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Crystalline form of 6-[(4r)-4-methyl-1,2-dioxido-1,2,6-thiadiazinan-2-yl]isoquinoline-1-carbonitrile

一种噻二嗪烷、二氧化的技术，应用在tril领域，能够解决不能确信地预测化合物是否会结晶等问题

Inactive Publication Date: 2017-02-22
PFIZER INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Based on chemical structure, it cannot be predicted with confidence whether a compound will crystallize, under what conditions it will crystallize, or the solid-state structure of any of the crystalline forms

Method used

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  • Crystalline form of 6-[(4r)-4-methyl-1,2-dioxido-1,2,6-thiadiazinan-2-yl]isoquinoline-1-carbonitrile
  • Crystalline form of 6-[(4r)-4-methyl-1,2-dioxido-1,2,6-thiadiazinan-2-yl]isoquinoline-1-carbonitrile
  • Crystalline form of 6-[(4r)-4-methyl-1,2-dioxido-1,2,6-thiadiazinan-2-yl]isoquinoline-1-carbonitrile

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0136]

[0137] program:

[0138] In a 2L three-necked round-bottomed flask equipped with a mechanical stirrer, reflux condenser, thermocouple, and heating mantle, place 2-methyltetrahydrofuran (2-MeTHF) (10mL / g; 8.15 moles; 817mL; 702g), followed by rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP) (0.04 equiv (mole); 14.0mmol; 8.74g) and bis(dibenzylideneacetone) Palladium (Pd 2 (dba) 3 ) (0.04 equivalents (moles); 14.0 mmol; 8.07 g). The mixture was degassed by evacuating and refilling with nitrogen three times, then heated to 75° C. for 15 minutes and cooled to ambient temperature. In a separate flask, (S)-3-amino-2-methylpropan-1-ol (1.60 equiv; 561 mmol; 50.0 g, using literature methods such as EP-A- 0089139) was dissolved in 2-methyltetrahydrofuran (5 mL / g; 4.08 moles; 409 mL; 351 g) and degassed by evacuating and refilling with nitrogen three times. In the pot containing the catalyst, 6-(bromoisoquinoline-1-carbonitrile) (1.00 equiv; 351 mmol; 81.75 g) an...

Embodiment 2

[0140]

[0141] program:

[0142] In a 1 L reactor equipped with a temperature probe and overhead stirrer, the product of Example 1 (20.0 g; 1.00 equiv; 82.9 mmol) and 2-methyltetrahydrofuran (2-MeTHF) (30 mL / g neat LR; 5.98 moles; 600 mL; 515 g). The reaction mixture was slowly heated to 40 °C to achieve partial dissolution. The reaction was cooled to 0 °C. Once the reaction reached 0°C, methanesulfonyl chloride (MsCl) (1.4 equiv (moles); 116 mmol; 8.98 mL; 13.3 g) was added in a single portion, followed immediately by the dropwise addition of triethylamine (TEA) (1.4 equiv. (moles); 116 mmol; 16.2 mL; 11.7 g). The reaction mixture was further stirred at 0 °C for 30 min, then warmed to 23 °C for 60 min. The product (26.47 g; 1.00 equiv; 82.88 mmol; 26.47 g; assumed 100% yield) was used in the sulfonylation reaction without purification.

Embodiment 3

[0144]

[0145] program:

[0146] To a solution of tert-butanol (t-BuOH) (1 equivalent (mole); 116mmol; 11.0mL; 8.60g) in 2-methyltetrahydrofuran (2-MeTHF) (1M; 1.16 mole; 116mL; 99.6 g) was added dropwise with chlorosulfonyl isocyanate (116 mmol; 1.00 equiv; 10.1 mL; 16.4 g). The homogeneous solution was stirred at ambient temperature for 30 minutes and then used directly in the sulfonylation reaction.

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Abstract

This invention relates to a novel crystalline form of 6-[(4R)-4-methyl-1, 1-dioxido- 1,2,6-thiadiazinan-2-yl]isoquinoline-1-carbonitrile which is useful as a selective androgen receptor modulator (SARM), and to compositions thereof and suitable processes for the preparation thereof.

Description

[0001] 【Technical field】 [0002] The present invention relates to 6-[(4R)-4-methyl-1,1-dioxide-1,2,6-thiadiazidin-2-yl]isoquinoline-1-carbonitrile (6-[(4R )-4-methyl-1,1-dioxido-1,2,6-thiadiazinan-2-yl]isoquinoline-1-carbonitrile), its composition and its preparation method. The present invention also relates to 6-[(4R)-4-methyl-1,1-dioxy-1,2,6-thiadiazinane- 2-yl]isoquinoline-1-carbonitrile in crystalline form. [0003] 【Background technique】 [0004] The androgen receptor ("AR") is a ligand-activated transcriptional regulatory protein that regulates male sexual development and the induction of sexual function through its activity with endogenous androgens. Androgenic steroids play an important role in many physiological processes including the development and maintenance of male sexual characteristics such as muscle and bone mass, prostate growth, sperm formation, and male hair pattern. Endogenous steroid androgens include testosterone and dihydrosterone ("DHT"). Steroid...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/04A61K31/549A61P7/06A61P25/00A61P19/02A61P29/00A61P19/08A61P21/00A61P5/00A61P7/00A61P15/08A61P3/04
CPCC07D417/04C07B2200/13A61K31/549A61P1/14A61P15/00A61P15/08A61P19/00A61P19/02A61P19/08A61P19/10A61P21/00A61P21/04A61P25/00A61P25/28A61P29/00A61P3/00A61P3/04A61P43/00A61P5/00A61P5/06A61P5/26A61P7/00A61P7/06A61K9/0053A61K9/20A61K9/48A61K31/4725A61K45/06
Inventor E·L·P·谢克莱R·L·多罗J·B·斯佩里
Owner PFIZER INC
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