Process for producing alkynylketone derivative

Patent metadata

Field	Value
Publication number	US-9951051-B2
Application number	US-201515314181-A
Country	US
Kind code	B2
Filing date	May 28, 2015
Priority date	May 29, 2014
Publication date	Apr 24, 2018
Grant date	Apr 24, 2018

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.

First claim

The invention claimed is:

1. A process for producing a compound represented by Formula (II):

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):

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

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 2 (dba) 3 , PdCl 2 dppf, PdCl 2 (PPh 3 ) 2 , Pd(OAc) 2 , Pd(PPh 3 ) 4 , Pd/C, PdCl 2 , Pd-PEPPSI™-IPr, Bis[cinnamyl palladium Cl], PdCl 2 (Xantphos) or Pd(OH) 2 .

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

wherein R 1 is a hydrogen atom, halogen, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy or a group represented by formula: —Y—R y , wherein —Y— is —O—, —S—, —SO 2 —, or alkylene which may be intervened with —O—, —S— or —N(R z )—; R y is substituted or unsubstituted aromatic carbocyclyl or substituted or unsubstituted aromatic heterocyclyl; and R 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 2 and R 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 1 is a group represented by formula: —Y—R y , wherein —Y— is alkylene which may be intervened with —O—; and R 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 2 is substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy or halogen; and
R 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″):

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

11. The crystalline form according to claim 10 , wherein diffraction angle 2θ of the powder X-Ray diffraction analysis are 5.6°±0.2°, 9.8°±0.2°, 17.9°±0.2°, 24.4°±0.2°, and 26.4°±0.2°.

12. The crystalline form according to claim 10 , wherein diffraction angle 2θ of the powder X-Ray diffraction analysis are 5.6°±0.2°, 8.3°±0.2°, 9.8°±0.2°, 13.7°±0.2°, 17.0°±0.2°, 17.9°±0.2°, 21.3°±0.2°, 24.4°±0.2°, 26.0°±0.2°, and 26.4°±0.2°.

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 1

Space Group
P2 1 /c

a (Å)
7.3750(2)

b (Å)
11.8395(3)

c (Å)
14.2325(4)

α (°)
90

β (°)
107.764(2)

γ (°)
90

V (Å 3 )
1183.47(5)

Z
4

Density(calculated value) (g/cm 3 )
1.724

Measured temperature (° C.)
−173.

16. The crystalline form of the complex according to claim 14 , wherein diffraction angle 2θ of the powder X-Ray diffraction analysis are 12.6°±0.2°, 16.9°±0.2°, 17.5°±0.2°, 26.3°±0.2°, and 28.9°±0.2°.

17. The crystalline form of the complex according to claim 14 , wherein diffra

Assignees

• Shionogi & Co

Inventors

• Tadano Genta
• Ikarashi Fumiya
• Okamoto Kazuya
• Maki Toshikatsu
• Hagihara Motoyuki

Classifications

• C07C49/794

  having unsaturation outside an aromatic ring · CPC title

• C07D295/03

  with the ring nitrogen atoms directly attached to acyclic carbon atoms · CPC title

• C07D239/94

  Nitrogen atoms · CPC title

• C07B61/00

  Other general methods · CPC title

• C07D403/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title