Palladium catalyzed synthesis of aminoaldehyde intermediates

Abstract

This article provides a method for synthesizing substituted fluoroalkyl tetrahydroacryl-amino-benzaldehyde derivatives.

Description

[Technical Field]

[0001] This article provides a method for synthesizing amino aldehyde compounds. [Previous Technology]

[0002] 2,6-Difluoro-4-[[1-(3-fluoropropyl)-3-tetrahydroacryl]amino]benzaldehyde (compound 1) has previously been shown to be an intermediate in the synthesis of the giredestrant. (See, for example, J. Med. Chem. 2021, 64, 11841-11856; Org. Process Res. Dev. 2022, 26, 568-582; Org. Process Res. Dev. 2022, 26, 560-567; U.S. Patent No. 9980947; U.S. Patent Publication Nos. 2020002331, 2022002304). These syntheses share common features including the use of a BrettPhos Pd G3 catalyst and downstream Pd scavenging. It has been reported that the yield and conversion percentage of 2,6-difluoro-4-[[1-(3-fluoropropyl)-3-tetrahydroacryl]amino]benzaldehyde using the BrettPhos Pd G3 catalyst are reasonable. However, it is known that pre-catalysts such as BrettPhos's G3 release carbazole upon activation (J. Org. Chem. 2015, 80, 6794-6813; J. Org. Chem. 2014, 79, 4161-4166).

[0003] Several drawbacks are known to exist with carbazole byproducts: 1) It inhibits the catalytic activity of palladium catalysts by coordinating with metal centers (Angew. Chem. Int. Ed. 2015, 54, 8259–8262); 2) It can act as a acceptor in N-arylation reactions, thereby consuming aryl halide reagents in a nonproductive manner and generating additional byproducts (Org. Lett. 2013, 15, 5602–5605); and 3) Carbazole is a suspected mutagen and carcinogen, requiring strict analytical control. Reported syntheses using BrettPhos Pd G3 have even higher requirements for catalyst loading. These reactions typically employ downstream metal scavengers and treatments for Pd removal, including, for example, the addition of triphenylphosphine (PPh3) and / or N-acetycysteine ​​after the reaction. These drawbacks and downstream treatments are not advantageous when scaling up the synthesis to a commercial scale.

[0004] Such benzaldehyde compounds can be used to prepare fused tricyclic compounds containing substituted phenyl or pyridyl moieties, such as giredestrant, as disclosed, for example, in U.S. Publication No. 2016 / 0175289. There is a need for improved methods for preparing benzaldehyde compounds, such as methods that can be used to synthesize estrogen receptor α (ER-α) targets. [Summary of the Invention]

[0005] This document provides solutions to the above-mentioned problems and other problems in this field.

[0006] In one embodiment, this document provides a method (P1) for preparing the compound of formula (I) described herein. The method comprises: step 1, which involves reacting a reaction mixture to form the compound of formula (Ia) described herein, the reaction mixture comprising: (a) an organic solvent comprising toluene, dialkylene, or tri-pentanol; (b) a compound of formula (II); (c) a compound of formula (III) or a salt thereof; (d) a Pd catalyst; and (e) a base; and step 2, which involves deprotecting the compound of formula (Ia) from step 1 in a reaction mixture comprising an aqueous acid to form the compound of formula (I). Method P1 can be carried out under the conditions described herein.

[0007] In another embodiment, a method (P2) for preparing the compound of formula (1) described herein is provided herein. The method comprises: step 1, which comprises reacting the compound of formula (2) described herein with the compound of formula (3) described herein in a reaction mixture comprising toluene, a Pd-ligand catalyst comprising [(Xanthphos)Pd(allyl)]Cl and a base selected from sodium tri-pentoxide or sodium tri-butoxide, thereby synthesizing the compound of formula (1a) described herein; and step 2, which comprises deprotecting the compound of formula (1a) obtained in step 1 in a reaction mixture comprising toluene and an aqueous acid, thereby synthesizing the compound of formula 1.

[0008] Such embodiments of the invention can be more fully understood by referring to the detailed description and examples which are intended to illustrate non-limiting embodiments.

Implementation Method

[0009] Cross-reference to related applications This case claims the benefit of European Patent Application No. 24185873.7, filed on July 02, 2024, the whole and all purposes of which are incorporated herein by reference.

[0010] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention pertains. See, for example, Singleton et al., DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY, 2nd edition, 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 to practice this invention.

[0011] The following definitions are provided to facilitate understanding of certain terms that are frequently used herein, but are not intended to limit the scope of this disclosure. All references cited herein are incorporated herein by reference in their entirety.

[0012] As used herein, the terms “part” and “substituent” refer to an atom or group of chemically bonded atoms that are attached to another atom or molecule by one or more chemical bonds to form a part of a molecule.

[0013] The term "alkyl" refers to a saturated straight-chain or branched monovalent hydrocarbon group. In one instance, the alkyl group has one to ten carbon atoms (C1-10). In other instances, the alkyl group is C1-8, C1-6, C1-5, C1-4, or C1-3. Examples of alkyl groups include methyl (Me), ethyl (Et), 1-propyl (n-Pr, n-propyl), 2-propyl (i-Pr, isopropyl), 1-butyl (n-Bu, n-butyl), 2-methyl-1-propyl (i-Bu, isobutyl), 2-butyl (s-Bu, sec-butyl), 2-methyl-2-propyl (t-Bu, tert-butyl), 1-pentyl (n-pentyl), 2-pentyl, 3-pentyl 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, 1-heptyl and 1-octyl.

[0014] The term "alkenyl" refers to a straight-chain or branched monovalent hydrocarbon group having at least one carbon-carbon double bond, and includes free radicals having "cis" and "trans" orientations or "E" and "Z" orientations. In one example, the alkenyl group is C2-8, C2-6, or C2-3.

[0015] The term "alkynyl" refers to a straight-chain or branched monovalent hydrocarbon group having at least one carbon-carbon triple bond. In one instance, the alkynyl group is C2-8, C2-6, or C2-3.

[0016] The term "haloalkyl" refers to an alkyl chain in which one or more hydrogen atoms have been replaced by a halogen. Examples of haloalkyl are trifluoromethyl, difluoromethyl, and fluoromethyl. "Fluoroalkyl" refers to an alkyl chain in which one or more hydrogen atoms have been replaced by fluorine. Substituted haloalkyl refers to a haloalkyl having a moiety other than a halogen.

[0017] As used herein, the terms “halogen”, “halogen” and “halide” are used interchangeably and refer to the substituents fluorine, chlorine, bromine or iodine.

[0018] Unless otherwise stated, the terms “hydrogen” or “hydrogen group” refer to the hydrogen atom (-H) and not the H2 part.

[0019] The term "alkoxy" refers to an alkyl group having the formula –O–.

[0020] The terms “cyano” and “nitrile” are used interchangeably in this document and refer to the -C≡N or CN substituent.

[0021] The term "carboxyl group" refers to -C(=O)OH.

[0022] The term "toluenesulfonate" refers to a compound.

[0023] The term "methanesulfonate" refers to a compound.

[0024] The term "trifluoromethanesulfonate" refers to a compound.

[0025] "alkoxide base" refers to the conjugate base of alkyl-alcohol and has the general structure RO-, where R is the alkyl group provided herein.

[0026] "Sulfonic acid" refers to organic sulfur compounds with the formula -SO3H.

[0027] The term "OTf" refers to a compound with the formula -OSO2CF3.

[0028] The term "allyl" refers to compounds with the formula -CH2-CH=CH2.

[0029] The terms “CAS number”, “CAS registration number” and “CAS number” are used interchangeably and refer to a unique and specific numerical identifier assigned to only one chemical substance.

[0030] The term “deprotection” refers to the removal of the protective base.

[0031] The term "Pd catalyst" refers to a transition metal catalyst comprising Pd and at least one ligand. In some embodiments, the Pd catalyst in the reaction mixture described herein is formed in situ after the addition of reactants.

[0032] As used herein, the term "substituted" means that at least one hydrogen atom in a compound or part is substituted by another substituent or partially substituted. Examples of such substituents include, but are not limited to, halogens, -OH, -CN, syloxy, alkoxy, alkyl, alkylene, aryl, heteroaryl, haloalkyl, haloalkoxy, cycloalkyl, and heterocyclic. For example, the term "haloalkyl" refers to the fact that one or more hydrogen atoms of an alkyl group (as defined below) are substituted by one or more halogen atoms (e.g., trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, etc.).

[0033] As used herein, the term "organic solvent" means any non-aqueous polar aprotic solvent, polar protic solvent and non-polar solvent.

