CN103833741A - Emtricitabine salicylate and preparation method and application thereof - Google Patents
Emtricitabine salicylate and preparation method and application thereof Download PDFInfo
- Publication number
- CN103833741A CN103833741A CN201210479527.8A CN201210479527A CN103833741A CN 103833741 A CN103833741 A CN 103833741A CN 201210479527 A CN201210479527 A CN 201210479527A CN 103833741 A CN103833741 A CN 103833741A
- Authority
- CN
- China
- Prior art keywords
- emtricitabine
- salicylate
- mixture
- peak
- crystal formation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an emtricitabine salicylate and a preparation method and application thereof. The emtricitabine salicylate has chemical structural formula shown as in a formula 2. The emtricitabine salicylate does not contain crystal water.
Description
Technical field
The present invention relates to a kind of new compound, relate in particular to emtricitabine salicylate and its production and use.
Background technology
Emtricitabine (emtricitabine), the chemistry fluoro-1-[2-of (2R, 5S)-5-(methylol)-1 by name, 3-oxathiolane-5-yl] cytosine(Cyt), chemical structural formula as shown in Equation 1, is efabirenz.Emtricitabine is clinically for infecting (acquired immune deficiency syndrome (AIDS)) with other anti-reverse transcription enzyme drug combination treatments HIV-1.In addition, the fixed dosage compound preparation based on emtricitabine and tenofovir disoproxil fumarate has very important status in the treatment of acquired immune deficiency syndrome (AIDS) and prevention.
Emtricitabine (1)
Emtricitabine can with mineral acid or organic acid salify.Chinese patent application CN10167133 report, utilizes the polystyrene resin of Whitfield's ointment functionalization to separate emtricitabine from the reaction mixture of synthetic emtricitabine.US Patent No. 6600044, PCT patent application WO2009084033 and WO2011107920, and Organic Process Research & Development, 2006,10 (3): 670-672 has reported emtricitabine hydrochloride, and report utilizes emtricitabine hydrochloride to realize the separation and purification of emtricitabine.US6600044 has also reported emtricitabine mesylate.WO2011083484 has reported emtricitabine succinate monohydrate, and the free emtricitabine of preparing that alkalized.WO2011095987 report, by by emtricitabine respectively with the organic acid salify such as 2-fluorobenzoic acid, O-Anisic Acid, 3-hydroxy-2-naphthoic acid and L-Glutimic acid, reach the object of separation and purification emtricitabine from reaction mixture.
Emtricitabine is an optical pure compound, has two chiral centres that are configured as (2R, 5S).Its main flow synthetic route is that the stereoselectivity based on chiral auxiliary is synthetic.Conventionally, chiral auxiliary MENTHOL need to by reduction reaction (conventionally adopt borane reagent, for example, sodium borohydride, POTASSIUM BOROHYDRIDE; Also can adopt other reductive agents, for example, Lithium Aluminium Hydride, two (2-methoxy ethoxy) the aluminium sodium (trade(brand)name RED-Al) of dihydro) remove.After cancellation reaction, add enough water to dissolve the emtricitabine generating, then with the immiscible organic solvent of water (for example, toluene) withdraw the MENTHOL in reaction mixture, finally must, from the aqueous solution that contains the complicated ingredient such as inorganic salt, boron-containing impurities of gained, obtain emtricitabine through separation and purification.Because emtricitabine has higher solubility in water, therefore, how reaction product emtricitabine to be implemented efficiently from moisture complex mixture to separation and purification, become and realize the difficult problem that industrialized production must solve.
Therefore, this area is in the urgent need to providing a kind of method of efficient separation and purification emtricitabine.
Summary of the invention
The present invention aims to provide a kind of new emtricitabine salicylate.
Another object of the present invention be to provide above-mentioned emtricitabine salicylate preparation method.
A further object of the present invention be to provide above-mentioned emtricitabine salicylate purposes.
In a first aspect of the present invention, a kind of emtricitabine salicylate is provided, its chemical structural formula is as shown in Equation 2; Described compound is not containing crystal water;
In another preference, in X-ray powder diffraction (XRPD) spectrum (Cu K α radiation) of described formula 2 compound crystal formation first, there is characteristic peak at 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 °.
In another preference, in means of differential scanning calorimetry (DSC) spectrum of described crystal formation first, there is a main endotherm(ic)peak, starting temperature is 123-127 DEG C, peak temperature is 125-129 DEG C.
In another preference, in the XRPD spectrum (Cu K α radiation) of described formula 2 compound crystal formation second, there is characteristic peak at following 2 θ angles: 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 °, 25.23.18 ± 0.2 °, 26.43 ± 0.2 ° and 28.72 ± 0.2 °.
In another preference, in the DSC of described crystal formation second spectrum, there is a main endotherm(ic)peak, starting temperature is 107-111 DEG C, peak temperature is 111-115 DEG C.
In another preference, by weight, the content of wherein said formula 2 compound crystal formation first is 0-100%, and the content of described formula 2 compound crystal formation second is 0-100%; Preferably, in its DSC spectrum, there are following two endotherm(ic)peaks: wherein, starting temperature is 106 DEG C-116 DEG C, is more preferably 108 DEG C-115 DEG C; The peak temperature of an endotherm(ic)peak is 112 DEG C-120 DEG C, is more preferably 115 DEG C-120 DEG C; The peak temperature of another endotherm(ic)peak is 120 DEG C-128 DEG C, is more preferably 120 DEG C-127 DEG C; Preferably, in its XRPD spectrum (Cu K α radiation), there is characteristic peak at following 2 θ angles: 7.91 ± 0.2 °, 10.12 ± 0.2 °, 12.42 ± 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 °, 28.46 ± 0.2 °, and 28.92 ± 0.2 °.
In a second aspect of the present invention, provide a kind of emtricitabine salicylate provided by the invention as above preparation method, described preparation method comprises the steps:
(a) emtricitabine and Whitfield's ointment are mixed in water, heating for dissolving, obtain mixture a; With
(b), by cooling mixture a, obtain emtricitabine salicylate provided by the invention as above.
In another preference, in step (a), be heated to 70-90 DEG C or be heated to emtricitabine and Whitfield's ointment dissolves completely.
In another preference, in step (b), be cooled to 15-50 DEG C, more preferably to room temperature-50 DEG C.
In a third aspect of the present invention, provide a kind of emtricitabine salicylate provided by the invention as above preparation method, described preparation method comprises the steps:
(i) by chemical structural formula compound and reductive agent reaction as shown in Equation 3, obtain the mixture i that contains emtricitabine;
Described reductive agent is selected from sodium borohydride, POTASSIUM BOROHYDRIDE;
(ii) in mixture i, add Whitfield's ointment salify, obtain containing emtricitabine salicylate mixture ii; With
(iii) from mixture ii, separate and obtain emtricitabine salicylate provided by the invention as above.
In another preference, described in contain emtricitabine mixture i in solvent, in gross weight, wherein the content of water is 80-100%, is more preferably 90-100%.
