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NOVEL METHOD FOR PRODUCING PERAMIVIR TRIHYDRATE, AND WATER-BASED DRYING THEREOF

20220380304 · 2022-12-01

    Inventors

    Cpc classification

    International classification

    Abstract

    The present invention relates to a method for producing peramivir trihydrate, which is an inhibitor of neuraminidase infection, as an anti-influenza agent. According to the production method of the present invention, peramivir trihydrate can be produced with high yield and stability through a process suitable for producing excellent pharmaceuticals and quality control standards (GMP) without using highly-toxic methanol and activated carbon.

    Claims

    1. A method for producing (1S,2S,3R,4R)-3-[(S)-1-acetylamido-2-ethylbutyl]-4-guanidino-2-hydroxycyclopentane-1-carboxylic acid trihydrate (peramivir trihydrate) represented by chemical formula 2: ##STR00007## the method comprising: dissolving (1S,2S,3R,4R)-3-[(S)-1-acetylamido-2-ethylbutyl]-4-guanidino-2-hydroxycyclopentane-1-carboxylic acid (peramivir) in water to prepare an aqueous solution; and adding an alcoholic solvent selected from 1-propanol, 2-propanol, 1-pentanol, 2-butanol, 3-methyl-1-butanol, 2-methyl-1-propanol, or a mixture thereof.

    2. The method of claim 1, wherein the peramivir and water are added such that the ratio of the weight of water to the weight of peramivir is 1:1 to 1:30.

    3. The method of claim 1, wherein the dissolving is conducted with heating and the heating is conducted at a temperature of 90 to 95° C.

    4. The method of claim 1, wherein the alcoholic solvent is added at 75 to 90° C.

    5. The method of claim 1, wherein the alcoholic solvent is added at a volume ratio, relative to the volume of water, of 1:1-10 (alcoholic solvent:water).

    6. The method of claim 1, further comprising cooling the aqueous solution with the alcoholic solvent added thereto, to a temperature of 15 to 30° C.

    7. The method of claim 6, further comprising performing stirring for 6 to 24 hours after the cooling.

    8. The method of claim 7, further comprising performing stirring with cooling to a temperature of 1 to 10° C. after the stirring.

    9. The method of claim 6, further comprising filtering peramivir trihydrate crystals generated by the cooling to prepare a peramivir trihydrate crystal cake.

    10. The method of claim 9, further comprising washing the peramivir trihydrate crystal cake with an alcoholic aqueous solution.

    11. The method of claim 10, wherein the alcoholic aqueous solution is an aqueous solution of 1-propanol, an aqueous solution of 2-propanol, an aqueous solution of 1-pentanol, an aqueous solution of 2-butanol, an aqueous solution of 3-methyl-1-butanol, an aqueous solution of 2-methyl-1-propanol, or a mixture thereof.

    12. The method of claim 10, wherein the concentration of the alcoholic aqueous solution is 1 to 30%.

    13. The method of claim 10, wherein the volume of the alcoholic aqueous solution is a volume corresponding to 0.1 to 20 times the initial weight of peramivir.

    14. The method of claim 1, further comprising subjecting a product, generated through the adding of the alcoholic solvent, to vacuum drying or decompression drying.

    15. The method of claim 14, wherein the drying is conducted in a temperature condition of 25 to 80° C.

    16. The method of claim 14, wherein the drying is humidification drying in a humidity condition of 20 to 80%.

    Description

    BRIEF DESCRIPTION OF THE DRAWINGS

    [0051] FIG. 1 is a schematic diagram for a production process of peramivir trihydrate of the present invention.

    [0052] FIG. 2A shows a liquid chromatography (HPLC) spectrum of peramivir trihydrate produced in Example 2 of the present invention.

    [0053] FIG. 2B shows a liquid chromatography (HPLC) spectrum of peramivir trihydrate produced in Example 2 of the present invention.

    [0054] FIG. 3 shows a .sup.1H-NMR spectrum of peramivir trihydrate, a compound produced in Example 2 of the present invention.

    [0055] FIG. 4 shows a .sup.13C-NMR spectrum of peramivir trihydrate, a compound produced in Example 2 of the present invention.