[0034] As used herein, the term "aldehyde protecting group" means any known substituent attached to an aldehyde group that blocks, shields, or protects the carbonyl group of the aldehyde functional group. Suitable aldehyde functional group protecting groups include, but are not limited to: (a) cyclic and acyclic acetals and ketals; (b) cyclic mono- or dithioacetals or ketals or other derivatives, such as imines, hydrazones, cyanols, oximes, or ureas, for example, dialkyl or diaryl acetals or 1,3-dithiazide; (c) cyclic imines, such as substituted methyl derivatives or N,N'-dimethylimidazolidine. Some non-limiting examples of aldehyde protecting groups include 1,3-dithiazide, 1,3-dithionecyclopentane, diethyl acetal, dimethyl acetal, dichloromethyl acetal, ethylene glycol acetal, neopentyl glycol acetal, and trimethylsilyl cyanohydrin. For a description of aldehyde protecting groups and their uses, see Wuts and Greene.

[0035] In this description, if there is a discrepancy between the described structure and the name given to that structure, the described structure shall prevail. Furthermore, if the stereochemistry of a structure or a portion thereof is not indicated by, for example, a thick wedge or dashed line, the structure or a portion thereof shall be interpreted as encompassing all its stereoisomers. However, in some cases, if more than one chiral center is present, the structure and name may be represented as a single enantiomer to aid in describing the relevant stereochemistry.

[0036] This document provides a method for preparing a compound of formula (I) or a salt thereof, wherein the method comprises the following steps: (1) reacting a reaction mixture according to step 1 below to form a compound of formula (Ia), the reaction mixture comprising: (a) an organic solvent comprising toluene, dialkyl, or tri-pentanol; (b) a compound of formula (II); (c) a compound of formula (III) or a salt thereof; (d) a Pd catalyst; and (e) a base: wherein ring A is phenyl or pyridyl; X is a halogroup, toluenesulfonate, methanesulfonate, or trifluoromethanesulfonate; PG is a protected aldehyde, wherein X and PG are para-positioned on each other on ring A; R1 is H, F, Cl, or CN; each R2 is independently a halogroup, Me, or CN; n is an integer of 1, 2, 3, 4, or 5; p is an integer of 0, 1, or 2; The base includes an alkoxide base; and the Pd catalyst includes the formula [Pd(L)(allyl)](X1), wherein L is selected from 1,1'-bis(diphenylphosphino)ferrocene (dppf) or a Xanthphos derivative having formula (T); (T) wherein: Ra and Rb are each independently hydrogen or C1-6 alkyl; Rc, Rd, Re and Rf are each independently hydrogen, halogen, NH2, C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 alkoxy or C1-3 haloalkyl; q, r, s and u are each independently an integer from 0 to 5; and X1 is a halogroup, OMs or OTf; and (2) the compound of formula (Ia) is deprotected in a reaction mixture containing an aqueous acid to form the compound of formula (I) according to step 2 below: The acid is an aqueous acid selected from the group consisting of: HCl, HNO3, H3PO4, NaH2PO4, H2SO4, sulfonic acid or carboxylic acid;

[0037] Step 1 of the method can be carried out, for example, in toluene or tri-pentanol. In one embodiment, step 1 of the method is carried out in toluene. In another embodiment, step 1 of the method is carried out in tri-pentanol.

[0038] In one embodiment, ring A is phenyl. In another embodiment, ring A is pyridyl. X may be a halogen group. In one such embodiment, X is Cl, Br, or I. In another such embodiment, X is Cl or Br. In another such embodiment, X is Br. In another embodiment, X is toluenesulfonate, methanesulfonate (Ms), or trifluoromethanesulfonate.

[0039] In some embodiments, ring A is phenyl, wherein X is a halogroup. In one such embodiment, X is Br. In one such embodiment, p is 0, 1, or 2. In one embodiment, p is 0. In one embodiment, p is 1. In another such embodiment, p is 2. In one embodiment, each R2 is independently a halogroup. In one such embodiment, each R2 is independently Cl or F. In another such embodiment, each R2 is independently F. In one such embodiment, each R2 is independently F and p is 2.

[0040] In another embodiment, each R2 is independently Me or CN. In one embodiment, ring A is phenyl, X is Br or Cl, each R2 is independently a halogen group, and p is 1 or 2. In another such embodiment, ring A is phenyl, X is Br or Cl, each R2 is independently F, and p is 2.

[0041] In one embodiment, R1 is F, Cl, or CN. In one embodiment, R1 is F, Cl, or CN, and n is 1, 2, or 3. In one embodiment, R1 is F, Cl, or CN, and n is 2. In one embodiment, R1 is F, Cl, or CN, and n is 3. In one embodiment, n of the compound of formula (III) is 1, 2, or 3. In one such embodiment, n is 2. In one embodiment, n is 3. In such an embodiment, R1 is F or CN. In one embodiment, R1 is Cl. In another embodiment, R1 is F. In one embodiment, R1 is F, and n is 1, 2, or 3. In another embodiment, R1 is F, and n is 2. In another embodiment, R1 is F, and n is 3. In another embodiment, R1 is CN, and n is 3. In yet another embodiment, R1 is Me, and n is 1 or 2. In another embodiment, R1 is H. In one such embodiment, R1 is H, and n is 1, 2, or 3.

[0042] Protected aldehydes, as defined herein and in non-limiting examples, include 1,3-dithiane, 1,3-dithionecyclopentane, diethyl acetal, dichloromethyl acetal, dimethyl acetal, ethylene glycol acetal, neopentyl glycol acetal, trimethylsilyl cyanohydrin, and triethyl orthoformate. In one embodiment, PG is diethyl acetal, dimethyl acetal, dichloromethyl acetal, ethylene glycol acetal, or neopentyl glycol acetal. In another embodiment, PG is diethyl acetal, dimethyl acetal, or dichloromethyl acetal. In the embodiments herein, PG is diethyl acetal. In other embodiments herein, PG is dichloromethyl acetal.

[0043] In one embodiment, the base in step 1 is a sodium alkoxide or a potassium alkoxide. In one embodiment, the alkyl group of the alkoxide is C1-6 alkyl, C1-5 alkyl, C1-4 alkyl, or C1-3 alkyl. In one embodiment, the alkyl group of the alkoxide is ethyl or methyl. In one embodiment, the base in step 1 is a sodium alkoxide. In another embodiment, the base in step 1 is a potassium alkoxide. In one embodiment, the base in step 1 is an alkoxide comprising a methanol salt, an ethanol salt, a butoxide, a tert-butoxide, a pentanol salt, or a tert-pentoxide. In one such embodiment, the base in step 1 is sodium tert-pentoxide, sodium tert-butoxide, potassium tert-pentoxide, or potassium tert-butoxide. In another such embodiment, the base in step 1 is sodium tert-pentoxide or sodium tert-butoxide. In yet another such embodiment, the base in step 1 is sodium tert-pentoxide.

[0044] In some embodiments of the methods described herein, the Pd catalyst of formula [Pd(L)(allyl)](X1) is paired with a combination of the solvents and bases described herein. For example, the reaction efficiency can be modified by combining the Pd catalyst described herein with the solvents and bases described herein. In one such embodiment, the Pd catalyst provided herein may be used in the reaction mixture described herein, which comprises toluene and an alkoxide base comprising a methanol salt, ethanol salt, butanol salt, tert-butanol salt, pentanol salt, or tert-pentanol salt. In another embodiment, the Pd catalyst provided herein may be used in the reaction mixture described herein, which comprises tert-pentanol and an alkoxide base comprising a methanol salt, ethanol salt, butanol salt, tert-butanol salt, pentanol salt, or tert-pentanol salt. In one such embodiment, the Pd catalyst provided herein may be used in the reaction mixture comprising a solvent and the alkoxide base described herein, the solvent comprising toluene. In another such embodiment, the Pd catalyst provided herein is used in a reaction mixture comprising a solvent and an alkoxide base, the solvent comprising toluene, the alkoxide base being selected from the group consisting of sodium terephthaloxide, potassium terephthaloxide, sodium terepentoxide, and potassium terepentoxide. In one such embodiment, the Pd catalyst provided herein is used in a reaction mixture comprising sodium terepentoxide, sodium terephthaloxide, potassium terepentoxide, or potassium terephthaloxide. In such embodiments, the Pd catalyst provided herein is used in a reaction mixture comprising a base comprising sodium terepentoxide or sodium terephthaloxide. In such embodiments, PG is diethyl acetal.

[0045] In one embodiment, the L of the Pd catalyst described herein comprises 1,1'-bis(diphenylphosphine)ferrocene (dppf). In one such embodiment, the X1 of such Pd catalyst is either Cl or OTf as described herein. In one embodiment, the Pd catalyst comprises the formula [(dppf)Pd(allyl)]OTf.

[0046] In another embodiment, the L of the Pd catalyst described herein comprises a Xanthphos derivative having formula (T); (T) wherein: Ra and Rb are each independently hydrogen or C1-6 alkyl; Rc, Rd, Re and Rf are each independently hydrogen, halogen, NH2, C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 alkoxy or C1-3 haloalkyl; and q, r, s and u are each independently an integer from 0 to 5.

[0047] In another embodiment, Ra and Rb are different and each is independently a C1-6 alkyl group. In one such embodiment, Ra and Rb are each independently Me, Et, or n-Pr. In another embodiment, Ra and Rb are the same. In one such embodiment, Ra and Rb are each hydrogen. In another such embodiment, Ra and Rb are each Me.

