JP2021075535A - Chemical process for preparing pyrimidine derivatives and intermediates thereof - Google Patents

Abstract

To provide a process for preparing ceritinib and/or intermediates thereof.SOLUTION: There is provided a process for preparing (C2-1), an intermediate of ceritinib synthesis, comprising the step of reacting (A) with (B) in a solvent in the presence of at least one catalyst, wherein P is a protecting group and T and X1 independently denote Cl and the like.SELECTED DRAWING: None

Description

Fields of Disclosure This disclosure belongs to the field of organic synthesis, 5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4- [2- (propane-2). -Sulfonyl) -phenyl] -pyrimidine-2,4-diamine (seritinib) and / or a method for synthesizing an intermediate thereof, a method for further preparing a drug and a pharmaceutical composition from ceritinib or an intermediate, ceritinib and the intermediate itself. Intended for the use of intermediates to prepare.

Disclosure Background Anaplastic lymphoma kinase (ALK) is a member of the insulin receptor superfamily to which the receptor tyrosine kinase belongs. Chromosomal rearrangements involving ALK have been detected in a variety of human malignancies, including carcinogenesis in hematopoietic and non-hematopoietic tumors, and impair the regulatory pathways of cells. Inhibition or suppression of the ALK pathway with ALK tyrosine kinase inhibitors results in cell proliferation arrest and apoptosis of malignant cells. AL
Studies of K fusion proteins have also shown the potential of new therapeutic agents for patients with ALK-positive malignancies.

Ceritinib has the chemical formula 5-chloro-N2- (2-isopropoxy-5-methyl-4- (2-isopropoxy-5-methyl-4- (
Piperidine-4-yl) phenyl) -N4- [2- (propane-2-sulfonyl) -phenyl] -pyrimidine-2,4-diamine is an ALK inhibitor. The preparation method is disclosed in International Publication No. 2008/073687 pamphlet.

Summary of Disclosure Chemical methods are usually carried out on a small scale during the research / initial development stage and are continuously scaled up in late development to eventually reach full size production scale. .. By scaling up the method, matters related to the safety of the method become more and more important. Failure to scale up properly can result in process control and accidents such as unexpected exothermic reactions (runaway reactions), high hazards and / or health hazards during the handling of toxic chemicals, or environmental hazards. There is.

Surprisingly, ceritinib (5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidine-4-yl) phenyl) -N4- [2- (propane-2-sulfonyl) -phenyl] -Pyrimidine-2,4-diamine) and its intermediates
It has become clear that preparations can be made using cost-effective and safer methods. Therefore, the present disclosure is a reproducible method that uses less harmful chemicals and / or reaction conditions, reduces waste generation, and is easier to scale up and handle, ie, more efficient. It is intended for novel synthetic methods of ceritinib and its intermediates, which provide a way to produce better quality compounds.

The first aspect of the present disclosure is a compound of formula (C2-1).

［式中、Ｐは保護基である］
である。

[In the formula, P is a protecting group]
Is.

Another aspect of the present disclosure is a method of preparing a compound of formula (C2-1), wherein the formula (A)

の化合物と、式（Ｂ）

Compound and formula (B)

の化合物を溶媒中で、少なくとも１種の触媒、および場合によって共触媒または添加剤の
存在下で反応させるステップを含み、式中、
Ｐは保護基であり、
ＴおよびＸ１は独立して、Ｃｌ、Ｂｒ、Ｉ、ＯＴｆ、ＯＴｓ、ＯＰｉｖ、ＭｇＣｌ、Ｍｇ
Ｂｒ、ＭｇＩ、Ｓｎ（アルキル）_３、Ｓｉ（アルキル）_３、Ｓｉ（Ｏアルキル）_３、Ｚｎ
Ｃｌ、ＺｎＢｒ、ＺｎＩ、Ｚｎ（アルキル）、Ｂ（ＯＨ）_２、Ｂ（ＯＣ（ＣＨ_３）_２Ｃ（
ＣＨ_３）_２Ｏ）、９−ＢＢＮ、Ｂ（Ｓｉａ）_２、Ｂ（Ｃａｔ）、Ｂ（Ｃｙ）_２、ＢＦ_３ ⁻
、Ｂ（ＭＩＤＡ）からなる群から選択することができる、方法を提供する。

In the formula, comprising the step of reacting the compounds of the above in a solvent in the presence of at least one catalyst and optionally a co-catalyst or additive.
P is a protecting group
T and X1 are independently Cl, Br, I, OTf, OTs, OPiv, MgCl, Mg
Br, MgI, Sn (alkyl) ₃ , Si (alkyl) ₃ , Si (O alkyl) ₃ , Zn
Cl, ZnBr, ZnI, Zn (alkyl), B (OH) ₂ , B (OC (CH ₃ ) ₂ C (
_{CH 3) 2 O), 9} -BBN, B (Sia) 2, B (Cat), B (Cy) 2, BF 3 -
, B (MIDA), which can be selected from the group.

Another aspect of the present disclosure is a method of preparing a compound of formula (C2-1), which is of formula (C2-3).
)

の化合物を、

Compound,

（ピリジニウム−Ｐ）と溶媒中で反応させて、化合物（Ｃ２−２）

Reaction with (pyridinium-P) in a solvent to compound (C2-2)

を生成させるステップと、
化合物（Ｃ２−２）を変換して、式（Ｃ２−１）

And the steps to generate
Converting compound (C2-2) to formula (C2-1)

の化合物を形成するステップと
を含み、式中、
Ｐは保護基であり、
ＺはＭｇＣｌ、ＭｇＢｒ、ＭｇＩ、ＺｎＣｌ、ＺｎＢｒ、ＺｎＩ、Ｚｎ（アルキル）から
選択される、
方法に関する。化合物（Ｃ２−２）は、還元およびニトロ化によって式（Ｃ２−１）の化
合物が得られるように変換される、方法である。

Including the step of forming the compound of
P is a protecting group
Z is selected from MgCl, MgBr, MgI, ZnCl, ZnBr, ZnI, Zn (alkyl),
Regarding the method. Compound (C2-2) is a method that is converted by reduction and nitration to obtain the compound of formula (C2-1).

Another aspect of the present disclosure is formula (C2).

の化合物またはその塩を調製する方法であって、式（Ｃ２−１）の化合物の還元および脱
保護のステップを含む方法に関する。

A method for preparing a compound of the above, or a salt thereof, which comprises the steps of reducing and deprotecting the compound of formula (C2-1).

Another aspect of the present disclosure is a method of preparing a compound of formula (C2) or a salt thereof, wherein formula (C)

の化合物を溶媒中で、少なくとも１種の触媒および水素の存在下で還元するステップ
を含む方法に関する。

The present invention relates to a method comprising a step of reducing a compound of the above in a solvent in the presence of at least one catalyst and hydrogen.

Another aspect of the present disclosure is a one-pot method of preparing a compound of formula (C) or a salt thereof, wherein the formula (AA) is in a solvent.

の化合物を、式Ｄ

Compound of, formula D

の化合物と、Ｘ_３Ｂ（Ｘ_２）_２、少なくとも１種の触媒、塩基、および場合によってリガ
ンドの存在下で、式（Ｅ）

In the presence of the compounds of X ₃ B (X ₂ ) ₂ , at least one catalyst, base, and optionally ligand, formula (E).

の化合物を単離することなく反応させるステップを含み、式中、
Ｙは、Ｂｒ、Ｃｌ、Ｉ、ＯＴｆ、ＯＴｓ、ＯＰｉｖおよびＯＭｓから選択され、
Ｘ_４は、Ｂｒ、Ｃｌ、Ｉ、ＯＴｆ、ＯＴｓ、ＯＰｉｖおよびＯＭｓから選択され、
Ｂ（Ｘ_２）_２は、Ｂ（ＯＨ）_２、Ｂ（ＯＣ（ＣＨ_３）_２Ｃ（ＣＨ_３）_２Ｏ）、９−ＢＢＮ
、Ｂ（Ｓｉａ）_２、Ｂ（ｃａｔ）、Ｂ（Ｃｙ）_２、ＢＦ_３ ⁻およびＢ（ＭＩＤＡ）から選
択され、
Ｘ_３はＨ、Ｂ（Ｘ_２）_２である、方法に関する。

In the formula, which comprises the step of reacting the compounds of
Y is selected from Br, Cl, I, OTf, OTs, OPiv and OMs.
X ₄ is selected from Br, Cl, I, OTf, OTs, OPiv and OMs.
B (X ₂ ) ₂ is B (OH) ₂ , B (OC (CH ₃ ) ₂ C (CH ₃ ) ₂ O), 9-BBN.
_{, B (Sia) 2, B} (cat), B (Cy) 2, BF 3 - is selected from and B (MIDA),
X ₃ relates to a method, H, B (X ₂ ) _2.

Another aspect of the present disclosure is formula (C3-1).

［式中、Ｘは、ハロゲン（Ｆ、Ｃｌ、Ｂｒ、Ｉ）、アルコキシ、アリールオキシ、アルキ
ルチオ、スルフィニルおよびスルホニルから選択される］
の化合物を提供する。

[In the formula, X is selected from halogen (F, Cl, Br, I), alkoxy, aryloxy, alkylthio, sulfinyl and sulfonyl]
Compounds are provided.

Another aspect of the present disclosure is a method of preparing a compound of formula (C3-1), wherein formula (F)

の化合物またはその塩を、式（Ｇ）

Compound or salt thereof, according to the formula (G)

の化合物と、塩基の存在下で、場合によって溶媒中で反応させるステップを含み、式中、
Ｘは、ハロゲン（Ｆ、Ｃｌ、Ｂｒ、Ｉ）、アルコキシ、アリールオキシ、アルキルチオ、
アリールチオ、スルフィニル、スルホニルから選択される、方法を提供する。

In the formula, it comprises the step of reacting with the compound of the above in the presence of a base, optionally in a solvent.
X is halogen (F, Cl, Br, I), alkoxy, aryloxy, alkylthio,
Provided is a method selected from arylthio, sulfinyl, sulfonyl.

Another aspect of the present disclosure is a method of preparing a compound of formula (C3).

（Ｃ３−１）を、溶媒中で酸化するプロセスを含み、式中、Ｘは、ハロゲン（Ｆ、Ｃｌ、
Ｂｒ、Ｉ）、アルコキシ、アリールオキシ、アルキルチオ、スルフィニル、スルホニルか
ら選択される、
方法に関する。

Including the process of oxidizing (C3-1) in a solvent, where X is halogen (F, Cl,
Selected from Br, I), alkoxy, aryloxy, alkylthio, sulfinyl, sulfonyl,
Regarding the method.

Another aspect of the present disclosure is a method of preparing a compound of formula (C3), wherein (i) formula (H).

の化合物を、式（Ｉ）

Compound of formula (I)

の化合物と反応させて、中間体を得るステップであって、式中、Ｍは、Ｌｉ、Ｎａ、Ｋ、
０．５Ｚｎ、０．５Ｃａから選択される、ステップと、
（ｉｉ）中間体を還元するステップと、
（ｉｉｉ）還元された中間体を、式（Ｇ）

In the formula, M is Li, Na, K, which is a step of reacting with the compound of
Steps selected from 0.5Zn and 0.5Ca,
(Ii) The step of reducing the intermediate and
(Iii) The reduced intermediate is expressed by the formula (G).

の化合物と塩基の存在下で反応させるステップであって、式中、Ｘは、ハロゲン（Ｆ、Ｃ
ｌ、Ｂｒ、Ｉ）、アルコキシ、アリールオキシ、アルキルチオ、スルフィニル、スルホニ
ルからなる群から選択される、ステップと
を含む方法を提供する。

In the formula, X is a halogen (F, C).
A method comprising a step selected from the group consisting of l, Br, I), alkoxy, aryloxy, alkylthio, sulfinyl, sulfonyl is provided.

Another aspect of the disclosure is a method of preparing ceritinib or a salt thereof.
i. Steps to prepare the compound of formula (C2-1) and
ii. The step of preparing the compound of formula (C2) or a salt thereof, and
iii. Steps to prepare compound (C3) and
iv. The present invention relates to a method comprising reacting a compound of formula (C2) or a salt thereof with a compound of formula (C3) to obtain ceritinib or a salt thereof.

Another aspect of the disclosure is a method of preparing ceritinib or a salt thereof.
(A) The step of preparing the compound of the formula (C2) or a salt thereof, and
(B) The step of preparing the compound of the formula (C3) and
(C) The present invention relates to a method comprising reacting a compound of formula (C2) or a salt thereof with a compound of formula (C3) to obtain ceritinib or a salt thereof.

Another aspect of the disclosure is a method of preparing ceritinib or a salt thereof.
(Aa) A step of preparing a compound of formula (C2) or a salt thereof, and
The step of preparing the compound of the formula (bb) formula (C3) and
(Cc) Provided is a method comprising reacting a compound of formula (C2) or a salt thereof with a compound of formula (C3) to obtain ceritinib or a salt thereof.

Another aspect of the disclosure is a method of preparing ceritinib or a salt thereof.
The step of preparing the compound of the formula (C2) or a salt thereof, and
The step of preparing the compound of formula (II) formula (C3-1) and
(III) A step of preparing a compound of formula (C3) from a compound of formula (C3-1), and
(IV) Provided is a method comprising reacting a compound of formula (C2) or a salt thereof with a compound of formula (C3) to obtain ceritinib or a salt thereof.

Another aspect of the present disclosure provides the use of a compound of formula (C2-1) for preparing ceritinib or a salt thereof.

Another aspect of the present disclosure provides the use of a compound of formula (C3-1) for preparing ceritinib or a salt thereof.

Another aspect of the present disclosure is formula (C2-2).

［式中、
Ｐは保護基である］
の化合物である。

[During the ceremony,
P is a protecting group]
It is a compound of.

Another aspect of the disclosure is the use of a compound of formula (C2-2) for preparing ceritinib or a salt thereof.

Detailed Description of Disclosure When increasing the amount of reactants and solvents to scale up the reaction to a full size production plant, process uncontrolled, unexpected exothermic reactions, accidents and large amounts of hazardous and / or toxic chemicals It has been found that it may pose some dangers such as safety issues during handling.

Surprisingly, seritinib (5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidine-4-yl) phenyl) -N4- [2- (propane-2-sulfonyl) -phenyl] By modifying the method of synthesizing −pyrimidine-2,4-diamine) and intermediates, it can be safely handled even when scaled up, the yield is reproducible, and there are few harmful / toxic chemicals. It has been clarified that a method that can be scaled up is obtained and that the amount of waste generated is reduced. Moreover, this method produces more efficient and better quality compounds at lower cost. The outline of this method is shown in Scheme 1. See below.

1.1 Compound of formula (C2-1) The first aspect of the present disclosure is an intermediate compound of formula (C2-1).

の化合物に関し、式中、Ｐは保護基であり、またはこの場合、窒素保護基である。式（Ｃ
２−１）の化合物を、セリチニブを調製するのに使用することができる。

In the formula, P is a protecting group, or in this case a nitrogen protecting group. Equation (C
The compound of 2-1) can be used to prepare ceritinib.

The terms "protecting group" or "nitrogen protecting group" may be present, from unwanted secondary reactions such as acylation, etherification, esterification, oxidation, solvolysis and similar reactions of functional groups. It shall be protected. Protecting groups are characterized by the fact that the protecting groups are typically solvolyzed.
By reduction, photolysis, or even by enzymatic activity, for example under conditions similar to physiological conditions, easily, i.e. without undesired secondary reactions or with very limited undesired 2
It is easy to remove only by the next reaction, and it is not present in the final product. Experts understand or can easily determine which protecting groups are suitable for the reactions described above and below. Preferably, if two or more protecting groups are present in one of the described intermediates, their selection is when one of the protecting groups needs to be removed, eg under different conditions, eg one of them. One class is mild hydrolysis, the other class is hydrolysis under more severe conditions, one class is hydrolysis in the presence of acid, the other class is hydrolysis in the presence of base, or one class Is reductively cleaved (eg, by catalytic hydrogenation), while the other class can be selectively removed using two or more different protecting groups that can be cleaved, such as by hydrolysis. Suitable nitrogen protecting groups are commonly used in peptide chemistry, eg JFW McOmie, "Protective Groups in Organic Chemistry", Plenum Pres.
s, London and New York 1973, TW Greene and PGM Wuts, "Greene's Protectiv
e Groups in Organic Synthesis ", Fourth Edition, Wiley, New York 2007," The Pepti
des "; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and
New York 1981, and "Methoden der organischen Chemie" (Methods of Organic Chem)
istry), Houben Weyl, 4th edition, Volume 15 / I, Georg Thieme Verlag, Stuttgart 19
It can be found in the relevant chapters of well-established references such as 74. Preferred nitrogen-protecting groups are generally trialkylsilyl-C _1- C ₇ -alkoxy (eg, trimethylsilylethoxy), aryl, preferably phenyl, or heterocyclic groups (eg, benzyl, cumyl, benzhydryl, pyrrolidinyl, trityl, pyrrolyl). Dinylmethyl, 1-methyl-1,1-dimethylbenzyl, (phenyl) methylbenzene) mono-substituted, di-substituted or tri-substituted C ₁
~ C ₆ -alkyl, preferably C _1- C ₄ -alkyl, more preferably C _1- C ₂ -alkyl (eg, acetyl, allyl, tertbutyl), most preferably C ₁ -alkyl, where Aryl rings or heterocyclic groups are unsubstituted or, for example, C _{1 to} C ₇ -alkyl, hydroxy, C _{1 to} C ₇ -alkoxy, C _{2 to} C ₈ -alkanoyl-oxy, halogen, nitro, cyano, and CF. Substituted with one or more residues selected from the group consisting of _{3 , eg, 2 or 3; aryl-C 1-} C ₂ -alkoxycarbonyl (preferably phenyl-C _1- C _2- alkoxycarbonyl (e.g., benzyloxycarbonyl (Cbz), benzyloxymethyl (BOM), pivaloyloxymethyl _{(POM)); C 1 ~C} 10 - _{alkenyloxycarbonyl;} C 1 _{~C 6} - alkylcarbonyl (e.g., Acetyl or pivaloyl); C _{6 to} C ₁₀ -arylcarbonyl;
C _{1 to} C ₆ -alkoxycarbonyl (eg, tert-butoxycarbonyl (Boc),
Methylcarbonyl, trichloroethoxycarbonyl (Troc), pivaloyl (Piv)
, Allyloxycarbonyl); C _{6 to} C ₁₀ -aryl C _{1 to} C ₆ -alkoxycarbonyl (eg, 9-fluorenylmethyloxycarbonyl (Fmoc)); allyl or cinnamyl; sulfonyl or sulfenyl; succinimidyl group, silyl It contains a group (eg, triarylsilyl, trialkylsilyl, triethylsilyl (TES), trimethylsilylethoxymethyl (SEM), trimethylsilyl (TMS), triisopropylsilyl or tertbutyldimethylsilyl).

According to the present disclosure, the preferred protecting group (P) is tert-butyloxycarbonyl (Bo).
c), can be selected from the group consisting of benzyloxycarbonyl, methyloxycarbonyl or benzyl.

The compound of formula (C2-1) is a compound of formula (A) and at least one catalyst in a solvent, optionally co-catalyst or added, as specified in Scheme 2. It can be prepared by a method including a step of reacting in the presence of an agent. The reaction is usually heated. Suitable solvents used in the reaction are, for example, tetrahydrofuran (THF), 2-methyl-tetrahydrofuran, 1,4-dioxane, diethyl ether, toluene, dimethylformamide (DMF), dimethylacetamide (DMA), dimethyl sulfoxide (D).
MSO), dimethoxyethane (DME), dichloromethane, N-methyl-2-pyrrolidone (NMP), 1-butyl-2-pyrrolidone (NBP), acetonitrile, acetone, ethyl acetate, isopropyl acetate, tert-butyl acetate, pentane, hexane , Heptane, anisole, pyridine, triethylamine, dimethyl carbonate, water, methanol, ethanol, n
-Propanol, 2-propanol, n-butanol, 2-butanol, tert-butanol, or a mixture thereof.

The selection of a suitable protecting group (P) is difficult, but the preferred protecting group (P) is tert-butyloxycarbonyl (Boc), benzyloxycarbonyl, methyloxycarbonyl, ethyloxycarbonyl, allyloxycarbonyl, phenyloxycarbonyl. , Formyl, acetyl or benzyl. The most preferred protecting groups in this method are tert-butyloxycarbonyl (Boc), benzyloxycarbonyl, methyloxycarbonyl or benzyl.

In reaction scheme 2, T and X ₁ are independent, eg Cl, Br, I, OTf,
It can be selected from the group consisting of OTs and OPiv, or T can be metal species M. M is preferably a metal species containing a metal ion selected from the group consisting of Mg, Al, Zn, Zr, B, Sn and Si, and M is more preferably ZnCl, ZnBr and Zn.
I, Zn (alkyl), B (OH) ₂ , B (OC (CH ₃ ) ₂ C (CH ₃ ) ₂ O), 9-
_{BBN, B (Sia) 2,} B (Cat), B (Cy) 2, BF 3 - or B (MIDA)
Is. In general, T and X ₁ are independent, eg Cl, Br, I, OTf, OTs, O
Piv, MgCl, MgBr, MgI, Sn (alkyl) ₃ , Si (alkyl) ₃ , Si
(O-alkyl) ₃ , ZnCl, ZnBr, ZnI, Zn (alkyl), B (OH) ₂ , B
(OC (CH ₃ ) ₂ C (CH ₃ ) ₂ O), 9-BBN, B (Sia) ₂ , B (Cat),
^{_{B (Cy) 2, BF 3}} -, can be B (MIDA).

As used herein, the term "alkyl" refers to a group or portion of a group that is a linear or branched (once, or if desired, multiple times) branched carbon chain. It is C _{1 to} C ₈ −
It can be alkyl. "C ₁ -C 8 _-" refers to a radical, defines a moiety containing up to 8 carbon atoms, including eight at maximum, said portion is (one or more times) branched or straight-chain, terminal or It is bonded via non-terminal carbon. C _{1 to} C ₈ -alkyl are, for example, n
-Pentyl, n-hexyl or n-heptyl, n-octyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, especially methyl, ethyl, n-propyl, Isopropyl, n-butyl, isobutyl, s
They are ec-butyl and tert-butyl.

