CN114671889A - Crystal form of substituted tricyclic pyridone derivative and preparation method thereof - Google Patents
Crystal form of substituted tricyclic pyridone derivative and preparation method thereof Download PDFInfo
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- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract
The invention relates to a crystal form of a substituted tricyclic pyridone derivative and a preparation method thereof, in particular to a crystal form of a marbalosavir intermediate 7- (benzyloxy) -3,4,12,12 a-tetrahydro-1H- [1,4] oxazine [3,4-c ] pyrido [2,1-f ] [1,2,4] triazine-6, 8 dione, wherein the crystal form A is obtained by screening a solvent, the crystal form is stable and difficult to agglomerate under a high-humidity condition, and a product obtained by taking the crystal form as a raw material through resolution has high chiral purity.
Description
Technical Field
The invention belongs to the field of drug synthesis, relates to a crystal form of a substituted tricyclic pyridone derivative and a preparation method thereof, and particularly relates to a crystal form of a mabarovir intermediate 7- (benzyloxy) -3,4,12,12 a-tetrahydro-1H- [1,4] oxazine [3,4-c ] pyrido [2,1-f ] [1,2,4] triazine-6, 8 dione and a preparation method thereof.
Background
The Marbaloxavir is a novel anti-influenza virus medicament which is jointly developed by salt wild-sense companies and Roche pharmaceutical companies, can inhibit influenza virus 5' CAP structure (CAP) dependent endonuclease, and plays a role in inhibiting virus replication. At present, mabarosavir is marketed in japan and the united states for the treatment of influenza in children and adults. An important intermediate for the synthesis of mabarosavir is 7- (benzyloxy) -3,4,12,12 a-tetrahydro-1H- [1,4] oxazin [3,4-c ] pyrido [2,1-f ] [1,2,4] triazine-6, 8 dione, shown in formula I below.
CN109311911A discloses preparation of chiral formula III, which is disclosed by referring to patent methods, and finds that the obtained crystal form of formula II is easy to absorb moisture and agglomerate, and the e.e value of the crystal form III obtained by resolution of the crystal form II by reaction with (R) - (+) -tetrahydrofuran-2-formic acid is lower, and the chiral purity of the crystal form III affects the content of related substances of the final product of the abacavir. Therefore, there is a need to develop a new crystalline form which has low hygroscopicity and can improve the chiral purity of formula III for resolution reactions.
Disclosure of Invention
The invention aims to provide a new crystal form, wherein the new crystal form is obtained by screening a solvent, the hygroscopicity of the crystal form is researched to obtain a stable crystal form A, and the crystal form is more efficient when being used for subsequent resolution reaction.
The invention provides a crystal form A with a structure shown in a formula I, which is characterized in that an X-ray powder diffraction pattern has characteristic peaks at 9.0 +/-0.2 degrees, 9.4 +/-0.2 degrees, 10.4 +/-0.2 degrees, 11.8 +/-0.2 degrees, 17.4 +/-0.2 degrees, 17.5 +/-0.2 degrees, 17.8 +/-0.2 degrees, 20.3 +/-0.2 degrees, 26.7 +/-0.2 degrees and 27.0 +/-0.2 degrees.
The embodiment of the invention is characterized in that the X-ray powder diffraction pattern has characteristic peaks at 9.0 +/-0.2 degrees, 9.4 +/-0.2 degrees, 10.2 +/-0.2 degrees, 10.4 +/-0.2 degrees, 11.6 +/-0.2 degrees, 11.8 +/-0.2 degrees, 17.4 +/-0.2 degrees, 17.5 +/-0.2 degrees, 17.8 +/-0.2 degrees, 20.3 +/-0.2 degrees, 26.7 +/-0.2 degrees and 27.0 +/-0.2 degrees.
An embodiment of the invention is characterized in that the X-ray powder diffraction pattern is as shown in figure 1.