[0048] Rc, Rd, Re, and Rf can be independently hydrogen or halogen. In one embodiment, Rc, Rd, Re, and Rf are independently hydrogen or C1-3 alkoxy. In one embodiment, Rc, Rd, Re, and Rf are independently hydrogen, halogen, C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 alkoxy, or C1-3 haloalkyl. In another embodiment, Rc, Rd, Re, and Rf are independently hydrogen, halogen, C1-3 alkyl, or C1-3 alkoxy. In another embodiment, Rc, Rd, Re, and Rf are independently halogen, C1-3 alkyl, C1-3 alkoxy, or C1-3 haloalkyl. In yet another embodiment, Rc, Rd, Re, and Rf are independently hydrogen or C1-3 alkoxy. In some such embodiments, Rc, Rd, Re, and Rf are the same. Therefore, in one embodiment, Rc, Rd, Re, and Rf are each hydrogen. In another such embodiment, Rc, Rd, Re, and Rf are each Me. In yet another such embodiment, Rc, Rd, Re, and Rf are each Et. In yet another such embodiment, Rc, Rd, Re, and Rf are each CF3. In yet another such embodiment, Rc, Rd, Re, and Rf are each OMe.

[0049] In some embodiments, when Rc, Rd, Re, and Rf are the same, q, r, s, and u are also the same. In one such embodiment, q, r, s, and u are each 0, 1, or 2. In another such embodiment, q, r, s, and u are each 1 or 2. In one embodiment, Rc, Rd, Re, and Rf are the same and selected from hydrogen, Me, CF3, or OMe, and q, r, s, and u are the same and selected from 0, 1, or 2. In one such embodiment, Rc, Rd, Re, and Rf are each OMe, and q, r, s, and u are each 1. In another embodiment, q, r, s, and u are each 0.

[0050] In one embodiment, the Pd catalyst of formula [Pd(L)(allyl)](X1) comprises L of a compound having formula (T) as described herein, wherein X1 is Cl or OTf. In one embodiment, the Pd catalyst of formula [Pd(L)(allyl)](X1) comprises L of a compound having formula (T) as described herein, wherein X1 is Cl. In one embodiment, L is Xanthphos or Xanthphos-OMe as described herein.

[0051] In one embodiment, L is a compound of formula (T) which comprises a compound having the following formula: (Xanthphos) or (Xanthphos-OMe).

[0052] In one embodiment, L is a compound of formula (T) that comprises a compound having the following formula: (Xanthphos)

[0053] Certain Xanthphos-derived Pd catalysts are known. In one such embodiment, L is a compound of formula (T) comprising CAS molecule selected from the group consisting of... The numbered compounds are: 161265-03-8, 205497-65-0, 2119686-40-5, 2119686-45-0, 2119686-39-2, 2119686-51-8, 2119686-52-9, 2119686-38-1, 1810068-85-9, 2119686-44-9, 2254460-12-1, 2119686-37-0, 2119686-49-4, 2119686-53-0, 2119686-36-9, 2119686-48-3, 2119686-43-8, 11 82710-75-3, 2143143-32-0, 2119686-35-8, 2119686-42-7, 2119686-13-2, 2119686-12-1, 2300982-02-7, 2172792-28-6, 2231776-00-2, 2119686-41-6, 221462-97-1, 2300978-33-8, 1372784-49-0, 757964-78-6, 2119686-47-2, 805248-24-2, 796113-87-6, 2119686-50-7, 2143143-50-2, 2143143-49-9, 2119686-46-1, 1607019-61-3, 2143143-36-4, 2143143-48-8, 757964-80-0, 805248-23-1, 2143143-37-5, 2904636-03-7, 2143143-38-6, 2143143-34-2, 2143143-47-7, 1642150-80-8, 639477-10-4, 2143143-42-2, 2143143-52-4, 2143143-44 -4, 2143143-39-7, 885029-01-6, 885028-98-8, 2143143-35-3, 2143143-51-3, 1215039-22-7, 2143143-53-5, 454479-88-0, 1446696-38-3, 2143143-33-1, 2143143-45-5, 791136-90-8, 454479-87-9, 1329705-38-5, 221463-01-0, 791136-91-9, 251941-32-9, 190788-99-9,2143143-43-3, 2143143-40-0, 1329705-34-1, 889676-72-6, 462945-71-7, 251941-33-0, 450417-22-8, 450417-21-7, 2143143-46-6, 2143143-41-1, 885029-00-5, 1372784-48-9, 757964-79-7, 454479-85-7, 791136-92-0, 2136630-99-2, 885029-02-7 1559060-17-1, 1372784-47-8, 805248-26-4, 796113-88-7, 2760688-12-6, 343256-85-9, 805248-25-3, 705282-10-6, 1330003-46-7, 1329705-36-3, 462945-76-2, 2459616-84-1, 2411643-30-4, 796113-86-5, 449214-10-2, 215792-51-1, 262420-61-1 or 594815-59-5.

[0054] In another embodiment of this kind, L is a compound of formula (T) which contains CAS having a group selected from the following groups. Compounds with the following numbers: 161265-03-8, 205497-65-0, 1182710-75-3, 2119686-35-8, 221462-97-1, 805248-24-2, 796113-87-6, 805248-23-1, 885028-98-8, 885029-00-5, 757964-79-7, 2459616-84-1, 2411643-30-4, 796113-86-5, 449214-10-2, 215792-51-1, 262420-61-1, or 594815-59-5.

[0055] In one embodiment, the Pd catalyst comprises a compound of the formula [(Xanthphos)Pd(allyl)]Cl having the following structure: (T1).

[0056] In one embodiment, the compound of formula T1 is formed in situ in the reaction mixture of step 1 described herein. In another embodiment, the compound of formula T1 is pre-formed prior to its addition as a reagent in step 1 described herein.

[0057] In one such embodiment of step 1 of method (P1), the Pd catalyst comprises the formula [(Xanthphos)Pd(allyl)]Cl, the reaction mixture comprises a solvent containing toluene or tri-pentanol, and the base is an alkoxide base selected from the group consisting of: sodium tri-butoxide, potassium tri-butoxide, sodium tri-pentanol, and potassium tri-pentanol. In another such embodiment, the Pd catalyst comprises the formula [(Xanthphos)Pd(allyl)]Cl, the reaction mixture comprises a solvent containing toluene or tri-pentanol, and the base is sodium tri-pentanol or sodium tri-butoxide.

[0058] In method P1, the compound of formula (II) can be one of the following compounds: , , , , , , , , , , , , , , , , or.

[0059] In method P1, the compound of formula (II) can be one of the following compounds: , , , , , .

[0060] In method P1, the compound of formula (II) can be one of the following compounds: , , , , or.

[0061] In method P1, the compound of formula (II) can be one of the following compounds: , , or.

[0062] In method P1, the compound of formula (II) can be one of the following compounds: , , , or.

[0063] In method P1, the compound of formula (II) can be one of the following compounds: or.

[0064] In method P1, the compound of formula (II) can be one of the following compounds:

[0065] In method P1, the compound of formula (II) can be one of the following compounds: , or.

[0066] In the preceding examples of compounds of formula (II), PG is diethyl acetal, dimethyl acetal, or dichloromethyl acetal. In one such example, PG is diethyl acetal. In another such example, PG is dimethyl acetal. In yet another such example, PG is dichloromethyl acetal.

[0067] In method P1, the compound of formula (II) can be one of the following compounds: , , , , , , , , , , , , , , , , or.

[0068] In method P1, the compound of formula (II) can be one of the following compounds: , , , , or.

[0069] In method P1, the compound of formula (II) can be one of the following compounds: , , , , or.

[0070] In method P1, the compound of formula (II) can be one of the following compounds: , , or.

[0071] In method P1, the compound of formula (II) can be one of the following compounds: , , , or.

[0072] In method P1, the compound of formula (II) can be one of the following compounds: , , , or.

[0073] In method P1, the compound of formula (II) can be one of the following compounds: or.

[0074] In one embodiment of method P1, the compound of formula (II) is the following compound: (2).

[0075] In method P1, the compound of formula (II) can be one of the following compounds: , or.

[0076] In one embodiment of method P1, the compound of formula (III) may be one of the following compounds: , , , , , , , , , or , or a salt thereof.

[0077] In method P1, the compound of formula (III) can be one of the following compounds: , , or, or a salt thereof.

[0078] In method P1, the compound of formula (III) can be one of the following compounds: or.

[0079] In method P1, the compound of formula (III) can be one of the following compounds: , , or, or a salt thereof.

[0080] In method P1, the compound of formula (III) can be one of the following compounds: , , or , or a salt thereof.

[0081] In method P1, the compound of formula (III) can be one of the following compounds: , or , or a salt thereof.

[0082] In one such embodiment, the compound of formula (III) is the following compound: (3).

[0083] In some such embodiments, the salt of the compound of formula (III) is an ethanedisulfonate (e.g., ethane-1,2-disulfonate). In another embodiment, the compound of formula (III) is not a salt (i.e., a free base). In one embodiment of the method described herein, the compound of formula (III) is a free base, which is used in situ after free alkalization.

