Method for synthesizing quinazoline compounds

Abstract

To provide a method for synthesizing a compound useful for treating cancer.SOLUTION: Contacting a compound of formula (II) with an organomagnesium compound, transferring the obtained compound to a continuous stirred tank reactor (CSTR) containing a zinc compound, and contacting the thereby obtained compound with a compound of formula (III), a transition metal catalyst precursor and a chiral ligand to obtain the target compound.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the interests of U.S. Provisional Patent Application No. 63 / 307529, filed on 7 February 2022, which is incorporated herein by reference in its entirety for all purposes.

[0002] A method for synthesizing compounds useful for the treatment of cancer, comprising a quinazolinyl core moiety and at least one stereoisomer or atropisomer moiety, is provided herein. [Background technology]

[0003] The arrangement of biaryl axes often plays a crucial role in the pharmacological properties of bioactive compounds and is a fundamental basis for useful reagents and catalysts in asymmetric synthesis. Highly atroposelective cross-coupling, particularly heterocyclic cross-coupling for the synthesis of biheteroaryls, remains a challenging and unresolved problem. Furthermore, scaling such processes to a commercial / industrial scale often introduces unforeseen and unexpected difficulties in the process and synthesis. This disclosure provides an improved method for the non-selective synthesis of aminopyridinyl-quinazolinyl compounds via Negishi coupling utilizing chiral ligands such as chiraphytes.

[0004] Therefore, there is an urgent need for methods that enable efficient and effective scale-up for the synthesis of compounds such as those described herein. [Overview of the project]

[0005] Solutions to the above-mentioned problems and other problems in the art are provided herein.

[0006] In a first aspect, a method for synthesizing the compound of formula (I) described herein is provided, the method comprising: (a) contacting the compound of formula (II) described herein with an organomagnesium compound to form the compound of formula (IIa) described herein; (b) transferring the compound of formula (IIa) from step (a) to a continuous stirred tank reactor (CSTR) containing a zinc compound to synthesize the compound of formula (IIb) described herein; and contacting the compound (IIb) from step (b) with the compound of formula (III) described herein, a transition metal catalyst precursor described herein, and a chiral ligand described herein to synthesize the compound of formula (I).

[0007] In one embodiment, the compound of formula (II) is prepared according to method P2 described herein.

[0008] In one embodiment, the compound of formula (III) is prepared according to method P4 described herein.

[0009] In one embodiment of the method described herein, formula (I) includes a compound of formula (Ia), (Ib), (Ic), or (Id) as described herein.

[0010] In one embodiment of the method described herein, formula (I) includes the compound of formula (1) described herein.

[0011] In another embodiment, a method (P5) for synthesizing the compound of formula (2) described herein, the method comprising: (a) contacting the compound of formula (4a) described herein with i-PrMgCl, followed by contact with hydroxylamine, thereby synthesizing the compound of formula (4c) described herein; (b) contacting the compound of formula (4c) described herein with TFAA and triethylamine in acetonitrile, then contact with ammonia, thereby synthesizing the compound of formula (4e) described herein; and contacting the compound of (4e) described herein with a chlorinating agent, thereby synthesizing the compound of formula (4) described herein. A method for synthesizing the compound of formula (2) described herein is provided herein, comprising the steps of: synthesizing a substance; contacting the compound of formula (4) described herein with CO2 in the presence of DBU to synthesize the compound of formula (5); contacting the compound of formula (5) described herein with POCl3 and DIPEA, and subsequently with tert-butyl(S)-3-methylpiperazine-1-carboxylate in DIPEA to synthesize the compound of formula (5b); and contacting the compound of formula (5b) described herein with KF, DABCO and MsOH to form the compound of formula (2) described herein.

[0012] In another embodiment, a method (P7) for synthesizing a compound of formula (G) described herein, its tautomer, stereoisomer, atropisomer or pharmaceutically acceptable salt thereof, wherein the method synthesizes a compound of formula (I), its solvate, tautomer, stereoisomer, atropisomer or salt thereof, in the presence of a base and an activator described herein, as described herein. A A step of bringing into contact with a portion containing the compound of formula (G1) described herein; from the compound of formula (G1), a PG group and optionally R 1A method for synthesizing a compound of formula (G) or a tautomer, stereoisomer, atropisomer or pharmaceutically acceptable salt thereof is provided herein, comprising the steps of: removing; and contacting the compound of step (b) with a compound of formula (VII) as described herein in the presence of an activator as described herein, and subsequently contacting it with a base as described herein, thereby producing a compound of formula (G), or a tautomer, stereoisomer, atropisomer or pharmaceutically acceptable salt thereof.

[0013] Furthermore, a method (P8) for synthesizing the compound of formula (1) or a pharmaceutically acceptable salt thereof as described herein, the method comprising the steps of: contacting a pre-cooled solution containing the compound of formula (2) or a salt thereof as described herein with a pre-cooled solution containing i-PrMgCl·LiCl at a flow rate that results in a residence time of approximately 15 to 150 seconds for Mg-Br exchange, thereby synthesizing the compound of formula (2a) as described herein; and bringing the compound of formula (2a) from step (a) into a continuous stirred tank reactor (CSTR) containing a solution of ZnCl2 or Zn(OPiv)2. a) A step of transferring the compound of formula (2b) as described herein and maintaining a constant residence time of about 3 to 7 minutes at about -20°C to 20°C, thereby synthesizing the compound of formula (2b) as described herein; a step of contacting the compound of formula (2b) with NaTFA and the compound of formula (3) as described herein; a step of contacting the mixture of step (c) or a salt thereof with a Pd or Ni catalyst precursor and a chiral ligand, thereby synthesizing the compound of formula (11) as described herein, or its solvate or salt thereof; a step of transferring the compound of formula (11), or its solvate or salt thereof, to formula HO-X A (In the formula, X A is an expression A step of contacting a compound of formula (1b) or its solvate or pharmaceutically acceptable salt (having TIFF0007925146000001.tif13170) with a base as described herein to synthesize the compound of formula (1b) or its solvate or pharmaceutically acceptable salt as described herein; a step of contacting the compound of formula (1b) with MsOH in an acid to synthesize the compound of formula (1a) or its solvate or pharmaceutically acceptable salt as described herein; and the compound of formula (1a) or its solvate or pharmaceutically acceptable salt A method for synthesizing the compound of formula (1) or a pharmaceutically acceptable salt thereof described herein is provided, comprising the step of contacting TIFF0007925146000002.tif18170 in the presence of an activator, followed by contact with a base, thereby producing the compound of formula (1) or a pharmaceutically acceptable salt thereof.

[0014] This embodiment can be better understood by referring to the detailed description and examples, which are intended to illustrate non-limiting embodiments. [Brief explanation of the drawing]

[0015] [Figure 1] Figure 1 shows an exemplary hardware configuration for the continuous flow reaction described herein. [Modes for carrying out the invention]

[0016] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those 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). Any methods, apparatus, and materials similar to or equivalent to those described herein may be used in carrying out the present invention.

[0017] The following definitions are provided to facilitate understanding of certain terms frequently used herein and are not intended to limit the scope of this disclosure. All references mentioned herein are incorporated by reference in their entirety.

[0018] Where used herein, unless otherwise specified, the terms “about” and “approximately” refer to a dose, volume, or weight percentage of an ingredient in a composition or dosage form, meaning a dose, volume, or weight percentage recognized by those skilled in the art to provide an equivalent pharmacological effect to that obtained from a specified dose, volume, or weight percentage. An equivalent dose, volume, or weight percentage may be 30%, 20%, 15%, 10%, 5%, 1%, or less than the specified dose, volume, or weight percentage.

[0019] 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.

[0020] The terms "halogen" and "halo" are used interchangeably herein and refer to F, Cl, Br, or I.

[0021] The term "alkyl" refers to a saturated linear or branched monovalent hydrocarbon group. In one example, the alkyl group has 1 to 18 carbon atoms (C 1-18 ). In other examples, the alkyl group is C 1-12 , C 1-10 , C 1-8 , C 1-6 , C 1-5 , C 1-4 , or C 1-3 . Examples of alkyl groups include methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3, 1-heptyl and 1-octyl.

[0022] The term "haloalkyl" refers to an alkyl chain in which one or more hydrogen atoms are replaced by halogens. Examples of haloalkyls include trifluoromethyl, difluoromethyl, and fluoromethyl. "Fluoroalkyl" refers to an alkyl chain in which one or more hydrogen atoms are replaced by fluorine (F).

[0023] The term "amino" refers to -NH2.

[0024] The terms "cyano" and "nitrile" are used interchangeably herein and mean -C≡N or -CN.

[0025] The term "cyanoalkyl" refers to an alkyl group substituted with one cyano substituent.

[0026] The term "hydroxy" means -OH.

[0027] "Condensed" means any cyclic structure described herein that shares one or more atoms (e.g., carbon or nitrogen atoms) with a cyclic structure present in the compound of the present invention.

[0028] As used herein, “halogenating agent” refers to any reagent that adds one or more halogens to the compounds described herein. As used herein, “chlorinating agent” refers to any reagent that adds one or more chlorine (Cl) atoms to the compounds described herein. In one embodiment, the chlorinating agent is NCS or DCH as described herein. As used herein, “brominating” or “iodinating” agent refers to any reagent that adds one or more bromine (Br) or iodine (I) atoms to the compounds described herein, respectively.

[0029] As used herein, “haloalkylating agent” refers to any reagent that adds one or more haloalkyl groups (e.g., CF3) to the compounds described herein. “Fluoroalkylating agent” refers to a reagent that adds one or more fluoroalkyl groups to the compounds described herein.

[0030] "Organomagnesium compounds" are organometallic compounds in which the metal is magnesium.

[0031] The compounds of the present invention may contain one or more chiral carbon atoms. Therefore, the compounds may exist as diastereomers, enantiomers, or mixtures thereof. Racemic compounds, diastereomers, or enantiomers may be used as starting materials or intermediates in the synthesis of the compounds. A mixture of specific diastereomer compounds may be separated or concentrated into one or more specific diastereomers by chromatography or crystallization. Similarly, enantiomixtures may be separated or enantiomerically concentrated using the same technique or other techniques known in the art. Each of the asymmetric carbon or nitrogen atoms may be present in the R or S configuration, and both of these configurations are within the scope of the present invention.

[0032] In the structures shown herein, if the stereochemistry of any specific chiral atom is not specified, all stereoisomers are conceived and included as compounds of the present invention. Where stereochemistry is indicated by a solid wedge or dashed line representing a specific configuration, the stereoisomers are indicated and defined in that way. Unless otherwise stated, relative stereochemistry is intended when solid wedges or dashed lines are used.

[0033] The term "stereoisomer" refers to compounds that have the same chemical structure but differ in the arrangement of atoms or groups in space. Stereoiomers include diastereomers, enantiomers, atropisomers, and conformational isomers.

[0034] The term "chiral" refers to molecules that have the property of not being able to be superimposed on their mirror image partners, while the term "achiral" refers to molecules that can be superimposed on those mirror image partners.

[0035] The term "diastereomer" refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectroscopic properties, or biological activity. Mixtures of diastereomers can be separated under high-resolution analytical procedures such as electrophoresis and chromatography such as HPLC.

[0036] The term "enantiomer" refers to two stereoisomers of a compound that are mirror images of each other but cannot be superimposed.

[0037] Atropisomers are stereoisomers resulting from rotations that are sterically hindered by a single bond or axis, where steric strain or other factors create a rotational barrier that is high enough to allow for the isolation of individual conformational isomers.

[0038] The stereochemical definitions and conventions used in this specification generally follow those of SP. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York, and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994. Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the prefixes D and L, or R and S, are used to indicate the absolute configuration of the molecule around its chiral center(s). The prefixes d and l, or (+) and (-), are used to indicate the sign of the rotation of plane-polarized light by the compound, with (-) or l meaning that the compound is levorotatory. Compounds with the prefix (+) or d are dextrorotatory. In a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Furthermore, certain stereoisomers are sometimes called enantiomers, and mixtures of such isomers are often called enantiomer mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or method. The terms "racemic mixture" and "racemate" refer to equimolar mixtures of two enantiomer species that are not optically active.

[0039] The term "tautomer" or "tautomer" refers to structural isomers with different energies that are interconvertible via a low-energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions by proton rearrangement, such as keto-enol and imine-enamine isomerization. Valence tautomers include interconversions by rearrangement of several bonding electrons.

[0040] As used herein, the term “amino protecting group” means a derivative of a group commonly used to block or protect an amino group. The reaction, on the other hand, takes place at another functional group of the compound. Examples of such protecting groups include carbamates, amides, alkyl and aryl groups, as well as imines, and many N-heteroatom derivatives that can be removed to regenerate the desired amine group. Specific amino protecting groups include PMB (p-methoxybenzyl), Boc (tert-butyloxycarbonyl), Fmoc (9-fluorenylmethyloxycarbonyl), Cbz (carbobenzyloxy), Ac (acetyl), trifluoroacetyl, phthalimide, Bn (benzyl), Tr (triphenylmethyl or trityl), benzylidenyl, p-toluenesulfonyl, or DMB (dimethoxybenzyl). In some embodiments, the amino protecting group may be a group used to block or protect an amino group, arising from the cyclization of a group bonded to the amino group, but which can later be removed or substituted. Examples of such groups include 1,3,5-dioxazinane, 2,4-dimethyl-1,3,5-dioxazinane, 2,2,5,5-tetramethyl-1,2,5-azadisyloridine, and isoindoline-1,3-dione. Further exemplary amino protecting groups are described in TWGreene and PGMWuts, "Protecting Groups in Organic Synthesis, Vol. 3." 版 This is found in John Wiley & Sons, Inc., 1999. The term "protected amino" refers to an amino group that has been substituted with one of the above amino protecting groups.

[0041] The term "leaving group" refers to a part of a first reactant that is replaced in a chemical reaction. Examples of leaving groups include, but are not limited to, halogen atoms, alkoxys, and sulfonyloxy groups. Exemplary sulfonyloxy groups include, but are not limited to, alkylsulfonyloxy groups (e.g., methylsulfonyloxy (mesylate group) and trifluoromethylsulfonyloxy (triflate group)) and arylsulfonyloxy groups (e.g., p-toluenesulfonyloxy (tosylate group) and p-nitrosulfonyloxy (nosylate group)).

[0042] The terms “inhibit” and “reduce / decrease,” or any variation thereof, include any measurable reduction / decrease or complete inhibition to achieve the desired result. For example, there may be a reduction of approximately, at most approximately, or at least approximately 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any range of these variables, a decrease in activity compared to normal.

[0043] The terms “antagonist” and “inhibitor” are used interchangeably and refer to compounds that have the ability to inhibit the biological function of a target protein, whether by inhibiting the activity or expression of the protein, such as K-Ras, H-Ras, or N-Ras G12C. Therefore, the terms “antagonist” and “inhibitor” are defined in the context of the biological role of the target protein. Preferred antagonists in this specification are those that specifically interact with the target (e.g., by binding to the target), while compounds that inhibit the biological activity of the target protein by interacting with other elements of the signaling pathway in which the target protein is an element are also specifically included within this definition. Preferred biological activities inhibited by antagonists are those associated with tumor progression, growth, or expansion.

[0044] As used herein, the term “agonist” means a compound that has the ability to initiate or enhance the biological function of a target protein, whether by inhibiting the activity or expression of the target protein. Therefore, the term “agonist” is defined in the context of the biological role of the target polypeptide. Preferred agonists as used herein are those that specifically interact with the target (e.g., by binding to the target), while compounds that initiate or enhance the biological activity of the target polypeptide by interacting with other elements of a signaling pathway in which the target polypeptide is an element are also specifically included within this definition.

[0045] The terms “cancer,” “malignant,” “neoplasm,” and “tumor,” as well as related terms, refer to or describe a physiological condition in mammals typically characterized by the uncontrolled growth of cells. A “tumor” contains one or more cancer cells. Examples of cancer include carcinoma, blastoma, sarcoma, seminoma, gliablastoma, melanoma, leukemia, and myeloid or lymphoid malignancies. More specific examples of such cancers include squamous cell carcinoma (e.g., epithelial squamous cell carcinoma) and lung cancer (such as small cell lung cancer, non-small cell lung cancer ("NSCLC"), lung adenocarcinoma, and lung squamous cell carcinoma). Other cancers include skin cancer, keratoacanthoma, follicular carcinoma, pilocytic cell leukemia, oral cancer, pharyngeal cancer, lip cancer, tongue cancer, mouth cancer, salivary gland cancer, esophageal cancer, laryngeal cancer, hepatocellular carcinoma, gastric cancer, stomach cancer, gastrointestinal cancer, small intestine cancer, colorectal cancer, pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, genitourinary cancer, biliary tract cancer, thyroid cancer, papillary cancer, liver cancer, endometrial cancer, uterine cancer, salivary gland cancer, kidney cancer or renal cancer, prostate cancer, testicular cancer, vulvar cancer, peritoneal cancer, anal cancer, penile cancer, bone cancer, multiple myeloma, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), central nervous system cancer, brain cancer, head and neck cancer, Hodgkin's disease, and associated metastases. Examples of neoplastic disorders include myeloproliferative disorders such as polycythemia vera, myelofibrosis such as essential thrombocytosis and primary myelofibrosis, and chronic myeloid leukemia (CML).

[0046] A “chemotherapeutic agent” is an active substance useful for treating a given disorder, such as cancer or an inflammatory disorder. Examples of chemotherapeutic agents are known in the prior art and include, for example, those disclosed in U.S. Patent Application Publication No. 2010 / 0048557, which is incorporated herein by reference. Furthermore, chemotherapeutic agents include pharmaceutically acceptable salts, acids, or derivatives of any of the chemotherapeutic agents, and combinations of two or more thereof.

