Process for producing alkynylketone derivative

Abstract

The present invention relates to a Sonogashira-Carbonylation reaction using two types of gas, as well as novel crystals which can control a heat of the said reaction and the process of producing the same. In addition, the present invention relates to a ligand (additive) to prevent the deactivation of a palladium catalyst.

Claims

1. A process for producing a compound represented by Formula (II): ##STR00061## wherein ring A is a substituted or unsubstituted aromatic heterocycle or a substituted or unsubstituted aromatic carbocycle, R is a hydrogen atom or methyl, characterized by reacting a compound represented by Formula (I): ##STR00062## wherein ring A is as defined above, X is a leaving group, with carbon monoxide and a compound represented by Formula (III): ##STR00063## wherein R is as defined above, in the presence of a palladium catalyst, a phosphine ligand, a catalyst comprising Group 11 element and a base.

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

3. The process according to claim 1, wherein the palladium catalyst is Pd.sub.2 (dba).sub.3, PdCl.sub.2 dppf, PdCl.sub.2 (PPh.sub.3).sub.2, Pd(OAc).sub.2, Pd(PPh.sub.3).sub.4, Pd/C, PdCl.sub.2, Pd-PEPPSI-IPr, Bis[cinnamyl palladium Cl], PdCl.sub.2 (Xantphos) or Pd(OH).sub.2.

4. The process according to claim 1, wherein the phosphine ligand is Xantphos, P(2-furyl).sub.3, PPh.sub.3, P(o-tol).sub.3, P(OPh).sub.3, P(OMe).sub.3, dppp, dppb, dppf, BINAP, X-Phos, P(t-Bu).sub.3, P(Oi-Pr).sub.3, P(p-MeOPh).sub.3 or DPEPhos.

5. The process according to claim 1, wherein the catalyst comprising Group 11 element is copper iodide(I), copper iodide(II), copper chloride(I), copper chloride(II), copper acetate(I), copper acetate(II), copper oxide(II), copper bromide(I), copper bromide(II) or silver acetate.

6. The process according to claim 1, wherein the base is N-methylmorpholine, triethylamine, diisopropylethylamine, pyridine, DABCO, N,N-dimethylbenzylamine, N,N-dimethylaniline, sodium acetate, potassium carbonate, sodium carbonate or potassium phosphate.

7. The process according to claim 2, wherein the compound represented by Formula (II) is a compound represented by Formula (II): ##STR00064## wherein R.sup.1 is a hydrogen atom, halogen, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy or a group represented by formula: YR.sup.y, wherein Y is O, S, SO.sub.2, or alkylene which may be intervened with O, S or N(R.sup.z); R.sup.y is substituted or unsubstituted aromatic carbocyclyl or substituted or unsubstituted aromatic heterocyclyl; and R.sup.z is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl or substituted or unsubstituted aromatic carbocyclyl alkyloxycarbonyl; R.sup.2 and R.sup.3 are each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, halogen, hydroxy, mercapto, cyano or substituted or unsubstituted amino.

8. The process according to claim 7, wherein R.sup.1 is a group represented by formula: YR.sup.y, wherein Y is alkylene which may be intervened with O; and R.sup.y is phenyl unsubstituted or substituted with a substituent selected from a substituent group p [substituent group p: halogen, carboxy, alkyl, haloalkyl, hydroxyalkyl, alkyloxy, alkyloxycarbonyl and substituted or unsubstituted amino], pyridyl unsubstituted or substituted with a substituent selected from a substituent group p, furyl unsubstituted or substituted with a substituent selected from a substituent group p, thienyl unsubstituted or substituted with a substituent selected from a substituent group p, thiazolyl unsubstituted or substituted with a substituent selected from a substituent group p, or oxazolyl unsubstituted or substituted with a substituent selected from a substituent group p; R.sup.2 is substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy or halogen; and R.sup.3 is a hydrogen atom.

9. The process according to claim 7, wherein the compound represented by Formula (II) is a compound represented by Formula (II): ##STR00065##

10. A crystalline form of methanesulfonate of the compound represented by Formula (II): ##STR00066##

11. The crystalline form according to claim 10, wherein diffraction angle 2 of the powder X-Ray diffraction analysis are 5.60.2, 9.80.2, 17.90.2, 24.40.2, and 26.40.2.

12. The crystalline form according to claim 10, wherein diffraction angle 2 of the powder X-Ray diffraction analysis are 5.60.2, 8.30.2, 9.80.2, 13.70.2, 17.00.2, 17.90.2, 21.30.2, 24.40.2, 26.00.2, and 26.40.2.

13. A complex comprising N-methylmorpholine, hydroiodic acid and dimethylsulfoxide.

14. The complex according to claim 13, wherein the complex is a crystalline form.

15. The crystalline form of the complex according to claim 14, wherein said crystalline form of the complex is characterized by the following crystal data: TABLE-US-00014 TABLE 1 Space Group P2.sub.1/c a () 7.3750(2) b () 11.8395(3) c () 14.2325(4) () 90 () 107.764(2) () 90 V (.sup.3) 1183.47(5) Z 4 Density(calculated value) (g/cm.sup.3) 1.724 Measured temperature ( C.) 173.

16. The crystalline form of the complex according to claim 14, wherein diffraction angle 2 of the powder X-Ray diffraction analysis are 12.60.2, 16.90.2, 17.50.2, 26.30.2, and 28.90.2.

17. The crystalline form of the complex according to claim 14, wherein diffraction angle 2 of the powder X-Ray diffraction analysis are 12.60.2, 16.90.2, 17.50.2, 19.50.2, 20.80.2, 25.80.2, 26.30.2, 27.00.2, 28.40.2, and 28.90.2.

18. The process according to claim 1, wherein the compound represented by Formula (I) is a compound represented by Formula (I): ##STR00067## wherein ring A is as defined in claim 1, and the base is N-methylmorphiline, characterized in that the process is carried out in the presence of the crystalline form of the complex comprising N-methylmorpholine, hydroiodic acid and dimethylsulfoxide.

19. The process according to claim 2, wherein the compound represented by Formula (I) is a compound represented by Formula (I): ##STR00068## wherein R.sup.1 is a hydrogen atom, halogen, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy or a group represented by formula: YR.sup.y, wherein Y is O, S, SO.sub.2, or alkylene which may be intervened with O, S or N(R.sup.z); R.sup.y is substituted or unsubstituted aromatic carbocyclyl or substituted or unsubstituted aromatic heterocyclyl, and R.sup.z is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl or substituted or unsubstituted aromatic carbocyclyl alkyloxycarbonyl; R.sup.2 and R.sup.3 are each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, halogen, hydroxy, mercapto, cyano or substituted or unsubstituted amino, the base is N-methylmorphiline, and the compound represented by Formula (II) is the compound represented by Formula (II): ##STR00069## wherein R.sup.1, R.sup.2 and R.sup.3 are as defined above, characterized in that the process is carried out in the presence of the crystalline form of the complex comprising N-methylmorpholine, hydroiodic acid and dimethylsulfoxide.

20. The process according to claim 2, wherein the compound represented by Formula (I) is a compound represented by Formula (I): ##STR00070## the base is N-methylmorphiline, and the compound represented by Formula(II) is the compound represented by Formula(II): ##STR00071## characterized in that the process is carried out in the presence of the crystalline form of the complex comprising N-methylmorpholine, hydroiodic acid and dimethylsulfoxide.

21. The process according to claim 1, characterized in that the process is carried out in the presence of N,N-dimethylglycine, picolinic acid, L-proline, 2-hydroxy-N,N-diethyl-benzamide, ethylene glycol, ethyl 2-oxocyclohexanecarboxylate, 2-acetylcyclohexanone, 2-hydroxybenzoic acid, 2-furoic acid, diethyl malonate, N,N-dimethylethylenediamine, acetic acid, copper(I) 2-thiophenecarboxylate, glycine, N-methylglycine, D-proline, N-methylproline, imidazole-4-carboxylic acid, oxazole-4-carboxylic acid, thiazole-4-carboxylic acid, imidazole-2-carboxylic acid, oxazole-2-carboxylic acid, thiazole-2-carboxylic acid, pyrrole-2-carboxylic acid, isoxazole-5-carboxylic acid, isoxazole-3-carboxylic acid, alanine, valine, leucine, isoleucine, 2-dimethylaminobenzoic acid, glycolamide, formic acid, propionic acid, butyric acid, oxalic acid, maleic acid, trifluoroacetic acid, malonic ester, acetoacetic ester, ethylene glycol dimethyl ether, 2-methoxyethanol, glycolic acid, glycolic ester, 1,3-propanediol, 1,4-butanediol, 1,5-pentanediol, diethylene glycol, catechol, 2-hydroxymethyl-1,3-propanediol, N,N-dimethylurea, N,N-diphenylurea or N,N-dimethylglycinamide.

22. The process according to claim 7, characterized in that the process is carried out in the presence of N,N-dimethylglycine, picolinic acid, L-proline, 2-hydroxy-N,N-diethyl-benzamide, ethylene glycol, ethyl 2-oxocyclohexanecarboxylate, 2-acetylcyclohexanone, 2-hydroxybenzoic acid, 2-furoic acid, diethyl malonate, N,N-dimethylethylenediamine, acetic acid, copper(I) 2-thiophenecarboxylate, glycine, N-methylglycine, D-proline, N-methylproline, imidazole-4-carboxylic acid, oxazole-4-carboxylic acid, thiazole-4-carboxylic acid, imidazole-2-carboxylic acid, oxazole-2-carboxylic acid, thiazole-2-carboxylic acid, pyrrole-2-carboxylic acid, isoxazole-5-carboxylic acid, isoxazole-3-carboxylic acid, alanine, valine, leucine, isoleucine, 2-dimethylaminobenzoic acid, glycolamide, formic acid, propionic acid, butyric acid, oxalic acid, maleic acid, trifluoroacetic acid, malonic ester, acetoacetic ester, ethylene glycol dimethyl ether, 2-methoxyethanol, glycolic acid, glycolic ester, 1,3-propanediol, 1,4-butanediol, 1,5-pentanediol, diethylene glycol, catechol, 2-hydroxymethyl-1,3-propanediol, N,N-dimethylurea, N,N-diphenylurea or N,N-dimethylglycinamide.

