CN1657517A - Synthesis method of new sodium decanoy acetal - Google Patents
Synthesis method of new sodium decanoy acetal Download PDFInfo
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- CN1657517A CN1657517A CN 200410039396 CN200410039396A CN1657517A CN 1657517 A CN1657517 A CN 1657517A CN 200410039396 CN200410039396 CN 200410039396 CN 200410039396 A CN200410039396 A CN 200410039396A CN 1657517 A CN1657517 A CN 1657517A
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- sodium
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- new houttuyfonate
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- 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 title claims abstract description 11
- 229910052708 sodium Inorganic materials 0.000 title claims abstract description 11
- 239000011734 sodium Substances 0.000 title claims abstract description 11
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 title 1
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 title 1
- 238000001308 synthesis method Methods 0.000 title 1
- 238000000034 method Methods 0.000 claims abstract description 32
- 150000002576 ketones Chemical class 0.000 claims abstract description 12
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 claims abstract description 9
- ZNDCJNWMQMVSQG-UHFFFAOYSA-N 3-(2-morpholin-4-ylethylamino)propanenitrile Chemical compound N#CCCNCCN1CCOCC1 ZNDCJNWMQMVSQG-UHFFFAOYSA-N 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 28
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 20
- 238000002360 preparation method Methods 0.000 claims description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 16
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 15
- 159000000007 calcium salts Chemical class 0.000 claims description 14
- 239000007788 liquid Substances 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 239000000284 extract Substances 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 239000008503 houttuyninum Substances 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 9
- 235000008733 Citrus aurantifolia Nutrition 0.000 claims description 8
- 235000011941 Tilia x europaea Nutrition 0.000 claims description 8
- 229960000583 acetic acid Drugs 0.000 claims description 8
- 238000005194 fractionation Methods 0.000 claims description 8
- 239000012362 glacial acetic acid Substances 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 8
- 238000002347 injection Methods 0.000 claims description 8
- 239000007924 injection Substances 0.000 claims description 8
- 229940033355 lauric acid Drugs 0.000 claims description 8
- 239000004571 lime Substances 0.000 claims description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 7
- 238000001556 precipitation Methods 0.000 claims description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- WQUFMARZEFBJEA-UHFFFAOYSA-N [Na].C(CCCCCCCCCCC)(=O)CC=O Chemical compound [Na].C(CCCCCCCCCCC)(=O)CC=O WQUFMARZEFBJEA-UHFFFAOYSA-N 0.000 claims description 6
- 239000011259 mixed solution Substances 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- 229910052573 porcelain Inorganic materials 0.000 claims description 6
- 239000000243 solution Substances 0.000 claims description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 5
- 239000000706 filtrate Substances 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 5
- 239000000843 powder Substances 0.000 claims description 5
- 239000002244 precipitate Substances 0.000 claims description 5
- 239000000376 reactant Substances 0.000 claims description 5
- 238000001953 recrystallisation Methods 0.000 claims description 5
- 238000007127 saponification reaction Methods 0.000 claims description 5
- 238000000967 suction filtration Methods 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- 238000003809 water extraction Methods 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 3
- 238000004821 distillation Methods 0.000 claims description 3
- -1 filtration Substances 0.000 claims description 3
- 239000011521 glass Substances 0.000 claims description 3
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 3
- 238000012856 packing Methods 0.000 claims description 3
- 235000011837 pasties Nutrition 0.000 claims description 3
- 239000000741 silica gel Substances 0.000 claims description 3
- 229910002027 silica gel Inorganic materials 0.000 claims description 3
- TWAMJBFDYCXUPL-UHFFFAOYSA-M sodium hydrogen sulfite 3-oxotetradecanal Chemical compound C(CCCCCCCCCCC)(=O)CC=O.S([O-])(O)=O.[Na+] TWAMJBFDYCXUPL-UHFFFAOYSA-M 0.000 claims description 3
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical group [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 claims description 2