[0047] The term “treatment” refers to a clinical intervention designed to alter the natural course of a patient or cell being treated during the course of a clinical lesion. Desired effects of treatment include a reduction in the rate of disease progression, recovery or mitigation of the disease state, and remission or improvement of the prognosis. A patient’s “treatment” is considered successful if one or more of the breast cancer-related symptoms described herein are reduced or eliminated, including, for example, a decrease (or destruction) of cancer cell proliferation, a reduction in disease-related symptoms, an improvement in the quality of life of the person affected by the disease, a reduction in the dose of other medications required to treat the disease, and / or an extension of the patient’s survival.

[0048] The term “delaying the progression” of a disease means delaying, preventing, slowing, stabilizing, and / or postponing the development of breast cancer as described herein. This delay may be of varying lengths depending on the patient’s cancer history and / or the patient being treated. As will be apparent to those skilled in the art, a sufficient or significant delay may substantially encompass prevention in that the patient does not develop cancer.

[0049] "Effective dose" means the minimum amount required to produce a measurable improvement or prevention of breast cancer as described herein. The effective dose as described herein may vary depending on factors such as the patient's disease status, age, sex and weight, and the ability of the active ingredient to induce the desired response in the patient. The effective dose is also the amount in which the therapeutically beneficial effect outweighs any toxic or adverse effects of the treatment. Beneficial or desired outcomes include the elimination or reduction of risk, reduction of severity, delay in the onset of the disease (including the biochemical, histological and / or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes that appear during the onset of the disease), reduction of one or more symptoms caused by the disease, improvement in the quality of life of the person with the disease, reduction in the dose of other drugs required to treat the disease, enhancement of the effect of another drug by targeting, etc., delay in disease progression, and / or extension of survival. In some embodiments, an effective dose of a drug may be effective in reducing the number of cancer cells; shrinking tumor size; inhibiting (i.e., delaying or stopping) cancer cell invasion into peripheral organs; inhibiting (i.e., delaying or stopping) tumor metastasis; inhibiting (i.e., delaying or stopping) tumor growth; and / or alleviating one or more symptoms associated with the disorder. An effective dose may be administered in one or more doses. An effective dose of a drug, compound, pharmaceutical composition or combination therapy described herein may be sufficient to achieve a therapeutic action directly or indirectly. As clinically understood, an effective dose of a drug, compound or pharmaceutical composition may or may not be achieved in combination with another drug, compound or pharmaceutical composition or combination therapy. Thus, “effective dose” may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered an effective dose if, in combination with one or more other agents, the desired result is obtained or achieved.

[0050] It is conceivable that any limitation discussed in relation to one embodiment of the present invention may also apply to any other embodiment of the present invention. Furthermore, any compound or composition of the present invention may be used in any manner of the present invention, and any compound or composition of the present invention may be produced or utilized using any manner of the present invention.

[0051] Throughout this application, the term “approximately” is used to indicate that the value includes the standard deviation of errors in the device or method used to measure that value.

[0052] Equation (I): Methods for synthesizing the compound TIFF0007925146000003.tif52170, or its solvates, tautomers, stereoisomers, atropisomers, or salts thereof, are provided herein.

[0053] In one embodiment, formula (I): TIFF0007925146000004.tif52170(in the formula, 1 and X 3 These are, independently, hydrogen or halogen; R 1 is hydrogen or PG 1 and; Each R 2 These are, independently, halogen, cyano, and unsubstituted C 1-6 Alkyl, unsubstituted C 1-6 Cyanoalkyl or unsubstituted C 1-6 It is a haloalkyl; R 3 is hydrogen, halogen, R 3A - Substitute or non-substitute C 1-3 Alkyl, R 3A - Substitute or non-substitute C 1-3 Haloalkyl, or R 3A - Substituted or unsubstituted cyclopropyl; R 3A This includes halogen, OH, CN, and unsubstituted C. 1-3 Alkyl or unsubstituted C 1-3 It is a haloalkyl; R 4 R 4A - Substitute or non-substitute C 1-3 It is a haloalkyl; R 4A is unsubstituted C 1-3 It is alkyl; n is either 1 or 2; Each PG is an amino protecting group independently; PG 1 A method for synthesizing compounds of an amino protecting group, or their solvates, tautomers, stereoisomers, atropisomers, or salts thereof, This method, (a) Equation (II) TIFF0007925146000005.tif43170(in the formula, 2 Compounds of (which are halogens) By contacting it with an organomagnesium compound, thereby formula (IIa): The process of forming the compound TIFF0007925146000006.tif47170(IIa), (b) The compound of formula (IIa) from step (a) is transferred to a continuous stirring tank reactor (CSTR) containing a zinc compound, thereby producing formula (IIb) TIFF0007925146000007.tif45170(wherein m is 0, 1 or 2; p is 1, 2, or 3; X 2 The process of synthesizing compounds (which are halogens or opioids); (c) Compound (IIb) of step (b) is given by formula (III) TIFF0007925146000008.tif27170(in the formula, 4 Compounds of halogens, A method (P1) is provided for synthesizing a compound of formula (I), or a solvate, tautomer, stereoisomer, atropisomer, or salt thereof, comprising the step of contacting a transition metal catalyst precursor and a chiral ligand to synthesize the compound of formula (I).

[0054] In one embodiment, X1 is a halogen. In such one embodiment, X 1 is F or Cl. In one embodiment, X 3 is a halogen. In such one embodiment, X 3 is F or Cl. In another embodiment, X 1 and X 3 These are all halogens independently. In such one embodiment, X 1 is F, and X 3 is a halogen. In such one embodiment, X 3 is Cl, X 1 is a halogen. In such one embodiment, X 1 is F, and X 3 It is Cl.

[0055] In one embodiment, the compound of formula (IIb) is: TIFF0007925146000009.tif48170(in the formula, 1 , X 2 , X 3 , R 1 , R 2 (and n are as described herein).

[0056] In one embodiment, X 2 is Cl, Br, or OPiv. In one embodiment, X 2 is Cl or Br. In one embodiment, X 2 is Br. In one embodiment, X 2 It is Cl.

[0057] In one embodiment of the compound of formula (IIb), X 2 is Cl, m is 1 or 2, and p is 1. In one embodiment of the compound of formula (IIb), X 2 is Cl, m is 1 or 2, and p is 2. In one embodiment of the compound of formula (IIb), X 2 is Cl, m is 1 or 2, and p is 3.

[0058] In one embodiment of the compound of formula (IIb), X2 is Cl, m is 0, and p is 2. In one embodiment of the compound of formula (IIb), X 2 is Cl, m is 0, and p is 3.

[0059] In one embodiment of the compound of formula (IIb), X 2 is Cl, m is 1, and p is 1. In one embodiment of the compound of formula (IIb), X 2 is Cl, m is 1, and p is 2. In one embodiment of the compound of formula (IIb), X 2 is Cl, m is 1, and p is 3.

[0060] In one embodiment of the compound of formula (IIb), X 2 is Cl, m is 2, and p is 1. In one embodiment of the compound of formula (IIb), X 2 is Cl, m is 2, and p is 2. In one embodiment of the compound of formula (IIb), X 2 is Cl, m is 2, and p is 3.

[0061] In one embodiment of the compound of formula (IIb), X 2 is Br, m is 1 or 2, and p is 1. In one embodiment of the compound of formula (IIb), X 2 is Br, m is 1 or 2, and p is 2. In one embodiment of the compound of formula (IIb), X 2 is Br, m is 1 or 2, and p is 3.

[0062] In one embodiment of the compound of formula (IIb), X 2 is Br, m is 0, and p is 2. In one embodiment of the compound of formula (IIb), X 2 is Br, m is 0, and p is 3.

[0063] In one embodiment of the compound of formula (IIb), X 2 is Br, m is 1, and p is 1. In one embodiment of the compound of formula (IIb), X 2is Br, m is 1, and p is 2. In one embodiment of the compound of formula (IIb), X 2 is Cl, m is 1, and p is 3.

[0064] In one embodiment of the compound of formula (IIb), X 2 is Br, m is 2, and p is 1. In one embodiment of the compound of formula (IIb), X 2 is Br, m is 2, and p is 2. In one embodiment of the compound of formula (IIb), X 2 is Br, m is 2, and p is 3.

[0065] In one embodiment of the compound of formula (IIb), X 2 is OPiv, m is 1 or 2, and p is 1. In one embodiment of the compound of formula (IIb), X 2 is OPiv, m is 1 or 2, and p is 2. In one embodiment of the compound of formula (IIb), X 2 is OPiv, m is 1 or 2, and p is 3.

[0066] In one embodiment of the compound of formula (IIb), X 2 is OPiv, m is 0, and p is 2. In one embodiment of the compound of formula (IIb), X 2 is OPiv, m is 0, and p is 3.

[0067] In one embodiment of the compound of formula (IIb), X 2 is OPiv, m is 1, and p is 1. In one embodiment of the compound of formula (IIb), X 2 is OPiv, m is 1, and p is 2. In one embodiment of the compound of formula (IIb), X 2 is OPiv, m is 1, and p is 3.

[0068] In one embodiment of the compound of formula (IIb), X 2 is OPiv, m is 2, and p is 1. In one embodiment of the compound of formula (IIb), X 2is OPiv, m is 2, and p is 2. In one embodiment of the compound of formula (IIb), X 2 is OPiv, m is 2, and p is 3.

[0069] In another embodiment, the compound of formula (IIb) has the formula: TIFF0007925146000010.tif43170 wherein p and m are as defined herein. In one embodiment, when the zinc compound comprises Cl, X 2 is Cl. In one embodiment, when the zinc compound comprises OPiv, X 2 is OPiv. In one embodiment, compound 2b is X 2 , a mixture of compounds differing in one or more of m and p. In one embodiment, compound 2b comprises at least two or three different species. In one such embodiment, such species are interconvertible.

[0070] In one embodiment, R 1 is PG 1 , and PG 1 is as defined herein. In one such embodiment, PG 1 is Ac (acetyl), trifluoroacetyl, Bn (benzyl), Tr (triphenylmethyl or trityl), benzylidenyl, p-toluenesulfonyl, PMB (p-methoxybenzyl), Boc (tert-butyloxycarbonyl), Fmoc (9-fluorenylmethyloxycarbonyl) or Cbz (carbobenzyloxy). In one embodiment, PG 1 is an acid-labile amino protecting group. In one embodiment, PG 1 is tert-butyloxycarbonyl (Boc).

[0071] In one embodiment, each R 2 is independently halogen or cyano. In another such embodiment, each R 2 is independently unsubstituted C 1-6 alkyl, unsubstituted C 1-6 cyanoalkyl, or unsubstituted C 1-6It is a haloalkyl. In one embodiment, each R 2 These are independent, non-substituted C 1-3 It is alkyl. In such one embodiment, each R 2 R is independently methyl or ethyl. In one embodiment, each R 2 R is independently methyl. In such one embodiment, R 2 R is methyl and n is 1. In such one embodiment, each R 2 is independently methyl or ethyl, and n is 1. In another embodiment, each R 2 Independently, non-substituted C 1-3 Cyanoalkyl or unsubstituted C 1-3 In one such embodiment, unsubstituted C 1-6 Cyanoalkyl or unsubstituted C 1-6 The haloalkyl CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, CH2CF3, CH2CN, or CH2CH2CN. In one such embodiment, unsubstituted C 1-6 Cyanoalkyl or unsubstituted C 1-6 The haloalkyl CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, CH2CF3, CH2CN, or CH2CH2CN, where n is 1. In one embodiment, R 2 is unsubstituted C 1-6 Alkyl or unsubstituted C 1-6 It is a cyanoalkyl compound.

[0072] In one embodiment, R 3 is hydrogen, halogen, or R 3A - Substitute or non-substitute C 1-3 It is alkyl. In one embodiment, R 3 R 3A - Substitute or non-substitute C 1-3 Haloalkyl, or R 3A It is a substituted or unsubstituted cyclopropyl. In one embodiment, R 3 is hydrogen or R 3A Substitute or non-substitute C 1-3 It is alkyl. In one embodiment, R 3 is hydrogen or methyl. In one embodiment, R3 is methyl. In one embodiment, R 3 is hydrogen, R 4 In another embodiment, R 3 is methyl, and R 4 This is CF3.

[0073] In one embodiment, R 4 These are CF3, CHF2, or CH2F.

[0074] In one embodiment, each PG is independently a protecting group selected from the group consisting of Ac (acetyl), trifluoroacetyl, phthalimide, Bn (benzyl), Tr (triphenylmethyl or trityl), benzylidenyl, p-toluenesulfonyl, DMB (dimethoxybenzyl), PMB (p-methoxybenzyl), Boc (tert-butyloxycarbonyl), Fmoc (9-fluorenylmethyloxycarbonyl), or Cbz (carbobenzyloxy). In one embodiment, each PG is the same. If each PG is the same, in such an embodiment, each PG is PMB.

[0075] The organomagnesium compound may be, for example, a Grignard reagent. In one embodiment, the organomagnesium compound is selected from the group consisting of isopropylmagnesium chloride, isopropylmagnesium bromide, isopropylmagnesium iodide, isopropylmagnesium chloride lithium chloride complex, sec-butylmagnesium chloride, lithium tri-n-butylmagnesiate, lithium triisopropylmagnesiate, and lithium (isopropyl)(di-n-butyl)magnesiate. In one embodiment, the organomagnesium compound of the method described herein is i-PrMgCl·LiCl.

[0076] In the methods described herein, the Zn compound is selected from the group consisting of ZnCl2, ZnBr2, ZnI2, Zn(TFA)2, Zn(OAc)2, and Zn(OPiv)2, including LiCl or LiTFA salts. In one embodiment, the Zn compound is ZnCl2, ZnBr2, or ZnI2. In one embodiment, the Zn compound is ZnCl2, ZnBr2, or Zn(OPiv)2. In one embodiment, the Zn compound is ZnCl2 or Zn(OPiv)2. In one embodiment, the Zn compound is ZnCl2. In one embodiment, the Zn compound is ZnCl2·LiCl. In one embodiment, the Zn compound is Zn(OPiv)2. In one embodiment, the Zn compound is a salt, which is Zn(OPiv)2·LiCl.

[0077] In one embodiment, the transition metal catalyst precursor is Pd or Ni catalyst precursor. In one embodiment, the transition metal catalyst precursor is Pd or Ni catalyst precursor, such as Pd(OAc)2, PdCl2, PdCl2(MeCN)2, Pd(benzonitrile)2Cl 2、 The following are selected from the group consisting of Pd(dba)2, Pd2(dba)3, Pd(PPh3)4, Pd(PCy3)2, Pd(PtBu3)2, Pd(TFA)2, [Pd(allyl)Cl]2, [Pd(cinnamyl)Cl]2, [PdCl(clotyl)]2, PdCl(η5-cyclopentadienyl), [(η3-allyl)(η5-cyclopentadienyl)palladium(II)], [Ni(η5-cyclopentadienyl)(allyl)], [bis(1,5-cyclooctadiene)nickel(0)], NiCl2, NiBr2, Ni(OAc)2, and nickel(II) acetylacetonate.

[0078] In one such embodiment of the method described herein (P1), the Pd catalyst precursor is a Pd catalyst precursor. In one embodiment, the Pd catalyst precursor is Pd(OAc)2, PdCl2, PdCl2(MeCN)2, Pd(dba)2, Pd2(dba)3, Pd(TFA)2, [Pd(allyl)Cl]2, [Pd(cinnamyl)Cl]2, [PdCl(clotyl)]2, PdCl(η5-cyclopentadienyl), or [(η3-allyl)(η5-cyclopentadienyl)palladium(II)]. In another embodiment of the method described herein (P1), the Pd catalyst precursor is Pd(OAc)2 or PdCl2. In another embodiment of the method described herein (P1), the Pd catalyst precursor is [PdCl(clotyl)]2, PdCl(η5-cyclopentadienyl), PdCl2(MeCN)2, Pd(dba)2, Pd2(dba)3, or Pd(TFA)2. In another embodiment of the method described herein (P1), the Pd catalyst precursor is [Pd(allyl)Cl]2, [Pd(cinnamyl)Cl]2, or (η3-allyl)(η5-cyclopentadienyl)palladium(II). In one embodiment, the Pd catalyst precursor is [Pd(allyl)Cl]2 or [Pd(cinnamyl)Cl]2. In one embodiment, the Pd catalyst precursor is [Pd(cinnamyl)Cl]2.

[0079] In another embodiment of the method described herein (P1), the Pd or Ni catalyst precursor is a Ni catalyst precursor. In one embodiment, the Ni catalyst precursor is NiCp(allyl), bis(1,5-cyclooctadiene)nickel(0), NiCl2, NiBr2, Ni(OAc)2, or nickel(II) acetylacetonate. In one embodiment, the Ni catalyst precursor is NiCl2, NiBr2, or Ni(OAc)2. In another embodiment, the Ni catalyst precursor is NiCp(allyl), bis(1,5-cyclooctadiene)nickel(0), or nickel(II) acetylacetonate.

[0080] In one embodiment of the method described herein (P1), a Pd precursor described herein and a chiral ligand described herein are brought into contact to form a Pd-ligand complex in situ. In another embodiment, a Pd precursor described herein may be treated with a chiral ligand described herein to form a Pd ligand complex, which may be isolated before use in the method described herein. In one embodiment, the Pd catalyst precursor is [Pd(cinnamyl)Cl]2, and the zinc compound is ZnCl2 or Zn(OPiv)2.

