WO2014079356A1 - Emtricitabine sylicylate and crystalline, preparing methods and uses thereof - Google Patents

Emtricitabine sylicylate and crystalline, preparing methods and uses thereof Download PDF

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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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emtricitabine
salicylate
mixture
crystal form
formula
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PCT/CN2013/087489
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French (fr)
Chinese (zh)
Inventor
张庆文
唐飞
戈耘
侯建
王国平
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上海现代制药股份有限公司
上海医药工业研究院
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Priority to CN201380038748.4A priority Critical patent/CN104487437B/en
Publication of WO2014079356A1 publication Critical patent/WO2014079356A1/en

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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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Abstract

Emtricitabine sylicylate crystalline, preparing methods and uses thereof are disclosed. The chemical structure of emtricitabine sylicylate is shown in formula 2, wherein, when n=0, formula 2 represents anhydrous emtricitabine sylicylate, and when n=1, it represents emtricitabine sylicylate monohydrate.

Description

恩曲他滨水杨酸盐及其晶型、 制备方法和用途 技术领域  Emtricitabine salicylate and its crystal form, preparation method and use thereof
本发明涉及化学药物领域， 尤其涉及恩曲他滨水杨酸盐的晶型及其制备方 法和用途。  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.
背景技术 Background technique
恩曲他滨 (emtricitabine)，化学名为 (2R，5S)-5-氟 - 1-[2- (羟甲基)- 1，3-氧硫杂环 戊垸 -5-基]胞嘧啶， 化学结构式如式 1 所示， 为核苷类逆转录酶抑制剂。 恩曲 他滨临床上用于与其他抗逆转录酶药物合用治疗 HIV-1感染 (艾滋病）。 此外， 基于恩曲他滨和富马酸替诺福韦酯的固定剂量复方制剂在艾滋病的治疗和预 防上具有举足轻重的地位。
Figure imgf000002_0001
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). In addition, fixed-dose combinations based on emtricitabine and tenofovir fumarate play a pivotal role in the treatment and prevention of AIDS.
Figure imgf000002_0001
恩曲他滨 （1 )  Emtricitabine (1)
恩曲他滨可以与无机酸或者有机酸成盐。中国专利申请 CN10167133报道， 利用水杨酸官能团化的聚苯乙烯树脂从合成恩曲他滨的反应混合物中分离恩 曲他滨。 美国专利 US6600044， PCT 专利 申请 WO2009084033 和 WO2011107920, 以及 Organic Process Research & Development, 2006, 10(3)： 670-672 报道了恩曲他滨盐酸盐， 并报道利用恩曲他滨盐酸盐实现恩曲他滨的 分离纯化。 US6600044还报道了恩曲他滨甲磺酸盐。 WO2011083484报道了恩 曲他滨琥珀酸盐一水合物， 以及将其碱化游离制备恩曲他滨。 WO2011095987 报道， 通过将恩曲他滨分别与 2-氟苯甲酸、 2-甲氧基苯甲酸、 3-羟基 -2-萘甲酸 和 L-焦谷氨酸等有机酸成盐， 达到从反应混合物中分离纯化恩曲他滨的目的。  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.
中国专利申请 CN101066971A报道了恩曲他滨水杨酸盐一水合物， 但并未 公开恩曲他滨水杨酸盐的晶型。 在说明书第 6页" 4、 恩曲他滨的水杨酸盐 (VI) 的制备"中披露的制备方法： 以 2摩尔当量硼氢化钾为还原剂， 在氢氧化钠存在 下， 在四氢呋喃和水中， 还原 (2R，5S)-(5-氟胞嘧啶 -1-基) -1，3-氧硫杂环戊垸 -2- 羧酸 L-薄荷酯。 反应完全后， 用 10%盐酸调 pH至 4-5， 再用氢氧化钠水溶液调 pH 至中性。 减压回收四氢呋喃后， 残留水层用甲苯洗涤后， 加入 1.1摩尔当量的水 杨酸成盐， 过滤水洗干燥得恩曲他滨水杨酸盐， 收率 84%。 除核磁共振氢谱外， 未见其他表征数据； 仅从公开的核磁数据无法得知该制备方法得到的究竟是恩 曲他滨水杨酸盐无水物或是一水合物。 Chinese patent application CN101066971A reports emtricitabine salicylate monohydrate, but does not disclose the crystal form of emtricitabine salicylate. Preparation method disclosed in "Preparation of salicylic acid salt (VI) of emtricitabine" on page 6 of the specification: using 2 molar equivalents of potassium borohydride as a reducing agent, in the presence of sodium hydroxide, in tetrahydrofuran and In water, (2R, 5S)-(5-fluorocytosin-1-yl)-1,3-oxathiolane-2-carboxylic acid L-menthyl ester was reduced. After the reaction is completed, adjust the pH to 4-5 with 10% hydrochloric acid, and adjust the pH with aqueous sodium hydroxide solution. To neutral. After recovering tetrahydrofuran under reduced pressure, the residual aqueous layer was washed with toluene, and then 1.1 molar equivalent of salicylic acid was added to form a salt, which was filtered and washed with water to obtain emtricitabine salicylate in a yield of 84%. Except for the nuclear magnetic resonance spectrum, no other characterization data was found; it is not known from the published nuclear magnetic data that the preparation method is obtained from the embrittate salicylate anhydride or monohydrate.
另外， CN101066971A报道的上述还原方法中， 采用硼氢化钾作为还原剂， 并且根本没有用到缓冲盐。 本发明人重复上述操作发现， 加入水杨酸后并无固 体析出，无法得到该实施例声称的恩曲他滨水杨酸盐一水合物。 CN101066971A 已于 2009年 11月 4日被视为公开后撤回专利申请。  Further, in the above reduction method reported in 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.
恩曲他滨是一个光学纯化合物， 具有构型为 (2R，5S)的两个手性中心。 其主 流合成路线为基于手性辅基的立体选择性合成。 通常， 手性辅基 L-薄荷醇需要 通过还原反应 (通常采用硼试剂， 例如， 硼氢化钠、 硼氢化钾； 也可以采用其他 还原剂， 例如， 四氢铝锂、 二氢双 (2-甲氧基乙氧基)铝钠 (商品名 RED-A1)脱除。 经淬灭反应后， 加入足量水溶解生成的恩曲他滨， 然后以与水不互溶的有机溶 剂 (例如， 甲苯)提走反应混合物中的 L-薄荷醇， 最后必须从所得的含有无机盐、 含硼杂质等复杂成分的水溶液中， 经分离纯化得到恩曲他滨。 由于恩曲他滨在 水中具有较高溶解度， 因此， 如何将反应产物恩曲他滨从含水的复杂混合物中 高效地实施分离纯化， 成为实现工业化大生产必须解决的难题。  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). Lifting out the L-menthol in the reaction mixture, and finally extracting and purifying the emtricitabine from the obtained aqueous solution containing complex components such as inorganic salts and boron-containing impurities. Since emtricitabine is higher in water Solubility, therefore, how to efficiently separate and purify the reaction product emtricitabine from a complex mixture containing water has become a problem that must be solved to achieve large-scale industrial production.
因此， 本领域迫切需要提供一种高效的分离纯化恩曲他滨的方法。  Therefore, there is an urgent need in the art to provide an efficient method for separating and purifying emtricitabine.
发明内容 Summary of the invention
本发明旨在提供新的恩曲他滨水杨酸盐的晶型。  The present invention is directed to providing a novel crystalline form of emtricitabine salicylate.
本发明的另一个目的是提供上述恩曲他滨水杨酸盐的晶型的制备方法。 本发明的再一个目的是提供上述恩曲他滨水杨酸盐的晶型的用途。  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.
在本发明的第一方面， 提供了化学结构式如式 2所示的恩曲他滨水杨酸盐 的晶型， 其中， 式 2中， n=0时代表恩曲他滨水杨酸盐无水物以及 n=l时代表 恩曲他滨水杨酸盐
Figure imgf000003_0001
在另一优选例中， 提供了所述式 2中， n=0的恩曲他滨水杨酸盐无水物晶 型甲， 其 X-射线粉末衍射 (XRPD)谱 (Cu Κα辐射)中， 在下述 2Θ角有特征峰： 7.92±0.2。， 9.51±0.2。， 13.26±0.2。， 14.37±0.2。， 16.23±0.2。， 19.94±0.2。， 20.33±0.2。， 22.26±0.2°, 23.59±0.2°, 26·69±0·2ο， 32·04±0·2°禾口 38·81±0·2ο。 In a first aspect of the present invention, there is provided a crystalline form of emtricitabine salicylate having a chemical structural formula of the formula 2, wherein, in the formula 2, n=0 represents no emtricitabine salicylate Water and n=l represent emtricitabine salicylate
Figure imgf000003_0001
In another preferred embodiment, a crystal form of emtricitabine salicylate anhydrate having a ratio of n = 0 in the formula 2 is provided in an X-ray powder diffraction (XRPD) spectrum (Cu Κα radiation). , There are characteristic peaks at the following 2 corners: 7.92 ± 0.2. , 9.51 ± 0.2. , 13.26 ± 0.2. , 14.37 ± 0.2. , 16.23 ± 0.2. , 19.94 ± 0.2. , 20.33 ± 0.2. , 22.26±0.2°, 23.59±0.2°, 26·69±0·2 ο , 32·04±0·2° and 38.81±0·2 ο .
在另一优选例中， 在所述晶型甲的差示扫描量热 (DSC)谱中， 有一个主要 吸热峰， 起始温度为 123-127°C， 峰温度为 125-129°C。  In another preferred embodiment, in the differential scanning calorimetry (DSC) spectrum of the crystal form A, there is a main endothermic peak, the onset temperature is 123-127 ° C, and the peak temperature is 125-129 ° C. .
在另一优选例中， 提供了所述式 2中， n=0的恩曲他滨水杨酸盐无水物晶 型乙的 XRPD谱 (CuKa辐射）中，在下述 2Θ角有特征峰： 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°禾口 28·72±0·2°。  In another preferred embodiment, in the XRPD spectrum (CuKa radiation) of the emtricitabine salicylate anhydrate form B of the formula 2 in the formula 2, 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°.
在另一优选例中， 在所述晶型乙的 DSC谱中， 有一个主要吸热峰， 起始温 度为 107-111°C， 峰温度为 111-115°C。  In another preferred embodiment, in the DSC spectrum of Form B, there is a main endothermic peak having an onset temperature of 107-111 ° C and a peak temperature of 111-115 ° C.
在另一优选例中， 提供了包含上述晶型甲和晶型乙的混合物， 以重量计， 所述晶型甲的含量为 0-100%， 所述晶型乙的含量为 0-100%; 较佳地， 该混合 物在其 DSC谱中有下述两个吸热峰： 其中， 起始温度为 105°C-116°C， 更佳地 为 108°C-115°C; —个吸热峰的峰温度为 112°C-120°C， 更佳地为 115°C-120°C; 另一个吸热峰的峰温度为 120°C-128°C， 更佳地为 120°C-127°C; 较佳地， 该混 合物在其 XRPD谱 (CuKa辐射）中，在下述 2Θ角有特征峰：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±0·2ο， 25·70±0·2ο， 26·47±0·2ο禾卩 28·92±0·2ο。 In another preferred embodiment, 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%. Preferably, 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. Preferably, 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 ο , 25·70±0·2 ο , 26·47±0·2 ο禾卩28·92 ±0·2 ο .
在另一优选例中， 提供了包含上述晶型甲和晶型乙的混合物， 该混合物在 其 XRPD谱 (Cu Κα辐射）中， 在下述 2Θ角有特征峰: 7.91±0.2°, 10.12±0.2°, 12.42±0.2°, 14.37±0.2°, 24·22±0·2°禾口 28·92±0·2。。  In another preferred embodiment, 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 Κα 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. .
在另一实施方式中， 提供了所述式 2中， η=1 的恩曲他滨水杨酸盐一水合 物晶型丙， 在其 X-射线粉末衍射谱 (Cu Ka辐射)中， 在下述 2Θ角有特征峰： 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±0·2ο， 23·67±0·2ο， 25·31±0·2ο， 26·77±0·2ο禾卩 27·73±0·2ο。 In another embodiment, the emtricitabine salicylate monohydrate form C of η=1 in the formula 2 is provided, in the X-ray powder diffraction spectrum (Cu Ka radiation), under The 2 corners have characteristic peaks: 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 ο , 23·67±0·2 ο , 25·31±0·2 ο , 26·77±0·2 ο禾卩27·73±0·2 ο .
在另一优选例中， 所述晶型丙在其 DSC谱有三个主要吸热峰， 分别是： 起 始温度为 68-72°C， 峰温度为 82-86°C; 起始温度为 107-111°C， 峰温度为 112-116°C以及峰温度为 117-121°C。  In another preferred embodiment, 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.
在本发明的第二方面， 提供了一种如上所述的本发明提供的恩曲他滨水杨 酸盐的晶型的制备方法， 所述制备方法包括下述步骤：  In a second aspect of the invention, there is provided 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:
(a)将恩曲他滨和水杨酸在水中混合、 加热溶解， 得到混合物 a; 和  (a) mixing emtricitabine and salicylic acid in water and heating to obtain a mixture a;
(b)将混合物 a冷却， 得到如上所述的本发明提供的恩曲他滨水杨酸盐。 在另一优选例中， 在步骤 (a)中加热至 70-90°C或加热至恩曲他滨和水杨酸 完全溶解。 (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.
在另一优选例中， 在步骤 (b)中冷却至 15-50°C， 更佳地至室温 -50°C。  In another preferred embodiment, it is cooled to 15-50 ° C, more preferably to room temperature - 50 ° C in step (b).
在本发明的第三方面， 提供了一种如上所述的本发明提供的恩曲他滨水杨 酸盐的晶型的制备方法， 所述制备方法包括下述步骤：  In a third aspect of the invention, there is provided 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:
ω将化学结构式如式 3所示的化合物和还原剂反应， 得到含有恩曲他滨的 混合物 i;  ω reacts a compound having a chemical formula of the formula 3 and a reducing agent to obtain a mixture i containing emtricitabine;
Figure imgf000005_0001
所述还原剂为硼氢化钠；
Figure imgf000005_0001
The reducing agent is sodium borohydride;
(ii)向混合物 i中加入水杨酸成盐，得到含有恩曲他滨水杨酸盐的混合物 ii; 禾口  (ii) adding salicylic acid to the mixture i to form a mixture containing emtricitabine salicylate ii;
(iii)从混合物 ii中分离得到如上所述的本发明提供的恩曲他滨水杨酸盐。 在另一优选例中， 所述含有恩曲他滨的混合物 i中的溶剂， 以总重量计， 其中水的含量为 80-100%， 更佳地为 90-100%。  (iii) The emtricitabine salicylate provided by the present invention as described above is isolated from the mixture ii. In another preferred embodiment, the solvent in the mixture i containing emtricitabine has a water content of 80-100%, more preferably 90-100% by weight.