In another preference, described preparation method comprises the steps:
(i) by chemical structural formula compound and reductive agent reaction as shown in Equation 3, after cancellation reaction, the concentrated residue obtaining and water are mixed, with organic solvent extraction, obtain the mixture i that contains emtricitabine;
Described reductive agent is selected from sodium borohydride, POTASSIUM BOROHYDRIDE;
(ii) in mixture i, add Whitfield's ointment salify, obtain containing emtricitabine salicylate mixture ii; With
(iii) from mixture ii, separate and obtain emtricitabine salicylate provided by the invention as above.
More preferably, described cancellation reaction is to be undertaken by regulation system pH value.
In another preference, described organic solvent is and the immiscible organic solvent of water; More preferably, described organic solvent is selected from toluene, hexanaphthene.
In another preference, step (i) is by chemical structural formula compound and reductive agent reaction as shown in Equation 3, operate and point get organic phase by separatory, react by the cancellation of regulation system pH value, solvent distillation concentrates, in gained residue, add enough water to dissolve the emtricitabine generating, then, to withdraw the MENTHOL in aqueous mixture with the immiscible organic solvent of water, obtain the mixture i that contains emtricitabine.
In a fourth aspect of the present invention, provide a kind of emtricitabine salicylate provided by the invention as above purposes, described formula 2 compounds are for the preparation of emtricitabine, and described preparation comprises the steps: formula 2 compounds to mix with alkalizing agent, obtains emtricitabine; Described alkalizing agent is selected from triethylamine, diisopropyl ethyl amine.
In a fifth aspect of the present invention, a kind of preparation method of emtricitabine is provided, by emtricitabine salicylate provided by the invention as above, as intermediate, described preparation method comprises step:
(1) by chemical structural formula compound and reductive agent reaction as shown in Equation 3, obtain mixture 1;
(2) mixture 1 and Whitfield's ointment are mixed, heating for dissolving obtains mixture 2;
(3), by cooling mixture 2, obtain emtricitabine salicylate provided by the invention as above; With
(4) emtricitabine salicylate provided by the invention as above gained is mixed with alkalizing agent, obtain emtricitabine;
Described reductive agent is selected from sodium borohydride, POTASSIUM BOROHYDRIDE;
Described alkalizing agent is selected from triethylamine, diisopropyl ethyl amine.
In another preference, described in contain emtricitabine mixture 1 in solvent, in gross weight, wherein the content of water is 80-100%, is more preferably 90-100%.
In another preference, described preparation method comprises the steps:
(1) by chemical structural formula compound and reductive agent reaction as shown in Equation 3, after cancellation reaction, the concentrated residue obtaining and water are mixed, with organic solvent extraction, obtain the mixture 1 that contains emtricitabine;
(2) mixture 1 and Whitfield's ointment are mixed, heating for dissolving obtains mixture 2;
(3), by cooling mixture 2, obtain emtricitabine salicylate provided by the invention as above; With
(4) emtricitabine salicylate provided by the invention as above gained is mixed with alkalizing agent, obtain emtricitabine;
Described reductive agent is selected from sodium borohydride, POTASSIUM BOROHYDRIDE;
Described alkalizing agent is selected from triethylamine, diisopropyl ethyl amine.
More preferably, described cancellation reaction is to be undertaken by regulation system pH value.
In another preference, described organic solvent is and the immiscible organic solvent of water; More preferably, described organic solvent is selected from toluene, hexanaphthene.
In another preference, step (1) is by chemical structural formula compound and reductive agent reaction as shown in Equation 3, operate and point get organic phase by separatory, react by the cancellation of regulation system pH value, solvent distillation concentrates, in gained residue, add enough water to dissolve the emtricitabine generating, then, to withdraw the MENTHOL in aqueous mixture with the immiscible organic solvent of water, obtain the mixture 1 that contains emtricitabine.
In another preference, in step (2), be heated to 70-90 DEG C or be heated to mixture 1 and Whitfield's ointment dissolves completely.
In another preference, in step (3), be cooled to 15-50 DEG C, more preferably to room temperature-50 DEG C.
Accordingly, the invention provides a kind of method of efficient separation and purification emtricitabine.
Brief description of the drawings
Fig. 1 has shown the XRPD spectrum of embodiment 1 gained emtricitabine salicylate crystal formation first.
Fig. 2 has shown the DSC spectrum of embodiment 1 gained emtricitabine salicylate crystal formation first.
Fig. 3 has shown the XRPD spectrum of embodiment 2 gained emtricitabine salicylate crystal formation second.
Fig. 4 has shown the DSC spectrum of embodiment 2 gained emtricitabine salicylate crystal formation second.
Fig. 5 shown embodiment 3 gained emtricitabine salicylates DSC spectrum.
Fig. 6 shown embodiment 4 gained emtricitabine salicylates DSC spectrum.
Fig. 7 shown embodiment 5 gained emtricitabine salicylates XRPD spectrum.
Fig. 8 shown embodiment 5 gained emtricitabine salicylates DSC spectrum.
Fig. 9 shown embodiment 6 gained emtricitabine salicylates DSC spectrum.
Embodiment
In the process of the effective separation and purification emtricitabine of exploration, inventor has been surprised to find that a kind of emtricitabine salicylate that does not contain crystal water,, dissociate and can effectively obtain the pharmaceutical grade emtricitabine of high purity (HPLC purity) through alkalizing as intermediate with described emtricitabine salicylate.Meanwhile, contriver be surprised to find that above-mentioned not containing the emtricitabine salicylate of crystal water the mixture of two kinds of new crystal and arbitrary proportion thereof, and find taking described two kinds of emtricitabine salicylates the mixture of new crystal and arbitrary proportion thereof as intermediate, can effectively obtain the pharmaceutical grade emtricitabine of high purity (HPLC purity) by alkalization.On this basis, completed the present invention.
Emtricitabine salicylate
Emtricitabine salicylate provided by the invention, molecular formula is C
15h
16fN
3o
6s(C
8h
10fN
3o
3sC
7h
6o
3), chemical structural formula is as shown in Equation 2.Emtricitabine salicylate provided by the invention, containing crystal water.Described emtricitabine salicylate can be single crystal form, for example crystal formation first or crystal formation second; Also can be the mixture of different crystal forms, the mixture of for example crystal formation first and crystal formation second arbitrary proportion.
In the time that emtricitabine salicylate provided by the invention (2) is crystal formation first, in the X-of crystal formation first ray powder diffraction (XRPD) spectrum (Cu K α radiation), there is characteristic peak at 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 °.The typical XRPD of described crystal formation first composes as shown in Figure 1.At means of differential scanning calorimetry (DSC) spectrum (the temperature range 30-300 DEG C of crystal formation first, 10 DEG C/min of heat-up rates) in, there is a main endotherm(ic)peak (starting temperature (onsettemperature) is 123-127 DEG C, and peak temperature (peak temperature) is 125-129 DEG C).The typical DSC of described crystal formation first composes as shown in Figure 2.