[0081] In one embodiment, the chiral ligand is given by formula: TIFF0007925146000011.tif47170 (in the formula, Y is O or NR 7 and; R 7 and R 8 Independently, non-substituted C 1-6 It is a compound (which is alkyl).

[0082] In one embodiment of the compound of formula L1, R 7 and R 8 In such one embodiment, R 7 and R 8 These are, independently, methyl, ethyl, or phenyl. In one embodiment, R 7 and R 8 Each of these is methyl (e.g., (R,R)-chiraphite). In one embodiment, R 7 and R 8 Each of these is ethyl. In one embodiment of the method described herein, the chiral ligand is (R,R)-chiraphite.

[0083] In one embodiment of the method described herein (P1), step (a) is carried out using a pre-cooled solution containing, respectively, the compound of formula (II) as described herein and the organomagnesium compound as described herein. In such an embodiment, the pre-cooling temperature is about -30°C to about 20°C; -30°C to about 15°C; -30°C to about 10°C; -30°C to about 5°C; -30°C to about 0°C; -25°C to about 20°C; -25°C to about 15°C; -25°C to about 10°C; -25°C to about 5°C; -25°C to about 0°C; -20°C to about 20°C; -20°C to about 15°C; -20°C to about 10°C; -20°C to about 5°C; or -20°C to about 0°C. In one embodiment, the compound of formula (IIb) is isolated (and optionally stored) before step (b). In such one embodiment, the compound of formula (IIa) is stable for at least 1, 2, 3, 4, 5, or 6 weeks.

[0084] In one embodiment, the organomagnesium compounds described herein are approximately 0.9~1.50; 0.9~1.45; 0.9~1.40; 0.9~1.35; 0.9~1.30; 0.9~1.25; 0.9~1.20; 0.9~1.15; 0.9~1.10; 0.9~1.05; 0.9~1.02; 0.9~1.00; 0.95~1.50; 0.95~1.45; 0.95~1.40; 0.95~1.35; 0.95~1.30; 0.9 It exists in molar equivalents of 5~1.25; 0.95~1.20; 0.95~1.15; 0.95~1.10; 0.95~1.08; 0.95~1.05; 0.95~1.03; 0.95~1.02; 0.95~1.01; 0.95~1.00; 1.00~1.15; 1.00~1.12; 1.00~1.11; 1.00~1.10; 1.00~1.09; 1.00~1.08; 1.00~1.07; 1.00~1.06; 1.00~1.05; 1.00~1.03; or 1.00~1.02.

[0085] In one embodiment of the method(P1) described herein, step(b) is carried out at approximately -30°C to approximately 20°C; -30°C to approximately 15°C; -30°C to approximately 10°C; -30°C to approximately 5°C; -30°C to approximately 0°C; -25°C to approximately 20°C; -25°C to approximately 15°C; -25°C to approximately 10°C; -25°C to approximately 5°C; -25°C to approximately 0°C; -20°C to approximately 20°C; -20°C to approximately 15°C; -20°C to approximately 10°C; -20°C to approximately 5°C; or -20°C to approximately 0°C. In one embodiment of the method(P1) described herein, step(b) is carried out at approximately -30°C, -25°C, -20°C, -15°C, -10°C, -5°C, 0°C, 5°C, or 10°C. In one such embodiment, step (b) is carried out at a temperature of approximately -5°C, 0°C, or 5°C.

[0086] In one embodiment, the Zn compounds described herein are present in molar equivalents of approximately 0.3-1.50, 0.3-1.45, 0.3-1.40, 0.3-1.35; 0.3-1.30; 0.3-1.25; 0.3-1.20; 0.3-1.15; 0.3-1.10; 0.3-1.05; 0.3-1.02; 0.3-1.00; 0.3-0.95, 0.3-0.90, 0.3-0.8, 0.3-0.75, or 0.3-0.6 relative to the compound of formula (IIa) in step (a) of method (P1). In one embodiment, the Zn compounds described herein are present in molar equivalents of approximately 0.4-1.50, 0.4-1.45, 0.4-1.40, 0.4-1.35; 0.4-1.30; 0.4-1.25; 0.4-1.20; 0.4-1.15; 0.4-1.10; 0.4-1.05; 0.4-1.02; 0.4-1.00; 0.4-0.95; or 0.4-0.90 relative to the compound of formula (IIa) in step (a) of method (P1).

[0087] In one embodiment, the Zn compounds described herein are present in molar equivalents of approximately 0.6-1.75, 0.6-1.70, 0.6-1.65, 0.6-1.60, 0.6-1.55, 0.6-1.50, 0.6-1.45, 0.6-1.40, 0.6-1.35; 0.6-1.30; 0.6-1.25; 0.6-1.20; 0.6-1.15; 0.6-1.10; 0.6-1.05; 0.6-1.02; 0.6-1.00; 0.6-0.95; or 0.6-0.90 relative to the compound of formula (IIa) in step (a) of method (P1). In one embodiment, the Zn compound described herein is present in a molar equivalent of about 0.3 to 0.6, 0.6 to 0.9, or 0.9 to 1.5 relative to the compound of formula (IIa) in step (a) of method (P1). In one embodiment, the Zn compound described herein is present in a molar equivalent of about 0.3 to 0.6 or 0.6 to 0.9 relative to the compound of formula (IIa) in step (a) of method (P1).

[0088] In one embodiment, the Zn compounds described herein are, relative to the compound of formula (IIa) in step (a) of method (P1), 0.95~1.50;0.95~1.45;0.95~1.40;0.95~1.35;0.95~1.30;0.95~1.25;0.95~1.20;0.95~1.15;0.95~1.10;0.95~1.08;0.95~1.05;0 It exists in molar equivalents of 0.95~1.03; 0.95~1.02; 0.95~1.01; 0.95~1.00; 1.00~1.15; 1.00~1.12; 1.00~1.11; 1.00~1.10; 1.00~1.09; 1.00~1.08; 1.00~1.07; 1.00~1.06; 1.00~1.05; 1.00~1.03; or 1.00~1.02.

[0089] In one embodiment, the Zn compounds described herein are approximately 0.9-1.75, 0.9-1.70, 0.9-1.65, 0.9-1.60, 0.9-1.55, 0.9-1.50, 0.9-1.45, 0.9-1.40, 0.9-1.35; 0.9-1.30; 0.9-1.25; 0.9-1.20; 0.9-1.15; 0.9-1.10; 0.9-1.05; 0.9-1.02; 0.9-1.00; 0.95-1.50; 0.95-1.45; 0.95-1.40; 0.95 It exists in molar equivalents of ~1.35; 0.95~1.30; 0.95~1.25; 0.95~1.20; 0.95~1.15; 0.95~1.10; 0.95~1.08; 0.95~1.05; 0.95~1.03; 0.95~1.02; 0.95~1.01; 0.95~1.00; 1.00~1.15; 1.00~1.12; 1.00~1.11; 1.00~1.10; 1.00~1.09; 1.00~1.08; 1.00~1.07; 1.00~1.06; 1.00~1.05; 1.00~1.03; or 1.00~1.02. In one embodiment, the compound of formula (IIb) is stable in solution for at least 1, 2, 3, 4, 5, or 6 weeks under inert conditions.

[0090] In one embodiment, the compound of formula (III) described herein is used in relation to the compound of formula (IIb) in step (c) of method (P1) by approximately 0.9~1.50; 0.9~1.45; 0.9~1.40; 0.9~1.35; 0.9~1.30; 0.9~1.25; 0.9~1.20; 0.9~1.15; 0.9~1.10; 0.9~1.05; 0.9~1.02; 0.9~1.00; 0.95~1.50; 0.95~1.45; 0.95~1.40; 0.95~1.35; 0.95~1.30; 0.95 It exists in molar equivalents of ~1.25; 0.95~1.20; 0.95~1.15; 0.95~1.10; 0.95~1.08; 0.95~1.05; 0.95~1.03; 0.95~1.02; 0.95~1.01; 0.95~1.00; 1.00~1.15; 1.00~1.12; 1.00~1.11; 1.00~1.10; 1.00~1.09; 1.00~1.08; 1.00~1.07; 1.00~1.06; 1.00~1.05; 1.00~1.03; or 1.00~1.02. In one embodiment,

[0091] In one embodiment, the compound of formula (II) is (a) Under CO2 conditions in the presence of a base, equation (IV) The compound TIFF0007925146000012.tif22170 (V) Cyclization of the compound TIFF0007925146000013.tif23170; (b) Contact the compound of formula (V) with a chlorinating agent, thereby producing formula (Va) To synthesize the compound TIFF0007925146000014.tif24170; (c) In the presence of a base, the compound from step (b) is given formula By bringing the piperazinyl moiety containing TIFF0007925146000015.tif24170 into contact, thereby formula (Vb) To synthesize the compound TIFF0007925146000016.tif42170; and (d) In the presence of a base, the compound from step (c) is brought into contact with a fluorinating agent to synthesize the compound of formula (II). It is prepared by a method (P2) that includes [the specified component].

[0092] In one embodiment of method (P2), the base is 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU). In another embodiment, the base is DBN(1,5-diazabicyclo[4.3.0]nona-5-ene), MTBD(7-methyl-1,5,7-triazabicyclo(4.4.0)deca-5-ene) or TBD(1,5,7-triazabicyclo(4.4.0)deca-5-ene). In yet another embodiment, the base is a carbonate, such as Na2CO3, K2CO3, or Cs2CO3, and the solvent for the reaction is water, and the reaction also works in water as a solvent.

[0093] In one embodiment of method (P2), the chlorinating agent in step (b) is POCl3, PCl3, PCl5, or SOCl2. In such an embodiment, the chlorinating agent in step (b) is POCl3.

[0094] In one embodiment of method (P2), the base in step (c) is N-ethylmorpholine (NEM), triethylamine (TEA), tri(n-propyl)amine (TPA), N,N-diisopropylethylamine (DIPEA), N-methylmorpholine (NMM), N-methylimidazole (NMI), DBU, tri(n-butyl)amine, pyridine, 2,6-lutidine, or 2,4,6-collidine. In one embodiment, the base in step (c) is DIPEA. In one embodiment, the base in step (c) is N-ethylmorpholine (NEM), triethylamine (TEA), or tri(n-propyl)amine (TPA). In one embodiment, the base in step (c) is N-methylmorpholine (NMM), N-methylimidazole (NMI), DBU, or tri(n-butyl)amine. In one embodiment, the base in step (c) is pyridine, 2,6-lutidine, or 2,4,6-collidine.

[0095] In another embodiment of method (P2), the fluorinating agent in step (d) is KF. In another embodiment of method (P2), the fluorinating agent in step (d) is CsF or NaF. In another embodiment of method (P2), the base is DABCO (1,4-diazabicyclo[2.2.2]octane). In such an embodiment, DABCO is present in a catalytic amount. In such another embodiment, step (d) of method (P2) further comprises MsOH as an additive.

[0096] Compound (IV) of method (P2) can be synthesized according to the method (P3) described herein, and the compound of formula (IV) is (a) Equation (IVa) The compound TIFF0007925146000017.tif18170 was brought into contact with i-PrMgCl, thereby producing formula (IVb). To synthesize the compound TIFF0007925146000018.tif19170; (b) The compound from step (a) is brought into contact with hydroxylamine (NH2OH), thereby producing formula (IVc) To synthesize the compound TIFF0007925146000019.tif27170; (c) Contact the compound from step (b) with a base and a dehydrating agent described herein in acetonitrile, thereby producing formula (IVd) The process of synthesizing the compound TIFF0007925146000020.tif19170; (d) The compound from step (c) is brought into contact with ammonia, thereby producing formula (IVe) To synthesize the compound TIFF0007925146000021.tif19170; and (e) The compound of step (d) is prepared by a method (P3) which includes the step of contacting the compound of step (d) with a halogenating agent to synthesize the compound of formula (IV). In one embodiment, the halogenating agent is a chlorinating agent, and X 3 It is Cl.

[0097] In one embodiment of method (P3), the base in step (c) is a tertiary amine. In one embodiment, the base in step (c) is N-ethylmorpholine (NEM), triethylamine (TEA), tri(n-propyl)amine (TPA), N,N-diisopropylethylamine (DIPEA), N-methylmorpholine (NMM), N-methylimidazole (NMI), 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU), or tri(n-butyl)amine. In such an embodiment, the base is triethylamine. In another embodiment of method (P3), the base in step (c) is pyridine or DBU. In another embodiment of method (P3), the base in step (c) may also potentially be an inorganic base, such as K2CO3, NaOAc, NaOH, or KOH.

[0098] In one embodiment of method (P3), the dehydrating agent in step (c) is trifluoroacetic anhydride (TFAA), acetic anhydride (Ac2O), methanesulfonic anhydride (Ms2O), p-toluenesulfonic anhydride (Ts2O), trifluoromethanesulfonic anhydride (Tf2O), propanephosphonic anhydride (T3P), methanesulfonyl chloride (MsCl), toluenesulfonyl chloride (TsCl), SOCl2, POCl3, or carbonyl diimidazole (CDI). In such an embodiment, the dehydrating agent is trifluoroacetic anhydride (TFAA) or acetic anhydride (Ac2O). In one such embodiment, the dehydrating agent in step (c) is trifluoroacetic anhydride (TFAA), acetic anhydride (Ac2O), methanesulfonic anhydride (Ms2O), p-toluenesulfonic anhydride (Ts2O), trifluoromethanesulfonic anhydride (Tf2O), or propanephosphonic anhydride (T3P). In another such embodiment, the dehydrating agent in step (c) is trifluoroacetic anhydride (TFAA), acetic anhydride (Ac2O), or trifluoromethanesulfonic anhydride (Tf2O). In yet another such embodiment, the dehydrating agent is trifluoroacetic anhydride (TFAA).

[0099] In one embodiment of method (P3), the halogenating agent in step (e) is 1,3-dichloro-5,5-dimethylhydantoin (DCDMH or DCH), SO2Cl2, TCCA (trichloroisocyanuric acid), N-chlorosaccharin, or N-chlorosuccinimide (NCS). In such an embodiment, the halogenating agent is NCS. In one embodiment of method (P3), step (e) further comprises a quasi-stoichiometric amount of acid. In such a real form, the acid is HCl.

[0100] In one embodiment of method (P1), the compound of formula (III) is (a)X 6 Equation (VIa) where Cl or I When the compound TIFF0007925146000022.tif22170 is brought into contact with a halogenating agent, formula (VIb) To form the compound TIFF0007925146000023.tif22170; (b) Brominate the compound of formula (VIb) to obtain formula (VI) To form the compound TIFF0007925146000024.tif19170; and (c) Contacting the compound of formula (VI) with a compound having formula NH(PG)2 to produce the compound of formula (III). It is prepared by a method including (P4).

[0101] In one embodiment of method (P4), each X 6 They are the same. In one embodiment of method (P4), each X 6 is Cl. In one embodiment of method (P4), the halogenating agent in step (a) is SF4 in HF.

[0102] In one embodiment of method (P4), the bromination in step (b) is carried out using HBr in an acid. In such one embodiment, the acid is acetic acid. In another such embodiment, the acid is trifluoroacetic acid.

[0103] In one embodiment of the method described herein, the compound of formula (III) is: It has TIFF0007925146000025.tif25170.

[0104] In such one embodiment, the compound of formula (III) is: It has TIFF0007925146000026.tif23170(3). Compound (3) can be synthesized according to the methods described herein (e.g., method (P4)).

[0105] In such one embodiment of method (P1), the compound of formula (III) has formula (3), and the compound of formula (3) is (a) Equation (6a) The compound TIFF0007925146000027.tif19170 was brought into contact with SF4 and HF, thereby producing formula (6b). To synthesize the compound TIFF0007925146000028.tif19170; (b) The compound of formula (6b) is brought into contact with HBr in AcOH to obtain formula (6) To form the compound TIFF0007925146000029.tif18170; (c) Synthesize the compound of formula (3) by contacting the compound of formula (6) with NH(PMB)2, triethylamine, and N-butylpyrrolidinone (NBP). It is synthesized by method (P6), which includes [the specified element].

[0106] In one embodiment, the compound of formula (I) is: It has TIFF0007925146000030.tif99170.

[0107] In one embodiment of the compounds of formulas (Ia), (Ib), (Ic), and (Id), R 2 is methyl. In one embodiment of the compounds of formulas (Ia), (Ib), (Ic), and (Id), X 3 X is a halo. In such one embodiment, X 3 It is Cl.

[0108] In one embodiment, the compound of formula (I) is: TIFF0007925146000031.tif47170(Ie) (where X 3 (has a halo).

[0109] In one embodiment, the compound of formula (I) is: It has TIFF0007925146000032.tif47170(11).

[0110] Furthermore, equation (2): A method for synthesizing the compound TIFF0007925146000033.tif38170(2) is provided herein.

[0111] In one embodiment, a method (P5) for synthesizing the compound of formula (2) is provided, and this method is (a) Equation (4a) The compound TIFF0007925146000034.tif18170 was contacted with i-PrMgCl, and then with hydroxylamine (NH2OH), thereby producing formula (4c). The process of synthesizing the compound TIFF0007925146000035.tif27170; (b) The compound of formula (4c) is contacted with TFAA and triethylamine in acetonitrile, and then with ammonia, thereby producing formula (4e). The process of synthesizing the compound TIFF0007925146000036.tif19170; (c) The compound (4e) is brought into contact with a chlorinating agent, thereby producing formula (4) The process of synthesizing the compound TIFF0007925146000037.tif19170; (d) In the presence of 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU), the compound of (4) is brought into contact with CO2, thereby producing formula (5). The process of synthesizing the compound TIFF0007925146000038.tif23170; (e) The compound of formula (5) is contacted with POCl3 and DIPEA, and then contacted with tert-butyl(S)-3-methylpiperazine-1-carboxylate, thereby producing formula (5b). The process of synthesizing the compound TIFF0007925146000039.tif38170; and (f) The process includes contacting the compound of (5b) with KF, 1,4-diazabicyclo[2.2.2]octane (DABCO), and MsOH to form the compound of formula (2).

