 EC-C18 (4.6 x 150 mm, 2.7 pm, PN 693975-902T) column with UV detection at X = 220 nm. The mobile phase consisted of water containing 0.025% trifluoroacetic acid as component A and acetonitrile containing 0.025% trifluoroacetic acid as component B. A gradient was run as follows: 0 min 60% A and 40% B, 8 min 100% B, 10.5 min 100% B, 10.51 min 60% A and 40% B, and 12 min 60% A and 40% B at a flow rate of 1.0 mL / min.Example 1. Synthesis of aryl tert-butyl ether via metalation and peroxide additionMetalating Agent Solvent, temp for metalationSolvent, temp for addition

[0045] Compound 2 is commercially available. Different metalating agents (Turbo Grignard, n- BuLi, and magnesium metal) were evaluated in the preparation of Compound 3.

[0046] General Procedure: A solution of 2 in THF was cooled to the temperature listed as the temp for metalation in Table 1. To this solution was added the metalating agent such that the temperature was well controlled. This combined solution was then adjusted to the temperature listed as the temp for addition, and tert-butyl peroxybenzoate was added such that the temperature was controlled. The resulting solution was analyzed by HPLC and NMR to identify major products and yields.

[0047] The reaction conditions and the results are summarized in Table 1.Table 1*inversed addition used, i.e. aryllithium added to the peroxide.

[0048] The results indicate that Turbo Grignard (iPrMgBr-LiCl) would require longer times / higher temperatures to metalate efficiently. The aryllithium generated from / ?-BuLi and Compound 2 seems to be too nucleophilic for a mono addition to be possible. Magnesium metal (Mg(0)) works best, which has the added benefit of being the cheapest metalating agent of those screened.Example 2. Synthesis of aryl tert-butyl ether in Batch i. Mg° (1.2 equiv), THF, 55 °C

[0049] The small scale reaction in Example 1 was scaled up using magnesium metal as the metalating agent. The scaleup proceeded similarly to the small scale reaction. The product was purified from the dehalogenated material using column chromatography. The results are shown in Table 2.Table 2Example 3. Grignard Formation in Batch

[0050] As described in Examples 1 and 2, an aryl tert-butyl ether (e.g., 3) can be prepared via Grignard formation and peroxide addition from an aryl bromide (e.g., 2).

[0051] In Example 3, Grignard formation was evaluated separately from the addition to tertbutyl peroxybenzoate (the peroxide).50 g scale2 Int-2

[0052] The Grignard formation reaction was carried out in a batch process according to the general procedure of Example 1 using magnesium metal as the metalating agent. The temperature of the TCU was set to be 25°C. The reaction temperature was monitored. As shown in FIG. 1 , which is a graph of the temperature versus reaction time, the reaction temperature varied from about 24.5 to about 33°C. In other words, the difference between the set temperature and the real reaction temperature was up to about 8°C.

[0053] The batch process results are summarized in Table 3. As shown in the table, the isolated yield of the Grignard agent (Int-2) is 75%, which suggests that the Grignard formation portion of the Grignard formation and peroxide addition sequence may be responsible for the -70% yield observed on the smaller scale batch process to prepare Compound 3.Table 3Example 4. Grignard Formation in Flow

[0054] Grignard agent Int-2 was formed in a continuous process. The CSTR setup for continuous Grignard formation is shown in FIG. 2. The angled dip tube can help to reduce the amount of Mg particles that are pulled into the collection vessel.

[0055] Prior to initial reaction startup, the magnesium turnings were conditioned with 3 mL of the previous lot of Grignard. Initiation was immediate upon addition of the aryl bromide (compound 2). As a general procedure, a suspension of magnesium metal in THF was activated by addition of Grignard solution prepared previously, typically 1-3 % of reactor volume. Thereactor was then warmed to 55 °C, and a solution of the bromide 2 was pumped into the reactor at a rate to fill the reactor in a specified residence time (20-60 minutes). Once the reactor was filled, a second pump started to pump out the Grignard at the same rate as the reactor was filled. This pump out was collected for the duration of the run. Both pumps were continued until the 2 solution, or the magnesium, was depleted. At that time, the residual contents of the reactor were pumped out, leaving any residual magnesium. The resulting solution was analyzed by NMR to determine yield and conversion. Reaction parameters are shown in Table 4 and Table 5.Table 4Table 5

[0056] The reaction temperature was monitored with a temperature probe, and compared with the jacket temperature. As shown in FIG. 3, aryl bromide 2 was processed at a temperature that is less than 2 °C higher than the jacket temperature (set temperature). The observed temperature difference (less than 2 °C) for the continuous process is significantly less than the temperature difference observed for a batch process (up to 8 °C). This minor temperature difference for the continuous process indicates that the reaction can be scaled up further if desired.