In the time that emtricitabine salicylate provided by the invention (2) is crystal formation second, in the XRPD spectrum (CuK α radiation) of crystal formation second, there is characteristic peak at following 2 θ angles: 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 °, 25.23.18 ± 0.2 °, 26.43 ± 0.2 ° and 28.72 ± 0.2 °.The typical XRPD of described crystal formation second composes as shown in Figure 3.In the DSC spectrum (temperature range 30-300 DEG C, 10 DEG C/min of heat-up rates) of crystal formation second, there is a main endotherm(ic)peak (starting temperature is 107-111 DEG C, and peak temperature is 111-115 DEG C).The typical DSC of described crystal formation second composes as shown in Figure 4.
In the time that emtricitabine salicylate provided by the invention (2) is the mixture of crystal formation first and crystal formation second, at its DSC spectrum (temperature range 30-300 DEG C, 10 DEG C/min of heat-up rates) in, there are two main endotherm(ic)peaks, starting temperature is 106-116 DEG C, peak temperature 1 is 112-120 DEG C, and peak temperature 2 is 120-128 DEG C.
In an embodiment provided by the invention, gained emtricitabine salicylate (2) is the mixture of crystal formation first and crystal formation second, its DSC spectrum (temperature range 30-300 DEG C, 10 DEG C/min of heat-up rates) as shown in Figure 5, wherein there are two endotherm(ic)peaks, starting temperature is 113.4 DEG C, and peak temperature 1 is 117.9 DEG C, and peak temperature 2 is 125.4 DEG C.
In another embodiment provided by the invention, gained emtricitabine salicylate (2) is the mixture of crystal formation first and crystal formation second, its DSC spectrum (temperature range 30-300 DEG C, 10 DEG C/min of heat-up rates) as shown in Figure 6, wherein also there are two endotherm(ic)peaks, starting temperature is 111.6 DEG C, and peak temperature 1 is 117.0 DEG C, and peak temperature 2 is 120.3 DEG C.
In another embodiment provided by the invention, gained emtricitabine salicylate (2) is the mixture of crystal formation first and crystal formation second, and its XRPD composes as shown in Figure 7.In its XRPD spectrum (Cu K α radiation), there is characteristic peak at following 2 θ angles: 7.91 ± 0.2 °, 10.12 ± 0.2 °, 12.42 ± 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 °, 28.46 ± 0.2 ° and 28.92 ± 0.2 °.Its DSC spectrum (temperature range 30-300 DEG C, 10 DEG C/min of heat-up rates) as shown in Figure 8, wherein has two endotherm(ic)peaks, and starting temperature is 114.7 DEG C, and peak temperature 1 is 119.0 DEG C, and peak temperature 2 is 123.6 DEG C.
In another embodiment provided by the invention, gained emtricitabine salicylate (2) is the mixture of crystal formation first and crystal formation second, its DSC spectrum (temperature range 30-300 DEG C, 10 DEG C/min of heat-up rates) as shown in Figure 9, wherein there are two endotherm(ic)peaks, starting temperature is 108.6 DEG C, and peak temperature 1 is 116.4 DEG C, and peak temperature 2 is 121.0 DEG C.
The present invention adopts " X-ray powder diffraction " (X-ray Powder Diffraction, XRPD) spectrum to carry out crystal formation sign.The method of the XRPD spectrum of working sample is well known in the art.For example use the x-ray powder diffraction instrument of Bruker D8 Advanced model, adopt copper K α radiation to obtain the XRPD spectrum of sample.
The present invention also adopts " differential scanning calorimetry " (Differential Scanning Calorimetry, DSC) spectrum to carry out crystal formation sign.The method of working sample DSC is well known in the art.For example can use Netzsch thermal analyzer, with the temperature rise rate of 10 DEG C of per minutes, be warming up to 300 DEG C from 30 DEG C, obtain the DSC spectrum of sample.
The preparation method of emtricitabine salicylate (2)
The preparation method of emtricitabine salicylate provided by the invention (2), can, by emtricitabine and Whitfield's ointment are mixed in solvent, after heating for dissolving, prepare through crystallisation by cooling.Described mixing includes but not limited to, in the solution that contains emtricitabine, adds Whitfield's ointment, or adds emtricitabine to containing in salicylic solution.
Does not limit in the source of the emtricitabine in the described solution that contains emtricitabine, its HPLC(HighPerformance Liquid Chromatography, high performance liquid chromatography) purity can be more than 60%, is preferably more than 80%, is more preferably more than 90%; Described solvent is selected from the mixing of water, organic solvent or water and organic solvent, preferably water.Described organic solvent for example comprises, such as ethers (, tetrahydrofuran (THF), 2-methyltetrahydrofuran), and alcohols (for example, methyl alcohol, ethanol).Emtricitabine and salicylic mol ratio are not particularly limited, and are generally 1:0.6-2, preferably 1:0.8-1.5, more preferably 1:1-1.2.Can pass through the common technique means in this area (for example, centrifugal, filtration), the emtricitabine salicylate of separating out is separated in salt-forming reaction mother liquor.Can carry out being dried to gained emtricitabine salicylate by the common technique means in this area.Drying means can be that constant pressure and dry, vacuum (decompression) are dry; Drying temperature is 0-100 DEG C, preferably 20-90 DEG C, more preferably 30-80 DEG C.The not special restriction of degree of drying, conventionally controls contained humidity and is less than 20%, preferably controls contained humidity and is less than 10%, more preferably controls contained humidity and is less than 5%.When crystallisation by cooling, can add crystal seed in order to crystallization.
In general, obtain single crystal form emtricitabine salicylate (2), as crystal formation first or crystal formation second, need more strictly crystallization control condition.
Obtaining in a kind of embodiment of emtricitabine salicylate (2) crystal formation first, emtricitabine, Whitfield's ointment and water are mixed, heating for dissolving to clarification, cooling, filter, the dry crystal formation first that obtains.The weight ratio of emtricitabine and water is 1: 80-120, is preferably 1: 90-110, more preferably 1: 95-105; Be heated to 70-90 DEG C; Leave standstill and be cooled to after the abundant crystallization of room temperature, filtration, the dry crystal formation first that obtains.From dilute solution, slowly crystallization trends towards obtaining emtricitabine salicylate (2) crystal formation first.
Obtaining in a kind of embodiment of emtricitabine salicylate (2) crystal formation second, Whitfield's ointment and water are mixed, heating for dissolving adds emtricitabine to dissolve to clarification, cooling, filter, the dry crystal formation second that obtains.The weight ratio of emtricitabine and water is 1: 5-15, is preferably 1: 8-14, more preferably 1: 10-12; Be heated to 70-90 DEG C; Stirring is cooled to 40-60 DEG C of (preferably 45-55 DEG C) time and just filters.From strong solution, crystallization trends towards obtaining emtricitabine salicylate (2) crystal formation second fast.
The content of recording according to the present invention, those skilled in the art, can, by crystallization processes parameter and processing condition such as the temperature of the concentration of regulation and control crystallization reaction liquid, crystallization reaction liquid, stirring velocity, cooling rate, anti-solvents, obtain emtricitabine salicylate (2) the crystal formation first of various ratios and the mixture of crystal formation second.
