CN107011252A - The method for drawing azole intermediate and medicine is prepared using the green technology for substituting the poisonous and harmful substances such as phosgene, thionyl chloride - Google Patents
The method for drawing azole intermediate and medicine is prepared using the green technology for substituting the poisonous and harmful substances such as phosgene, thionyl chloride Download PDFInfo
- Publication number
- CN107011252A CN107011252A CN201710431500.4A CN201710431500A CN107011252A CN 107011252 A CN107011252 A CN 107011252A CN 201710431500 A CN201710431500 A CN 201710431500A CN 107011252 A CN107011252 A CN 107011252A
- Authority
- CN
- China
- Prior art keywords
- azole
- azoles
- thionyl chloride
- reaction
- phosgene
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/68—One oxygen atom attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/69—Two or more oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The green technology for substituting the poisonous and harmful substances such as phosgene, thionyl chloride the invention discloses a kind of application prepares the method that high-purity draws azole intermediate.The preparation method is：By Ph3PO is dissolved in organic solvent and is placed in reaction bulb, and BTC is added dropwise, and forms efficient chlorinating agent, insulation reaction is for a period of time after completion of dropping, azoles hydroxylate will be drawn to be dissolved in after organic solvent the system that is added drop-wise to again, insulation reaction for a period of time after, suction filtration, which is dried to be made, draws azoles chloride.Ph in the process3PO equivalents are regenerated, and Ph is separated out under low temperature after mother liquor fraction concentration3PO, Ph3PO is applied mechanically through the washing of small polar solvent is repeatable.The present invention has side reaction few, and product quality is high, and " three wastes " pollution is few, the advantages of Atom economy is high, with preferable popularizing application prospect.Present invention also offers the drawing azole drug that the drawing azoles chloride prepared by green technology further obtains correlation, the medicine is substantially higher than the pharmaceutical purity obtained by conventional method.
Description
Technical field
Substitute phosgene, thionyl chloride etc. the present invention relates to the preparation field for drawing azole drug, more particularly to a kind of application and have
The green technology of malicious harmful substance prepares high-purity and draws the method for azole intermediate and further synthesize drawing azole with the intermediate
The technique of medicine.
Background technology
Draw the key agents that azole drug is current treatment peptic ulcer, including Pantoprazole Sodium, L-pantoprazole
Sodium, RABEPRAZOLE SODIUM, Omeprazole, esomeprazole, Lansoprazole etc..Draw azoles chloride (the 2- chlorine of different substituents substitution
It is picoline, as shown in Figure 1) key intermediate for drawing azole drug, the preparation of this intermediate is main to draw azoles hydroxylate (no
The 2- hydroxymethylpyridines derivative replaced with substituent) it is raw material.
The figure occurred in specification should be classified as Figure of description part, must not insert the main application of industrialization at present in word
The tradition chlorinating agent such as thionyl chloride draw chloro (the synthesis chemistry, 2007,15 (3), 391-393 of azoles hydroxylate；Middle traditional Chinese medical science
Medicine industry magazine, 2000,31 (10), 475-476) in this method course of reaction with alkyl halide (dichloromethane, chloroform) for solvent,
Reaction is evaporated off solvent after terminating and needs to add another solvent to be dispersed to precipitate product, during heating steams solvent, acid
In the presence of property condition, some side reactions may be generated.Meanwhile, there is also more shortcoming as reagent for thionyl chloride：1) normal temperature
It is liquid down, storage and transport have potential safety hazard；2) acidic materials that thionyl chloride is produced are to workshop appliance seriously corroded；3)
Excessive in thionyl chloride course of reaction, Atom economy is not high, and the accessory substance sulfide of generation is easily polluted to environment,
" three wastes " processing cost is larger；4) it is that the prazole chloride intermediate that chlorinating agent is generated comes relatively by thionyl chloride to draw azoles at present
Say that content is relatively low, the impurity introduced during chlorination can affect to subsequent reactions, so as to cause Lan Suola
Azoles, esomeprazole, Pantoprazole, L-pantoprazole etc. draw total miscellaneous rise of azole drug.
Due to drawing azoles hydroxylate all to contain electron-donating group substantially so that electron cloud on the pyridine ring of such pyridine derivate
Density is larger, if using other efficiently chlorinating agents such as：Except the position that can replace in hydroxyl chlorine occurs for Vilsmeier reagents
Generation reaction is outer also to occur acylation reaction on the pyridine ring, and the impurity for also resulting in product increases.
At present, it would be highly desirable to a kind of efficient, green, pollution-free, and selectivity good chlorinating agent prepares the drawing azoles of high-purity
The key intermediate of class medicine draws azoles chloride further to improve the quality of drawing azole drug.
Because double-(trichloromethyl) carbonic ester (BTC) is easy to store, transports easy to use, and reaction condition is gentle, easily behaviour
Make, good product quality, high income, the advantages of reacting accurate measurement, BTC industrially has irreplaceable practical value and wide
General application prospect.BTC can not only substitute phosgene and surpalite, and can also substitute SOCl2、POCl3、PCl3Deng environment not
Friendly reagent.
Also there is patent (CN103232389A, CN103664750A) report to make using double-(trichloromethyl) carbonic ester at present
Prepared for chlorinating agent and draw azoles chloride, but be a kind of multi-functional reagent by BTC, available for synthesizing substantial amounts of organic compound
Thing, including chloro-formate, carbonic ester, carbamate, isocyanates, urea, nitrile, isocyanide etc. (Organic
Preparations and Procedures International, 2009,41:93-141).Therefore using draw azoles hydroxylate as
Raw material, directly uses BTC as reagent, can carry out acyl chloride reaction to hydroxymethyl position, can form chloroformate product not
Be entirely pure drawing azoles hydroxylate (as shown in Figure 2), report and the checking of experiment by document, directly plus BTC, it is impossible to compared with
Good purity and yield, which are obtained, draws azoles chloride.
Therefore, it is badly in need of a kind of green high-efficient, Atom economy at present high, reaction condition is gentle, good reaction selectivity, purity
High drawing azole intermediate and the preparation method of medicine.
The content of the invention
It is an object of the invention to overcome prior art shortcoming there is provided a kind of green high-efficient, Atom economy are high, react
Mild condition, good reaction selectivity, the high application of purity substitutes the green technology system of the poisonous and harmful substances such as phosgene, thionyl chloride
The standby method drawn azole intermediate and draw azole drug.
For achieving the above object, the present invention is adopted the following technical scheme that：
A kind of preparation method of drawing azoles chloride as shown in Figure 3, it is characterised in that comprise the following steps：
By Ph3PO (Fig. 3 a) is dissolved in organic solvent and is placed in reaction bulb, and BTC (Fig. 3 b) is added dropwise, and forms efficient chloro
Insulation reaction is dissolved in after organic solvent the system that is added drop-wise to for a period of time, then by drawing azoles hydroxylate (Fig. 3 c) after reagent, completion of dropping,
Insulation reaction for a period of time after, suction filtration dry be made draw azoles chloride (Fig. 3 d).Ph in the process3PO equivalents regenerate, mother liquor
After partial concentration Ph is separated out under low temperature3PO, Ph3PO can continue to repeat to apply mechanically through the washing of small polar solvent.
In the present invention, the organic solvent is toluene, ethylbenzene, dimethylbenzene, tetrahydrofuran, 2- methyltetrahydrofurans, 1,2-
Dichloroethanes, dichloromethane, chloroform, DMF, N, N- diethylformamides, acetonitrile, benzonitrile, benzene second
Nitrile, ethyl acetate, Ethyl formate, methyl formate, ethyl propionate, acetone, butanone, MEK, ethylene glycol, ethanol, methanol, oil
One or more in ether, ether, tertiary butyl ether, ethamine, triethylamine Isosorbide-5-Nitrae-dioxane, dimethyl sulfoxide, hexamethylene；The small pole
Property solvent be petroleum ether, n-hexane, ether, tertiary butyl ether in one or more.
In the present invention, the organic solvent is selected from one of following：Toluene, 1,2- dichloroethanes, dimethyl sulfoxide, tetrahydrochysene furan
Mutter, 1,4- dioxane, acetonitrile.
In the present invention, the drawing azoles hydroxylate, BTC and Ph3PO mol ratio is 1.0:(0.33-1.0):(0.8-1.5),
Preferably 1.0:(0.33~0.7):(1.0~1.2).
In the present invention, the reaction BTC and Ph3The heating-up temperature of PO reactions is generally 25~100 DEG C, preferably 40~80
℃；
In the present invention, the reaction draws azoles hydroxylate to be added dropwise and be incubated at 25~100 DEG C, preferably 40~80 DEG C；
In the present invention, soaking time is generally 1.0~8.0 hours after the 2- hydroxymethylpyridines derivative completion of dropping,
Preferably 2.0~5.0 hours.