An embodiment of the invention is characterized in that the infrared spectrum is 3412cm-1、3189cm-1、3062cm-1、2968cm-1、2876cm-1、1674cm-1、1606cm-1、1567cm-1、1497cm-1、1423cm-1、1394cm-1、1283cm-1、1260cm-1、1184cm-1、1124cm-1、1047cm-1、979cm-1、913cm-1、849cm-1、750cm-1、704cm-1、640cm-1、528cm-1、489cm-1、451cm-1、406cm-1Has a characteristic absorption peak;
an embodiment of the invention is characterized by an infrared spectrum as shown in figure 2.
An embodiment of the present invention is characterized by a differential scanning calorimetry curve as shown in FIG. 3.
The invention also provides a method for preparing the crystal form A with the structure of the formula I, which comprises the following steps: dissolving 7- (benzyloxy) -3,4,12,12 a-tetrahydro-1H- [1,4] oxazine [3,4-c ] pyrido [2,1-f ] [1,2,4] triazine-6, 8-dione hemihydrate in methanol, heating under reflux, cooling to room temperature, adding methyl tert-butyl ether or ethyl acetate, and stirring to precipitate crystals.
In an embodiment of the present invention, the weight to volume ratio of 7- (benzyloxy) -3,4,12,12 a-tetrahydro-1H- [1,4] oxazine [3,4-c ] pyrido [2,1-f ] [1,2,4] triazine-6, 8 dione hemihydrate to methanol is 1: 3-70, the unit is g/mL, and the preferable weight volume ratio is 1: 3-50, and further preferably the weight volume ratio is 1: 3-30, and further preferably the weight volume ratio is 1:3 to 10.
In the embodiment of the invention, the volume ratio of the used solvent methanol/methyl tert-butyl ether is 1: 1-5, preferably the volume ratio of methanol/methyl tert-butyl ether is 1: 1-3, wherein the volume ratio of methanol to ethyl acetate is 1: 1-5, preferably the volume ratio of methanol to ethyl acetate is 1:1 to 3.
Wherein the heating step may be carried out by raising the temperature to 65 ± 5 ℃.
In addition, the method further includes filtration or drying in order to obtain a high purity product by removing impurities, remaining solvent, and the like. Filtration and/or drying may use methods known in the art without limitation.
Compared with the hemihydrate crystal form in the prior art, the crystal form A has low hygroscopicity, good particle dispersion and difficult agglomeration, and is very favorable for long-term storage of compounds. It was also found to be beneficial to improve the chiral purity of the subsequent resolution reaction by comparison with the subsequent resolution reaction.
Drawings
FIG. 1 is an X-ray powder diffraction pattern of form A of formula I;
FIG. 2 is an IR spectrum of form A of formula I;
FIG. 3 is a Differential Scanning Calorimetry (DSC) thermogram of form A of formula I;
FIG. 4 is an X-ray powder diffraction pattern of form B of formula I;
FIG. 5 is a chiral HPLC profile of formula III obtained in example 6;
FIG. 6 is a chiral HPLC profile of formula III obtained in example 7;
FIG. 7 is a chiral HPLC chromatogram of formula III obtained in comparative example 1;
figure 8 is an HPLC profile of form a of example 8 prior to standing;
FIG. 9 is an HPLC profile of form A of example 8 after standing for 24h under high humidity conditions;
figure 10 is an HPLC profile of form B of example 8 prior to standing;
figure 11 is an HPLC profile of form B of example 8 after standing for 24h under high humidity conditions;
fig. 12 is an HPLC profile of the crystalline form of hemihydrate of example 8 prior to standing;
fig. 13 is an HPLC profile of the crystalline form of hemihydrate of example 8 after standing for 24h under high humidity conditions;
Detailed Description
Hereinafter, the present invention will be described in more detail with reference to the following examples. However, these examples are for illustrative purposes only, and the present invention should not be limited by these examples.
