CN104072345B - A kind of method being applicable to prepare 1-cyclopentyl-2-methoxyl group-1-phenylethyl alcohol - Google Patents
A kind of method being applicable to prepare 1-cyclopentyl-2-methoxyl group-1-phenylethyl alcohol Download PDFInfo
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Abstract
The present invention discloses a kind of method being applicable to prepare 1-cyclopentyl-2-methoxyl group-1-phenylethyl alcohol, comprise and prepare 1 by benzyl ring amyl group first ketone, 1-benzyl ring amyl group oxyethane, again by 1, 1-benzyl ring amyl group oxyethane and highly basic reaction and obtain the process of 1-cyclopentyl-2-methoxyl group-1-phenylethyl alcohol, synthesis material is easy to get, synthesis impurity cost is lower, in actual mechanical process, 1-cyclopentyl-2-methoxyl group-1-phenylethyl alcohol is as one of the impurity component of Penequine hydrochloride, also can be the Qualitative and quantitative analysis of impurity in Penequine hydrochloride and reference substance is provided, thus improve the quality standard of Penequine hydrochloride, for the safe medication of Penequine hydrochloride provides important directive significance, there is extremely high practical value.
Description
Technical field
The present invention is a kind of method being applicable to prepare 1-cyclopentyl-2-methoxyl group-1-phenylethyl alcohol, and the synthesis being specifically related in Penequine hydrochloride impurity component 1-cyclopentyl-2-methoxyl group-1-phenylethyl alcohol, belongs to medicinal chemistry art.
Background technology
Penequine hydrochloride is the anticholinergic agent of the m receptor antagonist class of a kind of novel texture, chemical name: 3-(2-cyclopentyl-2-hydroxyl-2-phenyl ethoxy) quinuclidine hydrochloride, belong to ethyl cyclic hydrocarbon amido ether compounds. in the art, it is outside the pale of civilization that Penequine hydrochloride maintains coromegine afterwards except the emergency treatment poisoning for organophosphorus poisonous substance (agricultural chemicals), poisoning later stage or Pseudocholinesterase (ChE) are aging, before being more used successfully to anesthesia, administration is to suppress sialisterium and the Clinical practice of air flue glandular secretion, applied widely. show according to every preclinical study, Penequine hydrochloride also has stronger security, it is mainly manifested in and each system of whole body and target organ are not had potential toxicity, there is the features such as better tolerance, pharmacological action be strong, certainly, Penequine hydrochloride is compared with other m receptor inhibitor, and Penequine hydrochloride also has better potency ratio. just based on above-mentioned situation, we know, Penequine hydrochloride is in preanesthetic medication, organophosphate poisoning is rescued, shock, respiratory system disease, the clinical field such as cardiovascular disorder and detoxification starts extensively be promoted, a kind of medical compounds disclosed such as: patent documentation CN02134118.4 and composition thereof and the application in pharmacy, the application etc. in preparation treatment haemorrhagic shock medicine of the application of Penequine hydrochloride in pharmacy that patent documentation CN200510088052.X discloses and the Penequine hydrochloride that patent documentation CN200910058142.2 discloses.
At present, along with China to the increasingly stringent of the research requirement of impurity in drug research and development with clear and definite, especially to medicine by product, the research of degraded product etc. has entered the today in a brand-new stage, whether medicine can produce untoward reaction in Clinical practice becomes more and more important, so, carry out assorted Quality Research to specification, and controlled a safety, within rational limits, quality and the security of Penequine hydrochloride will be directly connected to, based on this purpose, we find, synthesis meaning for Penequine hydrochloride impurity 1-cyclopentyl-2-methoxyl group-1-phenylethyl alcohol is very great, it may be used for the Qualitative and quantitative analysis of impurity in Penequine hydrochloride production, thus improve the quality standard of Penequine hydrochloride, and provide important directive significance for safe medication, for this reason, the present invention arises at the historic moment.