One of preferred embodiment as the present invention, it is described to draw azoles hydroxylate to be the 2- hydroxymethylpyridines that different substituents replace
Derivative, specially 3,4- dimethoxy -2- hydroxymethylpyridines, 4- methoxyl groups -3,5- dimethyl -2- hydroxymethylpyridines or 3- first
Base -4- (2,2,2- trifluoro ethoxy) -2- hydroxymethylpyridines.
One of preferred embodiment as the present invention, when the drawing azoles hydroxylate is 3,4- dimethoxy -2- hydroxymethylpyridines
When, it is 3,4- dimethoxy -2- hydroxymethylpyridine hydrochlorides to draw azoles chloride；Azoles hydroxylate is drawn to be 4- methoxyl group -3 when described,
During 5- dimethyl -2- hydroxymethylpyridines, it is 4- methoxyl group -3,5- dimethyl -2- chloromethyl pyridine hydrochlorides to draw azoles chloride；When
When the drawing azoles hydroxylate is 3- methyl -4- (2,2,2- trifluoro ethoxy) -2- hydroxymethylpyridines, it is 3- first to draw azoles chloride
Base -4- (2,2,2- trifluoro ethoxy) -2- hydroxymethylpyridine hydrochlorides.
The specific preparation method for recommending described drawing azoles chloride of the invention is carried out in accordance with the following steps：By Ph3PO is dissolved in
Organic solvent is placed in reaction bulb, and BTC is dissolved in organic solvent and is put into constant pressure funnel, and BTC is added dropwise at room temperature, is added dropwise
25-100 DEG C is warming up to after finishing；After insulation reaction 3-5 hours, azoles hydroxylate will be drawn to be dissolved in organic solvent, at 25-100 DEG C
It is lower to add and insulation reaction 1.0-8.0 hour, during separate out white solid, stop after reaction, suction filtration obtains white solid, dry
The dry key intermediate that obtains draws azoles chloride；Ph is separated out under the concentrated rear 10-30 DEG C of low temperature of filtrate portion3PO, Ph3PO is through small pole
Property solvent washing after, suction filtration, drying, the Ph of acquisition3PO repeats to apply mechanically.
Azoles chloride is drawn present invention also offers the high-purity intermediate prepared by green technology, further passes through contracting
Reaction is closed, oxidation or asymmetric oxidation reaction obtain the drawing azole drug of correlation, comprised the following steps：
(1) sulfide intermediate is prepared
By the drawing azoles chloride, the 70-90 DEG C of temperature rising reflux in methanol or ethanol is molten with sulfhydryl benzimidazole derivative
After solution, insulation reaction, sulfide intermediate is made after drying in evaporation solvent and suction filtration acquisition white solid；
(2) prepare and draw azole drug
Sulfide intermediate is dissolved in toluene, chloroform or ethyl acetate, at -10-10 DEG C add hydrogen oxide diisopropylbenzene (DIPB) or
Metachloroperbenzoic acid, after completion of the reaction extract and separate must draw azole bulk drug；Azole bulk drug and corresponding auxiliary material will be drawn, will be added
After water for injection dissolving, freeze-drying obtains white loose shape and draws azole drug.
In the present invention, when the drawing azoles chloride is 3,4- dimethoxy -2- hydroxymethylpyridine hydrochlorides, sulfydryl benzo
Imdazole derivatives be 5- difluoro-methoxy -2- sulfydryl -1H- benzimidazoles, sulfide intermediate be 5- difluoro-methoxies -2- [(3,
4- dimethoxy-2-pyridinyls) methyl] sulphur } -1H- benzimidazoles, draw azole bulk drug to be Pantoprazole Sodium or left-handed dissolve Tuo La
Azoles sodium, corresponding auxiliary material is natrium adetate or mannitol and natrium adetate, and the white loose shape of final gained draws azole drug
For Pantoprazole sodium injection or injection Levpantoprazole Sodium.
In the present invention, when the drawing azoles chloride is 4- methoxyl group -3,5- dimethyl -2- chloromethyl pyridine hydrochlorides,
Sulfhydryl benzimidazole derivative be 2- sulfydryl -5- methoxybenzimidazols, sulfide intermediate be 5- methoxyl groups -2- (4- methoxyl groups -
3,5- dimethyl -2- pyridine radicals) methyl thio -1H- benzimidazoles, it is Esomeprazole sodium, corresponding auxiliary material to draw azole bulk drug
For natrium adetate, the white loose shape of final gained draws azole drug to be injection Esomeprazole sodium.
In the present invention, when the drawing azoles chloride is 3- methyl -4- (2,2,2- trifluoro ethoxy) -2- hydroxymethylpyridine salt
During hydrochlorate, sulfhydryl benzimidazole derivative is 2-mercaptobenzimidazole, and sulfide intermediate is [[[3- methyl -4- (2,2,2- trifluoros
Ethyoxyl) -2- pyridine radicals] methyl] sulfenyl] -1H- benzimidazoles, it is Lansoprazole to draw azole bulk drug, and corresponding auxiliary material is sweet dew
Alcohol and meglumine, the white loose shape of final gained draw azole drug to be Lansoprazole for injecting.
The advantage of the present invention compared with prior art is：
(1) one has been invented with BTC/Ph3PO chloros system prepares the new method for drawing azoles chloride hydrochloride, with original
Property；
(2) yield of chlorination is high, and stable yield is more than 95%, and reaction can obtain the drawing azoles chloride salt of high-purity
It is more than hydrochlorate, product HPLC content >=99.8%；
(3) " three wastes " pollution has been got rid of from source big, strong to equipment corrosion, atom utilization is low and easily environment is produced
The use of the poisonous and harmful reagents such as raw pollution thionyl chloride；Route " three wastes " amount used in the present invention is few, more green；
(4) system BTC/Ph used in the chloro of azoles chloride hydrochloride is drawn in synthesis3In PO, required BTC is cheap
The compound being easy to get, required Ph3PO recyclable regeneratives are simultaneously repeatedly applied mechanically (as shown in Figure 4), substantially increase the profit of atom
With rate, reaction cost is reduced, environmental pollution is also less.
In summary, the present invention have that side reaction is few, product quality is high, yield close to theoretical yield, and it is easy to operate, after
The advantages of processing is simple, pollution is few, is a kind of chemical synthesis process with preferable popularizing application prospect.
Azoles chloride is drawn present invention also offers the intermediate prepared by green technology, it is further anti-by condensation
Should, oxidation or asymmetric oxidation reaction obtain related drawing azole drug (as shown in Figure 5).The injection prepared using the present invention
Lansoprazole, injection Esomeprazole sodium, Pantoprazole sodium injection, injection Levpantoprazole Sodium etc. draw azole drug
Purity substantially it is higher than the pharmaceutical purity obtained by conventional method.
