CN108912018A - The preparation method and its usage of impurity compound in a kind of key intermediate for synthesizing Sulpiride - Google Patents
The preparation method and its usage of impurity compound in a kind of key intermediate for synthesizing Sulpiride Download PDFInfo
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- CN108912018A CN108912018A CN201810811170.6A CN201810811170A CN108912018A CN 108912018 A CN108912018 A CN 108912018A CN 201810811170 A CN201810811170 A CN 201810811170A CN 108912018 A CN108912018 A CN 108912018A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
- C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
- C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
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Abstract
The invention belongs to pharmaceutical technology fields, more particularly in a kind of key intermediate for synthesizing Sulpiride impurity compound preparation method and its usage, the impurity compound can be by the way that compound ii and compound III to be placed in solvent, it is obtained through condensation reaction, or by the way that compounds Ⅳ is refined, filtrate is taken to obtain or separate from compounds Ⅳ, purifying obtains, the standard items of impurity compound produced by the present invention can be used for the analysis of impurity in Sulpiride key intermediate drug, detection, solves the technical problem that there is no the impurity compound and its acceptable salt standard items of other forms that use as analysis of control at present, to improve and ensure the drug safety of Sulpiride.
Description
Technical field
The invention belongs to impurity chemical combination in pharmaceutical technology field more particularly to a kind of key intermediate for synthesizing Sulpiride
The preparation method and its usage of object.
Background technique
Sulpiride (sulpiride), entitled N- ((1- ethyl -2- pyrrolidinyl) the methyl) -2- methoxyl group -5- (ammonia of chemistry
Base sulfonyl) benzamide, there is formula (V) structure, be a kind of strongly active d2 dopamine receptor blocking agent.1967 by method
Compatriots' synthesis, then in the multinational listing in the world.Sulpiride has the function of depression and treatment phrenoblabia, due to its anti-essence
Refreshing disease effect is strong, and adverse reaction is few, has at home and abroad clinically used for many years.
It is miscellaneous in the quality requirement and pharmaceutical raw material medicine to drug with the continuous improvement that people require drug safety
Matter is both needed to further clear and control, therefore miscellaneous Quality Research becomes the weight of those skilled in the art's research in pharmaceutical raw material medicine
Point.
The synthetic route of Sulpiride following (Chinese Journal of Pharmaceuticals, 1999,27 (11) currently on the market：487-488)：
The route is at low cost, every step yield is relatively high.
Sulpiride synthetic route
But the key intermediate (compounds Ⅳ) for preparing Sulpiride is unstable during the preparation process, is also easy to produce impurity, at present
It there is no report and the record of its related impurities.
Summary of the invention
For above situation, impurity compound in the key intermediate that the present invention provides a kind of for synthesizing Sulpiride
Preparation method and its usage.
The present invention provides a kind of compound, chemical structural formula is as follows：
It is a further object of the present invention to provide a kind of preparation methods of above compound, and compound ii and compound III are set
It in solvent, is obtained through condensation reaction, reaction route is as follows：
Further, the halogenated alkanes of the solvent, alcohols, ketone, alkanes, one or more in tetrahydrofuran.
Further, preparation method is：Compound ii and compound III are dissolved in methylene chloride, triethylamine, room temperature is added
Stirring by product washing, is concentrated to dryness to obtain grease, water, which is added, is precipitated solid, by solid filtering, leaching to fully reacting
Wash, dry both chemical compounds I.
Further, the molar ratio of compound ii and compound III is 1:(0.4-1.8).
It is a further object of the present invention to provide a kind of preparation methods of above compound, by being separated from compounds Ⅳ,
Purifying obtains, and the chemical structural formula of the compounds Ⅳ is as follows：
Further, the compounds Ⅳ separation, purification process include any one of recrystallization, preparative liquid phase separation
Or it is a variety of.
Further, in the method for the recrystallization, the solvent used includes methanol, ethyl alcohol, normal propyl alcohol, isopropanol, just
Butanol, acetone, DMF, DMSO, acetonitrile are any one or more of.
Further, the method for the preparative liquid phase separation is：Using methanol-water, acetonitrile-water, methanol-acetonitrile-water
It is any one or more of to be used as mobile phase, isocratic or gradient elution is carried out, product fraction is collected, is evaporated or is freeze-dried.
It is a further object of the present invention to provide above compounds in the impurity research of Sulpiride intermediate or contamination levels product
And the application in reference substance.
It is a further object of the present invention to provide a kind of standard items, the standard items include above compound, compound it is pure
Degree is 90%-99%.
According to the above aspect of the present invention, the present invention has at least the following advantages：The control of impurity compound (i.e. I compound represented of formula)
Make most important in Sulpiride preparation process, not can control in key intermediate (compounds Ⅳ) such as, can next step with
1- ethyl-2-aminomethyl nafoxidine is reacted, and is introduced into Sulpiride finished product, can be impacted to the quality of bulk pharmaceutical chemicals, and
And since structure is close, it is not easy to remove.The standard items of impurity compound made from preparation method proposed by the present invention can be used for relaxing
Must in sharp key intermediate drug impurity analysis, detection, solve and there is no the impurity chemical combination used as analysis of control at present
The technical problem of object and its acceptable salt standard items of other forms, to improve and ensure the drug safety of Sulpiride.
