Process for preparing hydroxylated cyclopentylpyrimidine compounds

Abstract

Provided herein are methods for synthesizing intermediates of ipatasertib that are relevant to the large-scale production of (R)-5-methyl-4-(piperazin-1-yl)-5,6-dihydro-7H-cyclopenta[d]pyrimidin-7-one.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of, and priority to, European Patent Application No. 20180148.7, filed June 16, 2020, the entire contents of which are incorporated herein by reference.

[0002] Technical Field Provided herein are methods for the synthesis of intermediates of ipatasertib relevant to the large-scale production of (R)-5-methyl-4-(piperazin-1-yl)-5,6-dihydro-7H-cyclopenta[d]pyrimidin-7-one and its N-protected derivatives. [Background technology]

[0003] AKT (also known as protein kinase B) is a serine / threonine protein kinase that is overexpressed in certain human tumors. Ipatasertib is an AKT inhibitor that is currently being evaluated in clinical trials for the treatment of solid tumors, gastric cancer, and prostate cancer. Ipatasertib is disclosed, for example, in U.S. Patent No. 8,063,050 (see, for example, Example 14) and WO 2008 / 006040.

[0004] (R)-5-Methyl-4-(piperazin-1-yl)-5,6-dihydro-7H-cyclopenta[d]pyrimidin-7-one, or its N-protected derivative, is used as an intermediate in the synthesis of ipatasertib. A variety of different processes for the preparation of this intermediate have been reported, for example, in WO 2013 / 173736, WO 2013 / 173768, and WO 2016 / 049414. TIFF0007607057000001.tif47170

[0005] (R)-5-Methyl-4-(piperazin-1-yl)-5,6-dihydro-7H-cyclopenta[d]pyrimidin-7-one, or its N-protected derivative (R 1is hydrogen or an amino protecting group.

[0006] However, it is known that scale-up of chemical processes can lead to unexpected conditions, such as increased impurities or decreased yields, etc. Thus, there is a need for improved methods for the synthesis of ipatasertib that increase the yield and / or reduce the impurities. Summary of the Invention

[0007] Solutions to the above problems, as well as other problems in the art, are provided herein.

[0008] (R)-5-methyl-4-(piperazin-1-yl)-5,6-dihydro-7H-cyclopenta[d]pyrimidin-7-one (a compound of formula (1), where R 1 Provided herein is a method for preparing an N-protected derivative thereof (a compound of formula (1), where R is hydrogen), which comprises a continuous flow reaction. 1 is an amino protecting group.

[0009] In one embodiment, the continuous flow reaction described above comprises cyclizing a compound of formula (II) or a pharma- ceutically acceptable salt thereof to produce a compound of formula (I): TIFF0007607057000002.tif54170[In the formula, R 1 is hydrogen or an amino protecting group; and M is Li or MgX, where X is Br or I. or a pharma- ceutically acceptable salt thereof.

[0010] In certain embodiments, R 1 is an amino protecting group.

[0011] In one embodiment, the continuous flow reaction described above comprises reacting a compound of formula (II) TIFF0007607057000003.tif45170[In the formula, R1 is hydrogen or an amino protecting group; and M is Li or MgX, where X is Br or I. or a pharma- ceutically acceptable salt thereof.

[0012] In certain embodiments, R 1 is an amino protecting group.

[0013] In one embodiment, the continuous flow reaction described above comprises reacting a compound of formula (II) TIFF0007607057000004.tif44170[In the formula, R 1 is hydrogen or an amino protecting group; and M is MgX, where X is Br or I. or a pharma- ceutically acceptable salt thereof.

[0014] In certain embodiments, R 1 is an amino protecting group.

[0015] In certain embodiments, M is MgBr. In certain embodiments, R 1 is an amino protecting group and M is MgBr.

[0016] For example, in certain embodiments, the continuous flow reaction described above comprises the step of producing a compound of formula (II): TIFF0007607057000005.tif44170[In the formula, R 1 is an amino protecting group; and M is MgBr or a pharma- ceutically acceptable salt thereof. In one embodiment, the continuous flow reaction comprises iPrMgBr as the metallation reagent.

[0017] iPrMgBr allows for continuous mode processing, with a very fast reaction, reduced levels of (among other things) dimerization by-products, and an easily isolated end product.

[0018] In one aspect, provided herein is a process illustrated by FIG.

[0019] In another aspect, provided herein is a process illustrated by FIG.

[0020] In a third aspect, there is provided herein a process for the preparation of a compound of formula (I) or a pharma- ceutically acceptable salt thereof as described herein, the process comprising a continuous flow reaction, wherein in step (a), a compound of formula (III), or a pharma- ceutically acceptable salt thereof (wherein R 1 is defined above, and R 3 is iodo or bromo) reacts with iPrMgBr in MeTHF to form a solid Mg-imine complex, and in step (b), an aqueous acidic salt solution is added to the mixture resulting from step (a), thereby forming a compound of formula (I) or a pharma- ceutically acceptable salt thereof. TIFF0007607057000006.tif45170

[0021] The processes described herein have one or more of the following advantages: (i) Yield is improved by 10-20%; (ii) precipitation of a transient reaction intermediate protects it from further decomposition; (iii) improved process robustness and greater controllability; (iv) improved purity; (v) does not require additional recrystallization to meet specifications; (vi) minimal scale-up factors and short production hold times; and (vii) significant cost reduction in the scale-up process per tonne of ipatasertib;

[0022] The present embodiments can be more fully understood by reference to the detailed description and examples that are intended to illustrate non-limiting embodiments. [Brief description of the drawings]

[0023] [Figure 1] 1 is a diagram of one of the processes described herein showing the continuous flow reaction of compound 4 to compound 1 (or a pharma- ceutically acceptable salt thereof). The arrows indicate the flow between continuous stirred tank reactors (CSTRs). Flow rates are determined as described herein. [Diagram 2] 1 is a diagram of one of the processes described herein showing the continuous flow reaction of compound 4 to compound 1 (or a pharma- ceutically acceptable salt thereof). The arrows indicate the flow between continuous stirred tank reactors (CSTRs). Flow rates are determined as described herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.See, for example, Singleton et al., DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY 2nd ed., J. Wiley & Sons (New York, NY 1994); Sambrook et al., MOLECULAR CLONING, A LABORATORY MANUAL, Cold Springs Harbor Press (Cold Springs Harbor, NY 1989).In carrying out the present disclosure, any method, device, and material similar or equivalent to those described herein can be used.

[0025] Provided herein is a process for synthesizing a compound of formula (I) or a pharma- ceutically acceptable salt thereof described herein using a Li or Mg metallizing agent, such as iPrMgBr. The method described herein has advantages over previously described methods in that it allows for continuous mode operation and avoids the need for additional purification steps, including recrystallization. The reaction with iPrMgBr in MeTHF described herein results in a solid Mg-imine complex in suspension during the initial process steps. Compared to other processes, this surprising result contributes to increased yields and improved purity profiles by mitigating continuous over-reactions that form undesirable impurities. In some instances, scale-up reactions using the processes described herein increase the yield of a compound of formula (I) or a pharma- ceutically acceptable salt thereof by about 10-20% compared to other processes described herein.

[0026] Reference will now be made in detail to certain embodiments, examples of which are illustrated in the accompanying structures and formulas. It will be understood that these embodiments are not intended to limit the disclosure to these embodiments. On the contrary, the disclosure is intended to cover all alternatives, modifications, and equivalents which may be included within the scope of the present disclosure.

[0027] Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein that can be used to practice the present disclosure. The present disclosure is in no way limited to the methods and materials described. In the event that one or more of the incorporated literature and similar materials differs or contradicts with the present application, including but not limited to defined terms, term usage, described techniques, etc., the present application shall control.

[0028] The term "pharmaceutically acceptable salts" refers to salts that are not biologically or otherwise undesirable. Pharmaceutically acceptable salts include both acid and base addition salts. The phrase "pharmaceutically acceptable" indicates that a substance or composition must be chemically and / or toxicologically compatible with the other ingredients that make up the formulation and / or with the mammal being treated therewith.

[0029] The term "pharmaceutically acceptable acid addition salts" refers to pharmaceutically acceptable salts such as those formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and the like, and organic acids selected from the aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic acids of organic acids, such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid "mesylate", ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid.

[0030] The term "pharmaceutically acceptable base addition salt" refers to a pharmaceutically acceptable salt formed with an organic or inorganic base. Examples of acceptable inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines, including natural substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, and polyamine resins.