Brief description of the drawings
Fig. 1 is the structure chart of the 2- PMCs of different substituents substitution in background technology；
Fig. 2 is the direct accessory substance process schematic that reaction may be generated by chlorinating agent of BTC in background technology；
Fig. 3 is the preparation method process schematic that the present invention draws azoles chloride；
Fig. 4 is BTC/Ph of the present invention3The reaction schematic diagram that PO chloro system is participated in；
Fig. 5 is that the present invention draws azoles chloride to obtain related drawing azoles by condensation reaction, oxidation or asymmetric oxidation reaction
The specific reactions steps figure of class medicine；
Fig. 6 is the 2- hydroxymethyl-4-methoxy-3,5-dimethylpyridine liquid phase spectrograms in embodiment 1；
Fig. 7 is the Ph in embodiment 13PO liquid phase spectrograms；
Fig. 8 is 2- chloromethyl -4- methoxyl group -3,5- dimethyl pyrazole thiamine hydrochloride liquid chromatography(LC figures in embodiment 1；
Fig. 9 is 2- chloromethyl -4- methoxyl group -3,5- dimethyl pyrazole thiamine hydrochlorides in embodiment 11HNMR spectrograms；
Figure 10 is 2- chloromethyl -4- methoxyl group -3,5- dimethyl pyrazole thiamine hydrochloride ESI mass spectrograms in embodiment 1；
Figure 11 is the 5- methoxyl groups -2- (4- methoxyl group -3,5- dimethyl -2- prepared using the present invention in embodiment 11
Pyridine radicals) methyl thio -1H- benzimidazoles liquid phase spectrogram；
Figure 12 is 2- chloromethyl -4- methoxyl group -3,5- dimethyl prepared by the application thionyl chloride technique in embodiment 11
The esomeprazole sulfide intermediate 5- methoxyl groups -2- (4- methoxyl group -3,5- dimethyl -2- that pyridine hydrochloride is further generated
Pyridine radicals) methyl thio -1H- benzimidazoles liquid phase spectrogram；
Figure 13 is the injection Esomeprazole sodium liquid phase spectrogram of the method in embodiment 12；
Figure 14 is 2- chloromethyl -4- methoxyl group -3,5- dimethyl prepared by the application thionyl chloride technique in embodiment 12
The injection Esomeprazole sodium liquid phase spectrogram that pyridine hydrochloride is further prepared；
Figure 15 is 5- difluoro-methoxies -2- { [(3, the 4- dimethoxy -2- pyrroles prepared using the present invention in embodiment 13
Piperidinyl) methyl] sulphur -1H- benzimidazoles liquid phase spectrogram；
Figure 16 is 2- chloromethyl -3,4- dimethoxy-pyridine hydrochloric acid prepared by the application thionyl chloride technique in embodiment 13
Salt generates Pantoprazole sulfide intermediate 5- difluoro-methoxies -2- { [(3,4- dimethoxy-2-pyridinyl) methyl] sulphur } -1H-
The liquid phase spectrogram of benzimidazole；
Figure 17 is that the 2- chloromethyl-3,4-dimethoxypyridine hydrochlorides prepared using the present invention in embodiment 14 enter one
Walk the Pantoprazole sodium injection liquid phase spectrogram prepared；
Figure 18 is 2- chloromethyl -3,4- dimethoxy-pyridine hydrochloric acid prepared by the application thionyl chloride technique in embodiment 14
The Pantoprazole sodium injection liquid phase spectrogram that salt is further prepared；
Figure 19 is that the 2- chloromethyl-3,4-dimethoxypyridine hydrochlorides prepared using the present invention in embodiment 15 enter one
Walk the injection Levpantoprazole Sodium liquid phase spectrogram prepared；
Figure 20 is 2- chloromethyl -3,4- dimethoxy-pyridine hydrochloric acid prepared by the application thionyl chloride technique in embodiment 15
The injection Levpantoprazole Sodium liquid phase spectrogram that salt is further prepared；
Figure 21 is 2- chloromethyl -3- methyl -4- (the 2,2,2- trifluoroethoxies prepared using the present invention in embodiment 16
Base) Lansoprazole sulfide intermediate [[[3- methyl -4- (2,2,2- trifluoro ethoxies) -2- for further generating of pyridine hydrochloride
Pyridine radicals] methyl] sulfenyl] and -1H- benzimidazoles liquid phase spectrogram；
Figure 22 is 2- chloromethyl -3- methyl -4- (2,2,2- trifluoros prepared by the application thionyl chloride technique in embodiment 16
Ethyoxyl) Lansoprazole sulfide intermediate [[[3- methyl -4- (the 2,2,2- trifluoroethoxies that further generate of pyridine hydrochloride
Base) -2- pyridine radicals] methyl] sulfenyl] -1H- benzimidazoles liquid phase spectrogram；
Figure 23 is 2- chloromethyl -3- methyl -4- (the 2,2,2- trifluoroethoxies prepared using the present invention in embodiment 17
Base) the Lansoprazole for injecting liquid phase spectrogram that further prepares of pyridine hydrochloride；
Figure 24 is 2- chloromethyl -3- methyl -4- (2,2,2- trifluoros prepared by the application thionyl chloride technique in embodiment 17
Ethyoxyl) the Lansoprazole for injecting liquid phase spectrogram that further prepares of pyridine hydrochloride.
Embodiment
Embodiments of the invention are elaborated below, the present embodiment is carried out lower premised on technical solution of the present invention
Implement, give detailed embodiment and specific operating process, but protection scope of the present invention is not limited to following implementations
Example.
The preparation (reference implementation example 1-10) of drawing azole intermediate shown in Fig. 3
Embodiment 1
In 500mL there-necked flasks, by Ph3PO (43.78g, 157.5mmol) is dissolved in toluene (100mL), by BTC
(14.84g, 50mmol) is dissolved in toluene (60mL) and is put into 150mL constant pressure funnel, and BTC is added dropwise at room temperature, drips
60 DEG C are warming up to after finishing；After insulation reaction 4 hours, by 2- hydroxymethyl-4-methoxy-3,5-dimethylpyridines (25.05g,
150mmol) it is dissolved in toluene 75mL, is added at 40 DEG C, separate out white solid, insulation reaction stops after reaction after 2 hours,
Suction filtration obtains white solid, is dried to obtain 2- chloromethyl -4- methoxyl group -3,5- dimethyl pyrazole thiamine hydrochloride 32.49g, and product is received
Rate 98%, content 99.92%；After filtrate portion is concentrated Ph is separated out under 20 DEG C of low temperature3PO, Ph3PO takes out after petroleum ether
Filter, drying, the Ph of acquisition3PO repeats to apply mechanically；Wherein, 2- methylols -4- methoxyl group -3 during Fig. 6, Fig. 7, Fig. 8 are respectively,
5- lutidines, Ph3The liquid phase spectrogram of PO and 2- chloromethyl -4- methoxyl group -3,5- dimethyl pyrazole thiamine hydrochlorides；Fig. 9, Figure 10
Respectively 2- chloromethyls -4- methoxyl groups -3,5- dimethyl pyrazole thiamine hydrochloride1HNMR spectrograms and ESI mass spectrograms；
Embodiment 2
In 500mL there-necked flasks, by Ph3PO (43.78g, 157.5mmol) is dissolved in toluene (100mL), by BTC
(14.84g, 50mmol) is dissolved in toluene (60mL) and is put into 150mL constant pressure funnel, and BTC is added dropwise at room temperature, drips
40 DEG C are warming up to after finishing.After insulation reaction 4 hours, by 2- hydroxymethyl-4-methoxy-3,5-dimethylpyridines (25.05g,
150mmol) it is dissolved in toluene 75mL, is added at 25 DEG C, separate out white solid, insulation reaction stops reaction, taken out after 8 hours
Filter obtains white solid, is dried to obtain 2- chloromethyl -4- methoxyl group -3,5- dimethyl pyrazole thiamine hydrochloride 27.18g, product yield
82%, content 99.40%.After filtrate portion is concentrated Ph is separated out at 10 DEG C3PO, after being washed through n-hexane, suction filtration, drying is obtained
Ph3PO (43.27g) is reusable.
Embodiment 3
In 500mL there-necked flasks, by Ph3PO (43.78g, 157.5mmol) is dissolved in toluene (100mL), by BTC
(14.84g, 50mmol) is dissolved in toluene (60mL) and is put into 150mL constant pressure funnel, and BTC is added dropwise at room temperature, drips
40 DEG C are warming up to after finishing.After insulation reaction 4 hours, by 2- hydroxymethyl-4-methoxy-3,5-dimethylpyridines (25.05g,
150mmol) it is dissolved in toluene 75mL, is added at 100 DEG C, separate out white solid, insulation reaction stops reaction, taken out after 1 hour
Filter obtains white solid, is dried to obtain 2- chloromethyl -4- methoxyl group -3,5- dimethyl pyrazole thiamine hydrochloride 30.82g, product yield
93%, content 96.59%.After filtrate portion is concentrated Ph is separated out at 30 DEG C3PO, after being washed through ether, suction filtration, drying is obtained
Ph3PO (43.36g) is reusable.
Embodiment 4
In 500mL there-necked flasks, by Ph3PO (62.61g, 225mmol) is dissolved in toluene (100mL), by BTC
(44.55g, 150mmol) is dissolved in toluene (75mL) and is put into 150mL constant pressure funnel, and BTC is added dropwise at room temperature, is added dropwise
40 DEG C are warming up to after finishing.After insulation reaction 4 hours, by 2- hydroxymethyl-4-methoxy-3,5-dimethylpyridines (25.05g,
150mmol) it is dissolved in toluene 75mL, is added at 60 DEG C, separate out white solid, insulation reaction stops reaction, taken out after 2 hours
Filter obtains white solid, is dried to obtain 2- chloromethyl -4- methoxyl group -3,5- dimethyl pyrazole thiamine hydrochloride 31.49g, product yield
95%, content 95.5%.After filtrate portion is concentrated Ph is separated out at 20 DEG C3PO, after a small amount of tertiary butyl ether washing, suction filtration, drying
Obtain Ph3PO (62.12g) is reusable.
