Phosphoramidate Compound and Preparation Method and Crystal Thereof

Abstract

The present disclosure involves a composition enriched in compound 61501b, wherein the compound 61501b has a purity of not less than 90% or more. The composition has a significant advantage in preparing a high-purity compound Sp-1. In addition, the present disclosure also provides a preparation method of the composition enriched in compound 61501b. The method adopts a crystallization technique to perform separation and purification, has a simple and convenient operation and good reproducibility, and therefore the compound 61501b in the prepared composition has high purity and quality. Further, the present disclosure also involves a novel crystal form of compound 61501b.

Claims

1. A crystal of a compound 61501b, wherein an X-ray powder diffraction pattern of the crystal has peaks at the following 2 angles: 7.20.3, 9.60.3 and 23.10.3, ##STR00017##

2. The crystal according to claim 1, wherein the X-ray powder diffraction pattern of the crystal has peaks at the following 2 angles: 7.20.3, 8.10.3, 9.60.3, 10.50.3, 14.40.3 and 23.10.3.

3. The crystal according to claim 1, wherein the X-ray powder diffraction pattern of the crystal has peaks at the following 2 angles: 5.30.3, 7.20.3, 8.10.3, 9.60.3, 10.50.3, 11.60.3, 14.40.3, 19.40.3, 21.10.3 and 23.10.3.

4. The crystal according to claim 2, wherein the crystal has an X-ray powder diffraction pattern substantially as shown in FIG. 1.

5. The crystal according to claim 1, wherein the crystal has a purity of 90% by weight or more with respect to the total amount of the compound 61501b.

6. A method for preparing the crystal of a compound 61501b according to claim 1, comprising the following steps: (1) reacting a compound (61501h) with a compound (61501g) under alkaline conditions, and then reacting with a compound (61501f) to obtain a compound 61502: ##STR00018## (2) obtaining the crystal of compound 61501b by isomer separation of the compound 61502: ##STR00019## wherein the isomer separation in the step (2) comprises crystallization on the compound 61502 to obtain the crystal of compound 61501b.

7. The method according to claim 6, wherein the isomer separation in the step (2) comprises: a first step of dissolving the compound 61502 in an organic solvent and stirring for dissolving; and a second step of adding an anti-solvent dropwise to the above solution system, and crystallizing, thereby giving the compound 61501b.

8. The method according to claim 7, wherein the organic solvent comprises at least one of the following: C.sub.1-8 alcohols, C.sub.2-8 ethers, C.sub.3-7 ketones, C.sub.3-7 esters, C.sub.1-2 chlorocarbons, and C.sub.2-7 nitriles.

9. The method according to claim 8, wherein the organic solvent is selected from ethyl acetate, tert-butyl methyl ether, isopropanol or tetrahydrofuran.

10. The method according to claim 9, wherein the anti-solvent is selected from petroleum ether or hexane.

11. The method according to claim 10, wherein the volume ratio of the organic solvent to the anti-solvent is 1:4 to 6 (v/v), 1:3 (v/v), or 1:2 (v/v); the amount ratio of the compound 61502 to the organic solvent is 1:1.25 to 2.5 (w/v), or 1:10 (w/v).

12. The method according to claim 11, wherein the organic solvent is selected from ethyl acetate and the anti-solvent is selected from petroleum ether.

13. The method according to claim 6, wherein the isomer separation in the step (2) comprises: a first step of dissolving the compound 61502 in ethyl acetate, and stirring at room temperature for dissolving; and a second step of adding petroleum ether dropwise to the above solution system, crystallizing and filtering, thereby giving the compound 61501b.

14. The method according to claim 13, wherein the amount ratio of the compound 61502 to ethyl acetate is 1:1.25 to 2.5 (w/v), or 1:10 (w/v), and the amount ratio of ethyl acetate to petroleum ether is 1:4 to 6 (v/v), or 1:3 (v/v).

15. The method according to claim 14, wherein the temperature of the stirring for dissolving and crystallizing in the step (2) is 10 C. to 50 C.

