# US 12,110,271 B2 · Manufacturing method for 4-methoxypyrrole derivatives

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 12,110,271 B2
- Document ID: US12110271B2
- Status: Granted
- Kind: B2
- Application number: 17/273,390
- Filed: 2019-09-19
- Published: 2021-07-22
- Granted: 2024-10-08
- Earliest claimed: 2018-09-19
- Assignees: Daewoong Pharmaceutical Co., Ltd.
- Applicants: Daewoong Pharmaceutical Co., Ltd.
- Inventors: Jeong-Taek Shin; Jeong-Hyun Son; Deok Ki Eom
- Web page: https://patentgrep.com/patent/US12110271B2

## CPC

- C07D 207/48: Sulfur atoms
- A61K 31/40: having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present disclosure relates to a manufacturing method for 4-methoxypyrrole derivatives. The embodiment of the present disclosure is useful for industrial mass production of 4-methoxypyrrole derivatives, because the process efficiency and yield are improved, and the use of hazardous reagents and environmental polluting reagents is avoided.

## Claims

### Claim 1

A method for manufacturing 4-methoxypyrrole derivatives, comprising:
1) a step of preparing a compound represented by the following Chemical Formula 4 by reacting a compound represented by the following Chemical Formula 2 with a compound represented by the following Chemical Formula 3;
2) a step of preparing a compound represented by the following Chemical Formula 5 by reacting a compound represented by the following Chemical Formula 4 with sodium borohydride;
3) a step of preparing a compound represented by the following Chemical Formula 6 by reacting a compound represented by the following Chemical Formula 5 with an oxidant; and
4) a step of reacting a compound represented by the following Chemical Formula 6 with methylamine to produce an intermediate, and converting the intermediate to a compound represented by the following Chemical Formula 1 by adding a reductant:

### Claim 2 (depends on 1)

The method of claim 1, wherein the step 1 is performed in the presence of a base and 4-(dimethylamino)-pyridine.

### Claim 3 (depends on 2)

The method of claim 2, wherein the base of the step 1 is N,N-diisopropylethylamine, triethylamine, diisopropylamine, diisopropylethylamine, potassium carbonate, potassium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methylate, potassium butyrate, cesium carbonate, or a mixture of two or more thereof.

### Claim 4 (depends on 1)

The method of claim 1, wherein a molar ratio of the compound represented by the Chemical Formula 2 and the compound represented by the Chemical Formula 3 is 10:1 to 1:10 in the step 1.

### Claim 5 (depends on 1)

The method of claim 1, wherein a reaction solvent of the step 1 is acetonitrile, tetrahydrofuran, methylene chloride, methanol, ethanol, propanol, iso-propanol, butanol, tert-butanol, or a mixture of two or more thereof.

### Claim 6 (depends on 1)

The method of claim 1, wherein a reaction temperature in the step 1 is 10° C. to 35° C.

### Claim 7 (depends on 1)

The method of claim 1, wherein the step 2 is performed in the presence of zinc chloride and dimethylaniline.

### Claim 8 (depends on 7)

The method of claim 7, wherein the zinc chloride and the dimethylaniline are mixed to satisfy a molar ratio of the compound represented by the Chemical Formula 4 and the zinc chloride of 10:1 to 1:10, and a molar ratio of the compound represented by the Chemical Formula 4 and the dimethylaniline of 10:1 to 1:10 at the same time, and then used in the reaction of step 2.

### Claim 9 (depends on 1)

The method of claim 1, wherein a reaction solvent of the step 2 is dimethylacetamide, tetrahydrofuran, dimethyl sulfoxide, toluene, methanol, ethanol, dichloromethane, or a mixture of two or more thereof.

### Claim 10 (depends on 1)

The method of claim 1, wherein a reaction temperature in the step 2 is −15° C. to 80° C.