Embodiment 5
In 500mL there-necked flasks, by Ph3PO (62.61g, 225mmol) is dissolved in toluene (100mL), by BTC
(31.16g, 105mmol) is dissolved in toluene (75mL) and is put into 150mL constant pressure funnel, and BTC is added dropwise at room temperature, is added dropwise
25 DEG C are warming up to after finishing.After insulation reaction 4 hours, by 2- hydroxymethyl-4-methoxy-3,5-dimethylpyridines (25.05g,
150mmol) it is dissolved in toluene 75mL, is added at 40 DEG C, separate out white solid, insulation reaction stops reaction, taken out after 8 hours
Filter obtains white solid, is dried to obtain 2- chloromethyl -4- methoxyl group -3,5- dimethyl pyrazole thiamine hydrochloride 29.50g, product yield
89%.Content 98.55%.After filtrate portion is concentrated Ph is separated out at 10 DEG C3PO, after a small amount of petroleum ether, suction filtration, drying
Obtain Ph3PO (62.11g) is reusable.
Embodiment 6
In 500mL there-necked flasks, by Ph3PO (62.61g, 225mmol) is dissolved in toluene (100mL), by BTC
(31.16g, 105mmol) is dissolved in toluene (75mL) and is put into 150mL constant pressure funnel, and BTC is added dropwise at room temperature, is added dropwise
100 DEG C are warming up to after finishing.After insulation reaction 4 hours, by 2- hydroxymethyl-4-methoxy-3,5-dimethylpyridines (25.05g,
150mmol) it is dissolved in toluene 75mL, is added at 60 DEG C, separate out white solid, insulation reaction stops reaction, taken out after 1 hour
Filter obtains white solid, is dried to obtain 2- chloromethyl -4- methoxyl group -3,5- dimethyl pyrazole thiamine hydrochloride 30.17g, product yield
93%.Content 98.77%.After filtrate portion is concentrated Ph is separated out at 30 DEG C3PO, after being washed through a small amount of n-hexane, suction filtration, drying
Obtain Ph3PO (62.00g) is reusable.
Embodiment 7
In 500mL there-necked flasks, by Ph3PO (43.78g, 157.5mmol) is dissolved in 1,2- dichloroethanes (100mL), will
BTC (14.84g, 50mmol) is dissolved in 1,2- dichloroethanes (60mL) and is put into 150mL constant pressure funnel, drips at room temperature
Plus BTC, 40 DEG C are warming up to after completion of dropping.After insulation reaction 4 hours, by 2- hydroxymethyl-4-methoxy-3,5-dimethylpyridines
(25.05g, 150mmol) is dissolved in 1,2- dichloroethanes 75mL, is added at 60 DEG C, separates out white solid, and insulation reaction 2 is small
Shi Hou, stops reaction, and suction filtration obtains white solid, is dried to obtain 2- chloromethyl -4- methoxyl group -3,5- dimethyl pyrazole thiamine hydrochlorides
31.54g, product yield 95%.Content 98.50%.After filtrate portion is concentrated Ph is separated out at 20 DEG C3PO, through a small amount of tertiary butyl ether
After washing, suction filtration, drying obtains Ph3PO (43.24g) is reusable.
Embodiment 8
In 500mL there-necked flasks, by Ph3PO (43.78g, 157.5mmol) is dissolved in dimethyl sulfoxide (100mL), by BTC
(14.84g, 50mmol) is dissolved in dimethyl sulfoxide (60mL) and is put into 150mL constant pressure funnel, and BTC is added dropwise at room temperature, drop
Add and be warming up to 40 DEG C after finishing.After insulation reaction 4 hours, by 2- hydroxymethyl-4-methoxy-3,5-dimethylpyridines (25.05g,
150mmol) it is dissolved in dimethyl sulfoxide 75mL, is added at 60 DEG C, separate out white solid, insulation reaction stops anti-after 2 hours
Should, suction filtration obtains white solid, is dried to obtain 2- chloromethyl -4- methoxyl group -3,5- dimethyl pyrazole thiamine hydrochloride 31.21g, product
Yield 94%.Content 98.20%.After filtrate portion is concentrated Ph is separated out at 20 DEG C3PO, after a small amount of petroleum ether, suction filtration,
Drying obtains Ph3PO (43.29g) is reusable.
Embodiment 9
In 500mL there-necked flasks, by Ph3PO (43.78g, 157.5mmol) is dissolved in toluene (100mL), by BTC
(14.84g, 50mmol) is dissolved in toluene (60mL) and is put into 150mL constant pressure funnel, and BTC is added dropwise at room temperature, drips
60 DEG C are warming up to after finishing.It is after insulation reaction 4 hours, 2- methylols -3,4- dimethoxy-pyridine (25.35g, 150mmol) is molten
In toluene 75mL, added at 40 DEG C, separate out white solid, insulation reaction stops reaction after 2 hours, and suction filtration obtains white
Solid, is dried to obtain 2- chloromethyl-3,4-dimethoxypyridine hydrochloride 32.78g, product yield 98%, content 99.86%.
After filtrate portion is concentrated Ph is separated out at 10 DEG C3PO, after a small amount of petroleum ether, suction filtration, drying obtains Ph3PO(43.40g)
It is reusable.
Embodiment 10
In 500mL there-necked flasks, by Ph3PO (43.78g, 157.5mmol) is dissolved in toluene (100mL), by BTC
(14.84g, 50mmol) is dissolved in toluene (60mL) and is put into 150mL constant pressure funnel, and BTC is added dropwise at room temperature, drips
60 DEG C are warming up to after finishing.After insulation reaction 4 hours, by 2- methylol -3- methyl -4- (2,2,2- trifluoro ethoxy) pyridine
(33.15g, 150mmol) is dissolved in toluene 75mL, is added at 40 DEG C, separates out white solid, and insulation reaction stops after 2 hours
Reaction, suction filtration obtains white solid, is dried to obtain 2- chloromethyl -3- methyl -4- (2,2,2- trifluoro ethoxy) pyridine hydrochloride
40.01g, product yield 97%.Content 99.82%.After filtrate portion is concentrated Ph is separated out at 30 DEG C3PO, through a small amount of n-hexane
After washing, suction filtration, drying obtains Ph3PO (43.41g) is reusable.
Drawing azole drug shown in Fig. 5 is prepared (reference implementation example 11-17)
(the esomeprazole sulfide intermediate 5- methoxyl groups -2- (4- methoxyl group -3,5- dimethyl -2- pyridines of embodiment 11
Base) methyl thio -1H- benzimidazoles preparation)
In 1000mL there-necked flasks, sodium hydroxide (5g, 0.13mol) is added in ethanol (50mL), 70-90 is warming up to
DEG C dissolving after add 2- sulfydryl -5- methoxybenzimidazols (17.8g, 0.10mol), backflow dissolving, be cooled to less than 10 DEG C.
It is in 200mL constant pressure funnel, 2- chloromethyl -4- methoxyl group -3,5- dimethyl pyrazole thiamine hydrochlorides (20g, 0.09mol) is molten
In water (100mL), hydrochloric acid saline solution is slowly added dropwise, drop, which finishes, is warming up to 30 DEG C, and insulation reaction is cooled to 10 DEG C after 4 hours,
500mL water is added, is stirred 12 hours, suction filtration obtains white solid, is dried to obtain 5- methoxyl groups -2- (4- methoxyl group -3,5- diformazans
Base -2- pyridine radicals) methyl thio -1H- benzimidazoles, product yield 96%.According to high performance liquid chromatography (Chinese Pharmacopoeia 2015
Four general rules 0512 of version) carry out relevant material detection, single miscellaneous 0.04%, total miscellaneous 0.04%.Wherein, Figure 11 is 5- methoxyl groups -2-
The liquid phase spectrogram of (4- methoxyl group -3,5- dimethyl -2- pyridine radicals) methyl thio -1H- benzimidazoles.
Angstrom that 2- chloromethyl -4- methoxyl group -3, the 5- dimethyl pyrazole thiamine hydrochlorides prepared using the present invention are further generated
Suo Meila azoles sulfide intermediate detects data comparison such as with the relevant material of the sulfide intermediate prepared using thionyl chloride technique
Shown in table 1；Wherein, 2- chloromethyl -4- methoxyl group -3, the 5- dimethyl pyrazole thiamine hydrochlorides prepared using thionyl chloride technique enter one
Walk esomeprazole sulfide intermediate 5- methoxyl groups -2- (4- methoxyl group -3,5- dimethyl -2- pyridine radicals) methyl sulphur of generation
The generation liquid phase spectrogram of -1H- benzimidazoles is as shown in figure 12.