- 235000011054 acetic acid Nutrition 0.000 claims description 2
- 150000001243 acetic acids Chemical class 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 238000001514 detection method Methods 0.000 claims description 2
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 238000011003 system suitability test Methods 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 abstract description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 abstract 2
- 125000000400 lauroyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 abstract 2
- CYIFVRUOHKNECG-UHFFFAOYSA-N tridecan-2-one Chemical compound CCCCCCCCCCCC(C)=O CYIFVRUOHKNECG-UHFFFAOYSA-N 0.000 abstract 2
- 238000007259 addition reaction Methods 0.000 abstract 1
- 150000001299 aldehydes Chemical class 0.000 abstract 1
- 150000003839 salts Chemical class 0.000 abstract 1
- 229940079827 sodium hydrogen sulfite Drugs 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000012071 phase Substances 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- 238000010189 synthetic method Methods 0.000 description 7
- 238000010521 absorption reaction Methods 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 230000005526 G1 to G0 transition Effects 0.000 description 5
- 229940090044 injection Drugs 0.000 description 5
- 239000012085 test solution Substances 0.000 description 5
- 239000007791 liquid phase Substances 0.000 description 4
- 239000013558 reference substance Substances 0.000 description 4
- 239000012086 standard solution Substances 0.000 description 4
- 238000004448 titration Methods 0.000 description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 239000011630 iodine Substances 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 208000030208 low-grade fever Diseases 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- VDZOOKBUILJEDG-UHFFFAOYSA-M tetrabutylammonium hydroxide Chemical compound [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- QBDCOUHKEVYWLO-UHFFFAOYSA-N Decanoylacetaldehyde Natural products CCCCCCCCCC(=O)CC=O QBDCOUHKEVYWLO-UHFFFAOYSA-N 0.000 description 2
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000644 isotonic solution Substances 0.000 description 2
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical class [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 2
- HPPWMWCITPGPKK-UHFFFAOYSA-M sodium;1-hydroxy-3-oxododecane-1-sulfonate Chemical compound [Na+].CCCCCCCCCC(=O)CC(O)S([O-])(=O)=O HPPWMWCITPGPKK-UHFFFAOYSA-M 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000008215 water for injection Substances 0.000 description 2
- XLYLQUQHYUOPIW-UHFFFAOYSA-N 3-oxo-Tetradecanal Chemical compound CCCCCCCCCCCC(=O)CC=O XLYLQUQHYUOPIW-UHFFFAOYSA-N 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- 241000972773 Aulopiformes Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 206010019133 Hangover Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010021703 Indifference Diseases 0.000 description 1
- WVVOBOZHTQJXPB-UHFFFAOYSA-N N-anilino-N-nitronitramide Chemical compound [N+](=O)([O-])N(NC1=CC=CC=C1)[N+](=O)[O-] WVVOBOZHTQJXPB-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 150000001793 charged compounds Chemical class 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethanethiol Chemical compound CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 235000019688 fish Nutrition 0.000 description 1
- 229940093181 glucose injection Drugs 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 239000002075 main ingredient Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- FPLYNRPOIZEADP-UHFFFAOYSA-N octylsilane Chemical group CCCCCCCC[SiH3] FPLYNRPOIZEADP-UHFFFAOYSA-N 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 235000019515 salmon Nutrition 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical compound [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
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- Compounds Of Unknown Constitution (AREA)
Abstract
A process for synthesizing high-purity sodium decanoy acetaldehyde includes such steps as preparing dodecylic acid, preparing Ca salt, preparing mixed ketone, preparing tridecanone, preparing dodecanoyl aldehyde sodium, and addition reaction of dodecanoyl aldehyde-sodium hydrogen sulfite.
Description
Invention field
The present invention relates to a kind of synthetic method of Sodium New Houttuyfonate, belong to pharmacy field.
Background technology
Sodium New Houttuyfonate (Sodium Houttuyfonate) is the sodium bisulfite affixture of decanoylacetaldehyde, has now recorded the national drug standards (WS-10001-(HD-0484)-2002), is antibiosis anti-inflammatory drug.