在另一优选例中， 所述制备方法包括下述步骤：  In another preferred embodiment, the preparation method comprises the following steps:
ω将化学结构式如式 3所示的化合物和还原剂反应， 淬灭反应后， 将浓缩 得到的残留物和水混合， 用有机溶剂萃取， 得到含有恩曲他滨的混合物 i;  ω reacts a compound having a chemical formula of the formula 3 and a reducing agent, and after quenching the reaction, the concentrated residue is mixed with water, and extracted with an organic solvent to obtain a mixture i containing emtricitabine;
所述还原剂为硼氢化钠；  The reducing agent is sodium borohydride;
(ii)向混合物 i中加入水杨酸成盐，得到含有恩曲他滨水杨酸盐的混合物 ii; 和  (ii) adding salicylic acid to the mixture i to form a mixture containing emtricitabine salicylate ii;
(iii)从混合物 ii中分离得到如上所述的本发明提供的恩曲他滨水杨酸盐。 更佳地， 所述淬灭反应是通过调节体系 pH值进行。  (iii) The emtricitabine salicylate provided by the present invention as described above is isolated from the mixture ii. More preferably, the quenching reaction is carried out by adjusting the pH of the system.
在另一优选例中， 所述有机溶剂是与水不互溶的有机溶剂； 更佳地， 所述 有机溶剂选自甲苯、 环己垸。  In another preferred embodiment, 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.
在另一优选例中， 步骤 (i)是将化学结构式如式 3所示的化合物和还原剂反 应， 通过分液操作分取有机相， 通过调节体系 pH值淬灭反应， 蒸熘溶剂进行 浓缩， 向所得残留物中加入足量水溶解生成的恩曲他滨， 然后以与水不互溶的 有机溶剂提走水相混合物中的 L-薄荷醇， 得到含有恩曲他滨的混合物 i。 在一优选例中， 提供了上述恩曲他滨水杨酸盐的晶型的制备方法， 包括以 下步骤： In another preferred embodiment, 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. In a preferred embodiment, a method for preparing a crystalline form of the above-mentioned emtricitabine salicylate is provided, comprising the steps of:
ω在磷酸氢二钾缓冲液和氢氧化钠存在下， 在含水的极性溶剂中， 将化学 结构式如式 3所示的化合物和硼氢化钠反应， 经后处理， 得到含有恩曲他滨的 混合物 i;  The compound having the chemical formula of the formula (3) and sodium borohydride are reacted in an aqueous polar solvent in the presence of dipotassium hydrogen phosphate buffer and sodium hydroxide, and post-treated to obtain emtricitabine. Mixture i;
所述极性溶剂选自甲醇、 乙醇、 异丙醇， 极性溶剂与水的体积比为 2: 1至 所述后处理包括： 静置分层， 分取富含产物的有机层， 酸化并调节 pH至 4-4.5， 碱化中和并调节 pH至 6.8-7.2， 蒸熘溶剂； 向所得残留物中加入足量水， 溶解生成的恩曲他滨， 然后用与甲苯提走水相混合物中的 L-薄荷醇；  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;
(ii)向混合物 i中加入水杨酸成盐，得到含有恩曲他滨水杨酸盐的混合物 ii; 其中， 式 3的化合物和水杨酸的摩尔比为 1 :0.9至 1 : 1.1；  (ii) adding a salicylic acid salt to the mixture i to obtain a mixture ii containing emtricitabine salicylate; wherein, the molar ratio of the compound of the formula 3 to salicylic acid is 1:0.9 to 1:1.1;
(iii)从混合物 ii中， 经分离和干燥得到如权利要求 1所述的恩曲他滨水杨 酸盐的晶型； 其水分含量为 0-5%。  (iii) From the mixture ii, the crystal form of emtricitabine salicylate according to claim 1 is obtained by separation and drying; and its moisture content is from 0 to 5%.
在一优选例中， 通过卡尔费歇尔滴定法测定水分含量控制所述步骤 (iii)中 的干燥程度： 控制水分含量为 0-1%， 获得上述恩曲他滨水杨酸盐无水物的晶型 甲和晶型乙的混合物； 控制水分含量为 4-5%， 获得上述恩曲他滨水杨酸盐一水 合物的晶型丙。  In a preferred embodiment, 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.
在本发明的第四方面， 提供了一种如上所述的本发明提供的恩曲他滨水杨 酸盐的晶型的用途， 所述晶型用于制备高纯度恩曲他滨， 所述制备包括下述步 骤： 将式 2化合物与碱化试剂混合， 得到高纯度恩曲他滨； 所述碱化试剂为叔 胺， 优选三乙胺。  In a fourth aspect of the invention, there is provided a use of a crystalline form of emtricitabine salicylate provided by the invention as described above, said crystal form for preparing high purity emtricitabine, said The preparation comprises the steps of: mixing the compound of formula 2 with an alkalizing agent to give high purity emtricitabine; the alkalizing agent is a tertiary amine, preferably triethylamine.
在本发明的第五方面， 提供了一种高纯度恩曲他滨的制备方法， 将如上所 述的本发明提供的恩曲他滨水杨酸盐的晶型作为中间体， 所述的制备方法包括 步骤：  In a fifth aspect of the invention, there is provided 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:
(1)将化学结构式如式 3所示的化合物和还原剂反应， 得到混合物 1 ;  (1) reacting a compound having a chemical structural formula of the formula 3 and a reducing agent to obtain a mixture 1;
(2)将混合物 1和水杨酸混合， 加热溶解得到混合物 2;  (2) mixing mixture 1 with salicylic acid, heating to dissolve to obtain a mixture 2;
(3)将混合物 2冷却， 得到如上所述的本发明提供的恩曲他滨水杨酸盐； 和 (3) cooling the mixture 2 to obtain the emtricitabine salicylate provided by the present invention as described above;
(4)将所得如上所述的本发明提供的恩曲他滨水杨酸盐与碱化试剂混合， 得 到恩曲他滨； (4) mixing the obtained emtricitabine salicylate provided by the present invention as described above with an alkalizing agent to obtain emtricitabine;
所述还原剂为硼氢化钠； 所述碱化试剂为叔胺， 优选三乙胺。 The reducing agent is sodium borohydride; The alkalizing agent is a tertiary amine, preferably triethylamine.
在另一优选例中， 所述含有恩曲他滨的混合物 1中的溶剂， 以总重量计， 其中水的含量为 80-100%， 更佳地为 90-100%。  In another preferred embodiment, the solvent in the mixture 1 containing emtricitabine has a water content of 80-100%, more preferably 90-100% by weight.
在另一优选例中， 所述的制备方法包括下述步骤：  In another preferred embodiment, the preparation method comprises the following steps:
(1)将化学结构式如式 3所示的化合物和还原剂反应， 淬灭反应后， 将浓缩 得到的残留物和水混合， 用有机溶剂萃取， 得到含有恩曲他滨的混合物 1 ;  (1) reacting a compound having a chemical structural formula of the formula 3 and a reducing agent, and after quenching the reaction, mixing the concentrated residue with water, and extracting with an organic solvent to obtain a mixture 1 containing emtricitabine;
(2)将混合物 1和水杨酸混合， 加热溶解得到混合物 2;  (2) mixing mixture 1 with salicylic acid, heating to dissolve to obtain a mixture 2;
(3)将混合物 2冷却， 得到如上所述的本发明提供的恩曲他滨水杨酸盐的晶 型； 和  (3) cooling the mixture 2 to obtain a crystal form of emtricitabine salicylate provided by the present invention as described above;
(4)将所得如上所述的本发明提供的恩曲他滨水杨酸盐的晶型与碱化试剂 混合， 得到恩曲他滨；  (4) mixing the crystal form of the emtricitabine salicylate provided by the present invention as described above with an alkalizing agent to obtain emtricitabine;
所述还原剂为硼氢化钠；  The reducing agent is sodium borohydride;
所述碱化试剂为叔胺， 优选三乙胺。  The alkalizing agent is a tertiary amine, preferably triethylamine.
更佳地， 所述淬灭反应是通过调节体系 pH值进行。  More preferably, the quenching reaction is carried out by adjusting the pH of the system.
在另一优选例中， 所述有机溶剂是与水不互溶的有机溶剂； 更佳地， 所述 有机溶剂选自甲苯、 环己垸。  In another preferred embodiment, 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.
在另一优选例中， 步骤 (1)是将化学结构式如式 3所示的化合物和还原剂反 应， 通过分液操作分取有机相， 通过调节体系 pH值淬灭反应， 蒸熘溶剂进行 浓缩， 向所得残留物中加入足量水溶解生成的恩曲他滨， 然后以与水不互溶的 有机溶剂提走水相混合物中的 L-薄荷醇， 得到含有恩曲他滨的混合物 1。  In another preferred embodiment, 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.
在另一优选例中， 在步骤 (2)中加热至 70-90°C或加热至混合物 1和水杨酸 溶解。  In another preferred embodiment, it is heated to 70-90 ° C in step (2) or heated to dissolve mixture 1 and salicylic acid.
在另一优选例中， 在步骤 (3)中冷却至 15-50°C， 更佳地室温 -50°C。  In another preferred embodiment, it is cooled to 15-50 ° C in the step (3), more preferably -50 ° C at room temperature.
在一优选例中， 提供了高纯度恩曲他滨的制备方法， 包括以下步骤： （1) 在 磷酸氢二钾缓冲液和氢氧化钠存在下， 在含水的极性溶剂中， 将化学结构式如 式 3所示的化合物和硼氢化钠反应， 经后处理， 得到混合物 1 ;  In a preferred embodiment, a method for preparing high-purity emtricitabine is provided, 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;
其中所述极性溶剂选自甲醇、 乙醇、异丙醇， 极性溶剂与水的体积比为 2: 1 至 3: 1 ;  Wherein 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;
所述后处理包括： 静置分层， 分取富含产物的有机层， 酸化并调节 pH至 4-4.5， 碱化中和并调节 pH至 6.8-7.2， 蒸熘溶剂； 向所得残留物中加入足量水， 溶解生成的恩曲他滨， 然后用甲苯提走水相混合物中的 L-薄荷醇； (2)将混合物 1和水杨酸混合， 加热溶解得到混合物 2; 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;
式 3化合物和水杨酸的摩尔比为 1 :0.9至 1 : 1.1；  The molar ratio of the compound of formula 3 to salicylic acid is from 1:0.9 to 1:1.1;
(3)将混合物 2冷却， 分离析出的固体， 经干燥， 得到如权利要求 1所述的 恩曲他滨水杨酸盐的晶型； 其水分含量为 0-5%。  (3) The mixture 2 is cooled, and the precipitated solid is separated and dried to obtain a crystal form of emtricitabine salicylate according to claim 1; the moisture content thereof is from 0 to 5%.
(4)将所得如权利要求 1所述的晶型与碱化试剂混合， 得到恩曲他滨； 所述 碱化试剂为叔胺， 优选三乙胺。  (4) 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.
在一优选例中， 通过卡尔费歇尔滴定法测定水分含量控制所述步骤 (3)中的 干燥程度： 控制水分含量为 0-1%， 获得上述恩曲他滨水杨酸盐无水物的晶型甲 和晶型乙的混合物； 控制水分含量为 4-5%， 获得上述恩曲他滨水杨酸盐一水合 物的晶型丙。  In a preferred embodiment, 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.
据此， 本发明提供了一种高效的分离纯化恩曲他滨的方法。  Accordingly, the present invention provides an efficient method for separating and purifying emtricitabine.
附图说明 DRAWINGS
图 1显示了实施例 1所得恩曲他滨水杨酸盐无水物的晶型甲的 XRPD谱。 图 2显示了实施例 1所得恩曲他滨水杨酸盐无水物的晶型甲的 DSC谱。 图 3显示了实施例 2所得恩曲他滨水杨酸盐无水物的晶型乙的 XRPD谱。 图 4显示了实施例 2所得恩曲他滨水杨酸盐无水物的晶型乙的 DSC谱。 图 5显示了实施例 3所得恩曲他滨水杨酸盐无水物的甲乙混晶的 DSC谱。 图 6显示了实施例 4所得恩曲他滨水杨酸盐无水物的甲乙混晶的 DSC谱。 图 7显示了实施例 5所得恩曲他滨水杨酸盐无水物的甲乙混晶的 XRPD谱。 图 8显示了实施例 5所得恩曲他滨水杨酸盐无水物的甲乙混晶的 DSC谱。 图 9显示了实施例 6所得恩曲他滨水杨酸盐无水物的甲乙混晶的 DSC谱。 图 10显示了实施例 7所得恩曲他滨水杨酸盐一水合物的晶型丙的 DSC谱。 图 11显示了实施例 8所得恩曲他滨水杨酸盐一水合物的晶型丙的 TGA谱。 图 12显示了实施例 8所得恩曲他滨水杨酸盐一水合物的晶型丙的 XRPD 谱。  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. 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.
图 13显示了实施例 8所得恩曲他滨水杨酸盐一水合物的晶型丙的 DSC谱。 图 14显示了实施例 9所得恩曲他滨水杨酸盐无水物的甲乙混晶的 DSC谱。 具体实施方式  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
在探索有效分离纯化恩曲他滨的过程中， 本发明发明人意外地发现了恩曲 他滨水杨酸盐无水物的晶型甲、 晶型乙、 晶型甲和晶型乙任意比例的混合物 (或 称为甲乙混晶)， 以及恩曲他滨水杨酸盐一水合物的晶型丙。 以所述恩曲他滨水 杨酸盐的晶型作为中间体，经碱化游离可以有效获得高纯度 (HPLC纯度)的药用 级恩曲他滨。 与此同时， 发明人还发现， 通过形成上述恩曲他滨水杨酸盐无水 物的晶型甲、 晶型乙、 晶型甲及晶型乙任意比例的混合物 (或称为甲乙混晶）， 以及恩曲他滨水杨酸盐一水合物的晶型丙， 可以实现从还原式 3的化合物制备 高纯度的药用级恩曲他滨原料药的目的。 在此基础上， 完成了本发明。 In the process of exploring the effective separation and purification of emtricitabine, 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. At the same time, the inventors have also found that a mixture of crystal form A, crystal form B, crystal form A and form B in any proportion of the above-mentioned emtricitabine salicylate anhydrate is formed (or referred to as a mixed crystal of ethylene and ethylene). ), and the crystalline form C of emtricitabine salicylate monohydrate, can achieve the purpose of preparing a high-purity pharmaceutical grade emtricitabine bulk drug from the compound of the reduced formula 3. On the basis of this, the present invention has been completed.