[0112] In one embodiment, step (a) of method (P5) is carried out in DMF as the solvent.

[0113] In another embodiment, method (P1) is formula (G) according to method (P7): TIFF0007925146000040.tif52170(in formula:X A teeth, Further comprising synthesizing compounds (selected from the group consisting of TIFF0007925146000041.tif233170), or tautomers, solvates, or pharmaceutically acceptable salts thereof, This delicious, (a) A compound of formula (I) synthesized as described herein, or its solvate, tautomer, stereoisomer, atropisomer, or salt thereof, in the presence of a base and an activator, X A To bring a part containing the compound into contact with the compound of formula (G1) and thereby synthesize the compound of formula (G1); TIFF0007925146000042.tif53170(b) From the compound of formula (G1), a PG group and, if applicable, R 1 To remove and (c) In the presence of an activator, the compound from step (b) is R 5 is non-substituted C 1-6 Formula (VII) is alkyl or phenyl The process includes contacting the compound of TIFF0007925146000043.tif17170 with a base, thereby producing a compound of formula (G), or its tautomers, stereoisomers, atropisomers, or pharmaceutically acceptable salts. In one embodiment, R 5 is phenyl. In one embodiment, R 5 These are methyl, ethyl, propyl, or t-butyl.

[0114] In one embodiment, the compound of formula (VII) is of formula It has TIFF0007925146000044.tif18170(7).

[0115] In one embodiment, X A teeth, The filename is TIFF0007925146000045.tif131170.

[0116] In one embodiment, X A teeth, The filename is TIFF0007925146000046.tif97170.

[0117] In one embodiment, X A teeth This is TIFF0007925146000047.tif14170. In such one embodiment, X A teeth The filename is TIFF0007925146000048.tif13170.

[0118] Formula (1): A method (P8) for synthesizing the compound TIFF0007925146000049.tif52170 or a pharmaceutically acceptable salt thereof, wherein this method is (a) Formula (2) A pre-cooled solution containing the compound TIFF0007925146000050.tif40170 or a salt thereof is brought into contact with a pre-cooled solution containing i-PrMgCl·LiCl using a flow rate that results in a residence time of approximately 15-150 seconds for Mg-Br exchange, thereby producing equation (2a); Steps for synthesizing the compound TIFF0007925146000051.tif43170(2a); (b) Transfer the compound of formula (2a) from step (a) to a continuous stirred tank reactor (CSTR) containing a pre-cooled solution of ZnCl2 or Zn(OPiv)2, and maintain a constant residence time of approximately 3 to 7 minutes at approximately -20°C to 20°C to produce formula (2b); The process of synthesizing the compound TIFF0007925146000052.tif42170(2b); (c) Compound of formula (2b) with NaTFA and formula (3) The step of contacting the compound TIFF0007925146000053.tif19170; (d) The mixture or salt of step (c) is brought into contact with a Pd or Ni catalyst precursor and a chiral ligand, thereby producing formula (11) A process for synthesizing the compound TIFF0007925146000054.tif48170, or its solvate or salt. (e) A compound of formula (11), or its solvate or salt, of formula HO-X A (In the formula, X A is an expression The compound (containing TIFF0007925146000055.tif13170) is brought into contact with a base, thereby formula (1b); A process for synthesizing the compound TIFF0007925146000056.tif43170, or its solvate or pharmaceutically acceptable salt, (f) Contact the compound of formula (1b) with MsOH in acid, thereby producing formula (1a); A process for synthesizing the compound TIFF0007925146000057.tif39170, or its solvate or pharmaceutically acceptable salt; and (g) The compound of formula (1a) or its solvate or a pharmaceutically acceptable salt thereof, in the presence of an activator To bring TIFF0007925146000058.tif18170 into contact with a base, thereby producing the compound of formula (1) or a pharmaceutically acceptable salt thereof. Methods including (P8) are further provided herein.

[0119] In one embodiment, the residence time of step (a) of method (P8) is approximately 15-45 seconds, 15-60 seconds, 15-90 seconds, 15-100 seconds, or 15-120 seconds. In another embodiment, the residence time of step (a) of method (P8) is approximately 30-45 seconds, 30-60 seconds, 30-90 seconds, 30-120 seconds, or 30-150 seconds. In yet another embodiment, the residence time of step (a) of method (P8) is approximately 15-45 seconds or 60-90 seconds. In one embodiment, the residence time of step (a) of method (P8) is approximately 15-45 seconds. In another embodiment, the residence time of step (a) of method (P8) is approximately 60-90 seconds. In yet another embodiment, the residence time of step (a) of method (P8) is approximately 60-150 seconds. In one embodiment, the residence time of step (a) of method (P8) is approximately 90 to 150 seconds.

[0120] In one embodiment of the method (P8), the pre-cooled solution of ZnCl2 or Zn(OPiv)2 further comprises LiCl. In such an embodiment, the pre-cooled solution comprises Zn(OPiv)2·LiCl.

[0121] In one embodiment of the method (P8), compound 2b is as described herein. In such an embodiment, p is 1, m is 1, and X 2 is a halogen (e.g., Cl or Br). In another such embodiment, compound 2b is X 2 , is a mixture in which one or more of m and p are different. In one embodiment, compound 2b contains at least two or three different species. In such an embodiment, the number of species depends on the number of equivalents of zinc compound used. In such an embodiment, more equivalents of zinc compound compared to compound 2a result in more species. In such an embodiment, the species can be interconverted without affecting the kinetics of the subsequent reaction. In one embodiment, the species is X as Br only when m is 1. 2 Includes.

[0122] In one embodiment, the compound of formula (2) is prepared according to a method (P5) as described herein. In one embodiment, the compound of formula (3) is prepared according to a method (P6).

[0123] Formula (1): A method (P8) for synthesizing the compound TIFF0007925146000059.tif52170 or a pharmaceutically acceptable salt thereof, wherein this method is (a) Formula (2) A step of bringing a pre-cooled solution containing the compound TIFF0007925146000060.tif40170 or a salt thereof into contact with a pre-cooled solution containing i-PrMgCl·LiCl at a flow rate that results in a residence time of approximately 15-150 seconds for Mg-Br exchange; (b) Transferring the mixture from step (a) to a continuous stirring tank reactor (CSTR) containing a pre-cooled solution of ZnCl2 or Zn(OPiv)2, and maintaining a constant residence time of about 3 to 7 minutes at about -20°C to 20°C; (c) The mixture from step (b) contains NaTFA and formula (3) The step of contacting the compound TIFF0007925146000061.tif19170; (d) The mixture or salt of step (c) is brought into contact with a Pd or Ni catalyst precursor and a chiral ligand, thereby producing formula (11) A process for synthesizing the compound TIFF0007925146000062.tif48170, or its solvate or salt. (e) A compound of formula (11), or its solvate or salt, of formula HO-X A (In the formula, X A is an expression The compound (containing TIFF0007925146000063.tif13170) is brought into contact with a base, thereby formula (1b); A process for synthesizing the compound TIFF0007925146000064.tif43170, or its solvate or pharmaceutically acceptable salt, (f) Contact the compound of formula (1b) with MsOH in acid, thereby producing formula (1a); A process for synthesizing the compound TIFF0007925146000065.tif39170, or its solvate or pharmaceutically acceptable salt; and (g) The compound of formula (1a) or its solvate or a pharmaceutically acceptable salt thereof, in the presence of an activator A method (P9) is further provided herein, comprising the step of contacting TIFF0007925146000066.tif18170, followed by contact with a base, thereby producing a compound of formula (1) or a pharmaceutically acceptable salt thereof.

[0124] In one embodiment, the residence time of step (a) of method (P9) is approximately 15-45 seconds, 15-60 seconds, 15-90 seconds, 15-100 seconds, or 15-120 seconds. In another embodiment, the residence time of step (a) of method (P9) is approximately 30-45 seconds, 30-60 seconds, 30-90 seconds, 30-120 seconds, or 30-150 seconds. In yet another embodiment, the residence time of step (a) of method (P9) is approximately 15-45 seconds or 60-90 seconds. In one embodiment, the residence time of step (a) of method (P9) is approximately 15-45 seconds. In another embodiment, the residence time of step (a) of method (P9) is approximately 60-90 seconds. In yet another embodiment, the residence time of step (a) of method (P9) is approximately 60-150 seconds. In one embodiment, the residence time of step (a) of method (P9) is approximately 90 to 150 seconds.

[0125] In one embodiment of method (P9), the pre-cooled solution of ZnCl2 or Zn(OPiv)2 further comprises LiCl. In such an embodiment, the pre-cooled solution comprises Zn(OPiv)2·LiCl. In such an embodiment, the pre-cooled solution comprises Zn(OPiv)2·LiCl, and the residence time of step (a) of method (P9) is about 60–90 seconds or about 60–150 seconds.

[0126] In one embodiment, the compound of formula (2) is prepared according to a method (P5) as described herein. In one embodiment, the compound of formula (3) is prepared according to a method (P6).

[0127] As used herein, “continuous flow” refers to a chemical reaction carried out in a continuously flowing flow rather than in batch production. In such cases, a pump moves the fluid into the flow system, the fluids come into contact with each other, and the reaction takes place. In some embodiments, a microreactor is used. In some embodiments, a tubular or plug-in flow reactor (PFR) is used. In some other embodiments, a continuous stirred-tank reactor (CSTR) is used. In such embodiments, the reactor may be cooled before the movement of the agents or reactants within it. The continuous flow reactions described herein eliminate the need for the low temperatures (e.g., -78°C) typically used for such reactions. Eliminating the need for such low temperatures increases reaction efficiency and allows for more robust scaling up to commercial-scale product yields. Furthermore, the continuous flow reactions described herein improve the robustness and controllability of the reaction conditions. The methods described herein result in better purity of synthesized intermediates and compounds and reduce the time required for the reaction and the production of compound (1).

[0128] Cancer treatment methods Compound 1 or a pharmaceutically acceptable salt thereof is KRas G12C An effective dose (e.g., the dose described herein) may be administered to a patient to treat a mutation-mediated cancer. In one such embodiment, the cancer is a solid tumor (e.g., lung cancer, CRC, or pancreatic cancer). The methods described herein should also be understood to include treatment with a pharmaceutical composition as described herein, comprising compound 1 as described herein or a pharmaceutically acceptable salt thereof.

[0129] In one embodiment, KRas G12C A method for treating mutation-mediated lung cancer in a patient having such cancer, comprising administering an effective amount of compound 1 or a pharmaceutically acceptable salt thereof to the patient having the cancer.

[0130] In such embodiments, lung cancer is KRas G12CIn one embodiment, the lung cancer is non-small cell lung cancer (NSCLC) with a mutation. In another embodiment, the lung cancer is adenocarcinoma, squamous cell lung cancer, or large cell lung cancer. In one such embodiment, the cancer is lung adenocarcinoma. In another such embodiment, the lung cancer is small cell lung cancer. In yet another embodiment, the lung cancer is small cell lung carcinoma. In yet another embodiment, the lung cancer is an adenoma, carcinoid tumor, or undifferentiated carcinoma. The lung cancer may be stage I or stage II lung cancer. In one embodiment, the lung cancer is stage III or stage IV lung cancer.

[0131] The use of compound 1 or a pharmaceutically acceptable salt thereof for the treatment of lung cancer as described herein (UL1) is further provided herein.

[0132] KRas G12C A method for treating mutation-mediated colorectal cancer in a patient having such cancer is also provided herein, comprising administering an effective amount of compound 1 or a pharmaceutically acceptable salt thereof to the patient having the cancer.

[0133] The use of compound 1 or a pharmaceutically acceptable salt thereof (UC1) described herein for treating colorectal cancer described herein is further provided herein.

[0134] KRas G12C A method for treating mutation-mediated pancreatic cancer in a patient having such cancer is further provided herein, comprising administering an effective amount of Compound 1 described herein or a pharmaceutically acceptable salt thereof to the patient having the cancer.

[0135] The use of compound 1 or a pharmaceutically acceptable salt thereof (UP1) described herein for the treatment of pancreatic cancer as described herein is further provided herein.

[0136] KRas G12CFurther provided herein are methods for treating tumor-independent cancers, including mutations, in patients having such cancers. In one such embodiment, the method involves KRas G12C A method for treating tumor-independent cancers including mutations, (a) KRas in samples taken from patients diagnosed with suspected cancer G12C Determining the absence or presence of a mutation; and (b) Treatment of tumor-independent cancer in a patient having such cancer by administering to the patient an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof as described herein.

[0137] The use of compound 1 or a pharmaceutically acceptable salt thereof (UA1) described herein for treating tumor-independent cancers described herein is further provided herein.

[0138] In one embodiment of the methods and uses described herein, compound 1 or a pharmaceutically acceptable salt thereof is administered as a fixed-dose QD. In one embodiment, administration is oral (PO), and compound 1 or a pharmaceutically acceptable salt thereof is formulated as a tablet or capsule. In one embodiment, compound 1 or a pharmaceutically acceptable salt thereof is administered in doses of 5 mg to 600 mg, 5 mg to 500 mg, 5 mg to 400 mg, 5 mg to 300 mg, 5 mg to 250 mg, 5 mg to 200 mg, 5 mg to 150 mg, 5 mg to 100 mg, 5 mg to 50 mg, 5 mg to 25 mg, 25 mg to 600 mg, 25 mg to 500 mg, 25 mg to 400 mg, and 25 mg. QD is administered in amounts of mg-300mg, 25mg-250mg, 25mg-200mg, 25mg-150mg, 25mg-100mg, 25mg-50mg, 50mg-600mg, 50mg-500mg, 50mg-400mg, 50mg-300mg, 50mg-250mg, 50mg-200mg, 50mg-150mg, or 50mg-100mg. In another embodiment, compound 1 or a pharmaceutically acceptable volatile salt thereof is administered in amounts of approximately 5mg, 25mg, 50mg, 100mg, 150mg, 200mg, 250mg, 300mg, 400mg, or 500mg.

[0139] Embodiments: Several exemplary embodiments of the present invention are provided below.

[0140] Embodiment 1. Formula (I); TIFF0007925146000067.tif52170(in the formula, 1 and X 3 These are, independently, hydrogen or halogen; R 1 is hydrogen or PG 1 and; Each R 2 These are, independently, halogen, cyano, and unsubstituted C 1-6 Alkyl, unsubstituted C 1-6 Cyanoalkyl or unsubstituted C 1-6 It is a haloalkyl; R 3 is hydrogen, halogen, R 3A - Substitute or non-substitute C 1-3 Alkyl, R 3A - Substitute or non-substitute C 1-3 Haloalkyl, or R 3A - Substituted or unsubstituted cyclopropyl; R 3A This includes halogen, OH, CN, and unsubstituted C. 1-3 Alkyl or unsubstituted C 1-3 It is a haloalkyl; R 4 R 4A - Substitute or non-substitute C 1-3 It is a haloalkyl; R 4A is unsubstituted C 1-3 It is alkyl; n is either 1 or 2; Each PG is an amino protecting group independently; PG 1 A method for synthesizing compounds of an amino protecting group, or their solvates, tautomers, stereoisomers, atropisomers, or salts thereof, This method, (a) Equation (II) TIFF0007925146000068.tif43170(in the formula, 2 Compounds of (which are halogens) By contacting it with an organomagnesium compound, thereby formula (IIa): The process of forming the compound TIFF0007925146000069.tif47170(IIa), (b) The compound of formula (IIa) from step (a) is transferred to a continuous stirring tank reactor (CSTR) containing a zinc compound, thereby producing formula (IIb) TIFF0007925146000070.tif45170(wherein m is 0, 1 or 2; p is 1, 2, or 3; X 2 The process of synthesizing compounds (which are halogens or opioids); (c) Compound (IIb) of step (b) is given by formula (III) TIFF0007925146000071.tif26170(in the formula, 4 Compounds of halogens, A method for synthesizing a compound of formula (I), or a solvate, tautomer, stereoisomer, atropisomer, or salt thereof, comprising the step of contacting a transition metal catalyst precursor and a chiral ligand to synthesize the compound of formula (I).

[0141] Embodiment 2.X 2 The method according to Embodiment 1, wherein is Br, Cl, or OPiv.

[0142] Embodiment 3. The compound of formula (II) is: (a) Under CO2 conditions in the presence of a base, equation (IV) The compound TIFF0007925146000072.tif22170 (V) Cyclization of the compound TIFF0007925146000073.tif24170; (b) Contact the compound of formula (V) with a chlorinating agent, thereby producing formula (Va) To synthesize the compound TIFF0007925146000074.tif24170; (c) In the presence of a base, the compound from step (b) is given formula By bringing the piperazinyl moiety containing TIFF0007925146000075.tif24170 into contact, thereby formula (Vb) To synthesize the compound TIFF0007925146000076.tif42170; and (d) In the presence of a base, the compound from step (c) is brought into contact with a fluorinating agent to synthesize the compound of formula (II). The method according to Embodiment 1 or 2, prepared by a method including (P2).

[0143] Embodiment 4. The method according to Embodiment 3, wherein the base in step (a) is DBU.

[0144] Embodiment 5. The method according to Embodiment 3, wherein the chlorinating agent in step (b) is POCl3.