[0031] The term "about" is used herein to mean approximately, in the range of, roughly, or around. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the upper and lower limits of the numerical values ​​set forth. In general, the term "about" is used herein to modify numerical values ​​above and below the set forth value by a variance of 20%. "Amino protecting groups" are groups described in detail in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd edition, John Wiley & Sons, 1999, that protect an amino function in a given chemical reaction. Exemplary amino protecting groups include, but are not limited to, (i) amide R(C=O)- groups, such as formyl, acetyl, chloroacetyl, trichloroacetyl, trifluoroacetyl, and phenylacetyl; (ii) carbamate RO(C=O)- groups, where R is methyl, ethyl, 9-fluorenylmethyl (Fmoc), 2,2,2-trichloroethyl (Troc), 2-trimethylsilylethyl (Teoc), tert-butyl (Boc), and benzyl (Cbz); (iii) sulfonamide R-(SO2)- groups, where R is toluene, benzene, methyl, trifluoromethyl, and 2-nitrobenene; (iv) R-CH2- groups, where R is a benzene radical, a toluene radical, a paramethoxybenzene radical (PMB), or 2-(trimethylsilyl)ethoxy (SEM), and (v) (R)3C- groups, where R is a benzene radical (trityl). In one embodiment, the amino protecting group is acetyl (CHC=O)-, Ac), trifluoroacetyl (CFC=O)-), benzyl (PhCH-, Bn), triphenylmethyl ((Ph)C-, trityl), p-toluenesulfonyl (pCH-Ph-SO-), p-methoxybenzyl (pCHO-Ph-CH-, PMB), tert-butyloxycarbonyl (tBuOC(=O)-, Boc), 9-fluorenylmethyloxycarbonyl (9-fluorenylmethyl-C(=O), and carbobenzyloxy (PhCHOC(=O)-), some of which are believed to be labile under acidic conditions.In one embodiment, the amino protecting group is acetyl (CHC=O)-, Ac), trifluoroacetyl (CFC=O)-, triphenylmethyl ((Ph)C-, trityl), p-toluenesulfonyl (pCH-Ph-SO-), p-methoxybenzyl (pCHO-Ph-CH-, PMB), tert-butyloxycarbonyl (tBuOC(=O)-, Boc), 9-fluorenylmethyloxycarbonyl (9-fluorenylmethyl-C(=O), and carbobenzyloxy (PhCHOC(=O)-), each of which is believed to be labile under acidic conditions. In a preferred embodiment, the amino protecting group is tert-butyloxycarbonyl (Boc).

[0032] "Continuous flow reaction" is used herein to mean a chemical reaction that is carried out in a continuously flowing stream, rather than in a batch production. In other words, a pump moves fluids through a flow system where the fluids contact each other. If the fluids are reactive, a reaction occurs. In some embodiments, a microreactor is used. In some embodiments, a tubular reactor or a plug flow reactor is used. In some other embodiments, a continuous stirred tank reactor (CSTR) is used.

[0033] In one embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof, wherein the process comprises a continuous flow reaction, 1 is hydrogen or an amino protecting group.

[0034] In one embodiment herein, the continuous flow reaction comprises reacting a compound of formula (II) TIFF0007607057000008.tif44170[In the formula, R 1 is hydrogen or an amino protecting group; and M is Li or Mg. or a cyclization of a pharma- ceutically acceptable salt thereof.

[0035] In certain embodiments, R 1 is an amino protecting group.

[0036] In one embodiment, the continuous flow reaction described above comprises reacting a compound of formula (II) TIFF0007607057000009.tif45170[In the formula, R 1 is hydrogen or an amino protecting group; and M is Li or MgX, where X is Br or I. or a pharma- ceutically acceptable salt thereof.

[0037] In one embodiment, M is Mg in the form of MgX.

[0038] In certain embodiments, R 1 is an amino protecting group.

[0039] In one embodiment, the continuous flow reaction described above comprises reacting a compound of formula (II) TIFF0007607057000010.tif45170[In the formula, R 1 is hydrogen or an amino protecting group; and M is MgX, where X is Br or I. or a pharma- ceutically acceptable salt thereof.

[0040] In certain embodiments, R 1 is an amino protecting group.

[0041] In one particular embodiment, X is Br.

[0042] For example, in a preferred embodiment, the continuous flow reaction described above comprises reacting a compound of formula (II) TIFF0007607057000011.tif45170[In the formula, R 1 is an amino protecting group; and M is MgBr or a pharma- ceutically acceptable salt thereof.

[0043] In one embodiment, the continuous flow reaction comprises: (a) A compound of formula (III) TIFF0007607057000012.tif44170[In the formula, R 1 is hydrogen or an amino protecting group, R 3 is iodo or bromo] or a pharma- ceutically acceptable salt thereof with a Li or Mg metallizing agent to form a compound of formula (I). Includes.

[0044] In certain embodiments, R 1 is an amino protecting group.

[0045] In one embodiment, the compound of formula (III), 3 is bromo) to prepare a compound of formula (IV): TIFF0007607057000013.tif44170 or a pharma- ceutically acceptable salt thereof, wherein R 1 is hydrogen or an amino protecting group.

[0046] In one preferred embodiment, the compound of formula (III) is a compound of formula (IV) TIFF0007607057000014.tif44170 or a pharma- ceutically acceptable salt thereof, wherein R 1 is an amino protecting group.

[0047] In one embodiment, the metallation agent is iPrMgBr.

[0048] In one embodiment, the amino protecting group is acetyl, trifluoroacetyl, phthalimidyl, benzyl, triphenylmethyl, benzylidenyl, p-toluenesulfonyl, p-methoxybenzyl, tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, or carbobenzyloxy. In one embodiment, the amino protecting group is acetyl, trifluoroacetyl, benzyl, triphenylmethyl, p-toluenesulfonyl, p-methoxybenzyl, tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, or carbobenzyloxy. In a preferred embodiment, the amino protecting group is tert-butyloxycarbonyl.

[0049] In another embodiment, R 1 is hydrogen.

[0050] In one embodiment, the non-coordinating apolar solvent is hexane, heptane, toluene, xylene, or mixtures thereof. In one embodiment, the non-coordinating apolar solvent is toluene.

[0051] In one embodiment, the coordinating ether solvent is diethyl ether (EtOEt), tert-butyl methyl ether (MeOtBu), diisopropyl ether (iPrOiPr), dioxane, c-pentylOMe, tetrahydrofuran (THF), or methyltetrahydrofuran (MeTHF), or a mixture thereof. In one embodiment, the coordinating ether solvent is diethyl ether. In another embodiment, the coordinating ether solvent is MeTHF.

[0052] In one embodiment, the Li and Mg metallization agents are selected from the group consisting of iPrMgCl, iPrMgCl*LiCl, iPrMgBr, iPrMgI, tBuMgCl, sBuMgCl, sBuMgCl*LiCl, nBuLi, sBuLi, nHexLi.

[0053] In one preferred embodiment, the Li and Mg metallizing agent is iPrMgBr. In a further embodiment, iPrMgBr is in MeTHF.

[0054] In one embodiment, the compound of formula (III) is in EtOEt, MeOtBu, iPrOiPr, dioxane, cPentylOMe, THF, MeTHF, hexane, heptane, toluene, or xylene, or a mixture thereof. In a preferred embodiment, the compound of formula (III) is in a mixture comprising MeTHF and toluene.

[0055] In one embodiment of the process described herein, iPrMgBr is added to the compound of formula (III) by multiple dosing in one or more portions using a continuous stirred tank reactor (CSTR). When iPrMgBr is added to the compound of formula (III), the addition can be carried out over one or more steps (e.g., a first reaction step of the compound of formula (III) with iPrMgBr and a second reaction step of the compound of formula (III) with an additional amount of iPrMgBr). The heat generated during the Grignard reaction can be high, and separate or sequential addition of iPrMgBr can reduce the undesirable effects of excess heat. Furthermore, in the case of sequential addition, two or more additions of iPrMgBr can reduce the effective local concentration of iPrMgBr, promoting reaction efficiency and reducing the formation of undesirable by-products, including but not limited to dimerization of the compound of formula (III) with the compound of formula (I).

[0056] In one preferred embodiment, the compound of formula (IV) is in a mixture comprising MeTHF and toluene.

[0057] In one embodiment of the process described herein, iPrMgBr is added to the compound of formula (IV) in one or more steps. When iPrMgBr is added to the compound of formula (IV), the addition can be carried out over one or more steps (e.g., a first reaction step of the compound of formula (IV) with iPrMgBr and a second reaction step of the compound of formula (IV) with an additional amount of iPrMgBr). The heat generated during the Grignard reaction can be high, and separate or sequential addition of iPrMgBr can reduce the undesirable effects of excess heat. Furthermore, in the case of sequential addition, two or more additions of iPrMgBr can reduce the effective local concentration of iPrMgBr, promoting reaction efficiency and reducing the formation of undesirable by-products, including but not limited to dimerization of the compound of formula (IV) with the compound of formula (I).

[0058] In one embodiment, in step (a), a compound of formula (III) is transferred to a compound of formula (II), which is transferred to a Mg-imine complex, R 1 is hydrogen or an amino protecting group, and wherein in step (b), an aqueous acid salt solution is added to the mixture resulting from step (a), thereby forming a compound of formula (I).

[0059] In one embodiment, the Mg-imine complex is formed as a solid in suspension and R 1 is hydrogen or an amino protecting group. 1 is an amino protecting group. In one embodiment, R 1 is tert-butyloxycarbonyl.

[0060] In one embodiment, the Mg-imine complex is a solid in suspension until it is reacted with the acid salt. The solid is transported as a suspension with the overall continuous process flow. The solid is transported as a suspension between CSTRs with the overall process flow.

[0061] In one embodiment, the Mg-imine complex is selected from the group consisting of: [ka] where n is from 1 to infinity. In another embodiment, n is in a range to form a monomer, dimer, trimer, oligomer, or polymer complex.

[0062] In one preferred embodiment, the Mg-imine complex is selected from the group consisting of: [ka] where m goes from 0 to infinity.

