CN105175340A - Method for preparing high-purity dexmedetomidine hydrochloride crystal from high-purity intermediate crystal - Google Patents
Method for preparing high-purity dexmedetomidine hydrochloride crystal from high-purity intermediate crystal Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C07D233/58—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring nitrogen atoms
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- C—CHEMISTRY; METALLURGY
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B57/00—Separation of optically-active compounds
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention discloses a high-purity intermediate crystal of dexmedetomidine, a preparation method of the high-purity intermediate crystal, a high-purity dexmedetomidine hydrochloride crystal prepared from the high-purity intermediate crystal and a method for preparing the high-purity dexmedetomidine hydrochloride crystal from the high-purity intermediate crystal. The prepared intermediate crystal is dextro-4[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-L-(-) malate which has the purity of 99.9%, the total related substance impurity content of less than 0.10%, the single impurity content of less than 0.05%, the optical purity of 100.0% and the elemental analysis and theoretical value difference of less than 0.3% and is stable in property and easy to store; and the high-purity dexmedetomidine hydrochloride crystal, namely, 4-[1-2,3-dimethylphenyl)ethyl]-1H-imidazole hydrochloride, prepared from the intermediate crystal prepared by using the method, has the purity of 99.9%, the total related substance impurity content of less than 0.10%, the single impurity content of less than 0.05%, the optical purity of 100.0% and the elemental analysis and theoretical value difference of less than 0.3% and is stable in property and easy to store.
Description
Technical field
The present invention relates to the preparing technical field of crystal, be specifically related to a kind of Novel alpha
2-adrenoceptor agonists dexmedetomidine hydrochloride (chemical name: 4-[(1S)-1-(2,3-3,5-dimethylphenyl) ethyl] key intermediate dexmedetomidine malate (4-[(1S)-1-(2 of-1H-imidazole hydrochloride, 3-3,5-dimethylphenyl) ethyl]-1H-imidazoles-L MALIC ACID salt) preparation method of crystal, and the method for high-purity hydrochloric acid dexmedetomidine crystal is prepared with this crystalline intermediates.
Background technology
Dexmedetomidine hydrochloride (chemical name: 4-[(1S)-1-(2,3-3,5-dimethylphenyl) ethyl]-1H-imidazole hydrochloride) structural formula is as follows:
Its important intermediate dexmedetomidine malate (4-[(1S)-1-(2,3-3,5-dimethylphenyl) ethyl]-1H-imidazoles-L MALIC ACID salt) structural formula is as follows:
The calmness that U.S. FDA was ratified dexmedetomidine hydrochloride injection liquid be used for intensive care unit in 1999, approval in 2008 is used for non-intubated patient before operation and other operations and (or) calmness in art, within 2009, have approved for the calmness of patient with operation when trachea cannula and mechanical ventilation that anaesthetize sb. generally.In March, 2000 is at U.S.'s Initial Public Offering (trade(brand)name Precedex).In January, 2004 goes on the market in Japan.Subsequently in the granted listing of multiple country.Domesticly there is no import.
Splitting the form obtaining the mixtures such as highly purified dexmedetomidine and salt thereof is prepare the key of high-purity hydrochloric acid dexmedetomidine, directly affects the quality of end product.Meanwhile, the easy moisture absorption of dexmedetomidine hydrochloride, dexmedetomidine hydrochloride is prepared into crystal and preserves, product characteristics is stablized, and is convenient to preserve.
The crystal formation of current reference both domestic and external to intermediate dexmedetomidine malate crystal formation and product hydrochloric acid dexmedetomidine is not all reported.
Summary of the invention
For the deficiencies in the prior art, first object of the present invention is to provide a kind of dexmedetomidine malate crystal of not moisture and other solvents.
Another object of the present invention is the dexmedetomidine hydrochloride crystal adopting a kind of not moisture and other solvents of above-mentioned dexmedetomidine malate crystal preparation.
Applicant designs and groping test conditions by experiment, obtains the high-purity crystals of dexmedetomidine malate, and its purity reaches more than 99.9%, and related substance total impurities is less than 0.1%, and maximum list is assorted is less than 0.05%, and optical purity reaches 100%.With the end product dexmedetomidine hydrochloride crystal of this Intermediate Preparation, purity reaches more than 99.9%, and related substance total impurities is less than 0.1%, and maximum list is assorted is less than 0.05%, and optical purity reaches 100.0%.The preparation of the crystal of this intermediate and product has great technical superiority and researching value.
