CN111925281B - Preparation method of penehyclidine hydrochloride impurity 2-cyclopentyl-2-phenylacetaldehyde - Google Patents
Preparation method of penehyclidine hydrochloride impurity 2-cyclopentyl-2-phenylacetaldehyde Download PDFInfo
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- CN111925281B CN111925281B CN202010926372.2A CN202010926372A CN111925281B CN 111925281 B CN111925281 B CN 111925281B CN 202010926372 A CN202010926372 A CN 202010926372A CN 111925281 B CN111925281 B CN 111925281B
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Abstract
The invention belongs to the technical field of medicines, and particularly relates to a preparation method of penehyclidine hydrochloride impurity 2-cyclopentyl-2-phenylacetaldehyde. The method for preparing the 2-cyclopentyl-2-phenyl acetaldehyde by using the chromatographic silica gel is simple to operate, has low cost, does not need any reaction, finishes the preparation of the product by aging and eluting in the silica gel column, finishes the ring-opening reaction without using a noble catalyst, and has good economic value.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a preparation method of penehyclidine hydrochloride impurity 2-cyclopentyl-2-phenylacetaldehyde.
Background
Penehyclidine hydrochloride is an anticholinergic drug of an M receptor antagonist with a novel structure, and has the chemical name: 3- (2-cyclopentyl-2-hydroxy-2-phenylethoxy) quinuclidine hydrochloride having the following structural formula:
in the prior art, the penehyclidine hydrochloride is used for emergency treatment of organophosphorus toxicant (pesticide) poisoning, maintaining atropine after poisoning later or after cholinesterase (ChE) aging, is more successfully applied to clinical application of drug administration before anesthesia to inhibit secretion of salivary glands and airway glands, and has wide application range. According to various preclinical researches, the penehyclidine hydrochloride also has stronger safety, is mainly reflected in that no potential toxicity exists on all systems and target organs of the whole body, and has the characteristics of good tolerance, strong pharmacological action and the like. At present, the pharmaceutical composition is widely popularized in clinical fields of respiratory diseases, cardiovascular diseases and the like, for example, the application of the penehyclidine hydrochloride in pharmacy disclosed in patent document CN200510088052.X, the application of the penehyclidine hydrochloride in medicines for treating hemorrhagic shock diseases disclosed in patent document CN200910058142.2 and the like. The medicine is solely marketed by the special medicine of Yongtongshi GmbH in 1999 under the trade name of Changtuoning, is widely used for emergency treatment of organophosphorus toxicant and pre-anesthesia medicine administration in clinic, and is researched and sold by a plurality of enterprises in China at present.
CN110343036 uses phenyl cyclopentyl oxirane as a raw material, indium chloride is used for ring opening in tetrahydrofuran, and then column chromatography purification is carried out, so that the method is complex, precious metals are used, and the cost is high.
At present, with increasingly strict and standard impurity research requirements of China on the research of impurities in the research and development of drugs, the research of the impurities is controlled within a safe and reasonable limit range, and the quality and the safety of the penehyclidine hydrochloride are directly related, based on the aim, the synthetic significance of 2-cyclopentyl-2-phenyl acetaldehyde is very important, and in the actual operation process, the synthesis of 2-cyclopentyl-2-phenyl acetaldehyde can effectively provide a reference substance for qualitative and quantitative analysis for the detection of finished products of the penehyclidine hydrochloride, so that the quality standard of the penehyclidine hydrochloride is improved, and the guarantee is provided for the safe medication of the penehyclidine hydrochloride.
Disclosure of Invention
The invention aims to provide a method suitable for preparing 2-cyclopentyl-2-phenylacetaldehyde.
A preparation method of penehyclidine hydrochloride impurity 2-cyclopentyl-2-phenylacetaldehyde,
the reaction formula is as follows:
the method comprises the following steps:
A. sample dissolving: dissolving 2-cyclopentyl-2-phenyl ethylene oxide in a proper amount of petroleum ether or an eluant, wherein the eluant is a mixed solution of petroleum ether and ethyl acetate;
B. column assembling: weighing column chromatography silica gel, adding petroleum ether for homogenate, pouring into a glass column for sedimentation, wherein the mass ratio of the stationary phase silica gel to the 2-cyclopentyl-2-phenyl ethylene oxide in the step B is 10-30: 1;
C. aging: adding the dissolved sample into a glass column for aging for 12-48 hours;
D. and (3) elution: adding mixed solution of petroleum ether and ethyl acetate for elution, collecting the product, and evaporating the collected liquid under reduced pressure to obtain 2-cyclopentyl-2-phenylacetaldehyde.