The catalyst used to carry out the reaction outlined in Scheme 2 is any catalyst of skill in the art of choice based on general textbooks. The catalyst is, for example, Pd (PPh ₃ ) ₂ Cl ₂
, Pd (PPh ₃ ) ₄ , Pd (dba) ₂ , Pd ₂ (dba) ₃ , Pd (OAc) ₂ , [
Pd (allyl) Cl] ₂ , Pd (dppf) Cl ₂ , PdBr ₂ (PtBu ₃ ) ₂ , Pd
Cl (crotyl) (PtBu ₃ ), Pd (PtBu ₃ ) ₂ , PdCl ₂ (Amphos)
₂ , PdCl (allyl) (Amphos), PdBr ₂ (Binap), PdCl ₂ (D)
CPP), PdCl ₂ (DiPrPF), PdCl ₂ (DiPrPF), Pd-PEPP
SI-IPr, chloro (2-dicyclohexylphosphino-2', 4', 6'-triisopropyl-1,1'-biphenyl) [2- (2-aminoethyl) phenyl)] palladium (II) (first Also known as a generation XPhos precatalyst), chloro (2-dicyclohexylphosphino-2', 4', 6'-triisopropyl-1,1'-biphenyl) [2
-(2'-Amino-1,1'-biphenyl)] Palladium (II) (2nd Generation XPhos)
Also known as a pre-catalyst), chloro (2-dicyclohexylphosphino-2', 6')
-Dimethoxy-1,1'-biphenyl) [2- (2-aminoethylphenyl)] palladium (II) (also known as the first generation SPhos precatalyst), chloro (2-dicyclohexylphosphino-2', 6'-dimethoxy-1,1'-biphenyl) [2- (2'-
Amino-1,1'-biphenyl]] Palladium (II) (also known as a second generation XPhos precatalytic), chloro (2-dicyclohexylphosphino-2', 6'-diisopropoxy-1,1- Biphenyl) [2- (2-aminoethylphenyl)] palladium (I
I) (also known as the first generation RuPhos precatalyst), chloro (2-dicyclohexylphosphino-2', 6'-diisopropoxy-1,1'-biphenyl) [2- (2'
-Amino-1,1'-biphenyl] Palladium (II) (also known as a second generation RuPhos precatalyst), Pd / C, Pd, Ni (acac) ₂ , NiCl ₂ , Ni (P)
Ph ₃ ) ₂ Cl ₂ , Ni (cod) ₂ , Ni (dppf) (cod), Ni (dppf)
(Shinnamil), Ni (dppf) ₂ , Ni (dppf) Cl ₂ , Ni (dpppp) Cl
₂ , NiCl ₂ (PCy ₃ ) ₂ , Ni (dppe) Cl ₂ , or a mixture thereof can be selected from the group.

Cocatalysts or additives are ZnCl ₂ , ZnBr ₂ , CuI, LiCl, PPh ₃ , P (
oTol) ₃ , P (oTol) Ph ₂ , P (pTol) ₃ , PtBu ₃ , PtBu ₃ * H
BF ₄ , PCy ₃ , PCy ₃ * HBF ₄ , P (OiPr) ₃ , DPE-Phos, dpp
f, dppe, dpppp, dcppp, dppb, P (frill) ₃ , CPhos, SPho
You can choose from the group consisting of s, RuPhos, XPhos, DavePhos, JohnPhos and xantphos.

The catalyst can generally be present in an amount of up to 10.0 mol%. Typically, the catalyst may be present in an amount less than 5.0 mol%. The catalyst is further about 0.005 mol% to about 5.0 mol% and about 0.01 mol% to about 1.0 mo with respect to the starting compound of formula (A).
It can be present in the range of l%, or about 0.05 mol% to about 0.5 mol%. Typically, the catalyst may be present in an amount of about 0.1 mol%.

The reaction described in Scheme 2 _{is particularly successful when T is Br, X 1} is ZnI and P is tert-butyloxycarbonyl (Boc). The preferred solvent for the reaction is tetrahydrofuran (THF), the catalyst is Pd (PPh ₃ ) ₂ Cl ₂ , and the cocatalyst or additive is CuI. In particular, the reaction is successful at temperatures above 25 ° C, preferably about 50 ° C.

As used herein, the term "cocatalyst or additive" refers to a chemical that increases the rate of chemical reaction by lowering the activation energy. The co-catalyst can be a heterogeneous catalyst or a homogeneous catalyst, and the additive can be a ligand, salt or some other species that can enhance the reactivity of the catalyst.

The term "ligand" means any achiral or chiral compound that can form a complex with a transition metal. Chiral and achiral ligands are, for example, CPho
s, SPhos, XPhos, DavePhos, JohnPhos, DPE-Phos
And can be xantphos.

1.2 Another way to reach a compound of formula (C2-1) Another aspect of the present disclosure is a method of preparing a compound of formula (C2-1), as described in Scheme 3. , The step of reacting the compound of the formula (C2-3) with a pyridinium-P substituent in a solvent to obtain the compound (C2-2) and the conversion of the compound (C2-2) to the formula (C2-1). ) And the method including the step of obtaining the compound. According to the present disclosure, protecting groups (
P) can be a customary protecting group, especially those described herein (eg, tert-).
Butyloxycarbonyl (Boc), benzyloxycarbonyl, methyloxycarbonyl, ethyloxycarbonyl, allyloxycarbonyl, phenyloxycarbonyl, formyl, acetyl or benzyl) can be selected. Methyloxycarbonyl and Boc are preferred protecting groups used in the methods shown in Scheme 3. Methyloxycarbonyl is most preferred.

In the reaction between pyridinium-P and the compound of formula (C2-3), Z is MgBr, MgI, MgC.
It is best done when selected from l, ZnCl, ZnBr, ZnI, Zn (alkyl) and the like, preferably when Z is MgCl or MgBr, most preferably MgBr.

A suitable solvent for obtaining the compound of formula (C2-2) is, for example, an aprotic polar solvent. For example, the reaction can proceed successfully in tetrahydrofuran (THF), 2-methyl-tetrahydrofuran, acetonitrile, dichloromethane, 1,4-dioxane or diethyl ether, or mixtures thereof. The reaction is tetrahydrofuran (THF
) Is done especially well.

The synthesis of the compound of formula (C2-2) described in Scheme 3 is carried out in tetrahydrofuran (TH) when Z is selected as MgBr and P is selected as methyloxycarbonyl.
F) Medium, especially well at temperatures between −30 ° C. and reflux. When Z is selected from less reactive Mg or Zn species, etc., the temperature may need to be higher than room temperature in order to obtain good yields. For particularly reactive Grignard substituents such as MgBr or MgCl Z, the temperature can be between −30 ° C. and room temperature.

The compounds of formula (C2-2) are then subjected to formula (C2-1) as described in Scheme 3.
) Is converted to a compound.

The reduction is carried out with or without additives using hydrogen or a hydrogen donor in the presence of a catalyst (hydrogen transfer reaction). As the hydrogen donor, water, acid (for example, formic acid), alkali, alcohol, amine, liquid ammonia, ammonium formate and the like can be used.

The catalyst used to carry out the reduction of the compound of formula (C2-1) is any catalyst selected by those skilled in the art based on general textbooks. The catalyst is Raney nickel, Pt / C, Rh /
C, Pd / Al ₂ O ₃ , Pd / CaCO ₃ , RhCl (PPh ₃ ) ₃ , Lindlar catalyst,
PtO ₂ , Pd / C, [Rh (cod) (PPh ₃ ) ₂ ] ⁺ , [Ir (cod) (PCy)
₃ ) (Py)] ⁺ , Pd (OH) ₂ , Pd (OAc) ₂ , Pd ₂ (dba) ₃ , Zn, F
It can be selected from the group consisting of e, Sm, NiCl ₂ , Ni (OAc) ₂ , CoCl ₂ , ZrCl ₄ , and TiCl _3. The reaction is particularly successful with Pd / C. The catalyst can be present in the range of about 0.005 mol% to about 30.0 mol%. Typically, the catalyst may be present in an amount of about 10.0 mol%.

Additives can be added as the case may be, ZnCl ₂ , ZnBr ₂ , CuI, LiC.
l, PPh ₃ , P (oTol) ₃ , P (oTol) Ph ₂ , P (pTol) ₃ , PtBu
₃ , PtBu ₃ * HBF ₄ , PCy ₃ , PCy ₃ * HBF ₄ , P (OiPr) ₃ , DPE
-Phos, dppf, dppe, dpppp, dcppp, dppb, P (frill) ₃ , C
Phos, SPhos, RuPhos, XPhos, DavePhos, JohnPho
You can choose from the group of s and xantphos.

The reduction is, for example, water, methanol, ethanol, propanol, isopropanol, 1
-Butanol, 2-butanol, tert-butanol, acetic acid, tetrahydrofuran (TH)
It may be carried out in a solvent selected from the group consisting of F), dichloromethane, diethyl ether, tert butyl methyl ether, ethyl acetate, toluene, 1,4-dioxane, acetonitrile or acetone, or a mixture thereof.

The nitration of the benzene ring described in Scheme 3 is any nitration reaction selected by those skilled in the art based on general textbooks. The source of "NO _{2 " can be selected from HNO 3} or a salt thereof. Suitable solvents for conversion can be selected from, for example, acetic anhydride, sulfuric acid or trifluoroacetic acid.

The reduction described in Scheme 3 is particularly well performed in methanol and tetrahydrofuran (THF) at room temperature using 10% Pd / C, ammonium formate. Nitrolation is particularly successful in the presence of _{HNO 3 and acetic anhydride.} Nitro groups can be introduced into the benzene ring at temperatures below 0 ° C, especially at about −10 ° C.

1.3 Compound of formula (C2) The compound of formula (C2) or a salt thereof can be prepared according to the method summarized in Scheme 4. This method requires the compound of formula (C2-1) disclosed herein to be reduced and deprotected to prepare a compound of formula (C2) or a salt thereof.

In one embodiment, the reduction of the compound (C2-1) having the protecting group P described in Scheme 2 is carried out using hydrogen in the presence of a catalyst. The protecting group P is the above list (eg, t).
It refers to a nitrogen protecting group selected from ert-butyloxycarbonyl (Boc), benzyloxycarbonyl, methyloxycarbonyl, ethyloxycarbonyl, allyloxycarbonyl, phenyloxycarbonyl, formyl, acetyl or benzyl).

The catalyst used to reduce the compound of formula (C2-1) is any catalyst selected from general textbooks by those skilled in the art. The catalyst is Raney nickel, Pt / C, Rh / C, P
d / Al ₂ O ₃ , Pd / CaCO ₃ , RhCl (PPh ₃ ) ₃ , Lindlar catalyst, PtO
₂ , Pd / C, [Rh (cod) (PPh ₃ ) ₂ ] ⁺ , [Ir (cod) (PCy ₃ )) (
Py)] ⁺ , Pd (OH) ₂ , Pd (OAc) ₂ , Pd ₂ (dba) ₃ , Zn, Fe, S
It can be selected from the group consisting of m, NiCl ₂ , Ni (OAc) ₂ , CoCl ₂ , ZrCl ₄ , and TiCl _3. The catalyst can be present in the range of about 0.005 mol% to about 20.0 mol%. Typically, the catalyst is less than 10.0 mol% (about 0.005 mol).
Can be present in quantities (up to%).

As used herein, the term "catalyst" refers to a catalytic amount of a chemical that increases the rate of a chemical reaction by lowering the activation energy of the chemical reaction. The catalyst may be a heterogeneous catalyst or a homogeneous catalyst.

The term "homogeneous catalyst" refers to a catalyst carried on a carrier, a substrate that typically includes, but is not necessarily, an inorganic material, such as a porous material such as carbon, silicon and / or aluminum oxide. Point to.

The term "homogeneous catalyst" refers to a catalyst that is not supported on a carrier.

The term "hydrogen" or "hydrogenation" used to describe a chemical reaction refers to the action of reducing another compound in the presence of hydrogen. Sources of hydrogen are gaseous hydrogen (H ₂ ), hydrogen donors (hydrogen transfer reaction, eg formic acid or salts thereof), hydride reagents (BH ₃ , B ₂ H ₆ , N).
It can be selected from aBH _{4) and the like.}

The reduction can be carried out in a solvent such as an alcohol-based solution. Alcoholic solution is C ₁
~ C ₁₀ alcohols (eg methanol, ethanol, propanol, isopropanol and butanol) or mixtures thereof can be included or can consist of them.

The reduction reaction is best performed at high pressures, preferably between 1 and 10 bar, especially 4 bar. The reduction of the compound of formula (C2-1) or a salt thereof is best carried out by stirring the reaction mixture in the presence of ethanol with 10 mol% Pd / C and hydrogen at room temperature for 5 hours. The reduction is best performed with the protecting group P selected from tert-butyloxycarbonyl (Boc) or methyloxycarbonyl.

In this specification, the terms "room temperature" or "ambient temperature" are 20 to 20 unless otherwise specified.
It means a temperature of 15 to 30 ° C., such as 30 ° C., especially 20 to 25 ° C.

In addition to the reduction of compound (C2-1), the protecting groups are excised. Removal of protecting groups can be carried out under standard reaction conditions known in the art. Unless otherwise specified
Protecting groups can be removed in the absence of acids or bases, or customarily cause removal of acids or bases, preferably protecting groups, but at the same time do not cause chemical degradation of compounds and intermediates. It can be removed in the presence of a base. Removal of protecting groups can be carried out under reducing conditions, for example in the first nitro reduction step of (C2-1). Preferably, the protecting group is removed with an acid. An acid that is particularly suitable for removing the protecting group P is H.
F. pyridine, HF, triethylamine, ammonium fluoride, hexafluoroisopropanol, acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, or a combination thereof. The acid is preferably trifluoroacetic acid or hydrochloric acid. The reaction consisting of removing the protecting group can occur in a solvent that facilitates the removal of the protecting group. As an example, protecting groups can be removed in a solvent selected from the group consisting of dichloromethane, ethyl acetate, 1,4-dioxane, diethyl ether, tetrahydrofuran (THF), methanol or acetonitrile. Protecting groups are removed by stirring the reaction mixture at a temperature between −78 ° C. and 70 ° C., preferably between 0 ° C. and 70 ° C. for at least 8 hours, preferably 16 hours. tert
The deprotection reaction of the -butyloxycarbonyl (Boc) protecting group is best performed in dichloromethane, optionally at ambient temperature, with trifluoroacetic acid. The deprotection reaction of the methyloxycarbonyl protecting group is best performed with hydrochloric acid, in some cases at 60 ° C.

In one embodiment, reduction and protecting group removal are performed simultaneously.

1.4 Another route for preparing the compound of formula (C2) The compound of formula (C2) or a salt thereof can be prepared by another method. That is, as shown in Scheme 5, the compound of formula (C) is reduced in a solvent in the presence of at least one catalyst and hydrogen.

The reaction for preparing the compound of formula (C2) or a salt thereof may simultaneously reduce the two functional groups present in the compound of formula (C) to rapidly reach the compound of formula (C2) or a salt thereof. By being able to do so, it can be implemented as a one-pot method. The reduction step requires the presence of catalyst and hydrogen in the solvent.

The catalyst used to reduce the compound of formula (C) is any catalyst selected from general textbooks by those skilled in the art. The catalyst is, for example, Raney nickel, Pt / C, Rh / C,
Pd / Al ₂ O ₃ , Pd / CaCO ₃ , RhCl (PPh ₃ ) ₃ , Lindlar catalyst, Pt
O ₂ , Pd / C, [Rh (cod) (PPh ₃ ) ₂ ] ⁺ , [Ir (cod) (PCy ₃ ))
(Py)] ⁺ , Pd (OH) ₂ , Pd / Al, Pt / Al, Pt / SiAl and Pd /
It can be selected from the group consisting of ZrO _{2 or a mixture thereof.}

The catalyst is about 0.005 mol% to about 50.0% w / w (about 0.005 mol% to about 50.0% w / w) with respect to the starting compound of the formula (C).
Can exist in the range of dry). Typically, the catalyst may be present in an amount less than 20.0% w / w (dry).

Reduction of the compound of formula (C) allows the reaction mixture to be between 10 ° C and 40 ° C, preferably 20 ° C and 3 ° C.
This is done by stirring at a temperature between 0 ° C. for up to 16 hours, preferably 8 and 16 hours. The reaction is best performed at pressures between 1 bar and 15 bar, preferably between 2 bar and 6 bar.

The solvents used in the reaction are, for example, water, methanol, ethanol, propanol, isopropanol, 1-butanol, 2-butanol, tert-butanol, acetic acid, tetrahydrofuran (THF), dichloromethane, diethyl ether, tert-butyl methyl ether, ethyl acetate. , Toluene, benzene, 1,4-dioxane, acetonitrile and acetone, or mixtures thereof.

The method for reducing the compound of formula (C) to the compound of formula (C2) or a salt thereof is described in acetic acid, Pd.
This is especially well done in the presence of / Al and hydrogen. The reaction conditions are preferably set at about 60 ° C. and a pressure of about 80 bar. The reaction is successfully carried out in the presence of Pt / C and hydrogen, optionally in acetic acid. In this case, the temperature is best set to about 10 to about 50 ° C. and the pressure is best set to about 1 to about 10 bar.

1.5 Compound of formula (C) Compound (C) is a compound of formula (AA) in a solvent, as shown in Scheme 6.
It can be prepared in a one-pot method by reacting the compound of formula (D) with X ₃ B (X ₂ ) ₂ , in the presence of a base, a catalyst, and optionally a ligand.
Y is from Cl, Br, I, OTf, OTs, OPiv and OMs, preferably Cl.
Selected from Br,
X ₄ is preferably Cl from Cl, Br, I, OTf, OTs, OPiv and OMs.
, Selected from Br,
B (X ₂ ) ₂ is B (OH) ₂ , B (OC (CH ₃ ) ₂ C (CH ₃ ) ₂ O), 9-BBN.
, B (Sia) ₂ , B (Cat), B (Cy) ₂
X ₃ is H, B (X ₂ ) ₂ .

One embodiment of the present disclosure is in the presence of a catalyst, X ₃ B (X ₂ ) ₂ , a base, and optionally a ligand in a solvent, without isolating the compound of formula (E), formula (E). Provided is a method for in-situ forming the compound of. This reaction can be a one-pot reaction. The method for reacting the compound of the formula (AA) with the compound of the formula (D) is as follows: First, the reaction mixture containing the compound of the formula (D) and the catalyst is heated to a temperature between 40 ° C. and the reflux temperature, preferably about 1 at 100 ° C. It is carried out by stirring for 10 hours, preferably 3 hours. The compound of formula (AA) is then added and the reaction mixture is stirred at a temperature between 40 ° C. and reflux temperature, preferably about 100 ° C. for about 1-48 hours, preferably about 17 hours.

The catalyst used in the one-pot reaction is any catalyst selected from general textbooks by those skilled in the art. Examples of the catalyst include ligands, for example, Pd (PPh ₃ ) ₂
Cl ₂ , Pd (PPh ₃ ) ₄ , Pd (dba) ₂ , Pd ₂ (dba) ₃ , Pd (OAc)
₂ , [Pd (allyl) Cl] ₂ , Pd (dppf) Cl ₂ , PdBr ₂ (PtBu ₃ ) ₂
, PdCl (crotyl) (PtBu ₃ ), Pd (PtBu ₃ ) ₂ , PdCl ₂ (Amph)
os) ₂ , PdCl (allyl) (Amphos), PdBr ₂ (Binap), PdCl
₂ (dcpp), PdCl ₂ (DiPrPF), PdCl ₂ (DiPrPF), Pd-P
EPPSI-IPr, chloro (2-dicyclohexylphosphino-2', 4', 6'-triisopropyl-1,1'-biphenyl) [2- (2-aminoethyl) phenyl)] palladium (II), chloro ( 2-Dicyclohexylphosphino-2', 4', 6'-triisopropyl-1,1'-biphenyl) [2- (2'-amino-1,1'-biphenyl)]
Palladium (II), chloro (2-dicyclohexylphosphino-2', 6'-dimethoxy-1,1'-biphenyl) [2- (2-aminoethylphenyl)] palladium (II)
, Chloro (2-dicyclohexylphosphino-2', 6'-dimethoxy-1,1'-biphenyl) [2- (2'-amino-1,1'-biphenyl)] Palladium (II), Chloro (2- Dicyclohexylphosphino-2', 6'-diisopropoxy-1,1-biphenyl) [2- (2-aminoethylphenyl)] palladium (II), chloro (2-dicyclohexylphosphino-2', 6'- Diisopropoxy-1,1'-biphenyl) [2-(
2'-amino-1,1'-biphenyl)] Palladium (II), Pd / C, Pd, Ni (
acac) ₂ , NiCl ₂ , Ni (PPh ₃ ) ₂ Cl ₂ , Ni (cod) ₂ , Ni (dp)
pf) (cod), Ni (dppf) (sinner mill), Ni (dppf) ₂ , Ni (dp)
pf) Cl ₂ , Ni (dpppp) Cl ₂ , NiCl ₂ (PCy ₃ ) ₂ and Ni (dpp)
e) It can be selected from the group consisting of _{Cl 2.} The catalyst can be present in an amount of up to 10.0 mol%. Typically, the catalyst may be present in an amount less than 6.0 mol%.

The ligand used to carry out the one-pot reaction is any ligand selected by those skilled in the art based on common textbooks. The ligands are PPh ₃ , P (oTol) ₃ , P (o).
Tol) Ph ₂ , P (pTol) ₃ , PtBu ₃ , PtBu ₃ * HBF ₄ , PCy ₃ , P
Cy ₃ * HBF ₄ , P (OiPr) ₃ , DPE-Phos, dppf, dppe, dpp
p, dcpp, dppb, P (frills) ₃ , CPhos, SPhos, RuPhos, X
It can be selected from the group consisting of Phos, DavePhos, JohnPhos and xantphos. The ligand can be present in the range of about 0.005 mol% to about 20 mol%. Typically, the ligand may be present in an amount less than 10 mol%.

The reaction was carried out, for example, in 1,4-dioxane, tetrahydrofuran (THF), 2-methyltetrahydrofuran, diethyl ether, toluene, dimethylformamide (DMF), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), dimethoxyethane (DME), etc. Tetrahydrofuran, N-methyl-2-pyrrolidone (NMP), 1-butyl-2
-Pyrrolidone (NBP), acetonitrile, acetone, dimethyl carbonate, ethyl acetate, isopropyl acetate, tertbutyl acetate, pentane, hexane, heptane, anisole, pyridine, triethylamine, water, methanol, ethanol, n-propanol, 2-propanol, n It can be carried out in a solvent selected from -butanol, 2-butanol, tert-butanol, or mixtures thereof.

The base used to carry out the reaction is any base selected by those skilled in the art based on general textbooks. The bases are, for example, Na ₂ CO ₃ , K ₂ CO ₃ , Cs ₂ CO ₃ , and Tl ₂ CO.
₃ , NaHCO ₃ , KHCO ₃ , NaOAc, KOAc, Na ₃ PO ₄ , K ₃ PO ₄ , L
iOH, NaOH, KOH, CsOH, Ba (OH) ₂ , NaOMe, KOME, NaO
Et, KOEt, TlOEt, NaOPh, NEt ₃ , DIPEA, NaOtBu, KO
It can be tBu, KF or CsF.

The boronyl group or _{the substituent of X 3} B (X ₂ ) ₂ together with boron is of the formula −B (X ₂ ) ₂
It is possible to form a group, wherein or different are two X ₂ substituents are the same halogen,
Hydroxy, C 1 _-C 4 _- it can be alkoxy, or two X ₂ substituent to form the residue of a diol together. Preferably, the boronyl group of formula -B _{(X 2)} 2 ^{is' 'can} be a group wherein, R OR and ^{R "formula} -B ^(OR)' is irrespective of one another are identical different and are each hydrogen or C ₁ -C 12 _- can be an alkyl, also ^'it may be and R ^"are cross-linked in a ring, for example, bound R and R' R is
It is an alkylene that forms a 5- or 6-membered ring together with boron and oxygen atoms. The boron derivative used to carry out the reaction is any organoboron derivative selected by those skilled in the art based on common textbooks. Organoborons can be selected, for example, from the group consisting of bis (pinacolato) diborone, tetrahydroxydiborone, pinacol borane and neopentyl glycol borane.

