CN106478618A - The preparation method of emtricitabine halogen acid salt - Google Patents
The preparation method of emtricitabine halogen acid salt Download PDFInfo
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- CN106478618A CN106478618A CN201610898062.8A CN201610898062A CN106478618A CN 106478618 A CN106478618 A CN 106478618A CN 201610898062 A CN201610898062 A CN 201610898062A CN 106478618 A CN106478618 A CN 106478618A
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- emtricitabine
- acid salt
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- halogen acid
- solvent
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- 229960000366 emtricitabine Drugs 0.000 title claims abstract description 192
- -1 emtricitabine halogen Chemical class 0.000 title claims abstract description 104
- 238000002360 preparation method Methods 0.000 title claims abstract description 99
- 150000003839 salts Chemical class 0.000 title claims abstract description 97
- 229910052736 halogen Inorganic materials 0.000 title claims abstract description 96
- 239000002253 acid Substances 0.000 title claims abstract description 95
- XQSPYNMVSIKCOC-NTSWFWBYSA-N Emtricitabine Chemical compound C1=C(F)C(N)=NC(=O)N1[C@H]1O[C@@H](CO)SC1 XQSPYNMVSIKCOC-NTSWFWBYSA-N 0.000 claims abstract description 106
- 239000002904 solvent Substances 0.000 claims abstract description 104
- 150000001298 alcohols Chemical class 0.000 claims abstract description 58
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 40
- 239000012043 crude product Substances 0.000 claims abstract description 33
- 238000012805 post-processing Methods 0.000 claims abstract description 33
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims abstract description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 18
- 239000001257 hydrogen Substances 0.000 claims abstract description 18
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims abstract description 15
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims abstract description 15
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims abstract description 13
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims abstract description 4
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 4
- 239000000460 chlorine Substances 0.000 claims abstract description 4
- 229910052740 iodine Chemical group 0.000 claims abstract description 4
- 239000011630 iodine Chemical group 0.000 claims abstract description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims abstract description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229910000043 hydrogen iodide Inorganic materials 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 54
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 37
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 37
- 238000003756 stirring Methods 0.000 claims description 37
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 33
- 239000012046 mixed solvent Substances 0.000 claims description 27
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 21
- 150000002148 esters Chemical class 0.000 claims description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 19
- 238000001816 cooling Methods 0.000 claims description 15
- 238000002425 crystallisation Methods 0.000 claims description 15
- 230000008025 crystallization Effects 0.000 claims description 15
- 238000000746 purification Methods 0.000 claims description 15
- 238000001953 recrystallisation Methods 0.000 claims description 12
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 9
- 230000001476 alcoholic effect Effects 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 8
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 8
- 229940011051 isopropyl acetate Drugs 0.000 claims description 7
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 7
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 239000007789 gas Substances 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims 3
- 238000004458 analytical method Methods 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 13
- 239000003814 drug Substances 0.000 abstract description 9
- 239000000047 product Substances 0.000 abstract description 9
- 229940079593 drug Drugs 0.000 abstract description 6
- 239000000356 contaminant Substances 0.000 abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- 239000000243 solution Substances 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 20
- 238000001291 vacuum drying Methods 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 239000012065 filter cake Substances 0.000 description 10
- 238000005406 washing Methods 0.000 description 9
- 238000000034 method Methods 0.000 description 8
- 235000011121 sodium hydroxide Nutrition 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 7
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- 238000010009 beating Methods 0.000 description 5
- 238000007796 conventional method Methods 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 150000007530 organic bases Chemical class 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- AKPUJVVHYUHGKY-UHFFFAOYSA-N hydron;propan-2-ol;chloride Chemical compound Cl.CC(C)O AKPUJVVHYUHGKY-UHFFFAOYSA-N 0.000 description 3
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 2
- 208000035126 Facies Diseases 0.000 description 2
- 208000031886 HIV Infections Diseases 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 150000008282 halocarbons Chemical class 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 229910017053 inorganic salt Inorganic materials 0.000 description 2
- 229940041616 menthol Drugs 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000001226 triphosphate Substances 0.000 description 2
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 1
- 241000713340 Human immunodeficiency virus 2 Species 0.000 description 1
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 1
- 229940122313 Nucleoside reverse transcriptase inhibitor Drugs 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 108020005202 Viral DNA Proteins 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- 230000000798 anti-retroviral effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 238000001354 calcination Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229940001018 emtriva Drugs 0.000 description 1
- OEZNULIHEQCKJR-UHFFFAOYSA-N ethanol;hydrobromide Chemical compound Br.CCO OEZNULIHEQCKJR-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- LLYJISDUHFXOHK-GOCONZMPSA-N ferroptocide Chemical compound C[C@@H]1CC[C@@]23C[C@@H](C(=O)[C@]2([C@@]1([C@@H](C[C@H]([C@@H]3C)C4=CCN5C(=O)N(C(=O)N5C4)C6=CC=CC=C6)OC(=O)CCl)C)O)O LLYJISDUHFXOHK-GOCONZMPSA-N 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- XRECTZIEBJDKEO-UHFFFAOYSA-N flucytosine Chemical compound NC1=NC(=O)NC=C1F XRECTZIEBJDKEO-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Saccharide Compounds (AREA)
Abstract
The invention discloses the preparation method of emtricitabine halogen acid salt.The invention provides a kind of preparation method of emtricitabine halogen acid salt, it comprises the following steps：In alcohols solvent, emtricitabine crude product and hydrogen halides are carried out salt-forming reaction, obtains emtricitabine halogen acid salt；The HPLC purity of described emtricitabine crude product is more than 85.0%；Described hydrogen halides are hydrogen chloride, hydrogen bromide or hydrogen iodide, and X is chlorine, bromine or iodine.The preparation method of the present invention is simple to operate, post processing is easy, high income, prepared emtricitabine product purity high, can reach crude drug standard, HPLC purity is more than 99.60%, maximum single contaminant and is less than 0.10% low production cost, is suitable for industrialized production.