In the another kind of preparation method's of emtricitabine salicylate provided by the invention (2) embodiment, with (2R, 5S)-(5-flurocytosine-1-yl)-1,3-oxathiolane-2-carboxylic acid L-menthyl ester (3) is starting raw material, first slough chiral auxiliary MENTHOL through reduction reaction, obtain the moisture mixture that contains emtricitabine through aftertreatment, then by with Whitfield's ointment salify, make the emtricitabine generating form the emtricitabine salicylate (2) of poorly water-soluble, from moisture mixture, separate and obtain.Reduction reaction reductive agent used is selected from sodium borohydride, POTASSIUM BOROHYDRIDE, Lithium Aluminium Hydride, two (2-methoxy ethoxy) the aluminium sodium (trade(brand)name RED-Al) of dihydro, preferably sodium borohydride, POTASSIUM BOROHYDRIDE.Described aftertreatment comprises following key step, operate and point get organic phase by separatory, react by the cancellation of regulation system pH value, solvent distillation concentrates, in gained residue, add enough water to dissolve the emtricitabine generating, then for example, to withdraw the MENTHOL in aqueous mixture with the immiscible organic solvent of water (, toluene).Conventionally compound 3 and salicylic mol ratio are 1:0.8-1.5, preferably 1:1-1.2, more preferably 1:1.Solvent in the moisture mixture that emtricitabine salicylate (2) is therefrom separated out, in gross weight, wherein the content of water is 80-100%, preferably 90-100%.Whether emtricitabine salicylate (2) when crystallization, is inoculated and has no special requirements from moisture mixture, preferably inoculation.Can pass through the common technique means in this area (for example, centrifugal, filtration), the emtricitabine salicylate of separating out is separated in salt-forming reaction mother liquor.Can carry out being dried to gained emtricitabine salicylate by the common technique means in this area.Drying means can be constant pressure and dry, vacuum-drying; Drying temperature is 0-100 DEG C, preferably 20-90 DEG C, more preferably 30-80 DEG C.The not special restriction of degree of drying, conventionally controls contained humidity and is less than 20%, preferably controls contained humidity and is less than 10%, more preferably controls contained humidity and is less than 5%.Synthetic route is:
Described compound 3 can be according to the method preparation of bibliographical information.For example, European patent application EP 0515157; Chinese Journal of Pharmaceuticals, 2005,36 (10): 589-590; PCT patent application WO2007077505.
The purposes of emtricitabine salicylate (2)
Emtricitabine salicylate provided by the invention (2) can be used as the intermediate of preparing emtricitabine.The crystal formation of described emtricitabine salicylate (2) is not particularly limited, and for example, can be the mixture of crystal formation first, crystal formation second or crystal formation first and crystal formation second arbitrary proportion.Described emtricitabine salicylate content be not particularly limited, by weight, preferably 80-100%, more preferably 90-100%.Gained intermediate emtricitabine salicylate (2), through alkalization, can dissociate and obtain emtricitabine (1).Suitable alkalizing agent is selected from mineral alkali and organic bases, preferred tertiary amine, more preferably triethylamine, diisopropyl ethyl amine.The solvent of suitable quaternization is selected from methyl alcohol, ethanol, Virahol, propyl carbinol, isopropylcarbinol, acetone, ethyl acetate, isopropyl acetate, tetrahydrofuran (THF), 2-methyltetrahydrofuran, water, or its mixture.
For example, synthetic route of preparing emtricitabine taking emtricitabine salicylate (2) as intermediate as:
In said synthesis route, with (2R, 5S)-(5-flurocytosine-1-yl)-1,3-oxathiolane-2-carboxylic acid L-menthyl ester (3) starting raw material, first slough chiral auxiliary MENTHOL through reduction reaction, obtain the moisture mixture that contains emtricitabine through aftertreatment, then by with Whitfield's ointment salify, make the emtricitabine generating form the emtricitabine salicylate (2) of poorly water-soluble, from moisture mixture, separate.Reduction reaction reductive agent used is selected from sodium borohydride, POTASSIUM BOROHYDRIDE, Lithium Aluminium Hydride, two (2-methoxy ethoxy) the aluminium sodium (trade(brand)name RED-Al) of dihydro, preferably sodium borohydride, POTASSIUM BOROHYDRIDE.Described aftertreatment comprises following key step, operate and point get organic phase by separatory, react by the cancellation of regulation system pH value, solvent distillation concentrates, in gained residue, add enough water to dissolve the emtricitabine generating, then for example, to withdraw the MENTHOL in aqueous mixture with the immiscible organic solvent of water (, toluene).Conventionally compound 3 and salicylic mol ratio are 1:0.8-1.5, preferably 1:1-1.2, more preferably 1:1.Solvent in the moisture mixture that emtricitabine salicylate (2) is therefrom separated out, in gross weight, wherein the content of water is 80-100%, preferably 90-100%.Whether emtricitabine salicylate (2) when crystallization, is inoculated and has no special requirements from moisture mixture, preferably inoculation.Can pass through the common technique means in this area (for example, centrifugal, filtration), the emtricitabine salicylate of separating out is separated in salt-forming reaction mother liquor.Can carry out being dried to gained emtricitabine salicylate by the common technique means in this area.Drying means can be constant pressure and dry, vacuum-drying; Drying temperature is 0-100 DEG C, preferably 20-90 DEG C, more preferably 30-80 DEG C.The not special restriction of degree of drying, conventionally controls contained humidity and is less than 20%, preferably controls contained humidity and is less than 10%, more preferably controls contained humidity and is less than 5%.
Described compound 3 can be according to the method preparation of bibliographical information.For example, European patent application EP 0515157; Chinese Journal of Pharmaceuticals, 2005,36 (10): 589-590; PCT patent application WO2007077505.
As used herein, " HPLC purity " refers to the emtricitabine product preparing, detect through HPLC, according to obtained chromatogram collection of illustrative plates, carry out area normalization method and percentage ratio that the peak area of the compound as shown in Equation 1 that obtains occupies in all peak area summations.The HPLC adopting checks, with reference to American Pharmacopeia emtricitabine monograph draft exposure draft (USP Pending Monograph Draft 1-For PublicComment, Emtricitabine, 2010, The United States Pharmacopeia) three kinds of methods (Procedure 1, Procedure 2 and Procedure 3) of recording carry out.
As used herein, " room temperature " refers to 20-30 DEG C.
The above-mentioned feature that the present invention mentions, or the feature that embodiment mentions can arbitrary combination.All features that this case specification sheets discloses can with any composition forms use, each feature disclosing in specification sheets, can anyly provide the alternative characteristics of identical, impartial or similar object to replace.Therefore apart from special instruction, the feature disclosing is only the general example of equalization or similar features.
Major advantage of the present invention is:
1, the present invention has found a kind of new emtricitabine salicylate (2).
2, the present invention finds using described emtricitabine salicylate (2) as intermediate, and the emtricitabine that reaction can be generated is implemented efficiently separation and purification from moisture complex mixture, obtains efficiently highly purified pharmaceutical grade emtricitabine.