The resultant Sodium New Houttuyfonate purity of synthetic method is not high a few days ago, the raw material that the inventive method is prepared, and purity can reach more than 90%.
Summary of the invention
One object of the present invention is to disclose a kind of synthetic method of new Sodium New Houttuyfonate.
Technical scheme of the present invention is:
A kind of method of synthetic Sodium New Houttuyfonate newly may further comprise the steps:
(1) get Oleum Cocois after saponification and acidifying, at 100～300 ℃, under pressure 80～150mmHg condition, vacuum fractionation makes laurostearic acid;
(2) preparation of calcium salt: laurostearic acid and glacial acetic acid are mixed, pour in the lime paste, make calcium salt;
(3) mix the ketone preparation: with prepared calcium salt, in the crack tank of packing into, straight fiery heating pyrolyze makes mixed ketone;
(4) ten triketones-2 preparations: get mixed ketone, temperature in 80～150mmHg underpressure distillation, is collected the cut in this scope at 100～300 ℃, pressure, promptly gets ten triketones-2;
(5) dodecanoyl acetaldehyde sodium salt preparation: get ten triketones-2, ethyl formate, dry-out benzene mixing, get sodium Metal 99.5 again, after the chopping, gradation drops in the mixed solution, and shake well, makes reaction solution keep 0～50 ℃ and places liquid in room temperature, promptly gets dodecanoyl acetaldehyde sodium salt;
(6) dodecanoyl acetaldehyde sodium bisulfite addition: get water extraction 3-6 time of above-mentioned reactant, merge the water extract, other gets NaHSO
3Soluble in water, mix with glacial acetic acid, add above-mentioned water extract, generate a large amount of white precipitates immediately, placement is spent the night, and filters, placement is spent the night, and precipitation is put in the water-bath after the heated and boiled with 40-60% ethanol, filtration, filtrate in water-bath, place after the heated and boiled again spend the night carry out recrystallization after, suction filtration is to doing, with ether gradation washing, wash with water then, again with ether be washed till pure white after, 50～120 ℃ of oven dry promptly get Sodium New Houttuyfonate.
In the invention described above synthetic method:
Step (1) is got Oleum Cocois 3500 weight parts, puts in the enamelled vessel, adds sodium hydroxide 500～1000 weight parts respectively and sulfuric acid 100～500 weight parts carry out saponification and acidifying;
Learn from else's experience lime 1800 weight parts that sieve of step (2) add water 100～5000 parts by volume and stir into pasty state, in addition with laurostearic acid 100～1000 weight parts with the heating of porcelain bucket make dissolve fully after and glacial acetic acid 100～5000 weight parts mix, pour in the lime paste, constantly stir, calcium salt, placement is spent the night;
Pack in the crack tank straight fiery heating pyrolyze 5～20 hours of step (3) calcium salt;
Step (4) adds granulated glass sphere before mixing the ketone fractionation in container;
Step (5) is got ten triketones-2 100-500 weight part, ethyl formate 100～1000 weight parts, the mixing of dry-out benzene 100～3000 parts by volume, gets 100～150 weight part sodium Metal 99.5s again, and after the chopping, gradation drops in the mixed solution;
Step (6) is got water extraction 4 times of above-mentioned reactant: 2000 parts by volume * 2,1000 parts by volume * 2, merge 4 times the water extract, and other gets 100～1000 weight part NaHSO
3Be dissolved in 1000～2000 parts by volume water, mix with 100～500 parts by volume glacial acetic acids, add above-mentioned water extract, generate a large amount of white precipitates immediately, stir, placed liquid, filtered, after filter is done, placed liquid, precipitation is poured in the porcelain bucket, puts in the water-bath after the heated and boiled filtration with 50% ethanol, 5000～10000 parts by volume, filtrate in water-bath, place after the heated and boiled again spend the night carry out recrystallization after, suction filtration, washes with water with about 100～3000 parts by volume gradation washing of ether then to doing, again with ether be washed till pure white after, drain, 50～120 ℃ of oven dry are raw material;
Described weight part/parts by volume is corresponding with g/ml.
