JP2019196359A - Chemical process for preparing pyrimidine derivatives and intermediates thereof - Google Patents

Abstract

To provide a method for producing intermediates for preparing ceritinib.SOLUTION: There is provided a method for preparing (C2-1), comprising 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 can be independently C1 and the like.SELECTED DRAWING: None

Description

FIELD OF THE DISCLOSURE This disclosure belongs to the field of organic synthesis and includes 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 an intermediate thereof, a method of further preparing pharmaceuticals and pharmaceutical compositions from seritinib or an intermediate, ceritinib and the intermediate itself It is directed to the use of intermediates for preparation.

BACKGROUND OF THE DISCLOSURE Anaplastic lymphoma kinase (ALK) is a member of the insulin receptor superfamily to which receptor tyrosine kinases belong. Chromosomal rearrangements involving ALK have been detected in a variety of human malignancies, such as carcinogenesis in hematopoietic and non-hematopoietic tumors, leading to impairments in cellular regulatory pathways. Inhibiting or suppressing the ALK pathway using an ALK tyrosine kinase inhibitor results in cell growth arrest and apoptosis of malignant cells. AL
Studies of K fusion proteins have also shown the potential for new therapeutic treatments for patients with ALK positive malignancies.

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

Summary of Disclosure Chemical methods are typically performed on a small scale in the research / early development phase, 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 increasingly important. Failure to scale up properly may result in uncontrollable processes such as unexpected exothermic reactions (runaway reactions) and accidents, health hazards while handling large amounts of hazards and / or toxic chemicals, or environmental hazards There is.

Surprisingly, ceritinib (5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4- [2- (propane-2-sulfonyl) -phenyl] -Pyrimidine-2,4-diamine) and its intermediate
It has become clear that it can be prepared using a more cost effective and safer method. Accordingly, the present disclosure provides a reproducible method that uses less hazardous chemicals and / or reaction conditions, reduces generated waste, and is easier to scale up and handle, ie, more efficient And is directed to a novel synthesis of ceritinib and its intermediates that results in a method of producing better quality compounds.

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

[Wherein P is a protecting group]
It is.

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

And a compound of formula (B)

Reacting in a solvent in the presence of at least one catalyst, and optionally a cocatalyst or additive, wherein
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).

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

A compound of

Compound (C2-2) is reacted with (pyridinium-P) in a solvent.

Generating
Compound (C2-2) is converted to a compound of formula (C2-1)

Forming a compound of the formula:
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 give a compound of formula (C2-1).

  Another aspect of the present disclosure is directed to formula (C2)

Or a salt thereof comprising a reduction and deprotection step of the compound of formula (C2-1).

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

In a solvent in the presence of at least one catalyst and hydrogen.

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

The compound of formula D

And a compound of formula (E) in the presence of X ₃ B (X ₂ ) ₂ , at least one catalyst, a base, and optionally a ligand.

Comprising reacting the compound without isolation, wherein:
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 represents 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 ⁻ and B (MIDA),
X ₃ is H, B (X ₂ ) ₂ relates to the method.

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

[Wherein X is selected from halogen (F, Cl, Br, I), alkoxy, aryloxy, alkylthio, sulfinyl and sulfonyl]
Of the compound.

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

Or a salt thereof of the formula (G)

Comprising reacting with a compound of formula I in the presence of a base, optionally in a solvent, wherein
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 for preparing a compound of formula (C3) comprising:

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

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

A compound of formula (I)

To obtain an intermediate wherein M is Li, Na, K,
A step selected from 0.5Zn, 0.5Ca;
(Ii) reducing the intermediate;
(Iii) a reduced intermediate of formula (G)

In the presence of a base, wherein X is a halogen (F, C
l, Br, I), alkoxy, aryloxy, alkylthio, sulfinyl, sulfonyl.

Another aspect of the present disclosure is a method of preparing ceritinib or a salt thereof,
i. Preparing a compound of formula (C2-1);
ii. Preparing a compound of formula (C2) or a salt thereof;
iii. Providing a compound (C3);
iv. 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 is a method of preparing ceritinib or a salt thereof,
(A) preparing a compound of formula (C2) or a salt thereof;
(B) providing a compound of formula (C3);
(C) 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 is a method of preparing ceritinib or a salt thereof,
(Aa) preparing a compound of formula (C2) or a salt thereof;
(Bb) providing a compound of formula (C3);
(Cc) 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 is a method of preparing ceritinib or a salt thereof,
(I) providing a compound of formula (C2) or a salt thereof;
(II) preparing a compound of formula (C3-1);
(III) preparing a compound of formula (C3) from a compound of formula (C3-1);
(IV) 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 directed to formula (C2-2)

[Where:
P is a protecting group]
It is a compound of this.

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

Detailed Description of Disclosure Increasing reactants and solvents to scale the reaction up to a full-size production plant can lead to process uncontrollability, unexpected exothermic reactions, accidents and large amounts of hazardous and / or toxic chemicals It has been observed that it can cause several dangers, such as safety issues during handling.

Surprisingly, ceritinib (5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4- [2- (propane-2-sulfonyl) -phenyl] -By modifying the method of synthesizing pyrimidine-2,4-diamine) and intermediates, it can be handled safely even when scaled up, the yield is reproducible, and there are few harmful / toxic chemicals It became clear that a more scalable method was obtained and less waste was produced. Furthermore, this method produces more efficient and better quality compounds at lower cost. An overview of this method is shown in Scheme 1. See below.

1.1 Compound of Formula (C2-1) A first aspect of the present disclosure is a compound of the formula (C2-1) that is an intermediate compound

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

The terms “protecting group” or “nitrogen protecting group” may be present, which may result from undesirable secondary reactions such as acylation, etherification, esterification, oxidation, solvolysis and similar reactions of functional groups. Shall be protected. A protecting group is characterized by the fact that the protecting group is typically solvolyzed
Easy, i.e. without undesirable secondary reactions or with only limited undesirable 2 by reduction, photolysis or by enzymatic activity, for example under conditions similar to physiological conditions
It is easily removed by the next reaction alone and is not present in the final product. The expert understands or can easily determine which protecting groups are suitable for the reactions described above and below. Preferably, if more than one protecting group is present in one of the described intermediates, their selection is necessary if one of the protecting groups needs to be removed, eg under different conditions, eg one of the Class is mild hydrolysis, the other is hydrolysis under more severe conditions, one is hydrolysis in the presence of an acid, the other is hydrolysis in the presence of a base, or one is Is performed so that it can be selectively removed using two or more different protecting groups that can be cleaved by reductive cleavage (eg, by catalytic hydrogenation), the other class being hydrolyzed, and the like. 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 established reference materials 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, pyrrole). C ₁ monosubstituted, disubstituted or trisubstituted with dinymethyl, 1-methyl-1,1-dimethylbenzyl, (phenyl) methylbenzene)
-C ₆ - alkyl, preferably _C 1 -C ₄ - alkyl, more preferably _C 1 -C ₂ - alkyl, (e.g., acetyl, allyl, tert-butyl), most preferably _{C 1} - alkyl, wherein Aryl or heterocyclic groups are unsubstituted or, for example, C ₁ -C ₇ -alkyl, hydroxy, C ₁ -C ₇ -alkoxy, C ₂ -C ₈ -alkanoyl-oxy, halogen, nitro, cyano, and CF Substituted with one or more, eg 2 or 3 residues selected from the group consisting of ₃ ; aryl-C ₁ -C ₂ -alkoxycarbonyl (preferably phenyl-C ₁ -C _2- Alkoxycarbonyl (eg, benzyloxycarbonyl (Cbz), benzyloxymethyl (BOM), pivaloyloxymethyl ( _{OM)); C 1 ~C 10} - _{alkenyloxycarbonyl;} C 1 -C ₆ - alkylcarbonyl (e.g., acetyl or _{pivaloyl); C} 6 ~C ₁₀ - arylcarbonyl;
C ₁ -C ₆ -alkoxycarbonyl (eg tert-butoxycarbonyl (Boc),
Methylcarbonyl, trichloroethoxycarbonyl (Troc), pivaloyl (Piv)
Allyloxycarbonyl); C ₆ -C ₁₀ -aryl C ₁ -C ₆ -alkoxycarbonyl (eg 9-fluorenylmethyloxycarbonyl (Fmoc)); allyl or cinnamyl; sulfonyl or sulfenyl; succinimidyl group, silyl Groups such as triarylsilyl, trialkylsilyl, triethylsilyl (TES), trimethylsilylethoxymethyl (SEM), trimethylsilyl (TMS), triisopropylsilyl or tertbutyldimethylsilyl.

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

A compound of formula (C2-1) is prepared by combining a compound of formula (A) with a compound of formula (B) and at least one catalyst, optionally a cocatalyst or addition, 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, 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.