[0063] In one embodiment, m ranges from 0 to 100, 0 to 200, 0 to 300, 0 to 400, 0 to 500, 0 to 1000, 0 to 5000, or 0 to 10000. In certain embodiments, the complex is a monomer (wherein m is 0). In certain embodiments, the complex is a dimer (wherein m is 1). In certain embodiments, the complex is a tetramer (wherein m is 3). In certain embodiments, the complex is a polymer, e.g., m>1 to infinity, e.g., m ranges from 2 to 100, 2 to 200, 2 to 300, 2 to 400, 2 to 500, 2 to 1000, 2 to 5000, or 2 to 10000. In certain embodiments, the solids in the suspension comprise a mixture of Mg-imine complexes.

[0064] The ligand L is selected from the group consisting of Br, any solvent used in the reaction (e.g., a coordinating ether solvent), the N-N-ligands shown above, and any combination thereof. In another embodiment, the Mg-imine complex comprises a mixture of different Mg-imine complexes.

[0065] Due to the ionic nature of the Mg-imine complex, it forms a solid in suspension (in the non-polar solvent mixture MeTHF and toluene) in the continuous flow reaction. Under the conditions of the present invention, the Mg-imine complex precipitates and is transported as a solid with the continuous flow.

[0066] In one embodiment, the molar ratio of iPrMgBr to the compound of formula (III) is from about 1:1 to about 1.5:1. In another embodiment, the molar ratio of iPrMgBr to the compound of formula (III) is about 1.3:1. In yet another embodiment, the molar ratio of iPrMgBr to the compound of formula (III) is about 1:1.

[0067] In one embodiment, the molar ratio of iPrMgBr to the compound of formula (IV) is from about 1:1 to about 1.5:1. In another embodiment, the molar ratio of iPrMgBr to the compound of formula (IV) is about 1.3:1. In yet another embodiment, the molar ratio of iPrMgBr to the compound of formula (IV) is about 1:1.

[0068] Without being bound by any particular theory, the solid Mg-imine complex in suspension reacts slower than in solution, thereby reducing the formation of undesired continuous by-products and the loss of yield. Thus, the process described herein increases the purity of the compound of formula (I) and increases the overall yield compared to other processes. Moreover, in certain embodiments described herein, the method does not require a recrystallization step to obtain the compound of formula (I) due to a more selective and cleaner reaction.

[0069] In one embodiment, the aqueous acid salt solution is HCl, H2SO4, NaHSO4, H3PO4, NaH2PO4, Na2HPO4, Na2HPO4, NaH2 citrate, NH4Cl, or oxalic acid, or a mixture thereof.

[0070] By aqueous / aqueous solution is meant water or other solvent that contains water.

[0071] In one embodiment, the acid salt is an aqueous solution of HCl, H2SO4, NaHSO4, H3PO4, NaH2PO4, Na2HPO4, Na2HPO4, NaH2 citrate, NH4Cl, or oxalic acid, or a mixture thereof.

[0072] In one embodiment, the aqueous acid salt solution is aqueous H2SO4 or NaHSO4. In another embodiment, the acid salt is aqueous NaH2PO4, Na2HPO4, or Na2HPO4.

[0073] In one embodiment, the acid salt is an aqueous solution of NaHSO4.

[0074] The processes described herein can be carried out in one or more continuous stirred tank reactors (CSTRs). In such embodiments, the processes are carried out in 1, 2, 3, 4, 5, 6, or 7 CSTRs. In one embodiment, the processes are carried out in at least 5 CSTRs. In another embodiment, the processes are carried out in 5 CSTRs.

[0075] When the process is carried out using a CSTR, in one embodiment, the first CSTR comprises a solution of the compound of formula (III) in an organic solvent, the organic solvent comprising one or more of EtOEt, MeOtBu, iPrOiPr, dioxane, cPentylOMe, THF, MeTHF, hexane, heptane, toluene, or xylene, or mixtures thereof. In one embodiment, the mixture comprises MeTHF. In another embodiment, the mixture comprises toluene. In another embodiment, the compound of formula (III) is in a mixture of MeTHF and toluene.

[0076] In one such embodiment, the process comprises adding iPrMgBr in MeTHF to a solution of a compound of formula (III). The molar ratio of iPrMgBr to the compound of formula (III) in the first CSTR is as described herein. In one embodiment, the molar ratio of iPrMgBr to the compound of formula (III) in the first CSTR is about 1:1. In one embodiment, the residence time of the first CSTR is from about 5 minutes to about 30 minutes. In one embodiment, the residence time of the first CSTR is about 15 minutes. In one embodiment, the compound of formula (III) is a compound of formula (IV).

[0077] The term "residence time" refers to the residence time distribution (RTD) of a continuous flow system, which is a probability distribution function that represents the amount of time a molecule or compound can spend within a reactor setup.

[0078] When the reaction of the compound of formula (III) with iPrMgBr is carried out in a first CSTR, the process may further comprise a second CSTR. In one embodiment, 1.3 equivalents of iPrMgBr in MeTHF is added in one or two steps. In one embodiment, in the first addition, r1.0 equivalents of iPrMgB in MeTHF is added to the reaction mixture in the first CSTR and allowed to react, followed by a second addition of 0.3 equivalents of iPrMgBr in MeTHF. In one embodiment, the reaction comprises a second CSTR comprising a mixture of compounds of formula (IV) and Mg-imine complex in suspension in MeTHF and toluene, where about 0.3 equivalents of iPrMgBr in MeTHF is added to the mixture.

[0079] In one embodiment, the contents of a first CSTR are transferred to a second CSTR and reacted.

[0080] In one embodiment, the residence time of the second CSTR is from about 5 minutes to about 30 minutes. In one embodiment, the residence time of the second CSTR is about 15 minutes.

[0081] In one embodiment, the residence time of the second CSTR is sufficient to form the Mg-imine complex (e.g., the reaction is complete) in a suspension of MeTHF and toluene without leaving behind the compound of formula (III). In such an embodiment, if the residence time of the second CSTR is sufficient as described herein, the contents of the second CSTR can be transferred to a fourth CSTR provided herein (i.e., skipping the third CSTR described herein). If the third CSTR is skipped, the numbering of the CSTRs remains unchanged. In one embodiment, the compound of formula (III) is a compound of formula (IV).

[0082] In one embodiment, if the residence time of the second CSTR is insufficient to form the Mg-imine complex without leaving the compound of formula (III) (e.g., the reaction is not completed), the process includes a third CSTR, and the contents of the second CSTR are transferred to the third CSTR and stirred in the third CSTR. In one embodiment, the residence time of the third CSTR is about 5 minutes to about 30 minutes. In one embodiment, the residence time of the third CSTR is about 15 minutes. In one embodiment, the reaction with 1.3 equivalents of iPrMgBr in the third CSTR is carried out to completion (e.g., no starting material compound of formula (III) is present). In one embodiment, the compound of formula (III) is a compound of formula (IV).

[0083] In one embodiment, the Mg-imine complex is formed as a solid in suspension by reacting a compound of formula (III) with iPrMgBr and is transferred between the CSTRs as a suspension or slurry, hi another embodiment, the solid Mg-imine complex is in suspension.

[0084] In one embodiment, the Mg-imine complex is formed as a solid in suspension by reacting a compound of formula (IV) with iPrMgBr and transferred as a suspension between the CSTRs, hi another embodiment, the Mg-imine complex is in suspension in MeTHF and toluene.

[0085] In one embodiment, the contents of the second or third CSTR are transferred to a fourth CSTR, thereby forming a biphasic mixture (emulsion). The fourth CSTR comprises an aqueous acid salt solution as described herein. In one embodiment, the acid salt is an aqueous NaHSO4 solution. The pH of the biphasic mixture in the fourth CSTR can be adjusted and maintained at a pH of about 1 to about 3. In one embodiment, the pH of the biphasic mixture after addition of the aqueous NaHSO4 solution is about 2. In one embodiment, the residence time of the fourth CSTR is about 2 minutes to about 10 minutes. In another embodiment, the residence time of the fourth CSTR is about 3 minutes to about 8 minutes. In another embodiment, the residence time of the fourth CSTR is about 4 minutes to about 6 minutes. In another embodiment, the residence time of the fourth CSTR is about 4 minutes. In another embodiment, the residence time of the fourth CSTR is about 5 minutes. In another embodiment, the residence time of the fourth CSTR is about 4.45 minutes.

[0086] The formulation of the compound of formula (I) described above allows the compound of formula (I) to partition into the aqueous phase of the mixture in the fourth CSTR. In one embodiment, the nitrogen atom of the compound of formula (I) is protonated after contact with an aqueous solution of NaHSO4.

[0087] In one embodiment, the process includes a fifth CSTR comprising a base in water. The base is selected from the group consisting of NaOH, KOH, Na2CO3, and K2CO3. In one embodiment, the base is NaOH.

[0088] In another embodiment, the process includes a fifth CSTR containing NaOH in water. In one embodiment, the contents of the fourth CSTR as an emulsion are transferred to the fifth CSTR, thereby forming a biphasic mixture. In one embodiment, the biphasic mixture after the addition of NaOH in water has a pH of about 4 to about 7. In one embodiment, the biphasic mixture after the addition of NaOH in water has a pH of about 4 to about 5.5. In another embodiment, the pH of the biphasic mixture after the addition of NaOH in water is about 4.8±0.2. In another embodiment, the pH of the biphasic mixture after the addition of NaOH in water is about 4.6±0.2. In one embodiment, the nitrogen atom of the compound of formula (I) is deprotonated at a pH of about 5, and the compound of formula (I) partitions into the organic phase. In one embodiment, the residence time of the fifth CSTR is about 2 minutes to about 10 minutes. In another embodiment, the residence time of the fifth CSTR is about 3 minutes to about 8 minutes. In another embodiment, the residence time of the fifth CSTR is from about 4 minutes to about 6 minutes. In another embodiment, the residence time of the fifth CSTR is about 4 minutes. In another embodiment, the residence time of the fifth CSTR is about 5 minutes. In another embodiment, the residence time of the fifth CSTR is about 4.45 minutes.