[0145] Embodiment 6. The method according to Embodiment 3, wherein the base in step (c) is DIPEA.

[0146] Embodiment 7. The method according to Embodiment 3, wherein the fluorinating agent in step (d) is KF.

[0147] Embodiment 8. The compound of formula (IV) is: (a) Equation (IVa) The compound TIFF0007925146000077.tif23170 was brought into contact with i-PrMgCl, thereby producing formula (IVb). To synthesize the compound TIFF0007925146000078.tif19170; (b) The compound from step (a) is brought into contact with hydroxylamine, thereby producing formula (IVc) To synthesize the compound TIFF0007925146000079.tif27170; (c) The compound from step (b) is brought into contact with a base and a dehydrating agent in acetonitrile, thereby producing formula (IVd). To synthesize the compound TIFF0007925146000080.tif19170; (d) contacting the compound of step (c) with ammonia, thereby obtaining the compound of formula (IVe) TIFF0007925146000081.tif19170; and (e) contacting the compound of step (d) with a chlorinating agent, thereby synthesizing the compound of formula (IV) The method according to any one of embodiments 3 to 7, which is prepared by a method (P3) comprising the above steps.

[0148] Embodiment 9. The compound of formula (III) is: (a) wherein X 6 is Cl or I, contacting the compound of formula (VIa) TIFF0007925146000082.tif22170 with a halogenating agent to form the compound of formula (VIb) TIFF0007925146000083.tif22170; TIFF0007925146000083.tif22170; (b) brominating the compound of formula (VIb) to form the compound of formula (VI) TIFF0007925146000084.tif22170; and (c) contacting the compound of formula (VI) with a compound of formula NH(PG)₂, thereby producing the compound of formula (III) The method according to embodiment 1, which is prepared by a method (P4) comprising the above steps.

[0149] Embodiment 10. The method according to embodiment 9, wherein X 6 is Cl.

[0150] Embodiment 11. The method according to embodiment 9, wherein the halogenating agent is SF₄ in HF.

[0151] Embodiment 12. The method according to embodiment 9, wherein the bromination is carried out using HBr in an acid.

[0152] Embodiment 13. The method according to any one of embodiments 9 to 12, wherein the compound of formula (III) has: TIFF0007925146000085.tif24170.

[0153] Embodiment 14.X 1 The method according to any one of embodiments 1 to 13, wherein is a halogen.

[0154] Embodiment 15.X 1 The method according to any one of embodiments 1 to 13, wherein is F or Cl.

[0155] Embodiment 16.X 3 The method according to any one of embodiments 1 to 13, wherein is a halogen.

[0156] Embodiment 17.X 3 The method according to any one of embodiments 1 to 13, wherein is F or Cl.

[0157] Embodiment 18.R 1 PG 1 The method according to any one of Embodiments 1 to 17.

[0158] Embodiment 19.PG 1 The method according to any one of Embodiments 1 to 18, wherein the compound is Ac (acetyl), trifluoroacetyl, Bn (benzyl), Tr (triphenylmethyl or trityl), benzylidenyl, p-toluenesulfonyl, PMB (p-methoxybenzyl), Boc (tert-butyloxycarbonyl), Fmoc (9-fluorenylmethyloxycarbonyl), or Cbz (carbobenzyloxy).

[0159] Embodiment 20.R 1 The method according to any one of Embodiments 1 to 19, wherein is Boc(tert-butyloxycarbonyl).

[0160] Embodiment 21.R 2 is non-substituted C 1-6 Alkyl or unsubstituted C 1-6 The method according to any one of Embodiments 1 to 20, wherein the material is a cyanoalkyl group.

[0161] Embodiment 22.R2 The method according to any one of embodiments 1 to 21, wherein is methyl.

[0162] Embodiment 23. R 3 is hydrogen or R 3A -substituted or unsubstituted C 1-3 The method according to any one of embodiments 1 to 22, which is alkyl.

[0163] Embodiment 24. R 3 The method according to any one of embodiments 1 to 23, wherein is methyl.

[0164] Embodiment 25. R 4 The method according to any one of embodiments 1 to 24, wherein is CF₃, CHF₂, or CH₂F.

[0165] Embodiment 26. R 3 is methyl, and R 4 The method according to any one of embodiments 1 to 25, wherein is CF₃.

[0166] Embodiment 27. The method according to any one of embodiments 1 to 26, wherein each PG is independently a protecting group selected from the group consisting of Ac (acetyl), trifluoroacetyl, phthalimide, Bn (benzyl), Tr (triphenylmethyl or trityl), benzylidenyl, p-toluenesulfonyl, DMB (dimethoxybenzyl), PMB (p-methoxybenzyl), Boc (tert-butyloxycarbonyl), Fmoc (9-fluorenylmethyloxycarbonyl) or Cbz (carbobenzyloxy).

[0167] Embodiment 28. The method according to embodiment 27, wherein each PG is p-methoxybenzyl.

[0168] Embodiment 29. The method according to any one of Embodiments 1 to 28, wherein the organomagnesium compound is selected from the group consisting of isopropylmagnesium chloride, isopropylmagnesium bromide, isopropylmagnesium iodide, isopropylmagnesium chloride lithium chloride complex, sec-butylmagnesium chloride, lithium tri-n-butylmagnesiate, lithium triisopropylmagnesiate, and lithium (isopropyl)(di-n-butyl)magnesiate.

[0169] Embodiment 30. The method according to Embodiment 29, wherein the organomagnesium compound is i-PrMgCl·LiCl.

[0170] Embodiment 31. The method according to any one of Embodiments 1 to 30, wherein the zinc compound is selected from the group consisting of ZnCl2, ZnBr2, ZnI2, Zn(TFA)2, Zn(OAc)2, and Zn(OPiv)2.

[0171] Embodiment 32. The method according to Embodiment 31, wherein the zinc compound is Zn(OPiv)2·LiCl.

[0172] Embodiment 33. The transition metal catalyst precursor is Pd or Ni, such as Pd(OAc)2, PdCl2, PdCl2(MeCN)2, Pd(benzonitrile)2Cl 2、 The method according to any one of Embodiments 1 to 31, selected from the group consisting of Pd(dba)2, Pd2(dba)3, Pd(PPh3)4, Pd(PCy3)2, Pd(PtBu3)2, Pd(TFA)2, [Pd(allyl)Cl]2, [Pd(cinnamyl)Cl]2, [PdCl(clotyl)]2, PdCl(η5-cyclopentadienyl), [(η3-allyl)(η5-cyclopentadienyl)palladium(II)], [Ni(η5-cyclopentadienyl)(allyl)], [bis(1,5-cyclooctadiene)nickel(0)], NiCl2, NiBr2, Ni(OAc)2, and nickel(II) acetylacetonate.

[0173] Embodiment 34. The chiral ligand is TIFF0007925146000086.tif46170(in the formula, Y is O or NR 7 and; R 7 and R 8 Independently, non-substituted C 1-6 The method according to any one of Embodiments 1 to 32, wherein the alkyl is...

[0174] Embodiment 35.R 7 and R 8 The method according to embodiment 33, wherein the same applies.

[0175] Embodiment 36.R 7 and R 8 The method according to Embodiment 33, wherein each is independently methyl, ethyl, or phenyl.

[0176] Embodiment 37. The method according to any one of Embodiments 1 to 33, wherein the chiral ligand is a (R,R)-chiraffite ligand.

[0177] Embodiment 38. The method according to any one of Embodiments 1 to 34, wherein the zinc compound is Zn(OPiv)2·LiCl, the Pd catalyst precursor is [Pd(cinnamyl)Cl]2, and the chiral ligand is a (R,R)-chiraphite ligand.

[0178] Embodiment 39. A compound of formula (I) is, formula: The method according to Embodiment 1, comprising TIFF0007925146000087.tif100170.

[0179] Embodiment 40. A compound of formula (I) is, formula: TIFF0007925146000088.tif48170(in the formula, 3 The method according to Embodiment 1, wherein (is a halo).

[0180] Embodiment 41. A compound of formula (I) is, formula: The method according to Embodiment 1, comprising TIFF0007925146000089.tif46170(11).

[0181] Embodiment 42. Equation (2) A method (P5) for synthesizing the compound TIFF0007925146000090.tif38170(2): This method, (a) Equation (4a) The compound TIFF0007925146000091.tif19170 was contacted with i-PrMgCl, and then with hydroxylamine, thereby producing formula (4c). The process of synthesizing the compound TIFF0007925146000092.tif27170; (b) The compound of formula (4c) is contacted with TFAA and triethylamine in acetonitrile, and then with ammonia, thereby producing formula (4e). The process of synthesizing the compound TIFF0007925146000093.tif19170; (c) The compound (4e) is brought into contact with a chlorinating agent, thereby producing formula (4) The process of synthesizing the compound TIFF0007925146000094.tif19170; (d) The compound from (4) is brought into contact with CO2 in the presence of DBU, thereby producing formula (5). The process of synthesizing the compound TIFF0007925146000095.tif23170; (e) The compound of formula (5) is brought into contact with POCl3 and DIPEA, and then into contact with tert-butyl(S)-3-methylpiperazine-1-carboxylate in DIPEA, thereby producing formula (5b) The process of synthesizing the compound TIFF0007925146000096.tif38170; and (f) A method (P5) comprising the step of contacting the compound of (5b) with KF, DABCO and MsOH to form the compound of formula (2).

[0182] Embodiment 43. The compound of formula (III) is: It has TIFF0007925146000097.tif19170(3); The compound of formula (3) (a) Equation (6a) The compound TIFF0007925146000098.tif19170 was brought into contact with SF4 and HF, thereby producing formula (6b). To synthesize the compound TIFF0007925146000099.tif19170; (b) The compound of formula (6b) is brought into contact with HBr in AcOH to obtain formula (6) To form the compound TIFF0007925146000100.tif19170; (c) Synthesize the compound of formula (III) by contacting the compound of formula (6) with (PMB)2NH, triethylamine, and NBP. The method according to Embodiment 1, synthesized by method (P6), including the following.

[0183] Embodiment 44. Method (P7) by which formula (G) TIFF0007925146000101.tif52170(in formula:X A teeth, The method according to Embodiment 1, further comprising synthesizing a compound (selected from the group consisting of TIFF0007925146000102.tif234170), or a tautomer, stereoisomer, atropisomer, or pharmaceutically acceptable salt thereof, This delicious, (a) A compound of formula (I), or its solvate, tautomer, stereoisomer, atropisomer, or salt thereof, in the presence of a base and an activator, X A To bring a part containing the compound into contact with the compound of formula (G1) and thereby synthesize the compound of formula (G1); TIFF0007925146000103.tif53170(b) From the compound of formula (G1), a PG group and, if applicable, R 1 To remove and (c) The compound from step (b) is converted to formula (VII) in the presence of an activator. To produce a compound of formula (G), or its tautomers, stereoisomers, atropisomers, or pharmaceutically acceptable salts, by contacting the compound of TIFF0007925146000104.tif17170 with a base. Methods that include...

[0184] Embodiment 45. Formula: (1) A method (P8) for synthesizing the compound TIFF0007925146000105.tif52170 or a pharmaceutically acceptable salt thereof, wherein this method is (a) Formula (2) A step of bringing a pre-cooled solution containing the compound TIFF0007925146000106.tif40170 or a salt thereof into contact with a pre-cooled solution containing i-PrMgCl·LiCl using a flow rate that results in a residence time of approximately 15-150 seconds for Mg-Br exchange; (b) Transferring the mixture from step (a) to a continuous stirring tank reactor (CSTR) containing a pre-cooled solution of ZnCl2 or Zn(OPiv)2, and maintaining a constant residence time of about 3 to 7 minutes at about -20°C to 20°C; (c) The mixture from step (b) contains NaTFA and formula (3) The step of contacting the compound TIFF0007925146000107.tif19170; (d) The mixture or salt of step (c) is brought into contact with a Pd or Ni catalyst precursor and a chiral ligand, thereby producing formula (11) A process for synthesizing the compound TIFF0007925146000108.tif48170, or its solvate or salt. (e) A compound of formula (11), or its solvate or salt, of formula HO-X A (In the formula, X A is an expression The compound (containing TIFF0007925146000109.tif13170) is brought into contact with a base, thereby formula (1b); A process for synthesizing the compound TIFF0007925146000110.tif43170, or its solvate or pharmaceutically acceptable salt, (f) Contact the compound of formula (1b) with MsOH in acid, thereby producing formula (1a); A process for synthesizing the compound TIFF0007925146000111.tif39170, or its solvate or pharmaceutically acceptable salt; and (g) The compound of formula (1a) or its solvate or a pharmaceutically acceptable salt thereof, in the presence of an activator A method (P9) comprising the step of contacting TIFF0007925146000112.tif18170, followed by contact with a base, thereby producing compound (1) or a pharmaceutically acceptable salt thereof.

[0185] Embodiment 46. The method according to Embodiment 45, wherein the acid in step (f) is AcOH, trifluoroacetic acid, chlorosulfonic acid, sulfuric acid, HCl, HBr, p-toluenesulfonic acid, or trifluoromethanesulfonic acid.

[0186] Embodiment 47. The method according to Embodiment 45, wherein compound (2) is synthesized according to the method of Embodiment 42.

[0187] Embodiment 48. The method according to Embodiment 45, wherein the pre-cooling solution in step (b) contains Zn(OPiv)2·LiCl.

[0188] Examples: The following examples are presented as illustrations, not as limitations.

[0189] Example 1: Compound 2: tert-butyl(S)-4-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)-3-methylpiperazine-1-carboxylate TIFF0007925146000113.tif111170

[0190] Process 1

[0191] To a solution of 1,4-dibromo-2,3-difluorobenzene (100 g) in THF (200 mL), isopropylmagnesium bromide (1.1 equivalents, 2 M in THF) was added at 0°C over at least 2 hours. After stirring for 30 minutes, DMF (2.0 equivalents) was added over at least 3 hours. After aging for 1 hour (IPC conversion rate > 97.5% a / a), the mixture was added all at once to a chilled solution (0°C) of citric acid (1.2 equivalents) in water (1 Veq.). The mixture was heated to 45°C and the aqueous phase was separated.

[0192] Process 2

[0193] To the organic phase containing 4b, hydroxylamine (1.05 equivalents, 50% wt in water) was added at 45°C for at least 1 hour. After stirring for 30 minutes (IPC conversion > 98.8% - a / a), saline solution (100 mL) was added at the same temperature. The aqueous phase was separated, and the organic phase was concentrated to a total volume of 200 mL by vacuum distillation. Vacuum distillation was then carried out under constant volume by supplying acetic acid (200 mL). After adjusting the solution to 70°C, water (100 mL) was added over at least 30 minutes, and the seed was introduced. The resulting suspension was cooled to 20°C, followed by the addition of water (100 mL). The precipitate was filtered, the filter cake was washed with ACN / water (1:2), and the wet product was dried under reduced pressure to obtain 77.6 g of 4c (89% o.th.). 1 H NMR(400 MHz,DMSO-d6)δ [ppm]=11.89(s,1H),8.19(s,1H),7.56-7.46(m,2H).

[0194] Steps 3 and 4

[0195] Triethylamine (2.2 equivalents) was added to a suspension of 4c (100g) in ACN (200mL) at 20°C. TFAA (1.1 equivalents) was added to the resulting solution over at least 2.5 hours. After the addition was complete, the reaction mixture was stirred for 30 minutes (IPC conversion > 99.8% - a / a). The solution containing 4d was placed in an autoclave, and ammonia (6.8 equivalents, 25% wt in water) was added all at once. The container was sealed and heated at 120°C for at least 6 hours (IPC conversion > 99.0% - a / a). The mixture was adjusted to 90°C, then cooled to 50°C over at least 3 hours, after which water (220mL) was added over at least 1 hour. The suspension was then further cooled to 20°C and aged for 1 hour. The precipitate was filtered, and the filter cake was washed with ACN / water (1:2). The moist product was dried under reduced pressure to obtain 75.6 g of 4e (83% o.th.). 1 H NMR(400 MHz,DMSO-d6)δ [ppm]=7.23(br d,J=8.4 Hz,1H),6.86(dd,J=8.4,6.1 Hz,1H),6.49(bs,2H).

[0196] Step 5:

[0197] To a solution of 4e (100g) in DMF (500mL), HCl (4.0M, 0.25 equivalents) in dioxane was added at 0°C. The solution was cooled to -5°C, and NCS (1.15 equivalents) was added in small increments while maintaining the temperature below 2°C (target -5°C). After the addition was complete, the reaction mixture was stirred at -5°C for 1.5 hours (IPC). Then, n-PrOH (100mL) was added at 0°C to initiate product precipitation (visual IPC of the suspension). After stirring for at least 30 minutes, water (250mL) was added over at 0-5°C for at least 1.5 hours. The suspension was filtered, and the filter cake was washed twice with ACN / water (1:2) (100mL). The wet product was dried in a vacuum oven at 60°C to obtain 102.8g of 4 (89% o.th.). 1 H NMR(400 MHz,DMSO-d6)δ [ppm]=7.67(d,J=2.1 Hz,1H),6.49(bs,2H).

