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WO2014079356A1 - Sylicylate d'emtricitabine cristallin, procédés de préparation et d'utilisation associés - Google Patents

Sylicylate d'emtricitabine cristallin, procédés de préparation et d'utilisation associés Download PDF

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Publication number
WO2014079356A1
WO2014079356A1 PCT/CN2013/087489 CN2013087489W WO2014079356A1 WO 2014079356 A1 WO2014079356 A1 WO 2014079356A1 CN 2013087489 W CN2013087489 W CN 2013087489W WO 2014079356 A1 WO2014079356 A1 WO 2014079356A1
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WIPO (PCT)
Prior art keywords
emtricitabine
salicylate
mixture
crystal form
formula
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PCT/CN2013/087489
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English (en)
Chinese (zh)
Inventor
张庆文
唐飞
戈耘
侯建
王国平
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Shanghai Institute of Pharmaceutical Industry
Shanghai Shyndec Pharmaceutical Co Ltd
Original Assignee
Shanghai Institute of Pharmaceutical Industry
Shanghai Shyndec Pharmaceutical Co Ltd
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Priority to CN201380038748.4A priority Critical patent/CN104487437B/zh
Publication of WO2014079356A1 publication Critical patent/WO2014079356A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D411/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D411/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D411/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to the field of chemical medicines, and more particularly to the crystalline form of emtricitabine salicylate, and methods for its preparation and use.
  • Emtricitabine chemical name (2R,5S)-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine,
  • the chemical structural formula is as shown in Formula 1, and is a nucleoside reverse transcriptase inhibitor.
  • Emtricitabine is clinically used in combination with other antiretroviral drugs to treat HIV-1 infection (AIDS).
  • AIDS HIV-1 infection
  • fixed-dose combinations based on emtricitabine and tenofovir fumarate play a pivotal role in the treatment and prevention of AIDS.
  • Emtricitabine can form salts with inorganic or organic acids.
  • Chinese patent application CN10167133 reports the separation of emtricitabine from a reaction mixture for the synthesis of emtricitabine using a salicylic acid functionalized polystyrene resin.
  • U.S. Patent No. 6,6000,44, PCT Patent Application Nos. WO2009084033 and WO2011107920, and Organic Process Research & Development, 2006, 10(3): 670-672 report emtricitabine hydrochloride, and report on the use of emtricitabine hydrochloride to achieve Separation and purification of trebutine.
  • US 6600044 also reports emtricitabine mesylate.
  • WO2011083484 reports emtricitabine succinate monohydrate, and basifying it to prepare emtricitabine.
  • WO2011095987 reports that the reaction mixture is obtained by salting emtricitabine with an organic acid such as 2-fluorobenzoic acid, 2-methoxybenzoic acid, 3-hydroxy-2-naphthoic acid and L-pyroglutamic acid. The purpose of separating and purifying emtricitabine.
  • CN101066971A potassium borohydride is used as a reducing agent, and a buffer salt is not used at all.
  • the inventors of the present invention repeated the above operation and found that there was no solid precipitation after the addition of salicylic acid, and the emtricitabine salicylate monohydrate claimed in the examples could not be obtained.
  • CN101066971A was deemed to have been withdrawn from the patent application on November 4, 2009.
  • Emtricitabine is an optically pure compound with two chiral centers of configuration (2R, 5S). Its main synthetic route is stereoselective synthesis based on chiral auxiliary groups. Usually, the chiral auxiliary group L-menthol needs to pass a reduction reaction (usually a boron reagent such as sodium borohydride or potassium borohydride; other reducing agents such as lithium tetrahydrogenate or dihydrogen double (2-) may also be used. Sodium methoxyethoxy)aluminum (trade name: RED-A1) is removed. After quenching, add enough water to dissolve the resulting emtricitabine, then use an organic solvent that is immiscible with water (for example, toluene).
  • a boron reagent such as sodium borohydride or potassium borohydride
  • other reducing agents such as lithium tetrahydrogenate or dihydrogen double (2-
  • RED-A1 Sodium methoxyethoxy)alum
  • the present invention is directed to providing a novel crystalline form of emtricitabine salicylate.
  • Another object of the present invention is to provide a process for the preparation of the above crystalline form of emtricitabine salicylate. It is still another object of the present invention to provide the use of the above crystalline form of emtricitabine salicylate.
  • DSC differential scanning calorimetry
  • a mixture comprising the above crystal form A and form B is provided, the content of the crystal form A being 0-100% by weight, and the content of the form B being 0-100%.