3, a kind of method that the invention provides separation and purification emtricitabine of applicable industrialized production, has overcome the bottleneck of prior art, and has industrialization prospect.
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment are only not used in and limit the scope of the invention for the present invention is described.The experimental technique of unreceipted actual conditions in the following example, the condition of conventionally advising according to normal condition or according to manufacturer.Unless otherwise indicated, otherwise all percentage ratio, ratio, ratio or umber by weight.
Unless otherwise defined, the same meaning that all specialties that use in literary composition and scientific words and one skilled in the art are familiar.In addition, any method similar or impartial to described content and material all can be applicable in the inventive method.The use that better implementation method described in literary composition and material only present a demonstration.
The present invention is by the moisture in Ka Er Fischer (Karl Fischer) titration measuring sample.The determining instrument of x-ray diffraction pattern (XRPD) is Bruker D8 Advance x-ray diffractometer, and condition determination is: Cu K α line, tube voltage 40kV, tube current 40mA.Means of differential scanning calorimetry (DSC) spectrum determining instrument is Netzsch thermal analyzer, and condition determination is: 30 DEG C to 300 DEG C of temperature ranges, 10 DEG C/min of heat-up rates.Due to the difference of determining instrument and the deviation of condition determination, may there is error at measurment in XRPD spectrum and DSC spectrum.In the time screening and determine various crystalline structure, error at measurment should be taken into account.
The preparation of emtricitabine salicylate (2) crystal formation first
Emtricitabine (1) (0.5g, 2mmol), Whitfield's ointment (0.28g, 2mmol) are added in water (50g), be under agitation heated to 80 DEG C, moltenly stop stirring after clear, leave standstill room temperature crystallization two days.Filter, carefully choose several needle-like crystals and discard, vacuum-drying, obtains cotton shape white crystal (0.1g, yield 13%): moisture (Ka Er Karl Fischer titration) 0.68%, ultimate analysis (C
15h
16fN
3o
6s) C, H, N calculated value (%) 46.75,4.18,10.90, measured value (%) 46.26,3.95,11.02,
1hNMR (DMSO-d
6) δ 11.60 (brs, 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), 3.36 (br s, exchangeable, 1H), 3.13 (dd, J=4.4, 12.0Hz, 1H).Its XRPD spectrum is shown in Fig. 1, and its XRPD spectrum data are in table 1.Its DSC spectrum is shown in Fig. 2: have an endotherm(ic)peak, starting temperature is 124.7 DEG C, and peak temperature is 127.2 DEG C.
The XRPD spectrum data of table 1 embodiment 1 gained crystal formation first
Peak | 2θ(°) | d(A) | Peak area | Relative intensity (%) |
1 | 6.613 | 13.3547 | 3900 | 2.03 |
2 | 7.915 | 11.1613 | 153218 | 79.94 |
3 | 9.514 | 9.2886 | 44545 | 23.24 |
4 | 13.262 | 6.6704 | 14063 | 7.34 |
5 | 14.370 | 6.1585 | 191678 | 100.00 |
6 | 16.226 | 5.4582 | 182811 | 95.37 |
7 | 18.847 | 4.7045 | 11409 | 5.95 |
8 | 19.936 | 4.4499 | 25772 | 13.45 |
9 | 20.330 | 4.3647 | 29335 | 15.30 |
10 | 22.264 | 3.9896 | 35379 | 18.46 |
11 | 22.761 | 3.9037 | 13968 | 7.29 |
12 | 23.588 | 3.7687 | 35935 | 18.75 |
13 | 24.694 | 3.6023 | 3951 | 2.06 |
14 | 25.799 | 3.4504 | 11988 | 6.25 |
[0114]?
15 | 26.687 | 3.3375 | 15121 | 7.89 |
16 | 28.128 | 3.1698 | 6248 | 3.26 |
17 | 28.936 | 3.0831 | 8574 | 4.47 |
18 | 32.036 | 2.7915 | 15828 | 8.26 |
19 | 32.806 | 2.7277 | 6665 | 3.48 |
20 | 35.254 | 2.5437 | 13073 | 6.82 |
21 | 38.805 | 2.3187 | 19864 | 10.36 |
22 | 40.484 | 2.2263 | 9982 | 5.21 |
Embodiment 2
The preparation of emtricitabine salicylate (2) crystal formation second
Whitfield's ointment (2.79g, 20mmol) is added in water (55g), oil bath be heated to 88 DEG C molten clear after, add emtricitabine (5g, 20mmol) stirring and dissolving.Remove oil bath, be under agitation cooled to after 48 DEG C, filter.Vacuum-drying, obtains white solid (2.01g, yield 26%): moisture (Ka Er Karl Fischer titration) 0.72%; Ultimate analysis (C
15h
16fN
3o
6s) C, H, N calculated value (%) 46.75,4.18,10.90, measured value (%) 46.35,4.14,11.06.Its XRPD spectrum is shown in Fig. 3, and its XRPD spectrum data are in table 2.Its DSC spectrum is shown in Fig. 4: have an endotherm(ic)peak, starting temperature is 108.6 DEG C, and peak temperature is 112.8 DEG C.
The XRPD spectrum data of table 2 embodiment 2 gained crystal formation second
Peak | 2θ(°) | d(A) | Peak area | Relative intensity (%) |
1 | 7.636 | 11.5677 | 21400 | 16.16 |
2 | 10.066 | 8.7804 | 51949 | 39.24 |
3 | 10.985 | 8.0473 | 130969 | 98.93 |
4 | 12.357 | 7.1568 | 60309 | 45.56 |
5 | 13.563 | 6.5234 | 1805 | 1.36 |
6 | 15.159 | 5.8398 | 124129 | 93.76 |
7 | 15.436 | 5.7357 | 132386 | 100.00 |
8 | 16.659 | 5.3172 | 37253 | 28.14 |
9 | 17.211 | 5.1478 | 69092 | 52.19 |
10 | 17.523 | 5.0569 | 1918 | 1.45 |
11 | 17.983 | 4.9287 | 17252 | 13.03 |
[0120]?