The Sodium New Houttuyfonate chemical structure that makes is:
C
14H
27NaO
5S??330.41
The Sodium New Houttuyfonate that makes is white flake-like crystal, and the tool fish is stench, and fusing point 162-166 ℃ (decomposition) through ultimate analysis, meets C
14H
17O
5The carbon of Sna, hydrogen ratio; The UV spectrum maximum absorption band is 283 ± 1; Infrared spectra: it is V that 0.7 milligram/150 milligrams Potassium Bromides of this product record infrared absorption peak
KBr Max(centimetre
-1): 620,1042,1220,1720,2850,2904 etc.; Mass spectrum: molecular ion peak M
+=226.
The quality controlling means of the Sodium New Houttuyfonate that synthetic method of the present invention makes can be by the method experiment of following discriminating and/or inspection and/or assay, and it is the various preparations of main ingredient that this quality controlling means also can be applied to the Sodium New Houttuyfonate.
Differentiate:
(1) gets neo-houttuyninum sodium raw materials 0.1g, add ethanol 5ml, put in the water-bath warmly, get supernatant liquor, drip 2 of iron trichloride test solutions, promptly show red.
(2) get neo-houttuyninum sodium raw materials 50mg, after the hydro-oxidation sodium test solution 1ml dissolving, add the about 1ml of dilute hydrochloric acid, dropping iodine test solution number droplet, the yellow of demonstration promptly disappears.
(3) get neo-houttuyninum sodium raw materials 50mg, hydro-oxidation sodium test solution 1ml with dinitrophenylhydrazine test solution 1ml, promptly generates salmon precipitation.
Check: free sulphite; get this product fine powder 0.1g; put in the tool plug Erlenmeyer flask; add the water 10ml below 4 ℃; close plug, put that jolting added 2 of starch indicating liquids after 2～3 minutes in the ice-water bath; use iodine titration solution (0.02mol/L) titration to showing light blue immediately, consume iodine titration solution (0.02mol/L) and must not surpass 0.3ml.
Assay: measure according to high performance liquid chromatography (two appendix VD of Chinese Pharmacopoeia version in 2000).Chromatographic condition and system suitability test are weighting agent with octyl group silane group silica gel: methanol-water-TBAH (60-80: 20-35: 0.2-0.4) be moving phase; The detection wavelength is 280-290nm, and column temperature is 40-50 ℃, and number of theoretical plate calculates by the neo-houttuyninum peak should be not less than 2500.Assay method: get the about 50mg of this product, the accurate title, decide, and puts in the 100ml measuring bottle, adds the moving phase dissolving and be diluted to scale, shakes up, and precision is measured 2ml.Put in the 100ml measuring bottle, add moving phase and be diluted to scale, shake up, precision is measured and is won 20 μ l injection liquid chromatograph, record color atlas; Other gets the neo-houttuyninum reference substance, measures with method, presses external standard method with calculated by peak area.
The synthetic Sodium New Houttuyfonate can be added acceptable accessories, make clinical acceptable forms such as tablet, capsule, injection through conventional technology; Wherein said injection comprises " injection liquid ", " freeze-dried powder ", " aseptic powder injection ", " Sodium Houttuyfonate glucose injection or transfusion ".”
The synthetic method of Sodium New Houttuyfonate of the present invention, the synthesis technique advanced person, the Sodium New Houttuyfonate purity of preparation can reach more than 97%.
Following experimental example progress explanation the present invention.
The research of experimental example 1 Sodium New Houttuyfonate preparation quality standard
1, instrument and reagent.
The Waters high performance liquid chromatograph; Sample (0006003) and standard substance provide by Yongkang, Guangdong pharmaceutcal corporation, Ltd; All the other reagent are analytical pure.