[0084] In one embodiment, the compound of formula (II) is: , , , or the compound of formula (III) is: , or , or a salt thereof.

[0085] In one embodiment, the compound of formula 3 is: ∙HO3SCH2CH2SO3H (3.1).

[0086] In one embodiment, the compound of 3.1 is desalted before being used in the methods described herein.

[0087] In one embodiment of method P1, the compound of formula (Ia) is one of the following compounds: , ...

[0088] In one embodiment of method P1, the compound of formula (Ia) is one of the following compounds: , , , , or.

[0089] In one embodiment of method P1, the compound of formula (Ia) is one of the following compounds: or.

[0090] In one embodiment, the compound of formula (Ia) is one of the following compounds:

[0091] In one embodiment of method P1, the compound of formula (Ia) is one of the following compounds: , , , , , , , , , , , , , or.

[0092] In one embodiment of method P1, the compound of formula (Ia) is one of the following compounds: , , , , or.

[0093] In one embodiment of method P1, the compound of formula (Ia) is one of the following compounds: , , or.

[0094] In one embodiment of method P1, the compound of formula (Ia) is one of the following compounds: , , , or.

[0095] In one embodiment of method P1, the compound of formula (Ia) is one of the following compounds: , ...

[0096] In one embodiment of method P1, the compound of formula (Ia) is one of the following compounds: , , , , or.

[0097] In one embodiment of method P1, the compound of formula (Ia) is one of the following compounds: or.

[0098] In one embodiment, the compound of formula (Ia) is the following compound: (Ia).

[0099] In one embodiment of method P1, the compound of formula (Ia) is one of the following compounds: , , , , or.

[0100] In one embodiment of method P1, the compound of formula (Ia) is one of the following compounds: , , or.

[0101] In one embodiment of method P1, the compound of formula (Ia) is one of the following compounds: , , , or.

[0102] In the methods disclosed herein, the percentage of Pd-ligand catalyst may vary. Such catalysts may be difficult to manufacture or expensive to purchase. Therefore, it is necessary to minimize the equivalent amount of the Pd-ligand catalyst described herein while maintaining appropriate yield and purity. However, there is a balance between the amount of Pd-ligand catalyst used and the final total yield. Therefore, in one embodiment, the Pd-ligand catalyst described herein is present in the following amounts: about 0.1 mol% to about 1 mol%, about 0.1 mol% to about 0.8 mol%, about 0.1 mol% to about 0.6 mol%, about 0.1 mol% to about 0.5 mol%, about 0.125 mol% to about 0.5 mol%, about 0.05 mol% to about 0.8 mol%, about 0.05 mol% to about 0.6 mol%, about 0.05 mol% to 0.5 mol%. In another embodiment, the Pd catalyst is present in amounts of about 0.1 mol% to 0.6 mol% or about 0.125 mol% to about 0.6 mol%. In another embodiment, the Pd-ligand catalyst is present in amounts of about 0.1%, 0.125%, 0.25%, or about 0.5 mol%.

[0103] In such embodiments, the reaction of step 1 is carried out at a temperature of about 50°C to about 70°C. In another such embodiment, the reaction of step 1 is carried out at a temperature of 60°C + / - 10°C.

[0104] In step 1 of method (P1), the compound of formula (II) described herein is reacted with the compound of formula (III) described herein in an organic solvent comprising toluene, dialkylene, or tri-pentanol in the presence of the Pd catalyst described herein to form the compound of formula (Ia) described herein. The order in which the compounds of formula (II) and (III) are added does not affect the conversion percentage or product yield. Thus, in one embodiment, a solution comprising the compound of formula (II) is added to a solution comprising the compound of formula (III). In another embodiment, a solution comprising the compound of formula (III) is added to a solution comprising the compound of formula (II). In one such embodiment, the organic solvent is toluene. In one embodiment, the reaction mixture comprises the compounds of formula (II) and (III) described herein and is partially concentrated prior to the addition of the Pd catalyst and the base. In some embodiments, the base is added slowly to the reaction mixture. The base may be added at a temperature, for example, between 25°C and 45°C. In one embodiment, the base is added at 25°C. In another embodiment, the base is added at a temperature of 45°C. In some embodiments, the reaction progress is monitored by, for example, chromatography to determine the degree of completion before step 2. In some embodiments, the reaction is carried out at a temperature of about 60°C ± 10°C for at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 hours.

[0105] After the reaction is complete, the reaction mixture can be quenched. In some such embodiments, the reaction mixture can be quenched with cold water. In such embodiments, the phase can be separated into an aqueous phase and an organic phase containing the compound of formula (Ia). The organic phase containing the dissolved compound of formula (Ia) can be separated. The phases can be further extracted as understood in the art.

[0106] In some embodiments, the compound of formula (Ia) can be used in situ without further purification or crystallization prior to step 2. In such embodiments, the compound can still be post-treated by, for example, solvent exchange or solvent removal to remove minor impurities. In another embodiment, the compound of formula (Ia) is isolated prior to step 2.

[0107] The second step of the method (P1) described herein comprises deprotecting the compound of formula (Ia) from step 1 in a reaction mixture containing an aqueous acid to form compound of formula (I): wherein the acid is an aqueous acid selected from the group consisting of HCl, HNO3, H3PO4, NaH2PO4, H2SO4, sulfonic acid or carboxylic acid.

[0108] In one embodiment, the aqueous acid is H2SO4. In one embodiment, the aqueous acid is a sulfonic acid. In one such embodiment, the sulfonic acid is methanesulfonic acid, trifluoromethanesulfonic acid, or p-toluenesulfonic acid. In another such embodiment, the sulfonic acid is p-toluenesulfonic acid.

[0109] In another embodiment, the aqueous acid in step 2 is a carboxylic acid. In one such embodiment, the carboxylic acid is acetic acid, formic acid, or oxalic acid. In another such embodiment, the carboxylic acid is acetic acid.

[0110] In another embodiment, the aqueous acid is HCl, HNO3, or H3PO4. In one such embodiment, the aqueous acid is HCl. In another such embodiment, the aqueous acid is NaH2PO4.

[0111] In one embodiment, the reaction mixture comprises toluene.

[0112] In one embodiment, the reaction mixture containing the compound of formula (Ia) from step 1 of method (P1) is combined with an aqueous base, and the two-phase mixture is stirred until the compound of formula (I) is formed. In one such embodiment, the reaction progress is confirmed by, for example, chromatography (e.g., TLC, GC, or HPLC). In some embodiments, the reaction is added to an aqueous base (e.g., sodium hydroxide). In one embodiment, the aqueous base further comprises pre-inoculated crystals of compound (I). In one embodiment, the yield from compound (Ia) to compound (I) is at least 85%, at least 90%, at least 95%, at least 96%, or at least 97%. The purity of compound (IV) is at least 95%, at least 98%, or at least 99%.

[0113] In some embodiments, step 2 of method (P1) further comprises step (3): crystallizing compound (I) after deprotecting compound (Ia). Such crystallization can be carried out by adding the reaction mixture of step 2 to an aqueous solution containing a base. In one such embodiment, the base is a hydroxide base, such as sodium hydroxide or potassium hydroxide. In one such embodiment, the resulting solid is then filtered, washed with water, and dried to obtain compound (I).

[0114] In one embodiment of method (P1), the compound of formula (I) is one of the following compounds: , ...

[0115] In one embodiment of method (P1), the compound of formula (I) is one of the following compounds: , , , , or.

[0116] In one embodiment of method (P1), the compound of formula (I) is one of the following compounds: , , or .

[0117] In one embodiment of method (P1), the compound of formula (I) is one of the following compounds: or.

[0118] In one embodiment, the compound of formula (I) is one of the following compounds: (1).

[0119] In one embodiment of method (P1), the compound of formula (I) is one of the following compounds: , , , , or.

[0120] In one embodiment of method (P1), the compound of formula (I) is one of the following compounds: , , or.

[0121] In one embodiment of method (P1), the compound of formula (I) is one of the following compounds: , , , or.

[0122] This article also provides a method (P2) for synthesizing compound (1): (1). The method (P2) comprises: (1) reacting compound (2) with compound (3) in a reaction mixture containing toluene, a Pd-ligand catalyst containing [(Xanthphos)Pd(allyl)Cl] and a base selected from sodium tri-pentoxide or sodium tri-butoxide to synthesize compound (1a); (1a); and (2) deprotecting compound (1a) from step 1 in a reaction mixture containing toluene and an aqueous acid to synthesize compound 1.

[0123] In one embodiment of method (P2), the base in step 1 is sodium tripentoxide. In one such embodiment, the reaction is carried out at a temperature of about 50°C to about 70°C. In another such embodiment, the reaction is carried out at a temperature of 60°C + / - 10°C. The reaction progress can be monitored by, for example, chromatography (e.g., TLC, GC, or HPLC).