[0198] Another step 5: TIFF0007925146000114.tif35170

[0199] To a solution of 4e (100g) in DMF (700mL), HCl (4.0M, 0.25 equivalents) from dioxane was added at 40°C. The solution was cooled to -5°C, and 1,3-dichloro-5,5-dimethylhydantoin (DCH) (0.60 equivalents) was added in fractions. After the addition was complete, the reaction temperature was adjusted to -10 to 0°C, and the mixture was stirred for a further 1.5 hours. Then, n-PrOH (140mL) and water (350mL) were added at -5 to 5°C to initiate precipitation of the product (visual IPC of the suspension). After stirring at -5 to 5°C for at least 30 minutes, the suspension was filtered, and the filtered cake was washed twice with ACN / water (1:2) (2 × 100mL). The wet product was dried in a vacuum oven at 60°C to obtain 97.5g of 4 (84% o.th.). 1 H NMR(400 MHz,DMSO-d6)δ [ppm]=7.67(d,J=2.1 Hz,1H),6.49(bs,2H).

[0200] Step 6:

[0201] A suspension of 4 (50 g) in DMSO (150 mL) was stirred at 25°C for 15 minutes under a CO2 atmosphere, and then DBU (33.6 g) was added. After stirring at 25°C for 1 hour, the reaction mixture was heated to 70°C and stirred for a further 6 hours (IPC: 4 < 1.0% - a / a). Acetic acid (14.4 g) was then added over at least 1 hour. The mixture was stirred at 70°C for at least 1 hour, and then water (50 mL) was added over at least 2 hours. The resulting suspension was aged at 70°C for 3 hours, then cooled to 25°C over at least 3 hours, and then stirred at that temperature for 1 hour. The suspension was filtered and washed with DMSO / water (3:1, 50 mL) and IPA / water (1:1, 50 mL). The filtered cake was suspended in IPA / water (1:2, 200 mL), stirred for at least 30 minutes, filtered, washed with IPA / water (1:1, 20 mL), and dried in a vacuum oven at 60°C to obtain 55.0 g of 5 (93.5% o.th.). 1 H NMR(400 MHz,DMSO-d6)δ [ppm]=11.64(s,1H),11.60(s,1H),7.84(d,J=1.8 Hz,1H).

[0202] Step 7:

[0203] POCl3 (130.6g) was added to a suspension of 5 (50g) in toluene (300ml) at 25°C. After stirring the mixture for 30 minutes, DIPEA (49.5g) was added over at least 2 hours. The reaction mixture was heated to 35°C and stirred for 30 minutes. Water (0.77g) was added all at once to the resulting solution. The reaction mixture was heated to 70°C and stirred for at least 2 hours, then cooled to 25°C (IPC: 5a > 97.0% - a / a). The reaction mixture was added to water (400mL) over at least 1 hour at 25°C. After the addition was complete, the two-phase mixture was stirred for at least 30 minutes and then filtered through Harborlite 800 (10.3g). The filter cake was rinsed with toluene (25mL) to separate the phases. The organic phase was washed with saline solution (20% w / w in water, 100mL) and reduced to 160mL by vacuum distillation.

[0204] Step 8:

[0205] Subsequently, the solution from step 7 was telescoped and cooled to 25°C, and (S)-1-Boc-3-methylpiperazine (34.1 g) was added in five portions over at least 1 hour. After stirring for 30 minutes, DIPEA (24.2 g) was added within 1 hour, and the resulting suspension was stirred for 30 minutes (IPC: 5a < 0.4% - a / a). The mixture was heated to 40°C and stirred for 1 hour, after which heptane was added over at least 1 hour. After stirring for another 1 hour at 40°C, the suspension was cooled to 25°C over at least 1 hour and aged for at least 2 hours. The suspension was filtered and washed with heptane / toluene (2:1, 50 mL). The filtered cake was suspended in IPA / water (2:1,200 mL), stirred for at least 30 minutes, filtered, washed twice with IPA / water (2:1,100 mL), and dried in a vacuum oven at 45°C to obtain 74.1 g of 5b (88% o.th.). 1 ¹H NMR (400 MHz, chloroform-d) δ [ppm] = 7.69 (d, J=2.0 Hz, 1H), 4.74-4.65 (m, 1H), 4.30-3.85 (m, 3H), 3.68-3.56 (m, 1H), 3.33-2.97 (m, 2H), 1.48 (s, 9H), 1.45 (d, J=6.7 Hz, 3H).

[0206] Step 9:

[0207] Potassium fluoride (3.1g, 1.3 equivalents), DABCO (0.18g, 0.04 equivalents), and methanesulfonic acid (0.11ml, 0.04 equivalents) were added to a stirred suspension of 5b (20g) in DMSO (100mL) at room temperature. The mixture was heated to 65°C and stirred for at least 3 hours. After complete conversion (IPC: 5b < 0.1% - a / a), the mixture was cooled to 50°C and stirred at the same temperature for at least 1 hour (precipitation of the product occurred). The suspension was then cooled to 20°C over at least 3 hours, and 40mL of ACN / water (1:2) was added over at least 1 hour. After stirring for 30 minutes, the precipitate was filtered and washed with 20mL of ACN / water (1:1). The filtered cake was suspended in 60 mL of ACN / water (1:2), stirred for at least 30 minutes, filtered, washed with 20 mL of ACN / water (1:2), and dried in a vacuum oven at 60°C to obtain 17.9 g of 2 (95% o.th.). 1 H NMR(400 MHz,chloroform-d)δ [ppm]=7.76(d,J=1.9 Hz,1H),4.77-4.70(m,1H),4.28-4.22(m,1H),4.18-3.85(m,2H),3.66(dd,J=13.0,3.1 Hz,1H),3.34-3.00(m,2H),1.51(s,9H),1.49(d,J=6.9 Hz,3H).

[0208] Example 2: Continuous flow process of compound (2b) TIFF0007925146000115.tif71170

[0209] Feed preparation

[0210] Feed 1: 273 g of Feed 2 was dissolved in 1166 g of THF to obtain a 1500 mL solution (0.38 M) with a density of 0.96. Feed 2: i-PrMgCl·LiCl was used as a 1.20 M solution in THF (assay corrected for CoA). ZnCl2 was used as a 2.00 M (25.8 wt%) solution in 2-MeTHF (assay corrected for CoA).

[0211] The setup of the system described above is shown in Figure 1.

[0212] All pumps and transfer lines were purged with the corresponding feed liquids. Feed 1, containing compound 2 (1.00 equivalent), and feed 2, containing i-PrMgCl·LiCl (1.05 equivalent), were pre-cooled and continuously fed into a suitable flow reactor at a jacket temperature (JT) of -20 to 0°C. The flow rates of the two feeds were adjusted to achieve a residence time of approximately 30 seconds for the Mg-Br exchange.

[0213] The effluent reaction mixture (compound 2a) was introduced into a continuous stirring tank reactor (CSTR), and a ZnCl2 solution was added simultaneously while maintaining a constant residence time of approximately 5 minutes (1.15 equivalents). The temperature was kept constant at an internal temperature (IT) of -10°C.

[0214] Compound 2b was recovered into a receiving tank using an IT at 0-25°C. Compound 2b was found to be stable for several weeks at -20-25°C.

[0215] Example 2a: TIFF0007925146000116.tif64170

[0216] Feed preparation

[0217] Supply 1: 117 g of supply 2 was dissolved in 783 g of THF to obtain a 959.5 mL solution (0.25 M) with a density of 0.94. Supply 2: i-PrMgCl·LiCl was used as a 1.20 M solution in THF (assay corrected for CoA). Zn(OPiv)2·LiCl was used as a 0.67 M (20.0 wt%) solution in 2-MeTHF (assay corrected for CoA).

[0218] The setup of the system described above is shown in Figure 1.

[0219] All pumps and transfer lines were purged with the corresponding feed liquids. Feed 1, containing compound 2 (1.00 equivalent), and feed 2, containing i-PrMgCl·LiCl (1.15 equivalents), were pre-cooled and continuously fed into a suitable flow reactor at a jacket temperature (JT) of -20 to 0°C. The flow rates of the two feeds were adjusted to achieve a residence time of approximately 45 seconds for the Mg-Br exchange.

[0220] The effluent reaction mixture (compound 2a) was introduced into a continuous stirring tank reactor (CSTR), and a solution of Zn(OPiv)2·LiCl was added simultaneously while maintaining a constant residence time of approximately 5 minutes (0.75 equivalents). The temperature was kept constant at an internal temperature (IT) of -5 to 5°C.

[0221] Compound 2b was recovered into a receiving tank using an intra-tube (IT) at 0-30°C. Compound 2b was found to be stable for several weeks at -20-30°C.

[0222] Five different experiments were conducted in which the equivalent amounts of ZnCl2 and compound 2a were varied from 0.33, 0.50, 0.75, and 1.00-1.50. 19 1F NMR revealed the presence of three different species / compounds at varying levels depending on the amount of ZnCl2 used. 2D NOESY demonstrated that these species can be interconverted without significantly affecting the dynamics of the resulting sedge.

[0223] Des-bromo-compound 2a was found as another compound present in the spectrum, and it originates from a proton quenching reaction caused by residual water in the NMR solvent.

[0224] Example 3: TIFF0007925146000117.tif72170

[0225] Compound 2b in a suspension (32 mmol, 1.1 equivalents) was added to the first reactor under an argon atmosphere at a jacket temperature (TJ) of 10°C. NaTFA (11.8 g, 86.8 mmol, 3.00 equivalents) was added in three portions over 30 minutes. The resulting suspension was heated to an internal temperature (IT) of 50°C over 40 minutes (1°C / min). Compound 3 (14.4 g, 29.0 mmol, 1.00 equivalent) was added to the second reactor under an argon atmosphere, and the reactor was purged with argon for 10 minutes. Degassed THF (26 mL) was added, and after stirring for 10 minutes, a solution was obtained. The solution was transferred to the first reactor via a pump over 5 minutes. Next, a solution of palladium chloride (π-cinnamyl) dimer (75.1 mg, 0.005 equivalents) and (R,R)-quirafite (279.8 mg, 0.011 equivalents) in THF (8.0 mL) was transferred to the first reactor via syringe. The resulting solution was stirred at 50°C in an intestinal temperature (IT) until complete conversion was achieved (typically 15 hours). The reaction mixture was cooled to room temperature (rt).

[0226] In a third reactor under an argon atmosphere at 20°C, a tribasic sodium citrate aqueous solution (20% w / w, 110 g) and toluene (72 mL) were added. The reaction mixture from the second reactor was then transferred to the third reactor over 10 minutes. The two-phase mixture was stirred for 15 minutes, and then the lower aqueous layer was discharged from the third reactor. Next, a tribasic sodium citrate aqueous solution (20% w / w, 110 g) was added to the third reactor. The two-phase mixture was stirred for 15 minutes, and then the lower aqueous layer was discharged from the third reactor. Next, a sodium chloride aqueous solution (10% w / w, 36.5 g) was added to the third reactor. The two-phase mixture was stirred for 15 minutes, and then the lower aqueous layer was discharged from the third reactor. The organic layer was concentrated under reduced pressure at 50°C in a TJ to a volume of approximately 140 mL. Subsequently, the toluene layer was distilled under reduced pressure by a fixed volume (typically 64 g of toluene). The resulting solution was pumped to a fourth reactor under an argon atmosphere over a heated charcoal filter for 45-60 minutes. The third reactor and filter were rinsed with toluene (50 mL) and added to the fourth reactor. The resulting solution was concentrated to a volume of approximately 75 mL under reduced pressure at 50°C (TJ).

[0227] The solution was cooled to 20°C (IT), and n-heptane (14 mL) was added over 10 minutes to sow seeds. The suspension was allowed to mature for 1 hour, and n-heptane (160 mL) was added over 2 hours. The suspension was stirred overnight. The crystals were filtered off, washed with toluene / n-heptane solution (1:1 v / v), and dried under reduced pressure for 1 hour to obtain the unpurified product (24.0 g) as a solid. The unpurified product (24.0 g) was suspended in toluene (100 mL). The suspension was stirred at 50°C (TJ) until a solution was obtained. The solution was concentrated under reduced pressure to a volume of approximately 70 mL. The solution was cooled to 20°C (IT), and n-heptane (9 mL) was added over 10 minutes to sow seeds. The suspension was allowed to mature for 1 hour, and n-heptane (94 mL) was added over 2 hours. The suspension was stirred overnight. The crystals were filtered off, washed with toluene / n-heptane solution (1:1 v / v), and dried under reduced pressure until a constant weight was obtained. The indicated compound was isolated as crystals in 57% yield (15.2 g).

[0228] Example 3a: TIFF0007925146000118.tif67170

[0229] NaTFA (15.5 g, 114.3 mmol, 3.00 equivalents) was charged into the first reactor under an argon atmosphere at a jacket temperature (TJ) of 20°C. A solution of compound 2b in THF and 2-Me-THF (41.9 mmol, 1.10 equivalents, 230 g) was added. The resulting suspension was heated to an internal temperature (IT) of 50°C over 40 minutes (1°C / min). Compound 3 (18.9 g, 38.1 mmol, 1.00 equivalent) was added to the second reactor under an argon atmosphere, and the reactor was purged with argon for 10 minutes. Degassed THF (30.5 g) was added, and after stirring for 10 minutes, a solution was obtained. The solution was transferred to the first reactor over 5 minutes via a pump. The line was rinsed with THF (8.9 g). Next, a solution of palladium chloride (π-cinnamyl) dimer (148 mg, 0.0075 equivalents) and (R,R)-quirafite (551 mg, 0.0165 equivalents) in THF (11.6 g) was transferred to the first reactor via syringe. The resulting solution was stirred at 50°C in an intestinal temperature (IT) until complete conversion was achieved (typically 10 hours). The reaction mixture was cooled to room temperature (rt).

[0230] In a third reactor under an argon atmosphere at 20°C, a tribasic sodium citrate aqueous solution (20% w / w, 150 g) and toluene (82.4 g) were added. The reaction mixture from the second reactor was then transferred to the third reactor over 10 minutes. The two-phase mixture was stirred for 15 minutes, and then the lower aqueous layer was discharged from the third reactor. Next, tribasic sodium citrate aqueous solutions and sodium carbonate aqueous solutions (20% and 5% w / w, 150 g, respectively) were added to the third reactor. The two-phase mixture was stirred for 15 minutes, and then the lower aqueous layer was discharged from the third reactor. Next, a sodium chloride aqueous solution (10% w / w, 50.1 g) was added to the third reactor. The two-phase mixture was stirred for 15 minutes, and then the lower aqueous layer was discharged from the third reactor. The organic layer was concentrated under reduced pressure at 50°C in a TJ to a volume of approximately 140 mL. Subsequently, the toluene layer was distilled under reduced pressure at a constant volume until the desired solvent composition was obtained (typically, 120 g of toluene was replaced). The resulting solution was pumped to a fourth reactor under an argon atmosphere over a heated charcoal filter for 45-60 minutes. The third reactor and filter were rinsed with toluene (32.7 g) and added to the fourth reactor. The resulting solution was concentrated to a volume of approximately 140 mL under reduced pressure at 50°C (TJ).

[0231] The solution was cooled to 20°C, and n-heptane (12.9g) was added over 10 minutes to inoculate. The suspension was allowed to mature for 2 hours, and n-heptane (81g) was added over 2 hours. The suspension was cooled to 0°C over 2 hours and stirred overnight. The crystals were filtered off, washed with toluene / n-heptane solution (1:1 v / v), and dried under reduced pressure until a constant weight was obtained. The marked compound was isolated as crystals in 81.4% yield (28.7g, 88% assay).

[0232] Example 4: Compound 3: 2,6-Dichloro-4-methyl-5-(trifluoromethyl)pyridine

[0233] Step 1: TIFF0007925146000119.tif22170

[0234] 2,6-Dichloro-4-methylpyridine-3-carboxylic acid (1.0 equivalent, 22 kg) was placed in an autoclave at ambient temperature. The autoclave was cooled to -20°C, HF (1.37 relative weight) was added, and then it was further cooled to -78°C, and SF4 (2.5 equivalents) was added. The autoclave was sealed, the reaction mixture was heated to ambient temperature, and then slowly heated to 70-80°C, while being stirred at the same temperature.

[0235] After completion, volatile substances were removed by nitrogen sparging through a scrubber, and then MTBE (5 relative volumes) was added. The reaction mixture was slowly added to ice-cold demineralized water (DM) (5 relative volumes), and then basicized by adding 25% potassium carbonate aqueous solution (approximately 8 relative volumes) at below 10°C (pH 8-9). The reaction mixture was filtered through a Celite pad, washed with MTBE (2.5 relative volumes), and the layers were separated. The aqueous layer was extracted with MTBE (2.5 relative volumes). The combined organic layers were washed with DM water (2 × 2.5 relative volumes) and concentrated at below 30°C. The organic layers were concentrated under reduced pressure at below 30°C, then methanol (1.0 relative volume) was added, and distillation was performed again until a high-concentration slurry was obtained.

[0236] Methanol (4.0 relative volume), followed by activated carbon NoritCG1 (10% w / w), was added to the slurry at 20-30°C and stirred at the same temperature for 60 minutes. The reaction mixture was filtered through a Celite bed and washed with methanol (1.5 relative volume).

[0237] The product was purified as follows: To the MeOH solution of the product, DM water (1.3 relative volume) was added at 20-30°C for 60 minutes (approximately 4.5 ml / min), and then the mixture was stirred at the same temperature for 20 minutes. The pure product was seeded into the above solution and stirred at 20-30°C for 20 minutes. The mixture was slowly cooled to -4 to 2°C over 4 hours. 0.7 + 0.5 + 0.5 relative volumes (i.e., a total of 1.7 relative volumes) of DM water were added at -4 to 2°C for 30 minutes (approximately 6 ml / min) (the solid precipitate was checked after adding the water supernatant sample from each lot), and the mixture was stirred at the same temperature for 3 hours. The resulting solid was filtered and washed with cooled DM water.