Summary of the invention
It is an object of the invention to provide a kind of method being applicable to prepare 1-cyclopentyl-2-methoxyl group-1-phenylethyl alcohol, comprise and prepare 1 by benzyl ring amyl group first ketone, 1-benzyl ring amyl group oxyethane, again by 1, 1-benzyl ring amyl group oxyethane and highly basic reaction and obtain the process of 1-cyclopentyl-2-methoxyl group-1-phenylethyl alcohol, in actual mechanical process, the synthesis of 1-cyclopentyl-2-methoxyl group-1-phenylethyl alcohol, can effectively for Penequine hydrochloride finished product detection provide Qualitative and quantitative analysis reference substance, thus improve the quality standard of Penequine hydrochloride, for Penequine hydrochloride safe medication is given security, also it is step indispensable in Penequine hydrochloride finished product detection process.
The present invention is achieved through the following technical solutions: a kind of method being applicable to prepare 1-cyclopentyl-2-methoxyl group-1-phenylethyl alcohol, comprises the steps:
(A): prepare a kind of mixing solutions including catalyzer, Witting reagent and solvent, and the temperature keeping mixing solutions is less than 40 DEG C, count in molar ratio, catalyzer, Witting reagent: the ratio of solvent is (0.8��3.0): (0.8��3.0): (1��20);
(B): in described mixing solutions, add benzyl ring amyl group first ketone, stir after evenly, maintain the temperature at 30��40 DEG C, and then after boiling, cooling, extraction, washing, drying, distillation, obtain 1 successively, 1-benzyl ring amyl group oxyethane, counting in mass ratio, the ratio of benzyl ring amyl group first ketone and solvent is 1:(1��10);
(C): described 1,1-benzyl ring amyl group oxyethane adds alkaline matter, temperature of reaction is 0��70 DEG C, after question response completes, again after cancellation, extraction, merging organic phase, drying, distillation, obtain 1-cyclopentyl-2-methoxyl group-1-phenylethyl alcohol crude product, count in molar ratio, alkaline matter: the ratio of 1,1-benzyl ring amyl group oxyethane is (0.8��5.0): 1;
: purify, (D)
In the present invention, the chemical formula of benzyl ring amyl group first ketone, 1,1-benzyl ring amyl group oxyethane, 1-cyclopentyl-2-methoxyl group-1-phenylethyl alcohol is successively by formula I:(II):(III):Representing, its synthetic route is as follows:
In described step (A), described Witting reagent is mix, by methyl-sulfate and dimethyl sulphide, the dimethyl sulphide methyl-sulfate salt obtained.
Described solvent is one or more in anhydrous acetonitrile, toluene, tetrahydrofuran (THF), methyl tertiary butyl ether, ether, isopropyl ether, it is preferable that, described solvent can select anhydrous acetonitrile, and receipts rate is higher.
Described catalyzer is the one in sodium methylate, sodium ethylate, potassium tert.-butoxide or sodium tert-butoxide, and certainly, for improving rewinding and reduce reaction impurities, catalyzer can particular methanol sodium.
In the present invention, the preparation process of described mixing solutions comprises:
A: add dimethyl sulphide and solvent in a reservoir respectively, obtains solution A;
B: add methyl-sulfate and solvent in a reservoir respectively, obtains solution B;
C: be added dropwise in solution A by solution B, after dropwising, then adds catalyzer, obtains mixing solutions.
To better implement the present invention, described catalyzer, Witting reagent: the mol ratio of solvent is (1��1.6): (1��1.6): (3��20), optimization, and its mol ratio is 1.1:1:10.
To better implement the present invention, the mol ratio of described alkaline matter and 1,1-benzyl ring amyl group oxyethane is: 1.2:1.
Wherein, described alkaline matter is sodium methylate, usually adopts brand-new sodium methylate, throws away preparation in methyl alcohol by sodium Metal 99.5 and obtains, now-making-now-using, and therefore, its activity is also higher.
Described purification was that post is purified, and its operation steps comprises: first, with sherwood oil by dissolving crude product, adds silica gel, through stirring after evenly, steamed solvent; Then, post on solid will be obtained and make eluent, the material needed for collection, finally again this material being carried out underpressure distillation obtains product, and wherein, the eluent selected comprises sherwood oil and ethyl acetate, count in mass ratio, sherwood oil: ethyl acetate=(3��30): 1.
Further, described sherwood oil and the mass ratio of ethyl acetate are (3��6): 1.