  • the mixture has the following two endothermic peaks in its DSC spectrum: wherein the starting temperature is from 105 ° C to 116 ° C, more preferably from 108 ° C to 115 ° C; The peak temperature of the heat peak is from 112 ° C to 120 ° C, more preferably from 115 ° C to 120 ° C; the peak temperature of the other endothermic peak is from 120 ° C to 128 ° C, more preferably 120 ° C.
  • the mixture has characteristic peaks at the following 2 turns in its XRPD spectrum (CuKa radiation): 7.91 ⁇ 0.2°, 10.12 ⁇ 0.2°, 12.42 ⁇ 0.2°, 14.37 ⁇ 0.2°, 15.91 ⁇ 0.2°, 16.24 ⁇ 0.2°, 16.72 ⁇ 0.2°, 20.25 ⁇ 0.2°, 24 ⁇ 22 ⁇ 0 ⁇ 2 ⁇ , 25 ⁇ 70 ⁇ 0 ⁇ 2 ⁇ , 26 ⁇ 47 ⁇ 0 ⁇ 2 ⁇ ⁇ 28 ⁇ 92 ⁇ 0 ⁇ 2 ⁇ .
  • a mixture comprising the above crystal form A and form B is provided, the mixture having a characteristic peak at the following two corners in its XRPD spectrum (Cu ⁇ radiation): 7.91 ⁇ 0.2°, 10.12 ⁇ 0.2 °, 12.42 ⁇ 0.2°, 14.37 ⁇ 0.2°, 24 ⁇ 22 ⁇ 0 ⁇ 2° and 28 ⁇ 92 ⁇ 0 ⁇ 2. .
  • the crystalline form C has three main endothermic peaks in its DSC spectrum, namely: an initial temperature of 68-72 ° C, a peak temperature of 82-86 ° C; an initial temperature of 107 -111 ° C, peak temperature 112-116 ° C and peak temperature 117-121 ° C.
  • step (b) The mixture a is cooled to obtain the emtricitabine salicylate provided by the present invention as described above. In another preferred embodiment, it is heated to 70-90 ° C in step (a) or heated until emtricitabine and salicylic acid are completely dissolved.
  • step (b) it is cooled to 15-50 ° C, more preferably to room temperature - 50 ° C in step (b).
  • a process for the preparation of a crystalline form of emtricitabine salicylate provided by the invention as described above, the process comprising the steps of:
  • the reducing agent is sodium borohydride
  • the emtricitabine salicylate provided by the present invention as described above is isolated from the mixture ii.
  • the solvent in the mixture i containing emtricitabine has a water content of 80-100%, more preferably 90-100% by weight.
  • the preparation method comprises the following steps:
  • the reducing agent is sodium borohydride
  • the organic solvent is an organic solvent that is immiscible with water; more preferably, the organic solvent is selected from the group consisting of toluene and cyclohexanone.
  • the step (i) is a reaction of a compound having a chemical formula of the formula 3 and a reducing agent, and the organic phase is separated by a liquid separation operation, the reaction is quenched by adjusting the pH of the system, and the solvent is distilled to concentrate. To the resulting residue, a sufficient amount of water was added to dissolve the resulting emtricitabine, and then the L-menthol in the aqueous mixture was extracted with an organic solvent immiscible with water to obtain a mixture i containing emtricitabine.
  • a method for preparing a crystalline form of the above-mentioned emtricitabine salicylate comprising the steps of:
  • the polar solvent is selected from the group consisting of methanol, ethanol, and isopropanol, and the volume ratio of the polar solvent to water is 2:1 to the post-treatment including: standing layering, separating the organic layer rich in product, acidifying and Adjust the pH to 4-4.5, alkalinize and adjust the pH to 6.8-7.2, distill the solvent; add enough water to the residue, dissolve the resulting emtricitabine, and then extract the aqueous mixture with toluene.
  • L-menthol in
  • the moisture content in the step (iii) is controlled by Karl Fischer titration to control the degree of dryness in the step (iii): controlling the moisture content to be 0-1%, obtaining the above-mentioned emtricitabine salicylate anhydrate a mixture of crystal form A and form B; controlling the moisture content to 4-5%, obtaining the crystal form C of the above-mentioned emtricitabine salicylate monohydrate.
  • a process for the preparation of high-purity emtricitabine which comprises as an intermediate of the crystalline form of emtricitabine salicylate provided by the invention as described above, said preparation
  • the method includes the steps of:
  • the reducing agent is sodium borohydride;
  • the alkalizing agent is a tertiary amine, preferably triethylamine.
  • the solvent in the mixture 1 containing emtricitabine has a water content of 80-100%, more preferably 90-100% by weight.
  • the preparation method comprises the following steps:
  • the reducing agent is sodium borohydride
  • the alkalizing agent is a tertiary amine, preferably triethylamine.
  • the quenching reaction is carried out by adjusting the pH of the system.