By the reaction of the compound of formula (D) with organic boron, -B (OH) ₂ , -B (OC (CH ₃₎
) A compound of formula (E) having _{two -B (X 2} ) groups selected from the group consisting of ₂ C (CH ₃ ) _{2 O) is produced.}

The method for in situ producing the compound of formula (E) by reacting the compound of formula (D) is as follows: bis (pinacolato) diboron, XPhos, chloro (2-) in 1,4-dioxane.
Dicyclohexylphosphino-2', 4', 6'-triisopropyl-1,1'-biphenyl) [2- (2'-amino-1,1'-biphenyl)] palladium (II) and KO
It is especially well done in the presence of Ac. The temperature can be set to 100 ° C. Then
The in situ generated compound of formula (E) is reacted with the compound of formula (AA) in the presence of a base in a solvent. The reaction is best carried out at a temperature between 40 ° C. and reflux, preferably 100 ° C.
Water and K ₂ CO ₃ were added to the reaction mixture to form the newly formed compound (E) and formula (AA).
), The coupling reaction of the compound is started. The reaction can continue to be carried out at 100 ° C.

The term "one-pot method" refers to the related steps being performed sequentially without isolating the product of each step. Moreover, this method is further simplified by omitting the removal or replacement of any other component of the reaction mixture. Occupational safety is also increased by eliminating the need to isolate potential toxic or harmful intermediates. The use of the one-pot method is a simple and cost-effective method of synthetic organic synthesis, but it is of commercial value only if the levels of impurities can be minimized and reasonable yields can be achieved. In this case, the one-pot method described gives good results and is at acceptable levels of unreacted intermediates and by-products.

Alternatively, the compound of formula (C) or a salt thereof is isolated from the compound of formula (AA) (
It can also be prepared by Suzuki coupling of the compound of E). The reaction can be carried out in a solvent in the presence of a catalyst and a base. In formulas (AA) and (E), Y represents Cl, Br, I, OTf, OTs, OPiv and OMs, respectively, and B (X _{2 ) 2} is B (O).
H) ₂ , B (OC (CH ₃ ) ₂ C (CH ₃ ) ₂ O), 9-BBN, B (Sia) ₂ , B (
represents a and ^{B (MIDA) - cat),} B (Cy) 2, BF 3. In certain embodiments, Y is Cl and X ₂ is OH. The solvents used are, for example, water, methanol, ethanol, n-propanol, 2-propanol, n-butanol, 2-butanol, dimethylformamide (DMF), tetrahydrofuran, 2-methyltetrahydrofuran, etc.
It can be toluene, dioxane, or a mixture thereof. Preferably, the solvent is 2-butanol and water. The same catalysts and bases as above can be selected. In one embodiment, the catalyst is Pd (PPh ₃ ) ₂ Cl ₂ . The preferred base is K ₂ CO ₃
Is.

In one embodiment, the compound of formula (AA) is reacted with the compound of formula (E) in 2-butanol or water in the presence _{of Pd (PPh 3} ) ₂ Cl _{2 as a catalyst and K 2} CO ₃ as a base. , In the formula, Y is Cl and X ₂ is OH.

1.6 Another useful intermediate in the preparation of the compound ceritinib of formula (C3-1) is formula (C3-1).

の化合物であり、式中、Ｘは、ハロゲン（Ｆ、Ｃｌ、Ｂｒ、Ｉ）、アルコキシ（好ましく
はＯＭｅ、ＯＥｔ、ＯｔＢｕ）、アリールオキシ（好ましくはＯＰｈ）、アルキルチオ（
好ましくはＳＭｅ、ＳＥｔ）、アリールチオ（ＳＣＨ_２Ｐｈ）、スルフィニル（好ましく
はＳＯＭｅ、ＳＯＥｔ、ＳＯＣＨ_２Ｐｈ）、スルホニル（好ましくはＳＯ_２Ｍｅ、ＳＯ_２
Ｅｔ、ＳＯ_２ＣＨ_２Ｐｈ）から選択される。ＸはＣｌであることが最も好ましい。

In the formula, X is halogen (F, Cl, Br, I), alkoxy (preferably OMe, OEt, OtBu), aryloxy (preferably OPh), alkylthio (preferably OPh).
Preferably SMe, SET), arylthio (SCH ₂ Ph), sulfinyl (preferably SOME, SOEt, SOC H ₂ Ph), sulfonyl (preferably SO ₂ Me, SO _2).
Et, SO ₂ CH ₂ Ph) is selected. Most preferably X is Cl.

The term "alkoxy", which is a group or part of a group, refers to alkyl-O- (where the term alkyl is as defined herein), eg, C _1- C ₂₀ -alkoxy (-O-). C _{1 to} C ₂₀ -alkyl), preferably C _{1 to} C ₇ -alkoxy (-OC)
_{1 to} C ₇ -alkyl). In particular, as alkoxy, for example, methoxy (OMe)
), ethoxy (OEt), n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy (OtBu), pentyloxy, hexyloxy and heptyloxy groups. Preferred alkoxy substituents are methoxy (OMe), ethoxy (OEt) or tert-butyloxy (
OtBu).

Is part of the group or groups The term "aryl" refers to an aromatic hydrocarbon radical, for example C ₆
~ C ₁₀ -aryl, preferably monocyclic or polycyclic, particularly monocyclic, bicyclic or tricyclic aryl having 6 to 14 carbon atoms, for example 6 to 10 carbon atoms. It is a part. Preferably, aryl represents phenyl, benzyl, indenyl, indanyl or naphthyl. The term "aryloxy" refers to aryl-O-, where aryl is as defined above. In particular, the preferred aryloxy herein is phenoxy (OPh). The term "arylthio" refers to aryl-S-, where aryl is as defined above. The preferred aryl thio is benzyl thio (SCH ₂ Ph).
Is.

The term "alkylthio" refers to alkyl-S-, where alkyl is as defined herein. The alkyl group contains, for example, 1 to 8 carbon atoms. In particular, examples of alkylthio include methylthio (SMe), ethylthio (SET), and phenylthio (P).
hS) and pentilthio. Preferred alkylthio substituents herein are methylthio (SMe) and ethylthio (SEt).

The term "sulfinyl" refers to straight or branched _C 1 _{~C 8} - -S containing alkyl
Corresponds to the —O—alkyl group. In particular, sulfinyl includes, for example, methylsulfinyl (SOME), ethylsulfinyl (SOEt), phenylsulfinyl (SOPh) and benzylsulfinyl (SOCH ₂ Ph).

The term "sulfonyl" refers to a _{divalent -S (O) 2-group.} In particular, examples of the sulfonyl include methyl sulfonyl, ethyl sulfonyl, phenyl sulfonyl and benzyl sulfonyl.

The compound of formula (C3-1) is a compound of formula (F) or a salt thereof, as shown in Scheme 7, with a compound of formula (G) and optionally a solvent in the presence of a base. It can be prepared by reacting in. X is halogen (F, Cl, Br, I)
, Alkoxy (preferably OMe, OEt, OtBu) and aryloxy (preferably OPh), most preferably X is Cl.

The base used to carry out the reaction is any base selected by those skilled in the art based on textbooks. It is Na ₂ CO ₃ , K ₂ CO ₃ , Cs ₂ CO ₃ , NaHCO ₃ , KHCO.
It can be selected from the group consisting of ₃ , triethylamine, DIPEA, Na ₃ PO ₄ , K ₃ PO _{4, DBU and NaH.} Preferably, the base is DBU or DIPEA. Good efficacy can be obtained by using a mild base in the reaction. The base is easy to handle and safe, potentially preventing side reactions and thus allowing the compound of formula (C3-1) to be recovered in high yield.

The reaction can be carried out in either a protic solvent or an aprotic solvent. For example, the solvent is 1,4-dioxane, tetrahydrofuran (THF), 2-methyltetrahydrofuran, diethyl ether, toluene, N-methyl-2-pyrrolidone (NMP), 1-butyl-2-pyrrolidone (NBP), acetonitrile, etc. Acetone, dimethyl carbonate, ethyl acetate,
It can be selected from the group consisting of isopropyl acetate, tert-butyl acetate, water, methanol, ethanol, n-propanol, 2-propanol, n-butanol, 2-butanol, tert-butanol and toluene, or mixtures thereof. Alternatively, the solvent can be omitted.

The compound of formula (F) or a salt thereof and the compound of formula (G) can be reacted by stirring the reaction mixture for 1 hour to 72 hours, preferably about 18 hours. The temperature can be selected between 40 ° C. and the reflux temperature, but the temperature is preferably between 100 ° C. and 115 ° C.
Especially about 110 ° C.

The method of reacting a compound of formula (F) or a salt thereof with a compound of formula (G) is best practiced in toluene and 1-butanol in the presence of DIPEA. The temperature is 100-115
Best set to ° C. Such a reaction can be stirred for about 18 hours.

In one embodiment, X in the compounds of formulas (G) and (C3-1) represents Cl.
A particular embodiment of the present disclosure is a compound of formula (C3-1), where X is Cl.

The compound of formula (C3-1) can be used to prepare ceritinib.

1.7 Compound of formula (C3) From the compound of formula (C3-1), the compound of formula (C3) can be prepared. As shown in Scheme 8, compound (C3) can be prepared by oxidizing the resulting compound of formula (C3-1), where X is a halogen (F, Cl, Br, I), alkoxy (preferably OMe, OEt, OtBu) and aryloxy (preferably O)
Ph), sulfinyl (preferably SOME, SOEt, SOCH ₂ Ph), sulfonyl (preferably SO ₂ Me, SO ₂ Et, SO ₂ CH ₂ Ph), most preferably X is Cl.

Oxidation can be carried out in water or an organic solvent. Solvents include 1,4-dioxane, tetrahydrofuran (THF), 2-methyltetrahydrofuran, diethyl ether, toluene, dimethylformamide (DMF), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), dimethoxyethane (DME), dichloromethane, N-methyl-2-
Pyrrolidone (NMP), 1-butyl-2-pyrrolidone (NBP), acetonitrile, acetone, dimethyl carbonate, ethyl acetate, isopropyl acetate, tert-butyl acetate, pentane,
You can choose from hexane, heptane, anisole, pyridine, triethylamine, acetic acid, water, methanol, ethanol, n-propanol, 2-propanol, n-butanol, 2-butanol and tert-butanol, or mixtures thereof.

Oxidizing reagents include, among other things, KMnO ₄ , MnO ₂ , NaIO ₄ , NaClO, KHSO ₅
(Oxone), NaBO ₃ , CH ₃ CO ₃ H, H ₂ O ₂ , Na ₂ WO ₄ , O ₂ , O ₃ , Tetrapropylammonium perborate (TPAP), 3,3-dimethyldioxirane, 3-chloro Perbenzoic acid (mCPBA) and tert-butyl hydroperoxide (TB)
It can be selected from the group consisting of HP), or mixtures thereof, optionally with a catalyst.

To prepare a compound of formula (C3) from a compound of formula (C3-1), the reaction mixture is prepared at 10 ° C.
And 60 ° C., preferably a temperature between 20 ° C. and 40 ° C., particularly about 30 ° C. for 4-40 hours, preferably about 16 hours. Oxidation of the compound of formula (C3-1) can be carried out in ethyl acetate in the presence of a CH ₃ CO _{2 H solution of CH 3} CO ₃ H at 30 ° C. in high yield, or this method , H ₂ O ₂ and Na ₂ W in methanol
In the presence of O ₄ can be implemented as a high yield at a temperature of between 20 ° C. and 70 ° C..

1.7 Another route to prepare the compound of formula (C3) The compound of formula (C3) is alternative to formula (i) (H) as described in Scheme 9.
) Is reacted with the compound of formula (I) to obtain an intermediate, (ii) the intermediate is reduced to form compound (J), and (iii) compound (J) is formulated. (G)
It can be prepared by following the steps of reacting the compound with a base in the presence of a base. See below.

X is F, Cl, Br, I, alkoxy (preferably OMe, OEt, O) as described above.
tBu), aryloxy (preferably OPh), alkylthio (preferably SMe, S)
Et), arylthio (preferably SCH ₂ Ph), sulfinyl (preferably SOME)
, SOEt, SOCH ₂ Ph), Sulfonyl (preferably SO ₂ Me, SO ₂ CH ₂ Ph)
) Can be expressed. Most preferably X is Cl. M is Li, Na, K, 0
.. It can be selected from 5Zn and 0.5Ca, and M is preferably Na.

The compound of formula (H) is reacted with the compound of formula (I) in a solvent at a temperature between room temperature and reflux with stirring. In a specific embodiment, the reaction is carried out in a solvent at a temperature between 82 ° C and 86 ° C.

The solvents used in the reaction are, for example, dimethyl sulfoxide (DMSO), 1,4-dioxane, tetrahydrofuran (THF), 2-methyltetrahydrofuran, diethyl ether, toluene, dimethylformamide (DMF), dimethylacetamide (DMA), dimethoxyethane. (DME), dichloromethane, N-methyl-2-pyrrolidone (NMP),
1-Butyl-2-pyrrolidone (NBP), acetonitrile, acetone, dimethyl carbonate, ethyl acetate, isopropyl acetate, tert-butyl acetate, pentane, hexane, heptane, anisole, pyridine, triethylamine, acetic acid, water, methanol, ethanol, n- It can be propanol, 2-propanol, n-butanol, 2-butanol, tert-butanol, or a mixture thereof. DMSO is preferably selected.

The reduction step to obtain the compound of formula (J) can include the use of a catalyst and hydrogen in a solvent. The catalyst used to perform the reduction is any catalyst known to those skilled in the art to choose from common textbooks. The catalyst is, for example, Raney nickel,
Pt / C, Rh / C, Pd / Al ₂ O ₃ , Pd / CaCO ₃ , RhCl (PPh ₃ ) ₃ ,
Lindlar catalyst, PtO ₂ , Pd / C, [Rh (cod) (PPh ₃ ) ₂ ] ⁺ , [Ir (
cod) (PCy ₃ ) (Py)] ⁺ , Pd (OH) ₂ , Pd / Al, Pt / Al, Pt /
It can be SiAl, Pd / ZrO ₂ , or a mixture thereof.

The catalyst added to the reaction mixture is about 0.005 mol% with respect to the starting compound of formula (I).
It can be present in the range of ~ about 50.0% w / w (dry). Typically, the catalyst is 20
.. It may be present in an amount less than 0% w / w (dry).

In the reduction reaction, the mixture can be stirred at a temperature of up to 60 ° C., preferably about 40 ° C. for several hours.

The reduction reaction is best performed at high pressures, such as between 1 bar and 15 bar, preferably between 2 bar and 6 bar.

The reduction can be carried out in a solvent such as an alcohol-based solution. Alcoholic solution is C ₁ ~
C ₁₀ alcohols (e.g., methanol, ethanol, propanol, isopropanol and butanol) can be, or it is also possible to use mixtures of them as reaction medium. The solvent is preferably ethanol.

The compound of formula (C3) is obtained by reacting an intermediate of formula (J) with a compound of formula (G) in the presence of a base and in the absence of a solvent. Performing the reaction without solvent is a really attractive alternative as it is more efficient, reduces the amount of waste generated and reduces the total cost of synthesis.

The base used to carry out the reaction is any base selected by those skilled in the art based on general textbooks. The bases are, for example, Na ₂ CO ₃ , K ₂ CO ₃ , Cs ₂ CO ₃ , and NaHC.
O ₃ , KHCO ₃ , triethylamine, DIPEA, Na ₃ PO ₄ , K ₃ PO ₄ , DBU
And can be selected from the group consisting of NaH. The best conditions are DBU or DI
Achieved when PEA, especially DBU, is used. The mild bases defined herein allow for the realization of efficient methods, are easy and safe to handle, potentially prevent side reactions, and thus are of formula (C3) in high yield and purity. ) Compound can be recovered.

The reaction of the intermediate (J) with the compound of formula (G) works best at temperatures between 40 ° C and reflux, especially at 80 ° C.

1.8 Ceritinib The method described above can be extended to prepare ceritinib or a salt thereof. Depending on the starting material and the pathway chosen, one of ordinary skill in the art knows how to combine them to produce components and ultimately form ceritinib. Some variants or alternatives are described below. For example, as shown in Scheme 10, ceritinib or a salt thereof
i. The step of preparing the compound of formula (C2-1) as described in 1.1 or 1.2, and
ii. The step of preparing the compound of formula (C2) or a salt thereof, and
iii. Steps to prepare compound (C3) and
iv. It can be prepared by a method comprising reacting a compound of formula (C2) with a compound of formula (C3) to obtain ceritinib or a salt thereof.

As an alternative, ceritinib or its salt
(A) The step of preparing the compound of formula (C2) or a salt thereof, as described in 1.3 or 1.4.
(B) The step of preparing the compound of the formula (C3) and
It can be prepared by the method described in Scheme 11 by the step of reacting the compound of the formula (C2) or a salt thereof with the compound of the formula (C3) to obtain ceritinib or a salt thereof.

Ceritinib or its salt, as shown in Scheme 12,
(Aa) A step of preparing a compound of formula (C2) or a salt thereof, and
(Bb) As described in 1.6, the step of preparing the compound of formula (C3-1) and
(Cc) A step of preparing a compound of formula (C3) from a compound of formula (C3-1), and
It can also be produced by a method comprising the step of reacting the compound of formula (C2) or a salt thereof with the compound of formula (C3) to obtain ceritinib or a salt thereof.

Another variation of the disclosure is a method of preparing ceritinib or a salt thereof, as described in Scheme 13.
(I) As described in 1.5, the step of preparing the compound of formula (C) and
(II) A step of preparing a compound of formula (C2) or a salt thereof from a compound of formula (C), and
The step of preparing the compound of formula (III) (C3) and
(IV) The present invention relates to a method comprising reacting a compound of formula (C2) or a salt thereof with a compound of formula (C3) to obtain ceritinib or a salt thereof.

Coupling of the compound of formula (C2) or a salt thereof with the compound of formula (C3) can be carried out in the presence of a base in a solvent, where X is halogen (Br, Cl, I), alkoxy. (
Preferably OMe, OEt, OtBu) and aryloxy (preferably OPh), sulfinyl (preferably SOME, SOEt, SOCH ₂ Ph) or sulfonyl (preferably SO ₂ Me, SO ₂ Et, SO ₂ CH ₂ Ph). And most preferably X is Cl.

The bases used in the reaction are Na ₂ CO ₃ , K ₂ CO ₃ , Cs ₂ CO ₃ , NaHCO ₃ , and so on.
You can choose from a group of mild bases such as KHCO ₃ , triethylamine, DIPEA, DBU, Na ₃ PO ₄ or K ₃ PO _4. Alternatively, the solvent can be omitted.

The reaction can be carried out in a wide variety of solvents such as 1,4-dioxane, tetrahydrofuran (THF).
), 2-Methyl tetrahydrofuran, diethyl ether, toluene, N-methyl-2-pyrrolidone (NMP), 1-butyl-2-pyrrolidone (NBP), acetonitrile, acetone, dimethyl carbonate, ethyl acetate, isopropyl acetate, tert-butyl acetate , Water, methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-butanol, tert-butanol and toluene, or mixtures thereof. Preferably, tetrahydrofuran (THF), 2-methyltetrahydrofuran, water, methanol, ethanol, n-propanol, isopropanol, n-butanol, 2
-Butanol is used, most preferably isopropanol.

The method of reacting the compound of formula (C2) or a salt thereof to obtain the compound of formula (C3) is such that the reaction mixture is refluxed to a temperature between 40 ° C. and the reflux temperature, preferably reflux temperature, for 6 to 41 hours, preferably. Is carried out by stirring for about 16 hours.

The method of reacting a compound of formula (C2) with a compound of formula (C3) is best performed in isopropanol by refluxing without a base, thus preventing side reactions and in high yield and purity ceritinib. Or the salt can be recovered.

When a salt is referred to herein, it means a particularly pharmaceutically acceptable salt or other generally acceptable salt, unless excluded for chemical reasons readily apparent to those skilled in the art. Salts can be formed with final products or intermediates in which salt-forming groups are present, such as basic or acidic groups, and are at least partially dissociated in aqueous solution, eg, in the pH range of 4-10. It can be present in form or can be isolated, especially in the form of solids, especially crystals.

Such salts are made from either compounds having a basic nitrogen atom (eg, imino or amino) or intermediates described herein, preferably with organic or inorganic acids, eg, acid additions. It is formed as a salt, especially a pharmaceutically acceptable salt. Suitable inorganic acids are
For example, halogen acid such as hydrochloric acid, sulfuric acid, or phosphoric acid. Suitable organic acids are, for example, carboxylic acids, phosphonic acids, sulfonic acids or sulfamic acids, such as acetic acid, propionic acid,
Amino acids such as lactic acid, fumaric acid, succinic acid, citric acid, glutamate or aspartic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, benzoic acid, methanesulfonic acid or ethanesulfonic acid, ethane-1,2-disulfonic acid, Benzenesulfonic acid,
With other organic protonic acids such as 2-naphthalene sulfonic acid, 1,5-naphthalene-disulfonic acid, N-cyclohexylsulfamic acid, N-methylsulfamic acid, N-ethylsulfamic acid or N-propylsulfamic acid, or ascorbic acid. is there.

Ceritinib prepared as described above may optionally be further purified by recrystallization from a suitable solvent to obtain a pharmaceutically active final ingredient, and optionally milled or sieved. You may spend it.

The pharmaceutically active ingredient ceritinib (eg, as described in Section 1.8 above)
Once obtained, it can be mixed with pharmaceutically acceptable additives. This is mixed,
It can be realized by granulation, compression, etc. In this way, the pharmaceutical composition can be prepared and used in the preparation of final dosage forms such as tablets or capsules.

As used herein and in the appended claims, the singular forms "one (a)", "one (an)", and "the" are contextually specific indications. Includes more than one of them unless explicitly stated.

Similarly, "comprise", "comprises", "comprising", "include", "include"
s) ”and“ including ”are synonymous and are not intended to be limiting.

