CN114685327A

CN114685327A - anti-HIV drug intermediate crystal form and preparation method thereof

Info

Publication number: CN114685327A
Application number: CN202011628146.2A
Authority: CN
Inventors: 匡善明; 孔敏敏; 张心旭; 盛斐
Original assignee: PORTON FINE CHEMICALS Ltd
Current assignee: PORTON FINE CHEMICALS Ltd
Priority date: 2020-12-30
Filing date: 2020-12-30
Publication date: 2022-07-01

Abstract

The invention provides a novel crystal form of [ (1S,2R) -1-benzyl-2-hydroxy-3- [ isobutyl [ (4-nitrophenyl) sulfonyl ] amino ] propyl ] tert-butyl carbamate, which has good stability, solubility and reaction rate and is beneficial to the following synthetic reaction. The novel crystal form of [ (1S,2R) -1-benzyl-2-hydroxy-3- [ isobutyl [ (4-nitrophenyl) sulfonyl ] amino ] propyl ] tert-butyl carbamate is a white solid, has good stability and solubility, and can improve the reaction rate. The method for preparing the crystal form is simple and suitable for industrial production.

Description

anti-HIV drug intermediate crystal form and preparation method thereof

Technical Field

The invention relates to the field of chemical medicine, in particular to an anti-HIV drug intermediate crystal form and a preparation method thereof.

Background

In the prior art, more reports are made on crystal forms of medicines, but few reports are made on crystal forms of intermediates for synthesizing medicines. The tert-butyl [ (1S,2R) -1-benzyl-2-hydroxy-3- [ isobutyl [ (4-nitrophenyl) sulfonyl ] amino ] propyl ] carbamate shown as the formula I is an important intermediate of anti-HIV drugs. Different crystal forms of the intermediate affect the solubility, stability, reaction rate, etc. of the intermediate. Therefore, the research on the new crystal form of the [ (1S,2R) -1-benzyl-2-hydroxy-3- [ isobutyl [ (4-nitrophenyl) sulfonyl ] amino ] propyl ] tert-butyl carbamate is beneficial to the storage of an intermediate, and the problems of solubility, reaction rate and the like during industrial production.

Disclosure of Invention

The invention provides a novel crystal form of [ (1S,2R) -1-benzyl-2-hydroxy-3- [ isobutyl [ (4-nitrophenyl) sulfonyl ] amino ] propyl ] tert-butyl carbamate, which has good stability, solubility and reaction rate and is beneficial to the following synthetic reaction.

In a first aspect, a crystalline form of tert-butyl [ (1S,2R) -1-benzyl-2-hydroxy-3- [ isobutyl [ (4-nitrophenyl) sulfonyl ] amino ] propyl ] carbamate, characterized in that: the XRPD pattern has characteristic peaks at 7.14 +/-0.2 degrees, 11.30 +/-0.2 degrees, 14.28 +/-0.2 degrees, 14.73 +/-0.2 degrees, 16.03 +/-0.2 degrees, 18.23 +/-0.2 degrees, 21.45 +/-0.2 degrees and 21.77 +/-0.2 degrees.

The DSC analysis pattern has heat absorption peaks at 87 ℃,108 ℃ and 173 ℃.

In a second aspect, a process for preparing a crystalline form of tert-butyl [ (1S,2R) -1-benzyl-2-hydroxy-3- [ isobutyl [ (4-nitrophenyl) sulfonyl ] amino ] propyl ] carbamate, comprising the steps of: dissolving the crude tert-butyl [ (1S,2R) -1-benzyl-2-hydroxy-3- [ isobutyl [ (4-nitrophenyl) sulfonyl ] amino ] propyl ] carbamate in isopropanol at 55-65 ℃, filtering, cooling the filtrate to room temperature, and separating to obtain crystals.

Further, the mass volume of the tert-butyl [ (1S,2R) -1-benzyl-2-hydroxy-3- [ isobutyl [ (4-nitrophenyl) sulfonyl ] amino ] propyl ] carbamate and isopropanol is 500mg/12 ml.

Further, the crude tert-butyl [ (1S,2R) -1-benzyl-2-hydroxy-3- [ isobutyl [ (4-nitrophenyl) sulfonyl ] amino ] propyl ] carbamate was dissolved in isopropanol at 60 ℃.