  • the organic solvent is an organic solvent that is immiscible with water; more preferably, the organic solvent is selected from the group consisting of toluene and cyclohexanone.
  • the step (1) is a reaction of a compound having a chemical formula of the formula 3 and a reducing agent, and the organic phase is separated by a liquid separation operation, the reaction is quenched by adjusting the pH of the system, and the solvent is distilled to concentrate. To the resulting residue, a sufficient amount of water was added to dissolve the resulting emtricitabine, and then the L-menthol in the aqueous phase mixture was extracted with an organic solvent immiscible with water to obtain a mixture 1 containing emtricitabine.
  • it is heated to 70-90 ° C in step (2) or heated to dissolve mixture 1 and salicylic acid.
  • it is cooled to 15-50 ° C in the step (3), more preferably -50 ° C at room temperature.
  • a method for preparing high-purity emtricitabine comprising the steps of: (1) formulating a chemical structure in an aqueous polar solvent in the presence of dipotassium hydrogen phosphate buffer and sodium hydroxide The compound shown in Formula 3 is reacted with sodium borohydride, and post-treated to obtain a mixture 1;
  • the polar solvent is selected from the group consisting of methanol, ethanol, and isopropanol, and the volume ratio of the polar solvent to water is from 2:1 to 3:1;
  • the post-treatment comprises: standing layering, fractionating the organic layer rich in product, acidifying and adjusting the pH to 4-4.5, neutralizing and alkalizing and adjusting the pH to 6.8-7.2, evaporating the solvent; Add enough water to dissolve the resulting emtricitabine, and then extract the L-menthol in the aqueous mixture with toluene; (2) mixing mixture 1 and salicylic acid, heating to dissolve to obtain a mixture 2;
  • the molar ratio of the compound of formula 3 to salicylic acid is from 1:0.9 to 1:1.1;
  • the crystal form obtained according to claim 1 is mixed with an alkalizing agent to obtain emtricitabine; and the alkalizing agent is a tertiary amine, preferably triethylamine.
  • the moisture content in the step (3) is controlled by Karl Fischer titration to control the degree of dryness in the step (3): the moisture content is controlled to be 0-1%, and the above-mentioned emtricitabine salicylate anhydrate is obtained. a mixture of crystal form A and form B; controlling the moisture content to 4-5%, obtaining the crystal form C of the above-mentioned emtricitabine salicylate monohydrate.
  • the present invention provides an efficient method for separating and purifying emtricitabine.
  • Fig. 1 shows the XRPD spectrum of crystal form A of the emtricitabine salicylate anhydride obtained in Example 1.
  • Fig. 2 shows the DSC spectrum of the crystalline form A of the emtricitabine salicylate anhydride obtained in Example 1.
  • Figure 3 shows the XRPD spectrum of Form B of emtricitabine salicylate anhydrate obtained in Example 2.
  • Figure 4 shows the DSC spectrum of Form B of emtricitabine salicylate anhydrate obtained in Example 2.
  • Fig. 5 shows the DSC spectrum of the mixed crystal of ethyl bromide of the emtricitabine salicylate anhydride obtained in Example 3.
  • Fig. 1 shows the XRPD spectrum of crystal form A of the emtricitabine salicylate anhydride obtained in Example 1.
  • Fig. 2 shows the DSC spectrum of the crystalline form A of the emtricitabine salicylate anhydride obtained in Example 1.
  • Figure 3 shows the XRP
  • FIG. 6 shows the DSC spectrum of the mixed crystal of the ethyl bromide of the emtricitabine salicylate anhydride obtained in Example 4.
  • Fig. 7 shows the XRPD spectrum of the mixed crystal of the ethyl bromide of the emtricitabine salicylate anhydride obtained in Example 5.
  • Fig. 8 shows the DSC spectrum of the mixed crystal of the ethyl bromide of the emtricitabine salicylate anhydride obtained in Example 5.
  • Fig. 9 shows the DSC spectrum of the mixed crystal of the ethyl bromide of the emtricitabine salicylate anhydride obtained in Example 6.
  • FIG. 10 shows the DSC spectrum of the crystalline form C of emtricitabine salicylate monohydrate obtained in Example 7.
  • Figure 11 shows the TGA spectrum of the crystalline form C of emtricitabine salicylate monohydrate obtained in Example 8.
  • Fig. 12 shows the XRPD spectrum of the crystalline form C of emtricitabine salicylate monohydrate obtained in Example 8.
  • Figure 13 shows the DSC spectrum of Form C of emtricitabine salicylate monohydrate obtained in Example 8.