In the preparation method, the volume ratio of the petroleum ether or the eluent to the 2-cyclopentyl-2-phenyl oxirane in the step A is 1-5: 1.
In the preparation method, the mass ratio of the stationary phase silica gel to the 2-cyclopentyl-2-phenyl oxirane in the step B is 20-30: 1.
In the above preparation method, the aging time in the step C is 12 to 36 hours.
In the preparation method, the volume ratio of the petroleum ether to the ethyl acetate in the step D is 30-100: 1.
In the preparation method, the reduced pressure evaporation in the step D is carried out at 30-50 ℃.
In the preparation method, the volume ratio of the petroleum ether or the eluent to the 2-cyclopentyl-2-phenyl oxirane in the step A is 1-2: 1.
In the above preparation method, the aging time in the step C is 24 to 36 hours.
In the preparation method, the volume ratio of the petroleum ether to the ethyl acetate in the step D is 30-60: 1.
In the preparation method, the volume ratio of the petroleum ether to the ethyl acetate in the step D is 35-40: 1.
Compared with the prior art, the invention has the following advantages and beneficial effects:
the method provided by the invention is mainly applied to the detection process of the finished product of the penehyclidine hydrochloride, can effectively provide a reference substance for qualitative and quantitative analysis for the detection of the finished product of the penehyclidine hydrochloride, achieves the purpose of improving the quality standard of the penehyclidine hydrochloride, and simultaneously can provide guarantee for safe medication of the penehyclidine hydrochloride, and the practicability is strong.
The method for synthesizing the impurity reference substance 2-cyclopentyl-2-phenyl acetaldehyde has the advantages of easily obtained synthetic raw materials, column chromatography aging, simple operation, low cost, no need of any reaction, aging in a silica gel column, elution to complete the preparation of the product, no need of using a noble catalyst to complete a ring-opening reaction, and good economic value.
Drawings
FIG. 1 is a High Performance Liquid Chromatogram (HPLC) of 2-cyclopentyl-2-phenylacetaldehyde prepared in example 1.
Detailed Description
The present invention will be described in detail below with reference to specific embodiments and drawings, in order to make the advantages of the present invention more detailed, but not limiting the present invention. It will be appreciated by those skilled in the art that the present invention is not limited to these examples and preparation methods used, and any equivalent substitutions, combinations, modifications or alterations to the present invention are intended to be included within the scope of the present invention.
The 2-cyclopentyl-2-phenyloxirane used in the invention is a penehyclidine hydrochloride intermediate, can be purchased from commercial products, and can also be synthesized by the prior art.
The column chromatography silica gel (refined) is from Qingdao ocean chemical Co., Ltd, and comprises the following main components: silica, product index: the model is as follows: specification 3, particle size 100-200 mesh, pH (10% aqueous suspension) - - -6.0-7.0.
Examples 1,
A preparation method of penehyclidine hydrochloride impurity 2-cyclopentyl-2-phenylacetaldehyde comprises the following steps:
(1) 14g of 2-cyclopentyl-2-phenyloxirane was taken, and 25ml of petroleum ether: and dissolving the mixture in an eluent with the ratio of ethyl acetate to 50:1 for later use.
(2) 300g of column chromatography silica gel (100-.
(3) The dissolved sample was added to a glass column and aged for 24 hours.
(4) Using petroleum ether: eluting with 50:1 mixed solvent, collecting target point, and evaporating under reduced pressure to obtain 2-cyclopentyl-2-phenylacetaldehyde as colorless oil 11.6g, with yield of 82.8% and purity of 99.1%, and HPLC shown in figure 1.