The crystal characteristic of the intermediate dexmedetomidine malate that technical solution of the present invention obtains is as follows:
(1) melting range is: 156.0 DEG C-158.3 DEG C;
(2) Fig. 1 is shown in by differential thermal analysis (DSC) collection of illustrative plates, has an endotherm(ic)peak at 158 ± 5 DEG C; Onset=156.39 DEG C;
(3) infared spectrum is shown in collection of illustrative plates 2, and the collection of illustrative plates that dexmedetomidine malate crystal KBr compressing tablet records is 3128,2844,2583,1992,1673,1622,1344,1245,1108,1045,891,781,700,631 and 418cm
-1there is stronger absorption peak;
(4) collection of illustrative plates 3 is shown in by powder x-ray diffraction collection of illustrative plates, has obvious characteristic peak to spend 2 θ represented 2.0,12.0,18.0,21.5 and 24.0;
(5) results of elemental analyses: C60.97%, H6.57%, N8.36% (theoretical value C61.07%, H6.63%, N8.38%).
The crystal characteristic of the dexmedetomidine hydrochloride that technical solution of the present invention obtains is as follows:
(1) melting range is: 153.3 DEG C-155.5 DEG C;
(2) Fig. 4 is shown in by differential thermal analysis (DSC) collection of illustrative plates, has an endotherm(ic)peak at 154 ± 5 DEG C; Onset=154.9 DEG C;
(3) infared spectrum is shown in collection of illustrative plates 5, and the collection of illustrative plates that dexmedetomidine hydrochloride crystal KBr compressing tablet records is 3081,2993,2667,1807,1608,1463,1168,858,780 and 631cm
-1there is stronger absorption peak;
(4) collection of illustrative plates 6 is shown in by powder x-ray diffraction collection of illustrative plates, has obvious characteristic peak to spend 2 θ represented 14.15,17.10,18.00,19.23,23.35,25.45 and 31.15;
(5) results of elemental analyses: C65.75%, H7.38%, N11.99% (theoretical value C65.95%, H7.24%, N11.83%).
The preparation method of the crystal of dexmedetomidine malate:
By DL medetomidine under ethanol A existent condition, take acetone as solvent, L-(-)-oxysuccinic acid is that resolving agent splits, after obtaining dexmedetomidine malate crude product, pull an oar with methylene dichloride, filter the solid that obtains to join in immiscible two-phase solvent, add thermosol clear after, slowly stir lower cooling crystallization, filter the crystallization of separating out, dry except after desolventizing and get final product.Its purity is greater than 99.9%, and related substance total impurities is less than 0.10%, and single mixing is less than 0.05%, optical purity 100.0%, and ultimate analysis (C, H, N) is less than 0.3%, stable in properties with the difference of theoretical value, is easy to preserve.The preparation of this crystal has great technical superiority and researching value.This crystallization processes, without the need to special operation, is easy to industrialization.
The ethanol of described ethanol A to be concentration be 90-98wt%, is preferably 95wt% ethanol.
Described DL medetomidine and ethanol A magnitude relation are 1g:1.1-1..3mL, preferred 1g:1.2mL.
Described DL medetomidine and acetone magnitude relation are 1g:6-8mL, preferred 1g:7mL.
Described immiscible two-phase solvent is water and organic phase, and wherein organic phase is methylene dichloride, trichloromethane or toluene.In immiscible two-phase solvent, the ratio of the solid that water and filtration obtain is 5mL:1g ~ 20mL:1g, and in immiscible two-phase solvent, the volume ratio of water and organic phase is 1:1 ~ 10:1.The consumption of resolving agent L-(-)-oxysuccinic acid is 0.4 ~ 1.0 times of DL medetomidine amount of substance, and the temperature range of crystallization is 0-30 DEG C.
The DL Mei Tuoding as starting raw material adopted, the synthetic route can researched and developed voluntarily by applicant obtains, and concrete technique is as follows:
(1) reaction scheme.
(2) operation steps
Chloroform, titanium tetrachloride is added, cooling in there-necked flask.Drip the chloroformic solution of N-trimethyl silane imidazoles at-10 DEG C ~ 10 DEG C, and then drip the chloroformic solution of 1-(1-chloroethyl)-2,3-dimethyl benzenes, dropwise temperature rising reflux reaction 6h.Cooling is 9-11 by 4.0mol/L sodium hydroxide solution adjust ph again after the cancellation that adds water, after layering, and aqueous phase chloroform extraction, organic phase washes with water after merging, dry, filters, precipitation obtains DL medetomidine crude product, then uses mixed solvent ethanol/water (1:1, V/V) recrystallization.