Detailed description of the invention
Fig. 1 is chemical compounds I in embodiment 11H-NMR figure.
Fig. 2 is chemical compounds I in embodiment 113C-NMR figure.
Fig. 3 is the MS figure of chemical compounds I in embodiment 1.
Fig. 4 is the HPLC figure of chemical compounds I in embodiment 3.
Fig. 5 is the HPLC figure of compounds Ⅳ in embodiment 3.
Specific embodiment
Compound ii is purchased from lark prestige Science and Technology Ltd..
Compound III preparation method referring to Sulpiride synthetic route：The conjunction of peak Sulpiride is stepped on by Wang Fulan, Li Guiling, Tang
At, Chinese Journal of Pharmaceuticals, 1999,27 (11)：487-488.
Compounds Ⅳ is the key intermediate for synthesizing Sulpiride, synthesizes the route reference literature of Sulpiride：Wang Fulan, Li Gui
The synthesis of peak Sulpiride, Chinese Journal of Pharmaceuticals, 1999,27 (11) are stepped on by the tinkling of pieces of jade, Tang：487-488.
Embodiment 1
Compound ii 5.32g and compound III 3.09g are added in reaction flask, 20ml methylene chloride is added, has dissolved
Quan Hou, is added 1.50g triethylamine, and 20 DEG C of stir about 5h fully reactings are purified water washing 2 times using 50ml, are concentrated to dryness
Grease is obtained, 30ml purifying water solid is added and is largely precipitated, solid filtering is eluted using purified water 10ml, dries and both obtained
4.32g chemical compounds I.Yield 80%, using HPLC peak area normalization method, measuring its content is 97.175%
The chemical structural formula of chemical compounds I is：
The structural characterization figure of chemical compounds I is shown in Fig. 1-3.
Structure elucidation：
It can be seen that δ 3.772ppm, δ 3.829ppm, δ 3.974ppm are methyl hydrogen H-16/H-8/H- from Fig. 1 hydrogen spectrum
17；There are eight hydrogen in phenyl ring hydrogen region, wherein there are six phenyl ring hydrogen and two NH2Hydrogen, respectively H-3, H-4, H-6, H-14, H-
15, H-11 and H-9；δ 8.249-8.254ppm should be H-6；δ 8.063-8.072ppm should be H-11；δ 8.050-8.055ppm is answered
For H-15；δ 7.958-7.981ppm should be H-4；δ 7.622ppm should be H-9；δ 7.419-7.451ppm should be H-3/14；From hydrogen
Spectrum is it is found that each chemical shift of proton of sample and splitting point situation and being consistent with chemical compounds I structure.
From Fig. 2 carbon spectrum it can be seen that δ 164.59ppm is C-16；δ 163.82ppm should be as C-7；δ 163.46ppm should be
C-13；δ 149.03ppm is C-2；δ 143.68ppm is C-10；δ 134.41ppm is C-5；δ 131.75ppm is C-15；δ
131.73ppm is C-4；δ 129.64ppm is C-6；δ 126.07ppm should be as C-11；δ 125.54ppm should be C-3；δ
125.18ppm is C-1；δ 121.19ppm is C-12；δ 114.49ppm is C-14；δ 57.40ppm is C-18；δ 53.24ppm is
C-8；δ 53.00ppm is C-17.It was found from carbon spectrum：Each carbon chemical shifts situation of sample is consistent with chemical compounds I structure.
It can be seen that mass spectrum shows that molecular weight is m/z=458.0223 [M-H] from Fig. 3 mass spectrum-With the molecular weight of chemical compounds I
(C17H17NO10S2) calculated value 459.0294 meet.
Embodiment 2
By the synthetic method of Sulpiride, (synthesis of peak Sulpiride is stepped on by Wang Fulan, Li Guiling, Tang, and Chinese Medicine industry is miscellaneous
Will, 1999,27 (11)：It 487-488) is prepared into compounds Ⅳ, takes compounds Ⅳ 5.3g, is divided using preparative efficient liquid phase
From mobile phase used is acetonitrile-water (v:V=1:1), Detection wavelength 240nm, flow velocity 10ml/min, sample are infused by 30 DEG C of column temperature
Enter chromatograph, collect corresponding efflux, merges product fraction and receive product fraction, being concentrated to dryness after merging must both change
I 20mg of object is closed, is white solid, using HPLC peak area normalization method, measuring its content is 96.305%.