  • Fig. 14 shows the DSC spectrum of the mixed crystal of ethyl bromide of the emtricitabine salicylate anhydride obtained in Example 9. detailed description
  • the inventors of the present invention unexpectedly discovered any proportion of crystal form A, crystal form B, crystal form A and form B of emtricitabine salicylate anhydrate. a mixture (or known as a mixed crystal), and a crystalline form C of emtricitabine salicylate monohydrate.
  • the emtricita water As a kind of intermediate, the crystal form of salicylate can effectively obtain high-purity (HPLC purity) pharmaceutical grade emtricitabine by alkalization.
  • High purity refers to the three methods described in the USP Pending Monograph Draft 1 (For Public Comment, Emtricitabine, 2010, The United States Pharmacopeia), and the resulting emtricitabine The purity of the HPLC was checked, the single impurity content was not higher than 0.1%, and the total impurity content was not higher than 0.3%.
  • the crystal form of emtricitabine salicylate provided by the invention has the formula C 15 H 16 FN 3 O 6 S*nH 2 O (C 8 H 1Q FN 3 O 3 S*C 7 H 6 O 3 *nH 2 O), the chemical structural formula is as shown in Formula 2.
  • the emtricitabine salicylate provided by the present invention is a crystalline form A
  • XRPD X-ray powder diffraction
  • Cu Ka radiation X-ray powder diffraction
  • DSC differential scanning calorimetry
  • the emtricitabine salicylate provided by the present invention is a crystalline form B
  • the XRPD spectrum (Cu ⁇ radiation) of the crystalline form B there are characteristic peaks at the following two corners: 7 ⁇ 64 ⁇ 0 ⁇ 2. , 10.07 ⁇ 0.2 °, 10.99 ⁇ 0.2 °, 12.36 ⁇ 0.2 °, 15.16 ⁇ 0.2 °, 15.44 ⁇ 0.2 °, 16.66 ⁇ 0.2 °, 17.21 ⁇ 0.2 °, 20.17 ⁇ 0.2 °, 23.77 ⁇ 0.2 °, 24.18 ⁇ 0.2. , 25.23 ⁇ 0.2. , 26.43 ⁇ 0.2. And 28.72 ⁇ 0.2. .
  • a typical XRPD spectrum of Form B is shown in Figure 3.
  • DSC spectrum of crystal form B temperature range 30-300 ° C, heating rate 10 ° C / min
  • starting temperature is 107-li rC
  • peak temperature is 111-115 ° C
  • Crystal form B A typical DSC spectrum is shown in Figure 4.
  • the emtricitabine salicylate provided by the present invention is a mixture of a crystalline form A and a crystalline form B, in the DSC spectrum (temperature range 30-300 ° C, heating rate 10 ° C / minute), there are two The main endothermic peaks are: starting temperature of 105-116 ° C, peak temperature of 112-120 ° C and peak temperature of 120-128 ° C.
  • the obtained emtricitabine salicylate is a mixture of crystal form A and form B, and has a DSC spectrum (temperature range 30-300 ° C, temperature increase rate 10 ° C / min) As shown in Fig. 5, there are two endothermic peaks, which are: the starting temperature is 113.4 ° C, the peak temperature is 117.9 ° C and the peak temperature is 125.4 ° C.
  • the obtained emtricitabine salicylate is a mixture of crystal form A and form B, and has a DSC spectrum (temperature range 30-300 ° C, temperature increase rate 10 ° C / min As shown in Fig. 6, there are also two endothermic peaks, which are: the starting temperature is 111.6 ° C, the peak temperature is 117.0 ° C and the peak temperature is 120.3 ° C.
  • the resulting emtricitabine salicylate is a mixture of Form A and Form B, the XRPD spectrum of which is shown in FIG.
  • the XRPD spectrum of which is shown in FIG.
  • the XRPD spectrum Cu ⁇ radiation
  • the DSC spectrum (temperature range 30-300 ° C, heating rate 10 ° C / min) is shown in Figure 8, which has two endothermic peaks, respectively: The temperature was 114.7 ° C, the peak temperature was 119.0 ° C and
  • the obtained emtricitabine salicylate is a mixture of crystal form A and form B, and has a DSC spectrum (temperature range 30-300 ° C, temperature increase rate 10 ° C / min) As shown in Fig. 9, there are two endothermic peaks, which are: the starting temperature is 108.6 ° C, the peak temperature is 116.4 ° C, and the peak temperature is 121.0 ° C.
  • the XRPD spectrum (CuKa radiation) of the crystalline form C has a characteristic peak at the following two angles: 7.22 ⁇ 0.2. , 11.43 ⁇ 0.2°, 13.76 ⁇ 0.2°, 17.98 ⁇ 0.2°, 18.65 ⁇ 0.2 ⁇ , 20.76 ⁇ 0.2°, 21.44 ⁇ 0.2°, 22.17 ⁇ 0.2 ⁇ , 23.67 ⁇ 0.2°, 25.31 ⁇ 0.2°, 26.77 ⁇ 0.2° And 27.73 ⁇ 0.2. .