The novel crystal form of [ (1S,2R) -1-benzyl-2-hydroxy-3- [ isobutyl [ (4-nitrophenyl) sulfonyl ] amino ] propyl ] tert-butyl carbamate is a white solid, has good stability and solubility, and can improve the reaction rate. The preparation method of the crystal form is simple and suitable for industrial production.

Drawings

FIG. 1 is an XRPD characterization pattern of a crystalline form of tert-butyl [ (1S,2R) -1-benzyl-2-hydroxy-3- [ isobutyl [ (4-nitrophenyl) sulfonyl ] amino ] propyl ] carbamate;

FIG. 2 is a DSC characterization map of a crystalline form of tert-butyl [ (1S,2R) -1-benzyl-2-hydroxy-3- [ isobutyl [ (4-nitrophenyl) sulfonyl ] amino ] propyl ] carbamate.

DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION

The present invention is further illustrated by way of examples, which are intended to be illustrative of the principles, essential features and advantages of the invention, and are not to be construed as limiting the scope of the invention.

The [ (1S,2R) -1-benzyl-2-hydroxy-3- [ isobutyl [ (4-nitrophenyl) sulfonyl ] amino ] propyl ] tert-butyl carbamate used in the invention is self-made, and the preparation method refers to patent WO 2008132154.

The abbreviations used in the present invention are explained as follows:

XRPD — X-ray powder diffraction;

DSC-differential scanning calorimetry analysis.

Example 1

About 500mg of tert-butyl [ (1S,2R) -1-benzyl-2-hydroxy-3- [ isobutyl [ (4-nitrophenyl) sulfonyl ] amino ] propyl ] carbamate was dissolved in 12mL of isopropanol at 60 ℃ and then filtered. The clear solution was cooled to room temperature and the crystals were isolated and analyzed.

The crystalline form of tert-butyl [ (1S,2R) -1-benzyl-2-hydroxy-3- [ isobutyl [ (4-nitrophenyl) sulfonyl ] amino ] propyl ] carbamate is characterized by the XRPD pattern obtained using Cu-Ka radiation as shown in fig. 1, characterized by the following XRPD pattern with characteristic peaks expressed in degrees 2 θ:

7.14±0.2°,11.30±0.2°,14.28±0.2°,14.73±0.2°,16.03±0.2°,18.23±0.2°,21.45±0.2°,21.77±0.2°。

a DSC of crystalline form of tert-butyl [ (1S,2R) -1-benzyl-2-hydroxy-3- [ isobutyl [ (4-nitrophenyl) sulfonyl ] amino ] propyl ] carbamate with heat absorption peaks at 87 ℃,108 ℃ and 173 ℃ is shown in FIG. 2.

Claims

1. A crystalline form of tert-butyl [ (1S,2R) -1-benzyl-2-hydroxy-3- [ isobutyl [ (4-nitrophenyl) sulfonyl ] amino ] propyl ] carbamate characterized by: the XRPD pattern has characteristic peaks at 7.14 + -0.2 degrees, 11.30 + -0.2 degrees, 14.28 + -0.2 degrees, 14.73 + -0.2 degrees, 16.03 + -0.2 degrees, 18.23 + -0.2 degrees, 21.45 + -0.2 degrees, 21.77 + -0.2 degrees.

2. A crystalline form of tert-butyl [ (1S,2R) -1-benzyl-2-hydroxy-3- [ isobutyl [ (4-nitrophenyl) sulfonyl ] amino ] propyl ] carbamate according to claim 1, characterized in that: the DSC analysis pattern has heat absorption peaks at 87 ℃,108 ℃ and 173 ℃.

3. A process for preparing the crystalline form of claim 1, comprising the steps of: dissolving the crude tert-butyl [ (1S,2R) -1-benzyl-2-hydroxy-3- [ isobutyl [ (4-nitrophenyl) sulfonyl ] amino ] propyl ] carbamate in isopropanol at 55-65 ℃, filtering, cooling the filtrate to room temperature, and separating to obtain crystals.

4. The production method according to claim 3, characterized in that: the mass volume of the tert-butyl [ (1S,2R) -1-benzyl-2-hydroxy-3- [ isobutyl [ (4-nitrophenyl) sulfonyl ] amino ] propyl ] carbamate and isopropanol is 500mg/12 ml.

5. The method of claim 4, wherein: the crude tert-butyl [ (1S,2R) -1-benzyl-2-hydroxy-3- [ isobutyl [ (4-nitrophenyl) sulfonyl ] amino ] propyl ] carbamate is dissolved in isopropanol at 60 ℃.