The present invention compared with prior art, has the following advantages and useful effect:
(1) the method for the invention is mainly used in the testing process of Penequine hydrochloride finished product, can not only effectively for Penequine hydrochloride finished product detection provide Qualitative and quantitative analysis reference substance, reach the object of the quality standard improving Penequine hydrochloride, simultaneously, can also give security for Penequine hydrochloride safe medication, practical.
(2) the present invention comprises and prepares 1 by benzyl ring amyl group first ketone, 1-benzyl ring amyl group oxyethane, again by 1,1-benzyl ring amyl group oxyethane and highly basic reaction and obtain the process of 1-cyclopentyl-2-methoxyl group-1-phenylethyl alcohol, synthesis material is easy to get, synthesis impurity cost is lower, has good economic worth.
(3) synthetic route that the present invention relates to has more stereoselectivity, certainly, for optimizing the preparation process of the present invention, it is to increase receipts rate, wherein, the anhydrous acetonitrile and sodium methylate that receipts rate is higher all selected by solvent, catalyzer, meets atom economy.
Accompanying drawing explanation
Fig. 1 is the HPLC purity collection of illustrative plates of the embodiment of the present invention 1 gained Penequine hydrochloride impurity 1-cyclopentyl-2-methoxyl group-1-phenylethyl alcohol.
Fig. 2 is the HPLC purity collection of illustrative plates of the embodiment of the present invention 2 gained Penequine hydrochloride impurity 1-cyclopentyl-2-methoxyl group-1-phenylethyl alcohol.
Fig. 3 is the HPLC purity collection of illustrative plates of the embodiment of the present invention 3 gained Penequine hydrochloride impurity 1-cyclopentyl-2-methoxyl group-1-phenylethyl alcohol.
Embodiment
Below in conjunction with embodiment, the present invention is described in further detail, but embodiments of the present invention are not limited to this.
Embodiment 1:
The present invention provides a kind of method being applicable to prepare 1-cyclopentyl-2-methoxyl group-1-phenylethyl alcohol, the sample that the 1-cyclopentyl-2-methoxyl group-1-phenylethyl alcohol product prepared by the method can be used as the detection method of impurity 1-cyclopentyl-2-methoxyl group-1-phenylethyl alcohol in Penequine hydrochloride uses, in the present invention, the synthetic route of this preparation method comprises prepares 1 by benzyl ring amyl group first ketone, 1-benzyl ring amyl group oxyethane, again by 1, 1-benzyl ring amyl group oxyethane and highly basic reaction and obtain the process of 1-cyclopentyl-2-methoxyl group-1-phenylethyl alcohol, wherein, benzyl ring amyl group first ketone, 1, 1-benzyl ring amyl group oxyethane, the chemical formula of 1-cyclopentyl-2-methoxyl group-1-phenylethyl alcohol is successively by formula I:(II):(III):Representing, its synthetic route is then as follows:
In actual mechanical process, the synthesis of 1-cyclopentyl-2-methoxyl group-1-phenylethyl alcohol, can effectively for Penequine hydrochloride finished product detection provide Qualitative and quantitative analysis reference substance, thus improve the quality standard of Penequine hydrochloride, for Penequine hydrochloride safe medication is given security, this is also step indispensable in Penequine hydrochloride finished product detection process certainly.
The following is in the preparation method to 1-cyclopentyl-2-methoxyl group-1-phenylethyl alcohol further describing of the reaction group part related to and ratio thereof:
Catalyzer: can select the one in sodium methylate, sodium ethylate, potassium tert.-butoxide or sodium tert-butoxide, wherein using sodium methylate as its preference, acts predominantly in raising rewinding and reduces reaction impurities;
Witting reagent: dimethyl sulphide methyl-sulfate salt, obtains primarily of methyl-sulfate and dimethyl sulphide mixing;
Solvent: one or more the mixing in anhydrous acetonitrile, toluene, tetrahydrofuran (THF), methyl tertiary butyl ether, ether, isopropyl ether can be selected, wherein using anhydrous acetonitrile as preference, receipts rate is higher;
Alkaline matter: can selecting sodium methylate, especially brand-new sodium methylate, now-making-now-using, activity is higher.