Abbreviation δ chemical shift
¹³ C-NMR carbon nuclear magnetic resonance
¹ H-NMR Proton Nuclear Magnetic Resonance Ac Acetyl Acac Acetylacetone AcOH Acetic Acid ALK Undifferentiated Lymphoma Kinase Amphos Bis (di-tert-butyl (4-dimethylaminophenyl))
Phosphine)
B (cat) Catecholborane B (Sia) ₂ bis (1,2-dimethylpropyl) borane BBN borabicyclo [3.3.1] Nonan BINAP (1,1'-binaphthalene-2,2'-diyl) bis (diphenyl) Phosphine)
Boc tert-Butyloxycarbonyl BOM benzyloxymethyl br Broad br m Broad multiplex line br s Broad single line Bu Butyl CaCO ₃ Calcium carbonate cat. Catalytic amount Cbz benzyloxycarbonyl CDCl ₃ deuterated chloroform _CH 3 _CO 3 H peracetic acid cod cyclo-1,5-octadiene cy cyclohexyl d doublet dba dibenzylideneacetone DBU 1,8-diazabicyclo undecalactone 7- en DCPP 1,3-bis (dicyclohexylphosphanyl) propane DIPEA N, N-diisopropylethylamine or Hunig's base DMA dimethylacetamide DME dimethoxyethane DMF dimethylformamide DMSO dimethylsulfoxide _{DMSO-d 6} deuterated dimethylsulfoxide DPE-phos-bis (2 -Diphenyl phosphinophenyl) ether DPE-phos bis (2-diphenyl phosphinophenyl) ether Dppb 1,4-bis (diphenyl phosphino) butane Dppe 1,2-bis (diphenyl phosphino) ethane Dppf 1,1'- Bis (diphenylphosfanyl) ferrocene Dppp 1,3-bis (diphenylphosfanyl) propane Eq. Equivalent Et Ethyl Fmoc 9-fluorenylmethyloxycarbonyl g gram h time H ₂ O ₂ hydrogen peroxide HF hydrogen peroxide Hz Hertz J binding constant K ₂ CO ₃ potassium carbonate KH potassium hydride KOAc potassium acetate LCMS liquid chromatography- Mass Analysis m Multiple Lines M Mol Concentration / Mol mCPBA 3-Chloroperbenzoate Me Methyl mg Milligram MIDA N-Methylimino Diacetate min min ml Milliliter mol Mol Ms Mesyl Na ₂ WO ₄ Sodium Tungate Dihydrate NaH Hydrogenation Sodium NBP 1-butyl-2-pyrrolidone NMP N-methyl-2-pyrrolidone Pd / Al Aluminum-supported palladium Pd / C Carbon-supported palladium Pd-PEPPSI-Br [1,3-bis (2,6-diisopropylphenyl) imidazole- 2-Ilidene] (3-Chloropyridyl) Palladium (II) Dichloride PEPPSI Pyridine Accelerated Precatalyst Preparation, Stabilization and Initiation (pyridi)
ne enhanced precatalyst preparation stabilization and initiation)
Ph phenylphos phosphine piv pivaloyl POM pivaloyloxymethyl ppm parts per million Pt / C carbon-supported platinum Rh / C carbon-supported rhodium
s Single wire SEM trimethylsilylethoxymethyl Sept. Seven-fold wire T ° C. Temperature TBHP tert Butyl hydroperoxide TBME Methyl tert Butyl ether tBu tret Butyl TES Triethylsilyl Tf Triflate THF tetrahydrofuranTPAP Tetrapropylammonium tetrapropylammonium troc Trichloroethoxycarbonyl Ts Tosyl w / w Weight percentage

The following examples are merely examples of the present disclosure, as these examples and their other equivalents are expected to be apparent to those skilled in the art in the context of the present disclosure and the accompanying claims.
Nothing shall be deemed to limit the scope of this disclosure.

Synthesis of 2-isopropoxy-5-methyl-4- (piperidine-4-yl) aniline dihydrochloride (C2, 2HCl salt) according to the following order

ｔｅｒｔ−ブチル４−（５−イソプロポキシ−２−メチル−４−ニトロフェニル）ピペリ
ジン−１−カルボキシラート（Ｃ２−１、Ｐ＝Ｂｏｃ）
テトラヒドロフラン（１９ｍｌ）中のＰｄ（ＰＰｈ_３）_２Ｃｌ_２（６９ｍｇ、０．０９
９ｍｍｏｌ、１．５ｍｏｌ％）、ＣｕＩ（７５ｍｇ、０．３９ｍｍｏｌ、６ｍｏｌ％）、
１−ブロモ−５−イソプロポキシ−２−メチル−４−ニトロベンゼン（１．８０ｇ、６．
５７ｍｍｏｌ）の混合物に、（１−（ｔｅｒｔ−ブトキシカルボニル）ピペリジン−４−
イル）亜鉛（ＩＩ）ヨージドのテトラヒドロフラン溶液（０．９Ｍ溶液４．９５ｇ、１３
．１ｍｍｏｌ、２．０当量；文献の手順に従って調製）を５０℃で添加し、反応混合物を
この温度で２１時間撹拌した。室温に冷却した後、飽和ＮＨ_４Ｃｌ水溶液（５０ｍｌ）を
添加した。水相を酢酸エチル（３×７０ｍｌ）で抽出し、有機相を合わせて、塩水（８０
ｍｌ）で洗浄し、Ｎａ_２ＳＯ_４で脱水した。揮発性物質を真空下で除去し、粗製物をシリ
カゲルクロマトグラフィー（酢酸エチル／ヘプタン）で精製して、茶色がかった油のｔｅ
ｒｔ−ブチル４−（５−イソプロポキシ−２−メチル−４−ニトロフェニル）ピペリジン
−１−カルボキシラート（１．９６ｇ、収率７９％）を得た。¹H-NMR (400 MHz, CDCl₃):
δ = 1.30 (d, J = 6.1 Hz, 6H), 1.42 (s, 9H), 1.47-1.54 (m, 2H), 1.67-1.70 (m, 2
H), 2.24 (s, 3H), 2.72-2.82 (m, 3H), 4.05 (br. m, 2H), 4.53 (七重線, J = 6.1 Hz,
1H), 6.79 (s, 1H), 7.55 (m, 1H) ppm.

tert-Butyl 4- (5-isopropoxy-2-methyl-4-nitrophenyl) piperidine-1-carboxylate (C2-1, P = Boc)
_{Pd (PPh 3} ) ₂ Cl ₂ (69 mg, 0.09) in tetrahydrofuran (19 ml)
9 mmol, 1.5 mol%), CuI (75 mg, 0.39 mmol, 6 mol%),
1-Bromo-5-isopropoxy-2-methyl-4-nitrobenzene (1.80 g, 6.
57 mmol) to the mixture (1- (tert-butoxycarbonyl) piperidine-4-
Tetrahydrofuran solution of zinc (II) iodide (0.9M solution 4.95 g, 13)
.. 1 mmol, 2.0 eq; prepared according to the procedure in the literature) was added at 50 ° C. and the reaction mixture was stirred at this temperature for 21 hours. After cooling to room temperature, it was added saturated aqueous _NH 4 Cl (50ml). The aqueous phase is extracted with ethyl acetate (3 x 70 ml), the organic phases are combined and the salt water (80) is combined.
It was washed with (ml) and dehydrated with _{Na 2} SO _4. Volatile substances are removed under vacuum and the crude product is purified by silica gel chromatography (ethyl acetate / heptane) to give a brownish oil te.
rt-Butyl 4- (5-isopropoxy-2-methyl-4-nitrophenyl) piperidine-1-carboxylate (1.96 g, 79% yield) was obtained. ^{1 1} H-NMR (400 MHz, CDCl ₃ ):
δ = 1.30 (d, J = 6.1 Hz, 6H), 1.42 (s, 9H), 1.47-1.54 (m, 2H), 1.67-1.70 (m, 2)
H), 2.24 (s, 3H), 2.72-2.82 (m, 3H), 4.05 (br. M, 2H), 4.53 (seven-fold line, J = 6.1 Hz,
1H), 6.79 (s, 1H), 7.55 (m, 1H) ppm.

tert-Butyl 4- (4-amino-5-isopropoxy-2-methylphenyl) piperidin-1-carboxylate (C2-NBoc, P = Boc)
Ethanol (180) of tert-butyl 4- (5-isopropoxy-2-methyl-4-nitrophenyl) piperidine-1-carboxylate (1.96 g, 5.18 mmol)
Pd / C (10%, 0.4 g) was added to the (ml) solution and the reaction mixture was stirred in a hydrogen atmosphere (4 bar) at room temperature for 5 hours. The hydrogen atmosphere was released, the reaction vessel was purged with argon and the mixture was filtered through Celite®. The volatiles are removed under vacuum and the yellow oil tert-butyl 4- (4-amino-5-isopropoxy-2-methylphenyl) piperidine-1-carboxylate (1.67 g, 92% yield) Got It was used in the next step without further purification.

2-Isopropoxy-5-methyl-4- (piperidine-4-yl) aniline dihydrochloride (C)
2,2HCl salt)
Dissolve tert-butyl 4- (4-amino-5-isopropoxy-2-methylphenyl) piperidin-1-carboxylate (1.67 g) in dichloromethane (10 ml) and
The resulting solution was treated with trifluoroacetic acid (2 ml). After 16 hours at room temperature, water (50 ml) was added. The liquid was separated and the aqueous phase was washed with dichloromethane (30 ml). The aqueous phase was neutralized with aqueous NaOH solution (1M solution) and extracted with toluene (3 x 50 ml). HCl (3.8 ml of 5M solution in isopropanol) was added to the combined toluene phases. After evaporation, 2-isopropoxy-5-methyl-4- (piperidine-4-yl) aniline dihydrochloride was obtained (1.35 g, 88% yield). ^{1 1} H-NMR (400 MHz, D ₂ O): δ = 1.24 (d, J = 6)
.1 Hz, 6H), 1.76-1.96 (m, 4H), 2.22 (s, 3H), 3.04-3.14 (m, 3H), 3.45-3.49 (m, 2H)
), 4.71 (7-fold line, J = 6.1 Hz, 1H; overlap with solvent signal), 6.95 (s, 1H), 7.13 (s, 1H)
ppm. ¹³ C-NMR (100 MHz, D ₂ O): δ = 17.4, 20.9, 28.6, 35.4, 44.4, 72.3, 112.2, 11
7.6, 125.4, 128.9, 144.6, 148.8 ppm.

2-Isopropoxy-5-methyl-4- (piperidine-4-yl) aniline dihydrochloride (C2, 2HCl) by reduction of 4- (5-isopropoxy-2-methyl-4-nitrophenyl) pyridine (C) Synthesis of salt)

反応器に、４−（５−イソプロポキシ−２−メチル−４−ニトロフェニル）ピリジン（
１１０ｋｇ、４０４ｍｏｌ）、５ｍｏｌ％ Ｐｔ／Ｃ（３３ｋｇ、Ｈ_２Ｏ ５０〜７０％
）および酢酸（２２００ｋｇ）を加えた。懸濁液を３０℃未満の温度を維持しながら、水
素で２バールに加圧した。２時間後、水素圧力を６バールに上げ、混合物を３０℃に加熱
した。完全変換後、水素を室温で解放し、反応器を窒素でパージした。触媒を濾過し、酢
酸（８００ｋｇ）ですすいだ。濾液を一部濃縮し、次いでトルエン（２３５５ｋｇ）を添
加し、蒸留を続けた。このステップをもう２回繰り返した（溶媒をトルエンに変更）。追
加のトルエン（３１２ｋｇ）およびイソプロパノール（３５９ｋｇ）を溶液に添加した。
４０℃未満の温度を維持しながら、ＨＣｌ（イソプロパノール中の２２％ｗ／ｗ溶液１５
４ｋｇ）を加えた。添加した後、懸濁液を２５℃に冷却し、少なくとも９０分間保持し、
０℃に冷却し、少なくとも９０分間撹拌した。生成物を濾過し、トルエン／イソプロパノ
ール溶液で２回（２×２４０ｋｇ、２０％ｗ／ｗ）すすぎ、真空乾燥して、生成物２−イ
ソプロポキシ−５−メチル−４−（ピペリジン−４−イル）アニリン二塩酸塩（１０５ｋ
ｇ、収率８１％）を得た。¹H NMR (400 MHz, DMSO-d6): δ = 1.31 (d, J = 4 Hz, 6H),
1.79 (m, 2H), 1.98 (qd, J = 12, 4 Hz, 2H), 2.25 (s, 3H), 2.95-3.08 (br. m, 3H),
3.34 (br s, 1H), 4.66 (七重線, J = 4 Hz, 1H), 6.92 (s, 1H), 7.18 (s, 1H), 9.19 (
br. s, 2H), 9.86 (br. s, 3H) ppm. ¹³C NMR (125 MHz, DMSO-d6): δ = 18.1, 21.7, 2
8.4, 34.9, 43.5, 71.1, 112.1, 119.2, 125.6, 127.3, 144.0, 148.8 ppm.

In the reactor, 4- (5-isopropoxy-2-methyl-4-nitrophenyl) pyridine (
110 kg, 404 mol), 5 mol% Pt / C (33 kg, H ₂ O 50-70%)
) And acetic acid (2200 kg) were added. The suspension was pressurized to 2 bar with hydrogen while maintaining a temperature below 30 ° C. After 2 hours, the hydrogen pressure was raised to 6 bar and the mixture was heated to 30 ° C. After complete conversion, hydrogen was released at room temperature and the reactor was purged with nitrogen. The catalyst was filtered and rinsed with acetic acid (800 kg). The filtrate was partially concentrated, then toluene (2355 kg) was added and distillation was continued. This step was repeated twice more (solvent changed to toluene). Additional toluene (312 kg) and isopropanol (359 kg) were added to the solution.
HCl (22% w / w solution in isopropanol 15) while maintaining a temperature below 40 ° C.
4 kg) was added. After addition, the suspension is cooled to 25 ° C. and held for at least 90 minutes.
The mixture was cooled to 0 ° C. and stirred for at least 90 minutes. The product is filtered, rinsed twice with toluene / isopropanol solution (2 x 240 kg, 20% w / w), vacuum dried and product 2-isopropoxy-5-methyl-4- (piperidine-4-yl). ) Aniline dihydrochloride (105k)
g, yield 81%) was obtained. ^{1 1} H NMR (400 MHz, DMSO-d6): δ = 1.31 (d, J = 4 Hz, 6H),
1.79 (m, 2H), 1.98 (qd, J = 12, 4 Hz, 2H), 2.25 (s, 3H), 2.95-3.08 (br. M, 3H),
3.34 (br s, 1H), 4.66 (7-fold line, J = 4 Hz, 1H), 6.92 (s, 1H), 7.18 (s, 1H), 9.19 (
br. S, 2H), 9.86 (br. S, 3H) ppm. ¹³ C NMR (125 MHz, DMSO-d6): δ = 18.1, 21.7, 2
8.4, 34.9, 43.5, 71.1, 112.1, 119.2, 125.6, 127.3, 144.0, 148.8 ppm.

Synthesis of 4- (5-isopropoxy-2-methyl-4-nitrophenyl) pyridine (C) a) One-pot borylation / Suzuki reaction

４−ブロモピリジン塩酸塩（１．０ｇ、５．１ｍｍｏｌ、１．２当量）、ビス（ピナコ
ラト）ジボロン（１．３１ｇ、５．１ｍｍｏｌ、１．２当量）、酢酸カリウム（１．６８
ｇ、１７．１ｍｍｏｌ、４．０当量）、２−ジシクロヘキシルホスフィノ−２’，４’，
６’−トリイソプロピルビフェニル（＝ＸＰｈｏｓ；０．１２ｇ、６ｍｏｌ％）、クロロ
（２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピル−１，１’−
ビフェニル）［２−（２’−アミノ−１，１’−ビフェニル）］パラジウム（ＩＩ）（＝
ＸＰｈｏｓプレ触媒、第２世代；０．１０ｇ、３ｍｏｌ％）および１，４−ジオキサン（
５ｍｌ）の混合物を１００℃で３時間加熱した。次いで、Ｋ_２ＣＯ_３水溶液（３．６Ｍ溶
液３．６ｍｌ、１２．９ｍｍｏｌ、３．０当量）および１−クロロ−５−イソプロポキシ
−２−メチル−４−ニトロベンゼン（０．９８ｇ、４．３ｍｍｏｌ）を添加し、反応混合
物を１００℃でさらに１７時間加熱した。室温に冷却した後、混合物をＨｙＦｌｏ（登録
商標）で濾過し、酢酸エチル（３×２０ｍｌ）で洗浄した。有機相を水（３×２０ｍｌ）
およびＮａＣｌ水溶液（２４％ｗ／ｗ溶液２０ｍｌ）で洗浄し、Ｎａ_２ＳＯ_４で脱水した
。揮発性物質を真空下で除去し、粗製物をシリカゲルクロマトグラフィー（酢酸エチル／
ヘプタン）で精製して、黄色固体の４−（５−イソプロポキシ−２−メチル−４−ニトロ
フェニル）ピリジン（０．９５ｇ、収率８１％）を得た。
ｂ）鈴木カップリング

4-Bromopyridine hydrochloride (1.0 g, 5.1 mmol, 1.2 eq), bis (pinacolato) diboron (1.31 g, 5.1 mmol, 1.2 eq), potassium acetate (1.68)
g, 17.1 mmol, 4.0 equivalents), 2-dicyclohexylphosphino-2', 4',
6'-Triisopropylbiphenyl (= XPhos; 0.12 g, 6 mol%), chloro (2-dicyclohexylphosphino-2', 4', 6'-triisopropyl-1,1'-
Biphenyl) [2- (2'-amino-1,1'-biphenyl)] Palladium (II) (=
XPhos precatalyst, 2nd generation; 0.10g, 3mol%) and 1,4-dioxane (
The mixture (5 ml) was heated at 100 ° C. for 3 hours. Then K ₂ CO ₃ aqueous solution (3.6 M solution 3.6 ml, 12.9 mmol, 3.0 eq) and 1-chloro-5-isopropoxy-2-methyl-4-nitrobenzene (0.98 g, 4.3 mmol). ) Was added, and the reaction mixture was heated at 100 ° C. for an additional 17 hours. After cooling to room temperature, the mixture was filtered through HyFlo® and washed with ethyl acetate (3 x 20 ml). Water the organic phase (3 x 20 ml)
And was washed with aqueous NaCl solution (20 ml of 24% w / w solution) and dehydrated with _{Na 2} SO _4. Volatile substances are removed under vacuum and the crude is silica gel chromatographed (ethyl acetate /
Purification with heptane) gave a yellow solid 4- (5-isopropoxy-2-methyl-4-nitrophenyl) pyridine (0.95 g, 81% yield).
b) Suzuki coupling

Ｋ_２ＣＯ_３（５０．１ｋｇ、３５８ｍｏｌ、２．５当量）、Ｈ_２Ｏ（９３ｋｇ）、１−
クロロ−５−イソプロポキシ−２−メチル−４−ニトロベンゼン（３３．３ｋｇ、１４５
ｍｏｌ）、ピリジン−４−イルボロン酸（２３．２ｋｇ、１８９ｍｏｌ、１．３当量）、
ｔｒａｎｓ−ジクロロビス（トリフェニルホスフィン）パラジウム（ＩＩ）（５．１１ｋ
ｇ、７．２８ｍｏｌ、５ｍｏｌ％）および２−ブタノール（２１６ｋｇ）の混合物を不活
性雰囲気中、３．５時間加熱還流した。５５℃に冷却した後、混合物を濾過し、分液した
。有機相を真空下で一部濃縮し、５０℃に冷却し、水（１６７ｋｇ）を添加した。さらに
５℃に冷却した後、固体を濾取した。粗生成物をエタノール／水からの再結晶により精製
して、黄色固体の４−（５−イソプロポキシ−２−メチル−４−ニトロフェニル）ピリジ
ン（５２．９ｋｇ、収率７１％）を得た。¹H-NMR (400 MHz, CDCl₃): δ = 1.40 (d, J =
6.0 Hz, 6H), 2.23 (s, 3H), 4.65 (七重線, J = 6.1 Hz, 1H), 6.92 (s, 1H), 7.25-7.
26 (m, 2H), 7.72 (s, 1H) 8.71-8.73 (m, 2H) ppm; ¹³C-NMR (100 MHz, CDCl₃): δ = 1
9.2, 21.9, 73.1, 117.3, 123.6, 127.2, 127.4, 140.4, 144.4, 147.9, 149.2, 150.0 p
pm.

K ₂ CO ₃ (50.1 kg, 358 mol, 2.5 eq), H ₂ O (93 kg), 1-
Chloro-5-isopropoxy-2-methyl-4-nitrobenzene (33.3 kg, 145)
mol), pyridine-4-ylboronic acid (23.2 kg, 189 mol, 1.3 eq),
trans-dichlorobis (triphenylphosphine) palladium (II) (5.11k)
A mixture of g, 7.28 mol, 5 mol%) and 2-butanol (216 kg) was heated to reflux in an inert atmosphere for 3.5 hours. After cooling to 55 ° C., the mixture was filtered and separated. The organic phase was partially concentrated under vacuum, cooled to 50 ° C. and water (167 kg) was added. After further cooling to 5 ° C., the solid was collected by filtration. The crude product was purified by recrystallization from ethanol / water to give a yellow solid 4- (5-isopropoxy-2-methyl-4-nitrophenyl) pyridine (52.9 kg, 71% yield). .. ^{1 1} H-NMR (400 MHz, CDCl ₃ ): δ = 1.40 (d, J =
6.0 Hz, 6H), 2.23 (s, 3H), 4.65 (seven-fold line, J = 6.1 Hz, 1H), 6.92 (s, 1H), 7.25-7.
26 (m, 2H), 7.72 (s, 1H) 8.71-8.73 (m, 2H) ppm; ¹³ C-NMR (100 MHz, CDCl ₃ ): δ = 1
9.2, 21.9, 73.1, 117.3, 123.6, 127.2, 127.4, 140.4, 144.4, 147.9, 149.2, 150.0 p
pm.

Synthesis of 2,5-dichloro-N- (2- (isopropylsulfonyl) phenyl) pyrimidin-4-amine (C3, X = Cl) according to the following order

２，５−ジクロロ−Ｎ−（２−（イソプロピルチオ）フェニル）ピリミジン−４−アミン
（Ｃ３−１、Ｘ＝Ｃｌ）
Ｎ，Ｎ−ジイソプロピルエチルアミン（３１．０ｇ、０．２４ｍｏｌ、２．３当量）を
、トルエン（１６６ｇ）およびｎ−ブタノール（１７ｇ）中の２−（イソプロピルチオ）
アニリン塩酸塩（２１．３ｇ、０．１０ｍｏｌ）、２，４，５−トリクロロピリミジン（
１９．０ｇ、０．１０ｍｏｌ、１．０当量）の混合物に添加した。混合物を約２２時間還
流した。反応混合物を２５℃に冷却した後、水（７０ｇ）を添加し、分液し、有機相を水
（７０ｇ）で洗浄した。有機相を真空下で濃縮し、続いてエタノール（３４ｇ）を添加し
た。混合物を還流し、０〜５℃に徐冷し、濾過し、真空乾燥して、２，５−ジクロロ−Ｎ
−（２−（イソプロピルチオ）フェニル）ピリミジン−４−アミン（２６．４ｇ、収率８
１％）を得た。¹H-NMR (400 MHz, CDCl₃): δ = 1.30 (d, J = 7.0 Hz, 6H), 3.18 (七重
線, J = 6.7 Hz, 1H), 7.11-7.14 (m, 1H), 7.46-7.50 (m, 1H), 7.60-7.62 (m, 1H), 8.
25 (s, 1H), 8.67-8.68 (m, 1H), 9.30 (br. s, 1H) ppm. ¹³C-NMR (100 MHz, CDCl₃):
δ = 23.3, 40.7, 114.9, 119.8, 122.9, 124.0, 130.4, 137.1, 139.8, 154.6, 156.0,
158.1 ppm.