Description
Technical field
The present invention relates to the preparation method of emtricitabine halogen acid salt.
Background technology
Emtricitabine I (Emtriva, FTC) combines controlling for HIV-1 infection of being grown up with other antiretroviral drugs
Treat.Emtricitabine I is a kind of novel nucleoside reverse transcriptase inhibitors, all has antiviral activity to HIV-1, HIV-2 and HBV.
This product is phosphorylated to the 5 '-triphosphate with cytoactive after being administered orally, 5 '-triphosphate passes through to enter viral DNA main chain,
Be combined with main chain, lead to chain termination, thus suppressing HIV1-RT and HBV-DNA polymerase activity.Emtricitabine I structure
Shown in formula I：
The method preparing emtricitabine I under the conditions of prior art is all to be obtained by the reaction of emtricitabine intermediate III, due to
Emtricitabine I has larger water solublity, and the crude product that post processing obtains contains a large amount of inorganic salts, thus cannot direct crystallization purification,
Need to carry out post separation ability purification, operating condition is loaded down with trivial details, expend a large amount of materials, is unfavorable for industrialized production.It is thus desirable to seeking
Look for a kind of simple to operate, post processing is easy, high income, prepared product purity height can reach crude drug standard, production cost
The preparation method of emtricitabine that is low, being suitable for industrialized production.
Content of the invention
The technical problem to be solved is to overcome the operation of the preparation method of emtricitabine in prior art multiple
Miscellaneous, post-processing approach is complicated, production cost is high, be not suitable for the defects such as industrialized production and provide a kind of emtricitabine hydrogen halogen
The preparation method of hydrochlorate.The preparation method of the present invention is simple to operate, post processing is easy, high income, prepared emtricitabine product
Purity height can reach crude drug standard, low production cost, be suitable for industrialized production.
The invention provides a kind of preparation method of emtricitabine halogen acid salt, it comprises the following steps：In alcohols solvent
In, emtricitabine crude product and hydrogen halides are carried out salt-forming reaction, obtains emtricitabine halogen acid salt；Described emtricitabine
The HPLC purity of crude product is more than or equal to 85.0%；Described hydrogen halides are hydrogen chloride, hydrogen bromide or hydrogen iodide；X be chlorine, bromine or
Iodine；
In the preparation method of described emtricitabine halogen acid salt, the preferred methanol of described alcohols solvent, ethanol, isopropyl
One or more of alcohol and the tert-butyl alcohol；Further preferably isopropanol.
In the preparation method of described emtricitabine halogen acid salt, described emtricitabine crude product is molten with described alcohols
The mass volume ratio value preferably 1: 1g/mL～1: 30g/mL of agent, further preferred 1: 5g/mL～1: 20g/mL；Such as 1: 10g/
mL.
In the preparation method of described emtricitabine halogen acid salt, the preferred hydrogen chloride of described hydrogen halides or hydrogen bromide.
In the form of can be for the alcoholic solution of hydrogen chloride gas or hydrogen chloride when using hydrogen chloride；When using ethanolic hydrogen chloride solution,
Preferred 1mol/L～the 3mol/L of concentration, such as 2mol/L of described ethanolic hydrogen chloride solution.It can be bromine when using hydrogen bromide
Change the form of the alcoholic solution of hydrogen；When using hydrogen bromide alcoholic solution, the preferred 1mol/L of concentration of described hydrogen bromide alcoholic solution～
3mol/L, such as 2mol/L.
In the preparation method of described emtricitabine halogen acid salt, described hydrogen halides and described emtricitabine crude product
Molar ratio preferably 1～1.2, further preferred 1～1.1, such as 1.0.
In the preparation method of described emtricitabine halogen acid salt, preferably -20 DEG C of the temperature of described salt-forming reaction～
30 DEG C, further preferred 0 DEG C～30 DEG C, such as 10 DEG C～20 DEG C.
In the preparation method of described emtricitabine halogen acid salt, preferably 1 hour time of described salt-forming reaction～
10 hours, further preferred hour 1～5 hour, such as 2 hours.
The preparation method of described emtricitabine halogen acid salt, it is preferred to use following steps：The alcoholic solution of hydrogen halides is added
Enter in the solution being formed with alcohols solvent to emtricitabine crude product, carry out salt-forming reaction, obtain emtricitabine halogen acid salt.
The preferred Deca of mode of described addition, the speed preferred 1mL/ minute～50mL/ minute of Deca, such as 20mL/ minute～
30mL/ minute.
The preparation method of described emtricitabine halogen acid salt, preferably includes following post-processing step：After reaction terminates, mistake
Filter, wash, being dried to obtain emtricitabine halogen acid salt.
Described being filtered, washed and dried can be using the conventional method of this generic operation in this area.Described drying is excellent
Choosing vacuum drying；Preferably 40 DEG C～60 DEG C of described vacuum drying temperature, such as 60 DEG C；The described vacuum drying time is excellent
Select 1 hour～10 hours, further preferred 2 hours～6 hours, such as 4 hours～5 hours；Described vacuum drying pressure
Preferably -0.08MPa～-0.1MPa.
The preparation method of described emtricitabine halogen acid salt, preferably further includes following post-processing step：To obtain
Emtricitabine halogen acid salt be recrystallized to give emtricitabine halogen acid salt after purification.