[0057] The results in Table 6 also show that compared to a batch process, a continuous Grignard formation can lead to a higher yield (95.8% versus 75%).Table 6Example 5. Peroxide Addition in Batch

[0058] The reaction of Grignard agent Int-2 with tert- butyl peroxybenzoate was scaled up in a batch process. The results are shown in Table 7.Table 7Example 6. Peroxide Addition in Flow1.3 equiv lnt-2

[0059] The reaction of Grignard agent lnt-2 with tert- butyl peroxybenzoate was carried out in a CSTR setup shown in FIG. 4 under conditions summarized in Tables 8 and 9. A peristaltic pump was selected for collection as this reaction does precipitate solids toward the end of the Grignard addition. As a general procedure, a reactor was charged with THF (20% of reactor volume) and cooled to 0 °C to -10 °C. Solutions of Grignard and / / 7-butyl peroxy benzoate were then pumped into the reactor at a rate to match the desired equivalent ratio. Additionally, the total rate was adjusted to maintain a residence time of 10-15 minutes. Once the reactor was full, another pump was started to remove the product 3 solution as it was generated. The reaction continued until one of the starting solutions was depleted. The reactor was then drained andcombined with the rest of the product solution. The resulting solution was analyzed by HPLC to determine yield and conversion. Initial use tests of the Grignard solution demonstrated that ~1.3 equivalent of Grignard solution can achieve the > 99% conversion of the peroxide.Table 8Table 9

[0060] At the end of the collection, the collected material was broken up into three portions and extracted with NH4CI: water: brine (2:2: 1) followed by 2N NaOH: waterbrine (1:2:2). The basic extracts were then reextracted with MTBE to recover residual product. These organic extracts were assayed directly, and the results are shown in Table 10.Table 10

[0061] Based on the final collection, a small amount of the double addition product is observed (2.4 LCAP, RT 5.04). Increasing the residence time may help to suppress this byproduct.

[0062] The example shows that the peroxide is able to be processed at a reasonable rate and under dose-controlled conditions, which indicates that the reaction can be readily scaled up further if desired.

[0063] It is contemplated that the Grignard CSTR can be directly coupled to the subsequent peroxide CSTR to generate a completely continuous process to intermediate 3.

[0064] In order to generate 3 in sufficient purity for the subsequent steps, the concentrated organic extracts were subjected to a fractional distillation. Fraction 1 was collected at 25 torr, the subsequent fractions were collected at 17 torr. The results are shown in Table 11.Distillation of the product provided the material in sufficient purity for further studies (>96% LCAP). The purification method can be more efficient than a tedious chromatography purification.Table 11Example 7. Lithiation of Arene3

[0065] The aryl tert-butyl ether prepared from Grignard formation and peroxide addition can be lithiated and then coupled to another aryl to form a biaryl.

[0066] The stability of the lithiated species including benzyne was evaluated by ReactIR. FIG. 5 is a graph of normalized peak area (%) of starting material / ?-BuLi and the lithiated species versus reaction time. Based on this data, the benzyne seemed to decompose at a temperature above -60 °C. Accordingly, the reaction to generate benzyne may be conducted at a temperature that does not exceed -60 °C.Example 8. Biaryl Formation Screening3

[0067] In order to identify conditions that would lead to fast lithiation and minimal dimerization, a brief solvent / additive screening was carried out using ReactIR to facilitate faster data processing. As a general procedure, a reactor equipped with ReactIR probe was added a solution of 3 and any additives listed in the specified solvent in Table 12. The reactor was cooled to the specified internal temperature, and the lithiating agent listed was added dropwise. The ReactIR profile was collected during the addition and for a period of time after the addition. The Grignard of diisopropyl bromobenzene was added, and the solution was warmed to 20 °C. ReactIR data was collected for the duration of warming to identify when benzyne formation occurred. After warming, the resulting mixture was analyzed by HPLC to determine the LCAP of any biaryl generated. The results are shown in Table 12.Table 12