16. A method for preparing a compound S.sub.P-1, comprising steps of: reacting the crystal of the compound 61501b according to claim 1 and a compound 61501c to prepare a compound 61501a, and deprotecting hydroxyl protective group of the compound 61501a to obtain the compound S.sub.P-1 ##STR00020##

17. The method according to claim 16, wherein a Grignard reagent is added to the compound 61501c in a solvent selected from tetrahydrofuran and dichloromethane under the conditions of a temperature of 10 C. to 5 C. to react for 0.5 to 3 hours; thereafter, the crystal of the compound 61501b is added for reaction, and till the reaction is complete, water is added to the reaction solution; then ethyl acetate is used for extraction to give the crude compound 61501a.

18. The method according to claim 17, wherein the crude compound 61501a is purified by using silica gel column chromatography with dichloromethane-methanol as an eluent to obtain the compound 61501a.

19. The method according to claim 16, wherein under the protection of nitrogen gas, the hydroxyl protective group of the compound 61501a is deprotected by catalysis using an acid in a solvent selected from dichloromethane and ethyl acetate under the conditions of a temperature of 10 C. to 5 C.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0044] FIG. 1 shows an X-ray powder diffraction (XRPD) pattern of the compound 61501b prepared according to the method of Example 2; wherein:

TABLE-US-00001 FWHM LHM LHM RHM RHM Labe Position Intensity FWHM (sec) Position Intensity Position Intensity 1 5.2804 2979.8 0.535 1926.8646 4.9427 1489.9214 5.4779 1489.9214 2 7.1823 18790 0.21 757.3567 7.0672 9394.9969 7.2775 9394.9969 3 8.1302 11046 0.216 778.4982 8.0101 5522.8734 8.2263 5522.8734 4 9.6044 27189 0.192 689.8162 9.4976 13594.562 9.6893 13594.562 5 10.5144 11307 0.21 757.349 10.3989 5653.3292 10.6072 5653.3292 6 11.6526 6440 0.233 637.5713 11.5201 3219.999 11.7527 3219.999 7 13.7162 2308.4 0.376 1352.2786 13.4872 1154.2135 13.8626 1154.2135 8 14.3802 10937 0.223 603.8413 14.2503 5468.3332 14.4736 5468.3332 9 15.7764 3340.2 0.299 1074.523 15.6113 1670.1175 15.9098 1670.1175 10 16.1325 3149.2 0.358 1289.0177 15.927 1574.6181 16.2851 1574.6181 11 18.438 5503.7 0.224 806.0012 18.3048 2751.8554 18.5285 2751.8554 12 19.4135 8377 0.234 842.2961 19.2702 4188.4999 19.5041 4188.4999 13 21.0649 6813.1 0.236 848.0567 20.9271 3406.5389 21.1627 3406.5369 14 22.28 2369.7 0.355 1276.1935 22.0567 1184.6361 22.4112 1184.6381 15 23.1413 14030 0.222 800.8144 23.0087 7014.8613 23.2311 7014.8613 16 23.4262 2415.7 0.301 1083.961 23.2757 1207.8268 23.5768 1207.8268 17 27.5688 2471.8 0.466 1677.2255 27.3358 1235.8845 27.8017 1235.8845 18 32.3292 2274.1 0.43 1547.5242 32.1143 1137.0724 32.5442 1137.0724

[0045] FIG. 2 shows the purity of the compound 61501b by HPLC prepared according to the method of Example 2, wherein the HPLC purity of the compound (61501 b) is 100%, and the peak data thereof is shown as below.

TABLE-US-00002 Peak # Name Retention time Area Peak height Area % 1 61501b 26.628 566450 82468 100 Total 566450 82468 100

[0046] FIG. 3 shows an HPLC analysis chromatogram of the compound S.sub.P-1 prepared according to the method of Example 4, wherein the HPLC purity of the compound S.sub.P-1 is 100%, and the peak data thereof is shown as below.