In above-mentioned reaction group part, the mol ratio of catalyzer, Witting reagent and solvent is (0.8��3.0): (0.8��3.0): (1��20), optimization, can select the mol ratio of 1.1:1:10; The mass ratio of benzyl ring amyl group first ketone and solvent is 1:(1��10), it is preferable that 1:4; Alkaline matter: the mol ratio of 1,1-benzyl ring amyl group oxyethane is (0.8��5.0): 1, it is preferable that 1.2:1.
In the present embodiment, the preparation method of 1-cyclopentyl-2-methoxyl group-1-phenylethyl alcohol specifically comprises:
: first, (A) a kind of mixing solutions including catalyzer, Witting reagent and solvent is prepared:
A: add the dimethyl sulphide of 4.7g, 0.075mol and the anhydrous acetonitrile of 13ml in there-necked flask respectively, be warming up to 30��40 DEG C, after stirring 30min, obtains solution A;
B: the anhydrous acetonitrile that the methyl-sulfate of 8.7g, 0.069mol is dissolved in 30ml, obtains solution B;
C: be added dropwise in solution A by solution B, drips and adds time controling in 1h, after dropwising, continues to stir 2h, then adds the sodium methylate of 4.1g, stir 30min, and temperature is no more than 40 DEG C, acquisition mixing solutions in keeping.
(B): secondly, the mixing solutions that steps A is obtained slowly adds 8.0g, 0.046mol benzyl ring amyl group first ketone, after adding, stir 2��2.5h, then outside temperature less than 75 DEG C, steam except solvent (i.e. anhydrous acetonitrile) and dimethyl sulphide, and steam dry under the pressure of vacuum tightness 0.09Mpa under decompression, and after ice bath cools, slowly add water 50ml, by ether extraction 5 times, merge this ether extracted liquid, through washing 3 times, after anhydrous magnesium sulfate drying, recycling design (this solvent is ether), carry out underpressure distillation, collect boiling point: the product of 70��75 DEG C of 3mm parts, adopt hydrogen spectrum and mass spectrographic method that this product is carried out structural confirmation, obtain following data:
1HNMR(300M,CDCl3): 7.24-7.58 (m, 5H), 2.67-2.98 (d, 2H), 2.58-2.65 (m, 1H), 1.27-1.61 (m, 8H);
LC-MS:LC-MS:(M+,188)��
Through confirming as 1,1-benzyl ring amyl group oxyethane, in the present embodiment, the 1,1-benzyl ring amyl group oxyethane of acquisition is colourless liquid, and heavy 7.9g, product rate is 91.4%.
: in the there-necked flask of 100ml, add 25ml methyl alcohol, (C) sodium Metal 99.5 of 0.8g, 0.035mol is added under stirring, after sodium Metal 99.5 is dissolved, obtain the sodium methylate 26ml that concentration is 0.07g ml, this sodium methylate is brand-new sodium methylate, now-making-now-using, and activity is also higher;
By 5.0g, 0.029mol by 1 obtained by step B, 1-benzyl ring amyl group oxyethane is added dropwise in the reaction system of sodium methylate and methyl alcohol composition, and control is dripped and added more than 10 minutes time, rate of addition 0.5g/min, drip after finishing, it is warming up to 70 DEG C of reactions 5 hours, by TLC point plate detection reaction process, after question response, add 10ml shrend to go out reaction, then use the extraction into ethyl acetate three times of 10ml, first time extractive reaction liquid, separatory; Rear twice aqueous layer extracted, merge organic phase (organic phase comprises: ethyl acetate and methyl alcohol, product), again with after anhydrous magnesium sulfate drying, recycling design (this solvent refers to: the solvent contained in organic layer), carrying out underpressure distillation, obtain the crude product of 4.8g, this crude product is the crude product of 1-cyclopentyl-2-methoxyl group-1-phenylethyl alcohol, for weak yellow liquid, crude product product rate is 89.5%.
(D): the 1-cyclopentyl-2-methoxyl group-1-phenylethyl alcohol crude product that step C is obtained is purified, adopted the method that post is purified, first, the crude product of above-mentioned 4.5g is joined in single port flask, add 5g more respectively, the sherwood oil of 100 object silica gel and 20ml, stir after evenly, concentrating under reduced pressure steams solvent (this solvent is sherwood oil) then, post eluent on solid will be obtained and carry out wash-out, collect target product, finally again this material is carried out concentrating under reduced pressure, namely the 1-cyclopentyl-2-methoxyl group-1-phenylethyl alcohol 3.8g of clarified liq formula is obtained by vacuum pump, wherein, the eluent selected comprises sherwood oil and ethyl acetate, count in mass ratio, sherwood oil: ethyl acetate=3:1.