[0068] Based on these results, TMEDA as an additive can be ruled out for further exploration. Whilte it provides much faster lithiation, the subsequent benzyne formation does not seem to occur. Additionally, there doesn’t appear to be enough of an advantage of MeTHF to justify switching the solvent for this system. Toluene as a solvent will likely not be viable as lithiation was not observed until ~0 °C at which point the dimerization was too fast to trap with the Grignard reagent. Unexpectedly, the s-BuLi experiment indicates that lithiation was rapid. Furthermore, the trapping went significantly better than with / ?-BuLi.Example 9. Biaryl Formation in Flow

[0069] Biaryl formation was carried out in a PFR setup shown in FIG. 6 under conditions summarized in Tables 13 and 14 using s-BuLi as the organolithium agent. As a general procedure, solutions of 3 and aryl bromide were flowed into a PFR reactor that was externally cooled to -78 °C. These streams were precombined using a mixer before a stream of s-BuLi was mixed with them in line using another static mixer. The equivalents and residence time were controlled by the relative and total flowrates. The outlet of the reactor was connected to an online analysis probe for HPLC analysis of the reaction stream.Table 13Stock Solution C flow rate (e / min

[0070] The results in Table 14 indicate that Compound 3 can react with 2,6-diisopropyl bromobenzene in the presence of s-BuLi to form biaryl 5 in a flow process with a reasonable yield.Table 14Example 10. Synthesis of 3-(tert-butoxy)-2',6'-diisopropyl-6-methoxy-[l,r-biphenyl]-2- yl)dicyclohexylphosphane (GPhos) in Batch

[0071] With the success of s-BuLi in the lithiation and capture sequence demonstrated, a one- step sequence to GPhos was evaluated. Previous experiments using / ?-BuLi suffered from butylcapture products associated with the butyl bromide byproduct. Switching to s-BuLi should suppress these to a degree.

[0072] A reactor was charged with a solution of 3 and the aryl bromide in THF. The reaction was cooled to -78 °C and s-BuLi was added drop wise while monitoring by ReactIR. The resulting solution was held for 15-30 minutes before ClPCy2 was added dropwise. The mixture was warmed to 10 °C before water was added to quench the reaction. The resulting crude organic phase was analyzed by HPLC and NMR to determine the conversion, purity, and assay yields, and the results are summarized in Table 15.Table 15

[0073] Based on these results in Table 15, the generation of GPhos directly in a one pot sequence from 3 is possible. The yield can be improved by optimizing the reaction conditions. This route is evaluated in flow.Example 11. Synthesis of 3-( erZ-butoxy)-2',6'-diisopropyl-6-methoxy-[l,r-biphenyl]-2- yl)dicyclohexylphosphane (GPhos) in Flow

[0074] The synthesis of GPhos from Compound 3 in a flow process was evaluated. The PFR setup is shown in FIG. 7. And PFR conditions and results are summarized in Tables 16 and 17. As a general procedure, solutions of 3 and aryl bromide were flowed into a PFR reactor that was externally cooled to Tl. These streams were precombined using a mixer before a stream of s- BuLi was mixed with them in line using another static mixer. The equivalents and residence time were controlled by the relative and total flowrates. The outlet of this first reactor was connected to a second reactor at the specified temperature T2. In this reactor, the solution of the phosphine was mixed in line with the reaction stream from the first reactor. The resulting reaction stream was collected and analyzed by HPLC.Table 16Table 17Example 12. Lithiation / iodination of arene i. nBuLi, THF, -78 °C, time ii. I2, THF, -78 °C

[0075] The lithiation time for the lithiation / iodination sequence in Scheme 2 was evaluated, and the results are shown in Table 18.Table 18

[0076] Based on these results, a lithiation time of ~1 h can provide close to full conversion.Alternatively, a higher temperature may be preferred. The reaction was scaled up with alithiation time of 1 hour and the results are shown in Table 19. The only identified impurity is the starting material.Table 19Example 13. Biaryl from Grignard agent and aryl iodide

[0077] The benzyne chemistry was evaluated where the 2,6 diisopropyl phenyl Grignard is generated first followed by addition of the aryl iodide. The results are shown in Table 20.Table 20