The preparation method of dexmedetomidine hydrochloride crystal:
Dexmedetomidine hydrochloride crude product is first used dehydrated alcohol heating for dissolving, adds solvent ethyl acetate and gac afterwards, add thermosol clear after, filtered while hot gac, filtrate is cooling crystallization under slow stirring, filters the crystallization of separating out, dry except after desolventizing and get final product.Its purity reaches more than 99.9%, and related substance total impurities is less than 0.1%, and maximum list is assorted is less than 0.05%, and optical purity reaches 100%.Ultimate analysis (C, H, N) and theoretical value difference are less than 0.3%.The preparation of this crystal has great technical superiority and researching value.This crystallization processes, without the need to special operation, is easy to industrialization.
Wherein: recrystallization mixed solvent (dehydrated alcohol and ethyl acetate) is 5mL:1g ~ 20mL:1g with the ratio of dexmedetomidine hydrochloride crude product.In mixed solvent, the volume ratio of dehydrated alcohol and ethyl acetate is 1:1 ~ 10:1, and the consumption of gac is 2.0% of dexmedetomidine hydrochloride crude product quality.The temperature range of crystallization is 0-20 DEG C.
This step is as the dexmedetomidine hydrochloride crude product of raw material, and the synthetic route can researched and developed voluntarily by applicant obtains, and concrete technique is as follows:
(1) reaction scheme
(2) operation steps
Add dexmedetomidine malate crystal in there-necked flask, then add water, methylene dichloride as reaction solvent, regulate pH to be 11 with 4.0mol/L sodium hydroxide solution, isolate aqueous phase dichloromethane extraction after organic phase, organic phase merges after washing, drying, filters, precipitation.Be dissolved in dehydrated alcohol by the dexmedetomidine obtained, add saturated ethanol solution of hydrogen chloride salify, namely concentrating under reduced pressure obtains dexmedetomidine hydrochloride crude product afterwards.
In described reaction solvent, water and methylene chloride volume are than being 1:1; In described reaction solvent, water is 5mL:1g with the ratio of the dexmedetomidine malate crystal added.
Compared with prior art, advantage of the present invention and beneficial effect are:
(4-[(1S)-1-(2 of the present invention, 3-3,5-dimethylphenyl) ethyl]-1H-imidazoles-L MALIC ACID salt (important intermediate dexmedetomidine malate) is high-purity crystals, its purity reaches more than 99.9%, related substance controls less than 0.1%, and chiral purity reaches 100.0%.Final product 4-[(the 1S)-1-(2 adopting method of the present invention to synthesize with this intermediate, 3-3,5-dimethylphenyl) ethyl]-1H-imidazole hydrochloride (dexmedetomidine hydrochloride) is high-purity crystals, its purity reaches more than 99.9%, related substance controls less than 0.1%, chiral purity reaches 100.0%, and product is convenient to preserve, the preparation of this intermediate and crystalline product has great technical superiority and researching value.
Accompanying drawing explanation
Fig. 1 is the means of differential scanning calorimetry mensuration figure (DSC figure) of dexmedetomidine malate crystal prepared by embodiment 1
Fig. 2 is the infrared absorpting light spectra of dexmedetomidine malate crystal prepared by embodiment 1.
Fig. 3 is the x-ray diffraction pattern of dexmedetomidine malate crystal prepared by embodiment 1.
Fig. 4 is the means of differential scanning calorimetry mensuration figure (DSC figure) of dexmedetomidine hydrochloride crystal prepared by embodiment 1
Fig. 5 is the infrared absorpting light spectra of dexmedetomidine hydrochloride crystal prepared by embodiment 1.
Fig. 6 is the x-ray diffraction pattern of dexmedetomidine hydrochloride crystal prepared by embodiment 1.
Embodiment
Applicant will be described in further detail technical scheme of the present invention in conjunction with specific embodiments below.