In the further preferred post-processing step of the preparation method of emtricitabine halogen acid salt, described recrystallization is permissible
Conventional method using this generic operation in this area.The preferred alcohols solvent of solvent that described recrystallization adopts, alcohols solvent with
The mixed solvent of ether solvent or the mixed solvent of alcohols solvent and esters solvent.The preferred methanol of described alcohols solvent, ethanol,
One of isopropanol and the tert-butyl alcohol or many.The preferred diisopropyl ether of described ether solvent, dioxane, oxolane, 2- methyl
One or more of oxolane and n-butyl ether.Described esters solvent ethyl acetate and/or isopropyl acetate.When adopting
During with the mixed solvent of alcohols solvent and ether solvent, described ether solvent is preferred with the volume ratio of described alcohols solvent
1～2；Such as 1.6 or 1.3.The further preferred methanol of mixed solvent of described alcohols solvent and ether solvent and diisopropyl ether
Mixed solvent or the mixed solvent of ethanol and 2- methyltetrahydrofuran.When the mixed solvent using alcohols solvent and esters solvent
When, the volume ratio preferably 1～2, such as 1 or 1.7 of described esters solvent and described alcohols solvent；Described alcohols solvent
The mixed solvent of further preferred isopropanol and isopropyl acetate or ethanol and ethyl acetate with the mixed solvent of esters solvent
Mixed solvent.
In the post-processing step that the preparation method of emtricitabine halogen acid salt preferably further includes, described alcohols is molten
The mixed solvent of the mixed solvent of agent, alcohols solvent and ether solvent or alcohols solvent and esters solvent and described emtricitabine
The mass volume ratio value preferably 1: 1g/mL～1: 30g/mL of halogen acid salt, further preferred 1: 2g/mL～1: 20g/mL；Such as 1
: 5g/mL, 1: 10g/mL, 1: 13g/mL, 1: 14g/mL or 1: 16g/mL.
In the post-processing step that the preparation method of emtricitabine halogen acid salt preferably further includes, described recrystallization
Preferably 50 DEG C～80 DEG C of temperature, further preferred 55 DEG C～70 DEG C, such as 55 DEG C～65 DEG C or 60 DEG C～70 DEG C.
In the post-processing step that the preparation method of emtricitabine halogen acid salt preferably further includes, described recrystallization
Preferably employ following steps 1 or step 2：
Step 1：Emtricitabine halogen acid salt is dissolved in alcohols solvent, adds ether solvent or esters solvent, cold
But crystallize obtains emtricitabine halogen acid salt after purification；
Step 2：Emtricitabine halogen acid salt is dissolved in alcohols solvent, then cooling crystallization obtain grace after purification bent he
Shore halogen acid salt.
In step 1 or step 2, preferably 50 DEG C～80 DEG C of the temperature of described dissolving, further preferred 55 DEG C～70 DEG C, example
As 55 DEG C～65 DEG C or 60 DEG C～70 DEG C.
In step 1 or step 2, preferably 0 DEG C～20 DEG C of the temperature of described cooling crystallization, further preferred 5 DEG C～15 DEG C,
Such as 5 DEG C～10 DEG C or 10 DEG C～15 DEG C.Preferably 1 hour～5 hours time of described cooling crystallization, further preferred 1 is little
When～3 hours, such as 1 hour.
In step 1 or step 2, described dissolving and cooling crystallization are preferably carried out under conditions of stirring, described stirring
Preferably 60 revs/min～120 revs/min of speed, such as 60 revs/min, 80 revs/min, 90 revs/min, 100 revs/min
Or 120 revs/min.
The preparation method of described emtricitabine halogen acid salt, also includes still further preferably after recrystallization filtering, washs
Step with being dried.
In the step that the preparation method of emtricitabine halogen acid salt still further preferably includes, described filtration, washing
Can be using the conventional method of this generic operation in this area with drying.Described washs the preferred alcohols solvent of solvent adopting, ether
Class solvent or esters solvent；The preferred diisopropyl ether of described ether solvent, dioxane, oxolane, 2- methyltetrahydrofuran and
One or more of n-butyl ether.Described esters solvent ethyl acetate and/or isopropyl acetate.Described alcohols solvent
The preferably tert-butyl alcohol.The number of times of described washing preferably 1 time～3 times, such as 2 times.Described drying is preferably vacuum dried；Described
Preferably 40 DEG C～60 DEG C of vacuum drying temperature, such as 50 DEG C～60 DEG C；The described vacuum drying time preferably 1 hour～10
Hour, further preferred 2 hours～6 hours, such as 4 hours～8 hours；Described vacuum drying pressure preferably -0.08MPa
～-0.1MPa.
Present invention also offers a kind of preparation method of emtricitabine, it comprises the following steps：In alcohols solvent, will be upper
The emtricitabine halogen acid salt that method of stating is obtained is neutralized reaction with organic base, obtains emtricitabine；X be chlorine, bromine or
Iodine；
In the preparation method of described emtricitabine, the preferred methanol of described alcohols solvent, ethanol, isopropanol and tertiary fourth
One or more of alcohol；Further preferably methanol.
In the preparation method of described emtricitabine, described emtricitabine halogen acid salt and described alcohols solvent
Mass volume ratio value preferably 1: 1g/mL～1: 20g/mL, further preferred 1: 2g/mL～1: 10g/mL；Such as 1: 5g/mL or 1:
8g/mL.
In the preparation method of described emtricitabine, the preferred triethylamine of described organic base and/or N, N- diisopropyl
Ethylamine.
In the preparation method of described emtricitabine, described organic base is rubbed with described emtricitabine halogen acid salt
That ratio preferably 1～2；Further preferred 1～1.5；Such as 1,1.2 or 1.4.