The water content test method comprises the following steps: the determination is carried out according to the first method of 0832 in the four general rules of the 'Chinese pharmacopoeia' 2015 edition, a Wantong KF870 moisture determinator and a Karl Fischer reagent are purchased from Yonghua chemical technology Co., Ltd, and the titer is 3-5 mg/mL.
Chemical purity HPLC test method:
chromatographic column Waters Sunfire C18150 × 4.6mm, 3.5 μm, flow rate 1.0mL/min, wavelength 254nm, column temperature 35 ℃, sample size 10 μ L, mobile phase a as 0.05% trifluoroacetic acid in acetonitrile, mobile phase B as 0.05% trifluoroacetic acid in water, gradient program as follows:
time (min) | Mobile phase A (%) | Mobile phase B (%) |
0 | 10 | 90 |
5 | 10 | 90 |
33 | 70 | 30 |
33.5 | 10 | 90 |
40 | 10 | 90 |
Chiral purity HPLC test method:
column xylonite AD column 250 × 4.6mm, 5 μm, flow rate 0.5mL/min, wavelength 230nm, column temperature 25 ℃, sample size 10 μ L, mobile phase n-hexane: ethanol: diethylamine 70:30:0.1, eluting for 45 min.
The X-ray diffraction spectrum was measured using D2 Phaser from Bruker, and the scanning range: 3 to 40 °, step size 0.04 °, scan time 520 seconds;
the IR spectra were measured using a fourier infrared spectrometer (Bruker corporation);
differential scanning calorimetry the DSC thermogram was analyzed using a DSC thermogram from the company tas instruments.
Reference example 1 preparation of hemihydrate crystalline forms
A yellow solid is obtained according to the method of CN109311911A example 2, the melting point is 238-.
EXAMPLE 1 screening of crystalline forms
Adding single solvents of acetonitrile, ethanol, methanol, ethyl acetate, methyl tert-butyl ether and dichloromethane into 7- (benzyloxy) -3,4,12,12 a-tetrahydro-1H- [1,4] oxazine [3,4-c ] pyrido [2,1-f ] [1,2,4] triazine-6, 8 diketone hemihydrate of the formula II obtained in the reference example 1, respectively, and heating and refluxing to obtain a new crystal form; dissolving the formula II in methanol or ethanol, refluxing, adding ethyl acetate, methyl tert-butyl ether, isopropyl ether or dichloromethane, cooling, crystallizing, and screening to obtain two new crystal forms, named as crystal form A and crystal form B. It was found that form a was obtained when the solvent system was methanol/methyl tert-butyl ether, methanol/ethyl acetate and form B was obtained when the solvent system was methanol/isopropyl ether, the specific experimental results are shown in table 1.
TABLE 1 Crystal form screening experiments
Example 2
20.00g of the hemihydrate form 7- (benzyloxy) -3,4,12,12 a-tetrahydro-1H- [1,4] oxazine [3,4-c ] pyrido [2,1-f ] [1,2,4] triazine-6, 8-dione of the formula II is taken, methanol (60mL) is added, the temperature is increased to 65 +/-5 ℃, reflux pulping is carried out for 2H, methyl tert-butyl ether (100mL) is added, the temperature is reduced to 15 +/-5 ℃, stirring is carried out for 1H, filtering is carried out, a filter cake is rinsed by a methanol/methyl tert-butyl ether (v: v ═ 1:1) mixed solvent, the filter cake is baked for 16H at 70 +/-5 ℃, and 17.8g of orange solid, namely the novel anhydrous crystal form A of the formula I is obtained after collection (the yield: 91%, the melting point: 272 and 280 ℃, and the moisture content: 0.3%).