The preparation method of embodiment 1 one kinds of 4-[(1S)-1-(2,3-3,5-dimethylphenyl) ethyl]-1H-imidazole hydrochloride (dexmedetomidine hydrochloride) crystal, its step is as follows:
1) in dry 10L reaction flask, add 2200mL chloroform and 165mL titanium tetrachloride, stir, cooling.In-10 DEG C ~ 10 DEG C, the solution be made into by 246mLN-trimethyl silane imidazoles and 670mL chloroform is dripped in 0.5h, dropwise insulation-10 DEG C ~ 10 DEG C and stir 0.5h, and then at-10 DEG C ~ 10 DEG C, 169.0g1-(1-chloroethyl)-2 is dripped in 0.5h, the solution that 3-dimethyl benzene (purity 95.6%) and 670mL chloroform are made into, dropwises insulation-10 DEG C ~ 10 DEG C and stirs 0.5h.The 6h of temperature rising reflux reaction afterwards.Be cooled to less than 25 DEG C, add 3000mL shrend and go out, with 4mol/L sodium hydroxide solution, solution is adjusted to pH=9 afterwards.Mixed solution layering, aqueous phase with chloroform extraction (1500mL × 2), organic phase washes with water after merging, dry, filter and precipitation, obtain red gum 180.0g, wherein DL medetomidine content 71.4%, purity 96.6%, related substance (DL medetomidine T
r=14.3min): impurity A (T
r=16.2min) 0.8%.Impurity B (T
r=18.2min) 0.8%.
2) up walk in the 180.0g DL medetomidine crude product obtained and add 900mL ethanol, after heating for dissolving, under backflow, slowly add 900mL water, slow cooling after backflow 1h, separate out pale yellow powder, at continuing to be cooled to 20 DEG C ~ 25 DEG C, suction filtration after insulated and stirred 2h, obtains pale yellow powder.By yellow powder at 80 DEG C, dry 4h under-0.1Mpa, obtains DL medetomidine 110.0g, yield 55.4%, content 96.5%, purity 98.6%, related substance (DL medetomidine T
r=14.3min): maximum list impurity B (T
r=18.2min) 0.7%.
3) toward step 2) add 770mL acetone, 132mL95wt% ethanol and 74.0gL-(-)-oxysuccinic acid in gained 110.0g DL medetomidine, after reflux 1h, be chilled to suction filtration after 0 DEG C ~ 10 DEG C insulated and stirred 1h, 80 DEG C, dry 4h under-0.1Mpa, obtain white solid 79.6g, optical purity 94.3%.In gained white solid, add 796mL methylene dichloride, after backflow 0.5h, be cooled to 0 DEG C ~ 10 DEG C suction filtrations, dry, obtain dexmedetomidine malate 74.8g, optical purity 98.2%.
4) 37.4g step 3 is got) add 187mL purified water and 187mL methylene dichloride in gained dexmedetomidine malate, add thermosol clear after, stir lower slow cooling crystallization, be cooled to suction filtration after 0 DEG C ~ 5 DEG C insulated and stirred 6h, at 80 DEG C, dry 4h under-0.1Mpa, obtain dexmedetomidine malate crystal 35.0g, step 3) and 4) total recovery be 39.5% (theoretical 50.0%), purity 99.9%, related substance total impurities is less than 0.1%, maximum list is assorted is less than 0.05%, optical purity 100.0%, and recording its melting range is: 156.0 DEG C-158.3 DEG C.Gained dexmedetomidine malate crystal means of differential scanning calorimetry measures figure (DSC figure) and sees accompanying drawing 1, and infrared absorpting light spectra is shown in accompanying drawing 2, and x-ray diffraction pattern is shown in accompanying drawing 3.Results of elemental analyses: C60.97%, H6.57%, N8.36% (theoretical value C61.07%, H6.63%, N8.38%).
5) toward step 4) add 175mL water and 175mL methylene dichloride in gained dexmedetomidine malate crystal, 4.0mol/L sodium hydroxide solution is slowly added until the pH=11 of mixed phase under stirring, stratification after the 0.5h of continuation stirring afterwards, upper strata aqueous phase is with dichloromethane extraction (175mL × 2), with 100mL water washing, drying after organic phase merges, filter, precipitation, obtained dexmedetomidine.Add 350mL absolute ethyl alcohol and stirring molten clear after, drip the ethanol solution of hydrogen chloride that 35mL is saturated, after stirring 1h, decompression precipitation, obtains dexmedetomidine hydrochloride crude product 22.3g, yield 89.6%.