[0089] The processes described herein can further include one or more separation vessels. In one embodiment, the contents of the fifth CSTR are transferred to a first separation vessel, thereby separating the organic and aqueous phases. In one embodiment, the resulting organic phase is (i) washed with water; (ii) distilled; (iii) precipitated; and (iv) dried to isolate the compound of formula (I) or a pharma- ceutically acceptable salt thereof.

[0090] The process described herein can also further comprise a sixth CSTR comprising water. In one embodiment, the organic phase obtained from the separation vessel is added to the sixth CSTR. In another embodiment, the process described herein further comprises a second separation vessel, where the contents of the sixth CSTR are added to the second separation vessel, thereby separating the organic and aqueous phases. In one embodiment, the resulting separated organic phase is (i) distilled; (ii) precipitated; and (iii) dried to isolate the compound of formula (I) or a pharma- ceutically acceptable salt thereof.

[0091] In one embodiment, in the compound of formula (I), R 1 is H representing a compound of formula (1): TIFF0007607057000017.tif47170

[0092] It is formed by deprotecting its N-protected derivative, where R 1 is an amino protecting group. Deprotection of a compound of formula (I), or any other compound described herein, can be accomplished by any method known to one of skill in the art and is typically performed later in the synthesis of ipatasertib after the continuous flow reaction of the present invention.

[0093] The compounds described herein may contain asymmetric or chiral centers and therefore may exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present invention, including, but not limited to, diastereomers, enantiomers, and atropisomers, as well as mixtures thereof, such as racemic mixtures, are intended to form part of the present invention.

[0094] In yet another aspect, provided herein is a process for the preparation of a compound of formula (I) as described herein, the process comprising: (a) A compound of formula (IV) solubilizing TIFF0007607057000018.tif44170 in a mixture of toluene and MeTHF in a first continuous stirred tank reactor (CSTR); (b) first adding iPrMgBr in MeTHF to the solubilized compound of step (a), thereby forming the Mg-imine complex as a solid; (c) transferring the contents of the first CSTR to a second CSTR and adding iPrMgBr in MeTHF thereto, thereby forming additional Mg-imine complex as a solid; (d) transferring the contents of the second CSTR to a third CSTR and adding toluene thereto, thereby forming additional Mg-imine complex as a solid; (e) transferring the contents of the third CSTR to a fourth CSTR and adding aqueous NaHSO4 thereto to set the pH to about 2, thereby forming a compound of formula (I); (f) transferring the contents of the fourth CSTR to a fifth CSTR and adding a base in water thereto to set the pH to about 5; and (g) transferring the contents of the fifth CSTR to a first separation vessel to separate the compound of Formula (I); Includes.

[0095] In certain embodiments, R 1 is as described herein. In certain embodiments, R 1 is an amino protecting group.

[0096] In yet another aspect, provided herein is a process for the preparation of a compound of formula (I) as described herein, the process comprising: (a) A compound of formula (IV) solubilizing TIFF0007607057000019.tif45170 in a mixture of toluene and MeTHF in a first continuous stirred tank reactor (CSTR); (b) first adding iPrMgBr in MeTHF to the solubilized compound of step (a), thereby forming the Mg-imine complex as a solid in suspension; (c) transferring the contents of the first CSTR to a second CSTR and adding iPrMgBr in MeTHF thereto, thereby forming the Mg-imine complex as a solid in suspension; (d) transferring the contents of the second CSTR to a third CSTR and adding toluene thereto, thereby forming the Mg-imine complex as a solid in suspension; (e) transferring the contents of the third CSTR to a fourth CSTR and adding aqueous NaHSO4 thereto to set the pH to about 2, thereby forming a compound of formula (I); (f) transferring the contents of the fourth CSTR to a fifth CSTR and adding NaOH in water thereto to set the pH to about 5; and (g) transferring the contents of the fifth CSTR to a first separation vessel to separate the compound of Formula (I); Includes.

[0097] In certain embodiments, R 1 is as described herein. In certain embodiments, R 1 is an amino protecting group.

[0098] In yet another aspect, provided herein is a process for the preparation of a compound of formula (I) as described herein, the process comprising: (a) A compound of formula (IV) solubilizing TIFF0007607057000020.tif44170 in a mixture of toluene and MeTHF in a first continuous stirred tank reactor (CSTR); (b) adding iPrMgBr in MeTHF to the solubilized compound of step (a) in a first CSTR (the first CSTR having a residence time of about 15 minutes), thereby forming the Mg-imine complex as a solid; (c) transferring the contents of the first CSTR to a second CSTR (the second CSTR having a residence time of about 15 minutes) and adding iPrMgBr in MeTHF thereto, thereby forming the Mg-imine complex as a solid; (d) transferring the contents of the second CSTR to a third CSTR and adding toluene thereto (the third CSTR having a residence time of about 15 minutes), thereby forming the Mg-imine complex as a solid; (e) transferring the contents of the third CSTR to a fourth CSTR and adding aqueous NaHSO4 thereto to set the pH to about 2, thereby forming a compound of formula (I), and allowing the reaction to proceed for about 4.45 minutes; (f) transferring the contents of the fourth CSTR to a fifth CSTR, adding base in water thereto to set the pH to about 5, and allowing the reaction to proceed for about 4.45 minutes; and (g) transferring the contents of the fifth CSTR to a first separation vessel to separate the compound of Formula (I); Includes.

[0099] In certain embodiments, R 1 is as described herein. In certain embodiments, R 1 is an amino protecting group.

[0100] In yet another aspect, provided herein is a process for the preparation of a compound of formula (I) as described herein, the process comprising: (a) A compound of formula (IV) solubilizing TIFF0007607057000021.tif45170 in a mixture of toluene and MeTHF in a first continuous stirred tank reactor (CSTR); (b) adding iPrMgBr in MeTHF to the solubilized compound of step (a) in a first CSTR (the first CSTR having a residence time of about 15 minutes), thereby forming the Mg-imine complex as a solid; (c) transferring the contents of the first CSTR to a second CSTR (the second CSTR having a residence time of about 15 minutes) and adding iPrMgBr in MeTHF thereto, thereby forming additional Mg-imine complex as a solid; (d) transferring the contents of the second CSTR to a third CSTR and adding toluene thereto (the third CSTR having a residence time of about 15 minutes), thereby forming additional Mg-imine complex as a solid; (e) transferring the contents of the third CSTR to a fourth CSTR and adding aqueous NaHSO4 thereto to set the pH to about 2, thereby forming a compound of formula (I), and allowing the reaction to proceed for about 4.45 minutes; (f) transferring the contents of the fourth CSTR to a fifth CSTR, adding base in water thereto to set the pH to about 5, and allowing the reaction to proceed for about 4.45 minutes; and (g) transferring the contents of the fifth CSTR to a first separation vessel to separate the compound of Formula (I); Includes.

[0101] In certain embodiments, R 1 is as described herein. In certain embodiments, R 1 is an amino protecting group.

[0102] In yet another aspect, provided herein is a process for the preparation of a compound of formula (I) as described herein, the process comprising: (a) A compound of formula (IV) solubilizing TIFF0007607057000022.tif45170 in a mixture of toluene and MeTHF in a first continuous stirred tank reactor (CSTR); (b) adding iPrMgBr in MeTHF to the solubilized compound of step (a) in the first CSTR (the first CSTR having a residence time of about 15 minutes), thereby forming the Mg-imine complex as a solid in suspension: (c) transferring the contents of the first CSTR to a second CSTR (the second CSTR having a residence time of about 15 minutes) and adding iPrMgBr in MeTHF thereto, thereby forming additional Mg-imine complex as a solid in suspension; (d) transferring the contents of the second CSTR to a third CSTR and adding toluene thereto (the third CSTR having a residence time of about 15 minutes), thereby forming additional Mg-imine complex in suspension as a solid in suspension; (e) transferring the contents of the third CSTR to a fourth CSTR and adding aqueous NaHSO4 thereto to set the pH to about 2, thereby forming a compound of formula (I), and allowing the reaction to proceed for about 4.45 minutes; (f) transferring the contents of the fourth CSTR to a fifth CSTR, adding NaOH in water thereto to set the pH to about 5, and allowing the reaction to proceed for about 4.45 minutes; and (g) transferring the contents of the fifth CSTR to a first separation vessel to separate the compound of Formula (I); Includes.

[0103] In certain embodiments, R 1 is as described herein. In certain embodiments, R 1 is an amino protecting group.

[0104] In such embodiments of the above processes, conditions such as temperature, concentration, transfer rate, reaction time, and volume are as described herein.

[0105] In some embodiments, the process includes on-line monitoring by NMR, HPLC, or IR.