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

In Reaction Scheme 2, T and X ₁ are independently, for example, Cl, Br, I, OTf,
It can be selected from the group consisting of OTs, OPiv, or T can be the metal species M. M is preferably a metal species comprising a metal ion selected from the group consisting of Mg, Al, Zn, Zr, B, Sn, Si, and M is more preferably ZnCl, ZnBr, 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)
It is. In general, T and X ₁ are independently, for example, 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 ⁻ , and B (MIDA) can be used.

As used herein, the term “alkyl” refers to a group or portion of a group that is a straight or branched carbon chain (one time or multiple times if desired). It is _C 1 _{~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 Bonded via non-terminal carbon. C ₁ -C ₈ -alkyl is, for example, n
-Pentyl, n-hexyl or n-heptyl, n-octyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, in particular methyl, ethyl, n-propyl, Isopropyl, n-butyl, isobutyl, s
ec-butyl, tert-butyl.

The catalyst used to perform the reaction outlined in Scheme 2 is any catalyst selected by those skilled in the art 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 generation XPhos precatalyst), chloro (2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropyl-1,1′-biphenyl) [2
-(2'-amino-1,1'-biphenyl)] palladium (II) (second generation XPhos)
Also known as precatalyst), chloro (2-dicyclohexylphosphino-2 ′, 6 ′)
-Dimethoxy-1,1'-biphenyl) [2- (2-aminoethylphenyl)] palladium (II) (also known as first generation SPhos precatalyst), chloro (2-dicyclohexylphosphino-2 ', 6'-dimethoxy-1,1'-biphenyl) [2- (2'-
Amino-1,1′-biphenyl)] palladium (II) (also known as second generation XPhos precatalyst), chloro (2-dicyclohexylphosphino-2 ′, 6′-diisopropoxy-1,1- Biphenyl) [2- (2-aminoethylphenyl)] palladium (I
I) (also known as first generation RuPhos precatalyst), chloro (2-dicyclohexylphosphino-2 ′, 6′-diisopropoxy-1,1′-biphenyl) [2- (2 ′
- amino-1,1'-biphenyl)], also known as Palladium (II) (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)
(Cinnamil), Ni (dppf) ₂ , Ni (dppf) Cl ₂ , Ni (dppp) Cl
₂ , NiCl ₂ (PCy ₃ ) ₂ , Ni (dppe) Cl ₂ , or a mixture thereof.

Cocatalysts or additives include 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, dppp, dcpp, dppb, P (furyl) ₃ , CPhos, SPho
It can be selected from the group consisting of s, RuPhos, XPhos, DavePhos, JohnPhos and Xanthophos.

The catalyst can generally be present in an amount up to 10.0 mol%. Typically, the catalyst may be present in an amount less than 5.0 mol%. The catalyst is further from about 0.005 mol% to about 5.0 mol%, from about 0.01 mol% to about 1.0 mol, relative to the starting compound of formula (A).
1%, or in the range of 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). A 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 successfully carried out at a temperature above 25 ° C, preferably about 50 ° C.

As used herein, the term “cocatalyst or additive” refers to a chemical that increases the chemical reaction rate by lowering the activation energy. The cocatalyst can be a heterogeneous catalyst or a homogeneous catalyst, and the additive can be a ligand, salt or some other chemical species that can increase 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 xanthophos.

1.2 Alternative pathways to reach compounds of formula (C2-1) Another aspect of the disclosure is a method of preparing compounds of formula (C2-1), as described in Scheme 3 , Reacting the compound of formula (C2-3) with a pyridinium-P substituent in a solvent to obtain compound (C2-2), and converting compound (C2-2) to convert compound of formula (C2-1) And a step of obtaining a compound. According to the present disclosure, protecting groups (
P) can be a customary protecting group, in particular those described herein (eg tert-
Butyloxycarbonyl (Boc), benzyloxycarbonyl, methyloxycarbonyl, ethyloxycarbonyl, allyloxycarbonyl, phenyloxycarbonyl, formyl, acetyl or benzyl). Methyloxycarbonyl and Boc are the preferred protecting groups used in the method shown in Scheme 3. Most preferred is methyloxycarbonyl.

The reaction of pyridinium-P with the compound of formula (C2-3) is such that Z is MgBr, MgI, MgC
Performed best when selected from l, ZnCl, ZnBr, ZnI, Zn (alkyl), etc., preferably when Z is MgCl or MgBr, most preferably MgBr.

Suitable solvents for obtaining the compound of formula (C2-2) are, for example, aprotic polar solvents. 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 was tetrahydrofuran (THF
) Especially well done.

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

The compound of formula (C2-2) is then converted to formula (C2-1) as described in Scheme 3.
).

The reduction is carried out using hydrogen or a hydrogen donor in the presence of a catalyst, with or without additives (hydrogen transfer reaction). As a 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
e, Sm, NiCl ₂ , Ni (OAc) ₂ , CoCl ₂ , ZrCl ₄ , TiCl ₃ can be selected. 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 optionally be added, 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, dppp, dcpp, dppb, P (furyl) ₃ , C
Phos, SPhos, RuPhos, XPhos, DavePhos, JohnPho
It can be selected from the group of s and xanthophos.

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

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 the conversion can be selected, for example, from acetic anhydride, sulfuric acid or trifluoroacetic acid.

The reduction described in Scheme 3 is performed particularly well at room temperature in methanol and tetrahydrofuran (THF) using 10% Pd / C, ammonium formate. Nitration 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., in particular at about −10 ° C.

1.3 Compounds of Formula (C2) Compounds of formula (C2) or salts thereof can be prepared according to the methods summarized in Scheme 4. This method requires the reduction and deprotection of a compound of formula (C2-1) disclosed herein 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 performed using hydrogen in the presence of a catalyst. The protecting group P can be selected from the above list (eg, t
refers to a nitrogen protecting group selected from ert-butyloxycarbonyl (Boc), benzyloxycarbonyl, methyloxycarbonyl, ethyloxycarbonyl, allyloxycarbonyl, phenyloxycarbonyl, formyl, acetyl or benzyl).

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 from general textbooks. 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
m, NiCl ₂ , Ni (OAc) ₂ , CoCl ₂ , ZrCl ₄ , TiCl ₃ can be selected. 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
%).

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 “heterogeneous catalyst” refers to a catalyst, supported on a substrate comprising a support, typically but not necessarily an inorganic material, for example 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 support.

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 include gaseous hydrogen (H ₂ ), hydrogen donor (hydrogen transfer reaction, eg, formic acid or salts thereof), hydride reagents (BH ₃ , B ₂ H ₆ , N
aBH ₄ ) or the like.

The reduction can be performed in a solvent such as an alcohol solution. The alcoholic solution is C ₁
-C ₁₀ alcohols (e.g., methanol, ethanol, propanol, isopropanol and butanol) can contain or mixtures thereof, or can be made from them.

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

In this specification, the term “room temperature” or “ambient temperature” is 20 to 20 unless otherwise specified.
It means a temperature of 15-30 ° C., such as 30 ° C., in particular 20-25 ° C.

In addition to the reduction of compound (C2-1), the protecting group is cleaved. Removal of the protecting group can be carried out under standard reaction conditions known in the art. Unless otherwise specified,
A protecting group can be removed in the absence of an acid or base, or an acid or base that routinely causes the removal of an acid or base, preferably a protecting group, but at the same time does not cause chemical degradation of the compounds and intermediates. It can be removed in the presence of a base. Removal of the protecting group 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. Particularly suitable acids for the removal of the protecting group P are H
F.pyridine, HF.triethylamine, ammonium fluoride, hexafluoroisopropanol, acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, or combinations 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 removal of the protecting group. As an example, the protecting group 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. The protecting group is 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 with trifluoroacetic acid in dichloromethane and possibly at ambient temperature. The deprotection reaction of the methyloxycarbonyl protecting group is best performed with hydrochloric acid, optionally at 60 ° C.

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

1.4 Alternative routes for preparing compounds of formula (C2) Compounds of formula (C2) or salts thereof can be prepared by alternative methods. 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.

In the preparation reaction of the compound of formula (C2) or a salt thereof, two functional groups present in the compound of formula (C) can be simultaneously reduced to quickly reach the compound of formula (C2) or a salt thereof. By becoming possible, 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 carry out the reduction of the compound of formula (C) is any catalyst selected from general textbooks by those skilled in the art. Examples of the catalyst include 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 mixtures thereof.

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

Reduction of the compound of formula (C) is carried out by bringing the reaction mixture between 10 ° C. and 40 ° C., preferably 20 ° C. and 3 ° C.
It is carried out by stirring at a temperature between 0 ° C. for a maximum of 16 hours, preferably between 8 and 16 hours. The reaction is best carried out at a pressure between 1 and 15 bar, preferably between 2 and 6 bar.

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

A method for reducing a compound of formula (C) to a compound of formula (C2) or a salt thereof is described in Pd in acetic acid.
Particularly well 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 performed in the presence of Pt / C and hydrogen, optionally in acetic acid. In this case, the temperature is best set at about 10 to about 50 ° C. and the pressure is best set at about 1 to about 10 bar.