23. The process according to claim 9, characterized in that the process is carried out in the presence of N,N-dimethylglycine, picolinic acid, L-proline, 2-hydroxy-N,N-diethyl-benzamide, ethylene glycol, ethyl 2-oxocyclohexanecarboxylate, 2-acetylcyclohexanone, 2-hydroxybenzoic acid, 2-furoic acid, diethyl malonate, N,N-dimethylethylenediamine, acetic acid, copper(I) 2-thiophenecarboxylate, glycine, N-methylglycine, D-proline, N-methylproline, imidazole-4-carboxylic acid, oxazole-4-carboxylic acid, thiazole-4-carboxylic acid, imidazole-2-carboxylic acid, oxazole-2-carboxylic acid, thiazole-2-carboxylic acid, pyrrole-2-carboxylic acid, isoxazole-5-carboxylic acid, isoxazole-3-carboxylic acid, alanine, valine, leucine, isoleucine, 2-dimethylaminobenzoic acid, glycolamide, formic acid, propionic acid, butyric acid, oxalic acid, maleic acid, trifluoroacetic acid, malonic ester, acetoacetic ester, ethylene glycol dimethyl ether, 2-methoxyethanol, glycolic acid, glycolic ester, 1,3-propanediol, 1,4-butanediol, 1,5-pentanediol, diethylene glycol, catechol, 2-hydroxymethyl-1,3-propanediol, N,N-dimethylurea, N,N-diphenylurea or N,N-dimethylglycinamide.

24. A process for producing a compound represented by Formula (V): ##STR00072## wherein R.sup.1 is a hydrogen atom, halogen, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy or a group represented by formula: YR.sup.y, wherein Y is O, S, SO.sub.2, or alkylene which may be intervened with O, S or N(R.sup.z), R.sup.y is substituted or unsubstituted aromatic carbocyclyl or substituted or unsubstituted aromatic heterocyclyl, and R.sup.z is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl or substituted or unsubstituted aromatic carbocyclyl alkyloxycarbonyl; R.sup.2 and R.sup.3 are each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, halogen, hydroxy, mercapto, cyano or substituted or unsubstituted amino, R.sup.4 is substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl or substituted or unsubstituted amino, and R.sup.5 is substituted or unsubstituted C1 to 3 alkylene, characterized in that the compound represented by Formula (II) which is prepared by the process according to claim 7, is reacted with a compound represented by Formula (IV): R.sup.4R.sup.5ONH.sub.2, wherein R.sup.4 and R.sup.5 are as defined above.

25. A process for producing a compound represented by Formula (V): ##STR00073## wherein R.sup.4 is substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl or substituted or unsubstituted amino, and R.sup.5 is substituted or unsubstituted C1 to 3 alkylene, characterized in that the compound represented by Formula (II) which is prepared by the process according to claim 9, is reacted with the compound represented by Formula (IV): R.sup.4R.sup.5ONH.sub.2, wherein R.sup.4 and R.sup.5 are as defined above.

Description

BRIEF DESCRIPTION OF DRAWINGS

(1) FIG. 1 indicates data of powder X-Ray diffraction analysis pattern of the crystalline form of Compound 3 (methane sulfonate of the compound represented by Formula (II)).

(2) FIG. 2 indicates a crystal configuration in the asymmetric unit of Compound 4 (the complex comprising N-methylmorpholine, hydroiodic acid and dimethylsulfoxide).

(3) FIG. 3 indicates data of powder X-Ray diffraction analysis pattern of the crystalline form of Compound 4 (the complex comprising N-methylmorpholine, hydroiodic acid and dimethylsulfoxide).

(4) FIG. 4 indicates data of DSC analysis of the crystalline form of Compound 4 (the complex comprising N-methylmorpholine, hydroiodic acid and dimethylsulfoxide).

(5) FIG. 5 indicates the reaction heat flow of Sonogashira-carbonylation reaction in the absence of the crystalline form of the complex comprising N-methylmorpholine, hydroiodic acid and dimethylsulfoxide.

(6) FIG. 6 indicates the reaction heat flow of Sonogashira-carbonylation reaction in the presence of the crystalline form of the complex comprising N-methylmorpholine, hydroiodic acid and dimethylsulfoxide.

(7) FIG. 7 indicates data of TG/DTA analysis of the crystalline form of Compound 4 (the complex comprising N-methylmorpholine, hydroiodic acid and dimethylsulfoxide).

EMBODIMENTS FOR CARRYING OUT THE INVENTION

(8) The present invention comprises the process for producing a compound represented by Formula (II):

(9) ##STR00025##
wherein, a ring A is a substituted or unsubstituted aromatic heterocycle or a substituted or unsubstituted aromatic carbocycle; R is a hydrogen atom or methyl; characterized by reacting a compound represented by Formula (I);

(10) ##STR00026##
wherein ring A is as defined above, X is a leaving group,
with carbon monoxide and a compound represented by Formula (III);

(11) ##STR00027##
wherein, R is as defined above,
in the presence of a palladium catalyst, a phosphine ligand, a catalyst comprising Group 11 element and a base.

(12) The compound represented by Formula (I) which is a starting material can be prepared in accordance with the method described in Patent Document 1. Also, it can be prepared in accordance with the conventional method from commercially available reagents or it is possible to use commercially available products.

(13) Examples of a solvent, which is not limited as far as it does not inhibit the reaction, include dimethylacetamide (DMA), tetrahydrofuran (THF), dimethylsulfoxide (DMSO) and the mixed solvent thereof. For example, a mixed solvent of tetrahydrofuran and dimethylsulfoxide can be used.

(14) The reaction temperature is usually in the range of room temperature to the reflux temperature of the solvent. For example, the reaction can be carried out in the range of 10 C. to 60 C. For example, the reaction can be carried out in the range of 20 C. to 30 C.

(15) The amount of the compound represented by Formula (III) used is usually 1.0 to 5.0 equivalent(s), for example, 2.0 to 3.0 equivalents, for example, 2.2 to 2.5 equivalents, relative to the compound represented by Formula (I).

(16) The method to apply the compound represented by Formula (III) into the reaction vessel can be carried out by bubbling. Alternatively, a solution can be applied to the reaction vessel in which the solution is prepared by dissolving the compound represented by Formula (III) into a solvent in advance.

(17) The time to apply the compound represented by Formula (III) into the reaction vessel is usually over 0.2 to 10 hour(s), for example, 6 to 8 hours in the large scale synthesis.

(18) The method to apply carbon monoxide into the reaction vessel can be carried out by replacing the atmosphere in the reaction vessel with carbon monoxide before starting the reaction. Alternatively, carbon monoxide can be applied by bubbling.

(19) As for the pressure in the reaction vessel, the reaction can be carried out in both cases under atmospheric pressure and under increased pressure. When the reaction is carried out under increased pressure, the pressure in the reaction vessel is, for example, 0.01 to 0.5 MPa, for example, 0.1 to 0.3 MPa.

(20) Pd.sub.2(dba).sub.3, PdCl.sub.2 dppf, PdCl.sub.2(PPh.sub.3).sub.2, Pd(OAc).sub.2, Pd(PPh.sub.3).sub.4, Pd/C, PdCl.sub.2, Pd-PEPPSI-IPr, Bis[cinnamyl palladium Cl], PdCl.sub.2 (Xantphos), Pd(OH).sub.2 and the like can be used as palladium catalyst. The commercially available palladium catalysts for various cross coupling reaction (Negishi, Heck, Suzuki, Sonogashira, Stille, Buchwald-Hartwig and the like) can be used. Also, a palladium catalyst can be prepared by the conventional method from a precursor of palladium catalyst. For example, the following palladium catalysts can be used.

(21) Pd.sub.2 (dba).sub.3: Tris(dibenzylideneacetone)dipalladium(0),

(22) PdCl.sub.2 dppf: [1,1-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct,

(23) PdCl.sub.2 (PPh.sub.3).sub.2: Bis(triphenylphosphine)palladium(II) dichloride,

(24) Pd(OAc).sub.2: Palladium(II) diacetate,

(25) Pd(PPh.sub.3).sub.4: Tetrakis(triphenylphosphine)palladium(0),

(26) Pd/C: Palladium on carbon,

(27) PdCl.sub.2: Palladium(II) chloride,

(28) Pd-PEPPSI-IPr: [1,3-Bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride,

(29) Bis[cinnamyl palladium Cl: Bis[cinnamyl palladium(II) chloride],

(30) PdCl.sub.2(Xantphos): Dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene]palladium(II),

(31) Pd(OH).sub.2: Palladium hydroxide.

(32) Examples include PdCl.sub.2 dppf, PdCl.sub.2(PPh.sub.3).sub.2, Pd.sub.2(dba).sub.3 and Pd(OAc).sub.2.

(33) For example, Pd.sub.2(dba).sub.3 is exemplified.

(34) The amount of the palladium catalyst used is usually catalytic amount, relative to the compound represented by Formula (I), for example, 0.001 to 0.1 equivalent, for example, 0.001 to 0.01 equivalent.

(35) Xantphos, P(2-furyl).sub.3, PPh.sub.3, P(o-tol).sub.3, P(OPh).sub.3, P(OMe).sub.3, dppp, dppb, dppf, BINAP, X-Phos, P(t-Bu).sub.3, P(Oi-Pr).sub.3, P(p-MeOPh).sub.3, DPEPhos and the like can be used as phosphine ligand. The commercially available phosphine ligands for various cross coupling reaction (Negishi, Heck, Suzuki, Sonogashira, Stille, Buchwald-Hartwig and the like) can be used. Also, a phosphine ligand can be prepared by the conventional method from a precursor of phosphine ligand. For example, the following phosphine ligands can be used.

(36) Xantphos: 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene,

(37) P(2-furyl).sub.3: Tri(2-furyl)phosphine,

(38) PPh.sub.3: Triphenylphosphine,

(39) P(o-tol).sub.3: Tri(o-tolyl)phosphine,

(40) P(OPh).sub.3: Triphenyl phosphite,

(41) P(OMe).sub.3: Trimethyl phosphite,

(42) dppp: 1,3-Bis(diphenylphosphino)propane,

(43) dppb: 1,4-Bis(diphenylphosphino)butane,

(44) dppf: 1,1-Bis(diphenylphosphino)ferrocene,

(45) BINAP: 2,2-Bis(diphenylphosphino)-1,1-binaphthyl,

(46) X-Phos: 2-Dicyclohexylphosphino-2,4,6-triisopropylbiphenyl,

(47) P(t-Bu).sub.3: Tri-tert-butylphosphine,

(48) P(Oi-Pr).sub.3: Triisopropyl phosphite,

(49) P(p-MeOPh).sub.3: Tris(4-methoxyphenyl)phosphine,

(50) DPEPhos: Bis[2-(diphenylphosphino)phenyl] Ether.

(51) Examples include PPh.sub.3, P(o-tol).sub.3, P(OPh).sub.3, P(2-furyl).sub.3 and Xantphos.

