CN115028672A

CN115028672A - Ruideciclovir intermediate crystal and preparation method thereof

Info

Publication number: CN115028672A
Application number: CN202210676808.6A
Authority: CN
Inventors: 葛书旺; 付明伟; 芮琦
Original assignee: Nanjing Zhengji Pharmaceutical Research Co ltd
Current assignee: Nanjing Zhengji Pharmaceutical Research Co ltd
Priority date: 2022-06-14
Filing date: 2022-06-14
Publication date: 2022-09-09

Abstract

The invention discloses a Ruideciclovir intermediate crystal with a structure shown in formula I and a preparation method thereof. Compared with the existing crystal, the crystal is a completely new crystal form, and has the advantages of good stability, controllable product quality and the like. The preparation method adopts the isopropyl acetate as a single crystallization solvent, the product yield reaches more than 90 percent, the product purity reaches more than 99 percent, the solvent residue in the product is controllable, and the quality of the product and subsequent products is improved; the preparation method is simple and easy to implement, green and environment-friendly in process conditions, and suitable for industrial scale preparation.

Description

Ruideciclovir intermediate crystal and preparation method thereof

Technical Field

The invention relates to a ridciclovir intermediate crystal and a preparation method thereof, in particular to a novel ridciclovir intermediate crystal with stable crystal form and convenient preparation and a preparation method thereof.

Background

Reddesivir (Remdesivir) is a nucleoside analogue, has wide biological activity, and has inhibitory effect on Ebola virus, respiratory syncytial virus, Hendra virus and other viruses. Thus, the drug has been specifically approved for the treatment of SARS-CoV-2 infection, and its population for use has subsequently expanded to infants who are 28 days old and up to 3.5 kg in weight.

(3R,4R,5R) -2-2 (4-aminopyrrole [2,1-f ] [1,2,4] triazin-7-yl) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-ol (formula I) is an important intermediate for preparing the Reidesciclovir.

CN107074902, CN102596979, CN105899216 and CN103052631 all disclose preparation methods of Rudexilvir intermediates, and specifically, target intermediates are obtained by washing reaction liquid and then performing column chromatography gradient elution separation and concentration. The preparation methods all use ethyl acetate-cyclohexane eluent with different proportions, so the problems of large reagent consumption, easy generation of solid-liquid waste, environmental pollution, low production efficiency and low yield exist in industrial production. In addition, the above processes all result in amorphous products, which have poor stability and are not conducive to storage.

US20160122374 discloses a preparation method of a reed-civir intermediate, which is carried out by washing the reaction solution, concentrating, and adding methyl tert-butyl ether and heptane for crystallization. CN111620876 discloses a preparation method in which ethyl acetate and n-hexane are used as recrystallization solvents. The preparation process disclosed in CN111440176 uses methyl tert-butyl ether for pulping. Although the preparation methods all adopt a refining method of non-column chromatography separation, the reaction solution concentrate is viscous, easy to stick and cohere, and the difficulty of pulping operation is increased. Meanwhile, the adoption of multiple solvents for recrystallization is not beneficial to solvent recovery in industrial production, and can cause multiple solvent residues and influence the quality of the product per se and downstream products. In addition, although the crystallization methods all prepare the crystal form I, a part of amorphous products still have influence on the stability of the products. At present, pure crystal form I products cannot be obtained by the existing methods, which also indicates that the preparation difficulty is higher.

Disclosure of Invention

The purpose of the invention is as follows: aiming at the problems of poor stability, complex preparation, difficult control of product quality and the like of the existing Rudexiliwei intermediate crystal, the invention aims to provide a novel Rudexiliwei intermediate crystal with excellent stability and quality and also provides a preparation method of the crystal, which is convenient and fast to operate.

The technical scheme is as follows: as a first aspect, the invention relates to a Rudexilvir intermediate crystal with a structure shown in a formula I,

the above crystal has at least one characteristic diffraction peak at 5.2 °, 9.0 °, 10.4 °, 13.7 °, 14.0 °, 18.2 °, 18.7 °, 19.6 °, 20.7 ° by X-ray powder diffraction analysis (XRPD) at a diffraction angle 2 θ ± 0.2 °.