[0238] Step 2: 2,6-Dibromo-4-methyl-3-(trifluoromethyl)pyridine TIFF0007925146000120.tif36170

[0239] 2,6-Dichloro-4-methyl-5-(trifluoromethyl)pyridine (5.00 kg, 1.00 ×, 1.00 equivalent) and hydrobromic acid in acetic acid (21.0 kg) were added to a 3000 L-GL reactor. The reactor temperature was adjusted to 110-120°C, and hydrobromic acid in acetic acid (56.8 kg) was added to the reactor in several batches over 20 hours. The mixture was adjusted to 35-45°C. The mixture was stirred, and nitrogen was added at 35-45°C for 1-2 hours. The reactor temperature was adjusted to 110-120°C, and hydrobromic acid in acetic acid (7.0 kg) was added to the reactor. The mixture was adjusted to 35-45°C. Process water (72 kg) and MTBE (43 kg) were added to the reactor at 15-25°C, and stirred for 0.5-1.5 hours. The organic layer was recovered by separation, and the aqueous layer was extracted with MTBE (12 kg). All the organic layers were combined and adjusted to 0-10°C, then the organic layers were washed with 30% NaOH solution (68 kg) to adjust the pH of the mixture to 7-8. Water (10 kg) was added. The organic layer was obtained by separation and washed with 2% NaHCO3 aqueous solution (38 kg) and process water (12 kg). The organic layer was recirculated with molecular sieves (6 kg) through F909 for 3-5 hours to remove water, and after drying, the molecular sieves were washed with MTBE (20 kg). The organic solution was concentrated 2-3 times under reduced pressure below 50°C, and NBP (33 kg) was added. The mixture was concentrated under reduced pressure below 50°C to remove MTBE (<0.2%, sepc.:<2.0%). 6.16 kg of the product (purity 99.0 A%) was obtained as NBP solution in a yield of 90.1%.

[0240] Step 3: 6-Bromo-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine

[0241] A solution of 2,6-dibromo-4-methyl-3-(trifluoromethyl)pyridine NBP (6.16 kg, 1.00 ×, 1.0 equivalent) (assay corrected) was added to the reactor. (PMB)2NH (7.7 kg, 1.5 equivalents) and TEA (4.0 kg, 2.0 equivalents) were added to the reactor by pump. The reactor was adjusted to 70-75°C and stirred for 24 hours, then adjusted to 45-55°C. The reactor was adjusted to 70-75°C and stirred for 8 hours, then adjusted to 45-55°C. The mixture was adjusted to 45-55°C, and a 20% citric acid aqueous solution (68.0 kg) was added to the reactor over 2-3 hours. The mixture was adjusted to 15-25°C for 1-2 hours, the wet cake was isolated by centrifugation, and rinsed with process water (30 kg) and methanol (11 kg) to obtain 7.15 kg of wet cake. After drying under vacuum at 20-30°C for 20 hours, 7.15 kg of unpurified product was obtained.

[0242] Step 4: TIFF0007925146000121.tif23170

[0243] Unpurified 6-bromo-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (7.15 kg, 1.00 ×) and THF (31.15 kg) from step 2 were added to the reactor. The mixture was decolorized with CUNO at 15-25°C until it turned pale yellow. The mixture was concentrated under reduced pressure at less than 40°C to approximately 8.6 L. Methanol (6.79 kg) was added to the reactor. The reactor was adjusted to 45-55°C, and then methanol (23.70 kg) and crystal seed crystals (71.5 g) were added to the reactor and stirred for 1 hour. Methanol (11.30 kg) was added to the reactor over 4 hours and stirred for 0.5 hours. The reactor was adjusted to 0°C over 2 hours, stirred for 18 hours, and the wet cake was isolated by filtration and rinsed sequentially with methanol (11.30 kg) and heptane (4.86 kg). After drying under reduced pressure at 45°C for 18 hours, 6.75 kg of the dry, unpurified product was obtained.

[0244] 6.75 kg of the above-mentioned dried, unpurified product and heptane (20.4 kg) were added to the reactor. The suspension was adjusted to 50°C, stirred at 50°C for 2 hours, then cooled to 0°C over 1 hour, and stirred at 0°C for 16 hours. The suspension was filtered and rinsed with heptane (9.18 kg) to obtain a wet cake. The wet cake was dried in a single cone under reduced pressure at 50-55°C for 26 hours to obtain 6.2 kg of pure product.

[0245] Example 5: TIFF0007925146000122.tif42170

[0246] Solutions of tert-butyl(3S)-4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-2,8-difluoroquinazolin-4-yl]-3-methylpiperazine-1-carboxylate (50.0 g, 53.7 mmol, 1.00 equivalent, 87.3% assay) and [(2S)-1-methylpyrrolidine-2-yl]methanol (7.44 g, 64.6 mmol, 1.20 equivalent) in 2-Me-THF (320 g) were concentrated to 250 mL under reduced pressure (235 mbar). The solutions were cooled to -10°C. Next, sodium tert-pentoxide (NaOt-Am) (24.8 g, 64.6 mmol, 1.30 equivalents, 31% w / w) was added as a solution in toluene over 10-60 minutes. The reaction mixture was stirred at 0°C until complete conversion was achieved (typically 1 hour). The reaction mixture was then quenched with a stirred two-phase mixture of potassium carbonate (200 g, 10% w / w solution), N-acetyl-L-cysteine ​​(24 g, 16% w / w aqueous solution), and 2-Me-THF (107 g), maintaining the internal temperature at 15-30°C. The two-phase mixture was stirred at 25°C for 1-2 hours, and the layers were separated. The organic layer was further washed with potassium carbonate (100 g, 10% w / w aqueous solution), and then concentrated into a 250 mL solution under reduced pressure (235 mbar), cooled to 20-40°C, and filtered by polishing. The filtrate was further concentrated to 175 mL of solution under reduced pressure (235 mbar). 100 g of 1-PrOH was added, and 2-Me-THF was continuously exchanged for 1-PrOH under reduced pressure (150-160 mbar). Then, 100 g of water was added at 50°C, and the solution was seeded at this temperature. The resulting mixture was stirred at this temperature for at least 2 hours, and 100 g of water was added over at least 2 hours. The crystalline slurry was cooled to 20°C over at least 3 hours, and stirred at this temperature for at least 5 hours. The crystals were filtered off, washed with a 1-PrOH / water solution, and dried under reduced pressure until a constant weight was obtained. The marked compound was isolated as crystals in 96% yield (47.5 g). 1H NMR (600 MHz, DMSO-d6) δ ppm 7.82 (s, 1 H), 7.16 (d, J=8.7 Hz, 4 H), 6.87 (br d, J=8.3 Hz, 4 H), 6.82 (s, 1 H), 4.62-4.89 (m, 3 H), 4.56 (br d, J=15.6 Hz, 2 H), 4.39 (dd, J=10.7, 4.7 Hz, 1 H), 4.12-4.25 (m, 1 H), 4.05 (br d, J=13.4 Hz, 1 H), 3.89-4.00 (m, 1 H), 3.76-3.84 (m, 1 H), 3.51-3.67 (m, 1 H), 2.88-3.18 (m, 2 H), 2.55-2.84 (m, 1 H), 2.27-2.43 (m, 5 H), 2.07-2.31 (m, 1 H), 1.85-2.00 (m, 1 H), 1.68 (br dd, J=13.3, 7.9 Hz, 3 H), 1.42 (s, 9 H), 1.28 (br d, J=6.6 Hz, 3 H) ppm. HR-MS (ESI): Calcd. for C47H54ClF4N7O5 907.3811; Found: 907.3808.

[0247] Example 6: TIFF0007925146000123.tif44170

[0248] To a mixture of acetic acid (46.2 g), methanesulfonic acid (52.9 g), and toluene (34.7 g), a solution of tert-butyl(3S)-4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-8-fluoro-2-[[(2S)-1-methylpyrrolidine-2-yl]methoxy]quinazolin-4-yl]-3-methyl-piperazine-1-carboxylate (20.0 g, 22.0 mmol) in toluene (86.7 g) was added at 40°C over at least 15 minutes. The reaction mixture was then heated to 52°C until complete conversion was achieved (typically 2 hours). The reaction mixture was then cooled to 25°C and the layers were separated. The acidic layer was slowly quenched at 40–55°C (typically over 1 hour) with a mixture of sodium hydroxide aqueous solution (211.5 g, 28% w / w), water (80.0 g), and toluene (121.4 g). After quenching was complete, the line was rinsed with acetic acid (10.0 g). The two-phase mixture was heated to 50°C and the layers were separated. The organic layer was washed twice with sodium hydroxide aqueous solution (2 × 90.0 g, 0.1 N solution). The toluene layer was then distilled under reduced pressure at a constant volume (90 mbar; typically, 69 g of toluene was replaced). After polishing and filtration, the obtained toluene solution was concentrated to 94 mL under reduced pressure (90 mbar) and then heated to 60°C. Then, n-heptane (34.6 g) was added over at least 30 minutes, and the solution was seeded at this temperature. The resulting mixture was stirred at this temperature for at least 1 hour, the crystalline slurry was cooled to 0°C for at least 4 hours, and then stirred at this temperature for at least 1 hour. The crystals were filtered off, washed with toluene / n-heptane solution (1:1 v / v), and dried under reduced pressure until a constant weight was obtained. The marked compound was isolated as crystals in 89% yield (11.7 g). 1H NMR(600 MHz, DMSO-d6)δ ppm 7.74(d,J=0.9 Hz,1 H),6.84(s,2 H),6.49(s,1 H),4.54-4.65(m,1 H),4.38(dd,J=10.8,4.6 Hz,1 H),4.14(dd,J=10.7,6.5 Hz,1 H),3.96(br d,J=13.1 Hz,1 H),3.47-3.57(m,1 H),2.89-3.00(m,3 H),2.73-2.82(m,2 H),2.55-2.60(m,1 H),2.32-2.40(m,7 H),2.12-2.20(m,1 1.94 (dd, J=11.9, 7.6 Hz, 1 H), 1.67 (br d, J=8.3 Hz, 3 H), 1.40 (d, J=6.9 Hz, 3 H) ppm. HR-MS (ESI): Calculated value C26H30ClF4N7O 567.2136; Measured value: 567.2141.

[0249] Example 7: TIFF0007925146000124.tif105170

[0250] A solution of 3-(phenylsulfonyl)propionic acid (22.9 g, 106 mmol, 1.33 equivalents) and N-methylmorpholine (13.4 g, 133 mmol, 1.65 equivalents) in acetonitrile (180.7 g) was cooled to -10°C. Pivaloyl chloride (11.8 g, 97.9 mmol, 1.22 equivalents) was added over 30 minutes. The reaction mixture was further stirred at this temperature for 1 hour. Then, a solution of compound 1e (50.0 g, 80.4 mmol, 1.00 equivalent) in acetonitrile (176.9 g) was added to the cold reaction mixture over 1 hour, and the mixture was further stirred at -10°C until complete conversion to the sulfone intermediate was achieved (typically 1 hour). The reaction mixture was heated to 15°C and quenched by adding water (50.4 g), followed by the addition of aqueous sodium hydroxide solution (68.9 g, 483 mmol, 6.0 equivalents, 28% w / w solution). Stirring was continued until complete conversion was achieved (typically 15 hours), the mixture was seeded, and then water (900 g) was added over at least 2 hours. The crystalline slurry was further stirred at this temperature for at least 42 hours, the crystals were filtered off, washed with acetonitrile / water (3:7 v / v) solution, washed with water, and then dried under reduced pressure until a constant weight was obtained. The marked compound was isolated as crystals in 91% yield (45.6 g). 1H NMR(600 MHz,DMSO-d6)δ 7.82(s,1 H),6.73-6.98(m,3 H),6.50(s,1 H),6.10-6.28(m,1 H),5.68-5.81(m,1 H),4.66-4.85(m,1 H),4.32-4.46(m,1 H),4.25(br d,J=13.5 Hz,1 H),4.06-4.21(m,2 H),3.98(br d,J=13.4 Hz,1 H),3.38-3.76(m,2 H),2.91-3.27(m,2 H),2.53-2.68(m,1 H),2.37(br d,J=1.4 Hz,6 H), 2.11-2.26 (m, 1 H), 1.87-2.00 (m, 1 H), 1.56-1.79 (m, 3 H), 1.27 (br dd, J=11.7, 6.7 Hz, 3 H) ppm. HR-MS (ESI): Calculated value C29H32ClF4N7O2 621.2242; Measured value: 621.2257.

[0251] Example 7a TIFF0007925146000125.tif166170

[0252] N-methylmorpholine (10.67 g, 1.65 equivalents) was added at 20°C to a solution of 3-(phenylsulfonyl)propionic acid (18.91 g, 1.38 equivalents) in 2-Me-THF (136.6 g). Pivaloyl chloride (9.56 g, 1.24 equivalents) was administered over 30 minutes while maintaining the internal temperature at -20 to 0°C. The reaction mixture was further stirred at this temperature for 1 hour. Compound 1a (40.0 g, 1.00 equivalent, 90.8% assay) and a solution of N-methylmorpholine (6.47 g, 1.00 equivalent) in 2-Me-THF (136.6 g) were then added to the cold reaction mixture over 1 hour, and the mixture was further stirred at -10°C until complete conversion to the sulfone intermediate was achieved (typically 1 hour). The reaction mixture was filtered and quenched by adding an aqueous sodium hydroxide solution (31.2 g, 3.40 equivalents, 28% w / w solution), and tetrabutylammonium chloride hydrate (3.55 g, 0.19 equivalents) and water (17.2 g) were added at 0-25°C. The reaction mixture was stirred at 20-30°C until complete conversion to compound 1 was achieved (typically 2.5 hours), and an aqueous sodium chloride solution (46.0 g, 20% w / w solution) was added. The layers were separated. The organic layer was successively washed with aqueous sodium bicarbonate solution (82.4 g, 5% w / w) and sodium chloride (82.4 g, 5% w / w). The organic layer was then concentrated to 200 mL under reduced pressure, 2-Me-THF was replaced until the desired water content was achieved, and then cooled to 20°C. After polishing and filtration, the obtained 2-Me-THF solution was concentrated to 100 mL under reduced pressure. 2-BuOH (307.9g) was added at 35-45°C, and adipic acid (10.28g, 1.10 equivalents) was added at the same temperature to obtain a solution. The solution was seeded at 30-40°C and aged at this temperature for a further 1.5 hours. n-heptane (161.4g) was added to the crystal slurry over 30 minutes at 30-40°C. The crystallized mixture was aged at this temperature for at least 2 hours and then cooled to 0°C for at least 6 hours. After aging at at least 0°C for at least 6 hours, the crystals were filtered off, washed with a 2-BuOH / n-heptane solution (1:1 v / v), and dried under reduced pressure until a constant weight was obtained. The marked compound was isolated as crystals in 93% yield (45.2g). 1¹H NMR (600 MHz, DMSO-d₆) δ 7.77 (s, 1H), 6.81 (s, 2H), 6.76 (dd, J=16.8, 10.6 Hz, 1H), 6.45 (s, 1H), 6.18-6.10 (m, 1H), 5.70 (dd, J=10.4, 2.3 Hz, 1H), 4.75-4.66 (m, 1H), 4.38-4.30 (m, 2H), 4.25-3.89 (m, 4H), 3.61 (dq, J=21.3, 12.4, 10.9 Hz, 2H), 3.20 (dd, J=13.4, 3.8 Hz, 1H), 3.00 (td, J=12.6, 3.7 Hz, 1H), 2.91 (ddd, J=9.0, 6.0, 2.8 Hz, 1H), 2.59-2.51 (m, 1H), 2.32 (d, J=6.2 Hz, 6H), 2.15 (td, J=8.6, 7.7, 4.7 Hz, 5H), 1.94-1.85 (m, 1H), 1.61 (dddd, J=20.8, 12.3, 8.0, 4.1 Hz, 3H), 1.45 (h, J=3.4 Hz, 4H), 1.22 (dd, J=12.4, 6.6 Hz, 3H); 13 C{ 1 H, 19 F} NMR (151 MHz, DMSO-d₆) δ 174.9, 165.5, 164.8, 162.2, 161.4, 153.2, 148.8, 147.7, 143.0, 131.1, 128.5, 128.4, 128.3, 128.2, 125.6, 125.3, 121.0, 114.7, 112.2, 110.5, 69.8, 63.9, 57.4, 52.5, 52.4, 49.4, 45.9, 45.2, 44.9, 44.3, 42.0, 41.7, 40.6, 34.0, 29.1, 24.6, 23.1, 20.3, 15.9, 15.3; 19 ¹⁹F NMR (565 MHz, DMSO-d₆) δ -53.5, -125.9.