[0124] In one embodiment, the Pd-ligand catalyst is present in amounts of about 0.1 mol% to about 1 mol%, about 0.1 mol% to about 0.8 mol%, about 0.1 mol% to about 0.6 mol%, about 0.1 mol% to about 0.5 mol%, about 0.125 mol% to about 0.5 mol%, about 0.05 mol% to about 0.8 mol%, about 0.05 mol% to about 0.6 mol%, and about 0.05 mol% to 0.5 mol%. In one embodiment, the Pd-ligand catalyst is present in amounts of about 0.1 mol% to 0.6 mol% or about 0.125 mol% to about 0.6 mol%. In another embodiment, the Pd-ligand catalyst is present in amounts of about 0.1%, 0.125%, 0.25%, or about 0.5 mol%.

[0125] In one embodiment of the method (P2) described herein, the method further comprises the following steps: (3) crystallizing the compound of formula (1) after deprotecting the compound of formula (1a).

[0126] In one embodiment, step (3) comprises adding the compound of formula (1) to an aqueous solution containing a base. In one such embodiment, the base is sodium hydroxide or potassium hydroxide. In one embodiment, the base used for crystallization is sodium hydroxide. In one such embodiment, the aqueous solution further comprises seeded crystals of compound (1). In one embodiment, step (3) further comprises filtering the solid, washing the solid with water, and drying to obtain compound (1).

[0127] Selected Examples: Example 1. A method (P1) for preparing a compound of formula (I) or a salt thereof as described herein, wherein the method comprises the following steps: (1) reacting a reaction mixture according to step 1 described herein to form a compound of formula (Ia), the reaction mixture comprising: (a) an organic solvent comprising toluene, dialkyl, or tri-pentanol; (b) a compound of formula (II); (c) a compound of formula (III) or a salt thereof; (d) a Pd catalyst; and (e) a base: wherein ring A is phenyl or pyridyl; X is a halogroup, toluenesulfonate, methanesulfonate, or trifluoromethanesulfonate; PG is a protected aldehyde, wherein X and PG are para-positioned on each other on ring A; R1 is H, F, Cl, or CN; each R2 is independently a halogroup, Me, or CN; n is an integer of 1, 2, 3, 4, or 5; p The base is an integer of 0, 1, or 2; the base includes an alkoxide base; and the Pd catalyst includes the formula [Pd(L)(allyl)](X1), wherein L is selected from 1,1'-bis(diphenylphosphino)ferrocene (dppf) or a Xanthphos derivative having formula (T) as described herein; and wherein: Ra and Rb are each independently hydrogen or C1-6 alkyl; Rc, Rd, Re, and Rf are each independently hydrogen, halogen, NH2, C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 alkoxy, or C1-3 haloalkyl; and q, r, s, and u are each independently an integer from 0 to 5; and X1 is a halogen, OMs, or OTf; and (2) according to step 2 described herein, the compound of formula (Ia) from step 1 is deprotected in a reaction mixture containing an aqueous acid to form formula (I). Compounds, wherein the aqueous acid is HCl, HNO3, H3PO4, NaH2PO4, H2SO4, sulfonic acid, or carboxylic acid;

[0128] Example 2. The method as in Example 1, wherein ring A is phenyl.

[0129] Example 3. The method as in Example 1, wherein ring A is pyridyl.

[0130] Example 4. The method of any one of Examples 1 to 3, wherein X is a halogen group.

[0131] Example 5. The method of any one of Examples 1 to 4, wherein X is Br.

[0132] Example 6. The method of any one of Examples 1 to 3, wherein X is toluenesulfonate, methanesulfonate or trifluoromethanesulfonate.

[0133] Example 7. The method of any one of Examples 1 to 6, wherein n is 2.

[0134] Example 8. The method of any one of Examples 1 to 6, wherein n is 3.

[0135] Example 9. The method of any one of Examples 1 to 8, wherein R1 is H, F, Cl or CN;

[0136] Example 10. The method of any one of Examples 1 to 9, wherein R1 is F or CN.

[0137] Example 11. The method of any one of Examples 1 to 10, wherein R1 is F.

[0138] Example 12. The method of any one of Examples 1 to 11, wherein each R2 is independently a halogen group.

[0139] Example 13. The method of any one of Examples 1 to 12, wherein each R2 is independently F or Cl.

[0140] Example 14. The method of any one of Examples 1 to 13, wherein each R2 is independently F.

[0141] Example 15. The method of any one of Examples 1 to 11, wherein p is 0.

[0142] Example 16. The method of any one of Examples 1 to 14, wherein p is 2.

[0143] Example 17. The method of any one of Examples 1 to 14, wherein each R2 is independently F and p is 2.

[0144] Example 18. The method of any one of Examples 1 to 17, wherein PG is diethyl acetal.

[0145] Example 19. The method of any one of Examples 1 to 18, wherein the base is a sodium alkoxide or a potassium alkoxide.

[0146] Example 20. The method of Example 19, wherein the alkoxide base comprises a methanol salt, an ethanol salt, a butanol salt, a tert-butanol salt, a pentanol salt, or a tert-pentanol salt.

[0147] Example 21. The method of any one of Examples 1 to 20, wherein the base is sodium tri-pentoxide, sodium tri-butoxide, potassium tri-pentoxide or potassium tri-butoxide.

[0148] Example 22. The method of any one of Examples 1 to 20, wherein the base is sodium tripentoxide or sodium tributoxide.

[0149] Example 23. The method as in Example 22, wherein the base is sodium tripentoxide.

[0150] Example 24. The method of any one of Examples 1 to 23, wherein the organic solvent used in step 1 comprises toluene.

[0151] Example 25. The method of any one of Examples 1 to 24, wherein the L of the Pd catalyst comprises 1,1'-bis(diphenylphosphine)ferrocene (dppf).

[0152] Example 26. The method of any one of Examples 1 to 25, wherein the Pd catalyst comprises the formula [(dppf)Pd(allyl)]OTf.

[0153] Example 27. The method of any one of Examples 1 to 24, wherein the L of the Pd catalyst comprises a Xanthphos derivative having formula (T); (T) wherein: Ra and Rb are each independently hydrogen or C1-6 alkyl; Rc, Rd, Re and Rf are each independently hydrogen, halogen, NH2, C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 alkoxy or C1-3 haloalkyl; and q, r, s and u are each independently an integer from 0 to 5.

[0154] Example 28. The method as in Example 1 or 27, wherein Ra and Rb are the same.

[0155] Example 29. The method as in Examples 1, 27 or 28, wherein Rc, Rd, Re and Rf are the same.

[0156] Example 30. The method as in Example 1 or 27, wherein Rc, Rd, Re and Rf are independently hydrogen or C1-3 alkoxy groups.

[0157] Example 31. The method of any one of Examples 27 to 29, wherein q, r, s and u are each independently an integer of 0, 1 or 2.

[0158] Example 32. The method of any one of Examples 27 to 29, wherein L is a compound of formula (T) comprising CAS having a composition selected from the group consisting of The numbered compounds are: 161265-03-8, 205497-65-0, 2119686-40-5, 2119686-45-0, 2119686-39-2, 2119686-51-8, 2119686-52-9, 2119686-38-1, 1810068-85-9, 2119686-44-9, 2254460-12-1, 2119686-37-0, 2119686-49-4, 2119686-53-0, 2119686-36-9, 2119686-48-3, 2119686-43-8, 11827 10-75-3, 2143143-32-0, 2119686-35-8, 2119686-42-7, 2119686-13-2, 2119686-12-1, 2300982-02-7, 2172792-28-6, 2231776-00-2, 2119686-41-6, 221462-97-1, 2300978-33-8, 1372784-49-0, 757964-78-6, 2119686-47-2, 805248-24-2, 796113-87-6, 2119686-50-7, 214314 3-50-2, 2143143-49-9, 2119686-46-1, 1607019-61-3, 2143143-36-4, 2143143-48-8, 757964-80-0, 805248-23-1, 2143143-37-5, 2904636-03-7, 2143143-38-6, 2143143-34-2, 2143143-47-7, 1642150-80-8, 639477-10-4, 2143143-42-2, 2143143-52-4, 2143143-44-4, 214314 3-39-7, 885029-01-6, 885028-98-8, 2143143-35-3, 2143143-51-3, 1215039-22-7, 2143143-53-5, 454479-88-0, 1446696-38-3, 2143143-33-1, 2143143-45-5, 791136-90-8, 454479-87-9, 1329705-38-5, 221463-01-0, 791136-91-9, 251941-32-9, 190788-99-9, 2143143-43-3,2143143-40-0, 1329705-34-1, 889676-72-6, 462945-71-7, 251941-33-0, 450417-22-8, 450417-21-7, 2143143-46-6, 2143143-41-1, 885029-00-5, 1372784-48-9, 757964-79-7, 454479-85-7, 791136-92-0, 2136630-99-2, 885029-02-7, 155906 0-17-1, 1372784-47-8, 805248-26-4, 796113-88-7, 2760688-12-6, 343256-85-9, 805248-25-3, 705282-10-6, 1330003-46-7, 1329705-36-3, 462945-76-2, 2459616-84-1, 2411643-30-4, 796113-86-5, 449214-10-2, 215792-51-1, 262420-61-1, or 594815-59-5.