高纯度是指美国药典恩曲他滨专论草案征求意见稿（USP Pending Monograph Draft 1― For Public Comment, Emtricitabine, 2010, The United States Pharmacopeia)所记载的三种方法， 进行所得恩曲他滨的 HPLC纯度检查， 单一 杂质含量不高于 0.1%， 总杂质含量不高于 0.3%。  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%.
恩曲他滨水杨酸盐  Emtricitabine salicylate
本发明提供的恩曲他滨水杨酸盐的晶型， 分子式为 C15H16FN3O6S*nH2O (C8H1QFN3O3S*C7H6O3*nH2O)， 化学结构式如式 2所示。本发明提供的恩曲他滨 水杨酸盐的晶型， 不含结晶水 (n=0)或为一水合物 (n=0)。 所述恩曲他滨水杨酸 盐可以是单一晶型， 例如晶型甲 (n=0)、 晶型乙 (n=0)或晶型丙 (n=l); 也可以是 不同晶型的混合物， 物 (简称： 甲乙混晶)。
Figure imgf000009_0001
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 crystal form of emtricitabine salicylate provided by the present invention does not contain crystal water (n = 0) or is monohydrate (n = 0). The emtricitabine salicylate may be a single crystal form, such as crystal form A (n=0), crystal form B (n=0) or form C (n=l); or different crystal forms Mixture, substance (abbreviation: A and B mixed crystal).
Figure imgf000009_0001
2  2
当本发明提供的恩曲他滨水杨酸盐是晶型甲时， 在晶型甲的 X-射线粉末衍射 (XRPD)谱 (Cu Ka辐射)中，在下述 2Θ角有特征峰： 7.92±0.2°， 9.51±0.2°， 13.26±0.2°, 14.37±0.2°, 16.23±0.2°, 19.94±0.2°, 20.33±0.2°, 22.26±0.2°, 23.59±0.2°, 26.69±0.2°, 32.04±0.2°和 38.81±0.2°。 所述晶型甲的典型 XRPD谱如图 1所示。 在晶型甲的差 示扫描量热 (DSC)谱 (温度范围 30-300°C， 升温速度 10°C/分钟)中， 有一个主要吸热 峰， 其起始温度（onset temperature)为 123-127°C， 峰温度（peak temperature)为 125-129 °C。 所述晶型甲的典型 DSC谱如图 2所示。  When the emtricitabine salicylate provided by the present invention is a crystalline form A, in the X-ray powder diffraction (XRPD) spectrum (Cu Ka radiation) of the crystal form A, there are characteristic peaks at the following two corners: 7.92 ± 0.2°, 9.51±0.2°, 13.26±0.2°, 14.37±0.2°, 16.23±0.2°, 19.94±0.2°, 20.33±0.2°, 22.26±0.2°, 23.59±0.2°, 26.69±0.2°, 32.04± 0.2° and 38.81±0.2°. A typical XRPD spectrum of the crystal form A is shown in Figure 1. In the differential scanning calorimetry (DSC) spectrum of crystal form A (temperature range 30-300 ° C, heating rate 10 ° C / min), there is a main endothermic peak with an onset temperature of 123. -127 ° C, peak temperature is 125-129 °C. A typical DSC spectrum of the crystal form A is shown in Figure 2.
当本发明提供的恩曲他滨水杨酸盐是晶型乙时， 在晶型乙的 XRPD谱 (Cu Κα辐射）中，在下述 2Θ角有特征峰：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。和 28.72±0.2。。 所述晶型乙的典型 XRPD谱 如图 3所示。 在晶型乙的 DSC谱 (温度范围 30-300°C， 升温速度 10°C/分钟)中， 有一个主要吸热峰 (起始温度为 107-l i rC， 峰温度为 111-115°C)。 所述晶型乙 的典型 DSC谱如图 4所示。 When the emtricitabine salicylate provided by the present invention is a crystalline form B, in the XRPD spectrum (Cu Κα 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. In the DSC spectrum of crystal form B (temperature range 30-300 ° C, heating rate 10 ° C / min), there is a main endothermic peak (starting temperature is 107-li rC, peak temperature is 111-115 ° C ). Crystal form B A typical DSC spectrum is shown in Figure 4.
当本发明提供的恩曲他滨水杨酸盐是晶型甲和晶型乙的混合物时， 在其 DSC谱 (温度范围 30-300°C， 升温速度 10°C/分钟）中， 有两个主要吸热峰， 分 别是： 起始温度为 105-116°C， 峰温度为 112-120°C以及峰温度为 120-128°C。  When 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.
在本发明提供的一个实施例中， 所得恩曲他滨水杨酸盐是晶型甲和晶型乙 的混合物， 其 DSC谱 (温度范围 30-300°C， 升温速度 10°C/分钟)如图 5所示， 其中有两个吸热峰， 分别是： 起始温度为 113.4°C， 峰温度为 117.9°C以及峰温 度为 125.4°C。  In one embodiment provided by the present invention, 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.
在本发明提供的另一个实施例中， 所得恩曲他滨水杨酸盐是晶型甲和晶型 乙的混合物， 其 DSC谱 (温度范围 30-300°C， 升温速度 10°C/分钟)如图 6所示， 其中也有两个吸热峰， 分别是： 起始温度为 111.6°C， 峰温度为 117.0°C以及峰 温度为 120.3°C。  In another embodiment provided by the present invention, 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.
在本发明提供的又一个实施例中， 所得恩曲他滨水杨酸盐是晶型甲和晶型 乙的混合物， 其 XRPD谱如图 7所示。 在其 XRPD谱 (Cu Κα辐射）中， 在下述 2Θ 角有特征峰： 7·91±0·2ο， 10·12±0·2ο， 12·42±0·2ο， 15.91±0.2°, 16·24±0·2ο， 16.72±0.2°, 20·25±0·2ο， 24.22±0.2°, 25·70±0·2ο， 26·47±0·2ο， 28·46±0·2° 和 28.92±0.2°ο 其 DSC谱 (温度范围 30-300°C， 升温速度 10°C/分钟)如图 8所示， 其中有两个吸热峰， 分别是： 起始温度为 114.7°C， 峰温度为 119.0°C以及峰温 度为 123.6°C。 In still another embodiment of the present invention, the resulting emtricitabine salicylate is a mixture of Form A and Form B, the XRPD spectrum of which is shown in FIG. In its XRPD spectrum (Cu Κα radiation), there are characteristic peaks at the following 2 Θ angles: 7·91±0·2 ο , 10·12±0·2 ο , 12·42±0·2 ο , 15.91±0.2° , 16·24±0·2 ο , 16.72±0.2°, 20·25±0·2 ο , 24.22±0.2°, 25·70±0·2 ο , 26·47±0·2 ο , 28·46 ±0·2° and 28.92±0.2° 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 peak temperature was 123.6 ° C.
在本发明提供的再一个实施例中， 所得恩曲他滨水杨酸盐是晶型甲和晶型 乙的混合物， 其 DSC谱 (温度范围 30-300°C， 升温速度 10°C/分钟)如图 9所示， 其中有两个吸热峰， 分别是： 起始温度为 108.6°C， 峰温度为 116.4°C， 以及峰 温度为 121.0°C。  In still another embodiment of the present invention, 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.
当本发明提供的是恩曲他滨水杨酸盐一水合物晶型丙时， 在晶型丙的 XRPD 谱 (CuKa辐射）中，在下述 2Θ角有特征峰： 7.22±0.2。， 11.43±0.2°, 13.76±0.2°, 17.98±0.2°, 18.65±0.2ο， 20.76±0.2°, 21.44±0.2°, 22.17±0.2ο， 23.67±0.2°, 25.31±0.2°, 26.77±0.2°和 27.73±0.2。。所述晶型甲的典型 XRPD谱如图 12所示。在晶型丙的 DSC谱有三个主 要吸热峰， 分别是： 起始温度为 68-72°C， 峰温度为 82-86°C; 起始温度为 107-111°C， 峰 温度为 112-116°C以及峰温度为 117-121°Co When the present invention provides a crystalline form of embritabin salicylate monohydrate, 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 ο , 20.76±0.2°, 21.44±0.2°, 22.17±0.2 ο , 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. There are three main endothermic peaks in the DSC spectrum of Form C: the starting temperature is 68-72 ° C, the peak temperature is 82-86 ° C; the starting temperature is 107-111 ° C, and the peak temperature is 112. -116 ° C and peak temperature of 117-121 ° Co
本发明采用" X射线粉末衍射 "(X-ray Powder Diffraction, XRPD)谱进行晶 型表征。测定样品的 XRPD谱的方法在本领域中是已知的。例如使用 Bmker D8 Advanced型号的 X射线粉末衍射仪， 采用铜 Κα辐射获取样品的 XRPD谱。 本发明还采用 "示差扫描量热"（Differential Scanning Calorimetry, DSC) 谱 进行晶型表征。测定样品 DSC的方法在本领域中是已知的。例如可使用 Netzsch DSC 204 F1热分析仪， 以 10°C每分钟的升温速率， 从 30°C升温至 300°C， 获 取样品的 DSC谱。 The present invention uses a "X-ray Powder Diffraction" (XRPD) spectrum for crystal characterization. Methods for determining the XRPD spectrum of a sample are known in the art. For example using Bmker D8 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. Methods for determining sample DSC are known in the art. For example, 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.
本发明还采用 "热重分析"（Thermogravimetric Analysis, TGA) 谱进行水合 物表征。测定样品 TG的方法在本领域中是已知的。例如可使用 Netzsch TG 209 F1 热分析仪， 以 10°C每分钟的升温速率， 从 30°C升温至 350°C， 获取样品的 TGA谱。  The present invention also employs a "thermogravimetric analysis" (TGA) spectrum for hydrate characterization. Methods for determining sample TG are known in the art. For example, 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.
恩曲他滨水杨酸盐 (2)的制备方法  Preparation method of emtricitabine salicylate (2)
本发明提供的恩曲他滨水杨酸盐 (2)的制备方法， 可以通过将恩曲他滨和水 杨酸在溶剂中混合， 加热溶解后， 经冷却结晶来制备。 所述的混合包括但不限 于， 向含有恩曲他滨的溶液中加入水杨酸， 或向含有水杨酸的溶液中加入恩曲 他滨。  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.
所述含有恩曲他滨的溶液中的恩曲他滨的来源没有限制， 其 HPLC (High The source of emtricitabine in the solution containing emtricitabine is not limited, and its HPLC (High
Performance Liquid Chromatography, 高效液相色谱）纯度可以为 60%以上， 较 佳地为 80%以上， 更佳地为 90%以上； 所述的溶剂选自水、 有机溶剂、 或水和 有机溶剂的混合， 优选水。 所述有机溶剂包括诸如醚类 (例如， 四氢呋喃、 2- 甲基四氢呋喃）， 以及醇类 (例如， 甲醇、 乙醇)。 恩曲他滨和水杨酸的摩尔比为 1： 0.8至 1 : 1.5， 优选 1 : 0.9至 1 : 1.1； 最优选 1 : 1。 可以通过本领域通常 的技术手段 (例如， 离心、 过滤)， 将析出的恩曲他滨水杨酸盐从成盐反应母液 中分离出来。 可以通过本领域通常的技术手段对所得恩曲他滨水杨酸盐进行干 燥。 干燥方法可以是常压干燥、 真空 (减压)干燥； 干燥温度为 0-100°C， 优选 20-90 °C , 更优选 30-80°C。 干燥程度， 通常控制产品水分含量为 0-5%。 冷却结 晶时可以加入晶种以利结晶。 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%. When cooling the crystal, crystal seeds can be added to facilitate crystallization.
一般来说， 要获得恩曲他滨水杨酸盐无水物的单一晶型， 如晶型甲或晶型 乙， 需要更为严格地控制结晶条件。  In general, to obtain a single crystalline form of emtricitabine salicylate anhydrate, such as Form A or Form B, more stringent control of the crystallization conditions is required.
在获得恩曲他滨水杨酸盐无水物晶型甲的一种实施方式中， 将恩曲他滨、 水杨酸和水混合， 加热溶解至澄清后， 冷却、 过滤、 干燥得到晶型甲。 恩曲他 滨和水的重量比为 1： 80至 1： 120， 优选为 1： 90至 1： 1 10， 更优选为 1： 95 至 1： 105 ; 加热至 70-90°C ; 静置冷却至室温充分析晶后， 过滤、 干燥得到晶 型甲。 从稀溶液中缓慢析晶趋向于得到恩曲他滨水杨酸盐 (2)晶型甲。 In one embodiment of obtaining a crystalline form of emtricitabine salicylate anhydrate, emtricitabine, salicylic acid and water are mixed, dissolved by heating to clarification, cooled, filtered, and dried to obtain a crystal form. A. 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.
在获得恩曲他滨水杨酸盐无水物晶型乙的一种实施方式中， 将水杨酸和水 混合， 加热溶解至澄清后加入恩曲他滨溶解， 冷却、 过滤、 干燥得到晶型乙。 恩曲他滨和水的重量比为 1： 5至 1 ： 15，优选为 1 ： 8至 1 ： 14，更优选为 1： 10 至 1： 12; 加热至 70-90°C ; 搅拌冷却至 40-60°C (优选 45-55 °C )时便进行过滤。 从浓溶液中快速析晶趋向于得到恩曲他滨水杨酸盐无水物晶型乙。  In one embodiment of obtaining embrittate salicylate anhydrate form B, 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.
根据本发明记载的内容， 本领域的熟练技术人员， 可以通过调控结晶反应 液的浓度、 结晶反应液的温度、 搅拌速度、 降温速度、 反溶剂等结晶工艺参数 和工艺条件， 来获得各种比例的恩曲他滨水杨酸盐无水物晶型甲和晶型乙的混 合物。  According to the content described in the present invention, those skilled in the art can obtain various ratios by adjusting the concentration of the crystallization reaction solution, the temperature of the crystallization reaction solution, the stirring speed, the cooling rate, the anti-solvent and other crystallization process parameters and process conditions. a mixture of emtricitabine salicylate anhydrate Form A and Form B.