Table 1 using the esomeprazole sulfide intermediate for preparing of the present invention with the thioether that is prepared using thionyl chloride technique
The contrast of mesosome
| Esomeprazole thioether | Thionyl chloride technique | Present invention process |
| It is single miscellaneous | 0.16% | 0.04% |
| It is total miscellaneous | 0.22% | 0.04% |
| Impurity number | 4 | 1 |
Embodiment 12 (preparation of injection Esomeprazole sodium)
In 500mL there-necked flasks, by 5- methoxyl groups -2- (4- methoxyl group -3,5- dimethyl -2- pyridine radicals) methyl thio -
1H- benzimidazoles (14.8g, 45mmol) are added in 75mL toluene, are warming up to 65 DEG C, and D- ethyl tartrates are added after dissolving
(5.7g, 27.5mmol) and tetraisopropyl titanate (3.9g, 13.8mmol), while a small amount of purified water is added, after stirring 1 hour,
It is cooled to 10 DEG C.Add DIPEA (1.6g, 12mmol) and dilution with toluene cumyl hydroperoxide (8g,
45mmol), 20 DEG C are continued to react 1 hour.Ammoniacal liquor (60mL) and purified water are added after completion of the reaction, 20min is stirred, and are stood and are divided
Liquid.Ammoniacal liquor layer adds dichloromethane (150mL), stirs 20min, stands a point liquid.Dichloromethane layer adds anhydrous sodium sulfate (15g)
Dry, after drying 1 hour, suction filtration, vacuum rotary steam removes dichloromethane at 50 DEG C, obtains grease esomeprazole, and product is received
Rate 75%.
In 100mL there-necked flasks, esomeprazole (8.3g, 24mmol) is added in 50mL absolute ethyl alcohols, after dissolving
Sodium hydroxide (1g, 25mmol) is added, temperature rising reflux is stirred 2 hours.Activated carbon (0.3g) is added, after stirring 30 minutes, while hot
Filtering；Filtrate vacuum rotary steam at 60 DEG C is removed in solvent, gained grease is down to room after addition acetone (50mL), heating for dissolving
Temperature, is slowly stirred crystallization 4 hours, and suction filtration obtains Esomeprazole sodium, product yield 70%.
Esomeprazole sodium (43g), natrium adetate (1.5g) and appropriate sodium hydroxide is weighed to be dissolved in 2L waters for injection,
Stirring is to being completely dissolved；2g activated carbons are added, are stirred at room temperature 30 minutes, decarburization is filtered, filtrate is degerming through 0.22 μm of miillpore filter
Filtering；Bacteria-free filtrate is sub-packed in sterilizing cillin bottle by every bottle of 2mL, the block injection Esso of white loose is freeze-dried to obtain
Azoles sodium draws in U.S..Relevant material detection is carried out according to high performance liquid chromatography (four general rules 0512 of Chinese Pharmacopoeia version in 2015), it is single miscellaneous
0.08%, total miscellaneous 0.08%；Wherein, Figure 13 is injection Esomeprazole sodium liquid phase spectrogram.
The note that 2- chloromethyl -4- methoxyl group -3, the 5- dimethyl pyrazole thiamine hydrochlorides prepared using the present invention are further prepared
Penetrate and detect data with Esomeprazole sodium with the relevant material of the injection Esomeprazole sodium prepared using thionyl chloride technique
Contrast is as shown in table 2；Wherein, 2- chloromethyl -4- methoxyl group -3, the 5- lutidines hydrochloric acid prepared using thionyl chloride technique
The injection Esomeprazole sodium liquid phase spectrogram that salt is further prepared is as shown in figure 14.
The injection Esomeprazole sodium that table 2 is prepared using the present invention and the injection angstrom prepared using thionyl chloride technique
The data comparison of Suo Meila azoles sodium
| Injection Esomeprazole sodium | Thionyl chloride technique | Present invention process |
| It is single miscellaneous | 0.23% | 0.08% |
| It is total miscellaneous | 0.31% | 0.08% |
| Impurity number | 4 | 1 |
(Pantoprazole sulfide intermediate 5- difluoro-methoxies -2- { [(3, the 4- dimethoxy-2-pyridinyl) first of embodiment 13
Base] sulphur -1H- benzimidazoles preparation)
In 500mL there-necked flasks, sequentially add 2- chloromethyl-3,4-dimethoxypyridine hydrochlorides (22.4g,
100mmol), 5- difluoro-methoxies -2- sulfydryl -1H- benzimidazoles (21.6g, 104mmol), 80g/L sodium hydroxide solutions
(110mL), ethanol (150mL), stirring is warming up to 80 DEG C and flowed back 8 hours, reclaims ethanol, and residue is with dichloromethane (150mL)
Extraction.Plus anhydrous sodium sulfate drying is stayed overnight, dichloromethane is recovered under reduced pressure and obtains crude product.Recrystallize in vain through ethyl acetate-light petrol
Color solid, dry 5- difluoro-methoxies -2- { [(3,4- dimethoxy-2-pyridinyl) methyl] sulphur } -1H- benzimidazoles, production
Product yield 94%.Relevant material detection is carried out according to high performance liquid chromatography (four general rules 0512 of Chinese Pharmacopoeia version in 2015), it is single
Miscellaneous 0.04%, total miscellaneous 0.04%；Wherein, Figure 15 is 5- difluoro-methoxies -2- { [(3,4- dimethoxy-2-pyridinyl) methyl]
Sulphur } -1H- benzimidazoles liquid phase spectrogram.
The Pantoprazole sulphur that 3, the 4- dimethoxy -2- chloromethyl pyridine hydrochlorides prepared using the present invention are further generated
The relevant material detection data comparison of sulfide intermediate of the ether intermediate with being prepared using thionyl chloride technique is as shown in table 3.Its
In, 3, the 4- dimethoxy -2- chloromethyl pyridine hydrochlorides prepared using thionyl chloride technique are generated in the middle of Pantoprazole thioether
The liquid phase spectrogram of body 5- difluoro-methoxies -2- { [(3,4- dimethoxy-2-pyridinyl) methyl] sulphur } -1H- benzimidazoles is as schemed
Shown in 16.
Table 3 using the Pantoprazole sulfide intermediate for preparing of the present invention with the middle of the thioether that is prepared using thionyl chloride technique
The contrast of body
| Pantoprazole thioether | Thionyl chloride technique | Present invention process |
| It is single miscellaneous | 0.18% | 0.04% |
| It is total miscellaneous | 0.25% | 0.04% |
| Impurity number | 4 | 1 |
Embodiment 14 (preparation of Pantoprazole sodium injection)
In 250mL there-necked flasks, by 5- difluoro-methoxies -2- { [(3,4- dimethoxy-2-pyridinyl) methyl] sulphur } -
1H- benzimidazoles (11g, 30mmol) are dissolved in chloroform (50mL), are cooled to 0 DEG C, add metachloroperbenzoic acid
(6.9g, 40mmol), stirring reaction 4 hours.Saturated sodium carbonate solution (50mL) is added, divides and takes chloroform layer, water layer chloroform
(50mL) is extracted, and merges chloroform layer, plus anhydrous sodium sulfate drying is stayed overnight, and chloroform is recovered under reduced pressure and obtains crude product；Tied again through ethyl acetate
Brilliant white solid, dry Pantoprazole, product yield 85%.
In 250mL there-necked flasks, Pantoprazole (7.7g, 20mmol), sodium hydroxide (1g, 25mmol), second are sequentially added
Alcohol (50mL), stirring temperature rising reflux 5 hours.Less than 10 DEG C are cooled to, white solid precipitation is separated out, filters to obtain crude product.Through ethanol-
Petroleum ether recrystallizes to obtain white solid, dry Pantoprazole Sodium, product yield 95%.
Weigh Pantoprazole Sodium (40g), natrium adetate (20g) and appropriate sodium hydroxide to be dissolved in 4L waters for injection, stir
Mix to being completely dissolved.4g activated carbons are added, are stirred at room temperature 30 minutes, decarburization are filtered, filtrate is through 0.22 μm of degerming mistake of miillpore filter
Filter.Bacteria-free filtrate is sub-packed in sterilizing cillin bottle by every bottle of 2mL, be freeze-dried the block injection of white loose dissolves Tuo La
Azoles sodium.Relevant material detection is carried out according to high performance liquid chromatography (four general rules 0512 of Chinese Pharmacopoeia version in 2015), it is single miscellaneous
0.08%, total miscellaneous 0.08%.Wherein, Figure 17 is the injection that 2- chloromethyl-3,4-dimethoxypyridine hydrochlorides are further prepared
With Pantoprazole Sodium liquid phase spectrogram；
The injection that the 2- chloromethyl-3,4-dimethoxypyridine hydrochlorides prepared using the present invention are further prepared dissolves support
Draw azoles sodium and the relevant material detection data comparison such as institute of table 4 of the Pantoprazole sodium injection prepared using thionyl chloride technique
Show；Wherein, the injection that the 2- chloromethyl-3,4-dimethoxypyridine hydrochlorides prepared using thionyl chloride technique are further prepared
It is as shown in figure 18 with Pantoprazole Sodium liquid phase spectrogram.