1.5 Compound of Formula (C) As shown in Scheme 6, compound (C) is prepared by reacting compound of formula (AA) in a solvent,
It can be prepared in a one-pot process by reacting a compound of formula (D) with X ₃ B (X ₂ ) ₂ in the presence of a base, a catalyst, and optionally a ligand, wherein
Y is selected from Cl, Br, I, OTf, OTs, OPiv and OMs, preferably Cl,
Selected from Br,
X ₄ is selected from Cl, Br, I, OTf, OTs, OPiv and OMs, preferably Cl
, Br,
B (X ₂ ) ₂ represents 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 provides a compound of formula (E) without isolation of a compound of formula (E) in the presence of a catalyst, X ₃ B (X ₂ ) ₂ , a base, and optionally a ligand in a solvent. A method for in situ formation of the compound is provided. This reaction can be a one-pot reaction. The process of reacting formula (AA) with a compound of formula (D) is as follows: first, the reaction mixture containing the compound of formula (D) and the catalyst is about 1 at a temperature between 40 ° C. and reflux temperature, preferably 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 to 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 a ligand. 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) (cinnamil), Ni (dppf) ₂ , Ni (dp
pf) Cl ₂ , Ni (dppp) Cl ₂ , NiCl ₂ (PCy ₃ ) ₂ and Ni (dpp)
e) can be selected from the group consisting of Cl ₂ . The catalyst can be present in an amount up to 10.0 mol%. Typically, the catalyst may be present in an amount less than 6.0 mol%.

The ligand used to perform 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 (furyl) ₃ , CPhos, SPhos, RuPhos, X
It can be selected from the group consisting of Phos, DavePhos, JohnPhos and Xanthophos. 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 of less than 10 mol%.

For example, the reaction may be 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, tertbutyl acetate, pentane, hexane, heptane, anisole, pyridine, triethylamine, water, methanol, ethanol, n-propanol, 2-propanol, n 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 a person skilled in the art based on general textbooks. Bases are for example Na ₂ CO ₃ , K ₂ CO ₃ , Cs ₂ CO ₃ , 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 substituent of X ₃ B (X ₂ ) ₂ is taken together with boron to form the formula —B (X ₂ ) ₂
Wherein the _two X ₂ substituents are the same or different and are halogen,
It can be hydroxy, C ₁ -C ₄ -alkoxy, or the two X ₂ substituents together form the residue of a diol. Preferably, the boronyl group of formula —B (X ₂ ) ₂ may be a group of formula —B (OR ^′ ) OR ^″ , wherein R ^′ and R ^″ are independent of each other and are the same Differently, each may be hydrogen or C ₁ -C ₁₂ -alkyl, and R ^′ and R ^″ may be cyclically bridged, for example, R and R ′ attached may be
Alkylene which 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. The organoboron can be selected, for example, from the group consisting of bis (pinacolato) diboron, tetrahydroxydiboron, pinacolborane and neopentylglycolborane.

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

A method for in situ formation of a compound of formula (E) by reacting a compound of formula (D) is as follows: in 1,4-dioxane, bis (pinacolato) diboron, X-Phos, chloro (2-
Dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropyl-1,1′-biphenyl) [2- (2′-amino-1,1′-biphenyl)] palladium (II) and KO
This is particularly successful in the presence of Ac. The temperature can be set to 100 ° C. Then
The compound of formula (E) produced in situ is reacted with the compound of formula (AA) in a solvent in the presence of a base. The reaction is best carried out at a temperature between 40 ° C. and reflux, preferably 100 ° C.
Water and K ₂ CO ₃ are added to the reaction mixture to form the newly formed compound (E) and the formula (AA
The coupling reaction of the compound of The reaction can subsequently be carried out at 100 ° C.

The term “one-pot method” refers to the related steps performed sequentially without isolating the product of each step. Moreover, the process is further simplified by omitting the removal or exchange of any other components 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 organic synthesis method, but is only commercially valuable if the level of impurities can be minimized to provide a reasonable yield. In this case, the described one-pot method gives good results, and unreacted intermediates and by-products are at acceptable levels.

Alternatively, the compound of formula (C) or salt thereof may be isolated from the compound of formula (AA) and the isolated formula (
It can also be prepared by Suzuki coupling of compounds 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 represents 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. Examples of the solvent used include water, methanol, ethanol, n-propanol, 2-propanol, n-butanol, 2-butanol, dimethylformamide (DMF), tetrahydrofuran, 2-methyltetrahydrofuran,
It can be toluene, dioxane, or a mixture thereof. Preferably, the solvent is 2-butanol and water. The same catalyst and base 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
It is.

In one embodiment, a compound of formula (AA) is reacted with a 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. Where Y is Cl and X ₂ is OH.

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

Wherein X is halogen (F, Cl, Br, I), alkoxy (preferably OMe, OEt, OtBu), aryloxy (preferably OPh), alkylthio (
Preferably SMe, SEt), arylthio (SCH ₂ 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.

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 -C ₂₀ -alkyl), preferably C ₁ -C ₇ -alkoxy (—O—C)
₁ -C ₇ - embraces alkyl). In particular, alkoxy includes, 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).

The term “aryl” which is a group or part of a group refers to an aromatic hydrocarbon group such as C _6.
-C 10 _- refers to an aryl, preferably 6 to 14 carbon atoms, for example, monocyclic or polycyclic having 6 to 10 carbon atoms, especially monocyclic, bicyclic or tricyclic aryl Part. Preferably aryl represents phenyl, benzyl, indenyl, indanyl or naphthyl. The term “aryloxy” refers to aryl-O—, wherein aryl is as defined above. In particular, the preferred aryloxy herein is phenoxy (OPh). The term “arylthio” refers to aryl-S—, wherein aryl is as defined above. Preferred arylthio is benzylthio (SCH ₂ Ph)
It is.

The term “alkylthio” refers to alkyl-S—, where alkyl is as defined herein. Alkyl groups contain, for example, 1-8 carbon atoms. In particular, alkylthio includes, for example, methylthio (SMe), ethylthio (SEt), phenylthio (P
hS) and pentylthio. Preferred alkylthio substituents herein are methylthio (SMe) and ethylthio (SEt).

The term “sulfinyl” includes —S, including linear or branched C ₁ -C ₈ -alkyl.
Corresponds to —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, sulfonyl includes, for example, methylsulfonyl, ethylsulfonyl, phenylsulfonyl and benzylsulfonyl.

As shown in Scheme 7, the compound of formula (C3-1) can be prepared by combining a compound of formula (F) or a salt thereof with a compound of formula (G), optionally in the presence of a base, optionally in a solvent. 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
₃ , triethylamine, DIPEA, Na ₃ PO ₄ , K ₃ PO ₄ , DBU and NaH. Preferably the base is DBU or DIPEA. Good efficacy is obtained when a mild base is used in the reaction. The base is easy to handle and safe, potentially preventing side reactions and thus recovering the compound of formula (C3-1) in high yield.

The reaction can be carried out in a protic solvent or in 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, Acetone, dimethyl carbonate, ethyl acetate,
It can be selected from the group consisting of isopropyl acetate, tertbutyl 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. A temperature between 40 ° C and the reflux temperature can be selected, but the temperature is preferably between 100 ° C and 115 ° C,
In particular, it is about 110 ° C.

The process of reacting a compound of formula (F) or a salt thereof with a compound of formula (G) is best performed in the presence of DIPEA in toluene and 1-butanol. Temperature is 100-115
Best set to ℃. 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), wherein X is Cl.

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

1.7 Compound of Formula (C3) The compound of formula (C3) can be prepared from the compound of formula (C3-1). As shown in Scheme 8, compound (C3) can be prepared by oxidizing the resulting compound of formula (C3-1), wherein X is 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), and most preferably X is Cl.

The oxidation can be performed in water or an organic solvent. The solvent is 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, tertbutyl acetate, pentane,
It can be selected 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 others, 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 perruthenate (TPAP), 3,3-dimethyldioxirane, 3-chloro Perbenzoic acid (mCPBA) and tertbutyl hydroperoxide (TB)
HP), or a mixture thereof, optionally with a catalyst.

To prepare a compound of formula (C3) from a compound of formula (C3-1), the reaction mixture is
And a temperature of between 20 ° C. and 60 ° C., preferably between 20 ° C. and 40 ° C., in particular at 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 CH ₃ CO ₃ H in CH ₃ CO ₂ H in high yield at 30 ° C. H ₂ O ₂ and Na ₂ W in methanol
High yields can be carried out at temperatures between 20 ° C. and 70 ° C. in the presence of O ₄ .