(52) For example, Xantphos is exemplified.

(53) The amount of the phosphine ligand used is usually catalytic amount, relative to the compound represented by Formula (I), for example, 0.001 to 0.1 equivalent, for example, 0.01 to 0.03 equivalent.

(54) Copper, silver and gold are exemplified as Group 11 element.

(55) Examples include copper iodide(I), copper iodide(II), copper chloride(I), copper chloride(II), copper acetate(I), copper acetate(II), copper oxide(II), copper bromide(I), copper bromide(II) or silver acetate as the catalyst comprising Group 11 element.

(56) For example, copper chloride(I), copper acetate(I) and copper bromide(I) are exemplified.

(57) For example, copper chloride(I) is exemplified.

(58) The amount of the catalyst comprising Group 11 element used is usually catalytic amount, relative to the compound represented by Formula (I), for example, 0.001 to 0.5 equivalent, for example, 0.01 to 0.1 equivalent.

(59) Examples include N-methylmorpholine, triethylamine, diisopropylethylamine, pyridine, DABCO(1,4-Diazabicyclo[2.2.2]octane), N,N-dimethylbenzylamine, N,N-dimethylaniline, sodium acetate, potassium carbonate, sodium carbonate or potassium phosphate, metal hydride (e.g. sodium hydride and the like), metal alkoxide (e.g. sodium methoxide, sodium ethoxide, potassium t-butoxide and the like), metallic sodium, alkyllithium(n-BuLi, sec-BuLi, tert-BuLi) and the like as the base.

(60) Examples include N-methylmorpholine, triethylamine, diisopropylethylamine, pyridine, DABCO(1,4-Diazabicyclo[2.2.2]octane), N,N-dimethylbenzylamine, N,N-dimethylaniline, sodium acetate, potassium carbonate, sodium carbonate or potassium phosphate as the base.

(61) For example, N-methylmorpholine, triethylamine, diisopropylethylamine and pyridine are exemplified.

(62) For example, N-methylmorpholine is exemplified.

(63) The amount of the base used is usually 2 to 10 equivalents, relative to the compound represented by Formula (I), for example, 2 to 8 equivalents, for example, 3 to 5 equivalents.

(64) The above process can be carried out in the presence of N,N-dimethylglycine, picolinic acid, L-proline, 2-hydroxy-N,N-diethyl-benzamide, ethylene glycol, ethyl 2-oxocyclohexanecarboxylate, 2-acetylcyclohexanone, 2-hydroxybenzoic acid, 2-furoic acid, diethyl malonate, N,N-dimethylethylenediamine, acetic acid, copper(I) 2-thiophenecarboxylate, glycine, N-methylglycine, D-proline, N-methylproline, imidazole-4-carboxylic acid, oxazole-4-carboxylic acid, thiazole-4-carboxylic acid, imidazole-2-carboxylic acid, oxazole-2-carboxylic acid, thiazole-2-carboxylic acid, pyrrole-2-carboxylic acid, isoxazole-5-carboxylic acid, isoxazole-3-carboxylic acid, alanine, valine, leucine, isoleucine, 2-dimethylaminobenzoic acid, glycolamide, formic acid, propionic acid, butyric acid, oxalic acid, maleic acid, trifluoroacetic acid, malonic ester, acetoacetic ester, ethylene glycol dimethyl ether, 2-methoxyethanol, glycolic acid, glycolic ester, 1,3-propanediol, 1,4-butanediol, 1,5-pentanediol, diethylene glycol, catechol, 2-hydroxymethyl-1,3-propanediol, N,N-dimethylurea, N,N-diphenylurea or N,N-dimethylglycinamide.

(65) For example, the process can be carried out in the presence of N,N-dimethylglycine, picolinic acid, L-proline, 2-hydroxy-N,N-diethyl-benzamide, ethylene glycol, ethyl 2-oxocyclohexanecarboxylate, 2-acetylcyclohexanone, 2-hydroxybenzoic acid, 2-furoic acid, diethyl malonate, N,N-dimethylethylenediamine, acetic acid, copper(I) 2-thiophenecarboxylate.

(66) For example, the process can be carried out in the presence of N,N-dimethylglycine, picolinic acid or ethylene glycol.

(67) For example, the process can be carried out in the presence of N,N-dimethylglycine.

(68) The above process can be carried out in both cases in the presence and in the absence of the said compounds.

(69) The amount of the said compound used is usually catalytic amount, relative to the compound represented by Formula (I), for example, 0.01 to 0.5 equivalent, for example, 0.02 to 0.1 equivalent in which the process is carried out in the presence of the said compound.

(70) As hereinafter referred to Example 3, the said compound can control the deactivation of palladium catalyst when the process is carried out in the presence of the said compound.

(71) Additionally, the said compound can be used for other reactions (e.g. Negishi Heck, Suzuki, Sonogashira, Stille, Buchwald-Hartwigh and the like) by using palladium catalyst other than Sonogashira-carbonylation reaction of the present invention.

(72) In the above process, when the compound represented by Formula (I) is the compound represented by Formula (I):

(73) ##STR00028##
wherein, ring A is as defined above,
the compound represented by Formula (I):

(74) ##STR00029##
wherein, R.sup.1, R.sup.2 and R.sup.3 are as defined above,
or the compound represented by Formula (I):

(75) ##STR00030##
and the base is N-methylmorpholine, the process can be carried out even in the presence of the crystalline form of the complex comprising N-methylmorpholine, hydroiodic acid and dimethylsulfoxide.

(76) The above process can be carried out in both cases in the presence and in the absence of the crystalline form of the complex comprising N-methylmorpholine, hydroiodic acid and dimethylsulfoxide.

(77) When the above process is carried out in the presence of the crystalline form of the complex comprising N-methylmorpholine, hydroiodic acid and dimethylsulfoxide, the crystalline form of the said complex used is usually 0.1 to 61%, for example, 1 to 10%, for example 2 to 4%, relative to the compound represented by Formula (I), Formula (I) or Formula (I).

(78) As hereinafter referred to Example 1, when the above process is carried out in the presence of the crystalline form of the complex comprising N-methylmorpholine, hydroiodic acid and dimethylsulfoxide, it can prevent the exponential increase of reaction heat.

(79) As used herein, the complex includes crystalline form and amorphous form.

(80) As used herein, the crystalline form of the complex comprising N-methylmorpholine, hydroiodic acid and dimethylsulfoxide includes the crystalline form of the complex comprising N-methylmorpholine hydroiodide and dimethylsulfoxide solvate.

(81) Additionally, as used herein, the crystalline form of the complex comprising N-methylmorpholine, hydroiodic acid and dimethylsulfoxide includes the co-crystal comprising N-methylmorpholine hydroiodide and dimethylsulfoxide solvate.

(82) When the compound represented by Formula (II) is the following compound:

(83) ##STR00031##
the process can be carried out in the same manner as the above reaction condition. When ring A of the compound represented by Formula (II) is a substituted or unsubstituted aromatic heterocycle (e.g, benzene or the like) or a substituted or unsubstituted aromatic carbocycle (e.g, quinazoline, pyridine, thiazole, thiophene, imidazole, pyrazine, pyrimidine, furan or the like), the process can be carried out in the same manner as the above reaction condition.

(84) Also, the present invention includes methanesulfonate of the compound represented by Formula (II) or a step to obtain the crystalline form of it.

(85) Methanesulfonate of the compound represented by Formula (II) or the crystalline form of it can be prepared by adding methanesulfonic acid to the reaction solution after completion of the reaction of the above process.

(86) Examples of a solvent include the solvent which is used in the above process. Also, another solvent can be added after completion of the reaction of the above process. Examples include acetonitrile and tetrahydrofuran. For example, acetonitrile can be used.

(87) The reaction temperature is in the range of 10 C. to 40 C. For example, the reaction temperature is in the range of 5 C. to 25 C.

(88) The amount of methanesulfonic acid used is usually 2 to 10 equivalents, for example, 3 to 8 equivalents, for example 4.0 to 5.5 equivalents, relative to the compound represented by Formula (I).

(89) The present invention includes a step that methanesulfonate of the compound represented by Formula (II) or the crystalline form of it is converted to a free form of the compound represented by Formula (II). The free form of the compound represented by Formula (II) can be prepared by treating methanesulfonate of the compound represented by Formula (II) or the crystalline form of it with a base.

(90) Examples of the solvent, which is not limited as far as it does not inhibit the reaction, include methanol, ethanol, isopropanol and the like. For example, methanol is exemplified.

(91) The reaction temperature is in the range of 20 C. to 40 C. For example, the reaction temperature is in the range of 5 C. to 10 C.

(92) Examples of the base include the base which is used in the above process. For example, N-methylmorpholine can be used.

(93) The amount of the base used is usually 1 to 5 equivalent(s), for example, 1 to 3 equivalent(s), for example 1 to 1.5 equivalent(s), relative to methanesulfonate of the compound represented by Formula (II) or the crystalline form of it.

(94) Moreover, the present invention includes a step to prepare the crystalline form of the complex comprising N-methylmorpholine, hydroiodic acid and dimethylsulfoxide.

(95) The commercially available N-methylmorpholine, hydroiodic acid (aqueous solution is preferred) and dimethylsulfoxide (DMSO) can be used as the starting materials.

(96) Examples of the solvent, which is not limited as far as it does not inhibit the reaction, include tetrahydrofuran (THF), dimethylsulfoxide (DMSO) and a mixed solvent of them.

(97) The reaction temperature is usually in the range of 20 C. to 70 C., for example, in the range of 0 C. to 30 C., for example, in the range of 5 C. to 25 C.

(98) The amount of hydroiodic acid (aqueous solution) used is usually 1.0 to 2 equivalent(s), for example, 1.0 to 1.5 equivalent(s), for example, 1.0 to 1.1 equivalent, relative to N-methylmorpholine.

(99) The amount of dimethylsulfoxide (DMSO) used is usually the amount of solvent, relative to N-methylmorpholine. For example, the amount of 80% to 3000%, for example, 80% to 800% can be used.

(100) As an alternative method, the crystalline form of the complex comprising N-methylmorpholine, hydroiodic acid and dimethylsulfoxide can be obtained as by-product by Sonogashira-carbonylation reaction described above using the compound represented by Formula (I), Formula (I) or Formula (I) as the starting material, N-methylmorpholine as the base, dimethylsulfoxide or a mixed solvent [for example, a mixed solvent with tetrahydrofuran (THF)], and it can be used in the above process.

(101) Hereinafter, methods for identifying the crystalline form of the present invention are explained.