[0106] In a preferred embodiment, deprotection of the compound of formula (I) or any other compound described herein can be accomplished by any method known to one skilled in the art and is carried out after the continuous flow reaction. In some preferred embodiments, the compound of formula (I) is used in the next reaction step in amino-protected form and deprotection is carried out after some reaction steps.

[0107] Implementation: Embodiment 1: Compound of formula (I) or a pharma- ceutically acceptable salt thereof, comprising a continuous flow reaction, 1 is hydrogen or an amino protecting group.

[0108] Embodiment 1A: Compound of formula (I) TIFF0007607057000024.tif49170 or a pharma- ceutically acceptable salt thereof, comprising a continuous flow reaction, R 1 is an amino protecting group.

[0109] Embodiment 2: The continuous flow reaction comprises reacting a compound of formula (II) TIFF0007607057000025.tif45170[In the formula, R 1 is hydrogen or an amino protecting group; and M is Li or Mg. or a pharma- ceutically acceptable salt thereof.

[0110] Embodiment 2A: A continuous flow reaction comprising a compound of formula (II) TIFF0007607057000026.tif44170[In the formula, R 1 is hydrogen or an amino protecting group; and M is MgX, where X is Br or I. or a pharma- ceutically acceptable salt thereof.

[0111] Embodiment 2B: A continuous flow reaction comprising a compound of formula (II) TIFF0007607057000027.tif45170[In the formula, R 1 is an amino protecting group; and M is MgX, where X is Br or I. or a pharma- ceutically acceptable salt thereof.

[0112] Embodiment 2C: A continuous flow reaction comprising a compound of formula (II) TIFF0007607057000028.tif45170[In the formula, R 1 is an amino protecting group; and M is MgX, where X is Br. or a pharma- ceutically acceptable salt thereof.

[0113] Embodiment 3: The method of embodiment 2, wherein M is Mg.

[0114] Embodiment 4: The continuous flow reaction comprises: (a) A compound of formula (III) TIFF0007607057000029.tif45170[In the formula, R 1 is hydrogen or an amino protecting group; and R 3 is iodo or bromo]; or a pharma- ceutically acceptable salt thereof with a Li or Mg metallizing agent to form a compound of formula (I). 4. The method of embodiment 2 or embodiment 3, comprising:

[0115] Embodiment 4a: The continuous flow reaction comprises: (a) A compound of formula (III) TIFF0007607057000030.tif45170[In the formula, R 1 is an amino protecting group; and R 3 is iodo or bromo] or a pharma- ceutically acceptable salt thereof with a Li or Mg metallizing agent to form a compound of formula (I). 4. The method of embodiment 2 or embodiment 3, comprising:

[0116] Embodiment 5: The compound of formula (III) is a compound of formula (IV) TIFF0007607057000031.tif44170 or a pharma- ceutically acceptable salt thereof, wherein R 1 is hydrogen or an amino protecting group.

[0117] Embodiment 5: The compound of formula (III) is a compound of formula (IV) TIFF0007607057000032.tif46170 or a pharma- ceutically acceptable salt thereof, wherein R 1 is an amino protecting group.

[0118] Embodiment 6: The method of embodiment 5, wherein the metallating agent is iPrMgBr.

[0119] Embodiment 7: The method according to any of embodiments 1 to 6, wherein the continuous flow reaction is carried out in a coordinating ether solvent or a non-coordinating apolar solvent, or a mixture thereof.

[0120] Embodiment 8: The method of any of embodiments 1 to 7, wherein the continuous flow reaction is carried out in a coordinating ether solvent.

[0121] Embodiment 9: The method of any of embodiments 1 to 7, wherein the continuous flow reaction is carried out in a non-coordinating apolar solvent.

[0122] Embodiment 10: The method according to embodiment 8, wherein the coordinating ether solvent is EtOEt, MeOtBu, iPrOiPr, dioxane, cPentylOMe, THF, or MeTHF.

[0123] Embodiment 11: The method of embodiment 9, wherein the non-coordinating apolar solvent is hexane, heptane, toluene, or xylene, or a mixture thereof.

[0124] Embodiment 12: The method of any of embodiments 6 to 11, wherein iPrMgBr is in MeTHF.

[0125] Embodiment 13: The method according to any of embodiments 5 to 12, wherein the compound of formula (IV) is in EtOEt, MeOtBu, iPrOiPr, dioxane, centylOMe, THF, MeTHF, hexane, heptane, toluene, or xylene, or a mixture thereof.

[0126] Embodiment 14: The method according to embodiment 13, wherein the compound of formula (IV) is in a mixture comprising MeTHF and toluene.

[0127] Embodiment 15: A method according to any of embodiments 6 to 14, wherein iPrMgBr is added to a compound of formula (IV).

[0128] Embodiment 16: In step (a), a compound of formula (III) is transferred to a compound of formula (II), and the compound of formula (II) is transferred as a solid to a Mg-imine complex, R 1 is hydrogen or an amino protecting group, and wherein in step (b), an aqueous acid salt solution is added to the mixture resulting from step (a), thereby forming a compound of formula (I) or a pharma- ceutically acceptable salt thereof.

[0129] Embodiment 17: The Mg-imine complex is formed as a solid in suspension, R 1 is hydrogen or an amino protecting group.

[0130] Embodiment 17a: The Mg-imine complex is formed as a solid in suspension, R 1 is an amino protecting group.

[0131] Embodiment 18: The method according to any of embodiments 6 to 17, wherein the molar ratio of iPrMgBr to the compound of formula (IV) is from about 1:1 to about 1.5:1.

[0132] Embodiment 19: A method according to any of embodiments 6 to 18, wherein the ratio of iPrMgBr to the compound of formula (IV) is from about 1.3 to about 1.

[0133] Embodiment 20: A method according to any of embodiments 6 to 19, wherein the ratio of iPrMgBr to the compound of formula (IV) is about 1:1.

[0134] Embodiment 21: A method according to any of embodiments 6 to 20, wherein iPrMgBr is added to the compound of formula (IV) in one or more steps.

[0135] Embodiment 22: A method according to any of embodiments 16 to 21, wherein the aqueous acidic salt solution is selected from the group consisting of acetic acid, HCl, H2SO4, NaHSO4, H3PO4, NaH2PO4, Na2HPO4, NaH2 citrate, NH4Cl, or oxalic acid, or a mixture thereof.

[0136] Embodiment 23: The method of embodiment 22, wherein the aqueous acidic salt solution is NaHSO4.

[0137] Embodiment 24: The method of any of embodiments 1 to 23, wherein the compound of formula (I) is optionally (a) washed; (b) distilled; (c) precipitated; and (d) dried.

[0138] Embodiment 25: The method according to any of embodiments 1 to 24, wherein the method does not require a recrystallization step.

[0139] Embodiment 26: The method of any of embodiments 1 to 25, wherein the method is carried out in one or more continuous stirred tank reactors (CSTRs).

[0140] Embodiment 27: The method according to embodiment 26, wherein the method is carried out using 1, 2, 3, 4, 5, 6, or 7 CSTRs.

[0141] Embodiment 28: The method described in embodiment 26 or embodiment 27, wherein the method is carried out using five CSTRs.

[0142] Embodiment 29: The method of any of embodiments 26 to 28, comprising a first CSTR comprising a solution of a compound of formula (IV) in an organic solvent, the organic solvent comprising one or more of EtOEt, MeOtBu, iPrOiPr, dioxane, cPentylOMe, THF, MeTHF, hexane, heptane, toluene, or xylene, or mixtures thereof.

[0143] Embodiment 30: The method of embodiment 29, wherein the compound of formula (IV) is in a mixture of MeTHF and toluene.

[0144] Embodiment 31: A method according to embodiment 29 or embodiment 30, wherein iPrMgBr in MeTHF is added to a solution of a compound of formula (IV).

[0145] Embodiment 32: The method according to embodiment 31, wherein the molar ratio of iPrMgBr to the compound of formula (IV) is about 1:1.

[0146] Embodiment 33: The method of any of embodiments 26 to 32, comprising a second CSTR containing a mixture of a compound of Formula (IV), Mg-imine complex, in suspension in MeTHF and toluene, wherein about 0.3 equivalents of iPrMgBr in MeTHF is added to the mixture.

[0147] Embodiment 34: The method of embodiment 33, wherein the contents of the first CSTR are transferred to a second CSTR.

[0148] Embodiment 35: The method of any of embodiments 26 to 34, further comprising a third CSTR, wherein the contents of the second CSTR are transferred to the third CSTR and stirred within the third CSTR.

[0149] Embodiment 36: A method according to any of embodiments 26 to 35, wherein the compound of formula (IV) is reacted with iPrMgBr to form the Mg-imine complex as a solid in suspension and transferred between the CSTRs as a suspension.

[0150] Embodiment 37: The method of any of embodiments 26 to 36, comprising a fourth CSTR, to which aqueous NaHSO4 is added.

[0151] Embodiment 38: The method of embodiment 37, wherein the pH of the two-phase mixture after addition of the aqueous NaHSO4 solution in the fourth CSTR is from about 1 to about 3.

[0152] Embodiment 39: The method of embodiment 38, wherein the pH of the two-phase mixture in the fourth CSTR is about 2.

[0153] Embodiment 40: The method of any of embodiments 26 to 39, wherein the contents of the third CSTR are added to a fourth CSTR, thereby forming a compound of formula (I).