Further, the above crystal has at least one diffraction characteristic peak at 5.2 °, 9.0 °, 10.4 °, 13.7 °, 14.0 °, 15.8 °, 16.4 °, 18.2 °, 18.7 °, 18.9 °, 19.6 °, 20.7 °, 20.9 °, 22.8 °, 24.0 °, 25.4 ° expressed by diffraction angle 2 θ ± 0.2 °.

Further, the above crystal has at least one diffraction characteristic peak at 5.2 °, 7.9 °, 9.0 °, 10.4 °, 10.8 °, 11.9 °, 13.7 °, 14.0 °, 14.9 °, 15.5 °, 15.8 °, 16.4 °, 17.7 °, 18.2 °, 18.7 °, 18.9 °, 19.6 °, 20.3 °, 20.7 °, 20.9 °, 21.6 °, 22.2 °, 22.6 °, 22.8 °, 23.4 °, 24.0 °, 24.3 °, 24.5 °, 25.4 °, 26.2 °, 26.7 °, 27.2 °, 27.5 °, 28.2 °, 30.1 °, 31.9 °, 32.7 °, 39.8 °, expressed by a diffraction angle 2 θ ± 0.2 °.

The above crystals had a characteristic melting peak at 79.0. + -. 0.2 ℃ by differential scanning thermal analysis (DSC).

The crystal has a weight loss of 0.4% or less, specifically a non-solvate, at 25 to 112.5 ℃ by thermogravimetric analysis (TGA).

Through the detection and analysis, all the Ruidexiwei intermediate crystals prepared by the existing recrystallization and column chromatography separation refining method are crystal form I, while the crystal obtained by the invention is crystal form II and belongs to different crystal forms.

As a second aspect of the present invention, the above preparation method of the ridciclovir intermediate crystal comprises the following steps:

(1) adding isopropyl acetate with the mass being 1.0-5.5 times of the theoretical amount of the Reidesciclovir intermediate, preferably 3.5-5.5 times of the theoretical amount of the Reidesciclovir intermediate, and heating for dissolving;

(2) cooling, crystallizing, separating, and drying.

Wherein the heating and dissolving temperature in the step (1) is 40-50 ℃.

Specifically, seed crystals are added during heating in the step (1) or during cooling and crystallization in the step (2), and the mass percentage of the seed crystals is 0.3-1.0% of the theoretical amount of the Reideciclovir intermediate; the cooling speed of the cooling crystallization operation is 10 ℃/h, the crystallization temperature is-10 ℃ to 0 ℃, and the crystallization time is 1-2 h.

Has the advantages that: compared with the prior art, the invention has the following remarkable advantages:

(1) the new crystal form of the Rudexiluwei intermediate has the advantages of good stability, controllable product quality and the like, so that the quality of downstream products is ensured;

(2) the product yield reaches more than 90 percent, the product purity reaches more than 99 percent, the preparation method is simple, convenient and easy to operate, the process conditions are green and environment-friendly, and the method is suitable for industrial scale preparation.

Drawings

Figure 1 is an XRPD pattern of crystalline form II of the ridciclovir intermediate of the invention;

figure 2 is a DSC profile of crystalline form II of the ridciclovir intermediate;

figure 3 is a TGA profile of crystalline form II of the ridciclovir intermediate;

figure 4 is an XRPD pattern of crystalline form I of the redciclovir intermediate;

figure 5 is a DSC profile of crystalline form I of the ridciclovir intermediate;

figure 6 is a TGA profile of crystalline form I of the ridciclovir intermediate;

figure 7 is an XRPD pattern of an amorphous solid of the ridciclovir intermediate.

Detailed Description

The technical solution of the present invention is further illustrated by the following examples.

The invention relates to an instrument for detecting the crystal form structure and the performance of a medicament, which comprises the following parts:

1. the powder diffractometer was manufactured by the manufacturer Bruker, type: d8 advance.

2. The differential scanning calorimeter and the thermogravimetric analyzer are manufactured by the manufacturer TA Instrument and have the respective models: DSC25, and TGA 55. Adopting nitrogen atmosphere, and increasing the temperature rate: 10 ℃/min.