The Pantoprazole sodium injection that table 4 is prepared using the present invention dissolves support with the injection prepared using thionyl chloride technique
Draw the data comparison of azoles sodium
| Pantoprazole sodium injection | Thionyl chloride technique | Present invention process |
| It is single miscellaneous | 0.24% | 0.08% |
| It is total miscellaneous | 0.32% | 0.08% |
| Impurity number | 6 | 1 |
Embodiment 15 (preparation of injection Levpantoprazole Sodium)
In 250mL lucifuge there-necked flasks, 5- difluoro-methoxies -2- { [(3,4- dimethoxy-2-pyridinyl) methyl] is added
Sulphur } -1H- benzimidazoles (30g, 81.5mmol), D- ethyl tartrates (10.2g, 50mmol), tetraisopropyl titanate (7g,
24.5mmol), after rising temperature for dissolving, stirring reaction 1 hour is cooled to -5 DEG C, adds N, N- diisopropyl ethyl amines (4ml,
24mmol), stir.Di-isopropylbenzene hydroperoxide (23.6g, 120mmol) is slowly added dropwise, lucifuge temperature control is stirred at -5-0 DEG C
Mix 24 hours；10% NaOH solution (100mL) is added dropwise, is stirred at room temperature 1 hour.10% hypo solution is added dropwise to iodine
Change the detection reaction solution nondiscolouring of maculanin test paper, continue to stir 30 minutes, stratification.Water layer adjusts pH to 7.5, uses acetic acid second
Ester (150mL) is extracted twice, combined ethyl acetate layer, is added anhydrous sodium sulfate drying and is stayed overnight.Ethyl acetate is recovered under reduced pressure to obtain slightly
Product；White solid is recrystallized to obtain through methanol-ethyl acetate, dry L-pantoprazole, product yield 49%.
In 500mL there-necked flasks, L-pantoprazole (15g, 40mmol) is added in isopropanol (25mL) and stirred, be added dropwise
30% NaOH solution (200mL), is stirred at room temperature 1 hour, adds methyl tertiary butyl ether(MTBE) (150mL) and is cooled to less than -5 DEG C, analysis
Go out white solid precipitation, 40 DEG C of lucifuges are dried under reduced pressure to obtain Levpantoprazole Sodium, product yield 87%.
Levpantoprazole Sodium (20g), mannitol (80g), natrium adetate (10g) and appropriate sodium hydroxide is weighed to be dissolved in
In 2L waters for injection, stirring is to being completely dissolved.2g activated carbons are added, are stirred at room temperature 30 minutes, decarburization are filtered, filtrate is through 0.22 μm
Miillpore filter aseptic filtration.Bacteria-free filtrate is sub-packed in sterilizing cillin bottle by every bottle of 2mL, white loose bulk is freeze-dried to obtain
Injection Levpantoprazole Sodium.Carried out according to high performance liquid chromatography (four general rules 0512 of Chinese Pharmacopoeia version in 2015) relevant
Material detection, single miscellaneous 0.07%, total miscellaneous 0.07%.Wherein, Figure 19 is that 2- chloromethyl-3,4-dimethoxypyridine hydrochlorides enter one
Walk the injection Levpantoprazole Sodium liquid phase spectrogram prepared.
The injection Levpantoprazole Sodium prepared using the present invention and the injection prepared using thionyl chloride technique are left
The relevant material detection data comparison for revolving Pantoprazole Sodium is as shown in table 5, wherein, the 2- chloromethanes prepared using thionyl chloride technique
The injection Levpantoprazole Sodium liquid phase spectrogram that base -3,4- dimethoxy pyridine hydrochloride is further prepared is as shown in figure 20.
The injection Levpantoprazole Sodium that table 5 is prepared using the present invention and the injection prepared using thionyl chloride technique
The data comparison of Levpantoprazole Sodium
| Injection Levpantoprazole Sodium | Thionyl chloride technique | Present invention process |
| It is single miscellaneous | 0.21% | 0.07% |
| It is total miscellaneous | 0.29% | 0.07% |
| Impurity number | 3 | 1 |
(Lansoprazole sulfide intermediate [[[3- methyl -4- (2,2,2- the trifluoro ethoxies) -2- pyridine radicals] first of embodiment 16
Base] sulfenyl] -1H- benzimidazoles preparation)
In 250mL there-necked flasks, by 2- chloromethyl -3- methyl -4- (2,2,2- trifluoro ethoxy) pyridine hydrochloride (11g,
40mmol), 2-mercaptobenzimidazole (9g, 60mmol) and sodium hydroxide (6g, 150mmol) are dissolved in ethanol (80mL), heating
Back flow reaction 2 hours.Room temperature is cooled to, is filtered, filtrate evaporates 2/3 ethanol.0 DEG C is cooled to, suction filtration obtains white solid, done
It is dry to obtain [[[3- methyl -4- (2,2,2- trifluoro ethoxy) -2- pyridine radicals] methyl] sulfenyl] -1H- benzimidazoles, product yield
88%.Relevant material detection is carried out according to high performance liquid chromatography (four general rules 0512 of Chinese Pharmacopoeia version in 2015), it is single miscellaneous
0.05%, total miscellaneous 0.05%；Wherein, Figure 21 is that 2- chloromethyl -3- methyl -4- (2,2,2- trifluoro ethoxy) pyridine hydrochloride enters
Lansoprazole sulfide intermediate [[[3- methyl -4- (2,2,2- trifluoro ethoxies) -2- pyridine radicals] methyl] sulphur of one step generation
Base] -1H- benzimidazoles liquid phase spectrogram.
2- chloromethyl -3- methyl -4- (2,2,2- trifluoro ethoxies) pyridine hydrochloride prepared using the present invention is further
The Lansoprazole sulfide intermediate of generation detects data with the relevant material of the sulfide intermediate prepared using thionyl chloride technique
Contrast is as shown in table 6；Wherein, the 2- chloromethyl -3- methyl -4- (2,2,2- trifluoro ethoxy) prepared using thionyl chloride technique
Lansoprazole sulfide intermediate [[[3- methyl -4- (2,2,2- trifluoro ethoxies) -2- pyridines that pyridine hydrochloride is further generated
Base] methyl] sulfenyl] and -1H- benzimidazoles liquid phase spectrogram it is as shown in figure 22；
Table 6 using the Lansoprazole sulfide intermediate for preparing of the present invention with the middle of the thioether that is prepared using thionyl chloride technique
The data comparison of body
| Lansoprazole thioether | Thionyl chloride technique | Present invention process |
| It is single miscellaneous | 0.21% | 0.05% |
| It is total miscellaneous | 0.29% | 0.05% |
| Impurity number | 2 | 1 |
Embodiment 17 (preparation of Lansoprazole for injecting)
In 500mL there-necked flasks, by [[[3- methyl -4- (2,2,2- trifluoro ethoxy) -2- pyridine radicals] methyl] sulfenyl] -
1H- benzimidazoles (10.6g, 30mmol) are dissolved in ethyl acetate (200mL), are cooled to less than 5 DEG C, and m-chloro peroxide benzene first is added dropwise
Sour (6.9g, 40mmol) and ethyl acetate (80mL) mixed solution, completion of dropping are warming up to 20 DEG C and reacted 30 minutes.Reaction solution
Washed respectively with saturated sodium carbonate (100mL) and water (150mL), plus anhydrous sodium sulfate (5g) is dried.Filtering, filtrate evaporates 2/3
Ethyl acetate.0 DEG C is cooled to, suction filtration is dried to obtain Lansoprazole crude product；White solid is obtained through ethyl alcohol recrystallization, dry
Lansoprazole, product yield 80%.
Weigh Lansoprazole (30g), mannitol (60g), meglumine (10g) and appropriate sodium hydroxide and be dissolved in 2L waters for injection
In, stirring is to being completely dissolved.2g activated carbons are added, are stirred at room temperature 30 minutes, decarburization is filtered, filtrate is removed through 0.22 μm of miillpore filter
Bacterium is filtered.Bacteria-free filtrate is sub-packed in sterilizing cillin bottle by every bottle of 2mL, the block injection orchid of white loose is freeze-dried to obtain
Rope draws azoles；Relevant material detection is carried out according to high performance liquid chromatography (four general rules 0512 of Chinese Pharmacopoeia version in 2015), it is single miscellaneous
0.10%, total miscellaneous 0.16%.Wherein, Figure 23 is that 3- methyl -4- (2,2,2- trifluoro ethoxy) -2- chloromethyl pyridine hydrochlorides enter
Lansoprazole for injecting liquid phase spectrogram prepared by one step.