Example 3
Taking 10.00g of the hemihydrate form 7- (benzyloxy) -3,4,12,12 a-tetrahydro-1H- [1,4] oxazine [3,4-c ] pyrido [2,1-f ] [1,2,4] triazine-6, 8-dione of the formula II, adding methanol (700mL), heating to 65 +/-5 ℃, refluxing and pulping for 2H, adding methyl tert-butyl ether (3500mL), cooling to 15 +/-5 ℃, stirring for 1H, filtering, rinsing a filter cake by using a methanol/methyl tert-butyl ether (v: v ═ 1:1) mixed solvent, drying the filter cake at 70 +/-5 ℃ for 16H, and collecting 8.7g of an orange solid, namely the novel anhydrous crystal form A of the formula I (yield: 89%, moisture content: 0.2%).
Example 4
Taking 10.00g of the hemihydrate form 7- (benzyloxy) -3,4,12,12 a-tetrahydro-1H- [1,4] oxazine [3,4-c ] pyrido [2,1-f ] [1,2,4] triazine-6, 8-dione shown in the formula II, adding methanol (50mL), heating to 65 +/-5 ℃, refluxing and pulping for 2H, adding ethyl acetate (150mL), cooling to 15 +/-5 ℃, stirring for 1H, filtering, rinsing a filter cake by using a methanol/ethyl acetate (v: v ═ 1:3) mixed solvent, drying the filter cake at 70 +/-5 ℃ for 16H, and collecting 8.2g of an orange solid, namely the novel anhydrous crystal form A shown in the formula I (yield: 84%, moisture content: 0.4%).
Example 5
20.00g of 7- (benzyloxy) -3,4,12,12 a-tetrahydro-1H- [1,4] oxazine [3,4-c ] pyrido [2,1-f ] [1,2,4] triazine-6, 8 dione, which is a hemihydrate of the formula II, is taken, methanol (1400mL) is added, stirred and dissolved at 30 +/-5 ℃, isopropyl ether (2380mL) is slowly added, the temperature is reduced to 15 +/-5 ℃, stirring is carried out for 2H, filtering is carried out, a filter cake is rinsed by isopropyl ether, the filter cake is baked for 16H at 70 +/-5 ℃, and 11.0g of light pink solid, namely the novel anhydrous crystal form B of the compound of the formula I, is obtained after material collection (the yield is 56 percent and the water content is 0.3 percent).
Example 6 resolution reaction with form A
Step 1:
adding ethyl acetate (87mL) and 50 (w/w)% of T3P ethyl acetate solution (145.80g) into 7- (benzyloxy) -3,4,12,12 a-tetrahydro-1H- [1,4] oxazine [3,4-c ] pyrido [2,1-f ] [1,2,4] triazine-6, 8-dione (30.00g) of crystal form A, uniformly stirring, heating the reaction solution to 60 +/-5 ℃, dropwise adding triethylamine (18.55g), dropwise adding R-tetrahydrofuran formic acid (12.24g), reacting for 4.5H at 60 +/-5 ℃, cooling the reaction solution to 0 +/-5 ℃ under the protection of nitrogen, filtering, rinsing the filter cake with ethyl acetate (120mL), and drying under reduced pressure at 25 ℃ for 16H to obtain 18.27g of a light yellow solid target (yield: 46%).
Step 2:
ethyl acetate (120mL) and 1, 8-diazabicycloundec-7-ene (0.53g) were added to the solid obtained in step 1, stirred uniformly at 30 deg.C, a mixture of methanol (1.67g) and ethyl acetate (43mL) was slowly added dropwise, the mixture was allowed to react at 30 + -5 deg.C for 1h, filtered, the filter cake was rinsed with ethyl acetate (60mL), and the filter cake was dried under reduced pressure at 25 deg.C (16h) to give 11.06g of the compound of formula III as a pale pink powder (yield: 95%, e.e: 100%).