In the preparation method of described emtricitabine, preferably 0 DEG C～40 DEG C of the temperature of described neutralization reaction, further
Preferably 10 DEG C～30 DEG C, such as 15 DEG C～25 DEG C.
In the preparation method of described emtricitabine, preferably 1 hour～5 hours time of described neutralization reaction, enter
One step preferably 1 hour～3 hours, such as 1 hour.
The preparation method of described emtricitabine preferably employs following steps：To emtricitabine halogen acid salt and alcohols solvent
In the mixture being formed, add organic base, be neutralized reaction and obtain described emtricitabine.
The preferred Deca of mode of described addition；The speed of described Deca preferably 1 gram/minute～30 gram/minute, for example
3.6 gram/minute～5.5 gram/minute, 7.8 gram/minute～10.3 gram/minute or 9.3 gram/minute～14.0 gram/minute.
The preparation method of described emtricitabine preferably employs following post-processing step：After reaction terminates, remove solvent and obtain
To emtricitabine.The mode of the described removing preferred vacuum distillation of solvent.
The preparation method of described emtricitabine further preferably adopts following post-processing step：By the emtricitabine obtaining
Making beating, filters, and washing is dried, obtains emtricitabine after purification.
Described making beating can be excellent using the conventional method of this generic operation in this area, the solvent of described making beating and washing
Select halogenated hydrocarbon solvent, the preferred chlorinated hydrocarbon solvent of described halogenated hydrocarbon solvent；The preferred dichloro of described chlorinated hydrocarbon solvent
Methane.Preferably 20 DEG C～25 DEG C of the temperature of described making beating.Preferably 1 hour～3 hours time of described making beating, such as 1 is little
When.Described being filtered, washed and dried can be using the conventional method of this generic operation in this area.The preferred vacuum of described drying
It is dried；Preferably 50 DEG C～60 DEG C of described vacuum drying temperature；The described vacuum drying time preferably 1 hour～24 is little
When, further preferred 6 hours～12 hours；Described vacuum drying pressure preferably -0.08MPa～-0.1MPa.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can combination in any, obtain final product the present invention each preferably
Example.
Agents useful for same of the present invention and raw material are all commercially available.
In the present invention, described room temperature refers to ambient temperature, is 10 DEG C～35 DEG C.
The positive effect of the present invention is：The preparation method of the present invention is simple to operate, post processing is easy, high income,
Prepared emtricitabine product purity height can reach crude drug standard, and (HPLC purity is more than 99.60%, and maximum single contaminant is little
In 0.10%), low production cost, be suitable for industrialized production.
Specific embodiment
Further illustrate the present invention below by the mode of embodiment, but therefore do not limit the present invention to described reality
Apply among a scope.The experimental technique of unreceipted actual conditions in the following example, conventionally and condition, or according to business
Product description selects.
Embodiment 1：The preparation method (referenced patent CN200410023745.6, embodiment 1) of emtricitabine intermediate III
720g emtricitabine intermediate compound IV adds 7.2L dichloromethane, 20mLDMF, is cooled to 0～5 DEG C, Deca protochloride
Sulfone 192mL is in the solution of 1.2L dichloromethane.Stir 2 hours at 10～15 DEG C, concentrating under reduced pressure, be subsequently adding 2.2L toluene cold
Stand-by.324g 5-flurocytosine, 12g ammonium sulfate, 600mL hexamethyl two silicon substrate amine alkane, add 960mL toluene, are heated to reflux
1～2 hour.Somewhat it is cooled to less than 90 DEG C, Deca 350mL triethylamine, it is heated to backflow but inviolent.It is added dropwise to above-mentioned preparation
Chloro thing solution, washed with 240mL toluene.Backflow 2～3 hours, is cooled to 30～35 DEG C, Deca 180mL triethylamine is in water
In solution 2.9L, be cooled to 15～20 DEG C, stir 1 hour, Deca normal heptane 2.9L, stir 16 hours, filter, washing, do
Emtricitabine intermediate III, 504g, yield 50.5%, HPLC purity 98.17% is obtained after dry.
Embodiment 2：The preparation method of emtricitabine hydrochlorate II crude product
420g emtricitabine intermediate III (HPLC purity 98.17%) adds potassium dihydrogen phosphate 540g, water 600mL, ethanol
300mL, 10～15 DEG C of Deca 160g sodium borohydrides in 800mL water and 8mL mass percent be 25% sodium hydrate aqueous solution
(described mass percent refers to that the quality of sodium hydroxide accounts for the percentage ratio of sodium hydrate aqueous solution gross mass), at 20～30 DEG C
Stirring 2～3 hours, being adjusted to pH with the hydrochloric acid of 1mol/L is 4～5, stirs 0.5 hour, then the sodium hydroxide water with 2mol/L
It is 7 that solution is adjusted to pH, is extracted three times with toluene and water.Organic faciess discard for menthol.Aqueous phase is concentrated to dryness to obtain grace after separating
His shore I crude product (HPLC purity 95.73%) bent.
300g emtricitabine I crude product (HPLC purity 95.73%) uses isopropanol 3L to dissolve, Deca 0.6L at 10～20 DEG C
2N isopropanol hydrogen chloride solution, adds for about 20～30 minutes, and after adding, at 10～20 DEG C, stirring separates out emtricitabine salt in 2 hours
Hydrochlorate II.Filter, filter cake isopropanol (1L) drip washing twice, 60 DEG C of vacuum (pressure is -0.08MPa～-0.1MPa) dry 4～
Obtain within 5 hours 275g emtricitabine hydrochlorate II crude product.Yield 93.6%, HPLC purity 99.03%.