1H NMR(500MHz，CDCl3)：δH 9.678,9.684(d，J＝3.01Hz，1H)，7.195-7.359(m，5H)，3.280-3.307(dd，J＝13.49Hz,J＝3.02Hz,1H)，1.949-2.540(m，1H)，1.048-1.679(m，8H)。
13C NMR(125MHz，CDCl3)：δC 200.685，136.259，129.055，128.885，127.394，65.261，40.303，31.054，30.715，25.206，24.475ppm。
Examples 2,
A preparation method of penehyclidine hydrochloride impurity 2-cyclopentyl-2-phenylacetaldehyde comprises the following steps:
(1) 15g of 2-cyclopentyl-2-phenyloxirane was taken, and 25ml of petroleum ether: and dissolving the mixture in an eluent with the ratio of ethyl acetate to 50:1 for later use.
(2) Adding 300g of 100-200 mesh column layer chromatography silica gel into 2L petroleum ether, stirring uniformly, adding into a glass chromatography column for settling, and pressurizing to compact the column.
(3) The dissolved sample was added to a glass column and aged for 30 hours.
(4) Using petroleum ether: eluting with a mixed solvent of ethyl acetate 50:1, collecting target fractions, and evaporating to dryness under reduced pressure to obtain 2-cyclopentyl-2-phenylacetaldehyde as a colorless oil 12g, with a yield of 80% and a purity of 98.3%.
Examples 3,
A preparation method of penehyclidine hydrochloride impurity 2-cyclopentyl-2-phenylacetaldehyde comprises the following steps:
(1) 16g of 2-cyclopentyl-2-phenyloxirane was taken, and 25ml of petroleum ether: and dissolving the mixture in an eluent with the ratio of ethyl acetate to 50:1 for later use.
(2) Adding 300g of 100-200 mesh column layer chromatography silica gel into 2L petroleum ether, stirring uniformly, adding into a glass chromatography column for settling, and pressurizing to compact the column.
(3) The dissolved sample was added to a glass column and aged for 36 hours.
(4) Using petroleum ether: the ethyl acetate 50:1 mixed solvent was eluted, the desired fractions were collected and evaporated to dryness under reduced pressure to give 2-cyclopentyl-2-phenylacetaldehyde as a colorless oil 13.5g, yield 84.3% and purity 98.9%.
Examples 4,
A preparation method of penehyclidine hydrochloride impurity 2-cyclopentyl-2-phenylacetaldehyde comprises the following steps:
(1) 14g of 2-cyclopentyl-2-phenyloxirane was taken, and 25ml of petroleum ether: and dissolving the mixture in an eluent with the ratio of ethyl acetate to 30:1 for later use.
(2) Adding 300g of 100-200 mesh column layer chromatography silica gel into 2L petroleum ether, stirring uniformly, adding into a glass chromatography column for settling, and pressurizing to compact the column.
(3) The dissolved sample was added to a glass column and aged for 12 hours.
(4) Using petroleum ether: the ethyl acetate-30: 1 mixed solvent was eluted, the desired fractions were collected and evaporated to dryness under reduced pressure to give 2-cyclopentyl-2-phenylacetaldehyde as a colorless oil (11.6 g), in 82.8% yield and 99.02% purity.
Examples 5,
A preparation method of penehyclidine hydrochloride impurity 2-cyclopentyl-2-phenylacetaldehyde comprises the following steps:
(1) 14g of 2-cyclopentyl-2-phenyloxirane was taken, and 25ml of petroleum ether: and dissolving the mixture in an eluent with the ratio of 100:1 for later use.
(2) Adding 300g of 100-200 mesh column layer chromatography silica gel into 2L petroleum ether, stirring uniformly, adding into a glass chromatography column for settling, and pressurizing to compact the column.
(3) The dissolved sample was added to a glass column and aged for 48 hours.
(4) Using petroleum ether: the ethyl acetate-100: 1 mixed solvent was eluted, the desired fractions were collected and evaporated to dryness under reduced pressure to give 2-cyclopentyl-2-phenylacetaldehyde as a colorless oil (11.7 g), in 83.0% yield and 98.7% purity.