  • a typical XRPD spectrum of the crystal form A is shown in FIG.
  • the starting temperature is 68-72 ° C
  • the peak temperature is 82-86 ° C
  • the starting temperature is 107-111 ° C
  • the peak temperature is 112. -116 ° C and peak temperature of 117-121 ° Co
  • the present invention uses a "X-ray Powder Diffraction" (XRPD) spectrum for crystal characterization.
  • XRPD X-ray Powder Diffraction
  • Methods for determining the XRPD spectrum of a sample are known in the art.
  • the Advanced model of the X-ray powder diffractometer uses copper strontium alpha radiation to obtain the XRPD spectrum of the sample.
  • the invention also uses "Differential Scanning Calorimetry" (DSC) spectrum for crystal characterization.
  • DSC Different Scanning Calorimetry
  • Methods for determining sample DSC are known in the art.
  • the DSC spectrum of the sample can be obtained by using a Netzsch DSC 204 F1 thermal analyzer at a temperature increase rate of 10 ° C per minute from 30 ° C to 300 ° C.
  • the present invention also employs a "thermogravimetric analysis" (TGA) spectrum for hydrate characterization.
  • TGA thermogravimetric analysis
  • Methods for determining sample TG are known in the art.
  • the TGA spectrum of the sample can be obtained by using a Netzsch TG 209 F1 thermal analyzer at a temperature increase rate of 10 ° C per minute from 30 ° C to 350 ° C.
  • the preparation method of emtricitabine salicylate (2) provided by the present invention can be prepared by mixing emtricitabine and salicylic acid in a solvent, heating and dissolving, and then cooling and crystallizing.
  • the mixing includes, but is not limited to, adding salicylic acid to a solution containing emtricitabine or adding emtricitabine to a solution containing salicylic acid.
  • the source of emtricitabine in the solution containing emtricitabine is not limited, and its HPLC (High
  • Performance Liquid Chromatography, high performance liquid chromatography may have a purity of 60% or more, preferably 80% or more, more preferably 90% or more; the solvent is selected from water, an organic solvent, or a mixture of water and an organic solvent. , preferably water.
  • the organic solvent includes, for example, an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran), and an alcohol (e.g., methanol, ethanol).
  • the molar ratio of emtricitabine to salicylic acid is from 1:0.8 to 1:1.5, preferably from 1:0.9 to 1:1.1; most preferably 1:1.
  • the precipitated emtricitabine salicylate can be separated from the salt-forming reaction mother liquor by conventional techniques in the art (e.g., centrifugation, filtration).
  • the resulting emtricitabine salicylate can be dried by conventional techniques in the art.
  • the drying method may be atmospheric drying, vacuum (reduced pressure) drying; drying temperature is 0-100 ° C, preferably 20-90 ° C, more preferably 30-80 ° C.
  • the degree of dryness usually controls the moisture content of the product to be 0-5%.
  • crystal seeds can be added to facilitate crystallization.
  • emtricitabine, salicylic acid and water are mixed, dissolved by heating to clarification, cooled, filtered, and dried to obtain a crystal form.
  • the weight ratio of emtricitabine to water is 1:80 to 1:120, preferably 1:90 to 1:10, more preferably 1:95 to 1:105; heating to 70-90 ° C; standing After cooling to room temperature, the crystals are analyzed, filtered, and dried to obtain crystals.
  • Type A Slow crystallization from a dilute solution tends to give emtricitabine salicylate (2) crystal form A.
  • emtricitabine in one embodiment, salicylic acid and water are mixed, dissolved by heating until clarified, dissolved in emtricitabine, cooled, filtered, and dried to obtain crystals.
  • Type B The weight ratio of emtricitabine to water is 1:5 to 1:15, preferably 1:8 to 1:14, more preferably 1:10 to 1:12; heating to 70-90 ° C; stirring to cool to Filtration is carried out at 40-60 ° C (preferably 45-55 ° C). Rapid crystallization from the concentrated solution tends to give crystal form B of emtricitabine salicylate anhydrate.
  • the reducing agent used in the reduction reaction is selected from the group consisting of sodium borohydride, potassium borohydride, lithium aluminum hydride, sodium dihydrobis(2-methoxyethoxy)aluminum (trade name: RED-A1), preferably sodium borohydride, boron. Potassium hydride; sodium borohydride is more preferred.
  • the reduction is carried out in the presence of a phosphate buffer such as dipotassium hydrogen phosphate and an inorganic base such as sodium hydroxide in an aqueous polar solvent such as methanol, ethanol or isopropanol.