Embodiment 3：The preparation method of emtricitabine hydrobromate II ' crude product
42g emtricitabine intermediate III (HPLC purity 98.17%) adds potassium dihydrogen phosphate 54g, water 60mL, ethanol
30mL, 10～15 DEG C of Deca 16g sodium borohydrides in 80mL water and 1mL mass percent be 25% sodium hydrate aqueous solution (institute
The mass percent stated refers to that the quality of sodium hydroxide accounts for the percentage ratio of sodium hydrate aqueous solution gross mass), stir at 20～30 DEG C
Mix 2～3 hours, being adjusted to pH with the hydrochloric acid of 1mol/L is 4～5, stirs 0.5 hour, more water-soluble with the sodium hydroxide of 2mol/L
It is 7 that liquid is adjusted to pH, is extracted three times with toluene and water.Organic faciess discard for menthol.Aqueous phase is concentrated to dryness to obtain grace song after separating
His shore I crude product (HPLC purity 94.67%).
30g emtricitabine I crude product (HPLC purity 94.67%) uses isopropanol 300mL to dissolve, Deca at 10～20 DEG C
60mL 2N ethanol hydrogen bromide solution, adds for about 2～3 minutes, and after adding, at 10～20 DEG C, stirring separates out emtricitabine in 2 hours
Hydrobromate II '.Filter, twice, 60 DEG C of vacuum (pressure is -0.08MPa～-0.1MPa) dry 4 for filter cake isopropanol drip washing
Obtain within～5 hours 28.6g emtricitabine hydrobromate II ' crude product.Yield 84.2%, HPLC purity 98.66%.
Embodiment 4：The process for purification of emtricitabine hydrochlorate II
200g emtricitabine hydrochlorate II (HPLC purity 99.03%), adds methanol 1L, is heated to 55～65 DEG C of dissolvings,
Add diisopropyl ether 1.6L, cool to 10～15 DEG C, and stir 1 hour, the speed of stirring is 60 revs/min, filters, uses isopropyl
Ether 300mL washes twice.At -0.08～-0.1MPa and 50～60 DEG C, vacuum drying obtains emtricitabine hydrochloric acid in 4～8 hours
Salt II, 178g, HPLC purity 99.96%, yield 89.0%.
Embodiment 5：The process for purification of emtricitabine hydrochlorate II
10g emtricitabine hydrochlorate II (HPLC purity 99.03%), adds ethanol 60mL, is heated to 55～65 DEG C of dissolvings,
Add ethyl acetate 100mL, cool to 10～15 DEG C, and stir 1 hour, the speed of stirring is 80 revs/min, filters, and uses
Ethyl acetate 30mL washes twice.At -0.08～-0.1MPa and 50～60 DEG C, vacuum drying obtains emtricitabine in 4～8 hours
Hydrochlorate II, 8.74g, HPLC purity 99.90%, yield 87.4%.
Embodiment 6：The process for purification of emtricitabine hydrochlorate II
10g emtricitabine hydrochlorate II (HPLC purity 99.03%), add isopropanol 80mL, be heated to 55～65 DEG C molten
Solution, adds isopropyl acetate 80mL, cools to 10～15 DEG C, and stir 1 hour, and the speed of stirring is 100 revs/min, mistake
Filter, is washed twice with isopropyl acetate 30mL.It is vacuum dried at -0.08～-0.1MPa and 50～60 DEG C and obtain for 4～8 hours
Emtricitabine hydrochlorate II, 8.66g, HPLC purity 99.95%, yield 86.6%.
Embodiment 7：The process for purification of emtricitabine hydrochlorate II
10g emtricitabine hydrochlorate II (HPLC purity 99.03%), adds ethanol 60mL, is heated to 55～65 DEG C of dissolvings,
Add 2- methyltetrahydrofuran 80mL, cool to 10～15 DEG C, and stir 1 hour, the speed of stirring is 120 revs/min, mistake
Filter, is washed twice with 2- methyltetrahydrofuran 30mL.It is vacuum dried 4～8 hours at -0.08～-0.1MPa and 50～60 DEG C
Obtain emtricitabine hydrochlorate II, 8.37g, HPLC purity 99.81%, yield 83.7%.
Embodiment 8：The process for purification of emtricitabine hydrochlorate II
10g emtricitabine hydrochlorate II (HPLC purity 99.03%), add tert-butyl alcohol 100mL, be heated to 60～70 DEG C molten
Solution, cools to 5～10 DEG C, and stirs 1 hour, and the speed of stirring is 90 revs/min, filters, with being cooled to 0 DEG C of the tert-butyl alcohol
30mL washes twice.At -0.08～-0.1MPa and 50～60 DEG C, vacuum drying obtains emtricitabine hydrochlorate in 4～8 hours
II, 8.09g, HPLC purity：99.83%, yield 80.9%.
Embodiment 9：The process for purification of emtricitabine hydrobromate II '
23.1g emtricitabine hydrobromate II ' (HPLC purity 98.66%), adds methanol 116mL, is heated to 55～65
DEG C dissolving, add diisopropyl ether 185mL, cool to 10～15 DEG C, and stir 1 hour, filter, wash two with diisopropyl ether 35mL
Secondary.It is vacuum dried at -0.08～-0.1MPa and 50～60 DEG C and obtain within 4～8 hours emtricitabine hydrogen bromide II, 20.3g,
HPLC purity 99.92%, yield 87.9%.