(102) Unless otherwise noted, the numerical values described and claimed herein are approximate. Variation within the values may be attributed to equipment calibration, equipment errors, purity of the materials, crystal size, and sample size, among other factors.

(103) As used herein, crystalline or crystal means a substance having an ordered atom, ion, molecule and the like that consists a solid, thereby the substance has periodism and anisotropism. The degree of crystallinity of crystalline form can be determined by many techniques including, for example, powder X-ray diffraction, moisture sorption, differential scanning calorimetry, solution calorimetry, and dissolution properties.

(104) In general, crystalline organic compounds consist of a large number of atoms that are arranged in a periodic array in three-dimensional space. The structural periodicity normally manifests physical properties, which can be explicitly distinguished by most spectroscopic probes (e.g., X-ray diffraction, an infrared spectrum, a Raman spectrum and solid state NMR).

(105) The X-ray powder diffraction (XRPD) is acknowledged to be one of the most sensitive analytical methods for measuring solid crystallinity. X-rays which are irradiated to crystals are reflected by the crystal lattice planes and mutually interfere. Then, only the diffraction lines in the direction which fulfill the conditions predicted by Bragg's law are intensified and the ordered diffraction lines corresponding to the periodicity of the structure are observed. On the other hand, in the case of amorphous solids, the well-ordered diffraction lines over a long-range are not observed. Amorphous solids usually show broad XRPD patterns called halo patterns, because they do not have the ordered iteration periodicity in the structure, so that the diffraction phenomenon does not occur.

(106) The crystalline form of methanesulfonate of the compound represented by Formula (II) and the crystalline form of complex comprising N-methylmorpholine, hydroiodic acid and dimethylsulfoxide, which are disclosed in this description, have X-ray powder diffraction profiles.

(107) For example, the crystalline form can be specified by the presence of characteristic diffraction peaks. The characteristic diffraction peaks used in this description are the ones selected from the observed diffraction peaks. The characteristic diffraction peaks are selected from preferably about 20, more preferably about 10, and most preferably about 5 peaks in a diffraction pattern.

(108) Since an error in the range of 0.2 may occur in diffraction angles (2) in X-ray powder diffraction, in general, the value of the above diffraction angle should be understood as the one including values in a range of around 0.2. Therefore, the present invention includes not only crystalline forms whose diffraction angles of the peaks in X ray powder diffraction perfectly match, but also crystalline forms whose diffraction angles of the peaks match within an error of around 0.2.

(109) In general, it is known that the relative intensities of the peaks shown in the Tables and Figures below may vary due to a number of factors such as selected orientation effects of crystals in the X-ray beam, effect of coarse particle, purity of the material being analyzed or degree of crystallinity of the sample, for example. The peak positions may also shift for variations in sample height. Furthermore, measurements using a different wavelength will result in different shifts according to the Bragg equation (n=2d sin ). Such another XPRD patterns obtained by using a different wavelength are also within the scope of the present invention.

(110) Single crystal X-ray analysis is one of the most popular analytical method to identify the crystalline form, as described in Manual of X-ray structural analysis (1983), Sakurai Toshio: Shokabo Press, Stout & Jensen, X-Ray Structure Determination: A Practical Guide, Macmillan Co., New York (1968). The method can provide crystal parameters and atomic coordinates (the positions of individual atoms in a crystal) which can be graphically represented. Therefore, the method is useful to identify the crystalline form of this invention.

(111) The crystalline form of methanesulfonate of the compound represented by Formula (II) and the crystalline form of complex comprising N-methylmorpholine, hydroiodic acid and dimethylsulfoxide, which are prepared in the above process, are stable and easy to handle for conducting the above process, so that both crystalline forms are useful crystals as intermediate for producing the pharmaceutical composition.

(112) The crystalline form of the present invention can be specified by thermal analysis methods.

(113) Hereinafter, DSC (differential scanning calorimetry), one of the main measuring methods for thermal analysis, is a method of measuring the thermal properties of the substance as an aggregate of an atom(s) and a molecule(s).

(114) A differential scanning calorimetry curve can be obtained by measuring temperatures or change of heat capacity over time of a pharmaceutical active ingredient by DSC, and plotting the obtained data to temperatures or times. From a differential scanning calorimetry curve, the information about the onset temperature, melting endothermic maximum and enthalpy of a pharmaceutical active ingredient can be obtained.

(115) As to DSC, it is known that the observed temperature can depend on rate of temperature change, the sample preparations techniques or the specific devices. Therefore, in DSC, the melting point means the onset temperature which is unaffected by technique for preparing the sample. The error span in the onset temperature obtained from a differential scanning calorimetry curve is approximately 2 C. In specifying the identity of a crystal, overall pattern is important and may change somewhat depending on a measurement condition.

(116) Hereinafter, TG/DTA (Themogravimeter Differential Thermal Analyzer) is one of the major measuring methods of thermal analysis. It is a method of measuring the weight and the thermal property of a substance as an aggregate of atoms and molecules.

(117) TG/DTA is the method of measuring the changes in weight and quantity of heat of an active pharmaceutical ingredient concerning the temperature or the time. TG (thermo gravity) and DTA (Differential Thermal Analysis) curve are obtained by plotting the obtained data against temperature or time. TG/DTA curve provides the information about the changes in weight and quantity of heat related to decomposition, dehydration, oxidation, reduction, sublimation and evaporation of an active pharmaceutical ingredient.

(118) It is known that the temperature and the weight changes observed in TG/DTA may depend on a heating rate, a sample preparation technique and a specific device. Therefore, in TG/DTA, a melting point means onset temperature which is unaffected by technique for preparing the sample. In specifying the identity of a crystal, overall pattern is important and may change somewhat depending on a measurement condition.

(119) The present invention is explained in more detail by the following Examples, but these Examples do not limit the present invention. Although an effort to guarantee accuracy about numerical values (for example, quantity, temperature, etc.) is paid, some errors and deviations should be taken into consideration. If not shown in particular, % is weight % of a component, and weight % is weight % of the full weight of a composition. A pressure is an atmospheric pressure or a pressure near it.

(120) Terms used in the present description are explained below:

(121) g: gram

(122) L: liter

(123) mg: milligram

(124) mL: milliliter

(125) MeCN: acetonitrile

(126) DMSO: dimethylsulfoxide

(127) THF: tetrahydrofuran

(128) DMA: dimethylacetamide

(129) MsOH: methanesulfonic acid

(130) NMM: N-methylmorpholine

(131) CO: carbon monoxide

(132) rt: room temperature

(133) HPLC: High Performance Liquid Chromatography

(134) (Powder X-Ray Diffraction Measurement)

(135) Data of powder X-ray diffraction measurement of the obtained crystalline form in each Example is obtained according to powder X-ray diffraction analysis method in General tests in Japanese Pharmacopoeia as following conditions.

(136) (Method A)

(137) (Device)

(138) RINT-TTRIII by Rigaku

(139) (Operation Method)

(140) Samples were measured under the following conditions.

(141) Measuring method: Reflection method

(142) Light source: Cu tube

(143) Used Wavelength: CuK ray

(144) Tube current: 300 mA

(145) Tube voltage: 50 kV

(146) Sampling plate: Aluminum

(147) X-ray incident angle (): 2-40

(148) Sampling range: 0.020

(149) (Method B)

(150) (Device)

(151) D-8 Discover by Bruker

(152) (Operation Method)

(153) Samples were measured under the following conditions.

(154) Measuring method: Reflection method

(155) Light source: Cu tube

(156) Used Wavelength: CuK ray

(157) Tube current: 40 mA

(158) Tube voltage: 40 kV

(159) Sampling plate: glass

(160) X-ray incident angle (): 3-40

(161) (The Single Crystal X-Ray Analysis)

(162) All measurements were made on a Rigaku R-AXIS RAPID diffractometer using graphite monochromated CuK radiation (=1.54187 ). During the measurements, the crystals were kept in dark environment and kept frozen in nitrogen gas stream (173 C.). Data integration was carried out using the RAPID AUTO software package (Rigaku, 2006). The data were corrected for the Lorentz, polarization and absorption effects.

(163) The structure was solved by direct methods using the program SHELXS-97 (Sheldrick, 2008), and the structural refinement was carried out by fullmatrix least-squares of F2 using the program SHELXL-97 (Sheldrick, 2008). All non-hydrogen atoms were refined with anisotropic displacement parameters. All other hydrogen atoms were placed in the idealized positions using the riding mode in SHELXL-97. The hydrogen bonded to nitrogen (N1) was located using the difference Fourier maps. The final refinement converged to R1 (I>2.00 s(I))=0.0532. It was confirmed that no atom was misplaced or missing in the final difference Fourier map.

(164) FIG. 2 shows the displacement ellipsoid plot (50% probability level) using the PLUTON (Spek, 1991)/ORTEP (Johnson, 1976).

(165) (DSC Measurement)

(166) About 1 mg of the crystalline form obtained in each Example was weighted, stuffed in a high pressure pan made of gold-plated steal and measured under sealed system. The measurement conditions were as follows.

(167) (Measurement Condition)

(168) Device: DSC822e by Mettler Toledo

(169) Measurement temperature range: 25 C.-300 C.

(170) Rate of temperature increase: 10 C./min

(171) (TG/DTA Measurement)

(172) About 10 mg of the crystalline form obtained in each Example was weighted, stuffed in aluminum pan and measured under open system. The measurement conditions were as follows.

(173) (Measurement Condition)

(174) Device: TG/DTA 7200 by Hitachi High-Tech Science

(175) Measurement temperature range: 30 C.-300 C.

(176) Rate of temperature increase: 10 C./min

(177) (NMR Measurement)

(178) In NMR data shown in Examples and Reference Examples, not all measured peaks may be described.

(179) (HPLC Measurement)

(180) (Method A)

(181) Column: Unison UK-C18, 4.6150 mm, 3 m (Imtakt)

(182) Flow rate: 1.0 mL/min

(183) UV detection wavelength: 246 nm

(184) Mobile phase A: Aqueous solution of 0.01 mol/L ammonium acetate (pH5.0)

(185) Mobile phase B: Acetonitrile for HPLC

(186) Gradient program is shown in Table 2.

(187) TABLE-US-00002 TABLE 2 Time after Mobile phase A Mobile phase B injection(min) (vol %) (vol %) 0 to 10 40 60 10 to 20 40.fwdarw.10 60.fwdarw.90 20 to 25 10 90 .sup.25 to 25.1 10.fwdarw.40 90.fwdarw.60 25.1 to 30.sup. 40 60
(Method B)
Column: Unison UK-C18, 4.6150 mm, 3 m (Imtakt)
Flow rate: 1.0 mL/min
UV detection wavelength: 246 nm
Mobile phase A: Aqueous solution of 0.01 mol/L ammonium acetate (pH5.0)
Mobile phase B: Acetonitrile for HPLC
Gradient program for purity measurement is shown in Table 3.