2, method and result.
2.1 selection this product of measuring method can adopt precipitation titration, high-efficient liquid phase technique to measure, wherein the accurate height of high-efficient liquid phase technique, resolution are good, are the quality standard that improves this product, adopt high-efficient liquid phase technique.But because of Sodium New Houttuyfonate polarity is bigger, when adopting reversed phase high efficiency liquid phase method, in stationary phase, do not keep, thus ion-pair method adopted, satisfactory for result.
2.2 the selection of condition determination
2.2.1 selection this product of ion pair reverse-phase chromatography is a kind of organic sulphonyl salt of long-chain.Its polarity is big, solvent soluble in water, that the methyl alcohol isopolarity is big, and the retention time in reverse-phase chromatography is very short, in order to reduce the polarity of this product, thus make gegenion reagent with TBAH, satisfactory for result.
Select to get reference substance solution configuration proper concn 2.2.2 measure wavelength, add gegenion to after, do spectral scan with the UV-light photometer, its maximum absorption wavelength is 283nm, engages the performance of this instrument, the mensuration wavelength is selected in 286nm.
2.2.3 the selection octadecylsilane chemically bonded silica of stationary phase is a stationary phase, the ion reagent that TBAH is seriously trails through the test peak, and using cetyl trimethylammonium bromide instead is gegenion reagent, and the wide and serious hangover in peak is difficult to quantitatively.Gegenion reagent and octadecylsilane chemically bonded silica stationary phase commonly used can't obtain the ideal peak, therefore changing stationary phase is octyl silane group silica gel, and gegenion reagent is TBAH, and type is good through the test peak, number of theoretical plate is higher, plays good separation and quantitative effect.
2.2.4 the selection of moving phase is through test of many times, moving phase is defined as methanol-water-TBAH (70: 30: 0.3), and methanol content is too high, and appearance time is too short, and number of theoretical plate is lower; Methanol content is too low, and appearance time is long, and the peak type obviously broadens.About the mixed solution PH6.2 of methanol-water-TBAH (70: 30: 0.3).PH value is obvious to the new and power influence between sample ions and gegenion reagent side, and pH value is crossed newly low and power diminishes, and the too high chromatogram art infringement of pH value is bigger, so the pH value in this test should be about 6.2.
2.2.5 the selection of detected temperatures Temperature Influence in this test is also fairly obvious, temperature too ebb type broadens, and is difficult to quantitatively, and temperature is too high bigger to the infringement of chromatogram art, is chosen in 45 ℃ through the test of many times detected temperatures.
2.2.6 choice of Solvent this product is the Sodium New Houttuyfonate bulk drug, composition is single, so play direct mensuration behind the available mobile phased soln.
2.3 methodology test
2.3.1 linearity and linearity range compound concentration respectively are the standard solution of 60ug, 48ug, 36ug, 24ug, 18ug, 6ug, each accurate 6uL sample introduction of drawing.
| Sample size (ul) | ??6 | ??6 | ??6 | ??6 | ??6 | ??6 |
| Quality (mg) peak area | ??0.36 ??870.62 | ??0.288 ??696.93 | ??0.216 ??522.55 | ??0.144 ??349.40 | ??0.108 ??260.26 | ??0.036 ??85.38 |
Draw the 3uL sample introduction.
| A Standard | ????865.31 | ????867.09 | (866.20 on average) |
| A SampleA Standard is the sameRate of recovery average recovery rate | ????681.79 ????771.94 ????99.6％ ????99.7％ | ????680.90 ????775.55 ????100.4％ | (681.35 on average) 770.62 99.3% |
Take by weighing standard substance 0.0036g in the volumetric flask of 100mL 2.3.2 the precision test is accurate, add moving phase and be diluted to scale, low-grade fever makes its dissolving, shakes up, and is standby.The above standard solution 6uL of accurate absorption repeats sample introduction 6 times, measures peak area value, calculates RSD=0.32%.