[0154] Embodiment 41: The method of any of embodiments 26 to 34 and embodiments 36 to 40, further comprising a fourth CSTR, wherein the contents of the second CSTR are transferred to the fourth CSTR.

[0155] Embodiment 42: The method of any of embodiments 26 to 41, comprising a fifth CSTR to which a solution of a base in water is added. The base is selected from the group consisting of NaOH, KOH, Na2CO3, and K2CO3. The method of any of embodiments 26 to 41, comprising a fifth CSTR to which a solution of NaOH in water is added.

[0156] Embodiment 43: The method of claim 42, wherein the pH of the two-phase mixture in the fifth CSTR after the addition of NaOH is from about 4 to about 7.

[0157] Embodiment 43A: The method of claim 42, wherein the pH of the two-phase mixture in the fifth CSTR after the addition of NaOH is from about 4 to about 5.5.

[0158] Embodiment 44: The method of claim 43, wherein the pH of the two-phase mixture in the fifth CSTR after the addition of NaOH is about 4.8±0.2.

[0159] Embodiment 44A: The method of claim 43, wherein the pH of the two-phase mixture in the fifth CSTR after the addition of NaOH is about 4.6±0.2.

[0160] Embodiment 45: The method of any of embodiments 26 to 44, further comprising a first separation container.

[0161] Embodiment 46: The method of embodiment 45, wherein the contents of the fifth CSTR are transferred to a separation vessel, thereby separating the organic and aqueous phases.

[0162] Embodiment 47: The method according to embodiment 46, wherein the organic phase is (a) washed with water; (b) distilled; (c) precipitated; and (d) dried to isolate the compound of formula (I).

[0163] Embodiment 48: The method of any of embodiments 26 to 47, further comprising a sixth CSTR, to which water is added.

[0164] Embodiment 49: The method of embodiment 48, wherein the organic phase after separation is transferred to a sixth CSTR.

[0165] Embodiment 50: The method of embodiment 49, further comprising a second separation container.

[0166] Embodiment 51: The method of embodiment 50, wherein the contents of the sixth CSTR are transferred to a second separation vessel, thereby separating the organic and aqueous phases.

[0167] Embodiment 52: The method according to embodiment 51, wherein the organic phase is (i) distilled; (ii) precipitated; and (iii) dried to isolate the compound of formula (I).

[0168] Embodiment 53: A method according to any of embodiments 1 to 52, substantially carried out according to FIG. 1.

[0169] Embodiment 54: A method according to any of embodiments 1 to 52, substantially carried out according to FIG. 2.

[0170] Embodiment 55: R 1 The method of any one of embodiments 1 to 54, wherein is tert-butyloxycarbonyl.

[0171] Embodiment 56A: Compound of formula (I) 1. A method for preparing TIFF0007607057000033.tif49170 or a pharma- ceutically acceptable salt thereof, comprising the steps of: (a) A compound of formula (IV): solubilizing TIFF0007607057000034.tif45170 in a mixture of toluene and MeTHF in a first continuous stirred tank reactor (CSTR); (b) adding iPrMgBr in MeTHF to the solubilized compound of step (a) in the first CSTR, thereby forming the Mg-imine complex as a solid: (c) transferring the contents of the first CSTR to a second CSTR and adding iPrMgBr in MeTHF thereto, thereby forming the Mg-imine complex as a solid; (d) transferring the contents of the second CSTR to a third CSTR and adding toluene thereto, thereby forming the Mg-imine complex as a solid; (e) transferring the contents of the third CSTR to a fourth CSTR and adding aqueous NaHSO4 thereto to set the pH to about 2, thereby forming the compound of formula (I) and allowing the reaction to proceed; (f) transferring the contents of the fourth CSTR to a fifth CSTR, adding NaOH in water thereto to set the pH to about 5, and allowing the reaction to proceed; and (g) transferring the contents of the fifth CSTR to a first separation vessel to separate the compound of Formula (I) or a pharma- ceutically acceptable salt thereof; A method comprising:

[0172] Embodiment 56B: Compound of formula (I) 1. A method for preparing TIFF0007607057000035.tif48170 or a pharma- ceutically acceptable salt thereof, comprising the steps of: (a) A compound of formula (IV) solubilizing TIFF0007607057000036.tif44170 in a mixture of toluene and MeTHF in a first continuous stirred tank reactor (CSTR); (b) adding iPrMgBr in MeTHF to the solubilized compound of step (a) in the first CSTR, thereby forming the Mg-imine complex as a solid in suspension: (c) transferring the contents of the first CSTR to a second CSTR and adding iPrMgBr in MeTHF thereto, thereby forming the Mg-imine complex as a solid in suspension; (d) transferring the contents of the second CSTR to a third CSTR and adding toluene thereto, thereby forming the Mg-imine complex as a solid in suspension; (e) transferring the contents of the third CSTR to a fourth CSTR and adding aqueous NaHSO4 thereto to set the pH to about 2, thereby forming the compound of formula (I) and allowing the reaction to proceed; (f) transferring the contents of the fourth CSTR to a fifth CSTR, adding NaOH in water thereto to set the pH to about 5, and allowing the reaction to proceed; and (g) transferring the contents of the fifth CSTR to a first separation vessel to separate the compound of Formula (I) or a pharma- ceutically acceptable salt thereof; A method comprising:

[0173] Embodiment 56C: A compound of formula (I) 1. A method for preparing TIFF0007607057000037.tif49170 or a pharma- ceutically acceptable salt thereof, comprising the steps of: (a) A compound of formula (IV) solubilizing TIFF0007607057000038.tif45170 in a mixture of toluene and MeTHF in a first continuous stirred tank reactor (CSTR); (b) adding iPrMgBr in MeTHF to the solubilized compound of step (a) in a first CSTR (the first CSTR having a residence time of about 15 minutes), thereby forming the Mg-imine complex as a solid in suspension; (c) transferring the contents of the first CSTR to a second CSTR (the second CSTR having a residence time of about 15 minutes) and adding iPrMgBr in MeTHF thereto, thereby forming the Mg-imine complex as a solid in suspension; (d) transferring the contents of the second CSTR to a third CSTR and adding toluene thereto (the third CSTR having a residence time of about 15 minutes), thereby forming the Mg-imine complex as a solid in suspension; (e) transferring the contents of the third CSTR to a fourth CSTR and adding aqueous NaHSO4 thereto to set the pH to about 2, thereby forming a compound of formula (I), and allowing the reaction to proceed for about 4.45 minutes; (f) transferring the contents of the fourth CSTR to a fifth CSTR, adding NaOH in water thereto to set the pH to about 5, and allowing the reaction to proceed for about 4.45 minutes; and (g) transferring the contents of the fifth CSTR to a first separation vessel to separate the compound of Formula (I) or a pharma- ceutically acceptable salt thereof; A method comprising:

[0174] Embodiment 56D: Embodiment 56A: Compound of formula (I) 1. A method for preparing TIFF0007607057000039.tif48170 or a pharma- ceutically acceptable salt thereof, comprising the steps of: (a) A compound of formula (IV) solubilizing TIFF0007607057000040.tif44170 in a mixture of toluene and MeTHF in a first continuous stirred tank reactor (CSTR); (b) adding iPrMgBr in MeTHF to the solubilized compound of step (a) in the first CSTR, thereby forming the Mg-imine complex as a solid: (c) transferring the contents of the first CSTR to a second CSTR and adding iPrMgBr in MeTHF thereto, thereby forming additional Mg-imine complex as a solid; (d) transferring the contents of the second CSTR to a third CSTR and adding toluene thereto, thereby forming additional Mg-imine complex as a solid; (e) transferring the contents of the third CSTR to a fourth CSTR and adding aqueous NaHSO4 thereto to set the pH to about 2, thereby forming the compound of formula (I) and allowing the reaction to proceed; (f) transferring the contents of the fourth CSTR to a fifth CSTR, adding NaOH in water thereto to set the pH to about 5, and allowing the reaction to proceed; and (g) transferring the contents of the fifth CSTR to a first separation vessel to separate the compound of Formula (I) or a pharma- ceutically acceptable salt thereof; A method comprising:

[0175] Embodiment 56E: A compound of formula (I) 1. A method for preparing TIFF0007607057000041.tif49170 or a pharma- ceutically acceptable salt thereof, comprising the steps of: (a) A compound of formula (IV): solubilizing TIFF0007607057000042.tif46170 in a mixture of toluene and MeTHF in a first continuous stirred tank reactor (CSTR); (b) adding iPrMgBr in MeTHF to the solubilized compound of step (a) in a first CSTR (the first CSTR having a residence time of about 15 minutes), thereby forming the Mg-imine complex as a solid in suspension; (c) transferring the contents of the first CSTR to a second CSTR (the second CSTR having a residence time of about 15 minutes) and adding iPrMgBr in MeTHF thereto, thereby forming additional Mg-imine complex as a solid in suspension; (d) transferring the contents of the second CSTR to a third CSTR and adding toluene thereto (the third CSTR having a residence time of about 15 minutes), thereby forming additional Mg-imine complex as a solid in suspension; (e) transferring the contents of the third CSTR to a fourth CSTR and adding aqueous NaHSO4 thereto to set the pH to about 2, thereby forming a compound of formula (I), and allowing the reaction to proceed for about 4.45 minutes; (f) transferring the contents of the fourth CSTR to a fifth CSTR, adding NaOH in water thereto to set the pH to about 5, and allowing the reaction to proceed for about 4.45 minutes; and (g) transferring the contents of the fifth CSTR to a first separation vessel to separate the compound of Formula (I) or a pharma- ceutically acceptable salt thereof; A method comprising:

[0176] As noted above, the third CSTR may be skipped in any embodiment, in which case the numbering of the next CSTR remains the same.