[0078] The bulky aryl Grignard is slow to form at the tested temperatures. Subsequent addition of the aryl iodide is substantially more exothermic. The reaction was continued until there was no iodide remaining as determined by HPLC. At this point, the reaction was cooled, and iodinewas added. The stepwise reaction is substantially cleaner than the previous reactions with the primary impurities being derived from the quenched starting materials / product. A very small (<1% relative peak size) amount of an isomer of the product was detected by GC / MS.Example 14. Phosphine Synthesis

[0079] The final step in the sequence shown in Scheme 2 was to establish that / ?-BuLi would be competent for the final lithium halogen exchange reaction without leading to undesired byproducts. The results are shown in Table 21. Based on these results, / ?-BuLi is a suitable replacement for Z-BuLi for the phosphine synthesis.Table 21

[0080] An alternative to discretely forming the iodide 4 in Scheme 2 would be to conduct both steps (3 -> 4 and 4 -> Int-4) in a single pot. This was evaluated with both w-BuLi, and magnesium as the metalating agent for the 2,6-diisopropyl bromobenzene, and the results are summarized in Table 22.Table 22

[0081] The reaction utilizing / ?-BuLi for the metalation of both substrates was exceptionally messy. Many of the products identified include the butyl fragment presumably from the alkylation of the lithiated intermediates by / ?-BuBr that is generated in situ.

[0082] Switching the metalating agent to magnesium cleaned up the GC / MS trace substantially. The exact conditions can be optimized using the auto optimization setup.Example 1650 g scale

[0083] Evaluation of the second Grignard formation was carried out, and the results are shown inTable 23.Table 23Example 17

[0084] The ReactIR data indicates that the Grignard reacted immediately with the lithiated arene. HPLC analysis however reveals no benzyne trapped product, which indicates that the signal loss is likely due to formation of a mixed metalate or dilution. Tracking by HPLC indicated that the benzyne started to form around 0 °C.Example 18

[0085] The formation of a biaryl compound was evaluated in a flow process, and the results are shown in Table 24.Table 24

[0086] Based on these results, it seems likely that either lithiation is incomplete at -78 °C, or that the residence time in the second stage is insufficient. This is supported by the strong negative trend in product formation with zone 2 temperature (T2). Higher bath temperatures for zone 1, where lithiation occurs, and / or longer residence times for zone 2, where Grignard agent is added, may improve the reaction yield.

[0087] All ranges disclosed herein are inclusive of the endpoints, and the endpoints are independently combinable with each other (e.g., ranges of “up to 25 weight%, or, for example, 5weight% to 20 weight%,” are inclusive of the endpoints and all intermediate values of the ranges of “5 weight% to 25 weight%,” etc.). “Combinations” is inclusive of blends, mixtures, alloys, reaction products, and the like. The terms “a” and “an” and “the” do not denote a limitation of quantity and are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. “Or” means “and / or” unless clearly stated otherwise. A “combination thereof’ is open and includes any combination comprising at least one of the listed components or properties optionally together with a like or equivalent component or property not listed. The terms added before the flow reactor, such as “peroxide addition,” “ligand synthesis,” “biaryl synthesis,” and the like, do not denote structural differences between the flow reactors, but rather are used to distinguish one flow reactor from another.

[0088] Unless defined otherwise, technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this application belongs. All cited patents, patent applications, and other references are incorporated herein by reference in their entirety. However, if a term in the present application contradicts or conflicts with a term in the incorporated reference, the term from the present application takes precedence over the conflicting term from the incorporated reference.

[0089] While particular embodiments have been described, alternatives, modifications, variations, improvements, and substantial equivalents that are or may be presently unforeseen may arise to applicants or others skilled in the art.

Claims

CLAIMSWhat is claimed is:

1. A process of manufacturing a compound of Formula (I), the process comprising:reacting an aryl bromide of Formula (III)aryl tert- butyl ether of Formula (the presence of an organolithium agent to provide a biaryllithium compound of Formula(II)reacting the biaryllithium compound with chlorodicyclohexylphosphine, wherein Ri is hydrogen or a C1-5 alkyl; R2 is isopropyl (iPr); R3 is hydrogen or a C1-5 alkoxy; and Cy is cyclohexyl.