Example 1: preparation of washed intermediate reaction solution

With reference to example 4-a of CN107074902, with 7-iodopyrrolo [2,1-f][1,2,4]Triazine-4-amine and (3R,4R,5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) dihydrofuran-2 (3H) -one are used as raw materials and are subjected to NdCl ₃ Catalytic condensation to prepare (3R,4R,5R) -2-2 (4-aminopyrrole [2,1-f ]][1,2,4]Triazin-7-yl) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-ol is specifically manipulated as follows:

iodopyrazole (5.02g, 19.3mmol) was dissolved in tetrahydrofuran (38g) under nitrogen and the solution was cooled to about 0 ℃ with stirring. Chlorotrimethylsilane (2.45ml, 19.4mmol) was added and after about 1 hour phenylmagnesium chloride (2.0M in tetrahydrofuran, 19.75g, 38.0mmol) was added. The reaction mixture was cooled to-20 ℃ and isopropyl magnesium chloride (2.0M in tetrahydrofuran, 9.40g, 19.2mmol) was added slowly. After about 1.5 hours, the reaction mixture was transferred to a mixture of anhydrous neodymium (III) chloride (4.03g, 16.1mmol) and lactone (6.70g, 16.0mmol) in tetrahydrofuran (22g) at about-20 ℃. After about 1.5 hours, the reaction mixture was warmed to-10 ℃ and after another 2 hours, 2M HCl (36g) was added. The mixture was warmed to about 15 ℃ and isopropyl acetate (23g) was added. The layers were separated and the organic layer was washed with 2.5% NaHCO ₃ (2X 44g), 10% NaCl (1X 41g) and concentrated to a volume of about 30 ml. Isopropyl acetate (44g) was added and the solution was concentrated to a volume of about 30 ml. To obtain the intermediate isopropyl acetate solution. Theoretical yield 15.9g, HPLC purity 75.2%.

Example 2: preparation of crystalline form II seeds from intermediate isopropyl acetate solution

And adding 100mg of the crystal form I solid into 10ml of isopropyl acetate for dissolving and filtering, volatilizing at room temperature for 5 days, finding that a white solid is separated out in the process, and determining the crystal form II through XRPD detection.

Example 3

294g (containing 50g of intermediate) of reaction liquid is concentrated to be dry, 50g of isopropyl acetate is added, the temperature is raised to 40 ℃, 250mg of crystal form II is added, the mixture is stirred for 2 hours under heat preservation, the temperature is lowered to 0 ℃ at the speed of 10 ℃/h, then the mixture is stirred for 1 hour under heat preservation, and solid is obtained after suction filtration. Vacuum drying at 35 ℃ to obtain a product which is a crystal form II of a Redexilvir intermediate, wherein the yield is 49.0g, the yield is 98.0%, and the purity is 99.0%.

Example 4

294g (containing 50g of intermediate) of reaction liquid is concentrated to be dry, 180g of isopropyl acetate is added, the temperature is raised to 40 ℃, 250mg of crystal form II is added, the mixture is stirred for 2 hours under heat preservation, the temperature is lowered to 0 ℃ at the speed of 10 ℃/h, then the mixture is stirred for 1 hour under heat preservation, and solid is obtained after suction filtration. Vacuum drying at 35 ℃ to obtain a product which is a crystal form II of a Rudexilvir intermediate (shown in figures 1-3), wherein the yield is 48.7g, the yield is 97.4%, and the purity is 99.2%.

Example 5

294g (containing 50g of intermediate) of reaction liquid is concentrated to be dry, 275g of isopropyl acetate is added, the temperature is raised to 40 ℃, 250mg of crystal form II is added, the mixture is stirred for 2 hours under heat preservation, the temperature is lowered to 0 ℃ at the speed of 10 ℃/h, then the mixture is stirred for 1 hour under heat preservation, and solid is obtained after suction filtration. Vacuum drying at 35 ℃ to obtain the product which is a crystal form II of the intermediate of the Reidesciclovir, wherein the yield is 48.3g, the yield is 96.6 percent, and the purity is 99.5 percent.