Embodiment 3
Chemical compounds I is in the defects inspecting of Sulpiride key intermediate 3 (compounds Ⅳ) as the application of reference substance
The preparation of chemical compounds I reference substance solution：
The chemical compounds I for taking above-described embodiment 1 to prepare is appropriate, is placed in 20ml volumetric flask, and acetonitrile solution, acetonitrile is added：
Water=15:85(v:V), it is diluted to scale, ultrasound shakes up, the solution of every 1ml about 1mg containing chemical compounds I is made, as impurity pair
According to solution.
The preparation of test solution：
(synthesis of peak Sulpiride, Chinese Medicine are stepped on to the synthetic method for taking by above-mentioned by Sulpiride by Wang Fulan, Li Guiling, Tang
Industrial magazine, 1999,27 (11)：It is appropriate 487-488) to be prepared into compounds Ⅳ sample, is placed in 20ml volumetric flask, acetonitrile is added
Aqueous solution, acetonitrile：Water=15:85(v:V), it is diluted to scale, ultrasonic solvent is complete, shakes up, and every 1ml is made and contains compounds Ⅳ about
The solution of 1mg, as test solution.
Chromatographic condition is as follows：
It is filler with octadecylsilane chemically bonded silica；Potassium dihydrogen phosphate 4.8g is weighed to carry out using 1000ml purified water
Dissolution is 2.0 using phosphorus acid for adjusting pH, as potassium dihydrogen phosphate buffer solution；With potassium dihydrogen phosphate buffer solution-acetonitrile (80:
It 20) is mobile phase A, potassium dihydrogen phosphate buffer solution-acetonitrile (15:It 85) is Mobile phase B.It is eluted by table 1：
Table 1
Experimental procedure：Above-mentioned impurity contrast solution and test solution are taken, is injected separately into liquid chromatograph (purchased from the day island proper
Saliva company, model：LC-20AT), record liquid chromatogram is carried out, carries out calculating impurity content by area normalization method；Impurity pair
See that Fig. 4, the HPLC figure of test solution are shown in Fig. 5 according to the HPLC figure of solution.
The interpretation of result of test sample is shown in Table 2：
Table 2
As can be seen from Table 2, chemical compounds I is maximum contaminant in test sample；Regular course is in production prepare compound at present
The impurity can be generated during IV, and the impurity can be introduced in next step and can further be reacted, causing influence finished product to relax must
The quality of benefit sufficiently demonstrates in Sulpiride to the necessity of chemical compounds I research.
Although the present invention has been described by way of example and in terms of the preferred embodiments, it is not intended to limit the invention, any to be familiar with this skill
The people of art can do various change and modification, therefore protection model of the invention without departing from the spirit and scope of the present invention
Enclosing subject to the definition of the claims.
Claims (10)
1. a kind of compound, it is characterised in that：Its chemical structural formula is as follows：
2. the preparation method of compound described in claim 1, it is characterised in that：Compound ii and compound III are placed in solvent
It is interior, it is obtained through condensation reaction, reaction route is as follows：
3. preparation method according to claim 2, it is characterised in that：The solvent include halogenated alkanes, alcohols, ketone,
It is one or more in alkanes, tetrahydrofuran.
4. preparation method according to claim 2, it is characterised in that：Preparation method is：By compound ii and compound III
It is dissolved in methylene chloride, triethylamine is added, is stirred at room temperature to fully reacting, by product washing, grease is concentrated to dryness to obtain, adds
Entering water is precipitated solid, solid is filtered, is eluted, dry both chemical compounds I.
5. the preparation method of compound described in claim 1, it is characterised in that：It is separated from compounds Ⅳ, purifying obtains, institute
The chemical structural formula for stating compounds Ⅳ is as follows：
6. preparation method according to claim 5, it is characterised in that：The compounds Ⅳ separation, purification process include weight
Crystallization, preparative liquid phase separation are any one or more of.
7. preparation method according to claim 6, it is characterised in that：The method of the preparative liquid phase separation is：Using
Methanol-water, acetonitrile-water, methanol-acetonitrile-water are any one or more of to be used as mobile phase, carries out isocratic or gradient elution, receives
Collect product fraction, is evaporated or is freeze-dried.
8. preparation method according to claim 5, it is characterised in that：In the method for the recrystallization, the solvent packet that uses
It is any one or more of to include methanol, ethyl alcohol, normal propyl alcohol, isopropanol, n-butanol, acetone, DMF, DMSO, acetonitrile.
9. a kind of standard items, it is characterised in that：The standard items include compound described in claim 1 or claim 2-8
The compound being prepared, the purity of the compound are 90%-99%.
10. the compound that compound described in claim 1 or claim 2-8 are prepared is in the impurity of Sulpiride intermediate
Application in research or contamination levels product and reference substance.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114965749A (en) * | 2022-04-28 | 2022-08-30 | 南京海纳医药科技股份有限公司 | Detection method of related substances in sulpiride bulk drug |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114965749A (en) * | 2022-04-28 | 2022-08-30 | 南京海纳医药科技股份有限公司 | Detection method of related substances in sulpiride bulk drug |
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