TABLE-US-00003 Peak # Retention time Area Peak height Area % 1 8.388 5096820 317635 100 Total 5096820 317635 100

[0047] FIG. 4 shows the .sup.31P-NMR spectrum of the compound S.sub.P-1 prepared according to the method of Example 4, in which one peak is at Sp 3.64.

[0048] FIG. 5 shows the .sup.1H-NMR spectrum of the compound S.sub.P-1 prepared according to the method of Example 4.

[0049] FIG. 6 shows an HPLC chromatogram of the compound (61502) used in the preparation of the compound 1 in Comparative Example 1. The ratio of the isomers thereof, i.e., 61501e to 61501b is 26.25%:72.03%, and the peak data thereof is shown as below.

TABLE-US-00004 Peak # Name Retention time Area Peak height Area % 1 15.720 32073 3645 1.40 2 17.879 7237 1012 0.32 3 61501e 26.247 599792 86409 26.25 4 61501b 26.655 1645757 235596 72.03 Total 2284859 326662 100

[0050] FIG. 7 shows an HPLC chromatogram of the compound 1 prepared according to the method of Comparative Example 1. The ratio of the isomers thereof, i.e., R.sub.P-1 to S.sub.P-1 is 10.82%:89.18%, and the peak data thereof is shown as below.

[0051]

TABLE-US-00005 Peak # Name Retention time Area Peak height Area % 1 R.sub.p-1 6.833 554365 37166 10.82 2 S.sub.p-1 8.495 4569402 283636 89.18 Total 5123768 320802 100

EXAMPLES

[0052] The contents of the present disclosure is further explained and described below in conjunction with the Examples. It should be understood that these Examples are merely used to describe the present disclosure but are not intended to limit the scope of the present disclosure. As for the experimental methods whose specific conditions are not indicated in the following Examples, the conditions are usually in accordance with the conventional conditions or the conditions suggested by the manufacturers. Unless otherwise specified, all percentages, rates, ratios, or parts are in terms of weight.

[0053] The units in the percent weight in volume in the present disclosure are well known to those skilled in the art and refer to, for example, the weight (g) of a solute per milliliter of a solution. Unless otherwise defined, all the professional and scientific terms used herein have the same meanings as is familiar to one skilled in the art. In addition, any methods and materials similar or equivalent to the described contents can be used in the method of the present disclosure. The preferred embodiments and materials described herein are for illustrative purposes only.

[0054] In the present disclosure, the purity of the compound S.sub.P-1 is determined by an HPLC method, which is conducted with the following column and conditions: octadecylsilane-bonded silica is used as a filler (YMC-hydrosphere C18 column, 150 mm4.6 mm, 3 m), a 0.1% phosphoric acid solution serves as the mobile phase A; methanol-acetonitrile (30:70) serves as the mobile phase B; the gradient elution is run with mobile phase A:mobile phase B=4:1 to 1:4 if necessary; flow rate: 1.0 (ml/min); run time: 46 min; the detection wavelength is 220 nm.

[0055] The purity of the compound 61501b of the present disclosure is also determined by an HPLC method, which is conducted with the following column and conditions: YMC hydrosphere 1504.6 mm, 3 m; 40% to 85% methanol and 2 phosphoric acid/water are used as mobile phases; run time: 46 min; gradient elution and adjusting the proportion of the mobile phase if necessary, flow rate: 1.0 (ml/min).

Example 1 Preparation of the Compound 61502

[0056] ##STR00010##

[0057] To a solution of 61501h (20 g) in dichloromethane (60 ml) was added 61501g (20.6g) at 80 C., and then 19.3g of triethylamine (diluted in 20 ml of dichloromethane) was added. The mixture was stirred overnight at room temperature. To the mixture was added 61501f followed by 19.3 g of triethylamine (diluted in 20 ml of dichloromethane), and the mixture was stirred at room temperature for 4 hours. The mixture was directly deprived of the solvent, and the residue was dissolved in ethyl acetate (200 ml) and water (400 ml); after ethyl acetate was separated, the aqueous phase was washed with ethyl acetate (2100 ml); the ethyl acetate phases were combined, washed with saline and dried with anhydrous sodium sulfate. Ethyl acetate was eliminated by evaporation to give the target compound (61502), which was used directly in the subsequent purification.