Example 7 resolution reaction with form B
Step 1:
ethyl acetate (87mL) and 50 (w/w)% of T3P ethyl acetate solution (145.80g) were added to 7- (benzyloxy) -3,4,12,12 a-tetrahydro-1H- [1,4] oxazine [3,4-c ] pyrido [2,1-f ] [1,2,4] triazine-6, 8-dione (30.00g) of form B, stirred well, the reaction solution was warmed to 60 + -5 deg.C, triethylamine (18.55g) was added dropwise, R-tetrahydrofuran carboxylic acid (12.24g) was added dropwise, the reaction was allowed to react at 60 + -5 deg.C for 4.5H, the reaction solution was cooled to 0 + -5 deg.C under nitrogen protection, filtered, the filter cake was rinsed with ethyl acetate (120mL), and dried under reduced pressure at 25 deg.C for 16H) to give 17.27g of a pale yellow solid target (yield: 46%).
Step 2:
ethyl acetate (120mL) and 1, 8-diazabicycloundec-7-ene (0.53g) were added to the solid obtained in step 1, stirred well at 30 deg.C, a mixture of methanol (1.67g) and ethyl acetate (43mL) was slowly added dropwise, the reaction was carried out at 30 + -5 deg.C for 1h, filtered, the filter cake was rinsed with ethyl acetate (60mL), and the filter cake was dried under reduced pressure at 25 deg.C (16h) to give 13.02g of off-white compound of formula III (yield: 95%, e.e: 99.96%).
Comparative example 1 resolution reaction with formula II
Step 1:
ethyl acetate (87mL) and 50 (w/w)% of a T3P ethyl acetate solution (145.80g) were added to 7- (benzyloxy) -3,4,12,12 a-tetrahydro-1H- [1,4] oxazine [3,4-c ] pyrido [2,1-f ] [1,2,4] triazine-6, 8-dione (30.00g) of formula II, i.e., hemihydrate form, and stirred uniformly, the reaction mixture was heated to 60. + -. 5 ℃ and triethylamine (18.55g) was added dropwise, R-tetrahydrofuran carboxylic acid (12.24g) was added dropwise, the reaction was allowed to react at 60. + -. 5 ℃ for 4.5H, the reaction mixture was cooled to 0. + -. 5 ℃ under nitrogen protection, filtered, the filter cake was rinsed with ethyl acetate (120mL), and dried under reduced pressure at 25 ℃ for 16H to give 17.08g of a pale yellow solid target (yield: 43%).
Step 2:
ethyl acetate (120mL) and 1, 8-diazabicycloundec-7-ene (0.53g) were added to the solid obtained in step 1, stirred well at 30 deg.C, a mixture of methanol (1.67g) and ethyl acetate (43mL) was slowly added dropwise, the reaction was carried out at 30 + -5 deg.C for 1h, filtration was carried out, the cake was rinsed with ethyl acetate (60mL), and the cake was dried under reduced pressure at 25 deg.C (16h) to give 10.34g of the compound of formula III as a pale pink powder (yield: 95%, e.e: 96.82%).
Example 8 hygroscopicity test
And simultaneously exposing the crystal form A, the crystal form B and the hemihydrate crystal form to the conditions of room temperature 25 +/-5 ℃ and humidity 80 +/-2%, standing for 24 hours, and measuring the impurity content and the change degree of water, wherein the results are shown in table 2. .
TABLE 2 hygroscopicity test of the crystalline modification
As shown in table 2, the hemihydrate crystal form is already agglomerated in the initial stage, crystal form B is agglomerated after 24 hours, the moisture content of crystal form B is increased from 0.3% to 2.4% and crystal transformation occurs, impurities are also increased from 0.10% to 0.25%, and the appearance, moisture content and crystal form of crystal form a are not changed after being placed for 24 hours under a high-humidity condition, so that crystal form a shows low hygroscopicity and stability, and is more convenient to store and transport as an intermediate.
Claims (9)
1. A crystal form A with a structure shown in a formula I is characterized in that an X-ray powder diffraction pattern has characteristic peaks at 9.0 +/-0.2 degrees, 9.4 +/-0.2 degrees, 10.4 +/-0.2 degrees, 11.8 +/-0.2 degrees, 17.4 +/-0.2 degrees, 17.5 +/-0.2 degrees, 17.8 +/-0.2 degrees, 20.3 +/-0.2 degrees, 26.7 +/-0.2 degrees and 27.0 +/-0.2 degrees.