6) toward 22.3g step 5) add 45mL dehydrated alcohol in gained dexmedetomidine hydrochloride crude product, 225mL ethyl acetate and 0.45g gac is added after dissolving, after temperature rising reflux 0.5h, filtered while hot, filtrate makes crystallization evenly separate out in cooling with under stirring, the crystallizations that 0 DEG C ~ 10 DEG C filter collection are separated out, 80 DEG C, dry 4h obtains product 20.1g under-0.1Mpa.Yield: 90.1%, purity 99.9%, content 99.8%, related substance total impurities 0.08%, maximum list assorted 0.04%, optical purity 100.0%, recording its melting range is: 153.3 DEG C-155.5 DEG C.Gained dexmedetomidine hydrochloride crystal means of differential scanning calorimetry measures figure (DSC figure) and sees accompanying drawing 4, and infrared absorpting light spectra is shown in accompanying drawing 5, and x-ray diffraction pattern is shown in accompanying drawing 6.Results of elemental analyses: C65.75%, H7.38%, N11.99% (theoretical value C65.95%, H7.24%, N11.83%)
7) get 35.0g step 3) gained dexmedetomidine malate (the unformed powder of intermediate), according to step 5) and step 6) method, be prepared into dexmedetomidine hydrochloride.Products obtained therefrom and step 6) (intermediate is crystal) products obtained therefrom compares, and the results are shown in following table:
8) step 5 is got) gained dexmedetomidine hydrochloride (unformed powder) and step 6) gained dexmedetomidine hydrochloride (crystal), preserve in the uncovered preservation of room temperature, moisture eliminator under the same terms and seal preservation after 7 days, test its moisture absorption water content, the results are shown in following table:
The preparation method of embodiment 2 one kinds of 4-[(1S)-1-(2,3-3,5-dimethylphenyl) ethyl]-1H-imidazole hydrochloride (dexmedetomidine hydrochloride) crystal, its step is as follows:
1) in dry 10L reaction flask, add 2200mL chloroform and 165mL titanium tetrachloride, stir, cooling.In-10 DEG C ~ 10 DEG C, the solution be made into by 246mLN-trimethyl silane imidazoles and 670mL chloroform is dripped in 0.5h, dropwise insulation-10 DEG C ~ 10 DEG C and stir 0.5h, and then at-10 DEG C ~ 10 DEG C, 169.0g1-(1-chloroethyl)-2 is dripped in 0.5h, the solution that 3-dimethyl benzene (purity 95.6%) and 670mL chloroform are made into, dropwises insulation-10 DEG C ~ 10 DEG C and stirs 0.5h.The 6h of temperature rising reflux reaction afterwards.Be cooled to less than 25 DEG C, add 3000mL shrend and go out, with 4mol/L sodium hydroxide solution, solution is adjusted to pH=11 afterwards.Mixed solution layering, aqueous phase, with chloroform extraction (1500mL × 2), uses 100mL water washing, drying, filtration and precipitation after organic phase merges, obtain red gum 180.0g, wherein DL medetomidine content 71.4%, purity 96.6%, related substance (DL medetomidine T
r=14.3min): impurity A (T
r=16.2min) 0.8%.Impurity B (T
r=18.2min) 0.8%.
2) up walk in the 180.0g DL medetomidine crude product obtained and add 900mL ethanol, after heating for dissolving, under backflow, slowly add 900mL water, backflow 1h slow cooling, separate out pale yellow powder, at continuing to be cooled to 20 DEG C ~ 25 DEG C, suction filtration after insulated and stirred 2h, obtains pale yellow powder.By pale yellow powder at 80 DEG C, dry 4h under-0.1Mpa, obtain DL medetomidine 110.0g, yield 55.4%, content 96.5%, purity 98.6%, related substance (DL medetomidine T
r=14.3min): maximum list impurity B (T
r=18.2min) 0.7%.
3) toward step 2) add 770mL acetone, 132mL95wt% ethanol and 29.5gL-(-)-oxysuccinic acid in gained 110.0g DL medetomidine, after reflux 1h, be chilled to suction filtration after 0 DEG C ~ 10 DEG C insulated and stirred 1h, 80 DEG C, dry 4h under-0.1Mpa, obtain white solid 67.6g, optical purity 98.8%.In gained white solid, add 676mL methylene dichloride, after backflow 0.5h, be cooled to 0 DEG C ~ 10 DEG C suction filtrations, dry, obtain dexmedetomidine malate 66.6g, optical purity 99.3%.
4) toward step 3) add 1330mL purified water and 133mL toluene in products obtained therefrom, reflux molten clear after, stir lower slow cooling crystallization, be cooled to 25 DEG C ~ 30 DEG C insulated and stirred 6h, suction filtration, at 80 DEG C, dry 4h under-0.1Mpa, obtain dexmedetomidine malate crystal 61.2g, step 3) and 4) total recovery be 34.5% (theoretical 50.0%), purity 99.9%, optical purity 100.0%, related substance total impurities is less than 0.1%, and maximum list is assorted is less than 0.05%.The means of differential scanning calorimetry of gained dexmedetomidine malate crystal measures figure (DSC figure), infrared absorpting light spectra, x-ray diffraction pattern and results of elemental analyses are equal and embodiment 1 is basically identical.
