Intermediate of relugolian and preparation method and application thereof

Abstract

The invention discloses brand-new intermediates (including compounds shown in formulas B, C, D and E) of relugolian. The brand-new intermediates can be used for preparing relugolian and salts, derivatives or analogues of relugolian. The invention also discloses a preparation method of the rugolian, the preparation method is simple, the raw materials are easy to obtain, the content of a product uret byproduct is less than 0.10%, the purification cost of a crude product can be greatly reduced, and large-scale production is facilitated.

Description

technical field

[0001] The invention belongs to the technical field of chemical drug synthesis, and relates to an intermediate of relugoli and a preparation method thereof. Background technique

[0002] Relugoli is a gonadotropin-releasing hormone antagonist (GnRH) developed by Takeda Corporation of Japan. It was launched in Japan in 2018 and is used for bleeding and pain caused by uterine fibroids. Phase III trials for endometriosis-related pain and prostate cancer are ongoing.

[0003] Currently, there are only two synthetic routes for relugolis published. J.Med.Chem.2011,54,4998–5012, the disclosed synthetic route is as follows:

[0004]

[0005] This route is a compound route, and the yield in the last step is only 44%, which is low and has no industrial development value.

[0006] CN104703992B discloses another synthetic route, the synthetic route is as follows:

[0007]

[0008] In the cyclization step of this route, foamy solids are arranged in the reaction ...

Examples

Embodiment 1-2

[0110] Embodiment 1-2: formula B (R 1 is ethyl, R 2 Is the preparation of intermediate shown in isobutyl)

[0111]

Embodiment 1

[0113] Weigh 9.75g of compound formula A and add it to a 250mL single-necked bottle, then add 93mL of ethanol, and dropwise add 20mL of aqueous solution containing 1.41g of KOH under stirring. Adjust the pH to 2 with hydrochloric acid, concentrate under reduced pressure to remove most of the ethanol, add 93mL EA and 30mL water, extract and separate the liquid, add 46mL EA to the aqueous phase to extract once, combine the organic phase, add 93mL saturated saline to wash twice, anhydrous magnesium sulfate Dry, filter and concentrate to obtain 8.02g of white solid, namely compound formula B, with a yield of 95.23% and a purity of 97.88%;

[0114] The NMR data are as follows: 1 HNMR (DCCl 3 400MHz) δ: 0.86-0.88 (6H, m), 1.24-1.28 (1H, m), 1.93 (1H, s), 2.43 (3H, s), 3.97-3.98 (2H, d), 5.05 (2H, s ), 6.83-6.90 (2H, m), 7.23-7.30 (2H, m), 7.50-7.53 (1H, m), 8.25-8.28 (2H, m).

Embodiment 2

[0116] Weigh 9.75g of compound formula A into a 250mL single-necked bottle, then add 93mL of methanol, dropwise add 20mL of aqueous solution containing 1.35g of lithium hydroxide under stirring, after the addition is complete, heat up to 30°C, react for 10 hours, cool down to room temperature, drop Add 2N hydrochloric acid to adjust the pH to 2, concentrate under reduced pressure to remove most of the methanol, add 93mL EA and 30mL water, extract and separate the liquid, add 46mL EA to the water phase to extract once, combine the organic phase, add 93mL saturated saline to wash twice, dry Dried over magnesium sulfate, filtered and concentrated to obtain 8.11 g of white solid, namely compound formula B, with a yield of 96.32% and a purity of 96.79%.

technical field

[0001] The invention belongs to the technical field of chemical drug synthesis, and relates to an intermediate of relugoli and a preparation method thereof. Background technique

[0002] Relugoli is a gonadotropin-releasing hormone antagonist (GnRH) developed by Takeda Corporation of Japan. It was launched in Japan in 2018 and is used for bleeding and pain caused by uterine fibroids. Phase III trials for endometriosis-related pain and prostate cancer are ongoing.

[0003] Currently, there are only two synthetic routes for relugolis published. J.Med.Chem.2011,54,4998–5012, the disclosed synthetic route is as follows:

[0004]

[0005] This route is a compound route, and the yield in the last step is only 44%, which is low and has no industrial development value.

[0006] CN104703992B discloses another synthetic route, the synthetic route is as follows:

[0007]

[0008] In the cyclization step of this route, foamy solids are arranged in the reaction ...

Examples

Embodiment 1-2

[0110] Embodiment 1-2: formula B (R 1 is ethyl, R 2 Is the preparation of intermediate shown in isobutyl)

[0111]

Embodiment 1

[0113] Weigh 9.75g of compound formula A and add it to a 250mL single-necked bottle, then add 93mL of ethanol, and dropwise add 20mL of aqueous solution containing 1.41g of KOH under stirring. Adjust the pH to 2 with hydrochloric acid, concentrate under reduced pressure to remove most of the ethanol, add 93mL EA and 30mL water, extract and separate the liquid, add 46mL EA to the aqueous phase to extract once, combine the organic phase, add 93mL saturated saline to wash twice, anhydrous magnesium sulfate Dry, filter and concentrate to obtain 8.02g of white solid, namely compound formula B, with a yield of 95.23% and a purity of 97.88%;

[0114] The NMR data are as follows: 1 HNMR (DCCl 3 400MHz) δ: 0.86-0.88 (6H, m), 1.24-1.28 (1H, m), 1.93 (1H, s), 2.43 (3H, s), 3.97-3.98 (2H, d), 5.05 (2H, s ), 6.83-6.90 (2H, m), 7.23-7.30 (2H, m), 7.50-7.53 (1H, m), 8.25-8.28 (2H, m).

Embodiment 2

[0116] Weigh 9.75g of compound formula A into a 250mL single-necked bottle, then add 93mL of methanol, dropwise add 20mL of aqueous solution containing 1.35g of lithium hydroxide under stirring, after the addition is complete, heat up to 30°C, react for 10 hours, cool down to room temperature, drop Add 2N hydrochloric acid to adjust the pH to 2, concentrate under reduced pressure to remove most of the methanol, add 93mL EA and 30mL water, extract and separate the liquid, add 46mL EA to the water phase to extract once, combine the organic phase, add 93mL saturated saline to wash twice, dry Dried over magnesium sulfate, filtered and concentrated to obtain 8.11 g of white solid, namely compound formula B, with a yield of 96.32% and a purity of 96.79%.

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