2. Form a according to claim 1, characterized by an X-ray powder diffraction pattern having characteristic peaks at 9.0 ± 0.2 °, 9.4 ± 0.2 °, 10.2 ± 0.2 °, 10.4 ± 0.2 °, 11.6 ± 0.2 °, 11.8 ± 0.2 °, 17.4 ± 0.2 °, 17.5 ± 0.2 °, 17.8 ± 0.2 °, 20.3 ± 0.2 °, 26.7 ± 0.2 °, 27.0 ± 0.2 °.
3. Form a according to claim 2, characterized by an X-ray powder diffraction pattern as shown in figure 1.
4. Form A according to claim 1, characterized by an infrared spectrum at 3412cm-1、3189cm-1、3062cm-1、2968cm-1、2876cm-1、1674cm-1、1606cm-1、1567cm-1、1497cm-1、1423cm-1、1394cm-1、1283cm-1、1260cm-1、1184cm-1、1124cm-1、1047cm-1、979cm-1、913cm-1、849cm-1、750cm-1、704cm-1、640cm-1、528cm-1、489cm-1、451cm-1、406cm-1Has characteristic absorption peaks.
5. Form A according to claim 4, having an infrared spectrum as shown in figure 2.
6. Form a according to claim 1, characterized by a differential scanning calorimetry trace according to figure 3.
7. A process for preparing form a of the structure of formula I, comprising: dissolving 7- (benzyloxy) -3,4,12,12 a-tetrahydro-1H- [1,4] oxazine [3,4-c ] pyrido [2,1-f ] [1,2,4] triazine-6, 8-dione hemihydrate in methanol, heating under reflux, cooling to room temperature, adding methyl tert-butyl ether or ethyl acetate, and stirring to precipitate crystals.
8. The process of claim 7, wherein the weight to volume ratio of 7- (benzyloxy) -3,4,12,12 a-tetrahydro-1H- [1,4] oxazine [3,4-c ] pyrido [2,1-f ] [1,2,4] triazine-6, 8-dione hemihydrate to methanol is 1: 3-70, unit is g/mL.
9. The process according to claim 7, wherein the solvent methanol/methyl tert-butyl ether is used in a volume ratio of 1: 1-5, wherein the volume ratio of methanol to ethyl acetate is 1:1 to 5.
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107709321A (en) * | 2015-04-28 | 2018-02-16 | 盐野义制药株式会社 | The polycyclic Pyridione derivatives and its prodrug being substituted |
CN109311911A (en) * | 2016-06-20 | 2019-02-05 | 盐野义制药株式会社 | It is used to prepare the method for replacing polycyclic pyridines ketone derivatives and its crystal |
CN111925381A (en) * | 2019-10-30 | 2020-11-13 | 浙江工业大学 | Synthesis method of baroxavir key intermediate |
CN112079848A (en) * | 2020-09-24 | 2020-12-15 | 广东莱佛士制药技术有限公司 | Synthesis method of baroxavir key intermediate |
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2020
- 2020-12-24 CN CN202011548278.4A patent/CN114671889A/en active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107709321A (en) * | 2015-04-28 | 2018-02-16 | 盐野义制药株式会社 | The polycyclic Pyridione derivatives and its prodrug being substituted |
CN109311911A (en) * | 2016-06-20 | 2019-02-05 | 盐野义制药株式会社 | It is used to prepare the method for replacing polycyclic pyridines ketone derivatives and its crystal |
CN111925381A (en) * | 2019-10-30 | 2020-11-13 | 浙江工业大学 | Synthesis method of baroxavir key intermediate |
CN112079848A (en) * | 2020-09-24 | 2020-12-15 | 广东莱佛士制药技术有限公司 | Synthesis method of baroxavir key intermediate |
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