A
Standard510.46 513.37 512.37 512.19 509.16 513.19
2.3.3 the replica test precision takes by weighing sample 0.0033g in the volumetric flask of 100mL, adds moving phase and is diluted to scale, low-grade fever makes its dissolving, shakes up, and is standby.The above standard solution 6uL of accurate absorption repeats sample introduction 6 times, measures peak area value, calculates RSD=0.99%.
A
Standard471.94 468.02 474.52 470.73 473.93 461.98
Spend the night 2.3.4 the stability experiment reference substance is placed, the indifference of measuring in two days as a result shows reference substance tool stability in the daytime.
2.4 the mensuration precision of sample takes by weighing sample 0.0033g in the volumetric flask of 100mL, adds moving phase and is diluted to scale, low-grade fever makes its dissolving, shakes up, and is standby.The above standard solution 6uL of accurate absorption repeats sample introduction 2 times, measures peak area value, and the content of calculation sample is as follows:
| A Sample | ??A On average | Content (ug) | Samples contg (%) |
| 469.03 463.35 | ??466.19 | ????0.193 | ???97.41 |
2.5 definite dry product of pressing of acceptability limit calculates, and contains Sodium New Houttuyfonate and is less than 97.0% to cannot do without.
Conclusion: measure Sodium New Houttuyfonate content at least with the HPLC method, compare to, have the advantage that method is easy, quick, accuracy is high, can get rid of the interference of other synthetics or degradation production, help improving the quality of its preparation with its content of iodometric determination.
Synthesizing of embodiment 1 Sodium New Houttuyfonate
(1) gets Oleum Cocois 3500g, put in the enamelled vessel, add sodium hydroxide 750g and sulfuric acid 250g respectively, after saponification and acidifying; Put in the decompression fractionation unit, at 150 ℃, under the pressure 120mmHg condition, vacuum fractionation makes laurostearic acid;
(2) preparation of calcium salt
The lime 1800g that sieves of learning from else's experience adds water 2500ml and stirs into pasty state, makes fully dissolving after with the heating of 10,000 ml porcelain buckets laurostearic acid 500g in addition and glacial acetic acid 2500g mixes, and pours into during lime sticks with paste, constantly stir, calcium salt, placement spend the night (system calcium salt);
(3) mix the ketone preparation:
With prepared calcium salt, in the crack tank of packing into, straight fiery heating pyrolyze 10 hours makes and mixes the about 750ml of ketone;
(4) ten triketones-2 preparations (fractionation)
Get and mix ketone 1000ml, pour in the round-bottomed flask, add 2～3 granulated glass spherees, in case waterfall boils, connect fractionation plant, heat (temperature is controlled at 150 ℃, pressure-controlling at 120mmHg) underpressure distillation then, collect the cut in this scope, claim to decide weight, promptly get ten triketones-2;
(5) dodecanoyl acetaldehyde sodium salt preparation:
Get ten triketones-2 200g, ethyl formate 750g, dry-out benzene 1000ml, in the 5000ml Erlenmeyer flask, mix, get the 125g sodium Metal 99.5 again, after the chopping, gradation drops in the mixed solution, and shake well, the cooling of Erlenmeyer flask external application frozen water, make reaction solution keep 25 ℃ and placed liquid, promptly get dodecanoyl acetaldehyde sodium salt in room temperature;
(6) dodecanoyl acetaldehyde sodium bisulfite addition
Get water extraction 4 times of above-mentioned reactant: 2000ml * 2,1000ml * 2 merge 4 times the water extract, and other gets 750gNaHSO
3Be dissolved in the 1500ml water, mix, add above-mentioned water extract, generate a large amount of white precipitates immediately with the 250ml glacial acetic acid, stir, placed liquid, filter, after filter is done, placed liquid, precipitation is poured in the porcelain bucket, puts in the water-bath after the heated and boiled with 50% ethanol 8000ml, filter, filtrate in water-bath, place after the heated and boiled again spend the night carry out recrystallization after, suction filtration is to doing, with the about 1500ml gradation of ether washing, wash with water then, again with ether be washed till pure white after, drain, 80 ℃ of oven dry are raw material;
Embodiment 2 new houttuynine sodium bisulfite injections
Get Sodium New Houttuyfonate 1500mg, tween-80 25g with the dissolving of water for injection or isotonic solution, and regulates pH5.0 ~ 6.2, adds water for injection or isotonic solution to 1000 milliliter after filtering, again through smart filter back embedding, sterilization.