12 | 18.890 | 4.6940 | 12555 | 9.48 |
13 | 19.622 | 4.5206 | 14208 | 10.73 |
14 | 20.172 | 4.3984 | 23107 | 17.45 |
15 | 20.570 | 4.3142 | 4542 | 3.43 |
16 | 21.259 | 4.1759 | 20710 | 15.64 |
17 | 23.765 | 3.7409 | 31446 | 23.75 |
18 | 24.180 | 3.6777 | 88150 | 66.59 |
19 | 25.227 | 3.5273 | 62660 | 47.33 |
20 | 25.681 | 3.4661 | 13079 | 9.88 |
21 | 26.431 | 3.3693 | 26468 | 19.99 |
22 | 27.991 | 3.1850 | 1954 | 1.48 |
23 | 28.720 | 3.1058 | 77988 | 58.91 |
24 | 29.935 | 2.9825 | 2858 | 2.16 |
25 | 30.613 | 2.9179 | 11941 | 9.02 |
26 | 31.363 | 2.8498 | 2098 | 1.58 |
27 | 33.397 | 2.6808 | 19477 | 14.71 |
28 | 36.417 | 2.4651 | 13123 | 9.91 |
29 | 37.957 | 2.3685 | 10897 | 8.23 |
30 | 39.893 | 2.2580 | 3843 | 2.90 |
31 | 40.739 | 2.2130 | 5100 | 3.85 |
The preparation of emtricitabine salicylate (2) crystal formation first and crystal formation second mixture
Emtricitabine (0.5g, 2mmol) is added in water (10g), stir molten clearly, then add Whitfield's ointment (0.28g, 2mmol), add thermosol clear.Stirring is spent the night, and lets alone to be chilled to room temperature.Filter, water (20g) washing, vacuum-drying, obtains white solid (0.61g, yield 78%): moisture (Ka Er Karl Fischer titration) 0.35%; Ultimate analysis (C
15h
16fN
3o
6s) C, H, N calculated value (%) 46.75,4.18,10.90, measured value (%) 46.66,4.24,11.18.Its DSC spectrum is shown in Fig. 5: have two endotherm(ic)peaks, starting temperature is 113.4 DEG C, and peak temperature 1 is 117.9 DEG C, and peak temperature 2 is 125.4 DEG C.
Embodiment 4
The preparation of emtricitabine salicylate (2) crystal formation first and crystal formation second mixture
Whitfield's ointment (0.56g, 4mmol) and water (6g) are heated to 80 DEG C of dissolvings, then add after emtricitabine (1g, 4mmol) stirring and dissolving, stop insulation.Under agitation be cooled to after 35 DEG C, filter.Vacuum-drying, obtains white solid (1.03g, yield 66%).Its DSC spectrum is shown in Fig. 6: have two endotherm(ic)peaks, starting temperature is 111.6 DEG C, and peak temperature 1 is 117.0 DEG C, and peak temperature 2 is 120.3 DEG C.
Embodiment 5
The preparation of emtricitabine salicylate (2) crystal formation first and crystal formation second mixture
Dipotassium hydrogen phosphate (26.91g) is added in water (43g), stir molten clear after, add (2R, 5S)-(5-flurocytosine-1-yl)-1,3-oxathiolane-2-carboxylic acid L-menthyl ester (15g, 37.5mmol), then add ethanol (106g).Drip the 0.12mol/L aqueous sodium hydroxide solution (14.4g) of sodium borohydride (3g) in room temperature.After dropwising, then in stirring at room temperature to reacting completely.Stratification.Point get organic layer, regulate pH=4 with 6mol/L hydrochloric acid, then with 2mol/L aqueous sodium hydroxide solution adjusting pH=7.Concentrating under reduced pressure.In gained residue, add water (200g), with after toluene (3 × 110ml) washing, add Whitfield's ointment (5.19g, 37.5mmol), be heated to 70-80 DEG C molten clear.Inoculation, filters after cool to room temperature, and vacuum-drying, obtains emtricitabine salicylate (10.1g, yield 70%): moisture (Ka Er Karl Fischer titration) 0.35%.
Get above-mentioned gained emtricitabine salicylate (1g) and be heated to 70 DEG C water-soluble (39g), then add gac (0.1g) equality of temperature to stir decolouring 30min.Filtered while hot, filtrate hold over night.Filter, vacuum-drying (80 DEG C, 4h), obtains emtricitabine salicylate highly finished product, is white solid (0.27g, yield 27%): ultimate analysis (C
15h
16fN
3o
6s) C, H, N calculated value (%) 46.75,4.18,10.90, measured value (%) 46.66,4.24,11.18.Its XRPD spectrum is shown in Fig. 7, and its XRPD spectrum data are in table 3.Its DSC spectrum is shown in Fig. 8: have two endotherm(ic)peaks, starting temperature is 114.7 DEG C, and peak temperature 1 is 119.0 DEG C, and peak temperature 2 is 123.6 DEG C.
Table 3 embodiment 5 gained emtricitabine salicylates XRPD spectrum data
Peak | 2θ(°) | d(A) | Peak area | Relative intensity (%) |
1 | 6.691 | 13.1994 | 3417 | 1.62 |
2 | 7.914 | 11.1628 | 129062 | 61.13 |
3 | 9.514 | 9.2888 | 15553 | 7.37 |
4 | 10.124 | 8.7298 | 211143 | 100.00 |
5 | 12.415 | 7.1235 | 26495 | 12.55 |
[0133]?
6 | 14.368 | 6.1593 | 21646 | 10.25 |
7 | 15.086 | 5.8680 | 1162 | 0.55 |
8 | 15.378 | 5.7570 | 11320 | 5.36 |
9 | 15.910 | 5.5657 | 51091 | 24.20 |
10 | 16.243 | 5.4524 | 49680 | 23.53 |
11 | 16.719 | 5.2984 | 78529 | 37.19 |
12 | 18.060 | 4.9077 | 10358 | 4.91 |
13 | 18.909 | 4.6893 | 6732 | 3.19 |
14 | 19.759 | 4.4893 | 12104 | 5.73 |
15 | 20.252 | 4.3813 | 28387 | 13.44 |
16 | 20.571 | 4.3140 | 11368 | 5.38 |
17 | 21.298 | 4.1684 | 20437 | 9.68 |
18 | 22.187 | 4.0034 | 10359 | 4.91 |
19 | 22.758 | 3.9041 | 4264 | 2.02 |
20 | 23.528 | 3.7781 | 15787 | 7.48 |
21 | 24.219 | 3.6718 | 134051 | 63.49 |
22 | 25.701 | 3.4634 | 80911 | 38.32 |
23 | 26.470 | 3.3645 | 38208 | 18.10 |
24 | 26.746 | 3.3304 | 23799 | 11.27 |
25 | 28.464 | 3.1331 | 30704 | 14.54 |
26 | 28.918 | 3.0849 | 81004 | 38.36 |
27 | 29.846 | 2.9911 | 11808 | 5.59 |
28 | 32.136 | 2.7831 | 17907 | 8.48 |
29 | 33.437 | 2.6776 | 16220 | 7.68 |
30 | 36.380 | 2.4675 | 7118 | 3.37 |
31 | 38.431 | 2.3404 | 17369 | 8.23 |
32 | 39.534 | 2.2776 | 3499 | 1.66 |
33 | 40.660 | 2.2171 | 5530 | 2.62 |
34 | 43.582 | 2.0750 | 11235 | 5.32 |
[0134]embodiment 6
Prepare emtricitabine taking emtricitabine salicylate (2) as intermediate
Dipotassium hydrogen phosphate (71.76g) is added in water (115g), stir molten clear after, add (2R, 5S)-(5-flurocytosine-1-yl)-1,3-oxathiolane-2-carboxylic acid L-menthyl ester (3) (40g, 100mmol), then add ethanol (284g).Drip the 0.12mol/L aqueous sodium hydroxide solution (38.4g) of sodium borohydride (8g) in room temperature.After dropwising, then in stirring at room temperature to reacting completely.Static layering.Divide and get organic layer, add 6mol/L hydrochloric acid and regulate pH=4, then add 2mol/L aqueous sodium hydroxide solution adjusting pH=7.Concentrating under reduced pressure.In gained residue, add water (500g), with after toluene (3 × 300ml) washing, add Whitfield's ointment (13.83g, 100mmol), be heated to 70-80 DEG C molten clear.Add a little embodiment 5 gained emtricitabine salicylate as crystal seed, after cool to room temperature, filter.Constant pressure and dry, obtains emtricitabine salicylate (30.16g, yield 78%).Its DSC spectrum is shown in Fig. 9: have two endotherm(ic)peaks, starting temperature is 108.6 DEG C, and peak temperature 1 is 116.4 DEG C, and peak temperature 2 is 121.0 DEG C.
