Method for producing pyrrole compound

Patent metadata

Field	Value
Publication number	US-11066362-B2
Application number	US-202016739707-A
Country	US
Kind code	B2
Filing date	Jan 10, 2020
Priority date	Jun 30, 2015
Publication date	Jul 20, 2021
Grant date	Jul 20, 2021

Abstract

The present invention provides a production method of a 3-cyanopyrrole compound possibly useful as an intermediate for pharmaceutical products. A production method of compound (II) including subjecting compound (I) to a reduction reaction, in which the aforementioned reduction reaction is continuous hydrogenation reaction in a fixed bed reactor filled with a supported metal catalyst. A production method of compound (III) including subjecting compound (I) to a reduction reaction followed by a cyclization reaction, in which the aforementioned reduction reaction is continuous hydrogenation reaction in a fixed bed reactor filled with a supported metal catalyst.

First claim

The invention claimed is:

1. A method for producing a compound represented by the formula

wherein R 1 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, R 2 is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, a chlorine atom or a fluorine atom, R 3 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and R 4 is an alkyl group, or a salt thereof, comprising
(1) subjecting a compound represented by the formula

wherein each symbol is as defined above, or a salt thereof to a reduction reaction, and then to a cyclization reaction to give a compound represented by the formula

wherein each symbol is as defined above, or a salt thereof, wherein the reduction reaction is a continuous hydrogenation in a fixed bed reactor filled with a supported metal catalyst,
(2) subjecting the obtained compound to a reduction reaction, and then to hydrolysis to give a compound represented by the formula

wherein each symbol is as defined above, or a salt thereof,
(3) reacting the obtained compound with a compound represented by the formula
R 3 —SO 2 —X  (V)

wherein R 3 is as defined above, and X is a leaving group, or a salt thereof to give a compound represented by the formula

wherein each symbol is as defined above, or a salt thereof, and
(4) reacting the obtained compound with a compound represented by the formula
R 4 —NH 2   (VII)

wherein R 4 is as defined above, or a salt thereof.

2. The production method according to claim 1 wherein the supported metal catalyst comprises a metal selected from the group consisting of iron (Fe), nickel (Ni), palladium (Pd), platinum (Pt), rhodium (Rh), iridium (Ir), ruthenium (Ru), cobalt (Co), and a combination thereof.

3. The production method according to claim 1 wherein the supported metal catalyst comprises palladium (Pd) as a metal.

4. The production method according to claim 1 wherein the supported metal catalyst has a metal content of 0.1-15 wt % relative to the whole weight of the supported metal catalyst.

5. The production method according to claim 1 wherein the metal of the supported metal catalyst is supported by a carrier selected from the group consisting of carbon, alumina, silica, silica-alumina, zirconia, titania, zeolite, calcium carbonate, calcium carbonate-lead, molecular sieve and polymer.

6. The production method according to claim 1 wherein the metal of the supported metal catalyst is supported by alumina as a carrier.

7. The production method according to claim 1 wherein the hydrogenation is performed in a solvent containing an acid.

8. The production method according to claim 7 wherein the acid is acetic acid.

9. The production method according to claim 7 wherein the acid is mixed in a proportion of 0.1-50 molar equivalents relative to the compound represented by the formula (I) or a salt thereof.

10. The production method according to claim 7 wherein the solvent is selected from tetrahydrofuran and acetonitrile.

11. The production method according to claim 1 wherein the hydrogenation is performed at 40-100° C.

12. The production method according to claim 1 wherein the hydrogenation is performed under a pressure of 0.01-1 MPa.

13. The production method according to claim 1 wherein the compound represented by the formula (I) or a salt thereof is supplied into the fixed bed reactor at WHSV (weight hourly space velocity) of 0.01-1 h −1 .

14. The production method according to claim 1 wherein the compound represented by the formula (I) or a salt thereof is supplied into the fixed bed reactor at a concentration of 1-20 wt % in a solution.

15. The production method according to claim 1 wherein the fixed bed reactor is a trickle bed reactor.

16. A method for producing a compound represented by the formula

wherein R 1 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, R 2 is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, a chlorine atom or a fluorine atom, R 3 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and R 4 is an alkyl group, or a salt thereof, comprising
(1) subjecting a compound represented by the formula

wherein each symbol is as defined above, or a salt thereof to a reduction reaction, and then to a cyclization reaction to give a compound represented by the formula

wherein each symbol is as defined above, or a salt thereof, wherein the reduction reaction is a continuous hydrogenation in a fixed bed reactor filled with a supported metal catalyst (A),
(2) subjecting the obtained compound to a reduction reaction and then to hydrolysis to give a compound represented by the formula

wherein each symbol is as defined above, or a salt thereof, wherein the reduction reaction is a continuous hydrogenation in a fixed bed reactor filled with a supported metal catalyst (B),
(3) reacting the obtained compound with a compound represented by the formula
R 3 —SO 2 —X  (V)

wherein R 3 is as defined above, and X is a leaving group, or a salt thereof to give a compound represented by the formula

wherein each symbol is as defined above, or a salt thereof, and
(4) reacting the obtained compound with a compound represented by the formula
R 4 —NH 2   (VII)

wherein R 4 is as defined above, or a salt thereof.

Assignees

• Takeda Pharmaceuticals Co

Inventors

• Ouchi Takashi
• Goh Giho
• Kim Sunmi
• Choi Jinsoon
• Park Hunsoo

Classifications

• C07D401/12

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

• C07D207/34 Primary

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms · CPC title

• C07C253/30

  by reactions not involving the formation of cyano groups · CPC title

• C07C255/42

  the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being further bound to other hetero atoms · CPC title

• B01J23/44

  Palladium · CPC title