2,5-Dichloro-N- (2- (isopropylthio) phenyl) pyrimidine-4-amine (C3-1, X = Cl)
N, N-diisopropylethylamine (31.0 g, 0.24 mol, 2.3 eq) in 2- (isopropylthio) in toluene (166 g) and n-butanol (17 g).
Anilinium hydrochloride (21.3 g, 0.10 mol), 2,4,5-trichloropyrimidine (21.3 g, 0.10 mol)
It was added to a mixture of 19.0 g, 0.10 mol, 1.0 eq). The mixture was refluxed for about 22 hours. After cooling the reaction mixture to 25 ° C., water (70 g) was added, the liquid was separated, and the organic phase was washed with water (70 g). The organic phase was concentrated under vacuum followed by the addition of ethanol (34 g). The mixture is refluxed, slowly cooled to 0-5 ° C., filtered, vacuum dried and 2,5-dichloro-N.
-(2- (Isopropylthio) phenyl) pyrimidine-4-amine (26.4 g, yield 8)
1%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ = 1.30 (d, J = 7.0 Hz, 6H), 3.18 (7-fold line, J = 6.7 Hz, 1H), 7.11-7.14 (m, 1H), 7.46- 7.50 (m, 1H), 7.60-7.62 (m, 1H), 8.
25 (s, 1H), 8.67-8.68 (m, 1H), 9.30 (br. S, 1H) ppm. ¹³ C-NMR (100 MHz, CDCl ₃ ):
δ = 23.3, 40.7, 114.9, 119.8, 122.9, 124.0, 130.4, 137.1, 139.8, 154.6, 156.0,
158.1 ppm.

2,5-Dichloro-N- (2- (isopropylsulfonyl) phenyl) pyrimidine-4-
Amine (C3)
A solution of 2,5-dichloro-N- (2- (isopropylthio) phenyl) pyrimidine-4-amine (20.0 g, 63.7 mol) in ethyl acetate (180 g) at an internal temperature of 20 to 20 to
Peracetic acid (acetic acid solution 33.4 g; 5.7 mmol / g) was added while maintaining at 30 ° C. After the reaction time had elapsed for 16 hours, ethyl acetate (90 g) was added, and then an aqueous sodium sulfite solution (112 g of 11% w / w solution) was added to maintain an internal temperature of less than 45 ° C. The solution was separated, water (63 g) was added to the organic phase, and then an aqueous NaOH solution (25% w / w solution) was added to adjust the pH to 7-8. The liquid was separated, the organic phase was _{dehydrated with alkylene 4} and concentrated under vacuum. Ethanol (217 g) was added and the mixture was refluxed. After slowly cooling to 0-5 ° C
The precipitate was filtered and dried in vacuo to give a white powder of 2,5-dichloro-N- (2- (isopropylsulfonyl) phenyl) pyrimidin-4-amine (19.5 g, 88% yield).
^{1 1} H-NMR (400 MHz, CDCl ₃ ): δ = 1.33 (d, J = 6.7 Hz, 6H), 3.22 (seven-fold line, J = 6.8 Hz
, 1H), 7.31-7.35 (m, 1H), 7.72-7.76 (m, 1H), 7.92-7.94 (m, 1H), 8.31 (s, 1H), 8.
63-8.65 (m, 1H), 10.07 (br s, 1H) ppm. ¹³ C-NMR (100 MHz, CDCl ₃ ): δ = 153, 56.1,
115.2, 122.7, 124.2, 124.5, 131.5, 135.20, 137.4, 155.6, 156.3, 157.8 ppm.

Synthesis of 2,5-dichloro-N- (2- (isopropylsulfonyl) phenyl) pyrimidin-4-amine (C3, X = Cl) according to the following order

１−（イソプロピルスルホニル）−２−ニトロベンゼン（Ｊ’）
プロパン−２−スルフィン酸ナトリウム（２．４８ｋｇ、１９．１ｍｏｌ、１．５当量
）および１−クロロ−２−ニトロベンゼン（２．００ｋｇ、１２．７ｍｏｌ）をＤＭＳＯ
（５．５ｋｇ）に溶解し、８５℃に１２時間加熱した。２０℃に冷却した後、氷水（１５
ｋｇ）を添加し、続いて１−（イソプロピルスルホニル）−２−ニトロベンゼン（１ｇ）
を散布した。反応混合物を０〜１０℃で３０分間撹拌し、濾過し、真空乾燥して、灰色固
体の１−（イソプロピルスルホニル）−２−ニトロベンゼン（２．８ｋｇ、収率９６％）
を得た。

1- (Isopropylsulfonyl) -2-nitrobenzene (J')
DMSO with sodium propan-2-sulfinate (2.48 kg, 19.1 mol, 1.5 eq) and 1-chloro-2-nitrobenzene (2.00 kg, 12.7 mol)
It was dissolved in (5.5 kg) and heated to 85 ° C. for 12 hours. After cooling to 20 ° C, ice water (15
kg), followed by 1- (isopropylsulfonyl) -2-nitrobenzene (1 g)
Was sprayed. The reaction mixture is stirred at 0-10 ° C. for 30 minutes, filtered, dried in vacuo and gray solid 1- (isopropylsulfonyl) -2-nitrobenzene (2.8 kg, 96% yield).
Got

2- (Isopropylsulfonyl) aniline (J)
1- (Isopropylsulfonyl) -2-nitrobenzene (2) in autoclave
.. 50 kg, 10.9 mol), ethanol (7.9 kg) and Pd / C (125 g,
The mixture of 5% w / w) was placed under a hydrogen pressure of 3.4 bar and stirred at 40 ° C. for 48 hours.
After filtering the catalyst, the filtrate was concentrated under vacuum to about 2.5 liters and the precipitate was collected by filtration. The filtrate was concentrated again under vacuum to about 0.8 liters and the precipitate was collected by filtration. 1 of the two solids collected by filtration
Combined, vacuum dried, 2- (isopropylsulfonyl) aniline (1.83 kg,
Yield 84%) was obtained.

2,5-Dichloro-N- (2- (isopropylsulfonyl) phenyl) pyrimidine-4-
Amine (C3, X = Cl)
2,4,5-Trichloropyrimidine (6.1 kg), 2- (isopropylsulfonyl) aniline (950 g, 4.77 mol) and DBU (181 g, 1.19 mol, 0)
.. 25 eq) and the mixture was stirred at 80 ° C. for 7.5 hours. After cooling to 25 ° C, n
-Heptane (1.9 kg) was added and the mixture was stirred for 30 minutes. The mixture was cooled to −5 ° C., filtered and washed with n-heptane (325 g). The crude product is ethanol (4.5 kg)
), Stirred at 25 ° C. for 12 hours, then cooled to 0 ° C. After filtration, the crude product was vacuum dried to give 2,5-dichloro-N- (2- (isopropylsulfonyl) phenyl) pyrimidine-4-amine (1.07 kg, 65% yield). ^{1 1} H-NMR (400 MHz, CDCl ₃ ):
δ = 1.33 (d, J = 6.7 Hz, 6H), 3.22 (seven-fold line, J = 6.8 Hz, 1H), 7.31-7.35 (m, 1H),
7.72-7.76 (m, 1H), 7.92-7.94 (m, 1H), 8.31 (s, 1H), 8.63-8.65 (m, 1H), 10.07 (b)
r. s, 1H) ppm. ¹³ C-NMR (100 MHz, CDCl ₃ ): δ = 153, 56.1, 115.2, 122.7, 124.2, 12
4.5, 131.5, 135.20, 137.4, 155.6, 156.3, 157.8 ppm.

Synthesis of 2-isopropoxy-5-methyl-4- (piperidine-4-yl) aniline dihydrochloride (C2, 2HCl salt) in the following order

メチル４−（５−イソプロポキシ−２−メチルフェニル）ピリジン−１（４Ｈ）−カルボ
キシラート（Ｃ２−２、Ｐ＝ＣＯ_２ＣＨ_３）
予備乾燥させたＬｉＣｌ（０．４１ｇ、９．６ｍｍｏｌ、１．１当量）に、マグネシウ
ム（０．２８ｇ、１１．３ｍｍｏｌ、１．３当量）およびＴＨＦ（１３ｍｌ）を添加し、
続いて２−ブロモ−４−イソプロポキシ−１−メチルベンゼン（２．００ｇ、８．７３ｍ
ｍｏｌ）を添加した。室温で１０分経過した後、混合物を、７０℃に１時間加熱した。混
合物を室温に冷却し、１時間撹拌し、さらに−３０℃に冷却した。１−（メトキシカルボ
ニル）ピリジン−１−イウムクロリド（１３．１ｍｍｏｌ；文献の手順に従ってピリジン
、塩化アセチルおよびヨウ化銅（Ｉ）から調製）を添加し、得られた橙色懸濁液を室温に
温め、１６時間撹拌した。ＴＢＭＥ（８０ｍｌ）を添加し、有機相を飽和ＮＨ_４Ｃｌ水溶
液（３×３０ｍｌ）、塩水（３０ｍｌ）で洗浄し、Ｎａ_２ＳＯ_４で脱水した。揮発性物質
を真空下で除去した後、得られたメチル４−（５−イソプロポキシ−２−メチルフェニル
）ピリジン−１（４Ｈ）−カルボキシラート（２．０４ｇ、収率８６％）の粗製物を、さ
らに精製することなく次のステップで使用した。¹H-NMR (400 MHz, CDCl₃): δ = 1.31 (
d, J = 6.1 Hz, 6H), 2.24 (s, 3H), 2.28 (s, 3H), 4.37 (m, 1 H), 4.50 (七重線, J =
6.0 Hz, 1H), 4.93-4.96 (m, 1H), 5.03-5.07 (m, 1H), 6.62-6.68 (m, 2H), 6.82 (m,
1H), 7.04-7.06 (m, 1H), 7.28-7.31 (m, 1H) ppm.

Methyl 4- (5-isopropoxy-2-methylphenyl) Pyridine-1 (4H) -carboxylate (C2-2, P = CO ₂ CH ₃ )
Magnesium (0.28 g, 11.3 mmol, 1.3 eq) and THF (13 ml) were added to the pre-dried LiCl (0.41 g, 9.6 mmol, 1.1 eq).
Subsequently, 2-bromo-4-isopropoxy-1-methylbenzene (2.00 g, 8.73 m)
mol) was added. After 10 minutes at room temperature, the mixture was heated to 70 ° C. for 1 hour. The mixture was cooled to room temperature, stirred for 1 hour and further cooled to −30 ° C. 1- (Methoxycarbonyl) pyridine-1-ium chloride (13.1 mmol; prepared from pyridine, acetyl chloride and copper (I) iodide according to the procedures in the literature) was added and the resulting orange suspension was warmed to room temperature. The mixture was stirred for 16 hours. TBME (80 ml) was added, and the organic phase was _{washed with saturated NH 4} Cl aqueous solution (3 × 30 ml) and brine (30 ml), and dehydrated with _{Na 2} SO _4. A crude product of methyl 4- (5-isopropoxy-2-methylphenyl) pyridine-1 (4H) -carboxylate (2.04 g, yield 86%) obtained after removing the volatiles under vacuum. Was used in the next step without further purification. ^{1 1} H-NMR (400 MHz, CDCl ₃ ): δ = 1.31 (
d, J = 6.1 Hz, 6H), 2.24 (s, 3H), 2.28 (s, 3H), 4.37 (m, 1 H), 4.50 (seven-fold line, J =
6.0 Hz, 1H), 4.93-4.96 (m, 1H), 5.03-5.07 (m, 1H), 6.62-6.68 (m, 2H), 6.82 (m,
1H), 7.04-7.06 (m, 1H), 7.28-7.31 (m, 1H) ppm.

Methyl 4- (5-isopropoxy-2-methylphenyl) piperidine-1-carboxylate (C2-2')
4- (5-Isopropoxy-2) in THF (20 ml) and methanol (50 ml)
-Methylphenyl) Pyridine-1 (4H) -carboxylate (2.0 g, 7.5 mmo)
Ammonium formate (10 g, 159 mmol) was added to the solution of l), followed by Pd / C.
(2.0 g, 10%) was added. After stirring at room temperature for 18 hours, the mixture is filtered through Celite®, the filter cake is washed with ethyl acetate (40 ml) and the filtrate is water (80 ml).
Was added. The aqueous phase is extracted with ethyl acetate (3 x 50 ml), the organic extracts are combined and Na ₂
Dehydrated with SO _4. Volatile substances are removed under vacuum and the crude is purified by silica gel chromatography (ethyl acetate / heptane) to the yellow oil methyl 4- (5-isopropoxy-2).
-Methylphenyl) piperidine-1-carboxylate (2.1 g, yield 72%) was obtained. ^{1 1} H-NMR (400 MHz, CDCl ₃ ): δ = 1.31 (d, J = 6.1 Hz, 6H), 1.53-1.65 (m, 1H), 1.7
8-1.85 (m, 1H), 2.14 (s, 3H), 2.27 (s, 3H), 2.62 (m, 1H), 2.89 (m, 1H), 3.17 (m,
1H), 3.92-3.96 (m, 1H), 4.49 (7-fold line, J = 6.1 Hz, 1H), 4.78-4.82 (m, 1H), 6.64-
6.69 (m, 2H), 7.04-7.06 (m, 1H) ppm.

Methyl 4- (5-isopropoxy-2-methyl-4-nitrophenyl) piperidine-1-
Carboxylate (C2-1, P = CO ₂ CH ₃ )
A mixture of methyl 4- (5-isopropoxy-2-methylphenyl) piperidine-1-carboxylate (4.15 g) in acetic anhydride (51 ml) was cooled to −10 ° C. nitric acid(
1 ml (65%) was added and the mixture was stirred at −10 ° C. for 1 hour. Nitric acid again (1 ml
, 65%) was added and stirred for 3 hours to warm the mixture to room temperature. After adding water (100 ml) to the mixture, the aqueous phase was extracted with ethyl acetate (3 x 80 ml). The combined organic phases, saturated aqueous _NH 4 Cl (2 × 50 ml), washed with brine (50 ml), and dried over _Na 2 SO _4. Volatile substances are removed under vacuum and the crude is purified by silica gel chromatography (ethyl acetate / heptane) to the yellow oil methyl 4- (5-isopropoxy-2-methyl-4-).
Nitrophenyl) piperidine-1-carboxylate (2.1 g, yield 72%) was obtained.
LCMS: m / z (M + 1) 337.2 [M + H] ⁺ .

Methyl 4- (4-amino-5-isopropoxy-2-methylphenyl) piperidine-1-
Carboxylate (C2-NCO ₂ Me)
P in a solution of 4- (5-isopropoxy-2-methyl-4-nitrophenyl) piperidine-1-carboxylate (3.68 g, 10.9 mmol) in ethanol (200 ml).
d / C (0.5 g, 10%) was added. The mixture was stirred for 5 hours in a 5 bar hydrogen atmosphere. The reaction mixture was purged with nitrogen, filtered through Celite® and ethyl acetate (50).
It was washed with ml). The filtrate was extracted with aqueous HCl (2 x 30 ml, 1M solution). The aqueous phase was neutralized with aqueous NaOH solution (1M solution) and extracted with ethyl acetate (3 x 50 ml). Volatile substances are removed under vacuum and the crude is purified by silica gel chromatography (ethyl acetate / heptane) to methyl 4- (4-amino-5-isopropoxy-2-methylphenyl) piperidin-1-carboxy. Latte (3.36 g, yield 51%) was obtained. ¹ H-NMR (400 MHz,
CDCl ₃ ): δ = 1.25 (d, J = 6,1 Hz, 6H), 1.47 (br. M, 2H), 1.65-1.68 (m, 2H), 2.1
Overlapping with 3 (s, 3H), 2.65-2.81 (m, 3H), 3.59 (br. S, 2H), 3.65 (s, 3H), 4.22 (br. S,
2H), 4.37 (7-fold line, J = 6.1 Hz, 1H), 6.46 (s, 1H), 6.53 (s, 1H) ppm.

2-Isopropoxy-5-methyl-4- (piperidine-4-yl) aniline dihydrochloride (C)
2,2HCl salt)
Aqueous solution of HCl (26 ml of 8M solution), methyl 4- (4-amino-5-isopropoxy-2-methylphenyl) piperidine-1-carboxylate (1.00 g, 3.26 mm)
It was added to ol) and the mixture was stirred at room temperature for 16 hours. After washing with dichloromethane (30 ml), the aqueous phase was neutralized with aqueous NaOH solution (1M solution). Neutralized aqueous phase with toluene (3 ×
Extract with 50 ml), combine with the organic extracts, and combine HCl (5M solution 2 in isopropanol)
.. 6 ml). When volatile substances are vaporized under vacuum, 2-isopropoxy-5-
Methyl-4- (piperidine-4-yl) aniline dihydrochloride (1.05 g, 49% yield) was obtained. LCMS: m / z (M-2HCl) 337.2 [M + H] ⁺ ; ¹ H-NMR (400 MH)
z, D ₂ O): δ = 1.24 (d, J = 6.1 Hz, 6H), 1.76-1.96 (m, 4H), 2.22 (s, 3H), 3.04-3.
14 (m, 3H), 3.46-3.49 (m, 2H), 4.71 (seven-fold line, J = 6.1 Hz, 1H; overlap with solvent signal)
, 6.95 (s, 1H), 7.13 (s, 1H) ppm.

5-Chloro-N2- (2-isopropoxy-5-methyl-4- (piperidine-4-yl))
Phenyl) -N4- (2- (isopropylsulfonyl) phenyl) pyrimidine-2,4-
Synthesis of diamine (Ceritinib)

イソプロパノール（４４５ｋｇ）を、２，５−ジクロロ−Ｎ−（２−（イソプロピルス
ルホニル）フェニル）ピリミジン−４−アミン（７０．２ｋｇ、２０３ｍｏｌ、１．１５
当量）および２−イソプロポキシ−５−メチル−４−（ピペリジン−４−イル）アニリン
二塩酸塩（５６．７ｋｇ、１７６ｍｏｌ）に添加した。混合物を約１６時間加熱還流した
。水（４７ｋｇ）を添加し、混合物を０℃に冷却した。固体を濾過し、イソプロパノール
／水で洗浄した。湿った生成物に、イソプロパノール（６８０ｋｇ）および水（５５ｋｇ
）を添加し、スラリーを還流するまで加熱した。得られた清澄な溶液を０℃に冷却し、濾
過し、真空乾燥して、５−クロロ−Ｎ２−（２−イソプロポキシ−５−メチル−４−（ピ
ペリジン−４−イル）フェニル）−Ｎ４−（２−（イソプロピルスルホニル）フェニル）
ピリミジン−２，４−ジアミン二塩酸塩（＝セリチニブ二塩酸塩；８４．５ｋｇ［総量、
１０％ｗ／ｗイソプロパノールを含有］、７６．０ｋｇ［１００％］、収率６８％）を得
た。

Isopropanol (445 kg), 2,5-dichloro-N- (2- (isopropylsulfonyl) phenyl) pyrimidine-4-amine (70.2 kg, 203 mol, 1.15)
Equivalent) and 2-isopropoxy-5-methyl-4- (piperidine-4-yl) aniline dihydrochloride (56.7 kg, 176 mol) were added. The mixture was heated to reflux for about 16 hours. Water (47 kg) was added and the mixture was cooled to 0 ° C. The solid was filtered and washed with isopropanol / water. To the moist product, isopropanol (680 kg) and water (55 kg)
) Was added and the slurry was heated to reflux. The resulting clear solution was cooled to 0 ° C., filtered and dried in vacuo to 5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidine-4-yl) phenyl) -N4. -(2- (Isopropyl sulfonyl) phenyl)
Pyrimidine-2,4-diamine dihydrochloride (= ceritinib dihydrochloride; 84.5 kg [total amount,
Contains 10% w / w isopropanol], 76.0 kg [100%], yield 68%).

Ethanol (155 kg) and water (113 kg), 5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidine-4-yl) phenyl) -N4- (2- (isopropylsulfonyl) phenyl) Pyrimidine-2,4-dihydrochloride; 45.0 kg [total amount, containing 10% w / w isopropanol], 40.5 kg [100%], 64.2 mol
), And the mixture was heated to 55 ° C. Aqueous NaOH solution (147 L of 1M solution, 2.3 eq) was added slowly and then cooled to 20 ° C. After filtration, the product was recrystallized from ethanol and dried in vacuo to give a nearly white powder of ceritinib (33.2 kg, yield 93% based on ceritinib dihydrochloride). ^{1 1} H-NMR (400 MHz, CDCl ₃ ): δ = 1.33 (d, J = 6)
.8 Hz, 6H), 1.38 (d, J = 6.1 Hz, 6H), 1.59-1-78 (m, 5 H), 2.18 (s, 3H), 2.75-2.8
Overlapping with 3 (m, 3H), 3.20-3.24 (m, 2H), 3.28 (seven-fold line, J = 6.8 Hz, 1H), 4.56 (seven-fold line,
J = 6.1 Hz, 1H), 6.82 (s, 1H), 7.25-7.29 (m, 1 H), 7.56 (br. S, 1H), 7.64 (m, 1)
H), 7.94 (m, 1H), 8.01 (br. S, 1H), 8.16 (br. S, 1H), 8.60 (m, 1H), 9.51 (br. S,
1H) ppm. ¹³ C-NMR (100 MHz, CDCl ₃ ): δ = 15.4, 18.9, 22.3, 33.9, 38.6, 47.5, 55.
4, 71.4, 105.7, 111.0, 120.6, 123.1, 123.7, 124.9, 126.7, 127.3, 131.2, 134.7, 1
38.3, 138.5, 144.7, 155.3, 155.4, 157.5 ppm, Elemental analysis: C ₂₈ H ₃₆ ClN ₅ O ₃ S calculated value: C
60.26, H 6.50, N 12.55, O 8.60 Cl 6.35, S 5.74, Measured values: C 60.15, H 6.45, N 12.72
, O 8.58, Cl 6.43, S 5.67.)