Adopt hydrogen spectrum and mass spectrographic method that this product is carried out structural confirmation, obtain following data:
1HNMR(300M,CDCl3): 7.45 (d, 2H), 7.37-7.32 (m, 2H), 7.26-7.21 (m, 1H), 3.78 (d, 1H), 3.62 (d, 1H), 3.32 (s, 3H), 2.81 (s, 1H), 2.25-2.20 (m, 1H), 1.70-1.24 (m, 8H);
LC-MS:LC-MS:(M+,220.15)found:175(, 100%), 157 (),
107(), 91 ().45()��
Fig. 1 is the HPLC purity collection of illustrative plates of the present embodiment products therefrom, and its detect parameters is as shown in table 1:
Table 1
Through confirming, this product is 1-cyclopentyl-2-methoxyl group-1-phenylethyl alcohol, and in the present embodiment, the purifying product rate of the 1-cyclopentyl-2-methoxyl group-1-phenylethyl alcohol of acquisition is 84.4%, HPLC purity is 99.0%.
Embodiment 2:
The difference of the present embodiment and embodiment 1 is mainly, in the process of preparation 1,1-benzyl ring amyl group oxyethane, it may also be useful to solvent different, in the present embodiment, the preparation method of 1-cyclopentyl-2-methoxyl group-1-phenylethyl alcohol specifically comprises:
: first, (A) a kind of mixing solutions including catalyzer, Witting reagent and solvent is prepared:
A: add the dimethyl sulphide of 4.7g, 0.075mol and the toluene of 15ml in there-necked flask respectively, be warming up to 30��40 DEG C, after stirring 30min, obtains solution A;
B: the toluene that the methyl-sulfate of 8.7g, 0.069mol is dissolved in 30ml, obtains solution B;
C: be added dropwise in solution A by solution B, drips and adds time controling in 0.5h, after dropwising, continues to stir 30min, then adds the sodium methylate of 4.1g, stir 30min, and temperature is no more than 40 DEG C, acquisition mixing solutions in keeping.
(B): secondly, the mixing solutions that steps A is obtained slowly adds 8.0g, 0.046mol benzyl ring amyl group first ketone, after adding, stir 2��2.5h, then outside temperature less than 75 DEG C, steam except solvent (i.e. toluene) and dimethyl sulphide, and steam dry under the pressure of vacuum tightness 0.09Mpa under decompression, and after ice bath cools, slowly add water 50ml, by ether extraction 5 times, merge this ether extracted liquid, through washing 3 times, after anhydrous magnesium sulfate drying, recycling design (this solvent is ether), carry out underpressure distillation, collect boiling point: the product of 70-75 DEG C of 3mm part.
This product is 1,1-benzyl ring amyl group oxyethane, and in the present embodiment, the 1,1-benzyl ring amyl group oxyethane of acquisition is colourless liquid, and heavy 6.5g, product rate is 75.2%.
: in the there-necked flask of 100ml, add 25ml methyl alcohol, (C) sodium Metal 99.5 of 0.8g, 0.035mol is added under stirring, after sodium Metal 99.5 is dissolved, obtain the sodium methylate 26ml that concentration is 0.07g ml, this sodium methylate is brand-new sodium methylate, now-making-now-using, and activity is also higher;
By 5.0g, 0.029mol by 1 obtained by step B, 1-benzyl ring amyl group oxyethane is added dropwise in the reaction system of sodium methylate and methyl alcohol composition, and control is dripped and added more than 10 minutes time, rate of addition 0.5g/min, drip after finishing, it is warming up to 70 DEG C of reactions 5 hours, by TLC point plate detection reaction process, after question response, add 10ml shrend to go out reaction, then use the extraction into ethyl acetate three times of 10ml, first time extractive reaction liquid, separatory; Rear twice aqueous layer extracted, merge organic phase (organic phase comprises: ethyl acetate and methyl alcohol, product), again with after anhydrous magnesium sulfate drying, recycling design (this solvent refers to: the solvent contained in organic layer), carrying out underpressure distillation, obtain the crude product of 52g, this crude product is the crude product of 1-cyclopentyl-2-methoxyl group-1-phenylethyl alcohol, for weak yellow liquid, crude product product rate is 90.0%.