1.7 Alternative Routes for Preparing Compounds of Formula (C3) Compounds of formula (C3) are alternatively prepared from (i) formula (H
The compound of formula (I) is reacted with a compound of formula (I) to obtain an intermediate, (ii) the intermediate is reduced to form compound (J), and (iii) compound (J) is represented by the formula (G)
Can be prepared by following the step of reacting with a compound 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, 0.5Ca, preferably M is Na.

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

Solvents used for 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, tertbutyl 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 mixtures thereof. Preferably DMSO is selected.

The reduction step to obtain the compound of formula (J) can involve the use of a catalyst and hydrogen in a solvent. The catalyst used to effect the reduction is any catalyst known to those skilled in the art to select from common textbooks. Examples of the catalyst include 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% relative to the starting compound of formula (I)
To about 50.0% w / w (dry). Typically, the catalyst is 20
. It may be present in an amount of less than 0% w / w (dry).

In the reduction reaction, stirring can be carried out for several hours at a temperature usually up to 60 ° C., preferably about 40 ° C.

The reduction reaction is best carried out at high pressure, for example between 1 and 15 bar, preferably between 2 and 6 bar.

The reduction can be performed in a solvent such as an alcohol solution. Alcohol 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 the intermediate of formula (J) with the compound of formula (G) in the presence of a base in the absence of a solvent. Performing the reaction without a solvent is a very attractive alternative because it is more efficient, reduces the waste generated and reduces the overall cost of synthesis.

The base used to carry out the reaction is any base selected by a person skilled in the art based on general textbooks. Bases are, for example, Na ₂ CO ₃ , K ₂ CO ₃ , Cs ₂ CO ₃ , 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
This is achieved when PEA, especially DBU, is used. The mild base as defined herein enables the realization of an efficient process, is easy to handle and safe, potentially prevents side reactions, and thus has the formula (C3 ) Can be recovered.

The reaction of intermediate (J) with the compound of formula (G) is best performed at a temperature between 40 ° C. and reflux, in particular at 80 ° C.

1.8 Ceritinib The above method can be extended to prepare ceritinib or a salt thereof. Depending on the starting material and the route chosen, one skilled in the art knows how to combine them to produce components and ultimately form ceritinib. Some variations or alternatives are described below. For example, as shown in Scheme 10, ceritinib or a salt thereof is
i. Preparing a compound of formula (C2-1) as described in 1.1 or 1.2;
ii. Preparing a compound of formula (C2) or a salt thereof;
iii. Providing a compound (C3);
iv. 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 is
(A) preparing a compound of formula (C2) or a salt thereof as described in 1.3 or 1.4;
(B) providing a compound of formula (C3);
(C) reacting a compound of formula (C2) or a salt thereof with a compound of formula (C3) to give ceritinib or a salt thereof, and can be prepared by the method described in Scheme 11.

As shown in Scheme 12, ceritinib or a salt thereof is
(Aa) providing a compound of formula (C2) or a salt thereof;
(Bb) preparing a compound of formula (C3-1) as described in 1.6;
(Cc) preparing a compound of formula (C3) from a compound of formula (C3-1);
(Dd) reacting a compound of formula (C2) or a salt thereof with a compound of formula (C3) to obtain ceritinib or a salt thereof.

Another variation of the present disclosure is a method of preparing ceritinib or a salt thereof as described in Scheme 13,
(I) preparing a compound of formula (C) as described in 1.5;
(II) preparing a compound of formula (C2) or a salt thereof from a compound of formula (C);
(III) providing a compound of formula (C3);
(IV) 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 a solvent in the presence of a base, wherein 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). Most preferably, X is Cl.

Bases used in the reaction are Na ₂ CO ₃ , K ₂ CO ₃ , Cs ₂ CO ₃ , NaHCO ₃ ,
It can be selected from the 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-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. 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 the formula (C2) or a salt thereof to obtain the compound of the formula (C3) is preferably performed by refluxing the reaction mixture at a temperature between 40 ° C. and reflux temperature, preferably 6 to 41 hours. Is carried out by stirring for about 16 hours.

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

References herein to salts particularly mean pharmaceutically acceptable salts or other generally acceptable salts, unless excluded for chemical reasons readily apparent to those skilled in the art. A salt can be formed using a final product or intermediate in which a salt-forming group is present, such as a basic or acidic group, and is at least partially dissociated in an aqueous solution, eg, in the pH range of 4-10. It can exist in a form or can be isolated in particular in the form of a solid, in particular a crystal.

Such salts can be prepared from any of the compounds having a basic nitrogen atom (e.g. imino or amino) or intermediates described herein, preferably using organic or inorganic acids, e.g. acid addition. 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, glutamic acid 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-naphthalenesulfonic 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 pulverized or sieved. You may have.

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 a mixed,
It can be realized by granulation, compression or the like. In this way, pharmaceutical compositions can be prepared and used to prepare final dosage forms such as tablets or capsules.

As used herein and in the appended claims, the singular forms “a”, “an”, and “the” are used to indicate otherwise in the context. Unless specifically stated otherwise, the plural of them is also included.

Similarly, “comprise”, “comprises”, “comprising”, “include”, “include”
s) "and" including "are synonymous and 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 anaplastic lymphoma kinase Amphos bis (di-tert-butyl (4-dimethylaminophenyl)
Phosphine)
B (cat) catechol borane B _{(Sia) 2} bis (1,2-dimethylpropyl) borane BBN borabicyclo [3.3.1] nonane BINAP (1,1'-binaphthalene-2,2'-diyl) bis (diphenyl Phosphine)
Boc tert-butyloxycarbonyl BOM benzyloxymethyl br broad br m broad multiplet br s broad singlet 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- Endocpp 1,3-bis (dicyclohexylphosphanyl) propane DIPEA N, N-diisopropylethylamine or Hunig base DMA dimethylacetamide DME dimethoxyethane DMF dimethylformamide DMSO dimethyl sulfoxide DMSO-d ₆ deuterated dimethyl sulfoxide DPE-phos bis (2 -Diphenylphosphinophenyl) ether DPE-phos bis (2-diphenylphosphinophenyl) ether Dppb 1,4-bis (diphenylphosphino) Tan dppe 1,2-bis (diphenylphosphino) ethane Dppf 1,1'-bis (diphenylphosphanyl) ferrocene dppp 1,3-bis (diphenylphosphanyl) propane Eq. Equivalent Et Ethyl Fmoc 9-Fluorenylmethyloxycarbonyl g Gram h Time H ₂ O ₂ Hydrogen peroxide HF Hydrogen fluoride Hz Hertz J Binding constant K ₂ CO ₃ Potassium carbonate KH Potassium hydride KOAc Potassium acetate LCMS Liquid chromatography Mass Spectrometry m Multiplex M MCPBA 3-chloroperbenzoic acid Me Methyl mg Milligram MIDA N-Methyliminodiacetic acid min Minute ml Millimol Mole Ms Mesyl Na ₂ WO ₄ Sodium tungstate 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) i Imidazole-2-ylidene] (3-chloropyridyl) palladium (II) dichloride PEPPSI pyridine promote procatalyst preparation and stabilization and initiation (Pyridi
ne enhanced precatalyst preparation stabilization and initiation)
Ph phenyl phos phosphine piv pivaloyl POM pivaloyloxymethyl ppm parts per million Pt / C carbon supported platinum Rh / C carbon supported rhodium
s Singlet SEM Trimethylsilylethoxymethyl Sept. Triplet T ° C. Celsius temperature TBHP tert butyl hydroperoxide TBME methyl tert butyl ether tBu tret butyl TES triethylsilyl Tf triflate THF tetrahydrofuran TPAP tetrapropylammonium perruthenate troc trichloroethoxycarbonyl Ts tosyl w / w weight percentage

The following examples are merely illustrative of the present disclosure, and these examples and other equivalents are expected to be apparent to those skilled in the art in light of the present disclosure and the appended claims.
In no way shall it be considered as limiting the scope of the disclosure.