本发明提供的恩曲他滨水杨酸盐 (2)的另一种制备方法的实施方式中， 以 (2R，5S)-(5-氟胞嘧啶 -1-基) -1，3-氧硫杂环戊垸 -2-羧酸 L-薄荷酯 (3)为起始原料， 首先经还原反应脱去手性辅基 L-薄荷醇， 经后处理得到含有恩曲他滨的含水的 混合物， 然后通过与水杨酸成盐， 使得生成的恩曲他滨形成水溶性差的恩曲他 滨水杨酸盐 (2)， 从含水的混合物中分离得到。 还原反应所用的还原剂选自硼氢 化钠、 硼氢化钾、 四氢铝锂、 二氢双 (2-甲氧基乙氧基)铝钠 (商品名 RED-A1) , 优选硼氢化钠、 硼氢化钾； 更加优选硼氢化钠。 所述还原反应在磷酸盐缓冲液 (例如磷酸氢二钾)和无机碱 (例如氢氧化钠)存在下， 在含水的极性溶剂 (例如甲 醇、 乙醇、 异丙醇)中进行。 所述的后处理包括下述主要步骤， 通过分液操作分 取富含产物的有机相， 通过调节体系 pH值淬灭反应， 蒸熘溶剂进行浓缩， 向 所得残留物中加入足量水溶解生成的恩曲他滨， 然后以与水不互溶的有机溶剂 (例如， 甲苯)提走水相混合物中的 L-薄荷醇。 所述磷酸盐缓冲液选择磷酸氢二 钾， 磷酸氢二钾与式 3化合物的摩尔比为 2.5-3.5: 1，优选 2.8-3.2: 1 ; 所述无机碱 选择氢氧化钠，氢氧化钠与式 3化合物的摩尔比为 0.03-0.06: 1，优选 0.04-0.05: 1。 所述含水的极性溶剂中，极性溶剂与水的体积比优选 1.5-3.5: 1，更加优选 2-3 : 1。 通常化合物 3和水杨酸的摩尔比为 1 : 0.8至 1 : 1.5， 优选 1 : 0.9至 1 : 1.1， 更优选 1 : 1。 恩曲他滨水杨酸盐 (2)从中析出的含水的混合物中的溶剂， 以总重 量计， 其中水的含量为 80-100%， 优选 90-100%。 恩曲他滨水杨酸盐 (2)从含水 的混合物中析晶时， 接种与否并无特别要求， 优选接种。 可以通过本领域通常 的技术手段 (例如， 离心、 过滤)， 将析出的恩曲他滨水杨酸盐从成盐反应母液 中分离出来。 可以通过本领域通常的技术手段对所得恩曲他滨水杨酸盐进行干 燥。干燥方法可以是常压干燥、 真空干燥； 干燥温度为 0-100°C， 优选 20-90°C， 更优选 30-80°C。 干燥程度， 通常控制产品水分含量为 0-5%。 合成路线为： In another embodiment of the preparation method of emtricitabine salicylate (2) provided by the present invention, (2R,5S)-(5-fluorocytosin-1-yl)-1,3-oxygen The thietidine-2-carboxylic acid L-menthyl ester (3) is used as a starting material, and the chiral auxiliary L-menthol is first removed by reduction reaction, and post-treated to obtain an aqueous mixture containing emtricitabine. Then, by forming a salt with salicylic acid, the resulting emtricitabine forms a poorly water-soluble emtricitabine salicylate (2), which is isolated from the aqueous mixture. 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). 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. In the aqueous polar solvent, the volume ratio of the polar solvent to water is preferably 1.5 to 3.5:1, more preferably 2-3:1. Usually, 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. When 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:
1 .还原 Restore
2.水杨酸 2. Salicylic acid
Figure imgf000013_0001
所述化合物 3 可以按照文献报道的方法制备。 例如， 欧洲专利申请
Figure imgf000013_0001
The compound 3 can be produced according to the method reported in the literature. For example, European patent application
EP0515157 ; 中国医药工业杂志， 2005， 36(10)： 589-590； PCT 专利申请 WO2007077505。 EP0515157; Chinese Journal of Pharmaceutical Industry, 2005, 36(10): 589-590; PCT Patent Application WO2007077505.
恩曲他滨水杨酸盐的晶型的用途  Use of the crystalline form of emtricitabine salicylate
本发明提供的恩曲他滨水杨酸盐的晶型可以作为制备恩曲他滨的中间体。 所述恩曲他滨水杨酸盐 (2)的晶型并没有特别限定， 例如， 可以是恩曲他滨水杨 酸盐无水物晶型甲、 晶型乙、 或晶型甲和晶型乙任意比例的混合物， 或者是恩 曲他滨水杨酸盐一水合物晶型丙。 所得中间体恩曲他滨水杨酸盐的晶型经碱 化， 即可游离得到恩曲他滨 (1)。 适宜的碱化试剂选自无机碱和有机碱， 优选叔 胺， 更优选三乙胺、 二异丙基乙基胺、 三正丁胺， 最优选三乙胺。 适宜的碱化 反应的溶剂选自甲醇、 乙醇、 异丙醇、 正丁醇、 异丁醇、 丙酮、 乙酸乙酯、 乙 酸异丙酯、 四氢呋喃、 2-甲基四氢呋喃、 水， 或者其混合物， 优选甲醇、 乙醇、 异丙醇、 乙酸乙酯、 乙酸异丙酯或者其混合物， 更加优选甲醇、 乙醇或异丙醇 与乙酸乙酯或乙酸异丙酯的混合物。  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. Preference is given to methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate or a mixture thereof, more preferably a mixture of methanol, ethanol or isopropanol with ethyl acetate or isopropyl acetate.
例如， 一条以恩曲他滨水杨酸盐 (2)作为中间体制备恩曲他滨的合成路线 为  For example, a synthetic route for the preparation of emtricitabine with emtricitabine salicylate (2) as an intermediate is
Figure imgf000013_0002
在上述合成路线中，以 (2R，5S)-(5-氟胞嘧啶 -1-基) -U-氧硫杂环戊垸 -2-羧酸 L-薄荷酯 (3)起始原料， 首先经还原反应脱去手性辅基 L-薄荷醇， 经后处理得到 含有恩曲他滨的含水的混合物， 然后通过与水杨酸成盐， 使得生成的恩曲他滨 形成水溶性差的恩曲他滨水杨酸盐 (2)， 从含水的混合物中分离出来。 还原反应 所用的还原剂选自硼氢化钠、 硼氢化钾、 四氢铝锂、 二氢双 (2-甲氧基乙氧基) 铝钠 (商品名 RED-A1), 优选硼氢化钠、 硼氢化钾， 更加优选硼氢化钠。
Figure imgf000013_0002
In the above synthetic route, (2R,5S)-(5-fluorocytosin-1-yl)-U-oxathiolane-2-carboxylic acid L-menthol ester (3) starting material, firstly removing the chiral auxiliary L-menthol by reduction reaction, post-treatment to obtain an aqueous mixture containing emtricitabine, and then forming a salt with salicylic acid The resulting emtricitabine forms a poorly water-soluble emtricitabine salicylate (2) which is separated from the aqueous mixture. 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.
采用硼氢化钠、 硼氢化钾 (优选硼氢化钠)作为还原剂时， 通常添加磷酸盐 或硼酸盐缓冲液以及无机碱， 在含水的极性溶剂中进行反应。 所述磷酸盐缓冲 液， 选择磷酸氢二钾， 磷酸氢二钾与式 3化合物的摩尔比为 2.5 ： 1至 3.5 ： 1， 优选 2.8 : 1至 3.2 : 1 ; 所述无机碱， 选择氢氧化钠，氢氧化钠与式 3化合物的摩 尔比为 0.03： 1至 0.06： 1，优选 0.04： 1至 0.05： 1 ; 所述极性溶剂选自甲醇、 乙 醇、 异丙醇， 极性溶剂与水的体积比优选 1.5： 1至 3.5： 1， 更加优选 2 : 1至 3 : 1。 所述的后处理包括下述主要步骤， 通过分液操作分取富含产物的有机相， 通过调节体系 pH值至 pH 4-4.5淬灭反应， 再进行碱化中和至 pH 6.8-7.2， 蒸熘 溶剂进行浓缩， 向所得残留物中加入足量水溶解生成的恩曲他滨， 然后以与水 不互溶的有机溶剂 (例如， 甲苯)提走水相混合物中的 L-薄荷醇。 通常化合物 3 和水杨酸的摩尔比为 1： 0.8至 1： 1.5， 优选 1： 0.9至 1： 1.1， 更优选 1： 1。 恩 曲他滨水杨酸盐 (2)从中析出的含水的混合物中的溶剂， 以总重量计， 其中水的 含量为 80-100%， 优选 90-100%。 恩曲他滨水杨酸盐 (2)从含水的混合物中析晶 时，接种与否并无特别要求，优选接种。可以通过本领域通常的技术手段 (例如， 离心、 过滤)， 将析出的恩曲他滨水杨酸盐从成盐反应母液中分离出来。 可以通 过本领域通常的技术手段对所得恩曲他滨水杨酸盐进行干燥。 干燥方法可以是 常压干燥、 真空干燥； 干燥温度为 0-100°C， 优选 20-90°C， 更优选 30-80°C。 干燥程度， 通常控制产品水分含量为 0-5%。  When sodium borohydride or potassium borohydride (preferably sodium borohydride) is used as the reducing agent, 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. Usually, 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%.
所述化合物 3 可以按照文献报道的方法制备。 例如， 欧洲专利申请 EP0515157 ; 中国医药工业杂志， 2005， 36(10)： 589-590； PCT 专利申请 WO2007077505。  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.
如本文所用， "HPLC 纯度"是指将制备得到的恩曲他滨产品， 经过 HPLC 检测， 根据所得到的色谱图谱， 进行面积归一法而得到的如式 1所示化合物的 峰面积在所有峰面积总和中所占有的百分数。 采用的 HPLC检查， 参照美国药 典恩曲他滨专论草案征求意见稿 （USP Pending Monograph Draft 1— For Public Comment, Emtricitabine, 2010, The United States Pharmacopeia)所记载的三禾中方 法 (Procedure 1， Procedure 2 禾口 Procedure 3)进行。 As used herein, "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. The 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.
如本文所用， "室温" 是指 20-30°C。  As used herein, "room temperature" means 20-30 °C.
本发明提到的上述特征， 或实施例提到的特征可以任意组合。 本案说明书所 揭示的所有特征可与任何组合物形式并用，说明书中所揭示的各个特征，可以任何 可提供相同、均等或相似目的的替代性特征取代。 因此除有特别说明， 所揭示的特 征仅为均等或相似特征的一般性例子。  The above-mentioned features mentioned in the present invention, or the features mentioned in the embodiments, may be arbitrarily combined. All of the features disclosed in the present specification can be used in combination with any of the compositions, and the various features disclosed in the specification can be substituted for any alternative feature that provides the same, equal or similar purpose. Therefore, unless otherwise stated, the disclosed features are only general examples of equal or similar features.
本发明的主要优点在于：  The main advantages of the invention are:
1、 本发明提供了新的恩曲他滨水杨酸盐无水物的晶型甲、 晶型乙和甲乙 混晶， 以及恩曲他滨水杨酸盐一水合物的晶型丙。  1. 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.
2、 本发明提供了一种高纯度的药用级恩曲他滨的制备方法， 包括将所述 恩曲他滨水杨酸盐的晶型作为中间体， 碱化后， 将游离得到的恩曲他滨从含水 的复杂混合物中高效地实施分离纯化， 最终高效地获得高纯度的药用级恩曲他 滨。  2. 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.
3、 本发明提供了一种适合工业化大生产的分离纯化恩曲他滨的方法， 克 服了现有技术的瓶颈， 并具有产业化前景。  3. 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.
下面结合具体实施例， 进一步阐述本发明。 应理解， 这些实施例仅用于说 明本发明而不用于限制本发明的范围。 下列实施例中未注明具体条件的实验方 法， 通常按照常规条件或按照制造厂商所建议的条件。 除非另外说明， 否则所 有的百分数、 比率、 比例、 或份数按重量计。  The invention is further illustrated below in conjunction with specific embodiments. It is to be understood that the examples are not intended to limit the scope of the invention. The experimental methods in which the specific conditions are not indicated in the following examples are usually carried out according to conventional conditions or according to the conditions recommended by the manufacturer. All percentages, ratios, ratios, or parts are by weight unless otherwise indicated.
除非另行定义， 文中所使用的所有专业与科学用语与本领域熟练人员所熟 悉的意义相同。 此外， 任何与所记载内容相似或均等的方法及材料皆可应用于 本发明方法中。 文中所述的较佳实施方法与材料仅作示范之用。  Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those skilled in the art. In addition, any methods and materials similar or equivalent to those described may be employed in the methods of the invention. The preferred embodiments and materials described herein are for illustrative purposes only.
本发明通过卡尔费歇尔 (Karl Fischer)滴定法测定样品中的水分。 X-射线衍 射谱 (XRPD)的测定仪器为 Bmker D8 Advance X-射线衍射仪， 测定条件为： Cu Κα线，管电压 40kV， 管电流 40mA。差示扫描量热 (DSC)谱测定仪器为 Netzsch DSC 204 F1热分析仪， 测定条件为： 温度范围 30°C至 300°C， 升温速度 10°C/ 分钟。热重分析 (TGA)谱测定仪器为 Netzsch TG 209 F1热分析仪，测定条件为： 温度范围 30°C至 350°C， 升温速度 10°C/分钟。 由于测定仪器的不同和测定条 件的偏差， XRPD谱、 DSC谱和 TGA谱可能存在测定误差。 在甄别和确定各 种晶体结构时， 应当将测定误差考虑在内。  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 Κα 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.