    [0056] FIG. 5 shows a liquid chromatography-mass spectrometry (LC-MS) of peramivir trihydrate, a compound produced in Example 2 of the present invention.

    [0057] FIG. 6 shows X-ray diffraction (XRD) analysis values of crystal form A of peramivir trihydrate, a compound produced in Example 2 of the present invention.

    [0058] FIG. 7A shows a gas chromatography (GC) spectrum for acceptance limit of each detectable solvents.

    [0059] FIG. 7B shows a gas chromatography (GC) spectrum of peramivir trihydrate, a compound produced in Example 2 of the present invention.

    DETAILED DESCRIPTION

    [0060] Hereinafter, the present invention will be described in more detail with reference to exemplary embodiments. These exemplary embodiments are provided only for the purpose of illustrating the present disclosure in more detail, and therefore, according to the purpose of the present disclosure, it would be apparent to a person skilled in the art that these examples are not construed to limit the scope of the present disclosure.

    EXAMPLES

    [0061] Throughout the present specification, the “%” used to express the concentration of a specific material, unless otherwise particularly stated, refers to (wt/wt) % for solid/solid, (wt/vol) % for solid/liquid, and (vol/vol) % for liquid/liquid.

    [0062] Reagents and Analysis

    [0063] Peramivir (1S,2S,3R,4R)-3-[(S)-1-acetylamido-2-ethylbutyl]-4-guanidino-2-hydroxycyclopentane-1-carboxylic acid), purified water, 1-propanol, 2-propanol, 1-pentanol, and the like were used without purification. For the progression of reaction processes and the identification of purity in the present invention, an instrument, such as liquid chromatography (HPLC), was used to carry out analysis and measurement. For the identification of structures and the analysis of crystal forms, moisture, and residual solvent, nuclear magnetic resonance (.sup.1H NMR, .sup.13C NMR), liquid chromatography mass spectrometry (HPLC), X-ray diffraction analyzer (XRD), moisture meter (Karl Fischer), and gas chromatography (GC) were used to carry out analysis.

    Example 1: Preparation of Peramivir Trihydrate ((1S,2S,3R,4R)-3-[(S)-1-acetylamido-2-ethyl butyl]-4-guanidino-2-hydroxycyclopentane-1-carboxylic Acid Trihydrate) (1)

    [0064] ##STR00004##

    [0065] To a 500.0-L reactor, 30.0 kg of (1S,2S,3R,4R)-3-[(S)-1-acetylamido-2-ethylbutyl]-4-guanidino-2-hydroxycyclopentane-1-carboxylic acid (peramivir) was added, and suspended in 240.0 L of purified water. The reaction product was heated at about 95° C. to completely dissolve the suspension, followed by natural cooling with stirring. When the temperature of the reaction product was 85° C., 45.0 L of 1-propanol was slowly added, followed by natural cooling to 25° C. with stirring. Then, peramivir trihydrate crystal grains were generated at about 40° C. When the temperature of the reactor reached 25° C. through natural cooling, stirring was carried out for about 12 hours for phase transition to crystal form A. In addition, the temperature of the reactor was cooled to 5° C., followed by further stirring for about 3 hours, and after the completion of the reaction, filtration was carried out and washing with 15.0 L of 10% 1-propanol solvent was carried out once. The filtered solid cake was placed in a vacuum dryer with an inner humidity of about 40% in which a purified water bowl was placed in the lower portion, and the solid cake was dried at 40° C. for about 12 hours. After the completion of the drying, peramivir trihydrate was obtained (yield: 95.0%, purity: 99.9%, and moisture: 14.5%).

    [0066] .sup.1H NMR (500 MHz, D.sub.2O, δ): 4.30-4.27 (m, 2H), 3.79-3.74 (m, 1H, —CH), 2.65-2.63 (m, 1H, —CH), 2.48-1.45 (m, 1H, —CH), 2.16-2.12 (m, 1H, —CH), 1.88 (s, 3H, —CH.sub.3), 1.75-1.71 (m, 1H, —CH), 1.41-1.36 (m, 3H), 0.95-0.91 (m, 2H), 0.87-0.84 (t, 3H, —CH.sub.3), 0.82-0.79 (t, 3H, —CH.sub.3); .sup.13C NMR (500 MHz, D.sub.2O, δ): 181.671, 173.686, 155.584, 75.368, 55.201, 54.091, 50.314, 49.933, 43.409, 34.015, 22.780, 21.887, 20.942, 12.128, 11.276; LC-MS (m/z, C.sub.15H.sub.28N.sub.4O.sub.4): calcd for 329.21, found; 329.5.