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

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) was added to (1- (tert-butoxycarbonyl) piperidine-4-
Yl) zinc (II) iodide in tetrahydrofuran (0.9M solution, 4.95 g, 13
. 1 mmol, 2.0 eq; prepared according to literature procedures) was added at 50 ° C. and the reaction mixture was stirred at this temperature for 21 h. After cooling to room temperature, saturated aqueous NH ₄ Cl (50 ml) was added. The aqueous phase was extracted with ethyl acetate (3 × 70 ml) and the organic phases were combined and brine (80
ml) and dried over Na ₂ SO ₄ . Volatiles were removed in vacuo and the crude was 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, yield 79%) was obtained. 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 (sevent, J = 6.1 Hz,
1H), 6.79 (s, 1H), 7.55 (m, 1H) ppm.

tert-Butyl 4- (4-amino-5-isopropoxy-2-methylphenyl) piperidine-1-carboxylate (C2-NBoc, P = Boc)
tert-Butyl 4- (5-isopropoxy-2-methyl-4-nitrophenyl) piperidine-1-carboxylate (1.96 g, 5.18 mmol) in ethanol (180
ml) To the solution was added Pd / C (10%, 0.4 g) 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®. Volatiles were removed in vacuo to give a yellow oil of 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- (piperidin-4-yl) aniline dihydrochloride (C
2, 2HCl salt)
tert-butyl 4- (4-amino-5-isopropoxy-2-methylphenyl) piperidine-1-carboxylate (1.67 g) was dissolved in dichloromethane (10 ml),
The resulting solution was treated with trifluoroacetic acid (2 ml). After 16 hours at room temperature, water (50 ml) was added. The layers were separated and the aqueous phase was washed with dichloromethane (30 ml). The aqueous phase was neutralized with aqueous NaOH (1M solution) and extracted with toluene (3 × 50 ml). To the combined toluene phases was added HCl (3.8 ml of a 5M solution in isopropanol). After evaporation, 2-isopropoxy-5-methyl-4- (piperidin-4-yl) aniline dihydrochloride was obtained (1.35 g, 88% yield). 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 (sevent, 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- (piperidin-4-yl) aniline dihydrochloride (C2, 2HCl) by reduction of 4- (5-isopropoxy-2-methyl-4-nitrophenyl) pyridine (C) Salt)

The reactor was charged with 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 the temperature below 30 ° C. After 2 hours, the hydrogen pressure was increased to 6 bar and the mixture was heated to 30 ° C. After complete conversion, the 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 continued. This step was repeated two more times (change solvent 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 temperature below 40 ° C.
4 kg) was added. After the addition, the suspension is cooled to 25 ° C. and held for at least 90 minutes,
Cool to 0 ° C. and stir for at least 90 minutes. The product was filtered, rinsed twice with toluene / isopropanol solution (2 × 240 kg, 20% w / w), dried in vacuo and the product 2-isopropoxy-5-methyl-4- (piperidin-4-yl) Aniline dihydrochloride (105k
g, yield 81%). 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 (Sevent, 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-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; 0.10 g, 3 mol%) and 1,4-dioxane (
5 ml) was heated at 100 ° C. for 3 hours. _Then, K 2 CO ₃ solution (3.6M 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 ) And the reaction mixture was heated at 100 ° C. for a further 17 hours. After cooling to room temperature, the mixture was filtered through HyFlo® and washed with ethyl acetate (3 × 20 ml). The organic phase is water (3 x 20 ml)
And washed with aqueous NaCl solution (20 ml of 24% w / w solution) and dried over Na ₂ SO ₄ . Volatiles were removed in vacuo and the crude product was chromatographed on silica gel (ethyl acetate /
Heptane) to give 4- (5-isopropoxy-2-methyl-4-nitrophenyl) pyridine (0.95 g, 81% yield) as a yellow solid.
b) Suzuki coupling

K ₂ CO ₃ (50.1 kg, 358 mol, 2.5 equivalents), H ₂ O (93 kg), 1-
Chloro-5-isopropoxy-2-methyl-4-nitrobenzene (33.3 kg, 145
mol), pyridin-4-ylboronic acid (23.2 kg, 189 mol, 1.3 eq),
trans-dichlorobis (triphenylphosphine) palladium (II) (5.11k
g, 7.28 mol, 5 mol%) and 2-butanol (216 kg) were 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 4- (5-isopropoxy-2-methyl-4-nitrophenyl) pyridine (52.9 kg, 71% yield) as a yellow solid. . ¹ H-NMR (400 MHz, CDCl ₃ ): δ = 1.40 (d, J =
6.0 Hz, 6H), 2.23 (s, 3H), 4.65 (sevent, 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 sequence

2,5-dichloro-N- (2- (isopropylthio) phenyl) pyrimidin-4-amine (C3-1, X = Cl)
N, N-diisopropylethylamine (31.0 g, 0.24 mol, 2.3 eq) was added to 2- (isopropylthio) in toluene (166 g) and n-butanol (17 g).
Aniline hydrochloride (21.3 g, 0.10 mol), 2,4,5-trichloropyrimidine (
19.0 g, 0.10 mol, 1.0 equiv). The mixture was refluxed for about 22 hours. After the reaction mixture was cooled to 25 ° C., water (70 g) was added and separated, and the organic phase was washed with water (70 g). The organic phase was concentrated under vacuum followed by addition of ethanol (34 g). The mixture is refluxed, slowly cooled to 0-5 ° C., filtered, dried in vacuo, and 2,5-dichloro-N
-(2- (Isopropylthio) phenyl) pyrimidin-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 (sevent, 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)
To a solution of 2,5-dichloro-N- (2- (isopropylthio) phenyl) pyrimidin-4-amine (20.0 g, 63.7 mol) in ethyl acetate (180 g), the internal temperature was adjusted to 20-
While maintaining at 30 ° C., peracetic acid (33.4 g acetic acid solution; 5.7 mmol / g) was added. After a reaction time of 16 hours, ethyl acetate (90 g) was added, followed by sodium sulfite aqueous solution (112 g of 11% w / w solution) to maintain the internal temperature below 45 ° C. The solution was separated, and water (63 g) was added to the organic phase, followed by addition of aqueous NaOH (25% w / w solution) to adjust the pH to 7-8. The layers were separated and the organic phase was dried over MgSO ₄ and concentrated in vacuo. Ethanol (217 g) was added and the mixture was refluxed. After slow cooling to 0-5 ° C,
The precipitate was filtered and dried in vacuo to give 2,5-dichloro-N- (2- (isopropylsulfonyl) phenyl) pyrimidin-4-amine (19.5 g, 88% yield) as a white powder.
¹ H-NMR (400 MHz, CDCl ₃ ): δ = 1.33 (d, J = 6.7 Hz, 6H), 3.22 (sevent, 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 sequence

1- (Isopropylsulfonyl) -2-nitrobenzene (J ′)
Sodium propane-2-sulfinate (2.48 kg, 19.1 mol, 1.5 eq) and 1-chloro-2-nitrobenzene (2.00 kg, 12.7 mol) in DMSO
(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)
Sprayed. The reaction mixture was stirred at 0-10 ° C. for 30 minutes, filtered, and dried under vacuum to give gray solid 1- (isopropylsulfonyl) -2-nitrobenzene (2.8 kg, 96% yield).
Got.

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

2,5-dichloro-N- (2- (isopropylsulfonyl) phenyl) pyrimidine-4-
Amines (C3, X = Cl)
2,4,5-Trichloropyrimidine (6.1 kg) was added to 2- (isopropylsulfonyl) aniline (950 g, 4.77 mol) and DBU (181 g, 1.19 mol, 0
. 25 equivalents) 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 was ethanol (4.5 kg
) And stirred at 25 ° C. for 12 hours and then cooled to 0 ° C. After filtration, the crude product was dried under vacuum to obtain 2,5-dichloro-N- (2- (isopropylsulfonyl) phenyl) pyrimidin-4-amine (1.07 kg, yield 65%). ¹ H-NMR (400 MHz, CDCl ₃ ):
δ = 1.33 (d, J = 6.7 Hz, 6H), 3.22 (sevent, 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- (piperidin-4-yl) aniline dihydrochloride (C2, 2HCl salt) by the following sequence

Methyl 4- (5-isopropoxy-2-methylphenyl) pyridine-1 (4H) -carboxylate (C2-2, P = CO ₂ CH ₃ )
To pre-dried LiCl (0.41 g, 9.6 mmol, 1.1 eq), magnesium (0.28 g, 11.3 mmol, 1.3 eq) and THF (13 ml) were added,
This was followed by 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 literature procedure) was added and the resulting orange suspension was warmed to room temperature, Stir for 16 hours. TBME (80 ml) was added and the organic phase was washed with saturated aqueous NH ₄ Cl (3 × 30 ml), brine (30 ml) and dried over Na ₂ SO ₄ . After removal of the volatiles under vacuum, the crude methyl 4- (5-isopropoxy-2-methylphenyl) pyridine-1 (4H) -carboxylate (2.04 g, 86% yield) obtained. Was used in the next step without further purification. 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 (sevent, 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
l) to the solution of ammonium formate (10 g, 159 mmol) followed by Pd / C
(2.0 g, 10%) was added. After stirring for 18 hours at room temperature, the mixture was filtered through Celite®, the filter cake was washed with ethyl acetate (40 ml) and the filtrate was washed with water (80 ml).
Was added. The aqueous phase was extracted with ethyl acetate (3 × 50 ml) and the organic extracts were combined and washed with Na _2.
Dehydrated with SO ₄ . Volatiles were removed in vacuo and the crude was purified by silica gel chromatography (ethyl acetate / heptane) to give a yellow oil of methyl 4- (5-isopropoxy-2
-Methylphenyl) piperidine-1-carboxylate (2.1 g, 72% yield) was obtained. 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 (Sevent, 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. Once again nitric acid (1ml
65%) was added and stirred for 3 hours and the mixture was allowed to warm to room temperature. After water (100 ml) was added to the mixture, the aqueous phase was extracted with ethyl acetate (3 × 80 ml). The organic phases were combined, washed with saturated aqueous NH ₄ Cl (2 × 50 ml), brine (50 ml) and dried over Na ₂ SO ₄ . Volatiles were removed in vacuo and the crude was purified by silica gel chromatography (ethyl acetate / heptane) to give methyl 4- (5-isopropoxy-2-methyl-4-
Nitrophenyl) piperidine-1-carboxylate (2.1 g, 72% yield) was obtained.
LCMS: m / z (M + l) 337.2 [M + H] ^< +>.