［式中、Ｐは保護基である］
の化合物。
［２］ 前記保護基が、ｔｅｒｔ−ブチルオキシカルボニル（Ｂｏｃ）、ベンジルオキシカルボニル、メチルオキシカルボニル、エチルオキシカルボニル、アリルオキシカルボニル、フェニルオキシカルボニル、ホルミル、アセチルおよびベンジルからなる群から選択される、上記［１］に記載の式（Ｃ２−１）の化合物。
［３］ 式（Ｃ２−１）の化合物を調製する方法であって、式（Ａ）

の化合物を、式（Ｂ）の化合物

と溶媒中で、少なくとも１種の触媒、および場合によって共触媒または添加剤の存在下で反応させるステップを含み、式中、
Ｐは保護基であり、
ＴおよびＸ１は独立して、Ｃｌ、Ｂｒ、Ｉ、ＯＴｆ、ＯＴｓ、ＯＰｉｖ、Ｍｇ、Ａｌ、Ｚｎ、Ｚｒ、Ｂ、Ｓｎ、Ｓｉ、ＺｎＣｌ、ＺｎＢｒ、ＺｎＩ、Ｚｎアルキル、Ｂ（ＯＨ） _２ 、Ｂ（ＯＣ（ＣＨ _３ ） _２ Ｃ（ＣＨ _３ ） _２ Ｏ）、９−ＢＢＮ、Ｂ（Ｓｉａ） _２ 、Ｂ（Ｃａｔ）、Ｂ（Ｃｙ） _２ 、ＢＦ _３ ⁻ 、Ｂ（ＭＩＤＡ）からなる群から選択される、方法。
［４］ ＴがＢｒであり、Ｘ１がＺｎＩである、上記［３］に記載の式（Ｃ２−１）の化合物を調製する方法。
［５］ 前記触媒が、Ｐｄ（ＰＰｈ _３ ） _２ Ｃｌ _２ 、Ｐｄ（ＰＰｈ _３ ） _４ 、Ｐｄ（ｄｂａ） _２ 、Ｐｄ _２ （ｄｂａ） _３ 、Ｐｄ（ＯＡｃ） _２ 、［Ｐｄ（アリル）Ｃｌ］ _２ 、Ｐｄ（ｄｐｐｆ）Ｃｌ _２ 、ＰｄＢｒ _２ （ＰｔＢｕ _３ ） _２ 、ＰｄＣｌ（クロチル）（ＰｔＢｕ _３ ）、Ｐｄ（ＰｔＢｕ _３ ） _２ 、ＰｄＣｌ _２ （Ａｍｐｈｏｓ） _２ 、ＰｄＣｌ（アリル）（Ａｍｐｈｏｓ）、ＰｄＢｒ _２ （Ｂｉｎａｐ）、ＰｄＣｌ _２ （ＤＣＰＰ）、ＰｄＣｌ _２ （ＤｉＰｒＰＦ）、ＰｄＣｌ _２ （ＤｉＰｒＰＦ）、Ｐｄ−ＰＥＰＰＳＩ−ＩＰｒ、クロロ（２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピル−１，１’−ビフェニル）［２−（２−アミノエチル）フェニル）］パラジウム（ＩＩ）、クロロ（２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピル−１，１’−ビフェニル）［２−（２’−アミノ−１，１’−ビフェニル）］パラジウム（ＩＩ）、クロロ（２−ジシクロヘキシルホスフィノ−２’，６’−ジメトキシ−１，１’−ビフェニル）［２−（２−アミノエチルフェニル）］パラジウム（ＩＩ）、クロロ（２−ジシクロヘキシルホスフィノ−２’，６’−ジメトキシ−１，１’−ビフェニル）［２−（２’−アミノ−１，１’−ビフェニル）］パラジウム（ＩＩ）、クロロ（２−ジシクロヘキシルホスフィノ−２’，６’−ジイソプロポキシ−１，１−ビフェニル）［２−（２−アミノエチルフェニル）］パラジウム（ＩＩ）、クロロ（２−ジシクロヘキシルホスフィノ−２’，６’−ジイソプロポキシ−１，１’−ビフェニル）［２−（２’−アミノ−１，１’−ビフェニル）］パラジウム（ＩＩ）、Ｐｄ／Ｃ、Ｐｄ、Ｎｉ（ａｃａｃ） _２ 、ＮｉＣｌ _２ 、Ｎｉ（ＰＰｈ _３ ） _２ Ｃｌ _２ 、Ｎｉ（ｃｏｄ） _２ 、Ｎｉ（ｄｐｐｆ）（ｃｏｄ）、Ｎｉ（ｄｐｐｆ）（シンナミル）、Ｎｉ（ｄｐｐｆ） _２ 、Ｎｉ（ｄｐｐｆ）Ｃｌ _２ 、Ｎｉ（ｄｐｐｐ）Ｃｌ _２ 、ＮｉＣｌ _２ （ＰＣｙ _３ ） _２ 、およびＮｉ（ｄｐｐｅ）Ｃｌ _２ 、またはそれらの混合物から選択される、上記［３］または［４］に記載の式（Ｃ２−１）の化合物を調製する方法。
［６］ 前記触媒がＰｄ（ＰＰｈ _３ ） _２ Ｃｌ _２ である、上記［３］または［４］に記載の式（Ｃ２−１）の化合物を調製する方法。
［７］ 前記溶媒が、テトラヒドロフラン（ＴＨＦ）、２−メチル−テトラヒドロフラン、１，４−ジオキサン、ジエチルエーテル、トルエン、ジメチルホルムアミド（ＤＭＦ）、ジメチルアセトアミド（ＤＭＡ）、ジメチルスルホキシド（ＤＭＳＯ）、ジメトキシエタン（ＤＭＥ）、ジクロロメタン、Ｎ−メチル−２−ピロリドン（ＮＭＰ）、１−ブチル−２−ピロリドン（ＮＢＰ）、アセトニトリル、アセトン、酢酸エチル、酢酸イソプロピル、酢酸ｔｅｒｔブチル、ペンタン、ヘキサン、ヘプタン、アニソール、ピリジン、トリエチルアミン、炭酸ジメチル、水、メタノール、エタノール、ｎ−プロパノール、２−プロパノール、ｎ−ブタノール、２−ブタノール、ｔｅｒｔ−ブタノール、またはそれらの混合物から選択される、上記［３］から［６］のいずれか一項に記載の式（Ｃ２−１）の化合物を調製する方法。
［８］ 前記溶媒がテトラヒドロフランである、上記［３］から［６］のいずれか一項に記載の式（Ｃ２−１）の化合物を調製する方法。
［９］ 前記共触媒または添加剤が、ＺｎＣｌ _２ 、ＺｎＢｒ _２ 、ＣｕＩ、ＬｉＣｌ、ＰＰｈ _３ 、Ｐ（ｏＴｏｌ） _３ 、Ｐ（ｏＴｏｌ）Ｐｈ _２ 、Ｐ（ｐＴｏｌ） _３ 、ＰｔＢｕ _３ 、ＰｔＢｕ _３ ＊ＨＢＦ _４ 、ＰＣｙ _３ 、ＰＣｙ _３ ＊ＨＢＦ _４ 、Ｐ（ＯｉＰｒ） _３ 、ＤＰＥ−Ｐｈｏｓ、ｄｐｐｆ、ｄｐｐｅ、ｄｐｐｐ、ｄｃｐｐ、ｄｐｐｂ、Ｐ（フリル） _３ 、ＣＰｈｏｓ、ＳＰｈｏｓ、ＲｕＰｈｏｓ、ＸＰｈｏｓ、ＤａｖｅＰｈｏｓ、ＪｏｈｎＰｈｏｓおよびキサントホスからなる群から選択される、上記［３］から［８］のいずれか一項に記載の式（Ｃ２−１）の化合物を調製する方法。
［１０］ 前記共触媒または添加剤がＣｕＩである、上記［３］から［８］のいずれか一項に記載の式（Ｃ２−１）の化合物を調製する方法。
［１１］ 前記保護基が、ｔｅｒｔ−ブチルオキシカルボニル（Ｂｏｃ）、ベンジルオキシカルボニルおよびメチルオキシカルボニルからなる群から選択される、上記［３］から［１０］のいずれか一項に記載の式（Ｃ２−１）の化合物を調製する方法。
［１２］ 前記保護基がｔｅｒｔ−ブチルオキシカルボニル（Ｂｏｃ）である、上記［３］から［１０］のいずれか一項に記載の式（Ｃ２−１）の化合物を調製する方法。
［１３］ 式（Ｃ２−１）の化合物を調製する方法であって、式（Ｃ２−３）

の化合物を、

（ピリジニウム−Ｐ）と溶媒中で反応させて、化合物（Ｃ２−２）

を生成させるステップと、
前記化合物（Ｃ２−２）を変換して、前記式（Ｃ２−１）

の化合物を形成するステップと
を含み、式中、
Ｐは保護基であり、
Ｚは、ＭｇＢｒ、ＭｇＣｌ、ＭｇＩ、Ｍｇ、ＺｎＣｌ、ＺｎＢｒ、ＺｎＩまたはＺｎ（アルキル）から選択される、方法。
［１４］ 前記化合物（Ｃ２−２）が、前記式（Ｃ２−１）の化合物から還元およびニトロ化によって形成される、上記［１３］に記載の式（Ｃ２−１）の化合物を調製する方法。
［１５］ 前記保護基Ｐが、ｔｅｒｔ−ブチルオキシカルボニル（Ｂｏｃ）、ベンジルオキシカルボニル、メチルオキシカルボニルおよびベンジルからなる群から選択される、上記［１３］または［１４］に記載の式（Ｃ２−１）の化合物を調製する方法。
［１６］ 式（Ｃ２）

の化合物またはその塩を調製する方法であって、上記［３］から［１５］のいずれか一項に記載の方法と、前記式（Ｃ２−１）の化合物の還元および脱保護のステップとを含む方法。
［１７］ （Ｃ２−１）が、触媒および水素の存在下で（Ｃ２）に還元される、上記［１６］に記載の式（Ｃ２）の化合物またはその塩を調製する方法。
［１８］ 前記触媒が、ラネーニッケル、Ｐｔ／Ｃ、Ｒｈ／Ｃ、Ｐｄ／Ａｌ _２ Ｏ _３ 、Ｐｄ／ＣａＣＯ _３ 、ＲｈＣｌ（ＰＰｈ _３ ） _３ 、リンドラー触媒、ＰｔＯ _２ 、Ｐｄ／Ｃ、［Ｒｈ（ｃｏｄ）（ＰＰｈ _３ ） _２ ］ ^＋ 、［Ｉｒ（ｃｏｄ）（ＰＣｙ _３ ）（Ｐｙ）］ ^＋ 、Ｐｄ（ＯＨ） _２ 、Ｐｄ（ＯＡｃ） _２ 、Ｐｄ _２ （ｄｂａ） _３ 、Ｚｎ、Ｆｅ、Ｓｍ、ＮｉＣｌ _２ 、Ｎｉ（ＯＡｃ） _２ 、ＣｏＣｌ _２ 、ＺｒＣｌ _４ 、ＴｉＣｌ _３ からなる群から選択される、上記［１７］に記載の式（Ｃ２）の化合物またはその塩を調製する方法。
［１９］ 前記触媒がＰｄ／Ｃである、上記［１７］に記載の式（Ｃ２）の化合物またはその塩を調製する方法。
［２０］ 前記保護基Ｐが、ｔｅｒｔ−ブチルオキシカルボニル（Ｂｏｃ）、ベンジルオキシカルボニル、メチルオキシカルボニル、エチルオキシカルボニル、アリルオキシカルボニル、フェニルオキシカルボニル、ホルミル、アセチルおよびベンジルからなる群から選択される、上記［１６］から［１９］のいずれか一項に記載の式（Ｃ２）の化合物またはその塩を調製する方法。
［２１］ 前記保護基Ｐが、ｔｅｒｔ−ブチルオキシカルボニル（Ｂｏｃ）またはメチルオキシカルボニルである、上記［１６］から［１９］のいずれか一項に記載の式（Ｃ２）の化合物またはその塩を調製する方法。
［２２］ ＺがＭｇＣｌまたはＭｇＢｒである、上記［１３］から［１５］のいずれか一項に記載の式（Ｃ２−１）の化合物を調製する方法または上記［１６］から［２１］のいずれか一項に記載の式（Ｃ２）の化合物もしくはその塩を調製する方法。
［２３］ 式（Ｃ２）の化合物またはその塩を調製する方法であって、式（Ｃ）

の化合物を溶媒中で、少なくとも１種の触媒および水素の存在下で還元するステップを含む方法。
［２４］ 前記還元が一段階還元である、上記［２３］に記載の式（Ｃ２）の化合物またはその塩を調製する方法。
［２５］ 前記触媒が、ラネーニッケル、Ｐｔ／Ｃ、Ｒｈ／Ｃ、Ｐｄ／Ａｌ _２ Ｏ _３ 、Ｐｄ／ＣａＣＯ _３ 、ＲｈＣｌ（ＰＰｈ _３ ） _３ 、リンドラー触媒、ＰｔＯ _２ 、Ｐｄ／Ｃ、［Ｒｈ（ｃｏｄ）（ＰＰｈ _３ ） _２ ］ ^＋ 、［Ｉｒ（ｃｏｄ）（ＰＣｙ _３ ）（Ｐｙ）］ ^＋ 、Ｐｄ（ＯＨ） _２ 、Ｐｄ／Ａｌ、Ｐｔ／Ａｌ、Ｐｔ／ＳｉＡｌ、Ｐｄ／ＺｒＯ _２ 、またはそれらの混合物からなる群から選択される、上記［２３］または［２４］に記載の式（Ｃ２）の化合物またはその塩を調製する方法。
［２６］ 反応が、酢酸中でＰｄ／Ａｌおよび水素の存在下で６０℃および圧力８０バールで行われる、上記［２３］から［２５］のいずれか一項に記載の式（Ｃ２）の化合物またはその塩を調製する方法。
［２７］ 反応が、Ｐｔ／Ｃおよび水素の存在下で１０〜５０℃および圧力１〜１０バールで、場合によって酢酸中にて行われる、上記［２３］から［２５］のいずれか一項に記載の式（Ｃ２）の化合物またはその塩を調製する方法。
［２８］ 式（Ｃ）の化合物またはその塩を調製するワンポット方法であって、溶媒中で式ＡＡ

の化合物を、式Ｄ

の化合物と、Ｘ _３ Ｂ（Ｘ _２ ） _２ 、少なくとも１種の触媒、塩基、および場合によってリガンドの存在下で、式（Ｅ）

の化合物を単離することなく反応させるステップを含み、式中、
Ｙは、Ｃｌ、Ｂｒ、Ｉ、ＯＴｆ、ＯＴｓ、ＯＰｉｖおよびＯＭｓから選択され、
Ｘ _４ は、Ｃｌ、Ｂｒ、Ｉ、ＯＴｆ、ＯＴｓ、ＯＰｉｖおよびＯＭｓから選択され、
Ｂ（Ｘ _２ ） _２ は、Ｂ（ＯＨ） _２ 、Ｂ（ＯＣ（ＣＨ _３ ） _２ Ｃ（ＣＨ _３ ） _２ Ｏ）、９−ＢＢＮ、Ｂ（Ｓｉａ） _２ 、Ｂ（Ｃａｔ）、Ｂ（Ｃｙ） _２ から選択され、Ｘ _３ はＨまたはＢ（Ｘ _２ ） _２ である、方法。
［２９］ ＹがＣｌまたはＢｒであり、Ｂ（Ｘ _２ ） _２ がＢ（ＯＨ） _２ またはＢ（ＯＣ（ＣＨ _３ ） _２ Ｃ（ＣＨ _３ ） _２ Ｏ）であり、Ｘ _３ がＢ（Ｘ _２ ） _２ である、上記［２８］に記載の式（Ｃ）の化合物またはその塩を調製する方法。
［３０］ 式（Ｃ）の化合物またはその塩を調製する方法であって、式（ＡＡ）の化合物を、式（Ｅ）の化合物と、溶媒中で触媒および塩基の存在下で反応させるステップを含み、式中、Ｙは、Ｃｌ、Ｂｒ、Ｉ、ＯＴｆ、ＯＴｓ、ＯＰｉｖおよびＯＭｓから選択され、Ｂ（Ｘ _２ ） _２ は、Ｂ（ＯＨ） _２ 、Ｂ（ＯＣ（ＣＨ _３ ） _２ Ｃ（ＣＨ _３ ） _２ Ｏ）、９−ＢＢＮ、Ｂ（Ｓｉａ） _２ 、Ｂ（ｃａｔ）、Ｂ（Ｃｙ） _２ 、ＢＦ _３ ⁻ およびＢ（ＭＩＤＡ）から選択される、方法。
［３１］ ＹがＣｌであり、Ｘ _２ がＯＨである、上記［３０］に記載の式（Ｃ）の化合物またはその塩を調製する方法。
［３２］ 前記溶媒が２−ブタノールまたは水である、上記［３０］または［３１］に記載の式（Ｃ）の化合物またはその塩を調製する方法。
［３３］ 前記触媒がＰｄ（ＰＰｈ _３ ） _２ Ｃｌ _２ である、上記［３０］から［３２］のいずれか一項に記載の式（Ｃ）の化合物またはその塩を調製する方法。
［３４］ 前記塩基がＫ _２ ＣＯ _３ である、上記［３０］から［３３］のいずれか一項に記載の式（Ｃ）の化合物またはその塩を調製する方法。
［３５］ 式（Ｃ３−１）

［式中、Ｘは、ハロゲン（Ｆ、Ｃｌ、Ｂｒ、Ｉ）、アルコキシ、アリールオキシ、アルキルチオ、アリールチオ、スルフィニルおよびスルホニルから選択される］
の化合物。
［３６］ 式（Ｃ３−１）の化合物を調製する方法であって、式（Ｆ）

の化合物またはその塩を、式（Ｇ）

の化合物と、塩基の存在下で、場合によって溶媒中で反応させるステップを含み、式中、Ｘは、ハロゲン（Ｂｒ、Ｃｌ、Ｉ）、アルコキシ、アリールオキシ、アルキルチオ、スルフィニルおよびスルホニルからなる群から選択される、方法。
［３７］ 前記塩基が、Ｎａ _２ ＣＯ _３ 、Ｋ _２ ＣＯ _３ 、Ｃｓ _２ ＣＯ _３ 、ＮａＨＣＯ _３ 、ＫＨＣＯ _３ 、トリエチルアミン、ＤＩＰＥＡ、Ｎａ _３ ＰＯ _４ 、Ｋ _３ ＰＯ _４ 、ＤＢＵまたはＮａＨから選択される、上記［３６］に記載の式（Ｃ３−１）の化合物を調製する方法。
［３８］ 前記塩基がＤＢＵまたはＤＩＰＥＡである、上記［３６］に記載の式（Ｃ３−１）の化合物を調製する方法。
［３９］ 前記溶媒が、１，４−ジオキサン、テトラヒドロフラン（ＴＨＦ）、２−メチルテトラヒドロフラン、ジエチルエーテル、トルエン、Ｎ−メチル−２−ピロリドン（ＮＭＰ）、１−ブチル−２−ピロリドン（ＮＢＰ）、アセトニトリル、アセトン、炭酸ジメチル、酢酸エチル、酢酸イソプロピル、酢酸ｔｅｒｔブチル、メタノール、エタノール、ｎ−プロパノール、２−プロパノール、ｎ−ブタノール、２−ブタノール、ｔｅｒｔ−ブタノールおよびトルエン、またはそれらの混合物から選択される、上記［３６］から［３８］のいずれか一項に記載の式（Ｃ３−１）の化合物を調製する方法。
［４０］ 前記溶媒が、トルエンもしくは１−ブタノールまたはそれらの混合物である、上記［３６］から［３９］のいずれか一項に記載の式（Ｃ３−１）の化合物を調製する方法。
［４１］ 式（Ｃ３）の化合物を調製する方法であって、上記［３６］から［４０］のいずれか一項に記載の方法と、得られた（Ｃ３−１）を溶媒中で酸化するステップとを含み、

式中、Ｘは、ハロゲン（Ｂｒ、Ｃｌ、Ｉ）、アルコキシ、アリールオキシ、アルキルチオ、スルフィニルおよびスルホニルから選択される、方法。
［４２］ 前記溶媒が、１，４−ジオキサン、テトラヒドロフラン（ＴＨＦ）、２−メチルテトラヒドロフラン、ジエチルエーテル、トルエン、ジメチルホルムアミド（ＤＭＦ）、ジメチルアセトアミド（ＤＭＡ）、ジメチルスルホキシド（ＤＭＳＯ）、ジメトキシエタン（ＤＭＥ）、ジクロロメタン、Ｎ−メチル−２−ピロリドン（ＮＭＰ）、１−ブチル−２−ピロリドン（ＮＢＰ）、アセトニトリル、アセトン、炭酸ジメチル、酢酸エチル、酢酸イソプロピル、酢酸ｔｅｒｔブチル、ペンタン、ヘキサン、ヘプタン、アニソール、ピリジン、トリエチルアミン、酢酸、水、メタノール、エタノール、ｎ−プロパノール、２−プロパノール、ｎ−ブタノール、２−ブタノールおよびｔｅｒｔ−ブタノール、またはそれらの混合物から選択される、上記［４１］に記載の式（Ｃ３）の化合物を調製する方法。
［４３］ 酸化剤が、ＫＭｎＯ _４ 、ＭｎＯ _２ 、ＮａＩＯ _４ 、ＮａＣｌＯ、ＫＨＳＯ _５ （オキソン）、ＮａＢＯ _３ 、ＣＨ _３ ＣＯ _３ Ｈ、Ｈ _２ Ｏ _２ 、Ｎａ _２ ＷＯ _４ 、Ｏ _２ 、Ｏ _３ 、過ルテニウム酸テトラプロピルアンモニウム（ＴＰＡＰ）、３，３−ジメチルジオキシラン、３−クロロ過安息香酸（ｍＣＰＢＡ）およびｔｅｒｔブチルヒドロペルオキシド（ＴＢＨＰ）、またはそれらの混合物からなる群から選択される、上記［４１］または［４２］に記載の式（Ｃ３）の化合物を調製する方法。
［４４］ 酢酸エチル中で、ＣＨ _３ ＣＯ _３ ＨのＣＨ _３ ＣＯ _２ Ｈ溶液の存在下で、場合によって２０℃と４０℃の間の温度で実施される、上記［４１］から［４３］のいずれか一項に記載の式（Ｃ３）の化合物を調製する方法。
［４５］ メタノール中でＨ _２ Ｏ _２ およびＮａ _２ ＷＯ _４ の存在下で実施される、上記［４１］から［４４］のいずれか一項に記載の式（Ｃ３）の化合物を調製する方法。
［４６］ ２０℃と７０℃の間の温度で実施される、上記［４５］に記載の式（Ｃ３）の化合物を調製する方法。
［４７］ 式（Ｃ３）の化合物を調製する方法であって、
（ｉ）式（Ｈ）