实施例 1 恩曲他滨水杨酸盐无水物晶型甲的制备 Example 1 Preparation of emtricitabine salicylate anhydrate crystal form A
将恩曲他滨（l)(0.5g， 2mmol)、 水杨酸 (0.28g， 211111101)加入水(501111)中， 在 搅拌下加热到 80°C， 溶清后停止搅拌， 静置室温析晶两天。 过滤， 小心挑出几 颗针状晶体弃去， 真空干燥 (80°C， 6h), 得棉花状白色晶体 (O. lg, 收率 13%): 水分 (卡尔费歇尔滴定法） 0.68% ; 元素分析 (C15H16FN3O6S)C、 H、 计算值 (%)46.75 , 4.18 , 10.90 ,测定值(％)46.26， 3.95 , 1 1.02； 1HNMR (DMSO-d6) δ 1 1.60 (br s, exchangeable, 1H)， 8.22 (d, J=7.2Hz, 1H)， 7.85 (br s, exchangeable, 1H)， 7.79 (dd, J=1.6, 8.0Hz, 1H)， 7.61 (br s， exchangeable, 1H)， 7.51 (m, 1H)， 6.90-6.96 (m, 2H), 6.13-6.16 (m, 1H)， 5.45 (br s, exchangeable, 1H)， 5.19 (t, J=4.0Hz, 1H)， 3.72-3.82 (m, 2H), 3.43 (dd, J=5.6, 12.0Hz, 1H)， 3.13 (dd, J=4.4, 12.0Hz, 1H)。 其 XRPD谱见图 1， 其 XRPD谱数据见表 1。 其 DSC谱见图 2: 有一个吸热峰， 起始温度为 124.7°C， 峰温度为 127.2 °C。 Add emtricitabine (1) (0.5g, 2mmol), salicylic acid (0.28g, 211111101) to water (501111), stir to 80 ° C under stirring, dissolve after stirring, stop at room temperature Crystal two days. Filtration, carefully pick out a few needle-like crystals, discard it, and dry it in vacuo (80 ° C, 6 h) to obtain cotton-like white crystals (O. lg, yield 13%): Moisture (Karl Fischer titration) 0.68% Elemental analysis (C 15 H 16 FN 3 O 6 S) C, H, calculated (%) 46.75, 4.18, 10.90, measured (%) 46.26, 3.95, 1 1.02; 1HNMR (DMSO-d 6 ) δ 1 1.60 (br s, exchangeable, 1H), 8.22 (d, J=7.2Hz, 1H), 7.85 (br s, exchangeable, 1H), 7.79 (dd, J=1.6, 8.0Hz, 1H), 7.61 (br s , exchangeable, 1H), 7.51 (m, 1H), 6.90-6.96 (m, 2H), 6.13-6.16 (m, 1H), 5.45 (br s, exchangeable, 1H), 5.19 (t, J=4.0Hz, 1H), 3.72-3.82 (m, 2H), 3.43 (dd, J=5.6, 12.0 Hz, 1H), 3.13 (dd, J=4.4, 12.0 Hz, 1H). Its XRPD spectrum is shown in Figure 1, and its XRPD spectrum data is shown in Table 1. The DSC spectrum is shown in Figure 2: There is an endothermic peak with an onset temperature of 124.7 ° C and a peak temperature of 127.2 ° C.
表 1 实施例 1所得晶型甲的 XRPD谱数据  Table 1 XRPD spectral data of the crystal form A obtained in Example 1
峰 2Θ(°) d(A) 峰面积 相对强度(％) Peak 2Θ(°) d(A) Peak area Relative intensity (%)
1 6.613 13.3547 3900 2.03 1 6.613 13.3547 3900 2.03
2 7.915 11.1613 153218 79.94  2 7.915 11.1613 153218 79.94
3 9.514 9.2886 44545 23.24  3 9.514 9.2886 44545 23.24
4 13.262 6.6704 14063 7.34  4 13.262 6.6704 14063 7.34
5 14.370 6.1585 191678 100.00 5 14.370 6.1585 191678 100.00
6 16.226 5.4582 182811 95.37 6 16.226 5.4582 182811 95.37
7 18.847 4.7045 11409 5.95  7 18.847 4.7045 11409 5.95
8 19.936 4.4499 25772 13.45  8 19.936 4.4499 25772 13.45
9 20.330 4.3647 29335 15.30  9 20.330 4.3647 29335 15.30
10 22.264 3.9896 35379 18.46  10 22.264 3.9896 35379 18.46
11 22.761 3.9037 13968 7.29  11 22.761 3.9037 13968 7.29
12 23.588 3.7687 35935 18.75  12 23.588 3.7687 35935 18.75
13 24.694 3.6023 3951 2.06  13 24.694 3.6023 3951 2.06
14 25.799 3.4504 11988 6.25  14 25.799 3.4504 11988 6.25
15 26.687 3.3375 15121 7.89 15 26.687 3.3375 15121 7.89
16 28.128 3.1698 6248 3.26 17 28.936 3.0831 8574 4.47 16 28.128 3.1698 6248 3.26 17 28.936 3.0831 8574 4.47
18 32.036 2.7915 15828 8.26 18 32.036 2.7915 15828 8.26
19 32.806 2.7277 6665 3.48 19 32.806 2.7277 6665 3.48
20 35.254 2.5437 13073 6.82 20 35.254 2.5437 13073 6.82
21 38.805 2.3187 19864 10.36 21 38.805 2.3187 19864 10.36
22 40.484 2.2263 9982 5.21 22 40.484 2.2263 9982 5.21
实施例 2 Example 2
恩曲他滨水杨酸盐无水物晶型乙的制备  Preparation of emtricitabine salicylate anhydrate form B
将水杨酸 (2.79g， 20mmol)加入水 (55ml)中， 油浴加热到 88°C溶清后， 加入 恩曲他滨 (5g， 20mmol)搅拌溶解。 撤去油浴， 在搅拌下冷却到 48°C后， 过滤。 真空干燥 (65 °C， 4h) , 得白色固体 (2.01g， 收率 26%) : 水分 (卡尔费歇尔滴定 法 )0.72% ; 元素分析 (C15H16FN3O6S) C、 H、 N计算值(％) 46.75， 4.18 , 10.90 , 测定值(％) 46.35， 4.14 , 1 1.06 ο 其 XRPD谱见图 3， 其 XRPD谱数据见表 2。 其 DSC谱见图 4 : 有一个吸热峰， 起始温度为 108.6°C， 峰温度为 1 12.8 °C。 Salicylic acid (2.79 g, 20 mmol) was added to water (55 ml), heated to 88 ° C in an oil bath, and then added to emtricitabine (5 g, 20 mmol) to dissolve. The oil bath was removed, cooled to 48 ° C with stirring, and filtered. Vacuum drying (65 ° C, 4 h) gave white solid (2.01 g, yield 26%): water (Karl Fischer titration) 0.72%; elemental analysis (C 15 H 16 FN 3 O 6 S) C, H, N calculated value (%) 46.75, 4.18, 10.90, measured value (%) 46.35, 4.14, 1 1.06 ο The XRPD spectrum is shown in Figure 3. The XRPD spectrum data is shown in Table 2. Its DSC spectrum is shown in Figure 4: There is an endothermic peak with an onset temperature of 108.6 ° C and a peak temperature of 12.8 ° C.
表 2 实施例 2所得晶型乙的 XRPD谱数据  Table 2 XRPD spectral data of Form B obtained in Example 2
峰 2Θ(°) d(A) 峰面积 相对强度(％) Peak 2Θ(°) d(A) Peak area Relative intensity (%)
1 7.636 1 1.5677 21400 16.161 7.636 1 1.5677 21400 16.16
2 10.066 8.7804 51949 39.242 10.066 8.7804 51949 39.24
3 10.985 8.0473 130969 98.933 10.985 8.0473 130969 98.93
4 12.357 7.1568 60309 45.564 12.357 7.1568 60309 45.56
5 13.563 6.5234 1805 1.365 13.563 6.5234 1805 1.36
6 15.159 5.8398 124129 93.766 15.159 5.8398 124129 93.76
7 15.436 5.7357 132386 100.007 15.436 5.7357 132386 100.00
8 16.659 5.3172 37253 28.148 16.659 5.3172 37253 28.14
9 17.21 1 5.1478 69092 52.199 17.21 1 5.1478 69092 52.19
10 17.523 5.0569 1918 1.4510 17.523 5.0569 1918 1.45
1 1 17.983 4.9287 17252 13.031 1 17.983 4.9287 17252 13.03
12 18.890 4.6940 12555 9.4812 18.890 4.6940 12555 9.48
13 19.622 4.5206 14208 10.73 14 20.172 4.3984 23107 17.45 13 19.622 4.5206 14208 10.73 14 20.172 4.3984 23107 17.45
15 20.570 4.3142 4542 3.43  15 20.570 4.3142 4542 3.43
16 21.259 4.1759 20710 15.64 16 21.259 4.1759 20710 15.64
17 23.765 3.7409 31446 23.7517 23.765 3.7409 31446 23.75
18 24.180 3.6777 88150 66.5918 24.180 3.6777 88150 66.59
19 25.227 3.5273 62660 47.3319 25.227 3.5273 62660 47.33
20 25.681 3.4661 13079 9.88 20 25.681 3.4661 13079 9.88
21 26.431 3.3693 26468 19.99 21 26.431 3.3693 26468 19.99
22 27.991 3.1850 1954 1.48 22 27.991 3.1850 1954 1.48
23 28.720 3.1058 77988 58.91 23 28.720 3.1058 77988 58.91
24 29.935 2.9825 2858 2.16 24 29.935 2.9825 2858 2.16
25 30.613 2.9179 11941 9.02  25 30.613 2.9179 11941 9.02
26 31.363 2.8498 2098 1.58  26 31.363 2.8498 2098 1.58
27 33.397 2.6808 19477 14.71 27 33.397 2.6808 19477 14.71
28 36.417 2.4651 13123 9.91 28 36.417 2.4651 13123 9.91
29 37.957 2.3685 10897 8.23  29 37.957 2.3685 10897 8.23
30 39.893 2.2580 3843 2.90  30 39.893 2.2580 3843 2.90
31 40.739 2.2130 5100 3.85  31 40.739 2.2130 5100 3.85
实施例 3 Example 3
恩曲他滨水杨酸盐无水物晶型甲和晶型乙混合物的制备  Preparation of a mixture of emtricitabine salicylate anhydrate form A and Form B
将恩曲他滨 (0.5g， 2mmol)加入水（10ml)中，搅拌溶清，再加入水杨酸 (0.28g， 2mmol), 加热溶清。 搅拌过夜， 任其冷至室温。 过滤， 用水 (20ml)洗涤， 真空 干燥 (80°C， 4h)，得白色固体 (0.61g，收率 78%):水分 (卡尔费歇尔滴定法 )0.35%; 元素分析 (C15H16FN3O6S)C、H、N计算值(％)46.75， 4.18， 10.90，测定值(％)46.66， 4.24， 1 1.18。 其 DSC谱见图 5 : 有两个吸热峰， 分别是： 起始温度为 1 13.4°C， 峰温度为 1 17.9°C以及峰温度为 125.4 °C。 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.
实施例 4 Example 4
恩曲他滨水杨酸盐无水物晶型甲和晶型乙混合物的制备  Preparation of a mixture of emtricitabine salicylate anhydrate form A and Form B
将水杨酸 (0.56g， 4mmol)和水 (6ml)加热到 80°C溶解， 再加入恩曲他滨（lg， 4mmol)搅拌溶解后， 停止保温。 在搅拌下冷却到 35 °C后， 过滤。 真空干燥， 得 白色固体 (1.03g， 收率 66%)。 其 DSC谱见图 6: 有两个吸热峰， 分别是： 起始 温度为 1 1 1.6°C， 峰温度为 1 17.0°C以及峰温度为 120.3 °C。 Salicylic acid (0.56 g, 4 mmol) and water (6 ml) were heated to 80 ° C to dissolve, and then added to emtricitabine (lg, 4 mmol), stirred and dissolved, and the incubation was stopped. After cooling to 35 ° C with stirring, it was filtered. Vacuum drying, White solid (1.03 g, yield 66%). The DSC spectrum is shown in Figure 6: There are two endothermic peaks, which are: starting temperature is 1 1 1.6 ° C, peak temperature is 1 17.0 ° C and peak temperature is 120.3 °C.
实施例 5 Example 5
恩曲他滨水杨酸盐无水物晶型甲和晶型乙混合物的制备  Preparation of a mixture of emtricitabine salicylate anhydrate form A and Form B
将磷酸氢二钾 (26.91g， 1 17.9mmol)加到水 (43ml)中， 搅拌溶清后， 加入 Dipotassium hydrogen phosphate (26.91 g, 1 17.9 mmol) was added to water (43 ml), stirred and dissolved, and added.
(2R，5S)-(5-氟胞嘧啶 - 1-基) -1，3-氧硫杂环戊垸 -2-羧酸 L-薄荷酯（15g， 37.5mmol), 再加入乙醇（106ml)。 在室温滴加硼氢化钠 (3g， 79mmol)的 0.12mol/L氢氧化钠 水溶液 (14.4ml)。 滴加完毕后， 再在室温搅拌至反应完全。 静置分层。 分取有 机层， 用 6mol/L盐酸调节 pH=4， 再用 2mol/L氢氧化钠水溶液调节 pH=7。 减 压浓缩。 向所得残留物中加水 (200ml)， 用甲苯 (3x 1 10ml)洗涤后， 加入水杨酸 (5.19g, 37.5mmol), 加热到 70-80°C溶清。 接种， 冷却到室温后过滤， 真空干 燥 (80°C， 4h), 得恩曲他滨水杨酸盐 (lO. lg, 收率 70%): 水分 (卡尔费歇尔滴定 法) 0.35%。 (2R,5S)-(5-Fluorocytosin-1-yl)-1,3-oxathiolane-2-carboxylic acid L-menthyl ester (15g, 37.5mmol), followed by ethanol (106ml) . A 0.125 mol/L aqueous sodium hydroxide solution (14.4 ml) of sodium borohydride (3 g, 79 mmol) was added dropwise at room temperature. After the dropwise addition was completed, the mixture was stirred at room temperature until the reaction was completed. Let stand layering. The organic layer was separated, adjusted to pH = 4 with 6 mol/L hydrochloric acid, and adjusted to pH = 7 with a 2 mol/L aqueous sodium hydroxide solution. Concentrate under reduced pressure. Water (200 ml) was added to the residue, and washed with toluene (3×1 10 ml), and then,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, After inoculation, it was cooled to room temperature, filtered, and dried under vacuum (80 ° C, 4 h) to give emtricitabine salicylate (10 g, yield 70%): water (Karl Fischer titration) 0.35%.
取上述所得恩曲他滨水杨酸盐 (lg)加热至 70°C溶于水 (39ml)， 再加入活性 炭 (O. lg)同温搅拌脱色 30min。趁热过滤，滤液静置过夜。过滤，真空干燥 (80°C， 4h), 得恩曲他滨水杨酸盐精制品， 为白色固体 (0.27g， 收率 27%) : 元素分析 (C15H16FN3O6S)C、 H、 N计算值 (％)46·75， 4.18 , 10.90, 测定值 (％)46·66， 4.24, 1 1.18。 其 XRPD谱见图 7， 其 XRPD谱数据见表 3。 其 DSC谱见图 8 : 有两个 吸热峰，分别是：起始温度为 1 14.7°C，峰温度为 1 19.0°C以及峰温度为 123.6°C。 The obtained emtricitabine salicylate (lg) was heated to 70 ° C and dissolved in water (39 ml), and then activated charcoal (O.lg) was decolorized by stirring at room temperature for 30 min. It was filtered while hot and the filtrate was allowed to stand overnight. Filtration, vacuum drying (80 ° C, 4 h), esculin salicylide, white solid (0.27 g, yield 27%): Elemental 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. Its XRPD spectrum is shown in Figure 7, and its XRPD spectrum data is shown in Table 3. The DSC spectrum is shown in Figure 8: There are two endothermic peaks: the starting temperature is 1 14.7 ° C, the peak temperature is 1 19.0 ° C and the peak temperature is 123.6 ° C.