Example 6

294g (containing 50g of intermediate) of reaction liquid is concentrated to be dry, 180g of isopropyl acetate is added, the temperature is raised to 40 ℃, the temperature is kept for 2h, then the temperature is slowly lowered to-10 ℃, no solid is separated out in the process, at the moment, 250mg of crystal form II seed crystal is added, the mixture is stirred for 1 h, and the solid is obtained by suction filtration. Vacuum drying at 35 ℃ to obtain the product which is a crystal form II of a Redexilvir intermediate, wherein the yield is 47.3g, the yield is 94.6 percent, and the purity is 99.7 percent.

Comparative example 1: concentrating the isopropyl acetate solution of the intermediate, adding methyl tert-butyl ether and heptane for crystallization

93.5g of reaction liquid (containing 15.9g of intermediate) is concentrated to 45ml at 40 ℃, 75ml of isopropyl acetate is added, the mixture is concentrated to the residual 45ml, 23ml of isopropyl acetate is added, the mixture is concentrated to the residual 45ml, and the mixture is filtered by a sand core. The filtrate was concentrated to 26ml, 75ml of methyl tert-butyl ether was added, stirring was carried out at 25 ℃ for 2 hours, 23ml of heptane was added and stirring was continued for 2 hours, and then the temperature was reduced to-5 ℃ over 8 hours. The solid was filtered off with suction and rinsed with methyl tert-butyl ether/heptane (4:1, 23 ml). Vacuum drying at 35 deg.C to obtain 13.63g of dried product, yield 85.7%, and purity 97.2%.

Comparative example 2: concentrating the ethyl acetate solution of the intermediate, adding methyl tert-butyl ether and pulping

324g (containing 55.2g of intermediate) of the reaction mixture were concentrated to dryness at 40 ℃, 100ml of ethyl acetate was added to dissolve and clear, and then concentrated to dryness, and then 100ml of ethyl acetate was added and concentrated again to dryness. Then 200ml of ethyl acetate was added, and the mixture was concentrated to the remaining 100ml, and 200ml of methyl t-butyl ether was added and the mixture was pulped. After vacuum drying at 35 ℃, 49.2g of solid is obtained, the yield is 89.2 percent, and the purity is 98.9 percent.

Comparative example 3: concentrating the ethyl acetate solution of the intermediate to be dry and recrystallizing by using ethyl acetate/normal hexane mixed solvent

324g (containing 55.2g of intermediate) of the reaction mixture were concentrated to dryness at 40 ℃, 100ml of ethyl acetate was added to dissolve and clear, and then concentrated to dryness, and then 100ml of ethyl acetate was added and concentrated again to dryness. Then, 250ml of a mixed solution of n-hexane and ethyl acetate (volume ratio: 5:1) was added thereto, and the mixture was recrystallized to obtain 48.2g of a solid, which was 87.4% in yield and 96.8% in purity.

Comparative example 4: performing column chromatography elution with ethyl acetate-n-hexane

294g (containing 50g of intermediate) of the reaction mixture were taken and concentrated to dryness at 40 ℃ and then dissolved in 100ml of ethyl acetate and concentrated to dryness. Eluting with 0-50% ethyl acetate-n-hexane, and concentrating to obtain 41.4g of solid, with yield of 82.8% and purity of 99.4%.

Comparative example 5: preparation of solid by concentration of intermediate isopropyl acetate solution

294g (containing 50g of intermediate) of the reaction was concentrated to dryness and concentrated again to dryness by addition of 180g of isopropyl acetate solution to give a pale whitish foamy solid which was detected as an amorphous solid by XRPD (FIG. 7).

The preparation of the Reidesciclovir intermediate is carried out according to the disclosed method in the comparative examples, and the obtained intermediate is subjected to X-ray powder diffraction, differential scanning calorimetry and thermogravimetric analysis, and the results show that the crystal form I is uniform. Specifically, the XRPD pattern of form I is shown in figure 4. Differential Scanning Calorimetry (DSC) curves showed that form I has an endothermic peak at 91.43 ℃, which melts at 91.43 ℃ (fig. 5). The Thermogravimetric (TGA) curve shows 2.397% weight loss of form I upon heating to 110 ℃ as solvent residue (fig. 6). The XRPD pattern of the crystal form I is different from that of the crystal prepared by the invention, so that the Reidesciclovir intermediate solid prepared by the invention is proved to be a new crystal form.