[0177] Embodiment 57: The method according to embodiment 56, wherein the product-containing organic phase is (a) washed with water; (b) distilled; (c) precipitated; and (d) dried.

[0178] Embodiment 58: The method of embodiment 56, further comprising a sixth CSTR, to which water is added.

[0179] Embodiment 59: The method of embodiment 58, wherein the organic phase after separation is transferred to a sixth CSTR.

[0180] Embodiment 60: The method of embodiment 59, further comprising a second separation container.

[0181] Embodiment 61: The method of claim 60, wherein the contents of the sixth CSTR are transferred to a second separation vessel, thereby separating the organic and aqueous phases.

[0182] Embodiment 62: The method according to embodiment 61, wherein the organic phase comprises a compound of formula (I) and is (i) distilled; (ii) precipitated; and (iii) dried.

[0183] Embodiment 63: Compound of formula (I) 1. A method for preparing TIFF0007607057000043.tif49170 or a pharma- ceutically acceptable salt thereof, comprising the steps of: (a) A compound of formula (IV) solubilizing TIFF0007607057000044.tif44170 in a mixture of toluene and MeTHF; (b) adding iPrMgBr in MeTHF to the solubilized compound of step (a), thereby forming the Mg-imine complex as a solid in suspension; (c) adding an acidic salt solution; (d) adding a base to the water; and (e) isolating the compound of formula (I). A method comprising:

[0184] Embodiment 64: Compound of formula (I) 1. A method for preparing TIFF0007607057000045.tif49170 or a pharma- ceutically acceptable salt thereof, comprising the steps of: (a) A compound of formula (IV) solubilizing TIFF0007607057000046.tif44170 in a mixture of toluene and MeTHF; (b) adding iPrMgBr in MeTHF to the solubilized compound of step (a), thereby forming the Mg-imine complex as a solid in suspension; (c) adding an aqueous solution of NaHSO4; (d) adding NaOH in water; and (e) isolating the compound of formula (I). A method comprising:

[0185] Embodiment 65. Compound of formula (I) TIFF0007607057000047.tif49170 or a pharma- ceutically acceptable salt thereof, comprising a continuous flow reaction, wherein R 1 is hydrogen or an amino protecting group.

[0186] Embodiment 66. The continuous flow reaction comprises reacting a compound of formula (II) or a phenyl group thereof, 1 is hydrogen or an amino protecting group, and M is Li or Mg.

[0187] Embodiment 66a. The method according to embodiment 65, wherein the continuous flow reaction comprises reacting a compound of formula (II) or a phenolic salt thereof, 1 is an amino protecting group and M is Li or MgX, where X is Br or I. EXAMPLES

[0188] The following examples are offered by way of illustration and not by way of limitation.

[0189] Example 1: [ka] Equipment: 3 x 100 mL and 2 x 250 mL double jacketed reactors. An overflow tube (ID = 3.0 mm) was placed in each reactor and the filling volume was controlled at 50 mL. An overhead stirrer with impeller mixer was used. 4 x Huber thermostats and 6 x continuous Syrdos2 syringe pumps (syringe capacity 1.0-10.0 mL) were used. PTFE tubing (ID = 0.8 mm and 1.58 mm), 2 x pH Electode InLab-Semi-Micro-L and 5 x temperature probe PT100 were used. A horizontal glass separation column (50 mL) was used for liquid / liquid phase separation.

[0190] All continuous stirred tank reactors (CSTRs) were equipped with overflow tubes (ID = 3 mm) to individually adjust the reactor volume. CSTR1 was adjusted to exactly 48.8 mL, while CSTRs 2-5 had a volume of 50.0 mL. The residence time of each individual CSTR is the product of the reactor volume and flow rate, as shown by the following equation:

[0191] Residence time [min] = Volume [mL] / Flow rate [mL / min] TIFF0007607057000051.tif38170

[0192] Preparation of stock solutions: Feed A (tert-butyl (R)-4-(6-bromo-5-(1-cyanopropan-2-yl)pyrimidin-4-yl)piperazine-1-carboxylate (compound 4)): TIFF0007607057000052.tif43170

[0193] Compound 4 (143.6 g) was solubilized in a mixture of toluene (772.9 g) and MeTHF (295.3 g). The final concentration of the resulting brownish solution was 0.26 M.

[0194] Feed B (iPrMgBr in MeTHF): iPrMgBr was supplied as a 40% (w / w) solution in MeTHF (approximately 2.95 M) and was used directly as supplied.

[0195] Feed C (NaHSO4 aq.): NaHSO4*H2O (57.5 g) was solubilized in water (942.5 g). The final concentration of the resulting clear solution was 5.0% (w / w).

[0196] Feed D (NaOH aq.): NaOH (80.0 g) was solubilized in water (990.4 g). The final concentration of the resulting clear solution was 2.0 M.

[0197] Feed E (Toluene): Toluene was used as a pure solvent to dilute the product stream.

[0198] Example 2: Start-up phase (batch mode) All syringe pumps and transfer lines were purged with 2 volumes of feed solution.

[0199] CSTR1 and CSTR2 were each charged with Feed A (44.9 mL). Feed B (263.6 μL, 1.00 equiv.) was added to CSTR1 via dip tube over 15 min, maintaining the IT at 27° C. After addition, the resulting suspension showed approximately 75% conversion of compound 4 in CSTR1. Feed B (342.7 μL, 1.30 equiv.) was added to CSTR2 via dip tube over 15 min, maintaining the IT at 27° C. After addition, the resulting suspension showed approximately 95% conversion of compound 4 in CSTR2. Toluene (15 mL) was added to CSTR3 to reach minimum stirring and the IT was adjusted to 27° C. CSTR4 was charged with water (40 mL) and the pH controlled addition of Feed C (aqueous NaHSO4) was enabled to adjust and maintain pH 2 at an internal temperature of 15° C. CSTR5 was charged with water (40 mL) and the pH controlled addition of Feed D (aqueous NaOH) was enabled to adjust and maintain pH=5 at 25° C. IT.

[0200] Example 3: Fully continuous operation All six pumps were started simultaneously at their respective flow rates (see, e.g., Figures 1 and 2) and the reaction mass was allowed to continuously overflow from CSTR to CSTR by gravity. The rates are provided below for reference. TIFF0007607057000053.tif37170

[0201] The liquid / liquid two-phase stream exiting the CSTR 5 was directed to an in-line settler unit to separate the two layers (see Figures 1 and 2). The upper (organic) layer, containing the desired compound 1, was collected and the lower (aqueous) layer was directed to waste.

[0202] Isolation of compound 1 in batch mode The organic layer was concentrated to a given residual volume by distillation (IT 35 °C, ca. 10 mbar) followed by addition of an anti-solvent mixture (n-heptane:methyl-tert-butyl ether - 1:1.5 vol / vol) at an IT of 45 °C over a period of 90 min to complete the precipitation of compound 1. The slurry was cooled to an IT of 0 °C and then filtered. The resulting filter cake was washed with a solvent mixture (n-heptane:methyl-tert-butyl ether - 1:1.5 vol / vol) at an IT of 0 °C. The product was dried at a jacket temperature of 50 °C and under reduced pressure until constant weight. Compound 1 was isolated as a pale yellow to off-white powder in 80-85% yield. 1 H NMR (500 MHz, DMSO-cfe) δ 8.60 (s, 1 H), 3.82 (m, 2H), 3.72 (m, 1 H), 3.65 (m, 2H), 3.50 (m, 2H), 3.42 (m, 2H), 2.90 (dd, 1 H, J = 7, 19 Hz), 2.25 (dd, 1 H, J = 2, 19 Hz), 1.41 (s, 9H), 1.19 (d, 3H, J = 7 Hz); 13 C NMR (125 MHz, DMSO-d6) δ 205.75, 161.96, 158.89, 157.97, 154.34, 137.39, 79.67, 45.77, 43.39, 43.25, 31.22, 28.52, 20.40; [α] 436 20 + 453.7 (c = 1, MeOH);C 17 H 24 4 HRMS calculated value of 03 [M+H] + :333.1921, actual value:333.1916.

[0203] All technical and scientific terms used herein have the same meaning. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be accounted for.

[0204] Throughout this specification and the claims, the words "comprise," "comprises," and "comprising" are used in their non-exclusive sense, unless the context requires otherwise. It is understood that the embodiments described herein include "consisting of" and / or "consisting essentially of" embodiments.

[0205] Where a range of values ​​is provided, unless the context clearly dictates otherwise, it is understood that each intervening value, to the tenth of the unit of the lower limit, between the upper and lower limit of the range and any other stated or intervening value in that stated range is included herein. The upper and lower limits of these smaller ranges that may be independently included in the smaller ranges are also included herein, subject to any specifically excluded limit in the stated range. Where one or both of the limits are included in the stated range, ranges excluding either or both of those included limits are also included herein.