[0159] Embodiment 33. The method of Embodiment 32, wherein L is a compound of formula (T) comprising CAS having a group selected from the following. Compounds with the following numbers: 161265-03-8, 205497-65-0, 1182710-75-3, 2119686-35-8, 221462-97-1, 805248-24-2, 796113-87-6, 805248-23-1, 885028-98-8, 885029-00-5, 757964-79-7, 2459616-84-1, 2411643-30-4, 796113-86-5, 449214-10-2, 215792-51-1, 262420-61-1, or 594815-59-5.

[0160] Example 34. The method of Example 27, wherein L is a compound of formula (T) which comprises a compound having the following formula: or.

[0161] Example 35. The method of Example 34, wherein L is a compound of formula (T) which comprises a compound having the following formula:

[0162] Example 36. The method of any one of Examples 1 to 35, wherein the Pd catalyst comprises a compound of the formula [(Xanthphos)Pd(allyl)]Cl having the following structure:

[0163] Example 37. The method of any one of Examples 1 to 36, wherein the Pd-ligand catalyst is present in the following amounts: about 0.1 mol% to about 1 mol%, about 0.1 mol% to about 0.8 mol%, about 0.1 mol% to about 0.6 mol%, about 0.1 mol% to about 0.5 mol%, about 0.125 mol% to about 0.5 mol%, about 0.05 mol% to about 0.8 mol%, about 0.05 mol% to about 0.6 mol%, about 0.05 mol% to 0.5 mol%.

[0164] Example 38. The method of any one of Examples 1 to 37, wherein the Pd catalyst is present in an amount of about 0.1 mol% to 0.6 mol% or about 0.125 mol% to about 0.6 mol%.

[0165] Example 39. The method of any one of Examples 1 to 38, wherein the Pd-ligand catalyst is present in about 0.1%, 0.125%, 0.25% or about 0.5 mol%.

[0166] Example 40. The method of any one of Examples 1 to 39, wherein the aqueous acid is a carboxylic acid.

[0167] Example 41. The method of any one of Examples 1 to 40, wherein the aqueous acid is acetic acid, formic acid or oxalic acid.

[0168] Example 42. The method of any one of Examples 1 to 41, wherein the aqueous acid is acetic acid.

[0169] Example 43. The method of any one of Examples 1 to 39, wherein the aqueous acid is sulfonic acid.

[0170] Example 44. The method of any one of Examples 1 to 39, wherein the aqueous acid is H2SO4, methanesulfonic acid, trifluoromethanesulfonic acid or p-toluenesulfonic acid.

[0171] Example 45. The method of any one of Examples 1 to 39, wherein the aqueous acid is HCl, HNO3 or H3PO4.

[0172] Example 46. The method of any one of Examples 1 to 45, wherein step 1 is performed at a temperature of about 50°C to about 70°C.

[0173] Example 47. The method of any one of Examples 1 to 46, wherein step 1 is performed at a temperature of 60°C + / - 10°C.

[0174] Example 48. The method of any one of Examples 1 to 47, wherein step 2 further comprises crystallizing the compound of formula (I) after deprotecting the compound of formula (Ia).

[0175] Example 49. The method of Example 48, wherein the crystallization is carried out by adding a reaction mixture containing the compound of formula (I) to an aqueous solution containing a base.

[0176] Example 50. The method of any one of Examples 1 to 49, wherein the compound of formula (II) comprises the following compounds: , , , , , , , , , , , , , , , , or.

[0177] Example 51. The method of any one of Examples 1 to 49, wherein the compound of formula (III) comprises the following compounds: , , , , , , , , , or , or salts thereof.

[0178] Example 52. The method of any one of Examples 1 to 49, wherein the compound of formula (Ia) comprises the following compounds: , ...

[0179] Example 53. The method of any one of Examples 1 to 52, wherein the compound of formula (III) is not a salt.

[0180] Example 54. The method of any one of Examples 1 to 53, wherein the compound of formula (I) comprises the following compounds: , ...

[0181] Example 55. The method of any one of Examples 1 to 54, wherein the compound of formula (I) comprises the following compounds: , , , , or.

[0182] Example 56. The method of any one of Examples 1 to 55, wherein the compound of formula (I) comprises the following compound: or.

[0183] Example 57. A method for synthesizing compound of formula (1): (1) wherein the method comprises: (1) reacting compound of formula (2) with compound of formula (3) in a reaction mixture comprising toluene, a Pd-ligand catalyst comprising [(Xanthphos)Pd(allyl)]Cl and a base selected from sodium tri-pentoxide or sodium tri-butoxide, thereby synthesizing compound of formula (1a); and (2) deprotecting compound of formula (1a) from step 1 in a reaction mixture comprising toluene and an aqueous acid, thereby synthesizing compound of formula 1.

[0184] Example 58. The method as in Example 57, wherein the base is sodium tripentoxide.

[0185] Example 59. The method of Example 57, wherein the Pd-ligand catalyst is present in the following amounts: about 0.1 mol% to about 1 mol%, about 0.1 mol% to about 0.8 mol%, about 0.1 mol% to about 0.6 mol%, about 0.1 mol% to about 0.5 mol%, about 0.125 mol% to about 0.5 mol%, about 0.05 mol% to about 0.8 mol%, about 0.05 mol% to about 0.6 mol%, about 0.05 mol% to 0.5 mol%.

[0186] Example 60. The method of Example 60, wherein the Pd-ligand catalyst is present in an amount of about 0.1 mol% to 0.6 mol% or about 0.125 mol% to about 0.6 mol%.

[0187] Example 61. The method of any one of Examples 59 or 60, wherein the Pd-ligand catalyst is present in about 0.1%, 0.125%, 0.25% or about 0.5 mol%.

[0188] Example 62. The method of any one of Examples 59 to 61, wherein step 1 is performed at a temperature of about 50°C to about 70°C.

[0189] Example 63. The method of any one of Examples 59 to 62, wherein step 1 is performed at a temperature of 60°C + / - 10°C.

[0190] Example 64. The method of any one of Examples 59 to 63, wherein step 2 further comprises crystallizing the compound of formula (1) after deprotecting the compound of formula (1a).

[0191] Example 65. The method of Example 64, wherein the crystallization is carried out by adding a reaction mixture containing the compound of formula (1) to an aqueous solution containing a base.

[0192] Example: Synthesis of 2,6-difluoro-4-[[1-(3-fluoropropyl)-3-tetrahydroacryl]amino]benzaldehyde (compound 1)

[0193] Step 1: Dissolve 1-(3-fluoropropyl)-3-azacyclobutamine-1,2-ethanedisulfonic acid (1:1) (compound 3.1) (200.1 kg) in a mixture of acetonitrile (745 kg) and 1,8-diazabicyclo[5.4.0]undecyl-7-ene (DBU) (178.4 kg). Exchange the solvent for toluene at a constant volume under reduced pressure (using 1218 kg of toluene). Filter the resulting suspension, and wash the filter cake with toluene (900 kg) to obtain a toluene solution of 1-(3-fluoropropyl)-3-azacyclobutamine (compound 3). Discard the filter cake.

[0194] Step 2: A mixture of 4-bromo-2,6-difluorobenzaldehyde (118.3 kg), toluenesulfonic acid monohydrate (0.256 kg), and triethyl orthoformate (91.3 kg) in toluene (307 kg) was stirred at 20°C for 2 hours. The resulting toluene solution of 5-bromo-2-(diethoxymethyl)-1,3-difluorobenzene (compound 2) was combined with the toluene solution of compound 3. The mixture was concentrated to 10 L / kg under reduced pressure. [XantPhos Pd(allyl)]Cl (1.22 kg), toluene (30 kg), and NaOt-Pent (30% toluene solution; 284.8 kg) were added to the mixture. The mixture was stirred at 60°C for 3 hours. The reaction mixture was then quenched with water (323 kg). The layers were separated, and the aqueous layer was discarded.

[0195] Step 3: Add acetic acid (50.6 kg) and water (420 kg) to the organic layer containing N-[4-(diethoxymethyl)-3,5-difluorophenyl]-1-(3-fluoropropyl)-3-azacyclobutylamine (compound 1a), and stir the mixture at 20°C for 4 hours. Separate the layers. Add water (191 kg) to the organic layer and separate the layers. Discard the organic layer. Combine the aqueous layers, rinse with water (143 kg), and add a mixture of water (676 kg) and aqueous sodium hydroxide (28% w / w; 114.7 kg), and inoculate 2,6-difluoro-4-[[1-(3-fluoropropyl)-3-tetrahydroacryl]amino]benzaldehyde (compound 1) (0.143 kg) crystals at 20°C. Filter the suspension. The wet cake was washed with water (1440 kg) and then dried under reduced pressure. 100 kg of compound 1 was isolated (69% yield).