Embodiment 10：The preparation method of emtricitabine I
170g emtricitabine hydrochlorate II (HPLC purity 99.96%), add methanol 850mL, be heated to 50～60 DEG C molten
Solution, cools to 15～25 DEG C, is added dropwise to triethylamine 62g and adds for about 6～8 minutes.Stir 1 hour at 15～25 DEG C, concentrated in vacuo
Remove methanol, add 700mL dichloromethane, stir 1 hour at 20～25 DEG C, filter, filter cake adds 500mL dichloromethane,
20～25 DEG C are stirred 1 hour, filter, and filter cake is washed twice with 250mL dichloromethane.At -0.08～-0.1MPa and 50～60 DEG C
Lower vacuum drying obtains 138g emtricitabine I, HPLC purity 99.94%, maximum single contaminant 0.04%, calcination for 6～12 hours
Residue 0.03%, yield 93.2%.
Embodiment 11：The preparation method of emtricitabine I
8.5g emtricitabine hydrochlorate II (HPLC purity 99.81%), add methanol 68mL, be heated to 50～60 DEG C molten
Solution, cools to 15～25 DEG C, is added dropwise to N, N- diisopropyl ethyl amine 4.65g, adds within about 20 seconds～30 seconds.Stir at 15～25 DEG C
Mix 1 hour, removal methanol concentrated in vacuo, add 35mL dichloromethane, stir 1 hour at 20～25 DEG C, filter, filter cake adds
25mL dichloromethane, stirs 1 hour at 20～25 DEG C, filters, and filter cake is washed twice with 13mL dichloromethane.- 0.08～-
At 0.1MPa and 50～60 DEG C, vacuum drying obtains 6.76g emtricitabine I, HPLC purity 99.87%, maximum list for 6～12 hours
One impurity 0.05%, ignition residue 0.04%, yield 91.3%.
Embodiment 12：The preparation method of emtricitabine I
20g emtricitabine hydrobromate II ' (HPLC purity 99.92%), adds methanol 160mL, is heated to 50～60 DEG C
Dissolving, cools to 15～25 DEG C, is added dropwise to N, N- diisopropyl ethyl amine 10.94g, about 2 minutes～3 minutes.At 15～25 DEG C
Stirring 1 hour, removal methanol concentrated in vacuo, add 82mL dichloromethane, stir 1 hour at 20～25 DEG C, filter, filter cake adds
59mL dichloromethane, stirs 1 hour at 20～25 DEG C, filters, and filter cake is washed twice with 30mL dichloromethane.- 0.08～-
At 0.1MPa and 50～60 DEG C, vacuum drying obtains 13.4g emtricitabine I, HPLC purity 99.92%, maximum list for 6～12 hours
One impurity 0.04%, ignition residue 0.05%, yield 88.9%.
Embodiment 13：The preparation method of emtricitabine hydrochlorate II crude product
300g emtricitabine I crude product (HPLC purity 85.21%) uses isopropanol 3L to dissolve, Deca 0.6L at 10～20 DEG C
2mol/L isopropanol hydrogen chloride solution, adds for about 20～30 minutes, after adding at 10～20 DEG C stirring separate out within 2 hours grace bent he
Shore hydrochlorate II.Filter, twice, 60 DEG C of vacuum (pressure is -0.08MPa～-0.1MPa) are dried for filter cake isopropanol (1L) drip washing
Do and obtain within 4～5 hours 206g emtricitabine hydrochlorate II crude product.Yield 79.2%, HPLC purity 98.89%.
Embodiment 14：The preparation method of emtricitabine hydrochlorate II crude product
300g emtricitabine I crude product (HPLC purity 90.36%) uses isopropanol 3L to dissolve, Deca 0.6L at 10～20 DEG C
2mol/L isopropanol hydrogen chloride solution, adds for about 20～30 minutes, after adding at 10～20 DEG C stirring separate out within 2 hours grace bent he
Shore hydrochlorate II.Filter, twice, 60 DEG C of vacuum (pressure is -0.08MPa～-0.1MPa) are dried for filter cake isopropanol (1L) drip washing
Do and obtain within 4～5 hours 223g emtricitabine hydrochlorate II crude product.Yield 85.8%, HPLC purity 98.95%.
Comparative example 1：The original preparation method (with reference to patent documentation US5814639 and US5914331) of emtricitabine I
200～300 mesh silica fillers of 200g, add 3g emtricitabine I crude product (HPLC purity 98.17%), with containing
Dichloromethane solution 400～the 500mL of 10%～15% methanol rinses, and leacheate is concentrated in vacuo.With recrystallisation from isopropanol, obtain
0.91g emtricitabine finished product, yield 35.0%, HPLC purity 99.74%, maximum single contaminant 0.08%.
Comparative example 2：Original preparation method (the list of references of emtricitabine I：《Chinese pharmaceutical chemistry magazine》, 2002
Year, volume 12, page 34 and《Chinese Journal of Pharmaceuticals》2005, volume 36, page 589)
3g emtricitabine I crude product (HPLC purity 98.17%), uses methanol/isopropanol repeated recrystallize, obtains 2.23g grace
His shore finished product bent, yield 85.8%, HPLC purity 99.52%, maximum single contaminant 0.39%.Ignition residue 0.75% is (discontented
The requirement 0.1% of sufficient API).
From comparative example 1, in the preparation method prior art of emtricitabine I, such as patent documentation US5814639 and
US5914331 is reported, and forms water miscible emtricitabine I after intermediate III reduction, by recrystallization, inorganic salt is bent with grace
His shore I separation yield is low, needs to carry out column chromatography for separation except inorganic salt, needs silica gel amount and relatively more (the emtricitabine I of quantity of solvent
Hundred times, see comparative example 1), production cost is high, is not suitable for industrialized production (see comparative example 1).