(D): the 1-cyclopentyl-2-methoxyl group-1-phenylethyl alcohol crude product that step C is obtained is purified, adopted the method that post is purified, first, the crude product of above-mentioned 4.5g is joined in single port flask, add 5g more respectively, the sherwood oil of 100 object silica gel and 20ml, stir after evenly, concentrating under reduced pressure steams solvent (this solvent is sherwood oil) then, post eluent on solid will be obtained and carry out wash-out, collect target product, finally again this material is carried out concentrating under reduced pressure, namely the 1-cyclopentyl-2-methoxyl group-1-phenylethyl alcohol 3.1g of clarified liq formula is obtained by vacuum pump, wherein, the eluent selected comprises sherwood oil and ethyl acetate, count in mass ratio, sherwood oil: ethyl acetate=3:1.
Fig. 2 is the HPLC purity collection of illustrative plates of the present embodiment products therefrom, and its detect parameters is as shown in table 2:
Table 2
Through confirming, this product is 1-cyclopentyl-2-methoxyl group-1-phenylethyl alcohol, and in the present embodiment, the purifying product rate of acquisition 1-cyclopentyl-2-methoxyl group-1-phenylethyl alcohol is 68.8%, HPLC purity is 98.43%.
Embodiment 3:
The difference of the present embodiment and embodiment 1 is mainly step C:
(C) adding 25ml methyl alcohol in the there-necked flask of 100ml, add the sodium Metal 99.5 of 1.0g, 0.044mol under stirring, after sodium Metal 99.5 is dissolved, obtain the sodium methylate 26ml that concentration is 0.09g ml, this sodium methylate is brand-new sodium methylate, now-making-now-using, and activity is also higher;
By the 1 of 5.0g, 0.029mol, 1-benzyl ring amyl group oxyethane is added dropwise in the reaction system of sodium methylate and methyl alcohol composition, and control is dripped and added more than 10 minutes time, rate of addition 0.3g/min, drip after finishing, it is warming up to 65 DEG C of reactions 4 hours, by TLC point plate detection reaction process, after question response, add 10ml shrend to go out reaction, then use the extraction into ethyl acetate three times of 10ml, first time extractive reaction liquid, separatory; Rear twice aqueous layer extracted, merge organic phase (organic phase comprises: ethyl acetate and methyl alcohol, product), again with after anhydrous magnesium sulfate drying, recycling design (this solvent refers to: the solvent contained in organic layer), carrying out underpressure distillation, obtain the crude product of 4.9g, this crude product is the crude product of 1-cyclopentyl-2-methoxyl group-1-phenylethyl alcohol, for weak yellow liquid, crude product product rate is 91.3%.
(D): the 1-cyclopentyl-2-methoxyl group-1-phenylethyl alcohol crude product that step C is obtained is purified, adopted the method that post is purified, first, the crude product of above-mentioned 4.5g is joined in single port flask, add 5g more respectively, the sherwood oil of 100 object silica gel and 20ml, stir after evenly, concentrating under reduced pressure steams solvent (this solvent is sherwood oil) then, post eluent on solid will be obtained and carry out wash-out, collect target product, finally again this material is carried out concentrating under reduced pressure, namely the 1-cyclopentyl-2-methoxyl group-1-phenylethyl alcohol 4.9g of clarified liq formula is obtained by vacuum pump, wherein, the eluent selected comprises sherwood oil and ethyl acetate, count in mass ratio, sherwood oil: ethyl acetate=3:1.
Fig. 3 is the HPLC purity collection of illustrative plates of the present embodiment products therefrom, and its detect parameters is as shown in table 3:
Table 3
Through confirming, this product is 1-cyclopentyl-2-methoxyl group-1-phenylethyl alcohol, and in the present embodiment, the purifying product rate of the 1-cyclopentyl-2-methoxyl group-1-phenylethyl alcohol of acquisition is 77.8%, HPLC purity is 99.73%.