### Claim 11 (depends on 1)

The method of claim 1, wherein the oxidation of the step 3 is performed in the presence of
1) an oxidant selected from (diacetoxyiodo)benzene, iodine, iodobenzene dichloride, iodosylbenzene, and trichloroisocyanuric acid;
2) a catalyst selected from (2,2,6,6-tetramethylpiperidin-1-yl)oxyl, 4-acetamido-2,2,6,6-tetramethylpiperidine 1-oxyl, 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl, 4-methacryloyloxy-2,2,6,6-tetramethylpiperidine-1-oxyl, 4-oxo-2,2,6,6-tetramethyl-1-piperidinyloxy, 4-amino-2,2,6,6-tetramethylpiperidin-1-oxyl, 4-carboxy-2,2,6,6-tetramethylpiperidine 1-oxyl, 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl benzoate, 4-(2-iodoacetamido)-2,2,6,6-tetramethyl-1-piperidinyloxy, 4-maleimido-2,2,6,6-tetramethyl-1-piperidinyloxy, 4-isothiocyanato-2,2,6,6-tetramethylpiperidine 1-oxyl, 4-methoxy-2,2,6,6-tetramethyl-1-piperidinyloxy, and 4-phosphonooxy-2,2,6,6-tetramethyl-1-piperidinyloxy; or
a mixture of one oxidant selected from 1) and one catalyst selected from 2).

### Claim 12 (depends on 11)

The method of claim 11,
wherein the oxidation of the step 3 is performed in the presence of a mixture of the (diacetoxyiodo)benzene and the (2,2,6,6-tetramethylpiperidin-1-yl)oxyl, and
the (diacetoxyiodo)benzene and the (2,2,6,6-tetramethylpiperidin-1-yl)oxyl are mixed to satisfy a molar ratio of the compound represented by the Chemical Formula 5 and the (diacetoxyiodo)benzene of 10:1 to 1:10, and a molar ratio of the compound represented by the Chemical Formula 5 and the (2,2,6,6-tetramethylpiperidin-1-yl)oxyl of 10:1 to 1:10 at the same time.

### Claim 13 (depends on 1)

The method of claim 1, wherein a reaction solvent of the step 3 is dichloromethane, dichloroethane, acetonitrile, ethyl acetate, methanol, toluene, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, or a mixture of two or more thereof.

### Claim 14 (depends on 1)

The method of claim 1, wherein a reaction temperature in the step 3 is 10° C. to 40° C.

### Claim 15 (depends on 1)

The method of claim 1, wherein a reaction solvent of the step 4 is methanol, ethanol, isopropanol, dichloromethane, dichloroethane, tetrahydrofuran, ethyl acetate, dimethyl ether, acetonitrile, or a mixture of two or more thereof.

### Claim 16 (depends on 1)

The method of claim 1, wherein the reaction of the compound represented by the Chemical Formula 6 and the methylamine is performed at a reaction temperature of 10° ° C. to 30° ° C. in the step 4.

### Claim 17 (depends on 1)

The method of claim 1, wherein the reductant of the step 4 is sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, or a mixture of two or more thereof.

### Claim 18 (depends on 1)

The method of claim 1, wherein the reaction of the reductant and the intermediate is performed at a reaction temperature of −5° C. to 10° C. in the step 4.

### Claim 19 (depends on 1)

The method of claim 1, wherein a molar ratio of the compound represented by the Chemical Formula 6 and the methylamine is 10:1 to 1:10, and a molar ratio of the compound represented by the Chemical Formula 6 and the reductant is 10:1 to 1:10 in the step 4.

### Claim 20 (depends on 1)

The method of claim 1, further comprising a step preparing an acidic salt represented by the following Chemical Formula 1-1 by adding an acid to the compound represented by the Chemical Formula 1, after the step 4:

### Claim 21 (depends on 20)

The method of claim 20, wherein the step after step 4 comprises a step of crystallizing the acidic salt represented by the Chemical Formula 1-1 by supplying an organic solvent to the compound represented by the Chemical Formula 1 and then supplying an acid or a mixed solution thereof with an organic solvent.

### Claim 22 (depends on 21)

The method of claim 21, wherein the crystallization temperature is −15° C. to 20° C.