From comparative example 2, in the preparation method prior art of emtricitabine I, such as periodical literature《Chinese medicine
Learn magazine》, 2002, volume 12, page 34 and《Chinese Journal of Pharmaceuticals》2005, volume 36, page 589 reported, intermediate III
Form water miscible emtricitabine I after reduction, do not carry out the product purity that column chromatography for separation then obtains and do not reach crude drug requiring
(see comparative example 2) is it is difficult to industrialization and cost is also high.
Claims (10)
1. a kind of preparation method of emtricitabine halogen acid salt is it is characterised in that it comprises the following steps：In alcohols solvent, will
Emtricitabine crude product and hydrogen halides carry out salt-forming reaction, obtain emtricitabine halogen acid salt；Described emtricitabine crude product
HPLC purity be more than 85.0%；Described hydrogen halides are hydrogen chloride, hydrogen bromide or hydrogen iodide；X is chlorine, bromine or iodine；
2. emtricitabine halogen acid salt as claimed in claim 1 preparation method it is characterised in that：In described emtricitabine
In the preparation method of halogen acid salt, described alcohols solvent is one or more of methanol, ethanol, isopropanol and tert-butyl alcohol；
And/or,
In the preparation method of described emtricitabine halogen acid salt, described emtricitabine crude product and described alcohols solvent
Mass volume ratio value is 1: 1g/mL～1: 30g/mL；
And/or,
In the preparation method of described emtricitabine halogen acid salt, described hydrogen halides are hydrogen chloride or hydrogen bromide；
And/or,
In the preparation method of described emtricitabine halogen acid salt, described hydrogen halides are rubbed with described emtricitabine crude product
Your ratio is 1～1.2；
And/or,
In the preparation method of described emtricitabine halogen acid salt, the temperature of described salt-forming reaction is -20 DEG C～30 DEG C；
And/or,
In the preparation method of described emtricitabine halogen acid salt, the time of described salt-forming reaction is 1 hour～10 hours.
3. emtricitabine halogen acid salt as claimed in claim 2 preparation method it is characterised in that：
In the preparation method of described emtricitabine halogen acid salt, described alcohols solvent is isopropanol；
And/or,
In the preparation method of described emtricitabine halogen acid salt, described emtricitabine crude product and described alcohols solvent
Mass volume ratio value is 1: 5g/mL～1: 20g/mL；
And/or,
In the preparation method of described emtricitabine halogen acid salt, it is hydrogen chloride gas or hydrogen chloride when using hydrogen chloride
Alcoholic solution form；
And/or,
In the preparation method of described emtricitabine halogen acid salt, it is the shape of the alcoholic solution of hydrogen bromide when using hydrogen bromide
Formula；
And/or,
In the preparation method of described emtricitabine halogen acid salt, described hydrogen halides are rubbed with described emtricitabine crude product
Your ratio is 1～1.1；
And/or,
In the preparation method of described emtricitabine halogen acid salt, the temperature of described salt-forming reaction is 0 DEG C～30 DEG C；
And/or,
In the preparation method of described emtricitabine halogen acid salt, the time of described salt-forming reaction is 1 hour～5 hours.
4. emtricitabine halogen acid salt as claimed in claim 3 preparation method it is characterised in that：
In the preparation method of described emtricitabine halogen acid salt, described emtricitabine crude product and described alcohols solvent
Mass volume ratio value is 1: 10g/mL；
And/or,
In the preparation method of described emtricitabine halogen acid salt, when using ethanolic hydrogen chloride solution, described hydrogen chloride alcohol
The concentration of solution is 1mol/L～3mol/L；
And/or,
In the preparation method of described emtricitabine halogen acid salt, when using hydrogen bromide alcoholic solution, described hydrogen bromide alcohol
The concentration of solution is 1mol/L～3mol/L；
And/or,
In the preparation method of described emtricitabine halogen acid salt, described hydrogen halides are rubbed with described emtricitabine crude product
Your ratio is 1.0；
And/or,
In the preparation method of described emtricitabine halogen acid salt, the temperature of described salt-forming reaction is 10 DEG C～20 DEG C；
And/or,
In the preparation method of described emtricitabine halogen acid salt, the time of described salt-forming reaction is 2 hours.
5. emtricitabine halogen acid salt as claimed in claim 1 preparation method it is characterised in that：
The preparation method of described emtricitabine halogen acid salt, using following steps：The alcoholic solution of hydrogen halides is added to grace bent
In the solution that his shore crude product is formed with alcohols solvent, carry out salt-forming reaction, obtain emtricitabine halogen acid salt；
And/or,
The preparation method of described emtricitabine halogen acid salt, including following post-processing step：After reaction terminates, filter, wash,
It is dried to obtain emtricitabine halogen acid salt.
6. emtricitabine halogen acid salt as claimed in claim 5 preparation method it is characterised in that：Described emtricitabine hydrogen
The preparation method of halate, further includes following post-processing step：The emtricitabine obtaining halogen acid salt is recrystallized to give
Emtricitabine halogen acid salt after purification.
7. emtricitabine halogen acid salt as claimed in claim 6 preparation method it is characterised in that：
In the post-processing step that the preparation method of described emtricitabine halogen acid salt further includes, described recrystallization is adopted
Solvent is alcohols solvent, alcohols solvent and the mixed solvent of ether solvent or the mixing of alcohols solvent and esters solvent are molten
Agent；
And/or,
In the post-processing step that the preparation method of described emtricitabine halogen acid salt further includes, described recrystallization
Temperature is 50 DEG C～80 DEG C；
And/or,
In the post-processing step that the preparation method of described emtricitabine halogen acid salt further includes, described recrystallization is adopted
With following steps 1 or step 2：
Step 1：Emtricitabine halogen acid salt is dissolved in alcohols solvent, adds ether solvent or esters solvent, cooling analysis
Crystalline substance obtains emtricitabine halogen acid salt after purification；
Step 2：Emtricitabine halogen acid salt is dissolved in alcohols solvent, then cooling crystallization obtains emtricitabine hydrogen after purification
Halate.