表 3 实施例 5所得恩曲他滨水杨酸盐的 XRPD谱数据  Table 3 Example 5 XRPD spectral data of emtricitabine salicylate
峰 2Θ(°) d(A) 峰面积 相对强度(％) Peak 2Θ(°) d(A) Peak area Relative intensity (%)
1 6.691 13.1994 3417 1.62 1 6.691 13.1994 3417 1.62
2 7.914 11.1628 129062 61.13  2 7.914 11.1628 129062 61.13
3 9.514 9.2888 15553 7.37  3 9.514 9.2888 15553 7.37
4 10.124 8.7298 211 143 100.00 4 10.124 8.7298 211 143 100.00
5 12.415 7.1235 26495 12.55 5 12.415 7.1235 26495 12.55
6 14.368 6.1593 21646 10.25  6 14.368 6.1593 21646 10.25
7 15.086 5.8680 1162 0.55  7 15.086 5.8680 1162 0.55
8 15.378 5.7570 11320 5.36  8 15.378 5.7570 11320 5.36
9 15.910 5.5657 51091 24.20  9 15.910 5.5657 51091 24.20
10 16.243 5.4524 49680 23.53 1 1 16.719 5.2984 78529 37.1910 16.243 5.4524 49680 23.53 1 1 16.719 5.2984 78529 37.19
12 18.060 4.9077 10358 4.91 12 18.060 4.9077 10358 4.91
13 18.909 4.6893 6732 3.19  13 18.909 4.6893 6732 3.19
14 19.759 4.4893 12104 5.73  14 19.759 4.4893 12104 5.73
15 20.252 4.3813 28387 13.44  15 20.252 4.3813 28387 13.44
16 20.571 4.3140 1 1368 5.38  16 20.571 4.3140 1 1368 5.38
17 21.298 4.1684 20437 9.68  17 21.298 4.1684 20437 9.68
18 22.187 4.0034 10359 4.91  18 22.187 4.0034 10359 4.91
19 22.758 3.9041 4264 2.02  19 22.758 3.9041 4264 2.02
20 23.528 3.7781 15787 7.48  20 23.528 3.7781 15787 7.48
21 24.219 3.6718 134051 63.49  21 24.219 3.6718 134051 63.49
22 25.701 3.4634 8091 1 38.32  22 25.701 3.4634 8091 1 38.32
23 26.470 3.3645 38208 18.10  23 26.470 3.3645 38208 18.10
24 26.746 3.3304 23799 1 1.27  24 26.746 3.3304 23799 1 1.27
25 28.464 3.1331 30704 14.54  25 28.464 3.1331 30704 14.54
26 28.918 3.0849 81004 38.36  26 28.918 3.0849 81004 38.36
27 29.846 2.991 1 1 1808 5.59  27 29.846 2.991 1 1 1808 5.59
28 32.136 2.7831 17907 8.48  28 32.136 2.7831 17907 8.48
29 33.437 2.6776 16220 7.68  29 33.437 2.6776 16220 7.68
30 36.380 2.4675 71 18 3.37  30 36.380 2.4675 71 18 3.37
31 38.431 2.3404 17369 8.23  31 38.431 2.3404 17369 8.23
32 39.534 2.2776 3499 1.66  32 39.534 2.2776 3499 1.66
33 40.660 2.2171 5530 2.62  33 40.660 2.2171 5530 2.62
34 43.582 2.0750 1 1235 5.32  34 43.582 2.0750 1 1235 5.32
实施例 6 Example 6
以恩曲他滨水杨酸盐无水物晶型甲和晶型乙混合物为中间体制备恩曲他 滨  Preparation of emtricitabine by using a mixture of emtricitabine salicylate anhydrate form A and Form B as intermediates
将磷酸氢二钾（71.76g， 314mmol)加到水（1 15ml)中， 搅拌溶清后， 加入 (2R,5S)-(5-氟胞嘧啶 - 1-基） - 1，3-氧硫杂环戊垸 -2-羧酸 L-薄荷酯（3)(40g， lOOmmol)，再加入乙醇 (284ml)。在室温滴加硼氢化钠 (8g，21 1mmol)的 0.12mol/L 氢氧化钠水溶液 (38.4ml)。 滴加完毕后， 再在室温搅拌至反应完全。 静止分层。 分取有机层，加 6mol/L盐酸调节 pH=4，再加 2mol/L氢氧化钠水溶液调节 pH=7。 减压浓缩。 向所得残留物中加水 (500g)， 用甲苯 (3 x300ml)洗涤后， 加入水杨酸 (13.83g, lOOmmol), 加热到 70-80°C溶清。 加入少许实施例 5所得恩曲他滨水 杨酸盐作为晶种， 冷却到室温后过滤。常压干燥， 得恩曲他滨水杨酸盐 (30.16g， 收率 78%)。 其 DSC谱见图 9 : 有两个吸热峰， 分别是： 起始温度为 108.6°C， 峰温度为 1 16.4°C以及峰温度为 121.0°C。 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. The organic layer was separated, and 6 mol/L hydrochloric acid was added to adjust pH=4, and then 2 mol/L sodium hydroxide aqueous solution was added to adjust pH=7. Concentrate under reduced pressure. Water (500 g) was added to the residue, and the mixture was washed with toluene (3×300 ml), and then salicylic acid (13.83 g, 100 mmol) was added and heated to 70-80 ° C to dissolve. A little of the emtricitabine salicylate obtained in Example 5 was added as a seed crystal, cooled to room temperature, and filtered. It was dried under normal pressure to give emtricitabine salicylate (30.16 g, yield 78%). The DSC spectrum is shown in Figure 9: There are two endothermic peaks: the initial temperature is 108.6 ° C, the peak temperature is 1 16.4 ° C and the peak temperature is 121.0 ° C.
取上述所制备的恩曲他滨水杨酸盐 (27g)加入乙醇 (60ml)中， 加热回流， 滴 加三乙胺（10.5ml)， 然后缓慢滴加乙酸乙酯 (600ml)， lh滴加完毕。 然后冷却到 室温， 过滤， 以乙酸乙酯洗涤滤饼， 真空干燥 (60°C， 2h), 得恩曲他滨粗品， 为白色固体 (13.71g， 收率 79%)。 将所得恩曲他滨粗品在异丙醇中脱色重结晶， 得药用级恩曲他滨 (12.10g，收率 88%),熔点 154.5-155.7°C， [a] 20 D -143.51°(c=l , 甲醇 参照美国药典恩曲他滨专论草案征求意见稿 (USP Pending Monograph Draft 1― For Public Comment, Emtricitabine, 2010, The United States Pharmacopeia)所记载的三种方法， 进行所得恩曲他滨的 HPLC 纯度检查， Procedure 1纯度为 99.96%， 其中最大单杂 0.04% ; Procedure 2纯度为 99.82%, 其中最大单杂 0.05%; Procedure 3纯度为 99.89%， 其中最大单杂 0.05%。 The emtricitabine salicylate (27 g) prepared above 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) The obtained crude emtricitabine was decolorized and recrystallized in isopropanol to obtain pharmaceutical grade emtricitabine (12.10 g, yield 88%), melting point 154.5-155.7 ° C, [a] 20 D -143.51 ° ( c=l, Methanol refers to the three methods described in the USP Pending Monograph Draft 1 (For Public Comment, Emtricitabine, 2010, The United States Pharmacopeia) HPLC purity check of Procedure, Procedure 1 purity was 99.96%, of which the maximum single impurity was 0.04%; Procedure 2 purity was 99.82%, of which the maximum single impurity was 0.05%; Procedure 3 purity was 99.89%, of which the maximum single impurity was 0.05%.
实施例 7 Example 7
恩曲他滨水杨酸盐一水合物晶型丙的制备  Preparation of emtricitabine salicylate monohydrate crystal form C
将恩曲他滨 (0.5g， 2mmol)加入水（10ml)中，搅拌溶清，再加入水杨酸 (0.28g， Emtricitabine (0.5 g, 2 mmol) was added to water (10 ml), stirred and dissolved, and then salicylic acid (0.28 g,
2mmol), 加热溶清。 搅拌过夜， 任其冷至室温。 过滤， 用水 (20ml)洗涤， 常压 干燥 (50°C， 48h), 得恩曲他滨水杨酸盐一水合物， 为近白色固体 (0.60g， 收率 75%)： 水分 (卡尔费歇尔滴定法 )4.45%。 其 DSC谱见图 10 : 有三个吸热峰， 分 别为： 起始温度为 70.0°C， 峰温度为 83.1 °C ; 起始温度为 109.0°C， 峰温度为 1 14.8°C以及峰温度为 1 19.6°C。 2 mmol), heat-dissolved. Stir overnight and allow to cool to room temperature. Filtration, washing with water (20 ml), drying under normal pressure (50 ° C, 48 h) to give emtricitabine salicylate monohydrate as a white solid (0.60 g, yield 75%): Moisture Michelle titration method) 4.45%. The DSC spectrum is shown in Figure 10: There are three endothermic peaks, namely: starting temperature is 70.0 °C, peak temperature is 83.1 °C; initial temperature is 109.0 °C, peak temperature is 1 14.8 °C and peak temperature is 1 19.6 ° C.
实施例 8 Example 8
以恩曲他滨水杨酸盐一水合物晶型丙为中间体制备恩曲他滨  Preparation of emtricitabine with emtricitabine salicylate monohydrate form C as intermediate
将磷酸氢二钾（68.47g， 300mmol)加到水（1 15ml)中， 搅拌溶清后， 加入 (2R,5S)-(5-氟胞嘧啶 -1-基） -1，3-氧硫杂环戊垸 -2-羧酸 L-薄荷酯（3)(40g， lOOmmol) ,再加入乙醇 (365ml)。在室温滴加硼氢化钠 (8g，21 lmmol)的 0.12mol/L 氢氧化钠水溶液 (38.4ml)。 滴加完毕后， 再在室温搅拌至反应完全。 静止分层。 分取有机层，加 6mol/L盐酸调节 pH=4，再加 2mol/L氢氧化钠水溶液调节 pH=7。 减压浓缩。 向所得残留物中加水 (500ml)， 用甲苯 (3x300ml)洗涤后， 加入水杨 酸（13.83g， lOOmmol), 加热到 70-80 °C溶清。 加入少许实施例 5所得恩曲他滨 水杨酸盐作为晶种， 冷却到室温后过滤。 常压干燥 (50°C， 48h), 得恩曲他滨水 杨酸盐一水合物 (32.30g， 收率 80%): 水分 (卡尔费歇尔滴定法 )4.43%。 1HNMR (DMSO-d6) δ 8.18 (d, J=7.2Hz, 1H)， 7.79 (dd, J=1.6, 8.0Hz, 1H)， 7.72 (br s, exchangeable), 7.58 (br s， exchangeable), 7.51 (m, 1H)， 6.90-6.95 (m, 2H), 6.13-6.16 (m, 1H)， 5.41 (br s, exchangeable), 5.19 (t, J=4.0Hz, 1H)， 3.72-3.82 (m, 2H), 3.43 (dd, J=5.6, 12.0Hz, 1H)， 3.12 (dd, J=4.4, 12.0Hz, 1H)。 MS-ESI (电喷雾） m/z 248.05 [M (恩曲他滨) +H]+ ， 495.08 [2M (恩曲他滨) +H]+ ， 137.06 [M (水杨 酸) -H]_。 其 TGA谱见图 11: 52.6-114.8°C减重 4.12%。 其 XRPD谱见图 12， 其 XRPD谱数据见表 4。 其 DSC谱见图 13: 有三个吸热峰， 分别为： 起始温度为 70.0°C， 峰温度为 85.0°C; 起始温度为 108.7°C， 峰温度 2为 114.3°C以及峰温 度为 118.8°C。 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. The organic layer was separated, and 6 mol/L hydrochloric acid was added to adjust pH=4, and then 2 mol/L sodium hydroxide aqueous solution was added to adjust pH=7. Concentrate under reduced pressure. Water (500 ml) was added to the residue, and the mixture was washed with toluene (3×300 ml), and then,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, A little of the emtricitabine salicylate obtained in Example 5 was added as a seed crystal, cooled to room temperature, and filtered. Drying at atmospheric pressure (50 ° C, 48 h), enflutine salicylate monohydrate (32.30 g, yield 80%): moisture (Karl Fischer titration) 4.43%. 1 H NMR (DMSO-d 6 ) δ 8.18 (d, J = 7.2 Hz, 1H), 7.79 (dd, J = 1.6, 8.0 Hz, 1H), 7.72 (br s, exchangeable), 7.58 (br s, exchangeable) , 7.51 (m, 1H), 6.90-6.95 (m, 2H), 6.13-6.16 (m, 1H), 5.41 (br s, exchangeable), 5.19 (t, J=4.0Hz, 1H), 3.72-3.82 ( m, 2H), 3.43 (dd, J=5.6, 12.0 Hz, 1H), 3.12 (dd, J=4.4, 12.0 Hz, 1H). MS-ESI (electrospray) m/z 248.05 [M (entrozine) +H] + , 495.08 [2M (enstatin) +H] + , 137.06 [M (salicylic acid) -H]_ . Its TGA spectrum is shown in Figure 11: 52.6-114.8 °C weight loss 4.12%. Its XRPD spectrum is shown in Figure 12, and its XRPD spectrum data is shown in Table 4. The DSC spectrum is shown in Figure 13: There are three endothermic peaks, namely: starting temperature is 70.0 ° C, peak temperature is 85.0 ° C; initial temperature is 108.7 ° C, peak temperature 2 is 114.3 ° C and peak temperature is 118.8 ° C.