Get above-mentioned prepared emtricitabine salicylate (27g) and add in ethanol (60g), reflux, drips triethylamine (10.5ml), then slowly drips ethyl acetate (600g), and 1h dropwises.Then cool to room temperature, filters, and with ethyl acetate washing leaching cake, vacuum-drying (60 DEG C, 2h), obtains white solid (13.71g).By the gained emtricitabine crude product recrystallization that decolours in Virahol, obtain pharmaceutical grade emtricitabine: with reference to American Pharmacopeia emtricitabine monograph draft exposure draft (USP Pending Monograph Draft1-For Public Comment, Emtricitabine, 2010, The United States Pharmacopeia) three kinds of methods recording, carry out the HPLC purity test of gained emtricitabine, Procedure 1 purity is 99.96%, Procedure 2 purity are 99.82%, Procedure 3 purity are 99.89%, wherein maximum list assorted 0.05%.
The foregoing is only preferred embodiment of the present invention, not in order to limit essence technology contents scope of the present invention, essence technology contents of the present invention is to be broadly defined in the claim scope of application, any technology entity or method that other people complete, if defined identical with the claim scope of application, also or a kind of change of equivalence, be all covered by among this claim scope being regarded as.
Claims (19)
2. emtricitabine salicylate as claimed in claim 1, is characterized in that, in X-ray powder diffraction (XRPD) spectrum (Cu K α radiation) of described formula 2 compound crystal formation first, there is characteristic peak at 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. emtricitabine salicylate as claimed in claim 2, is characterized in that, in means of differential scanning calorimetry (DSC) spectrum of described crystal formation first, has a main endotherm(ic)peak, and starting temperature is 123-127 DEG C, and peak temperature is 125-129 DEG C.
4. emtricitabine salicylate as claimed in claim 1, it is characterized in that, in the XRPD spectrum (Cu K α radiation) of described formula 2 compound crystal formation second, there is characteristic peak at following 2 θ angles: 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 °, 25.23.18 ± 0.2 °, 26.43 ± 0.2 ° and 28.72 ± 0.2 °.
5. emtricitabine salicylate as claimed in claim 4, is characterized in that, in the DSC of described crystal formation second spectrum, has a main endotherm(ic)peak, and starting temperature is 107-111 DEG C, and peak temperature is 111-115 DEG C.
6. emtricitabine salicylate as claimed in claim 1, is characterized in that, by weight, the content of wherein said formula 2 compound crystal formation first is 0-100%, and the content of described formula 2 compound crystal formation second is 0-100%.
7. emtricitabine salicylate as claimed in claim 1, is characterized in that, has following two endotherm(ic)peaks: wherein, starting temperature is 106 DEG C-116 DEG C, preferably 108 DEG C-115 DEG C in its DSC spectrum; The peak temperature of an endotherm(ic)peak is 112 DEG C-120 DEG C, preferably 115 DEG C-120 DEG C; The peak temperature of another endotherm(ic)peak is 120 DEG C-128 DEG C, preferably 120 DEG C-127 DEG C.
8. emtricitabine salicylate as claimed in claim 1, is characterized in that, in its XRPD spectrum (CuK α radiation), there is characteristic peak at following 2 θ angles: 7.91 ± 0.2 °, 10.12 ± 0.2 °, 12.42 ± 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 °, 28.46 ± 0.2 °, and 28.92 ± 0.2 °.
Emtricitabine salicylate as claimed in claim 1 a preparation method, it is characterized in that, it comprises the steps:
(a) emtricitabine and Whitfield's ointment are mixed in water, heating for dissolving, obtain mixture a;
(b), by cooling mixture a, obtain emtricitabine salicylate as claimed in claim 1.
10. preparation method as claimed in claim 9, is characterized in that, is heated to 70-90 DEG C or be heated to emtricitabine and Whitfield's ointment dissolves completely in step (a).
11. preparation methods as claimed in claim 9, is characterized in that, are cooled to 15-50 DEG C, preferably to room temperature-50 DEG C in step (b).
12. 1 kinds of emtricitabine salicylates as claimed in claim 1 preparation method, it is characterized in that, it comprises the steps:
(i) by chemical structural formula compound and reductive agent reaction as shown in Equation 3, obtain the mixture i that contains emtricitabine;
Described reductive agent is selected from sodium borohydride, POTASSIUM BOROHYDRIDE;
(ii) in mixture i, add Whitfield's ointment salify, obtain containing emtricitabine salicylate mixture ii;
(iii) from mixture ii, separate and obtain emtricitabine salicylate as claimed in claim 1.
13. preparation methods as claimed in claim 12, is characterized in that, described in contain emtricitabine mixture i in solvent, in gross weight, wherein the content of water is 80-100%, preferably 90-100%.
14. 1 kinds of emtricitabine salicylates as claimed in claim 1 purposes, it is characterized in that, described formula 2 compounds are for the preparation of emtricitabine, it comprises the steps: formula 2 compounds to mix with alkalizing agent, obtains emtricitabine.
15. purposes as claimed in claim 14, is characterized in that, described alkalizing agent is selected from triethylamine, diisopropyl ethyl amine.
The preparation method of 16. 1 kinds of emtricitabines, is characterized in that, by emtricitabine salicylate as claimed in claim 1, as intermediate, described preparation method comprises step:
(1) by chemical structural formula compound and reductive agent reaction as shown in Equation 3, obtain mixture 1;
(2) mixture 1 and Whitfield's ointment are mixed, heating for dissolving obtains mixture 2;
(3), by cooling mixture 2, obtain emtricitabine salicylate as claimed in claim 1;
(4) emtricitabine salicylate as claimed in claim 1 gained is mixed with alkalizing agent, obtain emtricitabine;
Described reductive agent is selected from sodium borohydride, POTASSIUM BOROHYDRIDE;
Described alkalizing agent is selected from triethylamine, diisopropyl ethyl amine.
17. preparation methods as claimed in claim 16, is characterized in that, described in contain emtricitabine mixture 1 in solvent, in gross weight, wherein the content of water is 80-100%, preferably 90-100%.
18. preparation methods as claimed in claim 16, is characterized in that, are heated to 70-90 DEG C or be heated to mixture 1 and Whitfield's ointment dissolves completely in step (2).
19. preparation methods as claimed in claim 16, is characterized in that, are cooled to 15-50 DEG C, preferably to room temperature-50 DEG C in step (3).