[0196] Previous studies have identified BrettPhos Pd G3 as a catalyst for the synthesis of compound 1a and the final compound 1. (See, for example, J. Med. Chem. 2021, 64, 11841-11856; Org. Process Res. Dev. 2022, 26, 568-582; Org. Process Res. Dev. 2022, 26, 560-567; U.S. Patent No. 9980947; U.S. Patent Publication Nos. 2020002331, 2022002304). These syntheses share common features including the use of BrettPhos Pd G3 catalyst and downstream Pd removal. The reported yields and conversion percentages of compounds 1a to 1 are good. However, it is known that G3 pre-catalysts such as BrettPhos release carbazole upon activation. (J. Org. Chem. 2015, 80, 6794-6813; J. Org. Chem. 2014, 79, 4161-4166.).

[0197] Carbazole byproducts have been shown to have several drawbacks, including their ability to coordinate with metal centers and inhibit the catalytic activity of palladium catalysts (Angew. Chem. Int. Ed. 2015, 54, 8259–8262). Carbazole can also act as an acceptor in N-arylation reactions, thereby consuming aryl halide reagents in a nonproductive manner and generating additional byproducts (Org. Lett. 2013, 15, 5602–5605). Carbazole is a suspected mutagen and carcinogen, requiring strict analytical control. Reactions using BrettPhos Pd G3 typically employ downstream metal scavengers and treatment methods for Pd removal, including, for example, the addition of triphenylphosphine (PPh3) and / or N-acetycysteine ​​after the reaction. Finally, the reported synthesis using BrettPhos Pd G3 has a higher catalyst loading than that described and used herein, and may therefore significantly increase time, cost, and waste.

[0198] To help overcome the aforementioned difficulties and provide a more efficient synthetic route for compound 1, this paper investigates novel Pd catalysts. A novel Pd catalyst, [Pd(allyl)(XantPhos)]Cl, was found to replace BrettPhos Pd G3 and, in the presence of an alkoxy base such as sodium pentoxide, yields high conversion and product yield. Catalysts including those with different ligands and Pd sources were screened. Following the following protocol, for the conversion to compound 1a, the catalyst was tested in toluene using NaOtBu as a base at concentrations of 0.5–0.125 mol%. The reaction was tested at 60 °C for 4 hours, then stopped, and the conversion percentage and product yield were evaluated.

[0199] Table 1 below provides a comparison of the tests. BrettPhos Pd G3 was tested at 0.5 mol%.

[0200] Table 1: Comparison of Pd Catalysts BrettPhos Pd G3 0.5 mol % Conversion % product% 76.4 62.66 [(Xanthphos)Pd(allyl)]Cl 0.5 mol % 0.25 mol % 0.125 mol % Conversion % product% Conversion % product% Conversion % product% 99.21 88.27 98.97 88.10 98.94 88.48 [(dppf)Pd(allyl)]OTf 0.5 mol % 0.25 mol % 0.125 mol % Conversion % product% Conversion % product% Conversion % product% 98.82 87.39 91.27 80.07 67.29 53.76

[0201] Catalysts containing xanthphos and dppf ligands exhibited higher conversion percentages and product yields, exceeding the BrettPhos control under similar conditions (0.5 mol%). At the tested mol%, the conversion percentage or product yield of the catalyst containing xanthphos ligands showed almost no change. Conversely, the catalyst containing dppf ligands showed lower conversion and product yields with decreasing catalyst amount. Therefore, for the conversion provided in step 1 of the method presented herein, the catalyst containing xanthphos ligands is the preferred ligand.

[0202] Catalysts containing xanthphos ligands provide high conversion and yield. Modification of the xanthphos ligand was investigated to determine its effect on yield and conversion. Replacing the xanthphos ligand with a dimethyl "bridge" yielded almost no conversion or product yield. See Table 2. Similarly, replacing the phenyl moiety also yielded no conversion or product yield. However, the addition of substituents to the benzene ring is acceptable.

[0203] The xanthphos-derived ligands were tested using the conditions listed below. L represents the portion provided.

[0204] Table 2: Various Xanthphos ligands L-structure L Name Conversion % product% [(Xanthphos)Pd(allyl)]Cl 78.1 64.5 [Pd(N-XantPhos)(allyl)Cl] 0.3 0.2 [Pd(DPEPhos)(allyl)Cl] 1.3 0.8 [Pd(tBu-XantPhos)(allyl)Cl] 0 0 [Pd(4-OMe-XantPhos)(allyl)Cl] 71.9 58.0

[0205] Further testing of this method includes changing the palladium source. Various Pd sources are shown in Table 3. The reaction is carried out under the conditions listed below, where X is allyl, tBu-indenyl, G2, G3, or Cl2.

[0206] Table 3 shows the effect of the Pd source on conversion and product yield. The conversion and yield of XantPhos G2 and G3 catalysts and the dichloride catalyst were poor. 0.05 mol% of the allyl xanthphos catalyst described herein produced high conversion and yield.

[0207] Table 3: Various Pd Sources structure name Conversion % product% [(Xanthphos)Pd(allyl)]Cl 80.8 66.7 [(Xanthphos)Pd(tBu-indene)]Cl 70.87 56.84 Pd(XantPhos)G2 33.6 23.5 Pd(XantPhos)G3 34.3 23.7 Pd(XantPhos)Cl2 20.6 13.5

[0208] The Pd catalysts and conditions discovered in this paper provide a robust synthetic method for high conversion and product yield of compound 1a. As shown in Table 4, the catalyst loading of BrettPhos Pd G3 is 10 times that of the xanthphos catalyst described in this paper. The conditions of the method discovered in this paper also allow for the rationalization of downstream post-processing and the removal of Pd removal processes found in other methods.

[0209] Table 4: Comparison of [Pd(allyl)(Cl)(XantPhos)] and Brettphos Pd G3 Pd(BrettPhos)G3 [Pd(allyl))(XantPhos](Cl) Catalyst Support 1 mol % 0.1 mol % *purity >96% >96% Time to achieve >80% conversion 1-3 hours 3 h Yield percentage 78-84% 83% Pd removal treatment 1. Add PPH3 2. Add N-acetylcysteine none Pd amount 28-67 ppm 100 ppm *0.1-0.3 mol%, depending on the control of the reaction and other catalyst poisons (e.g., acetonitrile).

[0210] Although the invention has been described in detail with reference to illustrations and examples for clarity, such descriptions and examples should not be construed as limiting the scope of the invention. All disclosures of patents and scientific literature cited herein are expressly incorporated herein by reference in their entirety.

Claims

1. A method (P1) for preparing a compound of formula (I) or a salt thereof, the method comprising the steps of: (1) reacting a reaction mixture according to step 1 below to form a compound of formula (Ia), the reaction mixture comprising: (a) an organic solvent comprising toluene, dialkylene, or tri-pentanol; (b) a compound of formula (II); (c) a compound of formula (III) or a salt thereof; (d) a Pd catalyst; and (e) a base: wherein, Ring A is phenyl or pyridinyl; X is a halogroup, toluenesulfonate, methanesulfonate, or trifluoromethanesulfonate; PG is a protected aldehyde, wherein X and PG are para-positioned on each other on ring A; R1 is H, F, Cl, or CN; each R2 is independently a halogroup, Me, or CN; n is an integer of 1, 2, 3, 4, or 5; p is an integer of 0, 1, or 2; the base includes an alkoxide base; and the Pd catalyst includes the formula [Pd(L)(allyl)](X1), wherein L is selected from 1,1'-bis(diphenylphosphine)ferrocene (dppf) or a Xanthphos derivative having formula (T); and (T) wherein: Ra and Rb are each independently hydrogen or C1-6 alkyl; Rc, Rd, Re, and Rf Each of the following is independently hydrogen, halogen, NH2, C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 alkoxy or C1-3 haloalkyl; and q, r, s and u are each independently an integer from 0 to 5; and X1 is a halogen, OMs or OTf; and (2) the compound of formula (Ia) is deprotected in a reaction mixture containing an aqueous acid to form the compound of formula (I): , wherein the aqueous acid is HCl, HNO3, H3PO4, NaH2PO4, H2SO4, sulfonic acid or carboxylic acid.

2. The method of request item 1, wherein ring A is phenyl.

3. The method of claim 1, wherein ring A is pyridyl.

4. The method of any one of requests 1 to 3, where X is a halogen.

5. The method of any one of requests 1 to 3, where X is Br.

6. The method of any one of claims 1 to 3, wherein X is toluenesulfonate, methanesulfonate or trifluoromethanesulfonate.

7. The method of any one of requests 1 to 3, where n is 2.

8. The method of any one of the requests 1 to 3, where n is 3.

9. The method of any one of the requests 1 to 3, wherein R1 is H, F, Cl or CN.

10. The method of any one of requests 1 to 3, where R1 is F or CN.

11. The method of any one of the requests 1 to 3, where R1 is F.

12. The method of any one of claims 1 to 3, wherein each R2 is independently a halogen.

13. The method of any one of the requests 1 to 3, wherein each R2 is independently F or Cl.

14. The method of any one of the requests 1 to 3, wherein each R2 is independently F.

15. The method of any one of requests 1 to 3, where p is 0.

16. The method of any one of the requests 1 to 3, where p is 2.

17. The method of any one of requests 1 to 3, wherein each R2 is independently F and p is 2.

18. The method of any one of claims 1 to 3, wherein PG is diethyl acetal.

19. The method of any one of claims 1 to 3, wherein the base is a sodium alkoxide or a potassium alkoxide.

20. The method of claim 19, wherein the alkoxide base includes a methanol salt, an ethanol salt, a butanol salt, a tert-butanol salt, a pentanol salt, or a tert-pentanol salt.