8. emtricitabine halogen acid salt as claimed in claim 7 preparation method it is characterised in that：
In the post-processing step that the preparation method of described emtricitabine halogen acid salt further includes, described alcohols is molten
The mixed solvent of the mixed solvent of agent, alcohols solvent and ether solvent or alcohols solvent and esters solvent and described emtricitabine
The mass volume ratio value of halogen acid salt is 1: 1g/mL～1: 30g/mL；
And/or,
In the post-processing step that the preparation method of described emtricitabine halogen acid salt further includes, described alcohols solvent
For one or more of methanol, ethanol, isopropanol and tert-butyl alcohol；
And/or,
In the post-processing step that the preparation method of described emtricitabine halogen acid salt further includes, described ether solvent
For one or more of diisopropyl ether, dioxane, oxolane, 2- methyltetrahydrofuran and n-butyl ether；
And/or,
In the post-processing step that the preparation method of described emtricitabine halogen acid salt further includes, described esters solvent
For ethyl acetate and/or isopropyl acetate；
And/or,
In the post-processing step that the preparation method of described emtricitabine halogen acid salt further includes, when adopting alcohols solvent
During with the mixed solvent of ether solvent, described ether solvent is 1～2 with the volume ratio of described alcohols solvent；
And/or,
In the post-processing step that the preparation method of his shore halogen acid salt of the song described in grace further includes, when adopting alcohols solvent
During with the mixed solvent of esters solvent, described esters solvent is 1～2 with the volume ratio of described alcohols solvent；
And/or,
In the post-processing step that the preparation method of described emtricitabine halogen acid salt further includes, described recrystallization
Temperature is 55 DEG C～70 DEG C；
And/or,
In step 1 or step 2, the temperature of described dissolving is 50 DEG C～80 DEG C；
And/or,
In step 1 or step 2, the temperature of described cooling crystallization is 0 DEG C～20 DEG C；
And/or,
In step 1 or step 2, the time of described cooling crystallization is 1 hour～5 hours；
And/or,
In step 1 or step 2, described dissolving and cooling crystallization are carried out under conditions of stirring.
9. emtricitabine halogen acid salt as claimed in claim 8 preparation method it is characterised in that：
In the post-processing step that the preparation method of described emtricitabine halogen acid salt further includes, described alcohols is molten
The mixed solvent of the mixed solvent of agent, alcohols solvent and ether solvent or alcohols solvent and esters solvent and described emtricitabine
The mass volume ratio value of halogen acid salt is 1: 2g/mL～1: 20g/mL；
And/or,
In the post-processing step that the preparation method of described emtricitabine halogen acid salt further includes, when adopting alcohols solvent
During with the mixed solvent of ether solvent, described ether solvent is 1.6 or 1.3 with the volume ratio of described alcohols solvent；
And/or,
In the post-processing step that the preparation method of described emtricitabine halogen acid salt further includes, when adopting alcohols solvent
During with the mixed solvent of esters solvent, described esters solvent is 1 or 1.7 with the volume ratio of described alcohols solvent；
And/or,
In the post-processing step that the preparation method of described emtricitabine halogen acid salt further includes, described recrystallization
Temperature is 55 DEG C～65 DEG C or 60 DEG C～70 DEG C；
And/or,
In step 1 or step 2, the temperature of described dissolving is 55 DEG C～70 DEG C；
And/or,
In step 1 or step 2, the temperature of described cooling crystallization is 5 DEG C～15 DEG C；
And/or,
In step 1 or step 2, the time of described cooling crystallization is 1 hour～3 hours；
And/or,
In step 1 or step 2, when described dissolving and cooling crystallization are carried out under conditions of stirring, the speed of described stirring
Spend for 60～120 revs/min.
10. emtricitabine halogen acid salt as claimed in claim 9 preparation method it is characterised in that：
In the post-processing step that the preparation method of described emtricitabine halogen acid salt further includes, described alcohols is molten
The mixed solvent of the mixed solvent of agent, alcohols solvent and ether solvent or alcohols solvent and esters solvent and described emtricitabine
The mass volume ratio value of halogen acid salt is 1: 5g/mL, 1: 10g/mL, 1: 13g/mL, 1: 14g/mL or 1: 16g/mL；
And/or,
In the post-processing step that the preparation method of described emtricitabine halogen acid salt further includes, described alcohols solvent
Mixed solvent with ether solvent is that methanol is molten with the mixing of 2- methyltetrahydrofuran with the mixed solvent of diisopropyl ether or ethanol
Agent；
And/or,
In the post-processing step that the preparation method of described emtricitabine halogen acid salt further includes, described alcohols solvent
Mixed solvent with esters solvent is that isopropanol is molten with the mixing of ethyl acetate with the mixed solvent of isopropyl acetate or ethanol
Agent；
And/or,
In step 1 or step 2, the temperature of described dissolving is 55 DEG C～65 DEG C or 60 DEG C～70 DEG C；
And/or,
In step 1 or step 2, the temperature of described cooling crystallization is 5 DEG C～10 DEG C or 10 DEG C～15 DEG C；
And/or,
In step 1 or step 2, the time of described cooling crystallization is 1 hour；
And/or,
In step 1 or step 2, when described dissolving and cooling crystallization are carried out under conditions of stirring, the speed of described stirring
Spend for 60 revs/min, 80 revs/min, 90 revs/min, 100 revs/min or 120 revs/min.
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