の化合物を、式（Ｉ）

の化合物を反応させて、中間体を形成するステップと、
（ｉｉ）前記中間体を還元するステップと、
（ｉｉｉ）還元された前記中間体を、式（Ｇ）

の化合物と塩基の存在下で反応させるステップであって、式中、Ｘは、ハロゲン（Ｆ、Ｃｌ、Ｂｒ、Ｉ）、アルコキシ、アリールオキシ、アルキルチオ、スルフィニルおよびスルホニルからなる群から選択され、Ｍは、Ｌｉ、Ｎａ、Ｋ、０．５Ｚｎ、０．５Ｃａから選択される、ステップと
を含む方法。
［４８］ ＭがＮａである、上記［４８］に記載の式（Ｃ３）の化合物を調製する方法。
［４９］ ＸがＣｌである、上記［３５］に記載の化合物または上記［３６］から［４８］のいずれか一項に記載の方法。
［５０］ セリチニブまたはその塩を調製する方法であって、
ｉ．上記［３］から［１５］、または［２２］のいずれか一項に記載の式（Ｃ２−１）の化合物を調製するステップと、
ｉｉ．式（Ｃ２）の化合物またはその塩を調製するステップと、
ｉｉｉ．化合物（Ｃ３）を用意するステップと、
ｉｖ．式（Ｃ２）の化合物またはその塩を式（Ｃ３）の化合物と反応させて、セリチニブまたはその塩を得るステップと
を含む方法。
［５１］ セリチニブまたはその塩を調製する方法であって、
（ａ）上記［１６］から［２７］のいずれか一項に記載の式（Ｃ２）の化合物またはその塩を調製するステップと、
（ｂ）式（Ｃ３）の化合物を用意するステップと、
（ｃ）前記式（Ｃ２）の化合物またはその塩を式（Ｃ３）の化合物と反応させて、セリチニブまたはその塩を得るステップと
を含む方法。
［５２］ セリチニブまたはその塩を調製する方法であって、
（Ｉ）式（Ｃ２）の化合物またはその塩を用意するステップと、
（ＩＩ）上記［３６］から［４０］、または［４９］のいずれか一項に記載の式（Ｃ３−１）の化合物を調製するステップと、
（ＩＩＩ）前記式（Ｃ３−１）の化合物から式（Ｃ３）の化合物を調製するステップと、
（ＩＶ）前記式（Ｃ２）の化合物またはその塩を前記式（Ｃ３）の化合物と反応させて、セリチニブまたはその塩を得るステップと
を含む方法。
［５３］ セリチニブまたはその塩を調製する方法であって、
（ａａ）上記［２８］から［３４］のいずれか一項に記載の式（Ｃ）の化合物を調製するステップと、
（ｂｂ）前記式（Ｃ）の化合物から式（Ｃ２）の化合物またはその塩を調製するステップと、
（ｃｃ）式（Ｃ３）の化合物を用意するステップと、
（ｄｄ）前記式（Ｃ２）の化合物またはその塩を前記式（Ｃ３）の化合物と反応させて、セリチニブまたはその塩を得るステップと
を含む方法。
［５４］ 前記式（Ｃ２）の化合物またはその塩を、前記式（Ｃ３）の化合物と、溶媒中で、場合によって塩基の存在下で反応させ、前記溶媒は、１，４−ジオキサン、テトラヒドロフラン（ＴＨＦ）、２−メチルテトラヒドロフラン、ジエチルエーテル、トルエン、Ｎ−メチル−２−ピロリドン（ＮＭＰ）、１−ブチル−２−ピロリドン（ＮＢＰ）、アセトニトリル、アセトン、炭酸ジメチル、酢酸エチル、酢酸イソプロピル、酢酸ｔｅｒｔブチル、水、メタノール、エタノール、ｎ−プロパノール、イソプロパノール、ｎ−ブタノール、２−ブタノール、ｔｅｒｔ−ブタノールおよびトルエン、またはそれらの混合物から選択され、場合による前記塩基は、Ｎａ _２ ＣＯ _３ 、Ｋ _２ ＣＯ _３ 、Ｃｓ _２ ＣＯ _３ 、ＮａＨＣＯ _３ 、ＫＨＣＯ _３ 、トリメチルアミン、ＤＩＰＥＡ、ＤＢＵ、Ｎａ _３ ＰＯ _４ およびＫ _３ ＰＯ _４ から選択される、上記［５０］から［５３］のいずれか一項に記載のセリチニブまたはその塩を調製する方法。
［５５］ 前記溶媒がイソプロパノールである、上記［５４］に記載のセリチニブまたはその塩を調製する方法。
［５６］ 前記式（Ｃ２）の化合物またはその塩を前記式（Ｃ３）の化合物と前記塩基の非存在下で反応させる、上記［５４］または［５５］に記載のセリチニブまたはその塩を調製する方法。
［５７］ 医薬組成物を調製する方法であって、上記［５０］から［５６］のいずれか一項に記載の方法と、得られたセリチニブと薬学的に許容される添加物を混合するステップとを含む方法。
［５８］ セリチニブまたはその塩を調製するための式（Ｃ２−１）の化合物の使用。
［５９］ セリチニブまたはその塩を調製するための式（Ｃ３−１）の化合物の使用。
［６０］ セリチニブまたはその塩を調製するための式（Ｃ２−２）の化合物の使用。
［６１］ 式（Ｃ２−２）

［式中、Ｐは保護基である］
の化合物。 Ethanol (155 kg) and water (113 kg), 5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidine-4-yl) phenyl) -N4- (2- (isopropylsulfonyl) phenyl) Piperidin-2,4-dihydrochloride; 45.0 kg [total amount containing 10% w / w isopropanol], 40.5 kg [100%], 64.2 mol) was added and the mixture was heated to 55 ° C. Aqueous NaOH solution (147 L of 1M solution, 2.3 eq) was added slowly and then cooled to 20 ° C. After filtration, the product was recrystallized from ethanol and dried in vacuo to give a nearly white powder of ceritinib (33.2 kg, yield 93% based on ceritinib dihydrochloride). ^{1 1} H-NMR (400 MHz, CDCl ₃ ): δ = 1.33 (d, J = 6.8 Hz, 6H), 1.38 (d, J = 6.1 Hz, 6H), 1.59-1-78 (m, 5 H), Overlapping with 2.18 (s, 3H), 2.75-2.83 (m, 3H), 3.20-3.24 (m, 2H), 3.28 (seven-fold line, J = 6.8 Hz, 1H), 4.56 (seven-fold line, J = 6.1 Hz, 1H), 6.82 (s, 1H), 7.25-7.29 (m, 1H), 7.56 (br. S, 1H), 7.64 (m, 1H), 7.94 (m, 1H), 8.01 (br. S, 1H) ), 8.16 (br. S, 1H), 8.60 (m, 1H), 9.51 (br. S, 1H) ppm. ¹³ C-NMR (100 MHz, CDCl ₃ ): δ = 15.4, 18.9, 22.3, 33.9, 38.6, 47.5, 55.4, 71.4, 105.7, 111.0, 120.6, 123.1, 123.7, 124.9, 126.7, 127.3, 131.2, 134.7, 138.3, 138.5, 144.7, 155.3, 155.4, 157.5 ppm, Element analysis: C ₂₈ H ₃₆ ClN ₅ Calculated values of O ₃ S: C 60.26, H 6.50, N 12.55, O 8.60 Cl 6.35, S 5.74, Measured values: C 60.15, H 6.45, N 12.72, O 8.58, Cl 6.43, S 5.67.)

The following aspects can be included.
[1] Equation (C2-1)

[In the formula, P is a protecting group]
Compound.
[2] The protecting group is selected from the group consisting of tert-butyloxycarbonyl (Boc), benzyloxycarbonyl, methyloxycarbonyl, ethyloxycarbonyl, allyloxycarbonyl, phenyloxycarbonyl, formyl, acetyl and benzyl. The compound of the formula (C2-1) described in the above [1].
[3] A method for preparing a compound of formula (C2-1), wherein formula (A) is used.

The compound of the formula (B)

And in solvent, including the step of reacting in the presence of at least one catalyst, and optionally a co-catalyst or additive, in the formula.
P is a protecting group
T and X1 are independently Cl, Br, I, OTf, OTs, OPiv, Mg, Al, Zn, Zr, B, Sn, Si, ZnCl, ZnBr, ZnI, Znalkyl, B (OH) ₂ , B. _{(OC (CH 3) 2 C} (CH 3) 2 O), 9-BBN, B (Sia) 2, B (Cat), B (Cy) 2, BF 3 -, selected from the group consisting of B (MIDA) How to be done.
[4] A method for preparing a compound of the formula (C2-1) according to the above [3], wherein T is Br and X1 is ZnI.
[5] The catalyst is Pd (PPh ₃ ) ₂ Cl ₂ , Pd (PPh ₃ ) ₄ , Pd (dba) ₂ , Pd ₂ (dba) ₃ , Pd (OAc) ₂ , [Pd (allyl) Cl] ₂ , Pd (dppf) Cl ₂ , PdBr ₂ (PtBu ₃ ) ₂ , PdCl (crotyl) (PtBu ₃ ), Pd (PtBu ₃ ) ₂ , PdCl ₂ (Amphos) ₂ , PdCl (allyl) (Amphos), PdBr ₂ ( Binap), PdCl ₂ (DCPP), PdCl ₂ (DiPrPF), PdCl ₂ (DiPrPF), Pd-PEPPSI-IPr, Chloro (2-dicyclohexylphosphino-2', 4', 6'-triisopropyl-1,1 '-Biphenyl) [2- (2-aminoethyl) phenyl)] Palladium (II), Chloro (2-dicyclohexylphosphino-2', 4', 6'-triisopropyl-1,1'-biphenyl) [2 -(2'-Amino-1,1'-biphenyl)] palladium (II), chloro (2-dicyclohexylphosphino-2', 6'-dimethoxy-1,1'-biphenyl) [2- (2-amino Ethylphenyl)] palladium (II), chloro (2-dicyclohexylphosphino-2', 6'-dimethoxy-1,1'-biphenyl) [2- (2'-amino-1,1'-biphenyl)] palladium (II), Chloro (2-dicyclohexylphosphino-2', 6'-diisopropoxy-1,1-biphenyl) [2- (2-aminoethylphenyl)] Palladium (II), Chloro (2-dicyclohexylphos) Fino-2', 6'-diisopropoxy-1,1'-biphenyl) [2- (2'-amino-1,1'-biphenyl)] Palladium (II), Pd / C, Pd, Ni (acac) ) ₂ , NiCl ₂ , Ni (PPh ₃ ) ₂ Cl ₂ , Ni (cod) ₂ , Ni (dppf) (cod), Ni (dppf) (thinnamyl), Ni (dppf) ₂ , Ni (dppf) Cl ₂ , The formula (C2-1) according to the above [3] or [4], which is selected from Ni (dpp) Cl ₂ , NiCl ₂ (PCy ₃ ) ₂ , and Ni (dppe) Cl _{2, or a mixture thereof.} How to prepare a compound.
[6] A method for preparing a compound of the formula (C2-1) according to the above [3] or [4], wherein the catalyst is Pd (PPh ₃ ) ₂ Cl _2.
[7] The solvent is tetrahydrofuran (THF), 2-methyl-tetrahydrofuran, 1,4-dioxane, diethyl ether, toluene, dimethylformamide (DMF), dimethylacetamide (DMA), dimethylsulfoxide (DMSO), dimethoxyethane ( DME), dichloromethane, N-methyl-2-pyrrolidone (NMP), 1-butyl-2-pyrrolidone (NBP), acetonitrile, acetone, ethyl acetate, isopropyl acetate, tertbutyl acetate, pentane, hexane, heptane, anisole, pyridine , Triethylamine, dimethyl carbonate, water, methanol, ethanol, n-propanol, 2-propanol, n-butanol, 2-butanol, tert-butanol, or mixtures thereof, according to the above [3] to [6]. A method for preparing a compound of the formula (C2-1) according to any one of the above.
[8] A method for preparing a compound of the formula (C2-1) according to any one of the above [3] to [6], wherein the solvent is tetrahydrofuran.
[9] The cocatalyst or additive is ZnCl ₂ , ZnBr ₂ , CuI, LiCl, PPh ₃ , P (oTol) ₃ , P (oTol) Ph ₂ , P (pTol) ₃ , PtBu ₃ , PtBu ₃ * HBF. ₄ , PCy ₃ , PCy ₃ * HBF ₄ , P (OiPr) ₃ , DPE-Phos, dppf, dppe, dpppp, dcppp, dppb, P (frill) ₃ , CPhos, SPhos, RuPhos, XPhos, RuPhos, XPhos, XPhos, XPhos, XPhos A method for preparing a compound of the formula (C2-1) according to any one of the above [3] to [8], which is selected from the group consisting of.
[10] A method for preparing a compound of the formula (C2-1) according to any one of the above [3] to [8], wherein the cocatalyst or additive is CuI.
[11] The formula according to any one of the above [3] to [10], wherein the protecting group is selected from the group consisting of tert-butyloxycarbonyl (Boc), benzyloxycarbonyl and methyloxycarbonyl. A method for preparing the compound of C2-1).
[12] A method for preparing a compound of the formula (C2-1) according to any one of the above [3] to [10], wherein the protecting group is tert-butyloxycarbonyl (Boc).
[13] A method for preparing a compound of the formula (C2-1), which has the formula (C2-3).

Compound,

Reaction with (pyridinium-P) in a solvent to compound (C2-2)

And the steps to generate
The compound (C2-2) is converted into the formula (C2-1).

And the steps to form the compound
Including, in the formula,
P is a protecting group
Z is a method selected from MgBr, MgCl, MgI, Mg, ZnCl, ZnBr, ZnI or Zn (alkyl).
[14] A method for preparing a compound of the formula (C2-1) according to the above [13], wherein the compound (C2-2) is formed from the compound of the formula (C2-1) by reduction and nitration. ..
[15] The formula (C2-) according to the above [13] or [14], wherein the protecting group P is selected from the group consisting of tert-butyloxycarbonyl (Boc), benzyloxycarbonyl, methyloxycarbonyl and benzyl. 1) Method for preparing the compound.
[16] Equation (C2)

The method according to any one of [3] to [15] above, and the steps for reducing and deprotecting the compound of the formula (C2-1). How to include.
[17] A method for preparing a compound of the formula (C2) according to the above [16] or a salt thereof, wherein (C2-1) is reduced to (C2) in the presence of a catalyst and hydrogen.
[18] The catalysts are Raney nickel, Pt / C, Rh / C, Pd / Al ₂ O ₃ , Pd / CaCO ₃ , RhCl (PPh ₃ ) ₃ , Lindlar catalyst, PtO ₂ , Pd / C, [Rh (cod). ) (PPh ₃ ) ₂ ] ⁺ , [Ir (cod) (PCy ₃ ) (Py)] ⁺ , Pd (OH) ₂ , Pd (OAc) ₂ , Pd ₂ (dba) ₃ , Zn, Fe, Sm, NiCl _2. A method for preparing a compound of the formula (C2) according to the above [17] or a salt thereof, which is selected from the group consisting of Ni (OAc) ₂ , CoCl ₂ , ZrCl ₄ , and TiCl _3.
[19] A method for preparing a compound of the formula (C2) according to the above [17] or a salt thereof, wherein the catalyst is Pd / C.
[20] The protecting group P is selected from the group consisting of tert-butyloxycarbonyl (Boc), benzyloxycarbonyl, methyloxycarbonyl, ethyloxycarbonyl, allyloxycarbonyl, phenyloxycarbonyl, formyl, acetyl and benzyl. , The method for preparing the compound of the formula (C2) or a salt thereof according to any one of the above [16] to [19].
[21] A compound of the formula (C2) according to any one of the above [16] to [19] or a salt thereof, wherein the protecting group P is tert-butyloxycarbonyl (Boc) or methyloxycarbonyl. How to prepare.
[22] A method for preparing a compound of the formula (C2-1) according to any one of the above [13] to [15], or any of the above [16] to [21], wherein Z is MgCl or MgBr. A method for preparing a compound of the formula (C2) or a salt thereof according to the above item.
[23] A method for preparing a compound of formula (C2) or a salt thereof, wherein the compound of formula (C2) is prepared.

A method comprising the step of reducing a compound of the above in a solvent in the presence of at least one catalyst and hydrogen.
[24] A method for preparing a compound of the formula (C2) according to the above [23] or a salt thereof, wherein the reduction is a one-step reduction.
[25] The catalysts are Raney nickel, Pt / C, Rh / C, Pd / Al ₂ O ₃ , Pd / CaCO ₃ , RhCl (PPh ₃ ) ₃ , Lindlar catalyst, PtO ₂ , Pd / C, [Rh (cod). ) (PPh ₃ ) ₂ ] ⁺ , [Ir (cod) (PCy ₃ ) (Py)] ⁺ , Pd (OH) ₂ , Pd / Al, Pt / Al, Pt / SiAl, Pd / ZrO ₂ , or theirs. A method for preparing a compound of the formula (C2) according to the above [23] or [24] or a salt thereof, which is selected from the group consisting of a mixture.
[26] The compound of the formula (C2) according to any one of the above [23] to [25], wherein the reaction is carried out in acetic acid in the presence of Pd / Al and hydrogen at 60 ° C. and a pressure of 80 bar. Or a method of preparing the salt.
[27] The reaction is carried out in the presence of Pt / C and hydrogen at 10-50 ° C. and a pressure of 1-10 bar, optionally in acetic acid, according to any one of the above [23] to [25]. A method for preparing a compound of the above formula (C2) or a salt thereof.
[28] A one-pot method for preparing a compound of formula (C) or a salt thereof, wherein the formula AA is prepared in a solvent.

Compound of, formula D

In the presence of the compounds of X ₃ B (X ₂ ) ₂ , at least one catalyst, base, and optionally ligand, formula (E).

In the formula, which comprises the step of reacting the compounds of
Y is selected from Cl, Br, I, OTf, OTs, OPiv and OMs.
X ₄ is selected from Cl, Br, I, OTf, OTs, OPiv and OMs.
B (X ₂ ) ₂ is B (OH) ₂ , B (OC (CH ₃ ) ₂ C (CH ₃ ) ₂ O), 9-BBN, B (Sia) ₂ , B (Cat), B (Cy). _{A method} selected from 2, where X ₃ is H or B (X ₂ ) ₂ .
[29] Y is Cl or Br, B (X ₂ ) ₂ is B (OH) ₂ or B (OC (CH ₃ ) ₂ C (CH ₃ ) ₂ O), and X ₃ is B (X _2). ) ₂ , the method for preparing the compound of the formula (C) according to the above [28] or a salt thereof.
[30] A method for preparing a compound of formula (C) or a salt thereof, wherein the compound of formula (AA) is reacted with a compound of formula (E) in a solvent in the presence of a catalyst and a base. Including, in the formula, Y is selected from Cl, Br, I, OTf, OTs, OPiv and OMs, and B (X ₂ ) ₂ is B (OH) ₂ , B (OC (CH _{3 ) 2} C (CH ). _{3) 2 O), 9-} BBN, B (Sia) 2, B (cat), B (Cy) 2, BF 3 - is selected from and B (MIDA), method.
[31] A method for preparing a compound of the formula (C) according to the above [30] or a salt thereof, wherein Y is Cl and X _{2 is OH.}
[32] A method for preparing a compound of the formula (C) or a salt thereof according to the above [30] or [31], wherein the solvent is 2-butanol or water.
[33] A method for preparing a compound of the formula (C) according to any one of the above [30] to [32] or a salt thereof, wherein the catalyst is Pd (PPh ₃ ) ₂ Cl _2.
[34] A method for preparing a compound of the formula (C) or a salt thereof according to any one of the above [30] to [33], wherein the base is K ₂ CO _3.
[35] Equation (C3-1)

[In the formula, X is selected from halogen (F, Cl, Br, I), alkoxy, aryloxy, alkylthio, arylthio, sulfinyl and sulfonyl].
Compound.
[36] A method for preparing a compound of formula (C3-1), wherein formula (F)

Compound or salt thereof, according to the formula (G)

In the formula, X comprises the group consisting of halogen (Br, Cl, I), alkoxy, aryloxy, alkylthio, sulfinyl and sulfonyl, comprising the step of reacting with the compound of The method of choice.
[37] The base is selected from Na ₂ CO ₃ , K ₂ CO ₃ , Cs ₂ CO ₃ , NaHCO ₃ , KHCO ₃ , triethylamine, DIPEA, Na ₃ PO ₄ , K ₃ PO ₄ , DBU or NaH. A method for preparing a compound of the formula (C3-1) according to the above [36].
[38] A method for preparing a compound of the formula (C3-1) according to the above [36], wherein the base is DBU or DIPEA.
[39] The solvent is 1,4-dioxane, tetrahydrofuran (THF), 2-methyltetrahydrofuran, diethyl ether, toluene, N-methyl-2-pyrrolidone (NMP), 1-butyl-2-pyrrolidone (NBP), and the like. Selected from acetonitrile, acetone, dimethyl carbonate, ethyl acetate, isopropyl acetate, tert-butyl acetate, methanol, ethanol, n-propanol, 2-propanol, n-butanol, 2-butanol, tert-butanol and toluene, or mixtures thereof. The method for preparing the compound of the formula (C3-1) according to any one of the above [36] to [38].
[40] A method for preparing a compound of the formula (C3-1) according to any one of the above [36] to [39], wherein the solvent is toluene or 1-butanol or a mixture thereof.
[41] A method for preparing a compound of the formula (C3), wherein the method according to any one of the above [36] to [40] and the obtained (C3-1) are oxidized in a solvent. Including steps

In the formula, X is selected from halogen (Br, Cl, I), alkoxy, aryloxy, alkylthio, sulfinyl and sulfonyl, the method.
[42] The solvent is 1,4-dioxane, tetrahydrofuran (THF), 2-methyltetrahydrofuran, diethyl ether, toluene, dimethylformamide (DMF), dimethylacetamide (DMA), dimethylsulfoxide (DMSO), dimethoxyethane (DME). ), dichloromethane, N-methyl-2-pyrrolidone (NMP), 1-butyl-2-pyrrolidone (NBP), acetonitrile, acetone, dimethyl carbonate, ethyl acetate, isopropyl acetate, tertbutyl acetate, pentane, hexane, heptane, anisole. , Pyridine, triethylamine, acetic acid, water, methanol, ethanol, n-propanol, 2-propanol, n-butanol, 2-butanol and tert-butanol, or mixtures thereof, according to the formula according to [41] above. A method for preparing the compound of (C3).
[43] Oxidizing agents are KMnO ₄ , MnO ₂ , NaIO ₄ , NaClO, KHSO ₅ (oxonone), NaBO ₃ , CH ₃ CO ₃ H, H ₂ O ₂ , Na ₂ WO ₄ , O ₂ , O ₃ , and hydrogen peroxide. Selected from the group consisting of tetrapropylammonium ruthenate (TPAP), 3,3-dimethyldioxirane, 3-chloroperbenzoic acid (mCPBA) and tert-butyl hydroperoxide (TBHP), or mixtures thereof, [41] above. ] Or [42], a method for preparing a compound of the formula (C3).
[44] The above [41] to [43], which are carried out in ethyl acetate in the presence of a CH ₃ CO _{2 H solution of CH 3} CO _{3 H, optionally at a temperature between 20 ° C and 40 ° C.} A method for preparing a compound of the formula (C3) according to any one of the above.
[45] A method for preparing a compound of the formula (C3) according to any one of the above [41] to [44], which is carried out in the presence _{of H 2} O ₂ and Na ₂ WO _{4 in methanol.}
[46] A method for preparing a compound of the formula (C3) according to the above [45], which is carried out at a temperature between 20 ° C. and 70 ° C.
[47] A method for preparing a compound of the formula (C3), wherein the compound is prepared.
(I) Equation (H)

Compound of formula (I)

To form an intermediate by reacting the compounds of
(Ii) The step of reducing the intermediate and
(Iii) The reduced intermediate is expressed in the formula (G).