[0206] Many modifications and other embodiments of the inventions described herein will come to mind to one skilled in the art to which these inventions pertain having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. It is to be understood, therefore, that the invention is not to be limited to the specific embodiments disclosed, and that modifications and other embodiments are intended to be included within the scope of the appended claims. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

Claims

1. Compounds of formula (I) [In the formula, R １ is an amino protecting group. or a pharma- ceutically acceptable salt thereof, comprising the steps of: (a) A compound of formula (IV) [In the formula, R １ is an amino protecting group. in an organic solvent; (b) adding iPrMgBr in an organic solvent to the solubilized compound of step (a), thereby forming the Mg-imine complex as a solid in suspension; (c) adding an aqueous acid salt solution; (d) adding an aqueous solution of a base; and (e) isolating the compound of formula (I). A method comprising:

2. 2. The method of claim 1, wherein the organic solvent is a coordinating ether solvent or a non-coordinating apolar solvent, or a mixture thereof.

3. The method of claim 1 , wherein the organic solvent is a coordinating ether solvent.

4. The method of claim 1 , wherein the organic solvent is a non-coordinating apolar solvent.

5. 4. The method of claim 3, wherein the coordinating ether solvent is EtOEt, MeOtBu, iPrOiPr, dioxane, cPentylOMe, THF, MeTHF, or a mixture thereof.

6. 5. The method of claim 4, wherein the non-coordinating apolar solvent is hexane, heptane, toluene, or xylene, or a mixture thereof.

7. 2. The method of claim 1, wherein iPrMgBr is in MeTHF.

8. 2. The method of claim 1, wherein the compound of formula (IV) is in EtOEt, MeOtBu, iPrOiPr, dioxane, cPentylOMe, THF, MeTHF, hexane, heptane, toluene, or xylene, or a mixture thereof.

9. 9. The method of claim 8, wherein the compound of formula (IV) is in a mixture comprising MeTHF and toluene.

10. 10. The process according to any one of claims 1 to 9, wherein the molar ratio of iPrMgBr to the compound of formula (IV) is from 1:1 to 1.5:

1.

11. 11. The process of claim 10, wherein the molar ratio of iPrMgBr to the compound of formula (IV) is from 1:1 to 1.3:

1.

12. 12. The process according to claim 10 or claim 11, wherein the molar ratio of iPrMgBr to the compound of formula (IV) is 1:

1.

13. 13. The method of any one of claims 1 to 12, wherein iPrMgBr is added to the compound of formula (IV) multiple times.

14. The acid salt solution is acetic acid, HCl, H ２ SO ４ , NaHSO ４ , H ３ P.O. ４ , NaH ２ P.O. ４ , Na ２ H.P.O. ４ , NaH ２ Citrate, NH ４ 14. The method of claim 1, wherein the cation exchange agent is selected from the group consisting of chlorine, ...

15. The acid salt solution is NaHSO ４ The method of claim 14, wherein

16. 16. The method of any one of claims 1 to 15, wherein the compound of formula (I) is optionally: (a) washed; (b) distilled; (c) precipitated; and (d) dried.

17. 17. The method of any one of claims 1 to 16, wherein the method does not require a recrystallization step.

18. 18. The process of any one of claims 1 to 17, wherein the process is carried out in one or more continuous stirred tank reactors (CSTRs).

19. 20. The method of claim 18, wherein the method is carried out using 1, 2, 3, 4, 5, 6, or 7 CSTRs.

20. 20. The method of claim 18 or claim 19, wherein the method is carried out using five CSTRs.

21. 21. The method of any one of claims 18 to 20, comprising a first CSTR comprising a solution of a compound of formula (IV) in an organic solvent, the organic solvent comprising one or more components selected from the group consisting of EtOEt, MeOtBu, iPrOiPr, dioxane, cPentylOMe, THF, MeTHF, hexane, heptane, toluene, or xylene, or mixtures thereof.

22. 22. The method of claim 21 , wherein the compound of formula (IV) is in a mixture of MeTHF and toluene.

23. 23. A method according to claim 21 or claim 22, wherein a solution of iPrMgBr in MeTHF is added to the solution of the compound of formula (IV) in the first CSTR.

24. 24. The process of claim 23, wherein the molar ratio of iPrMgBr to the compound of formula (IV) is 1:

1.

25. 25. The process of any one of claims 18 to 24, comprising a second CSTR containing a mixture of the compound of formula (IV) and Mg-imine complex in suspension in MeTHF and toluene, wherein 0.3 equivalents of iPrMgBr in MeTHF is added to the mixture.

26. 26. The method of claim 25, wherein the contents of a first CSTR are transferred to a second CSTR.

27. 27. The method of any one of claims 18 to 26, further comprising a third CSTR, wherein the contents of the second CSTR are transferred to the third CSTR and agitated within the third CSTR.

28. 28. A method according to any one of claims 18 to 27, wherein the Mg-imine complex is formed as a solid in suspension by reacting a compound of formula (IV) with iPrMgBr and transferred as a suspension between the CSTRs.

29. a fourth CSTR containing NaHSO ４ 29. The method of any one of claims 18 to 28, wherein an aqueous solution is added.

30. In the fourth CSTR, NaHSO ４ 30. The method of claim 29, wherein the pH of the biphasic mixture after adding the aqueous solution is from 1 to 3.

31. 31. The method of claim 30, wherein the pH of the two-phase mixture in the fourth CSTR is 2.

32. 32. The method of any one of claims 18 to 31, wherein the contents of the third CSTR are added to the fourth CSTR, thereby forming a compound of formula (I).

33. 33. The method of any one of claims 18-26 and claims 28-32, further comprising a fourth CSTR, and wherein the contents of the second CSTR are transferred to the fourth CSTR.

34. 34. The method of any one of claims 18 to 33, comprising a fifth CSTR to which an aqueous solution of base is added.

35. 35. The method according to claim 34, wherein an aqueous solution of NaOH is added as the aqueous solution of base.

36. 36. The method of claim 35, wherein the pH of the two-phase mixture in the fifth CSTR after the addition of NaOH is from 4 to 7.

37. 37. The method of claim 36, wherein the pH of the two-phase mixture in the fifth CSTR after the addition of NaOH is 4.6±0.

2.

38. 38. The method of any one of claims 18 to 37, further comprising a first separation vessel.

39. 40. The method of claim 38, wherein the contents of the fifth CSTR are transferred to a first separation vessel, thereby separating the organic and aqueous phases.

40. 40. The method of claim 39, wherein the product-containing organic phase is (a) washed with water; (b) distilled; (c) precipitated; and (d) dried to isolate the compound of formula (I).

41. 40. The method of any one of claims 18 to 39, further comprising a sixth CSTR to which water is added.

42. 42. The method of claim 41 , wherein the organic phase after separation is transferred to a sixth CSTR.

43. 43. The method of claim 42, further comprising a second separation vessel.

44. 44. The method of claim 43, wherein the contents of the sixth CSTR are transferred to a second separation vessel, thereby separating the organic and aqueous phases.

45. 45. The process of claim 44, wherein the organic phase is (i) distilled; (ii) precipitated; and (iii) dried to isolate the compound of formula (I).

46. R １ The method of any one of claims 1 to 45, wherein is tert-butyloxycarbonyl.

47. Compounds of formula (I) [In the formula, R １ is an amino protecting group. or a pharma- ceutically acceptable salt thereof, comprising the steps of: (a) A compound of formula (IV) [In the formula, R １ is an amino protecting group. in a mixture of toluene and MeTHF in a first continuous stirred tank reactor (CSTR); (b) adding a solution of iPrMgBr in MeTHF to the solubilized compound of step (a) in the first CSTR, thereby forming the Mg-imine complex as a solid; (c) transferring the contents of the first CSTR to a second CSTR and adding thereto a solution of iPrMgBr in MeTHF, thereby forming the Mg-imine complex as a solid; (d) transferring the contents of the second CSTR to a third CSTR and adding toluene thereto, thereby forming the Mg-imine complex as a solid; (e) Transfer the contents of the third CSTR to a fourth CSTR and add NaHSO ４ adding an aqueous solution to set the pH to 2, thereby forming the compound of formula (I) and allowing the reaction to proceed; (f) transferring the contents of the fourth CSTR to a fifth CSTR, adding aqueous NaOH thereto to set the pH to 5, and allowing the reaction to proceed; and (g) transferring the contents of the fifth CSTR to a first separation vessel to separate the compound of Formula (I) in an organic phase; A method comprising:

48. The method of claim 47, wherein the residence time of the first CSTR is 15 minutes, the residence time of the second CSTR is 15 minutes, the residence time of the third CSTR is 15 minutes, the residence time of the fourth CSTR is 4.45 minutes, and the residence time of the fifth CSTR is 4.45 minutes.

49. A method according to claim 47 or claim 48, wherein the Mg-imine complex is formed as a solid in suspension.

50. 50. The process of any one of claims 47 to 49, wherein the product-containing organic phase is (i) washed with water; (ii) distilled; (iii) precipitated; and (iv) dried.

51. 50. The method of claim 49, further comprising a sixth CSTR to which water is added.

52. 52. The method of claim 51 , wherein the organic phase after separation is transferred to a sixth CSTR.

53. 53. The method of claim 52, further comprising a second separation vessel.

54. 54. The method of claim 53, wherein the contents of the sixth CSTR are transferred to a second separation vessel, thereby separating the organic and aqueous phases.

55. 55. The method of claim 54, wherein the organic phase is (i) distilled; (ii) precipitated; and (iii) dried.

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