5) toward step 4) add 306mL water and 306mL methylene dichloride in gained dexmedetomidine malate crystal, 4.0mol/L sodium hydroxide solution is slowly added until the pH=11 of aqueous phase under stirring, stratification after the 0.5h of continuation stirring afterwards, upper strata aqueous phase is with dichloromethane extraction (306mL × 2), with 100mL water washing, drying after organic phase merges, filter, precipitation, obtained dexmedetomidine.Add 612mL absolute ethyl alcohol and stirring molten clear after, drip the ethanol solution of hydrogen chloride that 62mL is saturated, after stirring 1h, decompression precipitation, obtains dexmedetomidine hydrochloride crude product 39.0g, yield 90.0%.
6) toward step 5) add 39mL dehydrated alcohol in gained dexmedetomidine hydrochloride crude product, 390mL ethyl acetate and 0.8g gac is added after dissolving, after temperature rising reflux 0.5h, filtered while hot, filtrate makes crystallization evenly separate out in cooling with under stirring, the crystallizations that 0 DEG C ~ 10 DEG C filter collection are separated out, 80 DEG C, dry 4h obtains product 36.1g under-0.1Mpa.Yield: 92.6%, purity 99.9%, content 99.8%, related substance total impurities 0.08%, maximum list assorted 0.04%, optical purity 100.0% gained dexmedetomidine hydrochloride crystal means of differential scanning calorimetry mensuration figure, infrared absorpting light spectra, x-ray diffraction pattern and results of elemental analyses are equal and embodiment 1 is basically identical.
The preparation method of embodiment 3 one kinds of 4-[(1S)-1-(2,3-3,5-dimethylphenyl) ethyl]-1H-imidazole hydrochloride (dexmedetomidine hydrochloride) crystal, its step is as follows:
1) in dry 10L reaction flask, add 2200mL chloroform and 165mL titanium tetrachloride, stir, cooling.In-10 DEG C ~ 10 DEG C, the solution be made into by 246mLN-trimethyl silane imidazoles and 670mL chloroform is dripped in 0.5h, dropwise insulation-10 DEG C ~ 10 DEG C and stir 0.5h, and then at-10 DEG C ~ 10 DEG C, 169.0g1-(1-chloroethyl)-2 is dripped in 0.5h, the solution that 3-dimethyl benzene (purity 95.6%) and 670mL chloroform are made into, dropwises insulation-10 DEG C ~ 10 DEG C and stirs 0.5h.The 6h of temperature rising reflux reaction afterwards.Be cooled to less than 25 DEG C, add 3000mL shrend and go out, with 4mol/L sodium hydroxide solution, solution is adjusted to pH=9 afterwards.Mixed solution layering, aqueous phase with chloroform extraction (1500mL × 2), organic phase washes with water after merging, dry, filter and precipitation, obtain red gum 180g, wherein DL medetomidine content 71.4%, purity 96.6%, related substance (DL medetomidine T
r=14.3min): impurity A (T
r=16.2min) 0.8%.Impurity B (T
r=18.2min) 0.8%.
2) up walk in the 180.0g DL medetomidine crude product obtained and add 900mL ethanol, after heating for dissolving, under backflow, slowly add 900mL water, backflow 1h slow cooling, separate out pale yellow powder, at continuing to be cooled to 20 DEG C ~ 25 DEG C, suction filtration after insulated and stirred 2h, obtains pale yellow powder.By yellow powder at 80 DEG C, dry 4h under-0.1Mpa, obtain DL medetomidine 110g, yield 55.4%, content 96.5%, purity 98.6%, related substance (DL medetomidine T
r=14.3min): maximum list impurity B (T
r=18.2min) 0.7%.
3) toward step 2) add 770mL acetone, 132mL95wt% ethanol and 44.3gL-(-)-oxysuccinic acid in gained DL medetomidine, after reflux 1h, be chilled to suction filtration after 0 DEG C ~ 10 DEG C insulated and stirred 1h, 80 DEG C, dry 4h under-0.1Mpa, obtain white solid 75.8g, optical purity 96.5%.In gained white solid, add 758mL methylene dichloride, after backflow 0.5h, be cooled to 0 DEG C ~ 10 DEG C suction filtrations, dry, obtain dexmedetomidine malate 72.1g.Optical purity 98.6%.