    Example 2: Preparation of Peramivir Trihydrate ((1 S,2S,3R,4R)-3-[(S)-1-acetylamido-2-ethyl butyl]-4-guanidino-2-hydroxycyclopentane-1-carboxylic Acid Trihydrate) (2)

    [0067] ##STR00005##

    [0068] To a 500.0-L reactor, 30.0 kg of (1S,2S,3R,4R)-3-[(S)-1-acetylamido-2-ethylbutyl]-4-guanidino-2-hydroxycyclopentane-1-carboxylic acid (peramivir) was added, and suspended in 240.0 L of purified water. The reaction product was heated at about 95° C. to completely dissolve the suspension, followed by natural cooling with stirring. When the temperature of the reaction product was 85° C., 45.0 L of 2-propanol was slowly added, followed by natural cooling to 25° C. with stirring. Then, peramivir trihydrate crystal grains were generated at about 40° C. When the temperature of the reactor reached 25° C. through natural cooling, stirring was carried out for about 12 hours for phase transition to crystal form A. In addition, the temperature of the reactor was cooled to 5° C., followed by further stirring for about 3 hours, and after the completion of the reaction, filtration was carried out and washing with 15.0 L of 10% 2-propanol solvent was carried out once. The filtered solid cake was placed in a vacuum dryer with an inner humidity of about 40% in which a purified water bowl was placed in the lower portion, and the solid cake was dried at 40° C. for about 12 hours. After the completion of the drying, peramivir trihydrate was obtained (yield: 95.5%, purity: 99.9%, and moisture: 14.6%).

    [0069] .sup.1H NMR (500 MHz, D.sub.2O, δ): 4.30-4.27 (m, 2H), 3.79-3.74 (m, 1H, —CH), 2.65-2.63 (m, 1H, —CH), 2.48-1.45 (m, 1H, —CH), 2.16-2.12 (m, 1H, —CH), 1.88 (s, 3H, —CH.sub.3), 1.75-1.71 (m, 1H, —CH), 1.41-1.36 (m, 3H), 0.95-0.91 (m, 2H), 0.87-0.84 (t, 3H, —CH.sub.3), 0.82-0.79 (t, 3H, —CH.sub.3); .sup.13C NMR (500 MHz, D.sub.2O, δ): 181.671, 173.686, 155.584, 75.368, 55.201, 54.091, 50.314, 49.933, 43.409, 34.015, 22.780, 21.887, 20.942, 12.128, 11.276; LC-MS (m/z, C.sub.15H.sub.28N.sub.4O.sub.4): calcd for 329.21, found; 329.5.

    [0070] Table 1 below shows 2-theta (deg) values of crystal form A of peramivir trihydrate, which was a compound produced in Example 2.