Claims (9)
1. the method for a synthetic Sodium New Houttuyfonate is characterized in that this method may further comprise the steps:
(1) get Oleum Cocois after saponification and acidifying, at 100～300 ℃, under pressure 80～150mmHg condition, vacuum fractionation makes laurostearic acid;
(2) preparation of calcium salt: laurostearic acid and glacial acetic acid are mixed, pour in the lime paste, make calcium salt;
(3) mix the ketone preparation: with prepared calcium salt, in the crack tank of packing into, straight fiery heating pyrolyze makes mixed ketone;
(4) ten triketones-2 preparations: get mixed ketone, temperature in 80～150mmHg underpressure distillation, is collected the cut in this scope at 100～300 ℃, pressure, promptly gets ten triketones-2;
(5) dodecanoyl acetaldehyde sodium salt preparation: get ten triketones-2, ethyl formate, dry-out benzene mixing, get sodium Metal 99.5 again, after the chopping, gradation drops in the mixed solution, and shake well, makes reaction solution keep 0～50 ℃ and places liquid in room temperature, promptly gets dodecanoyl acetaldehyde sodium salt;
(6) dodecanoyl acetaldehyde sodium bisulfite addition: get water extraction 3-6 time of above-mentioned reactant, merge the water extract, other gets NaHSO
3Soluble in water, mix with glacial acetic acid, add above-mentioned water extract, generate a large amount of white precipitates immediately, placement is spent the night, and filters, placement is spent the night, and precipitation is put in the water-bath after the heated and boiled with 40-60% ethanol, filtration, filtrate in water-bath, place after the heated and boiled again spend the night carry out recrystallization after, suction filtration is to doing, with ether gradation washing, wash with water then, again with ether be washed till pure white after, 50～120 ℃ of oven dry promptly get Sodium New Houttuyfonate.
2. the method for synthetic Sodium New Houttuyfonate as claimed in claim 1, it is characterized in that getting in this method steps (1) Oleum Cocois 3500 weight parts, put in the enamelled vessel, add sodium hydroxide 500～1000 weight parts respectively and sulfuric acid 100～500 weight parts carry out saponification and acidifying.
3. the method for synthetic Sodium New Houttuyfonate as claimed in claim 1, lime 1800 weight parts that sieve of it is characterized in that learning from else's experience in this method steps (2) add water 100～5000 parts by volume and stir into pasty state, after in addition laurostearic acid 100～1000 weight parts being made dissolving fully with the heating of porcelain bucket, mix with glacial acetic acid 100～5000 weight parts, pour in the lime paste, constantly stir, calcium salt, placement is spent the night.
4. the method for synthetic Sodium New Houttuyfonate as claimed in claim 1 is characterized in that in this method steps (3) pack in the crack tank straight fiery heating pyrolyze 5～20 hours of calcium salt.
5. the method for synthetic Sodium New Houttuyfonate as claimed in claim 1 before it is characterized in that mixing the ketone fractionation in this method steps (4), adds granulated glass sphere in container.
6. the method for synthetic Sodium New Houttuyfonate as claimed in claim 1, it is characterized in that getting in this method steps (5) ten triketones-2 100-500 weight part, ethyl formate 100～1000 weight parts, the mixing of dry-out benzene 100～3000 parts by volume, get 100～150 weight part sodium Metal 99.5s again, after the chopping, gradation drops in the mixed solution.