Methyl 4- (4-amino-5-isopropoxy-2-methylphenyl) piperidine-1-
Carboxylate (C2-NCO ₂ Me)
To a solution of 4- (5-isopropoxy-2-methyl-4-nitrophenyl) piperidine-1-carboxylate (3.68 g, 10.9 mmol) in ethanol (200 ml) was added P.
d / C (0.5 g, 10%) was added. The mixture was stirred in a 5 bar hydrogen atmosphere for 5 hours. The reaction mixture was purged with nitrogen, filtered through Celite®, and ethyl acetate (50
ml). The filtrate was extracted with aqueous HCl (2 × 30 ml, 1M solution). The aqueous phase was neutralized with aqueous NaOH (1M solution) and extracted with ethyl acetate (3 × 50 ml). Volatiles were removed in vacuo and the crude was purified by silica gel chromatography (ethyl acetate / heptane) to give methyl 4- (4-amino-5-isopropoxy-2-methylphenyl) piperidine-1-carboxyl. Lat (3.36 g, 51% yield) 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
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 (sevent, J = 6.1 Hz, 1H), 6.46 (s, 1H), 6.53 (s, 1H) ppm.

2-Isopropoxy-5-methyl-4- (piperidin-4-yl) aniline dihydrochloride (C
2, 2HCl salt)
Aqueous HCl (26 ml of 8M solution) was added to methyl 4- (4-amino-5-isopropoxy-2-methylphenyl) piperidine-1-carboxylate (1.00 g, 3.26 mm).
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 (1M solution). The neutralized aqueous phase was dissolved in toluene (3 ×
50 ml), the organic extracts are combined and HCl (5 M solution in isopropanol 2
. 6 ml). The volatile material was evaporated under vacuum to give 2-isopropoxy-5-
Methyl-4- (piperidin-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 (sevent, 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- (piperidin-4-yl)
Phenyl) -N4- (2- (isopropylsulfonyl) phenyl) pyrimidine-2,4-
Synthesis of diamine (seritinib)

Isopropanol (445 kg) was added to 2,5-dichloro-N- (2- (isopropylsulfonyl) phenyl) pyrimidin-4-amine (70.2 kg, 203 mol, 1.15).
Eq.) And 2-isopropoxy-5-methyl-4- (piperidin-4-yl) aniline dihydrochloride (56.7 kg, 176 mol). 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. The wet product was mixed with 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 give 5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4. -(2- (isopropylsulfonyl) phenyl)
Pyrimidine-2,4-diamine dihydrochloride (= seritinib dihydrochloride; 84.5 kg [total amount,
Containing 10% w / w isopropanol], 76.0 kg [100%], yield 68%).

Ethanol (155 kg) and water (113 kg) were added to 5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-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 (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 an almost white powder of ceritinib (33.2 kg, 93% yield based on ceritinib dihydrochloride). 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
3 (m, 3H), 3.20-3.24 (m, 2H), 3.28 (sevent, J = 6.8 Hz, 1H), 4.56 (sevent,
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: Calculated for C ₂₈ H ₃₆ ClN ₅ O ₃ S: C
60.26, H 6.50, N 12.55, O 8.60 Cl 6.35, S 5.74, Found: C 60.15, H 6.45, N 12.72
, O 8.58, Cl 6.43, S 5.67.)

Ethanol (155 kg) and water (113 kg) were added to 5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-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 (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 an almost white powder of ceritinib (33.2 kg, 93% yield based on ceritinib dihydrochloride). 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), 2.75-2.83 (m, 3H), 3.20-3.24 (m, 2H), 3.28 (sevent, J = 6.8 Hz, 1H), 4.56 (sevent, J = 6.1 Hz, 1H), 6.82 (s, 1H), 7.25-7.29 (m, 1 H), 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, Elemental analysis: C ₂₈ H ₃₆ ClN ₅ (Calculated value of O ₃ S: C 60.26, H 6.50, N 12.55, O 8.60 Cl 6.35, S 5.74, Actual value: C 60.15, H 6.45, N 12.72, O 8.58, Cl 6.43, S 5.67.)