4) toward step 3) add 721mL purified water and 144mL methylene dichloride in products obtained therefrom, add thermosol clear after, stir lower slow cooling crystallization, be cooled to about 10 DEG C insulated and stirred 6h, suction filtration, at 80 DEG C, dry 4h under-0.1Mpa, obtain dexmedetomidine malate crystal 65.2g, step 3) and 4) total recovery be 36.8% (theoretical 50.0%), purity 99.9%, optical purity 100.0%.The related substance total impurities of gained dexmedetomidine malate is less than 0.1%, and maximum list is assorted is less than 0.05%.The means of differential scanning calorimetry of gained dexmedetomidine malate crystal measures figure (DSC figure), infrared absorpting light spectra, x-ray diffraction pattern and results of elemental analyses are equal and embodiment 1 is basically identical.
5) toward rapid 4) add 326mL water and 326mL methylene dichloride in gained dexmedetomidine malate crystal, 4.0mol/L sodium hydroxide solution is slowly added until the pH=11 of aqueous phase under stirring, stratification after the 0.5h of continuation stirring afterwards, upper strata aqueous phase is with dichloromethane extraction (325mL × 2), with 100mL water washing, drying after organic phase merges, filter, precipitation, obtained dexmedetomidine.Add 650mL absolute ethyl alcohol and stirring molten clear after, drip the ethanol solution of hydrogen chloride that 65mL is saturated, after stirring 1h, decompression precipitation, obtains dexmedetomidine hydrochloride crude product 60.0g, yield 92.0%.
6) in 60.0g dexmedetomidine hydrochloride crude product, 300mL dehydrated alcohol is added, 300mL ethyl acetate and 0.8g gac is added after dissolving, after temperature rising reflux 0.5h, filtered while hot, filtrate makes crystallization evenly separate out in cooling with under stirring, the crystallization that 20 DEG C of filter collection are separated out, at 80 DEG C, under-0.1Mpa, dry 4h obtains product 42.1g.Yield: 70.2%, purity 99.9%, content 99.8%, related substance total impurities 0.08%, maximum list assorted 0.04%, optical purity 100.0%.Gained dexmedetomidine hydrochloride crystal means of differential scanning calorimetry mensuration figure, infrared absorpting light spectra, x-ray diffraction pattern and results of elemental analyses are equal and embodiment 1 is basically identical.
Claims (8)
1. the preparation method of a dexmedetomidine malate crystal:
by DL medetomidine under ethanol A existent condition, take acetone as solvent, L-(-)-oxysuccinic acid is that resolving agent splits, after obtaining dexmedetomidine malate crude product, pull an oar with methylene dichloride, filter the solid that obtains to join in immiscible two-phase solvent, add thermosol clear after, slowly stir lower cooling crystallization, filter the crystallization of separating out, the dry crystal except obtaining dexmedetomidine malate after desolventizing;
Described ethanol A is concentration is 90-98wt% ethanol;
Described DL medetomidine and ethanol A magnitude relation are 1g:1.1-1.3mL;
Described DL medetomidine and acetone magnitude relation are 1g:6-8mL;
Described immiscible two-phase solvent is water and organic phase, and wherein organic phase is methylene dichloride, trichloromethane or toluene;
In described immiscible two-phase solvent, the ratio of the solid that water and filtration obtain is 5mL:1g ~ 20mL:1g, and in immiscible two-phase solvent, the volume ratio of water and organic phase is 1:1 ~ 10:1;
The consumption of described resolving agent L-(-)-oxysuccinic acid is 0.4 ~ 1.0 times of DL medetomidine amount of substance, and the temperature range of cooling crystallization is 0-30 DEG C.
2. preparation method according to claim 1, is characterized in that: described ethanol A is 95wt% ethanol.
3. preparation method according to claim 1, is characterized in that: described DL medetomidine and ethanol A magnitude relation are 1g:1.2mL.
4. preparation method according to claim 1, is characterized in that: described DL medetomidine and acetone magnitude relation are 1g:7mL.