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201210479527.8A CN103833741A (en) | 2012-11-22 | 2012-11-22 | Emtricitabine salicylate and preparation method and application thereof |
PCT/CN2013/087489 WO2014079356A1 (en) | 2012-11-22 | 2013-11-20 | Emtricitabine sylicylate and crystalline, preparing methods and uses thereof |
CN201380038748.4A CN104487437B (en) | 2012-11-22 | 2013-11-20 | Emtricitabine salicylate and its crystal formation, preparation method and purposes |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201210479527.8A CN103833741A (en) | 2012-11-22 | 2012-11-22 | Emtricitabine salicylate and preparation method and application thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
CN103833741A true CN103833741A (en) | 2014-06-04 |
Family
ID=50775541
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201210479527.8A Pending CN103833741A (en) | 2012-11-22 | 2012-11-22 | Emtricitabine salicylate and preparation method and application thereof |
CN201380038748.4A Active CN104487437B (en) | 2012-11-22 | 2013-11-20 | Emtricitabine salicylate and its crystal formation, preparation method and purposes |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201380038748.4A Active CN104487437B (en) | 2012-11-22 | 2013-11-20 | Emtricitabine salicylate and its crystal formation, preparation method and purposes |
Country Status (2)
Country | Link |
---|---|
CN (2) | CN103833741A (en) |
WO (1) | WO2014079356A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105130972A (en) * | 2015-08-04 | 2015-12-09 | 山东潍坊制药厂有限公司 | Emtricitabine benzoate, preparation method thereof, and method of preparing emtricitabine from emtricitabine benzoate |
CN106496208A (en) * | 2016-10-19 | 2017-03-15 | 上海博志研新药物技术有限公司 | The preparation method of emtricitabine |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105585564A (en) * | 2014-11-18 | 2016-05-18 | 正大天晴药业集团股份有限公司 | Purifying method of emtricitabine |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004085432A1 (en) * | 2003-03-24 | 2004-10-07 | Clariant Life Science Molecules (Italia) Spa | Process and intermediates for preparing emtricitabine |
CN101066971A (en) * | 2007-05-24 | 2007-11-07 | 葛建利 | Non-enantioselective prepn process of emtricitabine |
CN101671333A (en) * | 2009-10-11 | 2010-03-17 | 沧州那瑞化学科技有限公司 | Method for separating emtricitabine |
CN102010404A (en) * | 2010-12-29 | 2011-04-13 | 刘建红 | Method for purifying and refining lamivudine and emtricitabine |
-
2012
- 2012-11-22 CN CN201210479527.8A patent/CN103833741A/en active Pending
-
2013
- 2013-11-20 CN CN201380038748.4A patent/CN104487437B/en active Active
- 2013-11-20 WO PCT/CN2013/087489 patent/WO2014079356A1/en active Application Filing
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004085432A1 (en) * | 2003-03-24 | 2004-10-07 | Clariant Life Science Molecules (Italia) Spa | Process and intermediates for preparing emtricitabine |
CN101066971A (en) * | 2007-05-24 | 2007-11-07 | 葛建利 | Non-enantioselective prepn process of emtricitabine |
CN101671333A (en) * | 2009-10-11 | 2010-03-17 | 沧州那瑞化学科技有限公司 | Method for separating emtricitabine |
CN102010404A (en) * | 2010-12-29 | 2011-04-13 | 刘建红 | Method for purifying and refining lamivudine and emtricitabine |
Non-Patent Citations (1)
Title |
---|
CHIEN-NENG CHANG,等: "Deoxycytidine Deaminase-resistant Stereoisomer Is the Active Form of (±)-2’,3’-Dideoxy-3’-thiacytidine in the Inhibition of Hepatitis B Virus Replication", 《THE JOURNAL OF BIOLOGICAL CHEMISTRY》 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105130972A (en) * | 2015-08-04 | 2015-12-09 | 山东潍坊制药厂有限公司 | Emtricitabine benzoate, preparation method thereof, and method of preparing emtricitabine from emtricitabine benzoate |
CN105130972B (en) * | 2015-08-04 | 2018-04-20 | 中孚药业股份有限公司 | Benzoic acid emtricitabine salt, its preparation method and the method for preparing emtricitabine with benzoic acid emtricitabine salt |
CN106496208A (en) * | 2016-10-19 | 2017-03-15 | 上海博志研新药物技术有限公司 | The preparation method of emtricitabine |
Also Published As
Publication number | Publication date |
---|---|
CN104487437A (en) | 2015-04-01 |
CN104487437B (en) | 2017-07-07 |
WO2014079356A1 (en) | 2014-05-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP2021536468A (en) | Methyl 6- (2,4-dichlorophenyl) -5- [4-[(3S) -1- (3-fluoropropyl) pyrrolidine-3-yl] oxyphenyl] -8,9-dihydro-7H-benzo [7 ] How to prepare annulene-2-carboxylate | |
CN107266449A (en) | The preparation method of chiral 8 (base of 3 amino piperidine 1) xanthine | |
CN108794491B (en) | Refining method of tofacitinib citrate | |
WO2010081865A1 (en) | Separation of an enantiomer mixture of (r)- and (s)-3-amino-1-butanol | |
WO1995022521A1 (en) | Aminoalkylcyclopropane derivative | |
CN103298793B (en) | The preparation method of high-purity medicament intermediate | |
CN103833741A (en) | Emtricitabine salicylate and preparation method and application thereof | |
US8975405B2 (en) | Indenopyridine derivatives | |
CN104341422A (en) | Tofacitinib intermediate and preparation method thereof | |
CN102603592B (en) | Preparation method for (R)-1-benzyl-3-aminopyrrolidine and (S)-1-benzyl-3-aminopyrrolidine | |
CN103242291A (en) | Mass production process of polycrystalline high-content benzoic acid alogliptin | |
CN103059013B (en) | Crystal formation of Dasatinib monohydrate and preparation method thereof | |
JP7355834B2 (en) | FGFR inhibitor compounds in solid form and methods for producing the same | |
CN104892609A (en) | Linagliptin intermediate, preparation method and applications thereof | |
CN103113408A (en) | Novel method for preparing fosfomycin phenylethylamine | |
CN109666019B (en) | Deuterated azolol compound and preparation method and application thereof | |
WO2016078584A1 (en) | Emtricitabine purification method | |
EP2540717B1 (en) | Lamivudine oxalate and preparation method thereof | |
CN104177271A (en) | Method for preparing acetyl levocarnitine hydrochloride | |
CN106008323B (en) | A method of preparing half tartrate crystal form C of piperazine Ma Selin | |
CN105732613A (en) | Synthesis method of 9-demethyl-(+)-alpha-dihydrotetrabenazine | |
CN103724323B (en) | The preparation method of pomalidomide | |
CN111892535B (en) | Synthesis method of montelukast sodium | |
CN100534989C (en) | Resolving process of (RS)-benzdioxan-2-formic acid | |
CN112608286B (en) | Preparation method of high-purity pramipexole |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20140604 |