2. The process of claim 1, wherein Ri is hydrogen or isopropyl; and R3 is hydrogen or methoxy.

3. The process of claim 1, wherein Ri is hydrogen; R3 is methoxy, the compound of Formula (I) is:the biaryllithium compound of Formula (II) is:

4. The process of any of claims 1 to 3, wherein the biaryllithium compound is reacted with chlorodi cyclohexylphosphine at a temperature of -78 °C to 10 °C.

5. The process of any of claims 1 to 3, wherein the biaryllithium compound is reacted with chlorodicyclohexylphosphine in a ligand synthesis flow reactor, and the process comprises passing the biaryllithium compound and chlorodicyclohexylphosphine through the ligand synthesis flow reactor to generate the compound of Formula (I).

6. The process of any of claims 1 to 3, wherein the organolithium agent is sec- butyllithium.

7. The process of any of claims 1 to 3, wherein the organolithium agent and the aryl tert-butyl ether have a molar ratio of 2: 1 to 3: 1.

8. The process of any of claims 1 to 3, wherein the aryl bromide is reacted with the aryl tert-butyl ether in a biaryl synthesis flow reactor, and the process comprises passing the aryl bromide, the aryl tert-butyl ether, and the organolithium agent through the biaryl synthesis flow reactor at a temperature of -78 °C to -60 °C to generate the biaryllithium compound.

9. The process of any of claims 1 to 3, wherein the aryl bromide is reacted with the aryl tert-butyl ether in a biaryl synthesis flow reactor, and the process comprises passing the arylbromide and the aryl tert-butyl ether through a mixer to form a mixture; and passing the mixture and the organolithium agent through the biaryl synthesis flow reactor at a temperature of -78 °C to -60 °C to generate the biaryllithium compound.

10. The process of any of claims 1 to 3, wherein the aryl bromide is reacted with the aryl tert-butyl ether in the presence of the organolithium agent in a biaryl synthesis flow reactor; the biaryllithium compound is reacted with chlorodicyclohexylphosphine in a ligand synthesis flow reactor; and the process comprises: passing the aryl bromide, the aryl tert-butyl ether, and the organolithium agent through the biaryl synthesis flow reactor at a temperature of -78 °C to -60 °C to generate the biaryllithium compound; and passing the biaryllithium compound and chlorodicyclohexylphosphine through the ligand synthesis flow reactor at a temperature of -20 °C to 10 °C to generate the compound of Formula (I).

11. The process of claim 10, wherein the biaryllithium compound generated from the biaryl synthesis flow reactor is reacted with the chlorodicyclohexylphosphine without purification.

12. The process of any of claims 1 to 3, further comprising: reacting a Grignard agent of Formula (V) with a peroxide to provide the aryl tert-butyl ether:wherein the peroxide is a tert-butyl ether of a peroxy acid.

13. The process of claim 12, wherein the peroxide is tert-butyl peroxybenzoate.

14. The process of claim 12, wherein the Grignard agent is reacted with the peroxide in a peroxide addition flow reactor, and the process comprises: passing the Grignard agent and the peroxide through the peroxide addition flow reactor at a temperature of -40 to 20 °C to generate the aryl tert-butyl ether.

15. The process of claim 12, further comprising: reacting an aryl halide of Formula (VI) with magnesium metal to provide the Grignard agent: nufacturing a compound of Formula (1-1)wherein iPr is isopropyl, and Cy is cyclohexyl, the process comprising:(a) reacting an aryl halide of Formula (VI- 1) with magnesium metal to generate a Grignard agent of Formula (V-l)(VI-1) (V-l)(b) reacting the Grignard agent with a peroxide being a tert-butyl ether of a peroxy acid to generate an aryl tert-butyl ether of Formula (IV- 1)(IV-1) ;(c) reacting the aryl tert-butyl ether with an aryl bromide of Formula (III-l ) in the presence of an organolithium agent to generate a biaryllithium compound of Formula (II- 1)(d) reacting the biaryllithium compound with chlorodicyclohexylphosphine to manufacture the compound of Formula (1-1).

17. The process of claim 16, wherein the organolithium compound is sec- butyllithium.

18. The process of claim 16 or claim 17, wherein the Grignard agent from (a) is reacted with the peroxide without purification.

19. The process of claim 16 or claim 17, wherein the biaryllithium compound from (c) is reacted with chlorodicyclohexylphosphine without purification.

20. The process of claim 16 or claim 17, wherein at least one of (a), (b), (c), or (d) is independently carried out in a flow reactor.

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