21. The method of any one of claims 1 to 3, wherein the base is sodium tripentoxide, sodium tributoxide, potassium tripentoxide, or potassium tributoxide.

22. The method of any one of claims 1 to 3, wherein the base is sodium tripentoxide or sodium tributoxide.

23. The method of claim 22, wherein the base is sodium tripentoxide.

24. The method of any one of claims 1 to 3, wherein the organic solvent used in step 1 comprises toluene.

25. The method of any one of claims 1 to 3, wherein the L of the Pd catalyst comprises 1,1'-bis(diphenylphosphine)ferrocene (dppf).

26. The method of any one of claims 1 to 3, wherein the Pd catalyst comprises the formula [(dppf)Pd(allyl)]OTf.

27. The method of any one of claims 1 to 3, wherein the L of the Pd catalyst comprises a Xanthphos derivative having formula (T); (T) wherein: Ra and Rb are each independently hydrogen or C1-6 alkyl; Rc, Rd, Re and Rf are each independently hydrogen, halogen, NH2, C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 alkoxy or C1-3 haloalkyl; and q, r, s and u are each independently an integer from 0 to 5.

28. The method of request item 27, wherein Ra and Rb are the same.

29. The method of request item 27, wherein Rc, Rd, Re and Rf are the same.

30. The method of claim 27, wherein Rc, Rd, Re and Rf are independently hydrogen or C1-3 alkoxy groups.

31. The method of request item 27, wherein q, r, s and u are each an independent integer of 0, 1 or 2.

32. The method of claim 27, wherein L is a compound of formula (T) comprising compounds having CAS numbers selected from the group consisting of: 161265-03-8; 205497-65-0; 2119686-40-5; 2119686-45-0; 2119686-39-2; 2119686-51-8; 2119686-52-9; 2119686-38-1; 1810068-85-9; 2119686-44-9; 2254460-12-1; 2119686-37-0; 2119686-49-4; 2119686-53-0; 2119686-36-9; 2119686-48-3; 2119686-43-8; 1182710-75-3; 2143143-32-0; 2119686-35-8; 2119686-42-7; 2119686-13-2; 2119686-12-1; 2300982-02-7; 2172792-28-6; 2231776-00-2; 2119686-41-6; 221462-97-1; 2300978-33-8; 1372784-49-0; 757964-78-6; 2119686-47-2; 805248-24-2; 796113-87-6; 2119686-50-7; 2143143-50-2; 2143143-49-9; 2119686-46-1; 1607019-61-3; 2143143-36-4; 2143143-48-8; 757964-80-0d; 805248-23-1; 2143143-37-5; 2904636-03-7 ; 2143143-38-6; 2143143-34-2; 2143143-47-7; 1642150-80-8; 639477-10-4; 2143143-42-2; 2143143-52-4; 2143143-44-4; 2143143-39-7; 885029-01-6; 885028-98-8; 2143143-35-3; 2143143-51-3; 1215039-22-7; 2143143-53-5; 454479-88-0; 1446696-38-3 ; 2143143-33-1 ;2143143-45-5; 791136-90-8; 454479-87-9; 1329705-38-5; 221463-01-0; 791136-91-9; 251941-32-9; 190788-99-9; 2143143-43-3; 2143143-40-0; 1329705-34-1; 889676-72-6; 462945-71-7; 251941-33-0; 450417-22-8; 450417-21-7; 2143143-46-6; 2143143-41-1; 885029-00-5; 1372784-48-9; 757964-79-7; 454479-85-7; 791136-92-0; 2136630-99-2; 885029-02-7; 1559060-17-1; 1372784-47-8; 805248-26-4; 796113-88-7; 2760688-12-6; 343256-85-9; 805248-25-3; 705282-10-6; 1330003-46-7; 1329705-36-3; 462945-76-2; 2459616-84-1; 2411643-30-4; 796113-86-5; 449214-10-2; 215792-51-1; 262420-61-1; or 594815-59-5.

33. The method of claim 32, wherein L is a compound of formula (T) comprising compounds having CAS numbers selected from the group consisting of: 161265-03-8; 205497-65-0; 1182710-75-3; 2119686-35-8; 221462-97-1; 805248-24-2; 796113-87-6; 805248-23-1; 885028-98-8; 885029-00-5; 757964-79-7; 2459616-84-1; 2411643-30-4; 796113-86-5; 449214-10-2; 215792-51-1; 262420-61-1; or 594815-59-5.

34. The method of claim 27, wherein L is a compound of formula (T) which includes compounds having the following formula: or.

35. The method of claim 34, wherein L is a compound of formula (T) which includes compounds having the following formula: .

36. The method of any one of claims 1 to 3, wherein the Pd catalyst comprises a compound of the formula [(Xanthphos)Pd(allyl)]Cl having the following structure:

37. The method of any one of claims 1 to 3, wherein the Pd-ligand catalyst is present in an amount of 0.1 mol% to 1 mol.

38. The method of claim 37, wherein the Pd catalyst is present in an amount of 0.1 mol% to 0.6 mol%.

39. The method of claim 37, wherein the Pd-ligand catalyst is present in an amount of 0.1%, 0.125%, 0.25%, or about 0.5 mol%.

40. The method of any one of claims 1 to 3, wherein the aqueous acid is a carboxylic acid.

41. The method of any one of claims 1 to 3, wherein the aqueous acid is acetic acid, formic acid or oxalic acid.

42. The method of any one of claims 1 to 3, wherein the aqueous acid is acetic acid.

43. The method of any one of claims 1 to 3, wherein the aqueous acid is a sulfonic acid.

44. The method of any one of claims 1 to 3, wherein the aqueous acid is H2SO4, methanesulfonic acid, trifluoromethanesulfonic acid or p-toluenesulfonic acid.

45. The method of any one of claims 1 to 3, wherein the aqueous acid is HCl, HNO3 or H3PO4.

46. ​​The method of any one of claims 1 to 3, wherein step 1 is performed at a temperature of 50°C to 70°C.

47. The method of any one of claims 1 to 3, wherein step 1 is performed at a temperature of 60°C + / - 10°C.

48. The method of any one of claims 1 to 3, wherein step 2 further comprises: crystallizing the compound of formula (I) after deprotecting the compound of formula (Ia).

49. The method of claim 48, wherein the crystallization is carried out by adding a reaction mixture containing a compound of formula (I) to an aqueous solution containing a base.

50. The method of any one of claims 1 to 3, wherein the compound of formula (II) comprises the following compounds: , ...

51. The method of any one of claims 1 to 3, wherein the compound of formula (III) comprises the following compounds: , , , , , , , , , or , or salts thereof.

52. The method of any one of claims 1 to 3, wherein the compound of formula (Ia) includes compounds of the following formulas: , ...

53. The method of any one of claims 1 to 3, wherein the compound of formula (III) is not a salt.

54. The method of any one of claims 1 to 3, wherein the compound of formula (I) includes compounds of the following formulas: , ...

55. The method of any one of claims 1 to 3, wherein the compound of formula (I) includes compounds of the following formulas: , , , , or.

56. The method of any one of claims 1 to 3, wherein the compound of formula (I) includes compounds of the following formulas: , or .

57. A method for synthesizing a compound of formula (1): (1) wherein the method comprises: (1) reacting a compound of formula (2) with a compound of formula (3) in a reaction mixture to synthesize a compound of formula (1a), the reaction mixture comprising: toluene; a Pd-ligand catalyst comprising [(Xanthphos)Pd(allyl)]Cl; and a base selected from sodium tri-pentoxide or sodium tri-butoxide; and (2) deprotecting the compound of formula (1a) from step 1 in a reaction mixture comprising toluene and an aqueous acid to synthesize a compound of formula (1).

58. The method of claim 57, wherein the base is sodium tripentoxide.

59. The method of claim 57, wherein the Pd-ligand catalyst is present in an amount of 0.1 mol% to 1 mol%.

60. The method of claim 59, wherein the Pd-ligand catalyst is present in an amount of 0.1 mol% to 0.6 mol%.

61. The method of claim 59 or 60, wherein the Pd-ligand catalyst is present in an amount of 0.1%, 0.125%, 0.25%, or 0.5 mol%.

62. The method of claim 57, wherein step 1 is performed at a temperature of 50°C to 70°C.

63. The method of claim 57, wherein step 1 is performed at a temperature of 60°C + / - 10°C.

64. The method of claim 57, wherein step 2 further comprises: crystallizing the compound of formula (1) after deprotecting the compound of formula (1a).

65. The method of claim 64, wherein the crystallization is carried out by adding a reaction mixture containing the compound of formula (1) to an aqueous solution containing a base.