CN114685326A - Novel crystal form of anti-HIV drug intermediate and preparation method thereof - Google Patents
Novel crystal form of anti-HIV drug intermediate and preparation method thereof Download PDFInfo
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- CN114685326A CN114685326A CN202011628133.5A CN202011628133A CN114685326A CN 114685326 A CN114685326 A CN 114685326A CN 202011628133 A CN202011628133 A CN 202011628133A CN 114685326 A CN114685326 A CN 114685326A
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- C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
- C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
- C07C311/18—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms, not being part of nitro or nitroso groups
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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 subsequent synthesis 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 preparation method of the crystal form is simple and suitable for industrial production.
Description
Technical Field
The invention relates to the field of chemical medicine, in particular to a novel crystal form of an anti-HIV drug intermediate 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 subsequent synthesis reaction.
In a first aspect, the invention provides a crystalline form I of tert-butyl [ (1S,2R) -1-benzyl-2-hydroxy-3- [ isobutyl [ (4-nitrophenyl) sulfonyl ] amino ] propyl ] carbamate having characteristic peaks at 6.79 ± 0.2 °,7.98 ± 0.2 °,8.42 ± 0.2 °,10.77 ± 0.2 °,13.50 ± 0.2 °,18.88 ± 0.2 °,21.36 ± 0.2 °,23.97 ± 0.2 ° in XRPD pattern.
The DSC analysis pattern has heat absorption peaks at 89 ℃,132 ℃ and 173 ℃.
In a second aspect, the present invention provides a process for preparing form I, comprising the steps of: tert-butyl [ (1S,2R) -1-benzyl-2-hydroxy-3- [ isobutyl [ (4-nitrophenyl) sulfonyl ] amino ] propyl ] carbamate is dissolved in methanol at 55-65 ℃, and then filtered. Cooling the clear solution to 20-30 ℃ at a speed of 0.05-0.15 ℃/min, separating and analyzing crystals.
Further, the mass/volume ratio of tert-butyl [ (1S,2R) -1-benzyl-2-hydroxy-3- [ isobutyl [ (4-nitrophenyl) sulfonyl ] amino ] propyl ] carbamate to methanol was 1.0g/12 ml.
Further, the crude tert-butyl [ (1S,2R) -1-benzyl-2-hydroxy-3- [ isobutyl [ (4-nitrophenyl) sulfonyl ] amino ] propyl ] carbamate was dissolved in methanol at 60 ℃.
Further, the filtrate was cooled at a rate of 0.1 ℃/min.
Further, the filtrate was cooled to 25 ℃.
In a third aspect, the present invention provides a process for preparing crystalline form II of tert-butyl [ (1S,2R) -1-benzyl-2-hydroxy-3- [ isobutyl [ (4-nitrophenyl) sulfonyl ] amino ] propyl ] carbamate by heating crystalline form I to 110 ℃.
In a fourth aspect, crystalline form II of tert-butyl [ (1S,2R) -1-benzyl-2-hydroxy-3- [ isobutyl [ (4-nitrophenyl) sulfonyl ] amino ] propyl ] carbamate has characteristic peaks in XRPD patterns at 6.83 ± 0.2 °,8.12 ± 0.2 °,8.84 ± 0.2 °,11.14 ± 0.2 °,14.35 ± 0.2 °,17.64 ± 0.2 °,18.98 ± 0.2 °,19.25 ± 0.2 °.
DSC analysis of crystalline form II of tert-butyl [ (1S,2R) -1-benzyl-2-hydroxy-3- [ isobutyl [ (4-nitrophenyl) sulfonyl ] amino ] propyl ] carbamate shows heat absorption peaks at 129 ℃ and 173 ℃.
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 tert-butyl [ (1S,2R) -1-benzyl-2-hydroxy-3- [ isobutyl [ (4-nitrophenyl) sulfonyl ] amino ] propyl ] carbamate form I;
FIG. 2 is a DSC characterization map of crystalline form I of tert-butyl [ (1S,2R) -1-benzyl-2-hydroxy-3- [ isobutyl [ (4-nitrophenyl) sulfonyl ] amino ] propyl ] carbamate;
FIG. 3 is an XRPD characterization pattern of tert-butyl [ (1S,2R) -1-benzyl-2-hydroxy-3- [ isobutyl [ (4-nitrophenyl) sulfonyl ] amino ] propyl ] carbamate crystalline form II;
FIG. 4 is a DSC characterization map of crystalline form II of tert-butyl [ (1S,2R) -1-benzyl-2-hydroxy-3- [ isobutyl [ (4-nitrophenyl) sulfonyl ] amino ] propyl ] carbamate;
FIG. 5 is an XRPD characterization pattern after stability test of crystalline form II 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
1.0g of tert-butyl [ (1S,2R) -1-benzyl-2-hydroxy-3- [ isobutyl [ (4-nitrophenyl) sulfonyl ] amino ] propyl ] carbamate was dissolved in 12mL of methanol at 60 ℃ and then filtered. The clear solution was then cooled to 25 ℃ at a rate of 0.1 ℃/min. The crystals were isolated and analyzed.