(188) TABLE-US-00003 TABLE 3 Time after Mobile phase A Mobile phase B injection(min) (vol %) (vol %) 0 to 10 40 60 10 to 20 40.fwdarw.10 60.fwdarw.90 20 to 25 10 90 .sup.25 to 25.1 10.fwdarw.5 90.fwdarw.95 25.1 to 35.sup. 5 95 .sup.35 to 35.1 5.fwdarw.40 95.fwdarw.60 35.1 to 45.sup. 40 60

(189) In the meantime, a retention time of HPLC should be construed as including some error.

Example 1

Synthesis of Compound 2

(190) ##STR00032##

(191) To aryl iodine compound (1) (4.04 g), Pd.sub.2 (dba).sub.3 (36.6 mg, 0.005 equivalent), Xantphos (92.6 mg, 0.02 equivalent) and CuCl (15.8 mg, 0.02 equivalent) were added tetrahydrofuran (6 mL), N-methylmorpholine (4.04 g, 5 equivalents) and dimethylsulfoxide (2 mL), successively. The slurry was stirred at 25 C. under carbon monoxide atmosphere, and about 2 mol/L of the solution in which propyne gas (2.2 equivalents) was preliminarily dissolved in tetrahydrofuran was added to the slurry over about 0.5 hours and the resulting slurry was stirred for about 19 hours. After completion of the reaction, the atmosphere in the vessel was replaced with nitrogen gas and acetonitrile (40.4 mL) was added to the slurry. The slurry was stirred at 0 C. for about 1 hour, filtered through and the obtained crystalline form was washed with cold acetonitrile (12.1 mL) to give Compound (2) (3.38 g, Yield 95%, Purity 81% (HPLC Method B)).

(192) .sup.1H-NMR (300 MHz, DMSO-D.sub.6) : 10.33 (1.0H, s), 9.22 (1.1H, d, J=1.7 Hz), 8.65 (0.8H, s), 8.43 (1.1H, dd, J=8.6, 1.7 Hz), 7.98 (0.9H, d, J=2.4 Hz), 7.87 (0.9H, d, J=8.6 Hz), 7.71 (1.0H, dd, J=9.0, 2.4 Hz), 7.47 (1.0H, ddd, J=8.0, 8.0, 5.8 Hz), 7.34-7.30 (2.0H, m), 7.28 (1.0H, d, J=9.0), 7.21-7.14 (0.9H, m), 5.27 (2.0H, s), 2.28 (2.9H, s).

(193) Elemental Analysis:

(194) calculated value: C, 67.34; H, 3.84; N, 9.42; C1, 7.95; F, 4.26

(195) measured value: C, 67.24; H, 3.92; N, 9.39; C1, 7.81; F, 4.26

Example 2

Synthesis of Compound 2

(196) ##STR00033##

Step 1 Synthesis of Compound 3

(197) To aryl iodine compound (1) (50.0 kg), Pd.sub.2 (dba).sub.3 (0.68 kg, 0.0075 equivalent), Xantphos (1.72 kg, 0.03 equivalent), CuCl (0.59 kg, 0.06 equivalent), Compound (4) (1.5 kg) obtained in Example 4 hereinafter described and N,N-dimethylglycine (0.41 kg, 0.04 equivalent) were added tetrahydrofuran (110 L), N-methylmorpholine (40 kg, 4 equivalents) and dimethylsulfoxide (25 L), successively under nitrogen atmosphere. The slurry was stirred at 25 C. under carbon monoxide atmosphere and propyne gas (9.1 kg, 2.3 equivalents) was applied for the vessel over about 7 hours, and stirred further for about 5 hours. After completion of the reaction, the vessel was replaced with nitrogen gas, and to the slurry were added acetonitrile (500 L) at 20 C., then methanesulfonic acid (47.5 kg, 5 equivalents) at 5 C. After the slurry was stirred for 1 hour, the resulting crystalline form was filtered and washed with acetonitrile (250 L) to give Compound (3).

(198) .sup.1H-NMR (DMSO-D.sub.6) : 11.62 (0.7H, brs), 9.33 (1.2H, s), 8.94 (1.1H, s), 8.63 (1.1H, d, J=8.6 Hz), 7.96 (2.0H, d, J=8.6 Hz), 7.90 (2.0H, d, J=2.3 Hz), 7.63 (1.1H, dd, J=8.9, 2.3 Hz), 7.48 (0.9H, ddd, J=7.8, 7.8, 6.3 Hz), 7.36 (1.0H, d, J=8.9 Hz), 7.34-7.30 (2.0H, m), 7.22-7.16 (0.8H, m), 5.31 (2.0H, s), 2.32 (2.4H, s), 2.29 (3.0H, s)

(199) The results of the powder X-ray diffraction were indicated in FIG. 1 and Table 4 (XRPD Method A).

(200) TABLE-US-00004 TABLE 4 2 5.620 8.280 9.760 13.740 14.520 16.460 16.960 17.860 18.320 19.240 19.760 20.500 21.260 21.760 22.600 23.080 24.420 25.960 26.360 27.840 29.120 36.720

(201) Diffraction angles of major peaks (2): 5.60.2, 9.80.2, 17.90.2, 24.40.2, 26.40.2.

Step 2 Synthesis of Compound 2

(202) To Compound (3) obtained in the step 1 was added methanol (475 L), and N-methylmorpholine (11.0 kg, 1.1 equivalent) was added dropwise to the slurry at 0 C. After the slurry was stirred for about 1 hour, the resulting crystalline form was filtered and washed with cold methanol to give Compound (2) (41.4 kg, Yield 94%, Purity 93% (HPLC Method B)).

Example 3

Synthesis of Compound 3

(203) ##STR00034##

(204) To aryl iodine compound (1) (27.5 g), Pd.sub.2(dba).sub.3 (374 mg, 0.0075 equivalent), Xantphos (943 mg, 0.03 equivalent), CuCl (323 mg, 0.06 equivalent) and N,N-dimethylglycine (224 mg, 0.04 equivalent) were added tetrahydrofuran (60.5 mL), N-methylmorpholine (22.0 g, 4 equivalents) and dimethylsulfoxide (13.8 mL), successively. The slurry was stirred at 25 C. under carbon monoxide atmosphere and propyne gas (2.2 equivalents) was applied for the vessel over about 7 hours, and stirred further for about 1 hour. After completion of the reaction, the vessel was replaced with nitrogen gas, and to the slurry were added acetonitrile (303 mL) at 20 C., then methanesulfonic acid (26.1 g, 5 equivalents) at 5 C. After stood overnight, the slurry was stirred at 5 C. for 1 hour, and the resulting crystalline form was filtered and washed with cold acetonitrile (138 mL) to give Compound 3 (26.65 g, Yield 90%, Purity 88% (HPLC method B)).

Example 4

Synthesis of Compound 4

(205) ##STR00035##

(206) To N-methylmorpholine (1.12 kg) were added tetrahydrofuran (4.98 kg) and dimethylsulfoxide (7.40 kg), and 57% solution of hydroiodic acid (2.48 kg, 1.0 equivalent) was added dropwise to the solution between 10 C. and 20 C. After the slurry was stirred for about 15 minutes, tetrahydrofuran (9.96 kg) was added. The slurry was stirred for about 40 minutes, the resulting crystalline form was filtered and washed with tetrahydrofuran (4.48 kg) to give Compound 4 (3.00 kg, Yield 88%).

(207) .sup.1H-NMR (CD.sub.3OD) : 3.92 (4H, brs), 3.48 (4H, brs), 2.94 (3H, s), 2.67 (6H, s)

(208) Elemental Analysis:

(209) calculated value: C, 27.37; H, 5.91; N, 4.56; S, 10.44; I, 41.31

(210) measured value: C, 26.83; H, 5.76; N, 4.76; S, 10.41; I, 40.76

(211) The crystal data was indicated in Table 5.

(212) TABLE-US-00005 TABLE 5 Space Group P2.sub.1/c a () 7.3750(2) b () 11.8395(3) c () 14.2325(4) () 90 () 107.764(2) () 90 V (.sup.3) 1183.47(5) Z 4 Density(calculated value) (g/cm.sup.3) 1.724 Measured temperature ( C.) 173
wherein, V indicates the unit lattice volume, Z indicates chemical unit number per unit cell.

(213) In addition, the atomic coordinates of non-hydrogen atoms were indicated in Table 6 and that of hydrogen atoms were indicated in Table 7.

(214) TABLE-US-00006 TABLE 6 atom x y z B.sub.eq I1 0.11884(4) 0.73719(3) 1.08563(2) 1.54(2) S1 0.2359(2) 0.6634(1) 0.88739(9) 1.77(3) O1 0.6214(4) 0.4722(4) 0.6416(3) 2.06(7) O2 0.3496(5) 0.6078(4) 0.8276(3) 2.07(7) N1 0.2607(5) 0.4596(4) 0.6767(3) 1.14(7) C1 0.4030(6) 0.3653(5) 0.7046(4) 1.57(9) C2 0.6012(6) 0.4126(5) 0.7257(4) 1.91(9) C3 0.4925(7) 0.5653(5) 0.6172(4) 1.88(9) C4 0.2900(6) 0.5252(5) 0.5922(4) 1.52(9) C5 0.0614(6) 0.4174(5) 0.6537(4) 1.77(9) C6 0.3224(7) 0.6047(6) 1.0077(4) 2.6(1) C7 0.0065(7) 0.6004(5) 0.8514(4) 1.86(9)
wherein, Beq indicates equivalent isotropic atomic displacement factor.
Beq=8/3.sup.2 (U.sub.11(aa*).sup.2+U.sub.22(bb*).sup.2+U.sub.33(cc*).sup.2+2U.sub.12(aebb*)cos +2U.sub.13(aa*cc*)cos +2U.sub.23(b b*cc*)cos )

(215) TABLE-US-00007 TABLE 7 atom x y z B.sub.iso H1 0.2029 0.5910 0.5775 1.82 H2 0.2596 0.4768 0.5327 1.82 H3 0.5106 0.6065 0.5602 2.26 H4 0.5200 0.6181 0.6738 2.26 H5 0.6280 0.4646 0.7828 2.29 H6 0.6949 0.3502 0.7431 2.29 H7 0.3782 0.3099 0.6501 1.89 H8 0.3909 0.3260 0.7638 1.89 H9 0.2834 0.5081 0.7304 1.37 H10 0.0496 0.3712 0.7087 2.12 H11 0.0297 0.3716 0.5935 2.12 H12 0.0262 0.4817 0.6438 2.12 H13 0.0613 0.6213 0.7831 2.23 H14 0.0653 0.6271 0.8948 2.23 H15 0.0195 0.5181 0.8565 2.23 H16 0.3162 0.5221 1.0033 3.11 H17 0.2441 0.6313 1.0478 3.11 H18 0.4547 0.6282 1.0383 3.11
wherein, Biso indicates isotropic atomic displacement factor.