表 4 实施例 8所得恩曲他滨水杨酸盐一水合物晶型丙的 XRPD谱数据  Table 4 XRPD spectral data of embrittate salicylate monohydrate crystal form C obtained in Example 8
Figure imgf000022_0001
15 21.870 4.0607 25104 46.1
Figure imgf000022_0001
15 21.870 4.0607 25104 46.1
16 22.167 4.0069 29483 54.2 16 22.167 4.0069 29483 54.2
17 23.668 3.7561 1 1388 20.9  17 23.668 3.7561 1 1388 20.9
18 24.518 3.6277 2279 4.2  18 24.518 3.6277 2279 4.2
19 25.310 3.5160 7350 13.5  19 25.310 3.5160 7350 13.5
20 26.767 3.3278 21804 40.1  20 26.767 3.3278 21804 40.1
21 27.143 3.2826 4193 7.7  21 27.143 3.2826 4193 7.7
22 27.734 3.2140 20977 38.6  22 27.734 3.2140 20977 38.6
23 28.769 3.1006 764 1.4  23 28.769 3.1006 764 1.4
24 29.315 3.0441 4969 9.1  24 29.315 3.0441 4969 9.1
25 30.302 2.9471 5488 10.1  25 30.302 2.9471 5488 10.1
26 30.847 2.8963 2190 4.0  26 30.847 2.8963 2190 4.0
27 31.383 2.8480 1233 2.3  27 31.383 2.8480 1233 2.3
28 32.670 2.7387 4856 8.9  28 32.670 2.7387 4856 8.9
29 34.821 2.5743 2697 5.0  29 34.821 2.5743 2697 5.0
30 35.293 2.5410 1918 3.5  30 35.293 2.5410 1918 3.5
31 36.478 2.461 1 5030 9.2  31 36.478 2.461 1 5030 9.2
32 38.291 2.3486 2271 4.2  32 38.291 2.3486 2271 4.2
33 39.162 2.2984 2738 5.0  33 39.162 2.2984 2738 5.0
34 40.665 2.2168 2666 4.9  34 40.665 2.2168 2666 4.9
取上述所制备的恩曲他滨水杨酸盐一水合物 (28.26g)加入乙醇 (80ml)中， 加 热回流， 滴加三乙胺（10.5ml)， 然后缓慢滴加乙酸乙酯 (700ml)， lh滴加完毕。 然后冷却到室温， 过滤， 以乙酸乙酯洗涤滤饼， 真空干燥 (60°C， 2h) , 得恩曲 他滨粗品， 为白色固体 (13.69g， 收率 79%)。  The emtricitabine salicylate monohydrate (28.26 g) prepared above was added to ethanol (80 ml), heated under reflux, triethylamine (10.5 ml) was added dropwise, and then ethyl acetate (700 ml) was slowly added dropwise. , lh drop added. It was then cooled to room temperature, filtered, and the filtered cake was washed with EtOAc EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
将所得恩曲他滨粗品在异丙醇中脱色重结晶， 得药用级恩曲他滨 (12.06g， 收率 88%), 熔点 154.6-156.8 °C， [a] 20 D - 143.59°(c=l , 甲醇）。 参照美国药典恩 曲他滨专论草案征求意见稿（USP Pending Monograph Draft 1— For Public Comment, Emtricitabine, 2010, The United States Pharmacopeia)所记载的三禾中 方法， 进行所得恩曲他滨的 HPLC纯度检查， Procedure 1纯度为 99.95%， 其中 最大单杂 0.05% ; Procedure 2纯度为 99.78%， 其中最大单杂 0.08%; Procedure 3纯度为 99.88%， 其中最大单杂 0.05%。 The obtained crude emtricitabine was decolorized and recrystallized in isopropanol to give pharmaceutical grade emtricitabine (12.06 g, yield 88%), melting point 154.6-156.8 ° C, [a] 20 D - 143.59 ° ( c=l, methanol). HPLC purity of the resulting emtricitabine according to the Sanhe method described in the USP Pending Monograph Draft 1 (For Public Comment, Emtricitabine, 2010, The United States Pharmacopeia) Check, Procedure 1 purity is 99.95%, of which the maximum single impurity is 0.05%; Procedure 2 purity is 99.78%, of which the largest single impurity is 0.08%; 3 purity is 99.88%, of which the maximum single impurity is 0.05%.
实施例 9 Example 9
恩曲他滨水杨酸盐无水物晶型甲和晶型乙混合物的制备  Preparation of a mixture of emtricitabine salicylate anhydrate form A and Form B
将实施例 8所得恩曲他滨水杨酸盐一水合物 (l .OOg) , 真空干燥 (50°C， 8h; 再 55 °C， 8h), 得恩曲他滨水杨酸盐无水物， 为近白色固体： 水分 (卡尔费歇尔 滴定法 )0.51%。其 DSC谱见图 14 :有两个吸热峰，分别为：起始温度为 105.1 °C， 峰温度为 1 14.6°C以及峰温度为 120.1 °C。 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. For near white solids: Moisture (Karl Fischer titration) 0.51%. 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.
比较实施例 1 Comparative Example 1
恩曲他滨的制备， 不采用恩曲他滨水杨酸盐  Preparation of emtricitabine, no emtricitabine salicylate
向磷酸氢二钾（ 13.71g,60mmol)的水（33.5ml)溶液中加入 (2R，5 S)-(5-氟胞嘧 啶 -1-基) -1，3-氧硫杂环戊垸 -2-羧酸 L-薄荷酯（3)(10g， 25mmol)和无水乙醇 (90ml)， 冰水浴冷却至 15 °C。 缓慢滴加含 l%NaOH(2ml)的硼氢化钠 (1.89g，50mmol)的水（16ml)溶液。 滴毕， 室温搅拌至反应完全。 静止分层。 分取 有机层， 加 6mol/L盐酸调节 pH为 4， 再用 2mol/L氢氧化钠水溶液调节 pH为 7。 减压浓缩， 加水 (60ml)稀释， 用甲苯 (3x50ml)洗涤。 水层用活性炭常温脱色 后， 减压蒸熘至干。 向所得残留物中加入无水乙醇 (120ml)， 加热至回流， 趁热 过滤。 滤液减压浓缩至大约 30ml， 室温搅拌析晶。 过滤， 真空干燥得恩曲他滨 粗品白色固体（4.25g， 69%) , 为白色固体： 熔点 145.8-148.5 °C， [a] 20 D -137.10°(c=l , 甲醇）。 To a solution of dipotassium hydrogen phosphate (13.71 g, 60 mmol) in water (33.5 ml) was added (2R,5S)-(5-fluorocytosin-1-yl)-1,3-oxathiolane- 2-carboxylic acid L-menthyl ester (3) (10 g, 25 mmol) and absolute ethanol (90 ml) were cooled to 15 ° C in ice water. A solution of sodium borohydride (1.89 g, 50 mmol) in water (16 ml) containing 1% NaOH (2 mL) was slowly added dropwise. After the dropwise addition, the mixture was stirred at room temperature until the reaction was completed. Static layering. The organic layer was separated, adjusted to pH 4 with 6 mol/L hydrochloric acid, and then adjusted to pH 7 with a 2 mol/L aqueous sodium hydroxide solution. Concentrate under reduced pressure, diluted with water (60 mL) andEtOAc. After the aqueous layer is decolorized with normal carbon at room temperature, it is evaporated to dryness under reduced pressure. Anhydrous ethanol (120 ml) was added to the residue, which was heated to reflux and filtered. The filtrate was concentrated to about 30 ml under reduced pressure and stirred and stirred at room temperature. Filtration and drying in vacuo afforded a crude white solid (4.25 g, 69%) as white solid: mp. 145.8 - 148.5 ° C, [A] 20 D - 137.10 (c = l, methanol).
将所得恩曲他滨粗品 (4.20g)在异丙醇中脱色重结晶， 得恩曲他滨 (3.40g， 收率 81%): 熔点 151.4-154.8 °。， [a] 20 D - 143.10°(c=l , 甲醇）。 参照美国药典恩 曲他滨专论草案征求意见稿（USP Pending Monograph Draft 1— For Public Comment, Emtricitabine, 2010, The United States Pharmacopeia)所记载的三禾中方 法， 进行所得恩曲他滨的 HPLC纯度检查， Procedure 1纯度为 99.24%， 其中最 大单杂 0.67%; Procedure 2纯度为 99.09%， 其中最大单杂 0.80%; Procedure 3 纯度为 99.18%， 其中最大单杂 0.65%。 The obtained crude emtricitabine (4.20 g) was decolorized and recrystallized from isopropanol to give emtricitabine (3.40 g, yield 81%): m.p. 151.4 - 154.8. , [a] 20 D - 143.10 ° (c = l, methanol). HPLC purity of the resulting emtricitabine according to the Sanhe method described in the USP Pending Monograph Draft 1 (For Public Comment, Emtricitabine, 2010, The United States Pharmacopeia) Exam, Procedure 1 has a purity of 99.24%, of which the maximum single impurity is 0.67%; Procedure 2 has a purity of 99.09%, of which the maximum single impurity is 0.80%; Procedure 3 has a purity of 99.18%, of which the maximum single impurity is 0.65%.
本发明采用水杨酸盐无水物甲乙混晶和水杨酸盐一水合物晶型丙， 恩曲他 滨粗品收率高于采用琥珀酸盐一水合物的 WO201 1/083484，与采用 2-氟苯甲酸 盐的 WO201 1/095987和采用盐酸盐的 WO2009/084033相当 (表 5)。 水杨酸与 2-氟苯甲酸相比， 更为价廉易得； 水杨酸与 WO2009/084033采用的氯化氢的异 丙醇溶液相比， 更为操作简便， 更为绿色环保。 另方面， 本发明采用水杨酸盐 无水物甲乙混晶和水杨酸盐一水合物晶型丙分离纯化恩曲他滨， 恩曲他滨总收 率与采用盐酸盐的 WO201 1/107920相当； 尤其， 本发明所制备的恩曲他滨具有 高纯度， 参照美国药典恩曲他滨专论草案征求意见稿所记载的三种方法， 进行 其 HPLC纯度检查， 单一杂质均不高于 0.1%， 总杂质均不高于 0.3% (表 5)。 水 杨酸与 WO201 1/107920采用的氯化氢的异丙醇溶液相比， 更为操作简便， 更为 绿色环保。此外，不通过成盐进行分离纯化的比较实施例 1所制备的恩曲他滨， 其 HPLC纯度最低，虽经重结晶仍然无法达到药用标准 (表 5)。总之，根据收率、 纯度、 成本和操作简便性等多项指标综合评价， 与现有技术相比， 本发明采用 所述水杨酸盐无水物或一水合物的晶型分离纯化恩曲他滨的技术效果最优。 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). Compared with 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. In another aspect, 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. According to the three methods described in the draft of the US Pharmacopoeia Emstabin monograph, 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). In summary, based on a comprehensive evaluation of a plurality of indexes such as yield, purity, cost, and ease of operation, 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.
表 5 恩曲他滨分离纯化方法比较  Table 5 Comparison of the separation and purification methods of emtricitabine
Figure imgf000025_0001
Figure imgf000025_0001
注 1 : 为还原成盐和碱化游离两步的收率。  Note 1: The yield of two steps of reduction to salt and alkalization.
注 2: 为还原成盐、 碱化游离和重结晶三步的收率。  Note 2: The yield for the three steps of reduction to salt, alkalization free and recrystallization.
注 3 : WO201 1/107920测定方法不详。 本发明采用美国药典恩曲他滨专论 草案征求意见稿所记载的三种方法， 进行 HPLC纯度检查。  Note 3: The measurement method of WO201 1/107920 is not known. The present invention adopts three methods described in the draft of the US Pharmacopoeia Emstabin Monograph Draft for the examination of HPLC purity.
以上所述仅为本发明的较佳实施例而已， 并非用以限定本发明的实质技术 内容范围， 本发明的实质技术内容是广义地定义于申请的权利要求范围中， 任 何他人完成的技术实体或方法， 若是与申请的权利要求范围所定义的完全相 同， 也或是一种等效的变更， 均将被视为涵盖于该权利要求范围之中。  The above is only the preferred embodiment of the present invention, and is not intended to limit the scope of the technical scope of the present invention. The technical content of the present invention is broadly defined in the scope of the claims of the application, any technical entity completed by others. The method or method, if it is identical to the scope of the claims, or equivalents, is considered to be within the scope of the claims.

Claims

权 利 要 求 书 Claim
1、 化学结构式如式 2所示的恩曲他滨水杨酸盐的晶型， 其中， 式 2 中， n=0时代表恩曲他滨水杨酸盐无水物以及 n=l时代表恩曲他滨水杨酸盐一水合 物。
Figure imgf000026_0001
1. The crystal form of emtricitabine salicylate represented by formula 2 in the chemical formula, wherein, in formula 2, n=0 represents the empathanine salicylate anhydrate and n=l represents Emtricitabine salicylate monohydrate.
Figure imgf000026_0001
2  2
2、 如权利要求 1所述的恩曲他滨水杨酸盐的晶型， 其特征在于， 所述式 2 中， n=0; 恩曲他滨水杨酸盐无水物晶型甲的 X-射线粉末衍射谱 (Cu Κα辐射) 中， 在下述 2Θ 角有特征峰： 7.92±0.2°, 9.51±0.2°, 13.26±0.2°, 14.37±0.2°, 16.23±0.2°, 19.94±0.2°, 20.33±0.2°, 22.26±0.2°, 23.59±0.2°, 26.69±0.2°, 32.04±0.2° 和 38.81±0.2°ο  2. The crystalline form of emtricitabine salicylate according to claim 1, wherein in the formula 2, n = 0; emtricitabine salicylate anhydrate crystal form A In the X-ray powder diffraction spectrum (Cu Κα radiation), there are characteristic peaks at the following 2 Θ angles: 7.92±0.2°, 9.51±0.2°, 13.26±0.2°, 14.37±0.2°, 16.23±0.2°, 19.94±0.2° , 20.33±0.2°, 22.26±0.2°, 23.59±0.2°, 26.69±0.2°, 32.04±0.2° and 38.81±0.2°
3、 如权利要求 2 所述的恩曲他滨水杨酸盐的晶型， 其特征在于， 在所述 晶型甲的差示扫描量热谱中， 有一个主要吸热峰， 起始温度为 123-127°C， 峰 温度为 125-129°C。  3. The crystal form of emtricitabine salicylate according to claim 2, wherein in the differential scanning calorimetry of the crystal form A, there is a main endothermic peak, an onset temperature It is 123-127 ° C and the peak temperature is 125-129 ° C.
4、 如权利要求 1所述的恩曲他滨水杨酸盐的晶型， 其特征在于， 所述式 2 中， n=0; 恩曲他滨水杨酸盐无水物晶型乙的 X-射线粉末衍射谱 (Cu Κα辐射) 中， 在下述 2Θ 角有特征峰： 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°禾口 28.72±0.2°。  4. The crystalline form of emtricitabine salicylate according to claim 1, wherein in the formula 2, n=0; emtricitabine salicylate anhydrate form B In the X-ray powder diffraction spectrum (Cu Κα radiation), there are characteristic peaks at the following 2 Θ angle: 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 °.