The following embodiments may be included.
[1] Formula (C2-1)
[Wherein 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 formula (C2-1) according to the above [1].
[3] A method for preparing a compound of formula (C2-1), which comprises formula (A)
A compound of formula (B)
And in a solvent, in the presence of at least one catalyst, and optionally a cocatalyst or additive,
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, 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) The way it is.
[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-dicyclohexyl) Sufino-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 (dppf) (cod), Ni (Dppf) (cinnamyl), Ni (dppf) ₂ , Ni (dppf) Cl ₂ , Ni (dppp) Cl ₂ , NiCl ₂ (PCy ₃ ) ₂ , and Ni (dppe) Cl ₂ , or mixtures thereof A method for preparing a compound of formula (C2-1) according to the above [3] or [4].
[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), 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-butanol, 2-butanol, tert-butanol, or mixtures thereof as described above [ [3] A method for preparing a compound of formula (C2-1) according to any one of [6].
[8] A method for preparing the compound of the formula (C2-1) according to any one of [3] to [6], wherein the solvent is tetrahydrofuran.
[9] The co-catalyst or _{additive, 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, dppp, dppb, P (furyl) ₃ , CPhos, SPhos, RuPhos, XPhos, DavoPhos The method of preparing the compound of the formula (C2-1) as described in any one of said [3] to [8] selected from the group which consists of these.
[10] A method for preparing a compound of formula (C2-1) according to any one of [3] to [8] above, wherein the cocatalyst or additive is CuI.
[11] The formula (1) according to any one of [3] to [10], wherein the protecting group is selected from the group consisting of tert-butyloxycarbonyl (Boc), benzyloxycarbonyl, and methyloxycarbonyl. A method for preparing a compound of C2-1).
[12] A method for preparing a compound of the formula (C2-1) according to any one of [3] to [10] above, wherein the protecting group is tert-butyloxycarbonyl (Boc).
[13] A method for preparing a compound of formula (C2-1), which comprises formula (C2-3)
A compound of
Compound (C2-2) is reacted with (pyridinium-P) in a solvent.
Generating
The compound (C2-2) is converted into the formula (C2-1)
Forming a compound of
Including
P is a protecting group,
A method wherein Z is selected from MgBr, MgCl, MgI, Mg, ZnCl, ZnBr, ZnI or Zn (alkyl).
[14] A method for preparing a compound of formula (C2-1) according to the above [13], wherein the compound (C2-2) is formed from the compound of formula (C2-1) by reduction and nitration .
[15] The formula (C2-) described in [13] or [14] above, wherein the protecting group P is selected from the group consisting of tert-butyloxycarbonyl (Boc), benzyloxycarbonyl, methyloxycarbonyl and benzyl. A method for preparing the compound of 1).
[16] Formula (C2)
The method according to any one of [3] to [15] above, and the reduction and deprotection steps of the compound of the formula (C2-1) Including methods.
[17] A method for preparing a compound of the formula (C2) or a salt thereof according to the above [16], wherein (C2-1) is reduced to (C2) in the presence of a catalyst and hydrogen.
[18] 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, Fe, Sm, NiCl ₂ , A method for preparing a compound of the formula (C2) or a salt thereof according to the above [17], which is selected from the group consisting of Ni (OAc) ₂ , CoCl ₂ , ZrCl ₄ , TiCl ₃ .
[19] The method for preparing a compound of the formula (C2) or a salt thereof according to the above [17], 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. A method for preparing a compound of the formula (C2) or a salt thereof according to any one of [16] to [19] above.
[21] The compound of formula (C2) or a salt thereof according to any one of the above [16] to [19], wherein the protecting group P is tert-butyloxycarbonyl (Boc) or methyloxycarbonyl. How to prepare.
[22] A method for preparing a compound of formula (C2-1) according to any one of [13] to [15] above, wherein Z is MgCl or MgBr, or any of [16] to [21] above A method for preparing a compound of the formula (C2) or a salt thereof according to claim 1.
[23] A method for preparing a compound of the formula (C2) or a salt thereof, comprising the formula (C)
Reducing the compound in a solvent in the presence of at least one catalyst and hydrogen.
[24] A method for preparing a compound of the formula (C2) or a salt thereof according to the above [23], wherein the reduction is a one-step reduction.
[25] 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 / Al, Pt / Al, Pt / SiAl, Pd / ZrO ₂ , or their A method for preparing a compound of the formula (C2) or a salt thereof according to the above [23] or [24], which is selected from the group consisting of a mixture.
[26] The compound of 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 a salt thereof.
[27] The reaction according to any one of [23] to [25] above, 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 of the formula (C2) or a salt thereof as described.
[28] A one-pot method for preparing a compound of formula (C) or a salt thereof, comprising formula AA in a solvent
The compound of formula D
And a compound of formula (E) in the presence of X ₃ B (X ₂ ) ₂ , at least one catalyst, a base, and optionally a ligand.
Comprising reacting the compound without isolation, wherein:
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 wherein X ₃ is selected from ₂ and 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} ) A method for preparing a compound of the formula (C) or a salt thereof according to [28] above.
[30] A method for preparing a compound of formula (C) or a salt thereof, comprising reacting a compound of formula (AA) with a compound of formula (E) in a solvent in the presence of a catalyst and a base. Wherein 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) or a salt thereof according to the above [30] , 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) or a salt thereof according to any one of the above [30] to [32], 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] Formula (C3-1)
[Wherein 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), which comprises formula (F)
Or a salt thereof of the formula (G)
And in the presence of a base, optionally in a solvent, wherein X is from the group consisting of halogen (Br, Cl, I), alkoxy, aryloxy, alkylthio, sulfinyl and sulfonyl. Selected method.
[37] The _{base, Na 2 CO 3, K 2} CO 3, Cs 2 CO 3, NaHCO 3, KHCO 3, _{triethylamine, DIPEA,} is selected from _{Na 3 PO 4, K 3 PO} 4, DBU , or NaH, A method for preparing the compound of formula (C3-1) described in [36] above.
[38] A method for preparing the 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), Selected from acetonitrile, acetone, dimethyl carbonate, ethyl acetate, isopropyl acetate, tertbutyl acetate, methanol, ethanol, n-propanol, 2-propanol, n-butanol, 2-butanol, tert-butanol and toluene, or mixtures thereof A method for preparing a compound of formula (C3-1) according to any one of [36] to [38] above.
[40] A method for preparing a compound of formula (C3-1) according to any one of [36] to [39] above, wherein the solvent is toluene, 1-butanol or a mixture thereof.
[41] A method for preparing a compound of formula (C3), the method according to any one of [36] to [40] above and oxidizing the obtained (C3-1) in a solvent Including steps,
A method wherein X is selected from halogen (Br, Cl, I), alkoxy, aryloxy, alkylthio, sulfinyl and sulfonyl.
[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 A method for preparing a compound of formula (C3) according to [41] above.
[43] The oxidizing agent is 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 , excess [41] selected from the group consisting of tetrapropylammonium ruthenate (TPAP), 3,3-dimethyldioxirane, 3-chloroperbenzoic acid (mCPBA) and tertbutyl hydroperoxide (TBHP), or mixtures thereof. Or a method of preparing the compound of formula (C3) according to [42].
[44] The above [41] to [43], which is carried out in ethyl acetate in the presence of CH ₃ CO ₃ H in CH ₃ CO ₂ H, optionally at a temperature between 20 ° C. and 40 ° C. A method for preparing a compound of 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 [41] to [44], which is carried out in methanol in the presence of H ₂ O ₂ and Na ₂ WO ₄ .
[46] A method for preparing the 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 formula (C3) comprising:
(I) Formula (H)
A compound of formula (I)
Reacting a compound of to form an intermediate;
(Ii) reducing the intermediate;
(Iii) said reduced intermediate is represented by formula (G)
Wherein X is selected from the group consisting of halogen (F, Cl, Br, I), alkoxy, aryloxy, alkylthio, sulfinyl and sulfonyl; Is selected from Li, Na, K, 0.5Zn, 0.5Ca, and
Including methods.
[48] A method for preparing a compound of the formula (C3) according to the above [48], wherein M is Na.
[49] The compound according to [35] above, or the method according to any one of [36] to [48] above, wherein X is Cl.
[50] A method for preparing ceritinib or a salt thereof,
i. Preparing a compound of formula (C2-1) according to any one of [3] to [15] or [22] above;
ii. Preparing a compound of formula (C2) or a salt thereof;
iii. Providing a compound (C3);
iv. Reacting a compound of formula (C2) or a salt thereof with a compound of formula (C3) to obtain ceritinib or a salt thereof;
Including methods.
[51] A method for preparing ceritinib or a salt thereof,
(A) preparing the compound of formula (C2) or a salt thereof according to any one of [16] to [27] above;
(B) providing a compound of formula (C3);
(C) reacting the compound of formula (C2) or a salt thereof with a compound of formula (C3) to obtain ceritinib or a salt thereof;
Including methods.
[52] A method for preparing ceritinib or a salt thereof,
(I) providing a compound of formula (C2) or a salt thereof;
(II) preparing a compound of formula (C3-1) according to any one of [36] to [40] or [49] above;
(III) preparing a compound of formula (C3) from the compound of formula (C3-1);
(IV) 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;
Including methods.
[53] A method for preparing ceritinib or a salt thereof,
(Aa) preparing a compound of formula (C) according to any one of [28] to [34] above;
(Bb) preparing a compound of formula (C2) or a salt thereof from the compound of formula (C);
(Cc) providing a compound of formula (C3);
(Dd) reacting the compound of formula (C2) or a salt thereof with the compound of formula (C3) to obtain ceritinib or a salt thereof;
Including methods.
[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 includes 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-acetate Selected from butyl, water, methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-butanol, tert-butanol and toluene, or mixtures thereof, optionally the base is Na ₂ CO ₃ , K ₂ CO ₃ , Cs ₂ CO ₃ , NaHCO ₃ , KHCO ₃ A method for preparing ceritinib or a salt thereof according to any one of [50] to [53] above, selected from the group consisting of , trimethylamine, DIPEA, DBU, Na ₃ PO ₄ and K ₃ PO ₄ .
[55] The method for preparing ceritinib or a salt thereof according to the above [54], wherein the solvent is isopropanol.
[56] The ceritinib or salt thereof according to [54] or [55] above, wherein the compound of formula (C2) or a salt thereof is reacted with the compound of formula (C3) in the absence of the base. Method.
[57] A method for preparing a pharmaceutical composition, the method comprising mixing the method according to any one of [50] to [56] above and the obtained ceritinib and a pharmaceutically acceptable additive. And a method comprising.
[58] Use of a compound of formula (C2-1) for the preparation of ceritinib or a salt thereof.
[59] Use of a compound of formula (C3-1) for preparing ceritinib or a salt thereof.
[60] Use of a compound of formula (C2-2) for preparing ceritinib or a salt thereof.
[61] Formula (C2-2)
[Wherein P is a protecting group]
Compound.

Claims (61)