(216) Moreover, the structure in asymmetric unit was shown in FIG. 2.

(217) As is apparent from the coordinate shown in FIG. 2, Table 6 and Table 7, the asymmetric unit was found to be consisted with the ratio of N-methylmorpholine, hydroiodic acid and dimethylsulfoxide being 1:1:1.

(218) In addition, proton donating/accepting between N-methylmorpholine and hydroiodic acid was found, and it was confirmed that the salt of N-methylmorpholine and hydroiodic acid was formed.

(219) Meanwhile, the number of non-hydrogen atom and hydrogen atom in Table 6 and Table 7 corresponds to that of FIG. 2, successively.

(220) The results of the powder X-ray diffraction were shown in FIG. 3 and Table 8 (XRPD Method B).

(221) TABLE-US-00008 TABLE 8 2 12.613 16.929 17.506 19.539 20.780 25.814 26.335 26.970 28.393 28.905

(222) Diffraction angles of major peaks (2): 12.60.2, 16.90.2, 17.50.2, 26.30.2, 28.90.2.

(223) DSC measurement was shown in FIG. 4. The observed onset temperature was 125 C.

(224) TG/DTA measurement was shown in FIG. 7. The observed onset temperature was 115 C. The weight loss of about 27% was observed on TG.

Example 5

Synthesis of Compound 6

(225) ##STR00036##

(226) To iodobenzene (5)(2.04 g), Pd.sub.2 (dba).sub.3 (69.8 mg, 0.0075 equivalent), Xantphos (174.0 g, 0.03 equivalent), CuCl (60.5 mg, 0.06 equivalent), Compound (4)(154.2 mg) obtained in the Example 4 and N,N-dimethylglycine (40.0 mg, 0.04 equivalent) were added tetrahydrofuran (2 mL), N-methylmorpholine (4.06 g, 4 equivalents) and dimethylsulfoxide (1 mL), successively under nitrogen atmosphere. The slurry was stirred at about 25 C. under carbon monoxide atmosphere, and about 0.64 mol/L of the solution in which propyne gas (2.3 equivalents) was preliminarily dissolved in tetrahydrofuran was added to the slurry over about 0.5 hours and the resulting slurry was stirred for about 22 hours. After completion of the reaction, the atmosphere in the vessel was replaced with nitrogen gas and the precipitated solids were collected by filtration and the filtrate was concentrated. The residue was purified by silicagel column chromatography (hexane:ethylacetate=80:20 and 95:5) to give 1.13 g of Compound 6 as yellow oil, yield 78%.

(227) .sup.1H-NMR (CDCl.sub.3) : 8.14 (2H, d, J=6 Hz), 7.60 (1H, t, J=6 Hz), 7.48 (2H, t, J=6 Hz), 2.16 (3H, s)

(228) .sup.13C-NMR (CDCl.sub.3) : 178.22, 136.85, 133.91, 129.58, 128.48, 92.46, 4.32

Example 6

Synthesis of 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-((S)-morpholine-2-yl-methoxyimino)-2-butyn-1-yl)quinazoline2HCl (V-1)

(229) ##STR00037##

(230) The compound represented by Formula (II) was prepared according to the above Example 2.

(2) Synthesis of 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-((S)-morpholine-2-yl-methoxyimino)-2-butyn-1-yl)quinazoline2HCl

(231) To a suspension of 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-oxo-2-butyn-1-yl)quinazoline (II) (786 mg) and tert-butyl (S)-2-aminoxymethyl-morpholine-4-carboxylate (614 mg) in 1,4-dioxane (31 mL) was added 2 mol/L methanesulfonic acid aq. solution (2.21 mL) and stirred for 22 hr at 80 C. 2 mol/L methanesulfonic acid aq. solution (1.32 mL) was added and stirred for additional 5.5 hr. After the reaction was completed, the mixture was poured into ice-sodium hydrogen carbonate aq. solution and extracted with ethyl acetate. After the aqueous layer was extracted again with ethylacetate, all the organic layers were combined, washed with water and dried over anhydrous magnesium sulfate. The filtrate was concentrated and the residue was purified by silicagel column chromatography (eluted with chloroform:methanol=9:1) to give yellow oil. A solution of this oil in ethyl acetate (50 mL) was filtered and 4 mol/L hydrochloric acid-ethyl acetate (0.95 mL) was added under stirring and stirred for 1 hr at room temperature. The precipitate was filtered and washed with ethyl acetate and then hexane. The precipitate was recrystallized from methanol-ethyl acetate to give 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-((S)-morpholine-2-yl-methoxyimino)-2-butyn-1-yl)quinazoline2HCl (V-1) (839 mg) as yellow crystalline form.

(232) .sup.1H-NMR (d.sub.6-DMSO, ): 11.69 (1H, bs), 9.49-9.37 (2H, m), 9.05 (1H, s), 8.88 (1H, s), 8.38 (1H, dd, J=1.5 Hz, J=8.7 Hz), 7.96 (1H, d, J=8.7 Hz), 7.89 (1H, d, J=2.7 Hz), 7.64 (1H, dd, J=2.4 Hz, J=9.0 Hz), 7.52-7.45 (1H, m), 7.36-7.30 (3H, m), 7.23-7.16 (1H, m), 5.31 (2H, s), 4.36-4.34 (1H, m), 4.25-4.22 (1H, m), 4.04-3.98 (1H, m), 3.84-3.77 (1H, m), 3.04-2.85 (3H, m), 2.28 (3H, s).

Example 7

Synthesis of 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-(2-ethylaminoethoxyimino)-2-butyn-1-yl)quinazoline (V-2)

(233) ##STR00038##

(234) The compound represented by Formula (II) was prepared according to the above Example 2.

(2) Synthesis of 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-(2-hydroxyethoxyimino)-2-butyn-1-yl)quinazoline (VI-1)

(235) To a solution of 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-oxo-2-butyn-1-yl)quinazoline (II)(10 g) in 1,4-dioxane (300 mL) was added 2-(acetoxy)ethoxyamine (1.5 equiv) and then 2 mol/L methane sulfonic acid aq. solution (28 mL) and stirred for 17 hr at 60 C. The reaction mixture was poured into saturated sodium hydrogen carbonate aq. solution and extracted with ethyl acetate. The organic layer was washed with water and dried over sodium sulfate. The filtrate was concentrated and the residue was recrystallized from hydrous ethanol-water, filtered and dried to give 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-(2-hydroxyethoxyimino)-2-butyn-1-yl)quinazoline (VI-1) (7.6 g) as a colorless solid.

(236) 1.sup.H NMR (d.sub.6-DMSO, ): 10.07 (1H, s), 8.74 (1H, s), 8.58 (1H, s), 8.22 (1H, d, J=8.8 Hz), 7.96 (1H, d, J=2.4 Hz), 7.80 (1H, d, J=8.8 Hz), 7.69 (1H, dd, J=2.4 Hz, J=8.8 Hz), 7.50-7.45 (1H, m), 7.35-7.24 (3H, m), 7.20-7.16 (1H, m), 5.27 (2H, s), 4.79 (1H, t, J=5.6 Hz), 4.29 (2H, t, J=5.6 Hz), 3.75 (2H, dd, J=5.2 Hz, J=10.4 Hz), 2.26 (3H, s).

(3) Synthesis of 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-(2-sulfonyloxyethoxyimino)-2-butyn-1-yl) quinazoline (VI-2)

(237) To a solution of 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-(2-hydroxyethoxyimino)-2-butyn-1-yl)quinazoline (VI-1) (7.6 g) in tetrahydrofuran (150 mL) was added triethylamine (4.19 mL) and methanesulfonyl chloride (2.33 mL) and stirred for 3.5 hr. After the reaction was completed, the reaction mixture was poured into water and sodium hydrogen carbonate aq. solution was added to it. The mixture was extracted with ethyl acetate and the organic layer was dried over sodium sulfate and the filtrate was concentrated. Ethyl acetate was added to the residue and stood still at room temperature to give crystalline form, and then diluted with hexane. The formed crystalline form was filtered to give 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-(2-sulfonyloxyethoxyimino)-2-butyn-1-yl)quinazoline (VI-2) (7.66 g) as pale yellow crystalline form.

(238) 1.sup.H NMR (d.sub.6-DMSO, ): 10.07 (1H, s), 8.77 (1H, s), 8.60 (1H, s), 8.24 (1H, d, J=8.8 Hz), 7.97 (1H, d, J=2.4 Hz), 7.81 (1H, d, J=8.8 Hz), 7.69 (1H, dd, J=2.4 Hz, J=8.8 Hz), 7.51-7.45 (1H, m), 7.35-7.27 (3H, m), 7.21-7.17 (1H, m), 5.27 (2H, s), 4.58 (2H, t, J=4.8 Hz), 4.54 (2H, t, J=4.8 Hz), 3.24 (3H, s), 2.27 (3H, s).

(4) Synthesis of 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-(2-ethylaminoethoxyimino)-2-butyn-1-yl)quinazoline (V-1)

(239) To a solution of 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-(2-sulfonyloxyethoxyimino)-2-butyn-1-yl)quinazoline (VI-2) (100 mg) in N,N-dimethylformamide (3 mL) was added 70% ethylamine aq. solution (160 l) and stirred for 14 hr at 60 C. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, the filtrate was concentrated and the residue was purified by an amino column chromatography (eluting with ethyl acetate) to give 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-(2-ethylaminoethoxyimino)-2-butyn-1-yl)quinazoline (V-2) (53 mg) as a colorless solid.

(240) .sup.1H NMR (d.sub.6-DMSO, ): 10.08 (1H, s), 8.74 (1H, s), 8.59 (1H, s), 8.21 (1H, d, J=8.4 Hz), 7.96 (1H, s), 7.80 (1H, d, J=8.8 Hz), 7.69 (1H, d, J=8.0 Hz), 7.51-7.45 (1H, m), 7.35-7.27 (3H, m), 7.21-7.16 (1H, m), 5.27 (2H, s), 4.31 (2H, t, J=5.6 Hz), 2.89 (2H, t, J=6.0 Hz), 2.61 (2H, q, J=7.2 Hz), 2.26 (3H, s), 1.02 (3H, t, J=7.6 Hz).