In the formula, X is selected from the group consisting of halogen (F, Cl, Br, I), alkoxy, aryloxy, alkylthio, sulfinyl and sulfonyl, and M Is selected from Li, Na, K, 0.5Zn, 0.5Ca, step and
How to include.
[48] A method for preparing a compound of the formula (C3) according to the above [48], wherein M is Na.
[49] The method according to any one of the compound according to the above [35] or the above [36] to [48], wherein X is Cl.
[50] A method of preparing ceritinib or a salt thereof, which is a method for preparing ceritinib or a salt thereof.
i. The step of preparing the compound of the formula (C2-1) according to any one of the above [3] to [15] or [22], and
ii. The step of preparing the compound of formula (C2) or a salt thereof, and
iii. Steps to prepare compound (C3) and
iv. The step of reacting the compound of formula (C2) or a salt thereof with the compound of formula (C3) to obtain ceritinib or a salt thereof.
How to include.
[51] A method for preparing ceritinib or a salt thereof.
(A) A step of preparing the compound of the formula (C2) according to any one of the above [16] to [27] or a salt thereof, and
(B) The step of preparing the compound of the formula (C3) and
(C) The step of reacting the compound of the formula (C2) or a salt thereof with the compound of the formula (C3) to obtain ceritinib or a salt thereof.
How to include.
[52] A method of preparing ceritinib or a salt thereof, which is a method for preparing ceritinib or a salt thereof.
The step of preparing the compound of the formula (C2) or a salt thereof, and
(II) The step of preparing the compound of the formula (C3-1) according to any one of the above [36] to [40] or [49], and
(III) A step of preparing a compound of the formula (C3) from the compound of the formula (C3-1), and
(IV) A step of reacting the compound of the formula (C2) or a salt thereof with the compound of the formula (C3) to obtain ceritinib or a salt thereof.
How to include.
[53] A method of preparing ceritinib or a salt thereof, which is a method for preparing ceritinib or a salt thereof.
(Aa) A step of preparing the compound of the formula (C) according to any one of the above [28] to [34], and
(Bb) A step of preparing a compound of formula (C2) or a salt thereof from the compound of formula (C),
(Cc) The step of preparing the compound of formula (C3) and
(Dd) A step of reacting the compound of the formula (C2) or a salt thereof with the compound of the formula (C3) to obtain ceritinib or a salt thereof.
How to include.
[54] The compound of the formula (C2) or a salt thereof is reacted with the compound of the formula (C3) in a solvent, optionally in the presence of a base, and the solvent is 1,4-dioxane, tetrahydrofuran ( THF), 2-methyl tetrahydrofuran, diethyl ether, toluene, N-methyl-2-pyrrolidone (NMP), 1-butyl-2-pyrrolidone (NBP), acetonitrile, acetone, dimethyl carbonate, ethyl acetate, isopropyl acetate, tert acetate Select from butyl, water, methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-butanol, tert-butanol and toluene, or mixtures thereof, optionally said bases are Na ₂ CO ₃ , K ₂ CO. ₃ , Cs ₂ CO ₃ , NaHCO ₃ , KHCO ₃ , trimethylamine, DIPEA, DBU, Na ₃ PO ₄ and K ₃ PO ₄ , the seritinib according to any one of [50] to [53] above. Or a method of preparing the salt.
[55] The method for preparing ceritinib or a salt thereof according to the above [54], wherein the solvent is isopropanol.
[56] Ceritinib according to the above [54] or [55] or a salt thereof is prepared by reacting the compound of the formula (C2) or a salt thereof with the compound of the formula (C3) in the absence of the base. Method.
[57] A method for preparing a pharmaceutical composition, wherein the method according to any one of the above [50] to [56] is mixed with the obtained ceritinib and a pharmaceutically acceptable additive. And how to include.
[58] Use of the compound of formula (C2-1) for preparing ceritinib or a salt thereof.
[59] Use of the compound of formula (C3-1) for preparing ceritinib or a salt thereof.
[60] Use of the compound of formula (C2-2) for preparing ceritinib or a salt thereof.
[61] Equation (C2-2)

[In the formula, P is a protecting group]
Compound.

Claims (61)

Equation (C2-1)

[In the formula, P is a protecting group]
Compound. The protecting group is selected from the group consisting of tert-butyloxycarbonyl (Boc), benzyloxycarbonyl, methyloxycarbonyl, ethyloxycarbonyl, allyloxycarbonyl, phenyloxycarbonyl, formyl, acetyl and benzyl, claim 1. The compound of the formula (C2-1) described in 1. A method for preparing a compound of formula (C2-1), wherein formula (A)

The compound of the formula (B)

And in solvent, including the step of reacting in the presence of at least one catalyst, and optionally a co-catalyst or additive, in the formula.
P is a protecting group
T and X1 are independently Cl, Br, I, OTf, OTs, OPiv, Mg, Al, Z
n, Zr, B, Sn, Si, ZnCl, ZnBr, ZnI, Znalkyl, B (OH) ₂
, B (OC (CH ₃ ) ₂ C (CH ₃ ) ₂ O), 9-BBN, B (Sia) ₂ , B (Cat)
^{_{), B (Cy) 2,}} BF 3 -, is selected from the group consisting of B (MIDA), method. The method for preparing a compound of the formula (C2-1) according to claim 3, wherein T is Br and X1 is ZnI. The catalysts are Pd (PPh ₃ ) ₂ Cl ₂ , Pd (PPh ₃ ) ₄ , Pd (dba) ₂ , P.
d ₂ (dba) ₃ , Pd (OAc) ₂ , [Pd (allyl) Cl] ₂ , Pd (dppf) C
l ₂ , PdBr ₂ (PtBu ₃ ) ₂ , PdCl (crotyl) (PtBu ₃ ), Pd (Pt)
Bu ₃ ) ₂ , PdCl ₂ (Amphos) ₂ , PdCl (allyl) (Amphos), P
dBr ₂ (Binap), PdCl ₂ (DCPP), PdCl ₂ (DiPrPF), Pd
Cl ₂ (DiPrPF), Pd-PEPPSI-IPr, chloro (2-dicyclohexylphosphino-2', 4', 6'-triisopropyl-1,1'-biphenyl) [2- (2)
-Aminoethyl) phenyl)] Palladium (II), chloro (2-dicyclohexylphosphino-2', 4', 6'-triisopropyl-1,1'-biphenyl) [2- (2'-
Amino-1,1'-biphenyl)] palladium (II), chloro (2-dicyclohexylphosphino-2', 6'-dimethoxy-1,1'-biphenyl) [2- (2-aminoethylphenyl)] palladium (II), Chloro (2-dicyclohexylphosphino-2',
6'-dimethoxy-1,1'-biphenyl) [2- (2'-amino-1,1'-biphenyl)] Palladium (II), chloro (2-dicyclohexylphosphino-2', 6'-diiso Propoxy-1,1-biphenyl) [2- (2-aminoethylphenyl)] palladium (II), chloro (2-dicyclohexylphosphino-2', 6'-diisopropoxy-1,1'-biphenyl) [ 2- (2'-amino-1,1'-biphenyl)] Palladium (II), Pd / C, Pd, Ni (acac) ₂ , NiCl ₂ , Ni (PPh ₃ ) ₂ Cl
₂ , Ni (cod) ₂ , Ni (dppf) (cod), Ni (dppf) (sinner mill)
, Ni (dppf) ₂ , Ni (dppf) Cl ₂ , Ni (dpppp) Cl ₂ , NiCl ₂
A method for preparing a compound of the formula (C2-1) according to claim 3 or 4, which is selected from (PCy ₃ ) ₂ , and Ni (dppe) Cl _{2, or a mixture thereof.} The formula (C2-1) according to claim 3 or 4, wherein the catalyst is Pd (PPh ₃ ) ₂ Cl _2.
) Method for preparing the compound. The solvent is tetrahydrofuran (THF), 2-methyl-tetrahydrofuran, 1,
4-dioxane, diethyl ether, toluene, dimethylformamide (DMF), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), dimethoxyethane (
DME), dichloromethane, N-methyl-2-pyrrolidone (NMP), 1-butyl-2-
Pyrrolidone (NBP), acetonitrile, acetone, ethyl acetate, isopropyl acetate, tertbutyl acetate, pentane, hexane, heptane, anisole, pyridine, triethylamine, dimethyl carbonate, water, methanol, ethanol, n-propanol, 2-propanol, n- The method for preparing a compound of the formula (C2-1) according to any one of claims 3 to 6, selected from butanol, 2-butanol, tert-butanol, or a mixture thereof. The formula (C) according to any one of claims 3 to 6, wherein the solvent is tetrahydrofuran.
2-1) Method for preparing the compound. The cocatalyst or additive is ZnCl ₂ , ZnBr ₂ , CuI, LiCl, PPh ₃ ,
P (oTol) ₃ , P (oTol) Ph ₂ , P (pTol) ₃ , PtBu ₃ , PtBu ₃
* HBF ₄ , PCy ₃ , PCy ₃ * HBF ₄ , P (OiPr) ₃ , DPE-Phos, d
ppf, dppe, dpppp, dcppp, dppb, P (frill) ₃ , CPhos, SP
The formula (C2-1) according to any one of claims 3 to 8, which is selected from the group consisting of hos, RuPhos, XPhos, DavePhos, JohnPhos and xantphos.
) Method for preparing the compound. The formula according to any one of claims 3 to 8, wherein the cocatalyst or additive is CuI.
A method for preparing the compound of C2-1). The compound of the formula (C2-1) according to any one of claims 3 to 10, wherein the protecting group is selected from the group consisting of tert-butyloxycarbonyl (Boc), benzyloxycarbonyl and methyloxycarbonyl. How to prepare. Claims 3-10, wherein the protecting group is tert-butyloxycarbonyl (Boc).
A method for preparing a compound of the formula (C2-1) according to any one of the above. A method for preparing a compound of formula (C2-1), which is of formula (C2-3).

Compound,

Reaction with (pyridinium-P) in a solvent to compound (C2-2)

And the steps to generate
The compound (C2-2) is converted into the formula (C2-1).

Including the step of forming the compound of
P is a protecting group
Z is a method selected from MgBr, MgCl, MgI, Mg, ZnCl, ZnBr, ZnI or Zn (alkyl). The method for preparing a compound of the formula (C2-1) according to claim 13, wherein the compound (C2-2) is formed from the compound of the formula (C2-1) by reduction and nitration. 13. The protecting group P is selected from the group consisting of tert-butyloxycarbonyl (Boc), benzyloxycarbonyl, methyloxycarbonyl and benzyl.
Alternatively, a method for preparing a compound of the formula (C2-1) according to 14. Equation (C2)

A method for preparing a compound or a salt thereof, comprising the method according to any one of claims 3 to 15 and the steps of reducing and deprotecting the compound of the formula (C2-1). The method for preparing a compound of formula (C2) or a salt thereof according to claim 16, wherein (C2-1) is reduced to (C2) in the presence of a catalyst and hydrogen. The catalyst is Raney nickel, Pt / C, Rh / C, Pd / Al ₂ O ₃ , Pd / CaC.
O ₃ , RhCl (PPh ₃ ) ₃ , Lindlar catalyst, PtO ₂ , Pd / C, [Rh (cod)
) (PPh ₃ ) ₂ ] ⁺ , [Ir (cod) (PCy ₃ ) (Py)] ⁺ , Pd (OH) ₂ ,
Pd (OAc) ₂ , Pd ₂ (dba) ₃ , Zn, Fe, Sm, NiCl ₂ , Ni (OAc)
A method for preparing a compound of the formula (C2) according to claim 17, or a salt thereof, which is selected from the group consisting of ₂ , CoCl ₂ , ZrCl ₄ , and TiCl _3. The method for preparing a compound of the formula (C2) or a salt thereof according to claim 17, wherein the catalyst is Pd / C. The protecting group P is tert-butyloxycarbonyl (Boc), benzyloxycarbonyl, methyloxycarbonyl, ethyloxycarbonyl, allyloxycarbonyl,
The method for preparing a compound of the formula (C2) or a salt thereof according to any one of claims 16 to 19, which is selected from the group consisting of phenyloxycarbonyl, formyl, acetyl and benzyl. The method for preparing a compound of the formula (C2) according to any one of claims 16 to 19, or a salt thereof, wherein the protecting group P is tert-butyloxycarbonyl (Boc) or methyloxycarbonyl. The formula according to any one of claims 13 to 15, wherein Z is MgCl or MgBr.
A method for preparing a compound of C2-1) or a method for preparing a compound of the formula (C2) according to any one of claims 16 to 21 or a salt thereof. A method for preparing a compound of formula (C2) or a salt thereof, wherein formula (C)

A method comprising the step of reducing a compound of the above in a solvent in the presence of at least one catalyst and hydrogen. The method for preparing a compound of the formula (C2) or a salt thereof according to claim 23, wherein the reduction is a one-step reduction. The catalyst is Raney nickel, Pt / C, Rh / C, Pd / Al ₂ O ₃ , Pd / CaC.
O ₃ , RhCl (PPh ₃ ) ₃ , Lindlar catalyst, PtO ₂ , Pd / C, [Rh (cod)
) (PPh ₃ ) ₂ ] ⁺ , [Ir (cod) (PCy ₃ ) (Py)] ⁺ , Pd (OH) ₂ ,
A method for preparing a compound of formula (C2) or a salt thereof according to claim 23 or 24, which is selected from the group consisting of Pd / Al, Pt / Al, Pt / SiAl, Pd / ZrO _{2, or a mixture thereof.} .. The compound of formula (C2) according to any one of claims 23 to 25 or a salt thereof is prepared, wherein the reaction is carried out in acetic acid in the presence of Pd / Al and hydrogen at 60 ° C. and a pressure of 80 bar. Method. The formula (C2) according to any one of claims 23 to 25, wherein the reaction is carried out in the presence of Pt / C and hydrogen at 10-50 ° C. and a pressure of 1-10 bar, optionally in acetic acid.
A method for preparing a compound or a salt thereof. A one-pot method for preparing a compound of formula (C) or a salt thereof, the formula AA in a solvent.

Compound of, formula D

In the presence of the compounds of X ₃ B (X ₂ ) ₂ , at least one catalyst, base, and optionally ligand, formula (E).

In the formula, which comprises the step of reacting the compounds of
Y is selected from Cl, Br, I, OTf, OTs, OPiv and OMs.
X ₄ is selected from Cl, Br, I, OTf, OTs, OPiv and OMs.
B (X ₂ ) ₂ is B (OH) ₂ , B (OC (CH ₃ ) ₂ C (CH ₃ ) ₂ O), 9-BBN.
, B (Sia) ₂ , B (Cat), B (Cy) ₂ and X ₃ is H or B (X ₂₎
) ₂ , the method. Y is Cl or Br, B (X ₂ ) ₂ is B (OH) ₂ or B (OC (CH ₃ ) ₂₎
The method for preparing a compound of formula (C) or a salt thereof according to claim 28, wherein C (CH ₃ ) ₂ O) and X ₃ is B (X ₂ ) _2. A method for preparing a compound of formula (C) or a salt thereof, wherein the compound of formula (AA) is expressed in formula (AA).
The step of reacting the compound of E) with the presence of a catalyst and a base in a solvent is included in the formula.
Y is selected from Cl, Br, I, OTf, OTs, OPiv and OMs, and B (X _2).
) ₂ is B (OH) ₂ , B (OC (CH ₃ ) ₂ C (CH ₃ ) ₂ O), 9-BBN, B (S).
_{ia) 2, B (cat)} , B (Cy) 2, BF 3 - is selected from and B (MIDA), method. The method for preparing a compound of formula (C) or a salt thereof according to claim 30, wherein Y is Cl and X _{2 is OH.} The method for preparing a compound of formula (C) or a salt thereof according to claim 30 or 31, wherein the solvent is 2-butanol or water. The method for preparing a compound of the formula (C) or a salt thereof according to any one of claims 30 to 32, wherein the catalyst is Pd (PPh ₃ ) ₂ Cl _2. The method for preparing a compound of the formula (C) or a salt thereof according to any one of claims 30 to 33, wherein the base is K ₂ CO _3. Equation (C3-1)

[In the formula, X is selected from halogen (F, Cl, Br, I), alkoxy, aryloxy, alkylthio, arylthio, sulfinyl and sulfonyl].
Compound. A method for preparing a compound of formula (C3-1), wherein formula (F)

Compound or salt thereof, according to the formula (G)

In the formula, it comprises the step of reacting with the compound of the above in the presence of a base, optionally in a solvent.
X is a method selected from the group consisting of halogen (Br, Cl, I), alkoxy, aryloxy, alkylthio, sulfinyl and sulfonyl. The bases are Na ₂ CO ₃ , K ₂ CO ₃ , Cs ₂ CO ₃ , NaHCO ₃ , KHCO ₃ ,
The method for preparing a compound of formula (C3-1) according to claim 36, which is selected from triethylamine, DIPEA, Na ₃ PO ₄ , K ₃ PO _{4, DBU or NaH.} The method for preparing a compound of the formula (C3-1) according to claim 36, wherein the base is DBU or DIPEA. The solvent is 1,4-dioxane, tetrahydrofuran (THF), 2-methyltetrahydrofuran, diethyl ether, toluene, N-methyl-2-pyrrolidone (NMP),
1-Butyl-2-pyrrolidone (NBP), acetonitrile, acetone, dimethyl carbonate, ethyl acetate, isopropyl acetate, tert-butyl acetate, methanol, ethanol, n-propanol, 2-propanol, n-butanol, 2-butanol, tert- The method for preparing a compound of the formula (C3-1) according to any one of claims 36 to 38, selected from butanol and toluene, or a mixture thereof. 3. The solvent is toluene or 1-butanol or a mixture thereof.
A method for preparing a compound of the formula (C3-1) according to any one of 6 to 39. A method for preparing a compound of formula (C3), which comprises the method according to any one of claims 36 to 40 and the step of oxidizing the obtained (C3-1) in a solvent.

In the formula, X is selected from halogen (Br, Cl, I), alkoxy, aryloxy, alkylthio, sulfinyl and sulfonyl, the method. The solvent is 1,4-dioxane, tetrahydrofuran (THF), 2-methyltetrahydrofuran, diethyl ether, toluene, dimethylformamide (DMF), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), dimethoxyethane (D).
ME), dichloromethane, N-methyl-2-pyrrolidone (NMP), 1-butyl-2-pyrrolidone (NBP), acetonitrile, acetone, dimethyl carbonate, ethyl acetate, isopropyl acetate, tert-butyl acetate, pentane, hexane, heptane, 41. The formula according to claim 41, which is selected from anisole, pyridine, triethylamine, acetic acid, water, methanol, ethanol, n-propanol, 2-propanol, n-butanol, 2-butanol and tert-butanol, or mixtures thereof. A method for preparing the compound of (C3). Oxidizing agents are KMnO ₄ , MnO ₂ , NaIO ₄ , NaClO, KHSO ₅ (Oxone)
, NaBO ₃ , CH ₃ CO ₃ H, H ₂ O ₂ , Na ₂ WO ₄ , O ₂ , O ₃ , Tetrapropylammonium tetrapropylammonium (TPAP), 3,3-dimethyldioxirane, 3-chloroperbenzoic acid Formula (C3) according to claim 41 or 42, selected from the group consisting of (mCPBA) and tert-butyl hydroperoxide (TBHP), or mixtures thereof.
How to prepare a compound of. In ethyl acetate, in the presence of a CH ₃ CO ₂ H solution of _{CH 3} CO _{3 H, optionally 20}
The formula (C) according to any one of claims 41 to 43, which is carried out at a temperature between ° C. and 40 ° C.
3) Method for preparing the compound. 41 to 4 performed in the presence of H ₂ O ₂ and Na ₂ WO _{4 in methanol.}
A method for preparing a compound of the formula (C3) according to any one of 4. The method of preparing a compound of formula (C3) according to claim 45, which is carried out at a temperature between 20 ° C. and 70 ° C. A method for preparing a compound of formula (C3).
(I) Equation (H)

Compound of formula (I)

To form an intermediate by reacting the compounds of
(Ii) The step of reducing the intermediate and
(Iii) The reduced intermediate is expressed in the formula (G).

In the formula, X is a halogen (F, C).
l, Br, I), alkoxy, aryloxy, alkylthio, sulfinyl and sulfonyl selected from the group, M selected from Li, Na, K, 0.5Zn, 0.5Ca, including steps. .. The method for preparing a compound of the formula (C3) according to claim 48, wherein M is Na. The compound according to claim 35 or the method according to any one of claims 36 to 48, wherein X is Cl. A method of preparing ceritinib or a salt thereof,
i. The step of preparing the compound of the formula (C2-1) according to any one of claims 3 to 15 or 22;
ii. The step of preparing the compound of formula (C2) or a salt thereof, and
iii. Steps to prepare compound (C3) and
iv. A method comprising the step of reacting a compound of formula (C2) or a salt thereof with a compound of formula (C3) to obtain ceritinib or a salt thereof. A method of preparing ceritinib or a salt thereof,
(A) A step of preparing the compound of the formula (C2) according to any one of claims 16 to 27 or a salt thereof, and
(B) The step of preparing the compound of the formula (C3) and
(C) A method comprising the step of reacting the compound of the formula (C2) or a salt thereof with the compound of the formula (C3) to obtain ceritinib or a salt thereof. A method of preparing ceritinib or a salt thereof,
The step of preparing the compound of the formula (C2) or a salt thereof, and
(II) The step of preparing the compound of the formula (C3-1) according to any one of claims 36 to 40 or 49.
(III) A step of preparing a compound of the formula (C3) from the compound of the formula (C3-1), and
(IV) The compound of the formula (C2) or a salt thereof is reacted with the compound of the formula (C3).
A method that includes steps to obtain ceritinib or a salt thereof. A method of preparing ceritinib or a salt thereof,
(Aa) A step of preparing the compound of the formula (C) according to any one of claims 28 to 34, and
(Bb) A step of preparing a compound of formula (C2) or a salt thereof from the compound of formula (C),
(Cc) The step of preparing the compound of formula (C3) and
(Dd) The compound of the formula (C2) or a salt thereof is reacted with the compound of the formula (C3).
A method that includes steps to obtain ceritinib or a salt thereof. The compound of the formula (C2) or a salt thereof is reacted with the compound of the formula (C3) in a solvent, optionally in the presence of a base, and the solvent is 1,4-dioxane, tetrahydrofuran (THF),. 2-Methyltetrahydrofuran, diethyl ether, toluene, N-methyl-2-pyrrolidone (NMP), 1-butyl-2-pyrrolidone (NBP), acetonitrile, acetone, dimethyl carbonate, ethyl acetate, isopropyl acetate, tertbutyl acetate, water , Methanol, ethanol, n-propanol, isopropanol, n-butanol, 2
-Butanol, tert-butanol and toluene, or mixtures thereof, optionally said bases are Na ₂ CO ₃ , K ₂ CO ₃ , Cs ₂ CO ₃ , NaHCO ₃ ,
The method for preparing ceritinib or a salt thereof according to any one of claims 50 to 53, which is selected from _{KHCO 3} , trimethylamine, DIPEA, DBU, Na ₃ PO ₄ and K ₃ PO _4. The method for preparing ceritinib or a salt thereof according to claim 54, wherein the solvent is isopropanol. The method for preparing ceritinib or a salt thereof according to claim 54 or 55, wherein the compound of the formula (C2) or a salt thereof is reacted with the compound of the formula (C3) in the absence of the base. A method for preparing a pharmaceutical composition, which comprises the method according to any one of claims 50 to 56, and a step of mixing the obtained ceritinib with a pharmaceutically acceptable additive. Use of the compound of formula (C2-1) for preparing ceritinib or a salt thereof. Use of the compound of formula (C3-1) for preparing ceritinib or a salt thereof. Use of the compound of formula (C2-2) for preparing ceritinib or a salt thereof. Equation (C2-2)

[In the formula, P is a protecting group]
Compound.