  • the post-treatment comprises the following main steps: the organic phase rich in product is separated by a liquid separation operation, the reaction is quenched by adjusting the pH of the system, the solvent is distilled, and concentrated, and sufficient water is added to the residue to dissolve. The emtricitabine is then stripped of the L-menthol in the aqueous mixture with an organic solvent that is immiscible with water (e.g., toluene).
  • an organic solvent that is immiscible with water e.g., toluene
  • the phosphate buffer is selected from dipotassium hydrogen phosphate, and the molar ratio of dipotassium hydrogen phosphate to the compound of formula 3 is 2.5-3.5:1, preferably 2.8-3.2:1; the inorganic base is selected from sodium hydroxide, sodium hydroxide and The molar ratio of the compound of the formula 3 is from 0.03 to 0.06:1, preferably from 0.04 to 0.05:1.
  • the volume ratio of the polar solvent to water is preferably 1.5 to 3.5:1, more preferably 2-3:1.
  • the molar ratio of the compound 3 to the salicylic acid is from 1:0.8 to 1:1.5, preferably from 1:0.9 to 1:1.1, more preferably 1:1.
  • the solvent in the aqueous mixture from which emtricitabine salicylate (2) is precipitated wherein the water content is from 80 to 100%, preferably from 90 to 100% by weight.
  • emtricitabine salicylate (2) is crystallized from an aqueous mixture, there is no particular requirement for inoculation or not, and it is preferred to inoculate.
  • the precipitated emtricitabine salicylate can be separated from the salt-forming reaction mother liquor by conventional techniques in the art (for example, centrifugation, filtration).
  • the resulting emtricitabine salicylate can be dried by the usual technical means in the art. Dry.
  • the drying method may be atmospheric drying, vacuum drying; the drying temperature is 0-100 ° C, preferably 20-90 ° C, more preferably 30-80 ° C.
  • the degree of dryness usually controls the moisture content of the product to be 0-5%.
  • the synthetic route is:
  • the compound 3 can be produced according to the method reported in the literature.
  • European patent application for example, European patent application
  • the crystal form of emtricitabine salicylate provided by the present invention can be used as an intermediate for preparing emtricitabine.
  • the crystal form of the emtricitabine salicylate (2) is not particularly limited, and for example, it may be emtricitabine salicylate anhydrate crystal form A, crystal form B, or crystal form A and crystal Type B in any proportion of the mixture, or emtricitabine salicylate monohydrate Form C.
  • the crystal form of the obtained intermediate, emtricitabine salicylate is alkalized to give emtricitabine (1).
  • Suitable alkalizing agents are selected from the group consisting of inorganic bases and organic bases, preferably tertiary amines, more preferably triethylamine, diisopropylethylamine, tri-n-butylamine, most preferably triethylamine.
  • the solvent for a suitable alkalization reaction is selected from the group consisting of methanol, ethanol, isopropanol, n-butanol, isobutanol, acetone, ethyl acetate, isopropyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, water, or a mixture thereof.
  • the reducing agent used in the reduction reaction is selected from the group consisting of sodium borohydride, potassium borohydride, lithium aluminum hydride, sodium dihydrobis(2-methoxyethoxy)aluminum (trade name: RED-A1), preferably sodium borohydride, boron.
  • Potassium hydride is more preferably sodium borohydride.
  • a phosphate or borate buffer and an inorganic base are usually added, and the reaction is carried out in an aqueous polar solvent.
  • the phosphate buffer solution is selected from the group consisting of dipotassium hydrogen phosphate, dipotassium hydrogen phosphate and the compound of formula 3 in a molar ratio of 2.5:1 to 3.5:1, preferably 2.8:1 to 3.2:1;
  • the molar ratio of sodium, sodium hydroxide to the compound of formula 3 is 0.03: 1 to 0.06: 1, preferably 0.04: 1 to 0.05: 1;
  • the polar solvent is selected from the group consisting of methanol, ethanol, isopropanol, polar solvent and water.
  • the volume ratio is preferably 1.5:1 to 3.5:1, more preferably 2:1 to 3:1.
  • the post-treatment includes the following main steps: the organic phase rich in product is separated by a liquid separation operation, the reaction is quenched by adjusting the pH of the system to pH 4-4.5, and then alkalized to pH 6.8-7.2. The solvent is distilled to concentrate, and the resulting residue is added with a sufficient amount of water to dissolve the resulting emtricitabine, and then the L-menthol in the aqueous phase mixture is removed in an organic solvent (for example, toluene) which is immiscible with water.
  • an organic solvent for example, toluene
  • the molar ratio of the compound 3 to the salicylic acid is from 1:0.8 to 1:1.5, preferably from 1:0.9 to 1:1.1, more preferably 1:1.