Crystalline form I 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, with characteristic peaks expressed in degrees 2 θ in the XRPD pattern as shown below:
6.79±0.2°,7.98±0.2°,8.42±0.2°,10.77±0.2°,13.50±0.2°,18.88±0.2°,21.36±0.2°,23.97±0.2°。
the DSC chart of crystalline form I of tert-butyl [ (1S,2R) -1-benzyl-2-hydroxy-3- [ isobutyl [ (4-nitrophenyl) sulfonyl ] amino ] propyl ] carbamate is shown in figure 2, which has heat absorption peaks at 89 ℃,132 ℃ and 173 ℃.
Example 2
10mg of crystalline form I of tert-butyl [ (1S,2R) -1-benzyl-2-hydroxy-3- [ isobutyl [ (4-nitrophenyl) sulfonyl ] amino ] propyl ] carbamate was placed in an aluminum DSC sample holder and heated to 110 ℃ using DSC to give crystalline form II of tert-butyl [ (1S,2R) -1-benzyl-2-hydroxy-3- [ isobutyl [ (4-nitrophenyl) sulfonyl ] amino ] propyl ] carbamate.
Crystalline form II 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. 3, characterized by the following XRPD pattern with characteristic peaks expressed in degrees 2 Θ as shown below:
6.83±0.2°,8.12±0.2°,8.84±0.2°,11.14±0.2°,14.35±0.2°,17.64±0.2°,18.98±0.2°,19.25±0.2°
the DSC chart of crystalline form I of tert-butyl [ (1S,2R) -1-benzyl-2-hydroxy-3- [ isobutyl [ (4-nitrophenyl) sulfonyl ] amino ] propyl ] carbamate is shown in figure 4, which has heat absorption peaks at 129 ℃ and 173 ℃.
Evaluation of stability:
the purity was determined by HPLC, and the determination conditions are shown in the following table:
the XRPD characterization patterns before and after the form II stability test are shown in fig. 5, from which it can be seen that: the crystal form II can keep good stability under various temperature and humidity conditions, the purity is hardly reduced, and the crystal form structure can also keep unchanged.
Claims (10)
1. Crystalline form I 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 6.79 +/-0.2 degrees, 7.98 +/-0.2 degrees, 8.42 +/-0.2 degrees, 10.77 +/-0.2 degrees, 13.50 +/-0.2 degrees, 18.88 +/-0.2 degrees, 21.36 +/-0.2 degrees and 23.97 +/-0.2 degrees.
2. Crystalline form I 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 89 ℃,132 ℃ and 173 ℃.
3. A process for preparing form I according to claim 1, comprising the steps of: tert-butyl [ (1S,2R) -1-benzyl-2-hydroxy-3- [ isobutyl [ (4-nitrophenyl) sulfonyl ] amino ] propyl ] carbamate is dissolved in methanol at 55-65 ℃, and then filtered. Cooling the clear solution to 20-30 ℃ at a speed of 0.05-0.15 ℃/min, separating and analyzing crystals.
4. The production method according to claim 3, characterized in that: the mass volume ratio of tert-butyl [ (1S,2R) -1-benzyl-2-hydroxy-3- [ isobutyl [ (4-nitrophenyl) sulfonyl ] amino ] propyl ] carbamate to methanol is 1.0g/12 ml.
5. The method of claim 4, wherein: the crude product of tert-butyl [ (1S,2R) -1-benzyl-2-hydroxy-3- [ isobutyl [ (4-nitrophenyl) sulfonyl ] amino ] propyl ] carbamate is dissolved in methanol at 60 ℃.
6. The method of claim 5, wherein: the filtrate was cooled at a rate of 0.1 deg.C/min.
7. The method of claim 5, wherein: the filtrate was cooled to 25 ℃.
8. A preparation method of a crystal form II of [ (1S,2R) -1-benzyl-2-hydroxy-3- [ isobutyl [ (4-nitrophenyl) sulfonyl ] amino ] propyl ] carbamic acid tert-butyl ester is characterized in that: form I was heated to 110 ℃.
9. The crystalline form II of tert-butyl [ (1S,2R) -1-benzyl-2-hydroxy-3- [ isobutyl [ (4-nitrophenyl) sulfonyl ] amino ] propyl ] carbamate of claim 8, wherein: the XRPD pattern has characteristic peaks at 6.83 + -0.2 degrees, 8.12 + -0.2 degrees, 8.84 + -0.2 degrees, 11.14 + -0.2 degrees, 14.35 + -0.2 degrees, 17.64 + -0.2 degrees, 18.98 + -0.2 degrees, 19.25 + -0.2 degrees.
10. The crystalline form II of tert-butyl [ (1S,2R) -1-benzyl-2-hydroxy-3- [ isobutyl [ (4-nitrophenyl) sulfonyl ] amino ] propyl ] carbamate according to claim 9, characterized in that: the DSC analysis pattern has heat absorption peaks at 129 ℃ and 173 ℃.
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| CN101193857A (en) * | 2005-06-10 | 2008-06-04 | Npil医药品（英国）有限公司 | Process and compound |
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