    TABLE-US-00001 TABLE 1 2-theta Height FWHM Phase Rel. int. I Rel. height No. (deg) d (ang.) (cps) (deg) name (a.u.) (a.u.)  1  4.655(6)  18.97(3) 8303(118)  0.137(10) Unknown 100.00 100.00  2  6.001(4) 14.715(10) 5183(93)  0.119(4) Unknown 37.75 62.43  3  6.499(2) 13.588(4) 2265(61)  0.154(5) Unknown 22.21 27.27  4  7.577(7) 11.658(11) 1895(56)  0.172(7) Unknown 22.44 22.83  5  8.899(6)  9.928(6) 1518(50)  0.116(6) Unknown 11.95 18.28  6 9.3155(19) 9.4858(19) 4543(87) 0.1282(17) Unknown 38.73 54.71  7 10.072(16)  8.775(14)  335(24)  0.130(13) Unknown 2.47 4.03  8  11.11(5)   7.96(3)   87(12)   0.20(4) Unknown 0.90 1.04  9 12.020(3) 7.3568(17) 2949(70)  0.135(3) Unknown 25.72 35.51 10 12.303(3) 7.1884(18) 1132(43)  0.133(6) Unknown 9.78 13.63 11 12.932(5)  6.840(3) 2225(61)  0.221(10) Unknown 30.47 26.79 12 13.168(4) 6.7181(19) 1914(56)  0.141(9) Unknown 16.73 23.05 13 13.611(7)  6.500(3)  769(36)  0.175(16) Unknown 8.33 9.27 14 13.841(11)  6.393(5)  766(36)   0.14(3) Unknown 6.45 9.23 15 13.992(9)  6.324(4) 1133(43)  0.147(19) Unknown 10.32 13.65 16 14.498(14)  6.105(6)  403(26)   0.21(3) Unknown 5.16 4.86 17 14.745(8)  6.003(3)  638(33)   0.17(2) Unknown 6.68 7.68 18 15.299(8)  5.787(3) 3390(75)  0.358(7) Unknown 75.12 40.82 19 15.923(14)  5.561(5)  185(18)   0.16(4) Unknown 1.85 2.23 20 16.658(13)  5.317(4)  981(40)  0.260(12) Unknown 15.29 11.81 21 17.131(11)  5.172(3)  534(30)  0.174(19) Unknown 5.57 6.43 22 17.406(10)  5.091(3)  454(28)   0.16(2) Unknown 4.46 5.47 23 17.854(11)  4.964(3)  307(23)   0.15(2) Unknown 2.82 3.70 24 18.718(6) 4.7367(16) 2038(58)  0.238(5) Unknown 30.19 24.55 25 19.575(8) 4.5313(19) 1340(47)  0.131(15) Unknown 10.73 16.14 26 19.716(13)  4.499(3) 1308(47)   0.16(3) Unknown 12.65 15.75 27 20.199(5) 4.3926(11) 3325(74)  0.208(6) Unknown 42.11 40.05 28 20.737(6) 4.2799(12) 1995(58)  0.219(8) Unknown 26.60 24.03 29 21.199(5) 4.1876(10) 1812(55)  0.200(8) Unknown 22.09 21.82 30 21.766(16)  4.080(3)  963(40)  0.140(12) Unknown 7.25 11.60 31 22.144(15)  4.011(3)  425(27)   0.12(2) Unknown 2.71 5.11 32 22.831(7) 3.8919(12)  990(41)  0.258(11) Unknown 13.97 11.93 33 23.256(7) 3.8217(12)  719(35)  0.217(15) Unknown 8.52 8.66 34 23.770(7) 3.7402(12)  476(28)   0.10(2) Unknown 2.71 5.73 35 24.158(7) 3.6809(10) 2767(68)  0.276(6) Unknown 41.65 33.33 36 24.783(8) 3.5895(12)  759(36)  0.237(17) Unknown 9.84 9.14 37 25.196(12) 3.5316(16)  415(26)  0.30(3) Unknown 6.70 5.00 38  26.35(3)  3.379(4)  806(37)  0.36(5) Unknown 15.65 9.70 39 26.584(8) 3.3503(10) 1116(43)  0.17(2) Unknown 10.47 13.44 40 27.305(12) 3.2635(14)  403(26)  0.32(3) Unknown 7.03 4.86 41 27.863(8) 3.1993(9) 1004(41)  0.331(13) Unknown 17.96 12.09 42 28.457(13) 3.1339(14)  728(35)  0.50(3) Unknown 19.55 8.77 43 29.659(9) 3.0096(9)  834(37)  0.32(2) Unknown 14.57 10.04 44 30.025(7) 2.9737(7)  918(39)  0.20(2) Unknown 10.09 11.06 45 30.308(7) 2.9466(6)  970(40)  0.20(2) Unknown 10.41 11.68 46 30.658(7) 2.9137(7) 1527(50)  0.276(12) Unknown 22.81 18.39 47 31.289(10) 2.8564(9)  699(34)  0.287(14) Unknown 10.85 8.42 48 31.668(7) 2.8230(6)  530(30)  0.120(19) Unknown 3.45 6.39 49 31.934(10) 2.8002(9)  463(28)  0.23(2) Unknown 5.67 5.58 50 32.862(13) 2.7232(11)  173(17)  0.13(3) Unknown 1.37 2.09 51 33.181(12) 2.6977(9)  386(25)  0.26(3) Unknown 6.07 4.65 52 33.785(10) 2.6509(8)  604(32)  0.244(14) Unknown 8.97 7.28 53 34.244(10) 2.6164(8)  332(24)  0.20(2) Unknown 4.12 4.00 54 35.169(13) 2.5496(9)  467(28)  0.20(2) Unknown 5.00 5.62 55 35.472(17) 2.5286(12)  307(23)  0.30(8) Unknown 4.93 3.70 56 35.827(15) 2.5043(10)  252(20)  0.20(5) Unknown 2.80 3.03 57  36.17(2) 2.4813(13)  398(26)  0.26(3) Unknown 5.58 4.79 58  39.60(17)  2.274(9)  89(12)    1.2(3) Unknown 6.63 1.07 59  40.13(4)  2.245(2)  87(12)  0.29(15) Unknown 1.59 1.04 60  42.38(3) 2.1312(12)  139(15)  0.11(6) Unknown 0.80 1.67 61  49.55(12)  1.838(4)  64(10)  0.55(10) Unknown 1.84 0.77 62  59.62(3) 1.5494(7)  57(10)  0.11(5) Unknown 0.60 0.69

