RU2021131198A

RU2021131198A - METHOD FOR MANUFACTURING (2S,3S,4S,5R,6S)-3,4,5-TRIHYDROXY-6-(((4AR,10AR)-7-HYDROXY-1-PROPYL-1,2,3,4,4А, 5,10,10A-OCTAHYDROBENZO[G]QUINOLIN-6-YL)OXY)TETRAHYDRO-2H-PYRAN-2-CARBOXY ACID AND INTERMEDIATES FOR ITS OBTAINING

Info

Publication number: RU2021131198A
Application number: RU2021131198A
Authority: RU
Inventors: Мартин Джухл; Миккель Фог ЯКОБСЕН; Лисбет Кваерно
Original assignee: Х. Лундбекк А/С
Priority date: 2019-05-20
Filing date: 2020-05-19
Publication date: 2023-06-20

Claims

1. A method for producing a compound (Id) with the following formula,

or a pharmaceutically acceptable salt thereof from compound (I) with the following formula,

where said method includes the following step

2) carrying out the reaction of compound (A2) with (2S,3S,4S,5R,6R)-2-(methoxycarbonyl)-6-(2,2,2-trichloro-1-iminoethoxy)tetrahydro-2H-pyran-3, 4,5-triyl triacetate to give compound (A3) according to the following reaction scheme:

where the specified reaction is carried out in an aprotic solvent in the presence of a Lewis acid.

2. A method for manufacturing the following compound (A3), comprising the following step

3. The method according to any one of paragraphs. 1, 2, wherein said aprotic solvent is dichloromethane or benzotrifluoride and said Lewis acid is boron trifluoride diethyl etherate.

4. Compound of the following formula (A3),

or its salt.

5. Use of a compound according to claim 4 in a process for the manufacture of a compound of formula (Id) or a pharmaceutically acceptable salt thereof.

6. A method for producing a compound (Id) or a pharmaceutically acceptable salt thereof with the following formula,

from compound (I) with the following formula,

where said method includes the following step

3) removing the protecting group from compound (A3) by contacting compound (A3) with a nucleophilic reagent to obtain compound (Id) or a pharmaceutically acceptable salt thereof, according to the following reaction scheme:

7. The method according to any one of paragraphs. 1 and 3, where step 2) is followed by the next step

8. The method according to any one of paragraphs. 6, 7, where the nucleophilic reagent used in step 3) is selected from potassium hydroxide and sodium hydroxide.

9. The method according to any one of paragraphs. 6-8 wherein said deprotection is carried out in a mixture of methanol and water.

10. The method according to any one of paragraphs. 1-3 and 6-9, where the compound (A2) was obtained using the following step

1) carrying out the reaction of the compound (I) or its salt with triisopropylsilyl chloride to obtain the compound (A2) in accordance with the following reaction scheme:

where the reaction is carried out in an aprotic solvent in the presence of a base.

11. The method of claim 10 wherein said aprotic solvent is dichloromethane and said base is N,N-diisopropylethylamine (DIPEA).

12. The method according to p. 11, where the specified N,N-diisopropylethylamine (DIPEA) is present in an amount of 4-5 eq. with respect to compound (I).

13. The method of obtaining the compound (Id) or its pharmaceutically acceptable salt from the compound (I);

where said method includes

stage 2) specified in any one of paragraphs. 1 and 3; followed by

stage 3) specified in any one of paragraphs. 7-9;

where the connection A2 used in stage 2) was obtained using stage 1) specified in any of paragraphs. 10-12.

14. Compound (Id) or a pharmaceutically acceptable salt thereof with the following formula,

obtained using the method according to any one of paragraphs. 1, 3, 6 and 8-13.

15. The method according to any one of paragraphs. 1 and 3, 6, 8-9 and 10-12, wherein the method comprises the additional step of formulating compound (Id) or a pharmaceutically acceptable salt thereof into a solid dosage form for oral administration.