(241) For above amination, commercially available amines, or amines or a salt thereof prepared according to the methods described in J. Syn. Org. Chem., Jpn., 2001, 59: 779-789, Tetrahedron Lett., 1995, 36: 6373-6374, Synlett, 1999: 1301-1303, or Tetrahedron, 2002, 58: 6267-6276 can be used.

Example 8

(242) ##STR00039##

(243) Compound (V-3)-(V-17) were prepared according to the same manner as those of the above Examples 6 or 7.

(244) ##STR00040##

(245) TABLE-US-00009 TABLE 9 Compound No. R .sup.1H-NMR(d.sub.6-DMSO) (V-3) 10.08(1H, s), 8.75(1H, s), 8.68(1H; s), 8.22(1H, d, J = 8.8 Hz), 7.79(1H, s), 7.80(1H, d, J = 7.2 Hz), 7.70 (1H, d, J = 8.8 Hz), 7.50-7.45(1H, m), 7.35-7.27(3H, m), 7.18(1H, t, J = 8.8 Hz), 5.27(2H, s), 4.34(2H, t, J = 5.6 Hz), 3.35-3.32(2H, m), 2.92(2H, t, J = 5.6 Hz), 2.65-2.61(1H, m), 2.26(3H, s), 1.75-1.70(1H, bs), 0.84(3H, d, J = 5.6 Hz). (V-4) 10.09(1H, s), 8.58(1H, s), 8.22(1H, dd, J = 8.7 Hz, 1.8 Hz), 7.95(1H, d, J = 2.7 Hz), 7.80(1H, d, J = 9.0 Hz), 7.68(1H, dd, J = 8.7 Hz, 2.7 Hz), 7.51-7.44 (1H, m), 7.35-7.16(4H, m), 3.22(3H, s), 2.77(2H, t, J = 5.7 Hz), 2.60(2H, t, J = 5.7 Hz), 2.29(3H, s), 2.24(3H, s). (V-5) 10.09(1H, bs), 8.74(1H, s), 8.58(1H, s), 7.96(1H, d, J = 2.1 Hz), 7.80(1H, d, J = 8.7 Hz), 7.68(1H, d, J = 9.0 Hz), 7.48(1H, dd, J = 8.1 Hz), 7.35-7.26(3H, m), 7.19(1H, t, J = 8.1 Hz), 5.27(2H, s), 4.32(2H, t, J = 6.0 Hz), 3.23(3H, s), 2.85(2H, t, J = 6.0 Hz), 2.87-2.59 (4H, m), 2.24(3H, s), 0.98(3H, t, J = 7.2 Hz). (V-6) (2 HCl salt) 10.70(1H, brs), 9.92(1H, brs), 8.94(1H, s), 8.69(1H, s), 8.30(1H, d, J = 12), 7.95-7.94(1H, m), 786(1H, d, J = 12), 7.71-7.68(1H, m), 7.52-7.44(1H, m), 7.35-7.28(3H, m), 7.22-7.15(1H, m), 5.40(1H, br), 5.30(2H, s), 4.74-4.60(2H, m), 3.83-3.75(2H, m), 3.70-3.55(2H, m), 2.92(3H, s), 2.28(3H, s) (V-7) 10.09(1H, s), 8,75(1H, s), 8.59(1H, s), 8,22(1H, d, J = 8.7 Hz), 7.95(1H, d, J = 2.1 Hz), 7.81 (1H, d, J = 9.0 Hz), 7.69(1H, d, J = 8.7 Hz), 7.51-7.34(1H, m), 7.34-7.26(2H, m), 7.21-7.16(1H, m), 5.27(2H, s), 4.34(2H, t, J = 6.3 Hz), 2.96(2H, t,, J = 6.9 Hz), 2.56(3H, s), 2.26(3H, s).

(246) TABLE-US-00010 TABLE 10 Compound No. R .sup.1H-NMR(d.sub.6-DMSO) (V-8) 10.08(1H, bs), 8.74(1H, s), 8.56(1H, s), 8.21(1H, d, J = 8.0 Hz), 7.93(1H, s), 7.79(1H, d, J = 8.8 Hz), 7.67- 7.65(1H, m), 7.50-7.40(1H, m), 7.33-7.24(2H, m), 7.20-7.12(1H, m), 5.25(2H, s), 4.36-4.30(1H, m), 4.22-4.17(1H, m), 4.08-3.92(2H, m), 2.98(2H, bs), 2.24(3H, s), 2.00-1.90(1H, m), 1.80-1.70(2H, m), 1.62-1.52(1H, m) (V-9) 10.45(1H, s), 8.92(1H, s), 8.65(1H, s), 8.31(1H, d, J = 8.4 Hz), 7.97(1H, s), 7.77(1H, d, J = 8.8 Hz), 7.71(1H, d, J = 9.2 Hz), 7.51-7.45(1H, m), 7.35- 7.28(2H, m), 7.19(1H, t, J = 8.4 Hz), 5.28(2H, s), 4.56-4.47(3H, m), 4.15(1H, bs), 3.60(1H, bs), 3.12(1H, bs), 2.28(3H, s), 2.09(1H, dd, J = 13.2 Hz,J = 6.0 Hz), 1.862-1.81(1H, m). (V-10) 10.08(1H, s), 8.75(1H, s), 8.59(1H, s), 8.22(1H, d, J = 8.8 Hz), 7.97(1H, s), 7.80(1H, d, J = 8.8 Hz), 7.69 (1H, d, J = 8.0 Hz), 7.51-7.45(1H, m), 7.35-7.27(m, 3H), 7.20-7.17(1H, m), 5.27(2H, s), 4.67(1H, bs), 4.29- 4.19(3H, m), 3.45-4.40(1H, m), 2.88(1H, dd, J = 11.2 Hz, J = 5.6 Hz), 2.70(1H, dd, J = 11.0, J = 3.6 Hz), 2.27(3H, s), 2.10-2.02(1H, m), 1.46-1.39(1H, m). (V-11) 10.09(1H, bs), 8.75(1H, s), 8.58(1H, s), 8.20(1H, d, J = 8.7 Hz), 7.95(1H, d, J = 2.1 Hz), 7.80(1H, d, J = 8.7 Hz), 7.68(1H, d, J = 9.0 Hz), 7.51-7.44(1H, m), 7.35- 7.26(3H, m), 7.21-7.16(1H, m), 5.27(2H, s), 4.20- 4.09(2H, m), 3.79(1H, dd, J = 2.7 Hz, J = 10.8 Hz), 3.68-3.64(1H, m), 3.13-3.08(1H, m), 2.82-2.71(3H, m), 2.26(3H, s). (V-12) 0 10.11(1H, bs), 8.74(1H, s), 8.57(1H, s), 8.22-8.19(1H, m), 7.96(1H, m), 7.80(1H, d, J = 9.0 Hz), 7.69- 7.66(1H, m), 7.51-7.44(1H, m), 7.35-7.26(3H, m), 7.21- 7.16(1H, m), 5.27(2H, s), 4.20-4.09(2H, m), 3.79(1H, dd, J = 3.0 Hz, J = 10.8 Hz), 3.68-3.64(1H, m), 3.25- 3.18(1H, m), 3.13-3.05(1H, m), 2.82-2.71(2H, m), 2.26(3H, s). (V-13) 10.09(1H, brs), 8.74(1H, s), 8.59(1H, s), 8.21(1H, d, 9.0 Hz), 7.96(1H, s), 7.79(1H, d, J = 9.0 Hz) 7.68(1H, d, J = 9.0 Hz), 7.49-7.44(1H, m), 7.34-7.22(3H, m), 7.19-7.15(1H, m), 5.27(2H, s), 4.11(2H, d, J = 4.8 Hz), 2.95-2.50(6H, m), 2.34-2.26(4H, m)

(247) TABLE-US-00011 TABLE 11 Compound No. R .sup.1H-NMR(d.sub.6-DMSO) (V-14) (E/Z mixture) 10.09(1H, s, major), 10.00(1H, s, minor), 8.74(1H, s, major), 8.59(1H, s), 8.22(1H, d, J = 9 Hz, major), 7.94-8.02(1H, m), 7.64-7.82(2H, m), 7.44-7.52(1H, m), 7.16-7.36(4H, m), 5.27(2H, s), 4.32-4.43(2H, m), 3.56-3.62(4H, m), 2.66-2.74(2H, m), 2.34(3H, s, minor), 2.25(3H, s, major) (V-15) 10.08(1H, s), 8.74(1H, s), 8.58(1H, s), 8.22(1H, d, J = 8.4 Hz), 7.96(1H, brs), 7.80(1H, d, J = 8.4 Hz), 7.68(1H, d, J = 9.6 Hz), 7.43-7.52(1H, m), 7.14-7.36(4H, m), 5.27(2H, s), 4.37(2H, t, J = 6.0 Hz), 2.80(2H, t, J = 6.0 Hz), 2.25(3H, s), 1.69(4H, brs), 1.24(4H, brs) (V-16) 10.10(1H, s), 8.76(1H, s), 8.60(1H, s), 8.25(1H, d, J = 8.7 Hz), 7.96(1H, brs), 7.82(1H, d, J = 9.0 Hz), 7.69(1H, d, J = 9.0 Hz), 7.43-7.52(1H, m), 7.14-7.36(4H, m), 5.28(2H, s), 4.43(2H, brs), 2.98(2H, brs), 2.54(3H, s), 2.27(3H, brs), 1.60(1H, s) (V-17) 10.10(1H, s), 8.77(1H, s), 8.60(1H, s), 8.25(1H, d, J = 8.7 Hz), 7.95(1H, brs), 7.82(1H, d, J = 9.6 Hz), 7.69(1H, d, J = 9.3 Hz), 7.43-7.52(1H, m), 7.14-7.36(4H, m), 5.28(2H, s), 4.45(2H, brs), 2.91(2H, brs), 2.27(3H, s), 2.00(2H, brs), 1.73(2H, brs), 1.60(1H, brs), 1.23(7H, brs)

Example 9

Synthesis of Compound 8

(248) ##STR00056##

(249) To 4-iodoanisle (7)(2.36 g), Pd.sub.2 (dba).sub.3 (69.9 mg, 0.0075 equivalent), Xantphos (173.0 mg, 0.03 equivalent), CuCl (61.2 mg, 0.06 equivalent), Compound (4)(152.0 mg) obtained in Example 4, and N,N-dimethylglycine (42.3 mg, 0.04 equivalent) were added tetrahydrofuran (2.3 mL), N-methylmorpholine (4.05 g, 4 equivalents) and dimethylsulfoxide (1.2 mL) successively under nitrogen atmosphere. The slurry was stirred at about 25 C. under carbon monoxide atmosphere, and about 0.50 mol/L of the solution in which propyne gas (2.3 equivalents) was preliminarily dissolved in tetrahydrofuran was added to the slurry over about 2 hours and the resulting slurry was stirred for about 2 hours at the same temperature. Then the slurry was warmed up to about 40 C. and stirred for additional 5 hours. After completion of the reaction, the atmosphere in the vessel was replaced with nitrogen gas and the precipitated solids were collected by filtration and the filtrate was concentrated. The residue was purified by silicagel column chromatography (hexane:ethylacetate=80:20 and 90:10) to give 1.22 g of Compound 8 as colorless solids, isolated yield 70%.