Example 2 Preparation of the Compound 61501b

[0058] ##STR00011##

[0059] The compound 61502 (120 g) was dissolved with ethyl acetate (240 ml), and the mixture was stirred constantly, petroleum ether (720 ml) was added dropwise and slowly thereto at room temperature; crystals precipitated and the filtrate was removed by filtration to obtain the compound 61501b (49.5 g) with a yield of 41.2%; the XRPD pattern thereof was shown in FIG. 1, and the purity thereof by HPLC was 100% (as shown in FIG. 2).

Example 3 Preparation of the Compound 61501c

[0060] ##STR00012##

[0061] At room temperature, to a mixed solution of the compound 61501d (20 g) in tetrahydrofuran (200 ml) and water (100 ml) was added sodium carbonate (35.4 g), followed by di-tert-butyl dicarbonate (17.5 g), and the mixture was stirred at room temperature until the completion of the reaction. The mixture was subjected to extraction with ethyl acetate (3200 ml), and ethyl acetate was combined, washed with saline and dried with anhydrous sodium sulfate. After the solvent was eliminated by evaporation, the residue was purified by silica gel chromatography (2.5% to 10% methanol/dichloromethane) to give 18 g of the compound (61501c) with a yield of 67%.

Example 4 Preparation of the Compound S.SUB.P.-1

[0062] ##STR00013##

[0063] (1) Preparation of the Compound 61501a: to a solution of the compound 61501c (5g) in tetrahydrofuran (25 ml) was added a solution of tert-butylmagnesium chloride (1.0 mol/L 41.28 ml) at 0 C.; after stirring and reacting for 1 hour, the compound 61501b (12.42g) was added and stirred at room temperature till the completion of the reaction. Water (250 ml) was added to the mixture, and the aqueous phase was subjected to extraction with ethyl acetate (3250 ml); the ethyl acetate phases were combined, washed with saline and dried with anhydrous sodium sulfate; and the solvent was removed. The compound 61501a (6.7 g) was obtained after purification by silica gel column chromatography (mobile phase: methanol/dichloromethane (the proportion of methanol increased from 2.5% to 5%), gradient elution) with a yield of 71.3%.

[0064] (2) Preparation of the Compound S.sub.P-1: trifluoroacetic acid (20.1 ml) was added to a solution of the compound 61501a (6.7 g) in dichloromethane (33.5 ml) at 0 C., and the mixture was stirred under heat preservation until the reaction was completed. After the mixture was deprived of the solvent, a solution of sodium bicarbonate (150 ml) was added, and the mixture was subjected to extraction with ethyl acetate (3150 ml); the ethyl acetate phases were combined, washed with saline, and dried with anhydrous sodium sulfate; after the solvent was removed, purification by silica gel column chromatography (mobile phase: methanol/dichloromethane (the proportion of methanol increased from 2.5% to 10%), gradient elution) was performed to give the compound S.sub.P-1 (2.7 g, yield: 47%), HPLC purity: 100% (as shown in FIG. 3); .sup.31P-NMR (202 MHz, MeOD): .sub.P 3.64. (as shown in FIG. 4); .sup.1H-NMR (500 MHz, MeOD): .sub.H: 7.56, 7.52 (2d, J=7.5 Hz, 1H, H-6), 7.38-7.33 (m, 7H, ArH), 7.26-7.19 (m, 3H, ArH), 6.25 (apparent q, J=7.5 Hz, 1H, H-1), 5.88, 5.84 (2<d, J=7.5 Hz, 1H, H-5), 5.18-5.12 (m, 2H, OCH.sub.2Ph), 4.49-4.42 (m, 1H, H-5), 4.38-4.31 (m, 1H, H-5), 4.25-4.18 (m, 1H, H-3), 4.07-4.01 (m, 2H, H-4, CHCH.sub.3), 1.38 (apparent t, J=8.5 Hz, 3H, CHCH.sub.3) (as shown in FIG. 5).