Examples 6,
HPLC detection method for 2-cyclopentyl-2-phenylacetaldehyde
Concentration of the test solution: 1mg/ml (acetonitrile)
The checking method comprises the following steps: high performance liquid chromatography 0512 of the four-part general rules of China pharmacopoeia 2015 edition
The test conditions are as follows: c18 column (specification: length 250mm, inner diameter 4.6mm, filler particle size 5 μm)
A detector: UV detector
Detection wavelength: 210nm
Column temperature: 35 deg.C
Flow rate: 1.5ml/min
Mobile phase A: acetonitrile-water (40:60)
Mobile phase B acetonitrile-water (80:20)
Gradient elution time program as follows:
wherein 20. mu.l of the test sample (example 1) solution was precisely measured, injected into a liquid chromatograph, and the chromatogram was recorded. If an impurity peak exists in the chromatogram of the test solution, the purity is 99.1 percent according to the calculation of a peak area normalization method.
Claims (10)
1. A preparation method of penehyclidine hydrochloride impurity 2-cyclopentyl-2-phenylacetaldehyde is characterized by comprising the following steps:
A. sample dissolving: dissolving 2-cyclopentyl-2-phenyl ethylene oxide in a proper amount of petroleum ether or an eluant, wherein the eluant is a mixed solution of petroleum ether and ethyl acetate;
B. column assembling: weighing column chromatography silica gel, adding petroleum ether for homogenate, pouring into a glass column for sedimentation, wherein the mass ratio of the stationary phase silica gel to the 2-cyclopentyl-2-phenyl ethylene oxide in the step B is 10-30: 1;
C. aging: adding the dissolved sample into a glass column for aging for more than 12 hours;
D. and (3) elution: adding mixed solution of petroleum ether and ethyl acetate for elution, collecting the product, and evaporating the collected liquid under reduced pressure to obtain 2-cyclopentyl-2-phenylacetaldehyde.
2. The preparation method of penehyclidine hydrochloride impurity 2-cyclopentyl-2-phenylacetaldehyde according to claim 1, wherein the volume ratio of petroleum ether or eluent to 2-cyclopentyl-2-phenyloxirane in the step A is 1-5: 1.
3. The preparation method of penehyclidine hydrochloride impurity 2-cyclopentyl-2-phenylacetaldehyde according to claim 1, wherein the mass ratio of stationary phase silica gel to 2-cyclopentyl-2-phenyloxirane in the step B is 20-30: 1.
4. The method for preparing penehyclidine hydrochloride impurity 2-cyclopentyl-2-phenylacetaldehyde according to claim 1, wherein the aging time in the step C is 12-36 hours.
5. The preparation method of penehyclidine hydrochloride impurity 2-cyclopentyl-2-phenylacetaldehyde according to claim 1, wherein the volume ratio of petroleum ether to ethyl acetate in the step D is 30-100: 1.
6. The preparation method of penehyclidine hydrochloride impurity 2-cyclopentyl-2-phenylacetaldehyde according to claim 1, wherein the reduced pressure evaporation in step D is performed at 30-50 ℃.
7. The preparation method of penehyclidine hydrochloride impurity 2-cyclopentyl-2-phenylacetaldehyde according to claim 2, wherein the volume ratio of petroleum ether or eluent to 2-cyclopentyl-2-phenyloxirane in the step A is 1-2: 1.
8. The method for preparing penehyclidine hydrochloride impurity 2-cyclopentyl-2-phenylacetaldehyde according to claim 4, wherein the aging time in the step C is 24-36 hours.
9. The preparation method of penehyclidine hydrochloride impurity 2-cyclopentyl-2-phenylacetaldehyde according to claim 5, wherein the volume ratio of petroleum ether to ethyl acetate in the step D is 30-60: 1.
10. The preparation method of penehyclidine hydrochloride impurity 2-cyclopentyl-2-phenylacetaldehyde according to claim 9, wherein the volume ratio of petroleum ether to ethyl acetate in the step D is 35-40: 1.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5691373A (en) * | 1993-08-19 | 1997-11-25 | Warner-Lambert Company | Nonpeptide endothelin antagonists I |
| CN110343036A (en) * | 2019-07-12 | 2019-10-18 | 武汉大安制药有限公司 | A kind of preparation method of cyclopentyl phenyl acetaldehyde |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5691373A (en) * | 1993-08-19 | 1997-11-25 | Warner-Lambert Company | Nonpeptide endothelin antagonists I |
| CN110343036A (en) * | 2019-07-12 | 2019-10-18 | 武汉大安制药有限公司 | A kind of preparation method of cyclopentyl phenyl acetaldehyde |
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