5、 如权利要求 4 所述的恩曲他滨水杨酸盐的晶型， 其特征在于， 在所述 晶型乙的差示扫描量热谱中， 有一个主要吸热峰， 起始温度为 107-11 C, 峰 温度为 111-115°C。  5. The crystalline form of emtricitabine salicylate according to claim 4, wherein in the differential scanning calorimetry of the crystalline form B, there is a main endothermic peak, an onset temperature It is 107-11 C and the peak temperature is 111-115 °C.
6、 如权利要求 1 所述的恩曲他滨水杨酸盐的晶型， 其特征在于， 其为包 含上述晶型甲和晶型乙的混合物； 以重量计， 所述晶型甲的含量为 0-100%， 所 述晶型乙的含量为 0-100%。  6. The crystalline form of emtricitabine salicylate according to claim 1, which is a mixture comprising the above crystalline form A and crystalline form B; and the content of said crystalline form A by weight It is 0-100%, and the content of the crystal form B is 0-100%.
7、 如权利要求 6 所述的恩曲他滨水杨酸盐的晶型， 其特征在于， 在其差 示扫描量热谱中有下述两个吸热峰： 其中， 起始温度为 105°C-116°C， 优选 108°C-115°C; 一个吸热峰的峰温度为 112°C-120°C， 优选 115°C-120°C; 另一 个吸热峰的峰温度为 120°C-128°C， 优选 120°C-127°C。 7. The crystalline form of emtricitabine salicylate according to claim 6, wherein there are two endothermic peaks in the differential scanning calorimetry: wherein the onset temperature is 105 °C-116 ° C, preferably 108 ° C -115 ° C; an endothermic peak peak temperature of 112 ° C -120 ° C, preferably 115 ° C -120 ° C; another endothermic peak peak temperature is 120 ° C - 128 ° C, preferably 120 ° C - 127 ° C.
8、 如权利要求 6所述的恩曲他滨水杨酸盐的晶型， 其特征在于， 在其 X- 射线粉末衍射谱 (Cu Ka辐射）中，在下述 2Θ角有特征峰： 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°和 28·92±0·2ο。 The crystal form of emtricitabine salicylate according to claim 6, wherein in the X-ray powder diffraction spectrum (Cu Ka radiation), there are characteristic peaks at the following two corners: 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° and 28.92±0·2 ο .
9、 如权利要求 8所述的恩曲他滨水杨酸盐的晶型， 其特征在于， 其 X-射 线粉末衍射谱 (Cu Ka辐射）中， 在下述 2Θ角有特征峰： 7.91±0.2。， 10.12±0.2°, 12.42±0.2°, 14.37±0.2°, 24·22±0·2°禾口 28·92±0·2。。  9. The crystalline form of emtricitabine salicylate according to claim 8, wherein the X-ray powder diffraction spectrum (Cu Ka radiation) has a characteristic peak at the following two corners: 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. .
10、 如权利要求 1所述的恩曲他滨水杨酸盐的晶型， 其特征在于， 所述式 2中， η=1 ; 恩曲他滨水杨酸盐一水合物晶型丙的 X-射线粉末衍射谱 (Cu Κα辐 射）中， 在下述 2Θ角有特征峰: 7.22±0.2°, 1 1.43±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° 禾口 27.73±0.2ο。 10. The crystalline form of emtricitabine salicylate according to claim 1, wherein in the formula 2, η = 1; emtricitabine salicylate monohydrate crystal form C In the X-ray powder diffraction spectrum (Cu Κα radiation), there are characteristic peaks at the following 2 Θ angles: 7.22±0.2°, 1 1.43±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 ο .
1 1、 如权利要求 10 所述的恩曲他滨水杨酸盐的晶型， 其特征在于， 在所 述晶型丙的差示扫描量热谱中有三个主要吸热峰，分别是：起始温度为 68-72 °C， 峰温度为 82-86°C ; 起始温度为 107-1 I C , 峰温度为 1 12-1 16°C以及峰温度为 1 17-121 °C。  1 1. The crystalline form of emtricitabine salicylate according to claim 10, wherein there are three main endothermic peaks in the differential scanning calorimetry of the crystalline form C, respectively: The initial temperature is 68-72 ° C, the peak temperature is 82-86 ° C; the starting temperature is 107-1 IC, the peak temperature is 1 12-1 16 ° C and the peak temperature is 1 17-121 ° C.
12、 一种如权利要求 1所述的恩曲他滨水杨酸盐的晶型的制备方法， 其特 征在于， 它包括下述步骤：  12. A method of preparing a crystal form of emtricitabine salicylate according to claim 1, wherein the method comprises the steps of:
将恩曲他滨和水杨酸在水中混合、 加热至 70-90 °C或加热至恩曲他滨和 水杨酸完全溶解， 得到混合物 a;  Mixing emtricitabine and salicylic acid in water, heating to 70-90 ° C or heating to emtricitabine and salicylic acid to completely dissolve, to obtain a mixture a;
(b)将混合物 a冷却至 15-50°C， 优选室温 -50°C， 得到如权利要求 1所述的 恩曲他滨水杨酸盐的晶型。  (b) cooling the mixture a to 15-50 ° C, preferably room temperature -50 ° C, to obtain the crystalline form of emtricitabine salicylate according to claim 1.
13、 一种如权利要求 1所述的恩曲他滨水杨酸盐的晶型的制备方法， 其特 征在于， 它包括下述步骤：  A method of preparing a crystal form of emtricitabine salicylate according to claim 1, which comprises the steps of:
(i)将化学结构式如式 3所示的化合物和还原剂反应， 得到含有恩曲他滨的 混合物 i; 其中， 混合物 i 中的溶剂以总重量计， 水的含量为 80-100%， 优选 90- 100%；  (i) reacting a compound having a chemical formula of the formula 3 with a reducing agent to obtain a mixture i containing emtricitabine; wherein the solvent in the mixture i is from 80 to 100% by weight based on the total weight, preferably 90-100%;
Figure imgf000027_0001
所述还原剂为硼氢化钠；
Figure imgf000027_0001
The reducing agent is sodium borohydride;
(ii)向混合物 i中加入水杨酸成盐，得到含有恩曲他滨水杨酸盐的混合物 ii; (ii) adding salicylic acid to the mixture i to form a mixture containing emtricitabine salicylate ii;
(iii)从混合物 ii中分离得到如权利要求 1所述的恩曲他滨水杨酸盐的晶型。 (iii) separating the crystalline form of emtricitabine salicylate according to claim 1 from mixture ii.
14、 一种如权利要求 13所述的制备方法， 其特征在于， 所述步骤 (i)至 （iii) 的具体反应条件为：  14. The preparation method according to claim 13, wherein the specific reaction conditions of the steps (i) to (iii) are:
ω在磷酸氢二钾缓冲液和氢氧化钠存在下， 在含水的极性溶剂中， 将化学 结构式如式 3所示的化合物和硼氢化钠反应， 经后处理， 得到含有恩曲他滨的 混合物 i;  The compound having the chemical formula of the formula (3) and sodium borohydride are reacted in an aqueous polar solvent in the presence of dipotassium hydrogen phosphate buffer and sodium hydroxide, and post-treated to obtain emtricitabine. Mixture i;
所述极性溶剂选自甲醇、 乙醇、 异丙醇， 极性溶剂与水的体积比为 2: 1至 3: 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 2:1 to 3:1;
所述后处理包括： 静置分层， 分取富含产物的有机层， 酸化并调节 pH至 4-4.5， 碱化中和并调节 pH至 6.8-7.2， 蒸熘溶剂； 向所得残留物中加入足量水， 溶解生成的恩曲他滨， 然后用甲苯提走水相混合物中的 L-薄荷醇；  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;
(ii)向混合物 i中加入水杨酸成盐，得到含有恩曲他滨水杨酸盐的混合物 ii; 其中， 式 3的化合物和水杨酸的摩尔比为 1 :0.9至 1 : 1.1 ;  (ii) adding a salicylic acid salt to the mixture i to obtain a mixture ii containing emtricitabine salicylate; wherein, the molar ratio of the compound of the formula 3 to salicylic acid is 1:0.9 to 1:1.1;
(iii)从混合物 ii中， 经分离和干燥得到如权利要求 1所述的恩曲他滨水杨 酸盐的晶型； 其水分含量为 0-5%。  (iii) From the mixture ii, the crystal form of emtricitabine salicylate according to claim 1 is obtained by separation and drying; and its moisture content is from 0 to 5%.
15、 一种如权利要求 14 所述的制备方法， 其特征在于， 通过卡尔费歇尔 滴定法测定水分含量控制所述步骤 (iii)中的干燥程度： 控制水分含量为 0-1%， 获得上述恩曲他滨水杨酸盐无水物的晶型甲和晶型乙的混合物； 控制水分含量 为 4-5%， 获得上述恩曲他滨水杨酸盐一水合物的晶型丙。  A method according to claim 14, wherein the moisture content in the step (iii) is controlled by Karl Fischer titration to control the degree of drying in the step (iii): controlling the moisture content to be 0-1%, a mixture of crystal form A and form B of the above-mentioned emtricitabine salicylate anhydrate; controlling the moisture content to 4 to 5%, obtaining the crystal form C of the above emtricitabine salicylate monohydrate.
16、 一种如权利要求 1所述的恩曲他滨水杨酸盐的晶型的用途， 其特征在 于， 所述晶型用于制备高纯度恩曲他滨， 它包括下述步骤： 将所述晶型与碱化 试剂混合， 得到高纯度恩曲他滨。  16. Use of a crystalline form of emtricitabine salicylate according to claim 1 wherein said crystalline form is used to prepare high purity emtricitabine comprising the steps of: The crystal form is mixed with an alkalizing agent to give high purity emtricitabine.
17、 如权利要求 16 所述的用途， 其特征在于， 所述碱化试剂为叔胺， 优 选三乙胺。  17. Use according to claim 16, characterized in that the alkalizing agent is a tertiary amine, preferably triethylamine.
18、 一种高纯度恩曲他滨的制备方法， 其特征在于， 将如权利要求 1所述 的恩曲他滨水杨酸盐的晶型作为中间体， 所述的制备方法包括步骤：  A method for producing high-purity emtricitabine, characterized in that the crystal form of emtricitabine salicylate according to claim 1 is used as an intermediate, and the preparation method comprises the steps of:
(1)将化学结构式如式 3所示的化合物和还原剂反应， 得到混合物 1 ; 其中， 混合物 1中的溶剂， 以总重量计， 其中水的含量为 80-100%， 优选 90-100%;  (1) reacting a compound having a chemical formula of the formula 3 and a reducing agent to obtain a mixture 1; wherein the solvent in the mixture 1 is, based on the total weight, the water content is 80-100%, preferably 90-100% ;
(2)将混合物 1和水杨酸混合， 加热至 70-90°C或加热至混合物 1和水杨酸 溶解得到混合物 2; (2) Mixing mixture 1 with salicylic acid, heating to 70-90 ° C or heating to mixture 1 and salicylic acid Dissolved to obtain a mixture 2;
(3)将混合物 2冷却至 15-50°C， 优选室温 -50°C， 得到如权利要求 1所述的 恩曲他滨水杨酸盐；  (3) cooling the mixture 2 to 15-50 ° C, preferably room temperature -50 ° C, to obtain emtricitabine salicylate according to claim 1;
(4)将所得如权利要求 1所述的恩曲他滨水杨酸盐与碱化试剂混合， 得到恩 曲他滨；  (4) mixing the obtained emtricitabine salicylate according to claim 1 with an alkalizing agent to obtain emtricitabine;
所述还原剂为硼氢化钠；  The reducing agent is sodium borohydride;
所述碱化试剂为叔胺， 优选三乙胺。  The alkalizing agent is a tertiary amine, preferably triethylamine.
19、 一种如权利要求 18所述的制备方法， 其特征在于， 所述步骤 (1)至 (4) 的具体反应条件为：  19. The preparation method according to claim 18, wherein the specific reaction conditions of the steps (1) to (4) are:
(1) 在磷酸氢二钾缓冲液和氢氧化钠存在下， 在含水的极性溶剂中， 将化 学结构式如式 3所示的化合物和硼氢化钠反应， 经后处理， 得到混合物 1 ; 其中所述极性溶剂选自甲醇、 乙醇、异丙醇， 极性溶剂与水的体积比为 2: 1 至 3: 1 ;  (1) reacting a compound of the formula of formula 3 with sodium borohydride in an aqueous polar solvent in the presence of dipotassium hydrogen phosphate buffer and sodium hydroxide, and post-treating 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 2:1 to 3:1;
所述后处理包括： 静置分层， 分取富含产物的有机层， 酸化并调节 pH至 4-4.5， 碱化中和并调节 pH至 6.8-7.2， 蒸熘溶剂； 向所得残留物中加入足量水， 溶解生成的恩曲他滨， 然后用甲苯提走水相混合物中的 L-薄荷醇；  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)将混合物 1和水杨酸混合， 加热溶解得到混合物 2;  (2) mixing mixture 1 with salicylic acid, heating to dissolve to obtain a mixture 2;
式 3化合物和水杨酸的摩尔比为 1 :0.9至 1 : 1.1；  The molar ratio of the compound of formula 3 to salicylic acid is from 1:0.9 to 1:1.1;
(3)将混合物 2冷却， 分离析出的固体， 经干燥， 得到如权利要求 1所述的 恩曲他滨水杨酸盐的晶型； 其水分含量为 0-5%。  (3) The mixture 2 is cooled, and the precipitated solid is separated and dried to obtain a crystal form of emtricitabine salicylate according to claim 1; the moisture content thereof is from 0 to 5%.
(4)将所得如权利要求 1所述的晶型与碱化试剂混合， 得到恩曲他滨； 所述 碱化试剂为叔胺， 优选三乙胺。  (4) 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.
20、 一种如权利要求 14 所述的制备方法， 其特征在于， 通过卡尔费歇尔 滴定法测定水分含量控制所述步骤 (3)中的干燥程度： 控制水分含量为 0-1%， 获得上述恩曲他滨水杨酸盐无水物的晶型甲和晶型乙的混合物； 控制水分含量 为 4-5%， 获得上述恩曲他滨水杨酸盐一水合物的晶型丙。  20. The preparation method according to claim 14, wherein the moisture content in the step (3) is controlled by Karl Fischer titration to control the degree of drying in the step (3): controlling the moisture content to be 0-1%, a mixture of crystal form A and form B of the above-mentioned emtricitabine salicylate anhydrate; controlling the moisture content to 4 to 5%, obtaining the crystal form C of the above emtricitabine salicylate monohydrate.
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