    [0071] The results of producing peramivir trihydrate by adjusting the amount of addition of 2-propanol from 40 L to 48 L for reactions are shown as follows (Table 2).

    TABLE-US-00002 TABLE 2 Volume Hydrate Water 2-Propanol ratio produced Yield 240.0 L 40.0 L   6:1 Peramivir   ~94% 240.0 L 45.0 L 5.3:1 trihydrate   95.5% 240.0 L 48.0 L   5:1   ~92%

    Example 3: Preparation of Peramivir Trihydrate ((1S,2S,3R,4R)-3-[(S)-1-acetylamido-2-ethyl butyl]-4-guanidino-2-hydroxycyclopentane-1-carboxylic Acid Trihydrate) (3)

    [0072] ##STR00006##

    [0073] To a 500.0-L reactor, 30.0 kg of (1S,2S,3R,4R)-3-[(S)-1-acetylamido-2-ethylbutyl]-4-guanidino-2-hydroxycyclopentane-1-carboxylic acid (peramivir) was added, and suspended in 240.0 L of purified water. The reaction product was heated at about 95° C. to completely dissolve the suspension, followed by natural cooling with stirring. When the temperature of the reaction product was 85° C., 45.0 L of 1-pentanol was slowly added, followed by natural cooling to 25° C. with stirring. Then, peramivir trihydrate crystal grains were generated at about 40° C. When the temperature of the reactor reached 25° C. through natural cooling, stirring was carried out for about 12 hours for phase transition to crystal form A. In addition, the temperature of the reactor was cooled to 5° C., followed by further stirring for about 3 hours, and after the completion of the reaction, filtration was carried out and washing with 15.0 L of 10% 1-pentanol solvent was carried out once. The filtered solid cake was placed in a vacuum dryer with an inner humidity of about 40% in which a purified water bowl was placed in the lower portion, and the solid cake was dried at 40° C. for about 12 hours. After the completion of the drying, peramivir trihydrate was obtained (yield: 95.1%, purity: 99.9%, and moisture: 14.1%).

    [0074] .sup.1H NMR (500 MHz, D.sub.2O, δ): 4.30-4.27 (m, 2H), 3.79-3.74 (m, 1H, —CH), 2.65-2.63 (m, 1H, —CH), 2.48-1.45 (m, 1H, —CH), 2.16-2.12 (m, 1H, —CH), 1.88 (s, 3H, —CH.sub.3), 1.75-1.71 (m, 1H, —CH), 1.41-1.36 (m, 3H), 0.95-0.91 (m, 2H), 0.87-0.84 (t, 3H, —CH.sub.3), 0.82-0.79 (t, 3H, —CH.sub.3); .sup.13C NMR (500 MHz, D.sub.2O, δ): 181.671, 173.686, 155.584, 75.368, 55.201, 54.091, 50.314, 49.933, 43.409, 34.015, 22.780, 21.887, 20.942, 12.128, 11.276; LC-MS (m/z, C.sub.15H.sub.28N.sub.4O.sub.4): calcd for 329.21, found; 329.5.