2- chloromethyl -3- methyl -4- (2,2,2- trifluoro ethoxies) pyridine hydrochloride prepared using the present invention is further
The Lansoprazole for injecting of preparation detects data with the relevant material of the Lansoprazole for injecting prepared using thionyl chloride technique
Contrast is as shown in table 7, wherein, the 2- chloromethyl -3- methyl -4- (2,2,2- trifluoro ethoxy) prepared using thionyl chloride technique
The Lansoprazole for injecting liquid phase spectrogram that pyridine hydrochloride is further prepared is as shown in figure 24.
The Lansoprazole for injecting that table 7 is prepared using the present invention and the injection Lan Suola prepared using thionyl chloride technique
The data comparison of azoles
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all essences in the present invention
Any modifications, equivalent substitutions and improvements made within refreshing and principle etc., should be included in the scope of the protection.
Claims (14)
1. the green technology that a kind of application substitutes the poisonous and harmful substances such as phosgene, thionyl chloride prepares high-purity drawing azole intermediate
Method, it is characterised in that comprise the following steps：By Ph3PO is dissolved in organic solvent and is placed in reaction bulb, and BTC, which is dissolved in, to be had
Machine solvent is put into constant pressure funnel and is added dropwise；After completion of dropping, insulation reaction, then azoles hydroxylate will be drawn；It is dissolved in organic solvent
In, under heating be added dropwise and insulation reaction for a period of time, during system separate out white solid；Stop after reaction, suction filtration is obtained
White solid, dries obtained key intermediate, that is, draws azoles chloride；After mother liquor fraction concentration Ph is separated out under low temperature3PO, Ph3PO is passed through
Small polar solvent washing continues to repeat to apply mechanically.
2. the green technology that application according to claim 1 substitutes the poisonous and harmful substances such as phosgene, thionyl chloride prepares height
The method that purity draws azole intermediate, it is characterised in that the organic solvent is selected from following a kind of or any several combination：First
Benzene, ethylbenzene, dimethylbenzene, tetrahydrofuran, 2- methyltetrahydrofurans, 1,2- dichloroethanes, dichloromethane, N, N- dimethyl formyls
Amine, N, N- diethylformamides, acetonitrile, benzonitrile, benzene acetonitrile, ethyl acetate, Ethyl formate, methyl formate, ethyl propionate, third
Ketone, butanone, MEK, ethylene glycol, ethanol, methanol, petroleum ether, ether, tertiary butyl ether, ethamine, triethylamine, 1,4- dioxane,
Dimethyl sulfoxide, hexamethylene；The small polar solvent is selected from one of following：Petroleum ether, n-hexane, ether, tertiary butyl ether.
3. the green technology that application according to claim 1 substitutes the poisonous and harmful substances such as phosgene, thionyl chloride prepares height
The method that purity draws azole intermediate, it is characterised in that the organic solvent is selected from one of following：Toluene, 1,2- dichloroethanes,
Dimethyl sulfoxide, tetrahydrofuran, 1,4- dioxane, acetonitrile.
4. it is prepared by the green technology that application according to claims 1 to 3 substitutes the poisonous and harmful substances such as phosgene, thionyl chloride
The method that high-purity draws azole intermediate, it is characterised in that the drawing azoles hydroxylate, BTC and Ph3PO mol ratio is 1.0:
(0.33-1.0):(0.8-1.5)。
5. it is prepared by the green technology that application according to claims 1 to 3 substitutes the poisonous and harmful substances such as phosgene, thionyl chloride
The method that high-purity draws azole intermediate, it is characterised in that draw azoles hydroxylate, BTC and Ph3PO mol ratio is 1.0:(0.33-
0.7):(1.0-1.2)。
6. it is prepared by the green technology that application according to claims 1 to 3 substitutes the poisonous and harmful substances such as phosgene, thionyl chloride
The method that high-purity draws azole intermediate, it is characterised in that the reaction is carried out under 25~100 DEG C of temperature conditionss, reaction
Time is 1.0~8.0 hours.
7. it is prepared by the green technology that application according to claims 1 to 3 substitutes the poisonous and harmful substances such as phosgene, thionyl chloride
The method that high-purity draws azole intermediate, it is characterised in that the reaction is carried out under 40~80 DEG C of temperature conditionss, during reaction
Between be 2.0~5.0 hours.
8. the green technology that application according to claim 1 substitutes the poisonous and harmful substances such as phosgene, thionyl chloride prepares height
The method that purity draws azole intermediate, it is characterised in that the drawing azoles hydroxylate is the 2- methylol pyrroles that different substituents replace
Piperidine derivatives, specially 3,4- dimethoxy -2- hydroxymethylpyridines, 4- methoxyl groups -3,5- dimethyl -2- hydroxymethylpyridines or 3-
Methyl -4- (2,2,2- trifluoro ethoxy) -2- hydroxymethylpyridines.
9. the green technology that application according to claim 8 substitutes the poisonous and harmful substances such as phosgene, thionyl chloride prepares height
The method that purity draws azole intermediate, it is characterised in that when the drawing azoles hydroxylate is 3,4- dimethoxy -2- hydroxymethylpyridines
When, it is 3,4- dimethoxy -2- hydroxymethylpyridine hydrochlorides to draw azoles chloride；Azoles hydroxylate is drawn to be 4- methoxyl group -3 when described,
During 5- dimethyl -2- hydroxymethylpyridines, it is 4- methoxyl group -3,5- dimethyl -2- chloromethyl pyridine hydrochlorides to draw azoles chloride；When
When the drawing azoles hydroxylate is 3- methyl -4- (2,2,2- trifluoro ethoxy) -2- hydroxymethylpyridines, it is 3- first to draw azoles chloride
Base -4- (2,2,2- trifluoro ethoxy) -2- hydroxymethylpyridine hydrochlorides.
10. the green technology that application according to claim 1 substitutes the poisonous and harmful substances such as phosgene, thionyl chloride prepares height
The method that purity draws azole intermediate, it is characterised in that specifically preparation process is：By Ph3PO is dissolved in organic solvent and is placed in instead
Answer in bottle, BTC is dissolved in organic solvent and is put into constant pressure funnel, 25- is warming up to after BTC, completion of dropping are added dropwise at room temperature
100℃；After insulation reaction 3-5 hours, azoles hydroxylate will be drawn to be dissolved in organic solvent, added and insulation reaction at 25-100 DEG C
1.0-8.0 hours, during separate out white solid, stop after reaction, suction filtration obtains white solid, is dried to obtain key intermediate
Draw azoles chloride；Ph is separated out under the concentrated rear 10-30 DEG C of low temperature of filtrate portion3PO, Ph3After PO is washed through small polar solvent, take out
Filter, drying, the Ph of acquisition3PO repeats to apply mechanically.
11. the application described in a kind of use the claims any one of 1-10 substitutes the venomous injurants such as phosgene, thionyl chloride
The drawing azole intermediate that the method that the green technology of matter prepares high-purity drawing azole intermediate is acquired further prepares drawing azole
The method of medicine, it is characterised in that comprise the following steps：
(1) sulfide intermediate is prepared
By the drawing azoles chloride, the 70-90 DEG C of temperature rising reflux in methanol or ethanol dissolves with sulfhydryl benzimidazole derivative, protects
After temperature reaction, sulfide intermediate is made after drying in evaporation solvent and suction filtration acquisition white solid；
(2) prepare and draw azole drug
Sulfide intermediate is dissolved in toluene, chloroform or ethyl acetate, hydrogen oxide diisopropylbenzene (DIPB) or m-chloro are added at -10-10 DEG C
Benzoyl hydroperoxide, after completion of the reaction extract and separate must draw azole bulk drug；Azole bulk drug and corresponding auxiliary material will be drawn, injection is added
After being dissolved with water, freeze-drying obtains white loose shape and draws azole drug.
12. the green technology according to claim 11 that the poisonous and harmful substances such as phosgene, thionyl chloride are substituted using application
The drawing azole intermediate that preparation high-purity draws the method for azole intermediate to acquire further prepares the side for drawing azole drug preparation
Method, it is characterised in that when the drawing azoles chloride is 3,4- dimethoxy -2- hydroxymethylpyridine hydrochlorides, sulfydryl benzo miaow
Zole derivatives are 5- difluoro-methoxy -2- sulfydryl -1H- benzimidazoles, and sulfide intermediate is 5- difluoro-methoxies -2- { [(3,4-
Dimethoxy-2-pyridinyl) methyl] sulphur } -1H- benzimidazoles, it is Pantoprazole Sodium or L-pantoprazole to draw azole bulk drug
Sodium, corresponding auxiliary material is natrium adetate or mannitol and natrium adetate, and the white loose shape drawing azole drug of final gained is
Pantoprazole sodium injection or injection Levpantoprazole Sodium.