[0253] Example 7b: TIFF0007925146000126.tif166170

[0254] Pivaloyl chloride (9.56 g, 1.24 equivalents) was added at -20 to 0°C to a solution of 3-(phenylsulfonyl)propionic acid (18.91 g, 1.38 equivalents) in 2-Me-THF (136.6 g). N-methylmorpholine (10.67 g, 1.65 equivalents) was slowly added while maintaining the internal temperature at -20 to 0°C. The reaction mixture was further stirred at this temperature for 1 hour. Compound 1a (40.0 g, 1.00 equivalent, 90.8% assay) and a solution of N-methylmorpholine (6.47 g, 1.00 equivalent) in 2-Me-THF (136.6 g) were then added to the cold reaction mixture over 1 hour, and the mixture was further stirred at -10°C until complete conversion to the sulfone intermediate was achieved (typically 1 hour). The reaction mixture was filtered and quenched by adding an aqueous sodium hydroxide solution (31.2 g, 3.40 equivalents, 28% w / w solution), and tetrabutylammonium chloride hydrate (18.2 g, 0.94 equivalents) and water (17.2 g) were added at 0-25°C. The reaction mixture was stirred at 20-30°C until complete conversion to compound 1 was achieved (typically 1 hour), and an aqueous sodium chloride solution (46.0 g, 20% w / w solution) was added. The layers were separated. The organic layer was successively washed with aqueous sodium bicarbonate solution (82.4 g, 5% w / w) and sodium chloride (82.4 g, 5% w / w). The organic layer was then concentrated to a volume of 200 mL under reduced pressure, and 2-Me-THF was replaced until the desired water content was achieved, and then cooled to 20°C. After polishing and filtration, the obtained 2-Me-THF solution was concentrated to a volume of 100 mL under reduced pressure. 2-BuOH (307.9g) was added at 35-45°C, and adipic acid (10.28g, 1.10 equivalents) was added at the same temperature to obtain a solution. The solution was seeded at 30-40°C and aged at this temperature for a further 1.5 hours. n-heptane (161.4g) was added to the crystal slurry at 30-40°C over 30 minutes. The crystallized mixture was aged at this temperature for at least 2 hours and then cooled to 0°C for at least 6 hours. After aging at at least 0°C for at least 6 hours, the crystals were filtered off, washed with a 2-BuOH / n-heptane solution (1:1 v / v), and dried under reduced pressure until a constant weight was obtained. The marked compound was isolated as crystals in 85% yield (42.7g). 1¹H NMR (600 MHz, DMSO-d₆) δ 7.77 (s, 1H), 6.81 (s, 2H), 6.76 (dd, J=16.8, 10.6 Hz, 1H), 6.45 (s, 1H), 6.18-6.10 (m, 1H), 5.70 (dd, J=10.4, 2.3 Hz, 1H), 4.75-4.66 (m, 1H), 4.38-4.30 (m, 2H), 4.25-3.89 (m, 4H), 3.61 (dq, J=21.3, 12.4, 10.9 Hz, 2H), 3.20 (dd, J=13.4, 3.8 Hz, 1H), 3.00 (td, J=12.6, 3.7 Hz, 1H), 2.91 (ddd, J=9.0, 6.0, 2.8 Hz, 1H), 2.59-2.51 (m, 1H), 2.32 (d, J=6.2 Hz, 6H), 2.15 (td, J=8.6, 7.7, 4.7 Hz, 5H), 1.94-1.85 (m, 1H), 1.61 (dddd, J=20.8, 12.3, 8.0, 4.1 Hz, 3H), 1.45 (h, J=3.4 Hz, 4H), 1.22 (dd, J=12.4, 6.6 Hz, 3H); 13 C{ 1 H, 19 F} NMR (151 MHz, DMSO-d₆) δ 174.9, 165.5, 164.8, 162.2, 161.4, 153.2, 148.8, 147.7, 143.0, 131.1, 128.5, 128.4, 128.3, 128.2, 125.6, 125.3, 121.0, 114.7, 112.2, 110.5, 69.8, 63.9, 57.4, 52.5, 52.4, 49.4, 45.9, 45.2, 44.9, 44.3, 42.0, 41.7, 40.6, 34.0, 29.1, 24.6, 23.1, 20.3, 15.9, 15.3; 19 ¹⁹F NMR (565 MHz, DMSO-d₆) δ -53.5, -125.9.

[0255] Example 8: TIFF0007925146000127.tif50170

[0256] Compound 1 (2.32 kg, 3.53 mol) and polished and filtered 2-butanone (17.42 L, 7.5 L / kg) were combined in a 25 L reactor equipped with an activated nitrogen line, overhead stirring, and a temperature probe. Adipic acid (0.46 kg, 3.17 mol, 0.9 equivalents) and polished and filtered 2-butanone (1.16 L, 0.5 L / kg) were added to a separate 5 L glass bottle. The reactor was then heated to 50°C ± 10°C, and once the desired internal temperature target of >45°C was reached, the adipic acid slurry in 2-butanone was introduced into the reactor by vacuum. Compound B seed crystals (0.02 kg, 1 wt%) were added to a 5 L glass bottle, followed by polished and filtered butanone (2.32 L, 1.0 L / kg). The slurry was again introduced into the reactor by vacuum. Finally, a 5L glass bottle was rinsed with polished and filtered 2-butanone (1.16L, 0.5L / kg) and then placed into the reactor under vacuum. The contents of the reactor were allowed to mature for at least 1 hour, cooled to 0°C over at least 2 hours, and then matured overnight (15 hours) at 0°C. The contents were transferred to a pre-cooled filter dryer at 0°C. In parallel, polished and filtered 2-butanone (9.29L, 4.0L / kg) was added to the reactor at 0°C and stirred for 30 minutes. The material in the filter dryer was then filtered, and the resulting cake was washed with cooled 2-butanone. After drying for at least 8 hours using vacuum and nitrogen sweeping, the contents of the filter dryer were discharged to obtain compound 1 adipate (2.137kg, 77%) as a solid. 1¹H NMR (600 MHz, DMSO-d₆) δ 7.77 (s, 1H), 6.81 (s, 2H), 6.76 (dd, J=16.8, 10.6 Hz, 1H), 6.45 (s, 1H), 6.18-6.10 (m, 1H), 5.70 (dd, J=10.4, 2.3 Hz, 1H), 4.75-4.66 (m, 1H), 4.38-4.30 (m, 2H), 4.25-3.89 (m, 4H), 3.61 (dq, J=21.3, 12.4, 10.9 Hz, 2H), 3.20 (dd, J=13.4, 3.8 Hz, 1H), 3.00 (td, J=12.6, 3.7 Hz, 1H), 2.91 (ddd, J=9.0, 6.0, 2.8 Hz, 1H), 2.59-2.51 (m, 1H), 2.32 (d, J=6.2 Hz, 6H), 2.15 (td, J=8.6, 7.7, 4.7 Hz, 5H), 1.94-1.85 (m, 1H), 1.61 (dddd, J=20.8, 12.3, 8.0, 4.1 Hz, 3H), 1.45 (h, J=3.4 Hz, 4H), 1.22 (dd, J=12.4, 6.6 Hz, 3H); 13 ¹³C 1 H, 19 ¹⁹F} NMR (151 MHz, DMSO-d₆) δ 174.9, 165.5, 164.8, 162.2, 161.4, 153.2, 148.8, 147.7, 143.0, 131.1, 128.5, 128.4, 128.3, 128.2, 125.6, 125.3, 121.0, 114.7, 112.2, 110.5, 69.8, 63.9, 57.4, 52.5, 52.4, 49.4, 45.9, 45.2, 44.9, 44.3, 42.0, 41.7, 40.6, 34.0, 29.1, 24.6, 23.1, 20.3, 15.9, 15.3; 19 ¹⁹F NMR (565 MHz, DMSO-d₆) δ -53.5, -125.9.

[0257] Example 9: TIFF0007925146000128.tif54170

[0258] Compound 1 (1 molar equivalent) and adipic acid (1 molar equivalent) were suspended in 2-butanol and 2-methyltetrahydrofuran and heated to approximately 70°C to dissolve. The polished and filtered solution was cooled to approximately 25°C. For sowing, jet-milled compound B material was used. The sowing material compound 1 adipate was suspended in 2-butanol / n-heptane. This suspension was used to sow the solution at approximately 25°C. The sowing apparatus was rinsed with n-heptane and then added to the sowing suspension. n-heptane was added within 15-30 minutes at approximately 25°C. The suspension was stirred at approximately 25°C for approximately 3 hours. The suspension was cooled to approximately 0°C and stirred for at least 5 hours. The solid was isolated by solid / liquid separation and rinsed with a mixture of 2-butanol / n-heptane, followed by n-heptane. The solid was dried under reduced pressure at approximately 40°C to obtain a powder in yield of 88-95%.

[0259] In a separate procedure, compound 1 (1 molar equivalent) and adipic acid (1 molar equivalent or excess) were suspended in 2-butanol and 2-methyltetrahydrofuran and heated to approximately 70°C to dissolve. The polished and filtered solution was cooled to the seeding temperature (approximately 25°C). For seeding, the adipic salt of compound 1 was used either without pretreatment or after using an impact mill, jet mill, or wet mill. The adipic acid of compound 1, which was the seeding material, was suspended in a solvent (n-heptane, or a 2-butanol / n-heptane mixture, or 2-butanol). This suspension was used for seeding at the seeding temperature. The seeding apparatus was rinsed with the solvent (n-heptane, or a 2-butanol / n-heptane mixture, or 2-butanol) and then added to the seeding suspension. n-heptane was added at the seeding temperature or lower (typically at approximately 25°C) for approximately 15-30 minutes. The suspension was stirred at the n-heptane addition temperature for at least 3 hours. The suspension was cooled to approximately 0°C and stirred for at least 5 hours. The solid was isolated by solid / liquid separation and rinsed with a mixture of 2-butanol / n-heptane, followed by n-heptane. The solid was dried under reduced pressure at approximately 40°C to obtain a powder in yield of 88–95%.

[0260] Example 10:

[0261] The adipic acid salt of compound 1 was heated to approximately 67°C and dissolved in 2-butanol and 2-methyltetrahydrofuran. The solution, after polishing and filtering, was cooled to the sowing temperature (approximately 45°C). For sowing, wet-ground adipic acid compound 1 was used. The adipic acid salt of compound 1 was wet-ground in a solvent (n-heptane or a 2-butanol / n-heptane mixture). This suspension was used for sowing at the sowing temperature. The sowing apparatus was rinsed with a solvent (n-heptane or a 2-butanol / n-heptane mixture, respectively) and then added to the sowing suspension. Pre-cooled n-heptane (approximately 0°C) was added over a period of approximately 15-30 minutes. The thus cooled suspension was stirred at a temperature of approximately 25°C for at least 3 hours. The suspension was cooled to approximately 0°C and stirred for at least 2 hours. The solid was isolated by solid / liquid separation and rinsed with n-heptane or a mixture of 2-butanol / n-heptane, followed by n-heptane. The solid was dried under reduced pressure at approximately 40°C, with a yield of 85–95%.

[0262] All technical and scientific terms used in this specification have the same meaning. While efforts have been made to ensure accuracy regarding the numerical values ​​used (e.g., quantities, temperatures, etc.), some experimental error and deviation should be taken into consideration.

[0263] Throughout this specification and the claims, the words “comprise,” “comprises,” and “comprising” are used in a non-exclusive sense unless otherwise required by context. Embodiments described herein are understood to include embodiments that “consist of” and / or “essentially consist of.”

[0264] Where a range of values ​​is provided, unless the context explicitly indicates otherwise, it should be understood that the upper and lower limits of the range and any other stated or intervening values ​​within that stated range, up to one-tenth of the lower limit unit, are included herein. The upper and lower limits of these smaller ranges, which can be independently included in smaller ranges, are also included herein, subject to the limits specifically excluded in the stated range. If a stated range includes one or both of the limits, the range excluding one or both of those limits is also included herein.

[0265] Many modifications and other embodiments of the inventions described herein will be conceivable to those skilled in the art, benefiting from the teachings presented in the preceding description and the accompanying drawings. Therefore, it should be understood that the invention should not be limited to the specific embodiments disclosed, and modifications and other embodiments are intended to be included within the scope of the appended claims. Certain terms are used herein, but these are used in a general and descriptive sense only and are not intended to be limiting.

Claims

1. formula; (In the formula, X １ and X ３ These are, independently, F or Cl; R １ is hydrogen or PG １ And PG １ This is an amino protecting group comprising Ac (acetyl), trifluoroacetyl, Bn (benzyl), Tr (triphenylmethyl or trityl), benzylidenyl, p-toluenesulfonyl, PMB (p-methoxybenzyl), Boc (tert-butyloxycarbonyl), Fmoc (9-fluorenylmethyloxycarbonyl), or Cbz (carbobenzyloxy); Each R ２ is independently unsubstituted C １－６ alkyl, unsubstituted C １－６ cyanoalkyl, or unsubstituted C １－６ haloalkyl; R ３ is hydrogen, halogen, or unsubstituted C １－３ It is alkyl; R ４ CF ３ CHF ２ , or CH ２ It is F; n is either 1 or 2; Each PG is an amino protecting group selected from the group consisting of Ac (acetyl), trifluoroacetyl, phthalimide, Bn (benzyl), Tr (triphenylmethyl or trityl), benzylidenyl, p-toluenesulfonyl, DMB (dimethoxybenzyl), PMB (p-methoxybenzyl), Boc (tert-butyloxycarbonyl), Fmoc (9-fluorenylmethyloxycarbonyl), or Cbz (carbobenzyloxy), and each PG is the same. A method for synthesizing a compound, or its solvate, stereoisomer, or salt thereof, The method described above is (a) Equation (II) (In the formula, X ２ Compounds of (which are halogens) By contacting an organomagnesium compound containing isopropylmagnesium chloride, isopropylmagnesium bromide, isopropylmagnesium iodide, isopropylmagnesium chloride lithium chloride complex, sec-butylmagnesium chloride, lithium tri-n-butylmagnesiate, lithium triisopropylmagnesiate, or lithium (isopropyl)(di-n-butyl)magnesiate, thereby formula (IIa): The step of forming compound (IIa), (b) The compound of formula (IIa) in step (a) is ZnCl, which includes its LiCl or LiTFA salt. ２ , ZnBr ２ , ZnI ２ Zn (TFA) ２ , Zn (OAc) ２ , or Zn (OPiv) ２ A zinc compound containing - is transferred to a continuous stirred tank reactor (CSTR) at approximately 20°C to 20°C, thereby producing formula (IIb). (wherein m is 0, 1, or 2; p is 1, 2, or 3; X ２ The process involves synthesizing compounds of halogens (or OPiv); and (c) Compound (IIb) of step (b) (1) Formula (III) (In the formula, X ４ Compounds of halogens; (2) [Pd(allyl)Cl] ２ [Pd (Cinnamyl) Cl] ２ , or a Pd catalyst precursor containing [(η3-allyl)(η5-cyclopentadienyl)palladium(II)], and (3) Formula: (In the formula, Y is O; R ７ and R ８ (Each is independently a chiral ligand, which is methyl, ethyl, or phenyl) By bringing it into contact with, the formula A method comprising the step of synthesizing a compound.

2. X ２ The method according to claim 1, wherein the element is Br, Cl, or OPiv.

3. The compound of formula (III) is: The method according to claim 1, comprising:

4. R １ PG １ The method according to claim 1.

5. R １ The method according to claim 4, wherein is Boc(tert-butyloxycarbonyl).

6. R ２ However, non-substituted C １－６ Alkyl or unsubstituted C １－６ The method according to claim 1, wherein the material is cyanoalkyl.

7. R ２ The method according to claim 1, wherein is methyl.

8. R ３ The method according to claim 1, wherein the substance is hydrogen or methyl.

9. R ３ is methyl, R ４ ga CF ３ The method according to claim 1.

10. The method according to claim 1, wherein each PG is p-methoxybenzyl.

11. The method according to claim 1, wherein the organomagnesium compound is i-PrMgCl・LiCl.

12. The aforementioned zinc compound is Zn(OPiv) ２ The method according to claim 1, wherein the material is LiCl.

13. The Pd catalyst precursor is [Pd(allyl)Cl] ２ or [Pd (cinnamyl)Cl] ２ The method according to claim 1.

14. The method according to claim 1, wherein the chiral ligand is a (R,R)-chiraffite ligand.

15. The Pd catalyst precursor is [Pd(cinnamyl)Cl] ２ The method according to claim 1.

16. The compound of formula (I) is: The method according to any one of claims 1 to 15, comprising:

17. Formula: (1) A method for synthesizing a compound or a pharmaceutically acceptable salt thereof, wherein the method is (a) Formula (2) A step of bringing a pre-cooled solution containing the compound or a salt thereof into contact with a pre-cooled solution containing i-PrMgCl·LiCl using a flow rate that provides a residence time of approximately 15 to 150 seconds for Mg-Br exchange; (b) ZnCl containing the LiCl or LiTFA salt ２ or Zn (OPiv) ２ The process involves transferring the mixture from step (a) to a continuous stirring tank reactor (CSTR) containing a pre-cooled solution, and maintaining a constant residence time of approximately 3 to 7 minutes at approximately -20°C to 20°C; (c) The mixture from step (b) contains NaTFA and formula (3) A step of contacting the compound; (d) The mixture or salt of step (c) [Pd(allyl)Cl] ２ or [Pd (cinnamyl)Cl] ２ The Pd catalyst precursor is then brought into contact with a chiral ligand containing a (R,R)-chiraffite ligand, thereby producing formula (11). A process for synthesizing the compound, or its solvate or salt thereof, (e) The compound of formula (11), or its solvate or salt, of formula HO-X Ａ (In the formula, X Ａ is an expression Contacting a compound (containing) and a base, thereby producing formula (1b); A process for synthesizing a compound, its solvate, or a pharmaceutically acceptable salt thereof. (f) Contact the compound of formula (1b) with MsOH in an acid, thereby obtaining formula (1a); A step of synthesizing a compound of, or a solvate or pharmaceutically acceptable salt thereof; and (g) The compound of formula (1a) or its solvate or a pharmaceutically acceptable salt thereof, in the presence of an activator. A method comprising the step of contacting with a compound, and subsequently with a base, thereby producing a compound of formula (1) or a pharmaceutically acceptable salt thereof.

18. The pre-cooling solution in step (b) is Zn(OPiv) ２ - Contains LiCl, and the Pd catalyst precursor is [Pd(cinnamyl)Cl] ２ The method according to claim 17.

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