Example 5S Preparation of the Compound 61501b

[0065] ##STR00014##

[0066] The compound 61502 (120 g) was dissolved in ethyl acetate (240 ml), and the mixture was stirred constantly at 20 C. to 30 C. for dissolving: petroleum ether (720 ml) was added dropwise and slowly, crystals precipitated and the filtrate was removed by filtration to give the compound 61501b (61.3 g) with a yield of 51%, and the XRPD pattern thereof was shown in FIG. 1, HPLC purity: 99.5%.

Example 6 Preparation of the Compound 61501b

[0067] ##STR00015##

[0068] The compound 61502 (120 g) was dissolved in isopropanol (150 ml), and the mixture was stirred constantly at 40 C. to 50 C. for dissolving: petroleum ether (600 ml) was added dropwise and slowly; crystals precipitated and the filtrate was removed by filtration to give the compound 61501b (54.08 g) with a yield of 45%, HPLC purity: 99.1%.

Example 7 Preparation of the Compound 61501b

[0069] The compound 61502 (120 g) was dissolved in ethyl acetate (300 ml), and the mixture was stirred constantly at 45 C. to 50 C. for dissolving; petroleum ether (1800 ml) was added dropwise and slowly; crystals precipitated and the filtrate was removed by filtration to give the compound 61501b (57.7 g) with a yield of 48%, and the HPLC purity was shown as 99.8%.

Example 8 Preparation of the Compound 61501b

[0070] The compound 61502 (120 g) was dissolved in acetonitrile (1200 ml), and the mixture was stirred constantly at 10 C. to 20 C. for dissolving; hexane (2400 ml) was added dropwise and slowly; crystals precipitated and the filtrate was removed by filtration to give the compound 61501b (36.1 g) with a yield of 30%, HPLC purity: 98.8%.

Comparative Example 1 Preparation of the Compound S.SUB.P.-1 from the Compound 61502

[0071] ##STR00016##

[0072] (1) Preparation of the Compound 615012a: to a solution of the compound (61501c) (2 g) in tetrahydrofuran (10 ml) was added a solution of tert-butylmagnesium chloride (1.0 mol/L, 16 ml) at 0 C.; after stirring and reacting for 1 hour, the compound (61502) (5 g) (the ratio of the isomers thereof. i.e., 61501e to 61501b was 26.25%:72.03%, as shown in FIG. 6) was added, and the mixture was stirred at room temperature until the completion of the reaction. Water (50 ml) was added to the mixture and the aqueous phase was subjected to extraction with ethyl acetate (3100 ml); the ethyl acetate phases were combined, washed with saline and dried with anhydrous sodium sulfate; and the solvent was removed. By purification through silica gel column chromatography (eluent: methanol/dichloromethane: 2.5% to 5%, gradient elution), 1.9g of the compound (615012a) was obtained with a yield of 53%.

[0073] (2) Preparation of the Compound (S.sub.P-1): trifluoroacetic acid (12 ml) was added to a solution of the compound (615012a) (3.98 g) in dichloromethane (10 ml) at 0 C., and the mixture was stirred under heat preservation until the reaction was completed. After the mixture was deprived of the solvent, a solution of sodium bicarbonate (100 ml) was added, and the mixture was subjected to extraction with ethyl acetate (380 ml); the ethyl acetate phases were combined, washed with saline, and dried with anhydrous sodium sulfate; after the solvent was removed, several purifications by silica gel column chromatography (mobile phase: methanol/dichloromethane (the proportion of methanol increased from 2.5% to 10%), gradient elution) were performed to give the compound (1) (1.1 g); the HPLC detection showed that the ratio of the isomers R.sub.P-1 to S.sub.P-1 was 10.82%:89.18% (as shown in FIG. 7); .sup.31P-NMR (202 MHz, MeOD): .sub.P 3.81, 3.64, where .sub.P 3.81 is the absorption site of P in the isomer R.sub.P-1, and .sub.P 3.64 is the absorption site of P in the isomer S.sub.P-1.