  • Entortabin salicylate (2) The solvent in the aqueous mixture precipitated therefrom, wherein the water content is 80-100%, preferably 90-100% by weight.
  • Emtricitabine salicylate (2) When crystallization is carried out from an aqueous mixture, there is no particular requirement for inoculation or not, and it is preferred to inoculate.
  • the precipitated emtricitabine salicylate can be separated from the salt-forming reaction mother liquor by conventional techniques in the art (e.g., centrifugation, filtration).
  • the resulting emtricitabine salicylate can be dried by conventional techniques in the art.
  • the drying method may be atmospheric drying, vacuum drying; drying temperature is 0-100 ° C, preferably 20-90 ° C, more preferably 30-80 ° C.
  • the degree of dryness usually controls the moisture content of the product to be 0-5%.
  • the compound 3 can be produced according to the method reported in the literature. For example, European Patent Application EP0515157; Chinese Journal of Pharmaceutical Industry, 2005, 36(10): 589-590; PCT Patent Application WO2007077505.
  • HPLC purity refers to the prepared emtricitabine product, which is subjected to HPLC detection and is subjected to the area normalization method according to the obtained chromatogram to obtain the peak area of the compound of Formula 1 at all. The percentage of the sum of the peak areas.
  • HPLC test used according to the USP Pending Monograph Draft 1 - For Public Comment, Emtricitabine, 2010, The United States Pharmacopeia The method (Procedure 1, Procedure 2 and Port Procedure 3) was carried out.
  • room temperature means 20-30 °C.
  • the present invention provides a crystalline form A, a crystalline form B and a mixed crystal of a new emtricitabine salicylate anhydrate, and a crystalline form C of emtricitabine salicylate monohydrate.
  • the present invention provides a method for preparing a high-purity pharmaceutical grade emtricitabine, which comprises using the crystal form of emtricitabine salicylate as an intermediate, and basifying, liberating Tritazine is efficiently separated and purified from a complex mixture containing water, and finally high-purity pharmaceutical grade emtricitabine is efficiently obtained.
  • the invention provides a method for separating and purifying emtricitabine suitable for industrial large-scale production, overcomes the bottleneck of the prior art, and has industrialization prospects.
  • the present invention measures moisture in a sample by Karl Fischer titration.
  • the X-ray diffraction spectrum (XRPD) measuring instrument was a Bmker D8 Advance X-ray diffractometer, and the measurement conditions were: Cu ⁇ line, tube voltage 40 kV, tube current 40 mA.
  • the differential scanning calorimetry (DSC) spectrometer is a Netzsch DSC 204 F1 thermal analyzer with the following conditions: temperature range 30 ° C to 300 ° C, temperature rise rate 10 ° C / min.
  • the thermogravimetric analysis (TGA) spectrometer was a Netzsch TG 209 F1 thermal analyzer with the following conditions: temperature range 30 ° C to 350 ° C, temperature rise rate 10 ° C / min.
  • XRPD spectra, DSC spectra, and TGA spectra may have measurement errors due to differences in assay instruments and deviations in assay conditions. Measurement errors should be taken into account when screening and determining various crystal structures.
  • Emtricitabine (0.5 g, 2 mmol) was added to water (10 ml), stirred and evaporated, and then salicylic acid (0.28 g, 2 mmol) was added and heated to dissolve. Stir overnight and allow to cool to room temperature. Filtered, washed with water and dried in vacuo (20ml) (80 ° C, 4h), as a white solid (0.61 g of, yield 78%): water (Karl Fischer titration) 0.35%; Elementary analysis (C 15 H 16 FN 3 O 6 S) C, H, N calculated values (%) 46.75, 4.18, 10.90, measured values (%) 46.66, 4.24, 1 1.18. The DSC spectrum is shown in Figure 5: There are two endothermic peaks: the starting temperature is 13.4 ° C, the peak temperature is 1 17.9 ° C and the peak temperature is 125.4 ° C.
  • Dipotassium hydrogen phosphate (26.91 g, 1 17.9 mmol) was added to water (43 ml), stirred and dissolved, and added.
  • Dipotassium hydrogen phosphate (71.76 g, 314 mmol) was added to water (1 15 ml), and after stirring, (2R,5S)-(5-fluorocytosin-1-yl)-1,3-oxosulfuric was added.
  • Heterocyclic pentamidine-2-carboxylic acid L-menthyl ester (3) (40 g, 100 mmol), followed by ethanol (284 ml).
  • 0.12 mol/L of sodium borohydride (8 g, 21 1 mmol) was added dropwise at room temperature.
  • Aqueous sodium hydroxide (38.4 ml). After the dropwise addition was completed, the mixture was stirred at room temperature until the reaction was completed. Static layering.