5. one kind utilizes the method for the dexmedetomidine malate crystal preparation dexmedetomidine hydrochloride crystal that arbitrary described preparation method prepares in claim 1-4:
Dexmedetomidine hydrochloride crude product is first used dehydrated alcohol heating for dissolving, adds ethyl acetate and gac afterwards, add thermosol clear after, filtered while hot gac, filtrate is cooling crystallization under slow stirring, filters the crystallization of separating out, and drying obtains dexmedetomidine hydrochloride crystal except after desolventizing;
Described dehydrated alcohol and ethyl acetate are attached most importance to crystallized mixed solvent;
The ratio of described recrystallization mixed solvent and dexmedetomidine hydrochloride crude product is 5mL:1g ~ 20mL:1g, and in described recrystallization mixed solvent, the volume ratio of dehydrated alcohol and ethyl acetate is 1:1 ~ 10:1, and the temperature range of cooling crystallization is 0-20 DEG C;
The preparation method of described dexmedetomidine hydrochloride crude product is as follows:
Add in container and utilize the dexmedetomidine malate crystal that in claim 1-4, arbitrary described preparation method prepares, add water and methylene dichloride again as reaction solvent, pH is regulated to be 11 with 4.0mol/L sodium hydroxide solution, isolate aqueous phase dichloromethane extraction after organic phase, organic phase merges after washing, drying, filter, precipitation, the dexmedetomidine obtained is dissolved in dehydrated alcohol, add saturated ethanol solution of hydrogen chloride salify, concentrating under reduced pressure obtains dexmedetomidine hydrochloride crystal crude product afterwards.
6. method according to claim 5, is characterized in that: in the preparation method of described dexmedetomidine hydrochloride crude product, and in reaction solvent, water and methylene chloride volume are than being 1:1; In described reaction solvent, water is 5mL:1g with the ratio of the dexmedetomidine malate crystal added.
7., based on an intermediate dexmedetomidine malate crystal prepared by described preparation method arbitrary in claim 1-4, it is characterized in that:
Melting range is 156.0 DEG C-158.3 DEG C;
Differential thermal analysis collection of illustrative plates has an endotherm(ic)peak at 158 ± 5 DEG C, Onset=156.39 DEG C;
The infared spectrum recorded with KBr compressing tablet is 3128,2844,2583,1992,1673,1622,1344,1245,1108,1045,891,781,700,631 and 418cm
-1there is absorption peak;
In powder x-ray diffraction collection of illustrative plates, there is characteristic peak to spend 2 θ represented 2.0,12.0,18.0,21.5 and 24.0.
8., based on a dexmedetomidine hydrochloride crystal prepared by the method described in claim 5 or 6, it is characterized in that:
Melting range is 153.3 DEG C-155.5 DEG C;
Differential thermal analysis collection of illustrative plates has an endotherm(ic)peak at 154 ± 5 DEG C; Onset=154.9 DEG C;
The infared spectrum recorded with KBr compressing tablet is 3081,2993,2667,1807,1608,1463,1168,858,780 and 631cm
-1there is absorption peak;
In powder x-ray diffraction collection of illustrative plates, there is characteristic peak to spend 2 θ represented 14.15,17.10,18.00,19.23,23.35,25.45 and 31.15.
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| CN105481774A (en) * | 2016-01-26 | 2016-04-13 | 江苏恩华药业股份有限公司 | Dexmedetomidine hydrochloride crystal form C and preparation method thereof |
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| CN111548308A (en) * | 2020-03-18 | 2020-08-18 | 遂成药业股份有限公司 | Synthesis process of dexmedetomidine hydrochloride |
| CN112979552A (en) * | 2019-12-16 | 2021-06-18 | 广安凯特制药有限公司 | Preparation method of high-purity dexmedetomidine hydrochloride |
| CN113321619A (en) * | 2020-09-01 | 2021-08-31 | 南京恒正药物研究院有限公司 | Novel dexmedetomidine hydrochloride impurity and preparation method thereof |
| CN114671811A (en) * | 2022-04-14 | 2022-06-28 | 南京正科医药股份有限公司 | Racemization recovery method of dexmedetomidine resolution byproduct |
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| CN105481774A (en) * | 2016-01-26 | 2016-04-13 | 江苏恩华药业股份有限公司 | Dexmedetomidine hydrochloride crystal form C and preparation method thereof |
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| CN112979552A (en) * | 2019-12-16 | 2021-06-18 | 广安凯特制药有限公司 | Preparation method of high-purity dexmedetomidine hydrochloride |
| CN111548308A (en) * | 2020-03-18 | 2020-08-18 | 遂成药业股份有限公司 | Synthesis process of dexmedetomidine hydrochloride |
| CN113321619A (en) * | 2020-09-01 | 2021-08-31 | 南京恒正药物研究院有限公司 | Novel dexmedetomidine hydrochloride impurity and preparation method thereof |
| CN114671811A (en) * | 2022-04-14 | 2022-06-28 | 南京正科医药股份有限公司 | Racemization recovery method of dexmedetomidine resolution byproduct |
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