(250) .sup.1H-NMR (CDCl.sub.3) : 8.11 (2H, d, J=8.9 Hz), 6.94 (2H, d, J=8.9 Hz), 3.88 (3H, s), 2.14 (3H, s)

(251) .sup.13C-NMR (CDCl.sub.3) : 176.91, 164.33, 131.94, 130.28, 113.73, 91.49, 79.00, 55.55, 4.27

Example 10

Synthesis of Compound 10

(252) ##STR00057##

(253) To 4-iodobenzotrifluoride (9)(2.73 g), Pd.sub.2 (dba).sub.3 (71.7 mg, 0.0075 equivalent), Xantphos (175.0 mg, 0.03 equivalent), CuCl (59.5 mg, 0.06 equivalent), Compound (4)(152.0 mg) obtained in Example 4, and N,N-dimethylglycine (43.1 mg, 0.04 equivalent) were added tetrahydrofuran (2.7 mL), N-methylmorpholine (4.05 g, 4 equivalents) and dimethylsulfoxide (1.4 mL) successively under nitrogen atmosphere. The slurry was stirred at about 25 C. under carbon monoxide atmosphere, and about 0.50 mol/L of the solution in which propyne gas (2.3 equivalents) was preliminarily dissolved in tetrahydrofuran was added to the slurry over about 2 hours and the resulting slurry was stirred for about 2 hours at the same temperature. Then the slurry was warmed up to about 40 C. and stirred for additional 5 hours. After completion of the reaction, the atmosphere in the vessel was replaced with nitrogen gas and the precipitated solids were collected by filtration and the filtrate was concentrated. The residue was purified by silicagel column chromatography (hexane:ethylacetate=80:20 and 90:10) to give 1.30 g of Compound 10 as brown solids, isolated yield 61%.

(254) .sup.1H-NMR (CDCl.sub.3) : 8.25 (2H, d, J=8.1 Hz), 7.75 (2H, d, J=8.1 Hz), 2.20 (3H, s)

(255) .sup.13C-NMR (CDCl.sub.3) : 176.85, 139.32, 135.54, 135.22, 134.89, 134.57, 129.80, 127.62, 125.62, 125.58, 125.54, 125.51, 124.91, 122.20, 119.48, 93.95, 78.76, 4.35

Example 11

Synthesis of Compound 12

(256) ##STR00058##

(257) To 2-iodothiophene (11)(2.10 g), Pd.sub.2 (dba).sub.3 (138.0 mg, 0.015 equivalent), Xantphos (347.0 mg, 0.06 equivalent), CuCl (120.0 mg, 0.12 equivalent), Compound (4)(155.0 mg) obtained in Example 4, and N,N-dimethylglycine (83.5 mg, 0.08 equivalent) were added tetrahydrofuran (2.1 mL), N-methylmorpholine (4.05 g, 4 equivalents) and dimethylsulfoxide (1.1 mL) successively under nitrogen atmosphere. The slurry was stirred at about 25 C. under carbon monoxide atmosphere, and about 0.98 mol/L of the solution in which propyne gas (2.3 equivalents) was preliminarily dissolved in tetrahydrofuran was added to the slurry over about 1 hour and the resulting slurry was stirred for about 3 hours at the same temperature. Then the slurry was warmed up to about 40 C. and stirred for additional three and a half hours. After completion of the reaction, the atmosphere in the vessel was replaced with nitrogen gas and the precipitated solids were collected by filtration and the filtrate was concentrated. The residue was purified by silicagel column chromatography (n-hexane:ethylacetate=90:10) to give 1.31 g of Compound 12 as yellow oil, isolated yield 87%.

(258) .sup.1H-NMR (CDCl.sub.3) : 7.90 (1H, dd, J=3.8, 1.2 Hz), 7.68 (1H, dd, J=4.9, 1.2 Hz), 7.14 (1H, dd, 4.9, 1.2 Hz). 2.13 (3H, s)

(259) .sup.13C-NMR (CDCl.sub.3) : 170.02, 144.93, 135.01, 134.88, 128.18, 90.98, 78.60, 4.22

Test Example 1 Reaction Heat Flow in Sonogashira-Carbonylation Reaction

(260) ##STR00059##

(261) In the process described in the above scheme, the reaction heat flow of Sonogashira-carbonylation reaction in the absence of the crystalline form of the complex comprising N-methylmorpholine, hydroiodic acid and dimethylsulfoxide is described as FIG. 5.

(262) In the process described in the above scheme, the reaction heat flow of Sonogashira-carbonylation reaction in the presence of the crystalline form of the complex comprising N-methylmorpholine, hydroiodic acid and dimethylsulfoxide is described as FIG. 6.

(263) From FIG. 5, in the absence of the said crystalline form, it was found that the reaction heat flow was exponentially increased as the complex comprising N-methylmorpholine, hydroiodic acid and dimethylsulfoxide was generated as by-product. Also, it was found that the ratio (%) to total heat was not pursued propyne addition. Therefore, the large scale synthesis is dangerous because the heat flow is not able to be controlled.

(264) In contrast, as is apparent from FIG. 6, in the reaction system in which small amount of the said crystalline form was added before the reaction was started; (in the presence of the said crystalline form), it was found that the phenomenon that the heat flow was exponentially increased was not observed. Also, it was found that the ratio (%) to total heat was nearly pursued propyne addition. Even in the large scale synthesis, the heat flow is able to be controlled, so that the industrial production can be carried out.

(265) Therefore, the desired product is able to be obtained more safely in the presence of the said crystalline form by Sonogashira-carbonylation reaction of the present invention, and it may be said that the present invention is industrially excellent process.

Test Example 2 Solubility Test of Methanesulfonate of Compound Represented by Formula (II)

(266) Crystalline form of methanesulfonate of Compound represented by Formula (II) and crystalline form of free form of Compound represented by Formula (II) were suspended in tetrahydrofuran or acetonitrile, respectively. The slurries were stirred at 20 C. to 25 C. for over two hours, and then the concentration in each supernatant solution was measured (HPLC method A). The HPLC results of the concentration in each supernatant solution are indicated as Table 12.

(267) TABLE-US-00012 TABLE 12 Temperature MsOH salt of Free form of Solvent ( C.) Formula (II) Formula (II) Tetrahydrofuran 20 to 25 0.05% 3.6% Acetonitrile 20 to 25 0.05% 0.3% Conditions in 0 3.1% 15.7% Example 2 (DMSO/ NMM/THF/MeCN)

(268) As indicated in Table 12, it was found that the solubility of the crystalline form of methanesulfonate of Compound represented by Formula (II) in each solvent was low compared to that of the crystalline form of free form of Compound represented by Formula (II). Here, it means that the crystalline form that has low solubility is not easily dissolved into a solvent which is used to wash the crystalline form.

(269) Moreover, the concentration of each crystalline form being dissolved into the solution at 0 C. in Step 1 (Step to obtain the crystalline form of methanesulfonate) and Step 2 (Step to obtain the crystalline form of free form) in Example 2 was measured by HPLC method A and compared (Table 12). It was found that only 3.1% of the crystalline form of methanesulfonate of Compound represented by (II) was dissolved into the solution, whereas 15.7% of the crystalline form of free form of Compound represented by (II) was dissolved into the solution.

(270) Therefore, the crystalline form of methanesulfonate of Compound represented by Formula (II) is not easy dissolved into the solvent, because it has low solubility to the solvent, and it may be said that it is industrially excellent crystalline form, because the amount of loss becomes small in industrial process.

Test Example 3 Palladium Black Precipitate Inhibition Test

(271) In Sonogashira-carbonylation reaction as shown in the following scheme, the result of yield of the desired product and the result of precipitate of palladium black are indicated in Table 13.

(272) ##STR00060##

(273) TABLE-US-00013 TABLE 13 Yield of Precipitate of the desired palladium black** product after After 8 After 22 Additive 22 hours* hours hours None 94% +++ N,N-Dimethylglycine 93% Picolinic acid 91% L-Proline 93% ++ 2-Hydroxy-N,N-diethyl-benzamide 95% + ++ Ethylene glycol 93% Ethyl 2-oxocyclohexanecarboxylate 93% ++ 2-Acetylcyclohexanone 92% ++ 2-Hydroxybenzoic acid 91% ++ 2-Furoic acid 93% ++ Diethyl malonate 92% ++ N,N-Dimethylethylenediamine 94% + Acetic acid 94% ++ Copper(I) 2-thiophenecarboxylate 88% + (Reference Example) 1H-Pyrrole-2-carboxylic acid 94% + +++ N,N-Dimethylethanolamine 94% + +++ Dipivaloylmethane 92% + +++ (*Area percentage of HPLC; **Evaluated by visual judgment non-precipitate, + minimal precipitate, ++ thinly precipitated on the whole inner wall of flask, +++: thickly precipitated on the whole inner wall of flask; Additives judged as ++ after 22 hours can be considered within practical use.

(274) As indicated in Table 13, it was found that N,N-Dimethylglycine, Picolinic acid, L-Proline, 2-Hydroxy-N,N-diethyl-benzamide, Ethylene glycol, Ethyl 2-oxocyclohexanecarboxylate, 2-Acetylcyclohexanone, 2-Hydroxybenzoic acid, 2-Furoic acid, Diethyl malonate, N,N-Dimethylethylenediamine, Acetic acid and Copper(I) 2-thiophenecarboxylate can inhibit the precipitate of palladium black.

INDUSTRIAL APPLICABILITY

(275) The present invention is useful as process for producing the compound having a dual inhibitory activity of both EGF receptor tyrosine kinase and HER2 tyrosine kinase, and the intermediate thereof.