Example 7: long-term stability comparison of Reidesciclovir intermediate to crystal form I and crystal form II

And respectively carrying out stability tests on the crystalline form I and the crystalline form II solid of the Ruideciclovir intermediate in a constant temperature and humidity box for 6 months. The test conditions were: sampling at 25 ℃/75% Relative Humidity (RH) at 0, 1,2, 3 and 6 months respectively, and carrying out purity and impurity detection.

TABLE 1 stability test results for different crystal forms

As can be seen from table 1, crystalline form II, a redciclovir intermediate, exhibits higher stability in long-term stability tests than crystalline form I.

In addition, the invention also provides a preparation method which is different from the prior refining method, and has better industrial production suitability and operational convenience in actual production, and the specific advantages are as follows:

from the above, the novel crystal form and the preparation method thereof provided by the invention have the advantages of no substitution in industrial production, are technical schemes suitable for industrial production, and have the advantages of controllable quality, low cost, short working hours, high yield and good purification effect.

Claims

1. A Rudexilvir intermediate crystal with a structure shown in a formula I,

characterized by having at least one diffraction characteristic peak at 5.2 °, 9.0 °, 10.4 °, 13.7 °, 14.0 °, 18.2 °, 18.7 °, 19.6 °, 20.7 °, expressed as diffraction angle 2 θ ± 0.2 °.

2. The crystal according to claim 1, characterized by having at least one characteristic diffraction peak, expressed in diffraction angle 2 θ ± 0.2 °, at 5.2 °, 9.0 °, 10.4 °, 13.7 °, 14.0 °, 15.8 °, 16.4 °, 18.2 °, 18.7 °, 18.9 °, 19.6 °, 20.7 °, 20.9 °, 22.8 °, 24.0 °, 25.4 °.

3. The crystal according to claim 1, characterized in that it has at least one diffraction characteristic peak, expressed in diffraction angle 2 θ ± 0.2 °, at 5.2 °, 7.9 °, 9.0 °, 10.4 °, 10.8 °, 11.9 °, 13.7 °, 14.0 °, 14.9 °, 15.5 °, 15.8 °, 16.4 °, 17.7 °, 18.2 °, 18.7 °, 18.9 °, 19.6 °, 20.3 °, 20.7 °, 20.9 °, 21.6 °, 22.2 °, 22.6 °, 22.8 °, 23.4 °, 24.0 °, 24.3 °, 24.5 °, 25.4 °, 26.2 °, 26.7 °, 27.2 °, 27.5 °, 28.2 °, 30.1 °, 31.9 °, 32.7 °, 39.8 °.

4. The crystal of claim 1, having a characteristic melting peak at 79.0 ± 0.2 ℃.

5. The crystal according to claim 1, having a weight loss of 0.4% or less at 25 to 112.5 ℃.

6. A preparation method of the ridciclovir intermediate crystal according to any one of claims 1 to 5, characterized by comprising the following steps:

(1) adding isopropyl acetate with the mass being 1.0-5.5 times of the theoretical amount of the Reidesciclovir intermediate, and heating for dissolving;

(2) cooling, crystallizing, separating, and drying.

7. The method according to claim 6, wherein the temperature for the heating dissolution in the step (1) is 40 to 50 ℃.

8. The preparation method according to claim 6 or 7, wherein the amount of isopropyl acetate used in step (1) is 3.5 to 5.5 times by mass of the theoretical amount of the Reidesciclovir intermediate.

9. The preparation method according to claim 6 or 7, characterized in that the seed crystal is added during the heating in the step (1) or during the cooling and crystallization in the step (2), and the mass percent of the seed crystal is 0.3-1.0% of the theoretical amount of the Reidesciclovir intermediate.

10. The production method according to claim 6 or 7, wherein the cooling speed of the cooling crystallization operation is 10 ℃/h, and the crystallization temperature is-10 ℃ to 0 ℃.