7. the method for synthetic Sodium New Houttuyfonate as claimed in claim 1 is characterized in that getting in this method steps (6) above-mentioned reactant with water extraction 4 times: 2000 parts by volume * 2,1000 parts by volume * 2, merge 4 times the water extract, and other gets 100～1000 weight part NaHSO
3Be dissolved in 1000～2000 parts by volume water, mix with 100～500 parts by volume glacial acetic acids, add above-mentioned water extract, generate a large amount of white precipitates immediately, stir, placed liquid, filtered, after filter is done, placed liquid, precipitation is poured in the porcelain bucket, puts in the water-bath after the heated and boiled filtration with 50% ethanol, 5000～10000 parts by volume, filtrate in water-bath, place after the heated and boiled again spend the night carry out recrystallization after, suction filtration, washes with water with about 100～3000 parts by volume gradation washing of ether then to doing, again with ether be washed till pure white after, drain, 50～120 ℃ of oven dry promptly get Sodium New Houttuyfonate.
8. quality controlling means that mainly contains the neo-houttuyninum preparation of sodium, it is characterized in that the content assaying method in this method is: according to high performance liquid chromatography, chromatographic condition and system suitability test are weighting agent: 60-80: 20-35 with octyl group silane group silica gel: 0.2-0.4 methanol-water-TBAH is a moving phase; The detection wavelength is 280-290nm, and column temperature is 40-50 ℃, and number of theoretical plate calculates by the neo-houttuyninum peak should be not less than 2500.
9. a kind of quality controlling means that mainly contains the neo-houttuyninum preparation of sodium as claimed in claim 8 is characterized in that the described neo-houttuyninum preparation of sodium that mainly contains comprises tablet, capsule, injection liquid, freeze-dried powder, aseptic powder injection.
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| CN102964276A (en) * | 2012-11-28 | 2013-03-13 | 康普药业股份有限公司 | Preparation method of sodium new houttuyfonate |
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| CN102153492A (en) * | 2010-01-29 | 2011-08-17 | 刘力 | Treatment medicament for resisting infectious diseases, and preparation method and application thereof |
| CN102153492B (en) * | 2010-01-29 | 2016-01-13 | 刘力 | Medicine of anti-infectious disease and its production and use |
| CN101869593A (en) * | 2010-06-29 | 2010-10-27 | 广东逸舒制药有限公司 | Detection method of pill capable of dissipating phlegm and stopping coughing |
| CN101869593B (en) * | 2010-06-29 | 2014-07-02 | 广东逸舒制药有限公司 | Detection method of pill capable of dissipating phlegm and stopping coughing |
| CN102827039A (en) * | 2011-06-17 | 2012-12-19 | 广东东阳光药业有限公司 | Herba Houttuyniae derivative and its application in drugs |
| CN103936635A (en) * | 2011-06-17 | 2014-07-23 | 广东东阳光药业有限公司 | Houttuynia cordata derivatives and applications thereof in drug |
| CN102827039B (en) * | 2011-06-17 | 2014-09-17 | 广东东阳光药业有限公司 | Herba Houttuyniae derivative and its application in drugs |
| CN103936635B (en) * | 2011-06-17 | 2016-10-12 | 广东东阳光药业有限公司 | Herba Houttuyniae derivant and the application in medicine thereof |
| CN102964276A (en) * | 2012-11-28 | 2013-03-13 | 康普药业股份有限公司 | Preparation method of sodium new houttuyfonate |
| CN106316892A (en) * | 2016-07-26 | 2017-01-11 | 上海青平药业有限公司 | Synthetic method of sodium houttuyfonate |
| CN109293533A (en) * | 2018-10-23 | 2019-02-01 | 湖北天舒药业有限公司 | A kind of synthesis technology of laruyl alcohol sulfoacetic acid ester sodium salt |
| CN109799311A (en) * | 2019-02-01 | 2019-05-24 | 上海玉丹药业有限公司 | A kind of detection method of Compound Sijiqing Tablets |
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