Formula (C2-1)
[Wherein 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. A compound of formula (C2-1) as described in. A process for preparing a compound of formula (C2-1) comprising the formula (A)
A compound of formula (B)
And in a solvent, in the presence of at least one catalyst, and optionally a cocatalyst or additive,
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, 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). 4. A process for preparing a compound of formula (C2-1) according to claim 3, wherein T is Br and X1 is ZnI. The catalyst is 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) (cinnamil)
, Ni (dppf) ₂ , Ni (dppf) Cl ₂ , Ni (dppp) Cl ₂ , NiCl _{2
(PCy 3) 2,} and Ni (dppe) Cl _2, or mixtures thereof, methods of preparing the compounds of formula (C2-1) according to claim 3 or 4. Wherein the catalyst is _{Pd (PPh 3) 2 Cl 2} , the formula of claim 3 or 4 (C2-1
). 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- A process for preparing a compound of formula (C2-1) according to any one of claims 3 to 6, selected from butanol, 2-butanol, tert-butanol, or mixtures thereof. The formula (C) according to any one of claims 3 to 6, wherein the solvent is tetrahydrofuran.
A method for preparing the compound of 2-1). 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 <sub>3
* HBF 4, PCy 3, PCy</sub> 3 * HBF 4, P (OiPr) 3, DPE-Phos, d
ppf, dppe, dppp, dcpp, dppb, P (furyl) ₃ , CPhos, SP
9. The formula (C2-1) according to any one of claims 3 to 8, selected from the group consisting of hos, RuPhos, XPhos, DavePhos, JohnPhos and Xanthophos.
). The formula (1) according to any one of claims 3 to 8, wherein the cocatalyst or additive is CuI.
A method for preparing a compound of C2-1). The compound of 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. 11. The protecting group is tert-butyloxycarbonyl (Boc).
A method for preparing the compound of formula (C2-1) according to any one of the above. A process for preparing a compound of formula (C2-1) comprising the formula (C2-3)
A compound of
Compound (C2-2) is reacted with (pyridinium-P) in a solvent.
Generating
The compound (C2-2) is converted into the formula (C2-1)
Forming a compound of the formula:
P is a protecting group,
A method wherein Z is selected from MgBr, MgCl, MgI, Mg, ZnCl, ZnBr, ZnI or Zn (alkyl). 14. The method of preparing a compound of formula (C2-1) according to claim 13, wherein the compound (C2-2) is formed from the compound of formula (C2-1) by reduction and nitration. 14. The protecting group P is selected from the group consisting of tert-butyloxycarbonyl (Boc), benzyloxycarbonyl, methyloxycarbonyl and benzyl.
Or a method for preparing a compound of formula (C2-1) according to 14. Formula (C2)
A method for preparing a compound of formula (I) or a salt thereof, comprising the method of any one of claims 3 to 15 and the steps of reduction and deprotection of the compound of formula (C2-1). The process 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
) ₂ , CoCl ₂ , ZrCl ₄ , 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,
20. A method for preparing a compound of formula (C2) or a salt thereof according to any one of claims 16 to 19 selected from the group consisting of phenyloxycarbonyl, formyl, acetyl and benzyl. The method for preparing a compound of the formula (C2) or a salt thereof according to any one of claims 16 to 19, wherein the protecting group P is tert-butyloxycarbonyl (Boc) or methyloxycarbonyl. The formula (1) 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 formula (C2) or a salt thereof according to any one of claims 16 to 21. A process for preparing a compound of formula (C2) or a salt thereof, comprising the formula (C)
Reducing the compound in a solvent in the presence of at least one catalyst and hydrogen. 24. A method for preparing a compound of 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 ,
Pd / Al, Pt / Al, Pt / SiAl, is selected from the group consisting of Pd / ZrO ₂ or mixtures thereof, a process for preparing compound of the formula (C2) according to claim 23 or 24 . The compound of formula (C2) or a salt thereof according to any one of claims 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. Method. 26. 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, optionally in acetic acid at 10-50 <0> C and a pressure of 1-10 bar.
Or a salt thereof. A one-pot method for preparing a compound of formula (C) or a salt thereof, comprising a compound of formula AA in a solvent
The compound of formula D
And a compound of formula (E) in the presence of X ₃ B (X ₂ ) ₂ , at least one catalyst, a base, and optionally a ligand.
Comprising reacting the compound without isolation, wherein:
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 represents 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, and B (X ₂ ) ₂ is B (OH) ₂ or B (OC (CH ₃ ) ₂
C _{(CH 3)} a 2 O), _{X 3} is _{B (X 2)} 2, a method of preparing a compound of the formula (C) according to claim 28. A process for preparing a compound of formula (C) or a salt thereof, wherein the compound of formula (AA)
Reacting with a compound of E) in a solvent in the presence of a catalyst and a base, wherein
Y is selected from Cl, Br, I, OTf, OTs, OPiv and OMs, and B (X ₂
) _{2, B (OH) 2, B} (OC (CH 3) 2 C (CH 3) 2 O), 9-BBN, B (S
ia) A method selected from ₂ , B (cat), B (Cy) ₂ , BF ₃ ⁻ and B (MIDA). Y is Cl, X ₂ is OH, a method of preparing a compound of the formula (C) according to claim 30. 32. A 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. Wherein the catalyst is _{Pd (PPh 3) 2 Cl 2} , for preparing a compound of the formula (C) according to any one of claims 30 32. Wherein the base is K ₂ CO _3, for preparing a compound of the formula (C) according to any one of claims 30 33. Formula (C3-1)
[Wherein X is selected from halogen (F, Cl, Br, I), alkoxy, aryloxy, alkylthio, arylthio, sulfinyl and sulfonyl]
Compound. A process for preparing a compound of formula (C3-1) comprising the formula (F)
Or a salt thereof of the formula (G)
Comprising reacting with a compound of formula I in the presence of a base, optionally in a solvent, wherein
A method wherein X is selected from the group consisting of halogen (Br, Cl, I), alkoxy, aryloxy, alkylthio, sulfinyl and sulfonyl. The base is 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, is selected from DBU, or NaH, process for preparing a compound of formula (C3-1) of claim 36. 37. A method for preparing a compound of 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, tertbutyl acetate, methanol, ethanol, n-propanol, 2-propanol, n-butanol, 2-butanol, tert- 39. A method of preparing a compound of formula (C3-1) according to any one of claims 36 to 38, selected from butanol and toluene, or a mixture thereof. 4. The solvent is toluene or 1-butanol or a mixture thereof.
40. A method of preparing a compound of formula (C3-1) according to any one of 6 to 39. A process for preparing a compound of formula (C3) comprising the process according to any one of claims 36 to 40 and the step of oxidizing the resulting (C3-1) in a solvent,
A method wherein X is selected from halogen (Br, Cl, I), alkoxy, aryloxy, alkylthio, sulfinyl and sulfonyl. 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, tertbutyl acetate, pentane, hexane, heptane, 42. The formula of claim 41, 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). The oxidizing agent is KMnO ₄ , MnO ₂ , NaIO ₄ , NaClO, KHSO ₅ (oxon)
, NaBO ₃ , CH ₃ CO ₃ H, H ₂ O ₂ , Na ₂ WO ₄ , O ₂ , O ₃ , tetraruthenium perruthenate (TPAP), 3,3-dimethyldioxirane, 3-chloroperbenzoic acid 43. The formula (C3) of claim 41 or 42, selected from the group consisting of (mCPBA) and tertbutyl hydroperoxide (TBHP), or mixtures thereof.
To prepare a compound of In ethyl acetate in the presence of CH ₃ CO ₃ H in CH ₃ CO ₂ H, optionally 20
44. Formula (C) according to any one of claims 41 to 43, carried out at a temperature between 0C and 40C.
A method for preparing the compound of 3). It is carried out in the presence of _H 2 _{O 2} and _Na 2 WO ₄ in methanol claims 41 4
5. A process for preparing a compound of formula (C3) according to any one of 4 above. 46. A method for preparing a compound of formula (C3) according to claim 45, carried out at a temperature between 20 <0> C and 70 <0> C. A process for preparing a compound of formula (C3) comprising:
(I) Formula (H)
A compound of formula (I)
Reacting a compound of to form an intermediate;
(Ii) reducing the intermediate;
(Iii) said reduced intermediate is represented by formula (G)
In the presence of a base, wherein X is a halogen (F, C
l, Br, I), selected from the group consisting of alkoxy, aryloxy, alkylthio, sulfinyl and sulfonyl, and M is selected from Li, Na, K, 0.5Zn, 0.5Ca .   49. A method for preparing a compound of formula (C3) according to claim 48, wherein M is Na. 49. A compound according to claim 35 or a method according to any one of claims 36 to 48, wherein X is Cl. A method of preparing ceritinib or a salt thereof,
i. Preparing a compound of formula (C2-1) according to any one of claims 3 to 15 or 22;
ii. Preparing a compound of formula (C2) or a salt thereof;
iii. Providing a compound (C3);
iv. 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) preparing a compound of formula (C2) according to any one of claims 16 to 27 or a salt thereof;
(B) providing a compound of formula (C3);
(C) 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,
(I) providing a compound of formula (C2) or a salt thereof;
(II) preparing a compound of formula (C3-1) according to any one of claims 36 to 40 or 49;
(III) preparing a compound of formula (C3) from the compound of formula (C3-1);
(IV) reacting the compound of the formula (C2) or a salt thereof with the compound of the formula (C3),
Obtaining ceritinib or a salt thereof. A method of preparing ceritinib or a salt thereof,
(Aa) preparing a compound of formula (C) according to any one of claims 28 to 34;
(Bb) preparing a compound of formula (C2) or a salt thereof from the compound of formula (C);
(Cc) providing a compound of formula (C3);
(Dd) reacting the compound of the formula (C2) or a salt thereof with the compound of the formula (C3),
Obtaining 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, is selected from tert- butanol and toluene, or mixtures thereof, said by case _{base, Na 2 CO 3, K 2} CO 3, Cs 2 CO 3, NaHCO 3,
KHCO _3, trimethylamine, DIPEA, DBU, is selected from _Na 3 PO ₄ and _K 3 PO _4, Serichinibu or process for preparing a salt thereof according to any one of claims 50 53. 55. The method of preparing ceritinib or a salt thereof according to claim 54, wherein the solvent is isopropanol. 56. 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. 57. A method of preparing a pharmaceutical composition, comprising the method of any one of claims 50 to 56, and mixing the resulting ceritinib with a pharmaceutically acceptable additive.   Use of a compound of formula (C2-1) for the preparation of ceritinib or a salt thereof.   Use of a compound of formula (C3-1) for the preparation of ceritinib or a salt thereof.   Use of a compound of formula (C2-2) for the preparation of ceritinib or a salt thereof. Formula (C2-2)
[Wherein P is a protecting group]
Compound.