  • emtricitabine salicylate 27 g was added to ethanol (60 ml), heated under reflux, triethylamine (10.5 ml) was added dropwise, and then ethyl acetate (600 ml) was added dropwise, and the mixture was added dropwise. Finished. It was then cooled to room temperature, filtered, and the filtered cake was washed with ethyl acetate.
  • EtOAc EtOAc
  • Emtricitabine (0.5 g, 2 mmol) was added to water (10 ml), stirred and dissolved, and then salicylic acid (0.28 g,
  • Dipotassium hydrogen phosphate (68.47 g, 300 mmol) was added to water (1 15 ml), and after stirring, (2R,5S)-(5-fluorocytosin-1-yl)-1,3-oxosulfuric was added.
  • Heterocyclic pentamidine-2-carboxylic acid L-menthyl ester (3) (40 g, 100 mmol), followed by ethanol (365 ml).
  • Sodium borohydride (8 g, 21 lmmol) in 0.12 mol/L aqueous sodium hydroxide (38.4 ml) was added dropwise at room temperature. After the dropwise addition was completed, the mixture was stirred at room temperature until the reaction was completed. Static layering.
  • Example 8 The emtricitabine salicylate monohydrate (1.0 g) obtained in Example 8 was vacuum dried (50 ° C, 8 h ; 55 ° C, 8 h) to give emtricitabine salicylate anhydrous.
  • Moisture Karl Fischer titration
  • Its DSC spectrum is shown in Figure 14: There are two endothermic peaks: the starting temperature is 105.1 °C, the peak temperature is 1 14.6 °C and the peak temperature is 120.1 °C.
  • the invention adopts the salicylate anhydrate mixed crystal of ethyl and ethylene and the crystalline form of salicylate monohydrate, the crude yield of emtricitabine is higher than that of WO201 1/083484 using succinate monohydrate, and adopts 2 WO201 1/095987 of fluorobenzoate is equivalent to WO2009/084033 using hydrochloride (Table 5).
  • 2-fluorobenzoic acid salicylic acid is cheaper and more readily available; salicylic acid is more convenient and greener than the isopropanol solution of hydrogen chloride used in WO2009/084033.
  • the invention employs salicylate
  • the anhydrate-free mixed crystal of methyl ethyl ethoxide and the crystalline form of salicylate monohydrate were used to separate and purify emtricitabine.
  • the total yield of emtricitabine was comparable to that of WO201 1/107920 using hydrochloride; in particular, the preparation of the present invention Emtricitabine is of high purity.
  • the HPLC purity check is performed.
  • the single impurity is not higher than 0.1%, and the total impurity is not higher than 0.3. % (table 5).
  • Salicylic acid is more convenient and greener than the isopropanol solution of hydrogen chloride used in WO201 1/107920. Further, emtricitabine prepared in Comparative Example 1 which was not isolated and purified by salt formation had the lowest HPLC purity, and was not able to reach the pharmaceutical standard by recrystallization (Table 5).
  • the present invention uses the crystal form of the salicylate anhydrate or monohydrate to separate and purify the entropy as compared with the prior art. The technical effect of his shore is optimal.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne le sylicylate d'emtricitabine cristallin, ainsi que des procédés de préparation et d'utilisation associés. La structure chimique du sylicylate d'emtricitabine est montrée dans la formule 2, où, lorsque n=0, la formule 2 représente du sylicylate d'emtricitabine anhydre, et lorsque n=1, il représente du sylicylate d'emtricitabine monohydraté.
PCT/CN2013/087489 2012-11-22 2013-11-20 Sylicylate d'emtricitabine cristallin, procédés de préparation et d'utilisation associés Ceased WO2014079356A1 (fr)

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CN105130972B (zh) * 2015-08-04 2018-04-20 中孚药业股份有限公司 苯甲酸恩曲他滨盐、其制备方法以及用苯甲酸恩曲他滨盐制备恩曲他滨的方法
CN106496208A (zh) * 2016-10-19 2017-03-15 上海博志研新药物技术有限公司 恩曲他滨的制备方法

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CN101671333A (zh) * 2009-10-11 2010-03-17 沧州那瑞化学科技有限公司 一种恩曲他滨的分离方法
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CN101671333A (zh) * 2009-10-11 2010-03-17 沧州那瑞化学科技有限公司 一种恩曲他滨的分离方法
CN102010404A (zh) * 2010-12-29 2011-04-13 刘建红 拉米夫定和恩曲他滨的提纯精制方法

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WO2016078584A1 (fr) * 2014-11-18 2016-05-26 正大天晴药业集团股份有限公司 Procédé de purification de l'emtricitabine

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