13. the green technology according to claim 11 that the poisonous and harmful substances such as phosgene, thionyl chloride are substituted using application
The drawing azole intermediate that preparation high-purity draws the method for azole intermediate to acquire further prepares the side for drawing azole drug preparation
Method, it is characterised in that when the drawing azoles chloride is 4- methoxyl group -3,5- dimethyl -2- chloromethyl pyridine hydrochlorides, sulfydryl
Benzimidizole derivatives are 2- sulfydryl -5- methoxybenzimidazols, and sulfide intermediate is 5- methoxyl groups -2- (4- methoxyl groups -3,5-
Dimethyl -2- pyridine radicals) methyl thio -1H- benzimidazoles, it is Esomeprazole sodium to draw azole bulk drug, corresponding auxiliary material be according to
Ground acid disodium, the white loose shape of final gained draws azole drug to be injection Esomeprazole sodium.
14. the green technology according to claim 11 that the poisonous and harmful substances such as phosgene, thionyl chloride are substituted using application
The drawing azole intermediate that preparation high-purity draws the method for azole intermediate to acquire further prepares the side for drawing azole drug preparation
Method, it is characterised in that when the drawing azoles chloride is 3- methyl -4- (2,2,2- trifluoro ethoxy) -2- hydroxymethylpyridine hydrochloric acid
During salt, sulfhydryl benzimidazole derivative is 2-mercaptobenzimidazole, and sulfide intermediate is [[[3- methyl -4- (2,2,2- trifluoro second
Epoxide) -2- pyridine radicals] methyl] sulfenyl] -1H- benzimidazoles, it is Lansoprazole to draw azole bulk drug, and corresponding auxiliary material is mannitol
With meglumine, the white loose shape of final gained draws azole drug to be Lansoprazole for injecting.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710431500.4A CN107011252B (en) | 2017-06-09 | 2017-06-09 | The method for drawing azole intermediate and drug is prepared using the green technology for substituting the poisonous and harmful substances such as phosgene, thionyl chloride |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710431500.4A CN107011252B (en) | 2017-06-09 | 2017-06-09 | The method for drawing azole intermediate and drug is prepared using the green technology for substituting the poisonous and harmful substances such as phosgene, thionyl chloride |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107011252A true CN107011252A (en) | 2017-08-04 |
| CN107011252B CN107011252B (en) | 2018-06-08 |
Family
ID=59452369
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710431500.4A Active CN107011252B (en) | 2017-06-09 | 2017-06-09 | The method for drawing azole intermediate and drug is prepared using the green technology for substituting the poisonous and harmful substances such as phosgene, thionyl chloride |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107011252B (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108947967A (en) * | 2018-08-24 | 2018-12-07 | 威海迪素制药有限公司 | A kind of preparation method of Lansoprazole |
| CN111153869A (en) * | 2020-01-19 | 2020-05-15 | 浙江新和成股份有限公司 | Method for preparing oxazole compound |
| CN111909088A (en) * | 2020-08-04 | 2020-11-10 | 浙江工业大学 | Utilizing BTC/Ph3Method for preparing isoquinoline hydrochloride intermediate and Rho kinase inhibitor by PO chloro system |
| CN112707889A (en) * | 2020-06-15 | 2021-04-27 | 南京国星生物技术研究院有限公司 | Synthesis method of lansoprazole |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1660862A (en) * | 2004-12-23 | 2005-08-31 | 浙江大学 | Method for synthesizing triphenyl phosphine dichloride |
| CN103044415A (en) * | 2012-12-17 | 2013-04-17 | 浙江华方药业有限责任公司 | Synthesis method for aztreonam |
| CN103232389A (en) * | 2013-05-08 | 2013-08-07 | 浙江新三和医药化工股份有限公司 | Preparation method of 2-chloromethyl-4-methoxyl-3,5-dimethyl pyridine hydrochloride |
| CN103664750A (en) * | 2013-12-09 | 2014-03-26 | 惠州市莱佛士制药技术有限公司 | Synthetic method of prazole chloride |
-
2017
- 2017-06-09 CN CN201710431500.4A patent/CN107011252B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1660862A (en) * | 2004-12-23 | 2005-08-31 | 浙江大学 | Method for synthesizing triphenyl phosphine dichloride |
| CN103044415A (en) * | 2012-12-17 | 2013-04-17 | 浙江华方药业有限责任公司 | Synthesis method for aztreonam |
| CN103232389A (en) * | 2013-05-08 | 2013-08-07 | 浙江新三和医药化工股份有限公司 | Preparation method of 2-chloromethyl-4-methoxyl-3,5-dimethyl pyridine hydrochloride |
| CN103664750A (en) * | 2013-12-09 | 2014-03-26 | 惠州市莱佛士制药技术有限公司 | Synthetic method of prazole chloride |
Non-Patent Citations (1)
| Title |
|---|
| 傅超美等: "《质子泵抑制剂》", 29 February 2008, 中国中医药出版社 * |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108947967A (en) * | 2018-08-24 | 2018-12-07 | 威海迪素制药有限公司 | A kind of preparation method of Lansoprazole |
| CN108947967B (en) * | 2018-08-24 | 2020-10-30 | 迪嘉药业集团有限公司 | Preparation method of lansoprazole |
| CN111153869A (en) * | 2020-01-19 | 2020-05-15 | 浙江新和成股份有限公司 | Method for preparing oxazole compound |
| CN111153869B (en) * | 2020-01-19 | 2021-06-01 | 浙江新和成股份有限公司 | Method for preparing oxazole compound |
| CN112707889A (en) * | 2020-06-15 | 2021-04-27 | 南京国星生物技术研究院有限公司 | Synthesis method of lansoprazole |
| CN112707889B (en) * | 2020-06-15 | 2024-02-06 | 江苏中邦制药有限公司 | Synthesis method of lansoprazole |
| CN111909088A (en) * | 2020-08-04 | 2020-11-10 | 浙江工业大学 | Utilizing BTC/Ph3Method for preparing isoquinoline hydrochloride intermediate and Rho kinase inhibitor by PO chloro system |
| CN111909088B (en) * | 2020-08-04 | 2022-03-01 | 浙江工业大学 | Method for preparing isoquinoline hydrochloride intermediate and Rho kinase inhibitor by using BTC/Ph3PO chloro-system |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107011252B (en) | 2018-06-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107011252A (en) | The method for drawing azole intermediate and medicine is prepared using the green technology for substituting the poisonous and harmful substances such as phosgene, thionyl chloride | |
| DE602004011806T2 (en) | USE OF TRICYCLIC COMPOUNDS AS INHIBITORS OF GLYCIN TRANSPORT | |
| CN103415513B (en) | The benzo dioxane inhibitor of leukotriene product | |
| CN107540594A (en) | The substituted formamide of pyrrolidines 2 | |
| CN102171183A (en) | Organic compounds | |
| EP2465852A1 (en) | Capped pyrazinoylguanidine sodium channel blockers | |
| CN107428727A (en) | Novel crystal forms of HKI-272 maleate and preparation method thereof | |
| Lusic et al. | A new photocaging group for aromatic N-heterocycles | |
| CN107188813A (en) | Phenethanolamine derivative and its production and use | |
| CN114507235A (en) | Compound capable of degrading BTK kinase, preparation method and pharmaceutical application thereof | |
| CN107235959A (en) | A kind of novel method for synthesizing for preparing cancer therapy drug Niraparib | |
| CN113149962A (en) | Preparation method and application of probe molecule containing photoaffinity group bisaziridine | |
| CN107200734A (en) | Quinuclidine derivatives and its production and use | |
| CN106928191B (en) | A kind of preparation process of Lansoprazole | |
| CN106632306A (en) | Amorphous dexrabeprazole sodium and preparation method thereof | |
| CN103502240B (en) | Azole derivatives | |
| CN113248473B (en) | Preparation and medical application of targeted GSK3 alpha/beta degradation agent | |
| CN107163045A (en) | The preparation method of piperidines with platelet aggregation-against function and the triazole compound of pyrido 1,2,3 | |
| CN110590747B (en) | Compound, preparation method, pharmaceutical composition and application thereof | |
| CN108373469A (en) | Diaryl second diether compound and its pharmaceutically acceptable hydrate or salt, synthetic method and its application on antitumor | |
| CN106800539A (en) | A kind of acotiamide hydrochloride hydrate intermediate and its synthesis technique and application | |
| CN107235973A (en) | The preparation method of the adjoining fluorobenzene calcium composition of piperidones chain with pharmaceutical activity | |
| EP2670745B1 (en) | Spiro aminic compounds with nk1 antagonist activity | |
| Thomaidi et al. | Local anesthetics via multicomponent reactions | |
| CN107266444A (en) | The preparation method of piperidines with pharmaceutical activity and pyridine calcium composition |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |