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Phthalazones compound crystal form N and preparation method thereof

The technology of a compound and phthalazine is applied in the field of medicinal chemistry, which can solve the problems affecting the process of prescription preparations, the performance of pharmacokinetics in the body of the storage method, and the safety and effectiveness of drugs, and achieve good physical and chemical stability, good particle size, and so on. The effect of diameter distribution uniformity

Inactive Publication Date: 2019-02-15
NANJING ADVANCED BIOLOGICAL MATERIALS & PROCESS EQUIP INST CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

These differences directly affect the prescription preparation process, storage method, and pharmacokinetic performance of the drug in vivo, which in turn affects the safety and effectiveness of the drug.

Method used

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  • Phthalazones compound crystal form N and preparation method thereof
  • Phthalazones compound crystal form N and preparation method thereof
  • Phthalazones compound crystal form N and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 12

[0034] Example 1 [2(1H)-but-2-enoyl-3,4-dihydroisoquinolin-5-yl]-carbamic acid-4-[8-fluoro-(2H)-phthalazine-1- Preparation of keto]benzyl ester

[0035]

[0036] Step 1: Weigh 5-amino-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate (50mmol) and DIPEA (100mmol) into a reaction flask, add 300ml of dichloromethane, and stir at room temperature Slowly add p-chlorobenzyl chloroformate (51 mmol) dropwise. After the drop is complete, continue stirring at room temperature for 1 h to stop the reaction. Concentrate the reaction mixture, add 70 ml of ethyl acetate, wash with dilute aqueous hydrochloric acid (0.2-0.3 N) and saturated brine, Dry over anhydrous sodium sulfate, filter, and concentrate to give (3,4-dihydroisoquinoline-2(1H)-tert-butyl-carboxylate-5-yl)-p-chlorobenzyl carbamate, which is directly used in the next step, ESI –MS:[M+H] + m / z 417.

[0037] Step 2: Weigh 3-fluoro-1-dimethoxymethylbenzene (500mmol) into a reaction flask, add tetrahydrofuran (800ml) to dis...

Embodiment 2

[0042] Example 2: [2(1H)-but-2-enoyl-3,4-dihydroisoquinolin-5-yl]-carbamic acid-4-[8-fluoro-(2H)-phthalazine-1 Preparation of -keto]benzyl ester methanesulfonate

[0043] Weigh the compound of Example 1 (0.5 mmol) into a reaction flask, add 5 mL of acetone and stir at room temperature for 0.5 h, add dropwise 1 mL of methanesulfonic acid acetone solution (containing 0.55 mmol of methanesulfonic acid), and continue stirring for 1 h at room temperature. The solvent was distilled off under pressure and dried under vacuum at room temperature to obtain the title compound.

[0044] 1 H NMR (600MHz, CDCl 3 )(δ,ppm):9.50(s,1H,disappeared after heavy water exchange),8.10(s,1H),7.88~7.85(m,1H),7.77~7.75(m,1H),7.54~7.52(m, 3H),7.34~7.32(m,2H),7.21~7.18(m,3H),6.57~6.55(m,1H),6.41~6.39(m,1H),5.17(s,2H),4.22(s, 2H), 3.61~3.59(m,2H), 3.13~3.11(m,2H), 2.84~2.81(s,3H), 2.05~2.03(m,3H).

Embodiment 3

[0045] Example 3: [2(1H)-but-2-enoyl-3,4-dihydroisoquinolin-5-yl]-carbamic acid-4-[8-fluoro-(2H)-phthalazine-1 Preparation of N crystal form of -keto]benzyl ester methanesulfonate

[0046] Weigh 1.0g [2(1H)-but-2-enoyl-3,4-dihydroisoquinolin-5-yl]-carbamic acid-4-[8-fluoro-(2H)-phthalazine-1 -Keto]benzyl ester methanesulfonate in the reaction flask, add 5mL ethanol-dichloromethane-water mixed solution with a volume ratio of 15:5:3, reflux for 30min, cool naturally to room temperature, and crystallize at 0-5°C 12h, [2(1H)-but-2-enoyl-3,4-dihydroisoquinolin-5-yl]-carbamic acid-4-[8-fluoro-(2H)-phthalazine-1- Keto]benzyl ester methanesulfonate N crystal form.

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Abstract

The invention discloses a phthalazone compound crystal form N and a preparation method thereof, and belongs to the field of the medical chemistry, and specifically relates to a new crystal form of a compound [2(1H)-butyl-2-enoyl-3,4- dihydroisoquinoline-5-yl]-carbamic acid-4-[8-fluoro-(2H)-phthalazine-1-ketone] benzyl methanesulfonate with a tumor effect, a preparation method of the compound, a composition containing the crystal form, and application of the crystal form or the composition containing the crystal form in the medicine preparation. The N crystal form has good physical-chemical stability and particle size distribution uniformity, and is suitable for preparing the medicine preparation.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular to a compound [2(1H)-but-2-enoyl-3,4-dihydroisoquinolin-5-yl]-carbamic acid-4-[8- A new crystalline form of fluoro-(2H)-phthalazin-1-onyl]benzyl ester methanesulfonate, its preparation method, a composition comprising the crystalline form, and the crystalline form or comprising the crystalline form Use of the composition in the preparation of medicines. Background technique [0002] Bruton's tyrosine kinase (BTK) is a member of the Tec family. It consists of a unique N-terminal domain, namely PH (pleckstrin homology) domain, TH (Tec homology) homology region, SH3 (Srchomology3) domain, SH2 (Src homology2) domain and catalytic domain, also known as SH1 / TK (Srchomologyl / Tyrosine kinase) domain or kinase domain composition (Akinleye et al: Ibrutinib and novel BTK inhibitors in clinical development. Journal of Hematology & Oncology 2013, 6: 59). During the normal development of B ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12A61K31/502A61P35/00
CPCA61P35/00C07D401/12C07B2200/13
Inventor 郭程杰
Owner NANJING ADVANCED BIOLOGICAL MATERIALS & PROCESS EQUIP INST CO LTD
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