Embodiment 4:
In the present invention, all can be used as the sample of the detection method of impurity 1-cyclopentyl-2-methoxyl group-1-phenylethyl alcohol in Penequine hydrochloride to use by the 1-cyclopentyl-2-methoxyl group-1-phenylethyl alcohol product prepared by above-described embodiment 1��3, its concrete detection method is as follows:
A: prepare need testing solution: get lot number be 130501 Penequine hydrochloride 50mg be placed in measuring bottle, add moving phase and dissolve and be settled to 25ml, shake even, as need testing solution, stand-by;
B: preparation reference substance solution: 1-cyclopentyl-2-methoxyl group-1-phenyl-ethanol control product that Example 1 is produced are appropriate, is mixed with the solution of every 1ml containing 2.0 �� g by moving phase, product solution in contrast, stand-by;
C: measure: draw reference substance solution and each 10 �� l of need testing solution respectively, injects high performance liquid chromatograph and measures, and wherein, the condition determination of high performance liquid chromatography comprises:
Chromatographic column: take octadecyl silane as weighting agent;
Moving phase: volume ratio is the methyl alcohol-0.02mol/L potassium dihydrogen phosphate-triethylamine of 80:20:0.5, and by phosphoric acid solution adjust ph to 5.0;
Flow velocity: 1.0ml/min;
Post temperature: 35 DEG C;
Determined wavelength: 210nm.
After testing it will be seen that in Penequine hydrochloride the content of by product 1-cyclopentyl-2-methoxyl group-1-phenyl-ethanol be 0.026%.
The above is only the better embodiment of the present invention, and the present invention not does any restriction in form, every above embodiment is done according to the technical spirit of the present invention any simple modification, equivalent variations, all fall within protection scope of the present invention.
Claims (5)
1. one kind is applicable to prepare the method for 1-cyclopentyl-2-methoxyl group-1-phenylethyl alcohol, it is characterised in that: comprise the steps:
(A): prepare a kind of mixing solutions including catalyzer, Witting reagent and solvent, and the temperature keeping mixing solutions is less than 40 DEG C, count in molar ratio, catalyzer, Witting reagent: the ratio of solvent is (0.8��3.0): (0.8��3.0): (1��20), and the preparation process of described mixing solutions comprises:
A: add dimethyl sulphide and solvent in a reservoir respectively, obtains solution A;
B: add methyl-sulfate and solvent in a reservoir respectively, obtains solution B;
C: be added dropwise in solution A by solution B, after dropwising, then adds catalyzer, obtains mixing solutions;
(B): in described mixing solutions, add benzyl ring amyl group first ketone, stir after evenly, maintain the temperature at 30��40 DEG C, and then after boiling, cooling, extraction, washing, drying, distillation, obtain 1-cyclopentyl-1-phenyl ethylene oxide successively, counting in mass ratio, the ratio of benzyl ring amyl group first ketone and solvent is 1:(1��10);
(C): in described 1-cyclopentyl-1-phenyl ethylene oxide, add alkaline matter, temperature of reaction is 0��70 DEG C, after question response completes, again after cancellation, extraction, merging organic phase, drying, distillation, obtain 1-cyclopentyl-2-methoxyl group-1-phenylethyl alcohol crude product, count in molar ratio, alkaline matter: the ratio of 1-cyclopentyl-1-phenyl ethylene oxide is (0.8��5.0): 1;
: purify, (D)
Described Witting reagent is mix, by methyl-sulfate and dimethyl sulphide, the dimethyl sulphide methyl-sulfate salt obtained, described solvent is one or more in anhydrous acetonitrile, toluene, tetrahydrofuran (THF), methyl tertiary butyl ether, ether, isopropyl ether, described catalyzer is the one in sodium methylate, sodium ethylate, potassium tert.-butoxide or sodium tert-butoxide, and described alkaline matter is sodium methylate.
2. a kind of method being applicable to prepare 1-cyclopentyl-2-methoxyl group-1-phenylethyl alcohol according to claim 1, it is characterised in that: described catalyzer, Witting reagent: the mol ratio of solvent is (1��1.6): (1��1.6): (3��20).
3. a kind of method being applicable to prepare 1-cyclopentyl-2-methoxyl group-1-phenylethyl alcohol according to claim 1, it is characterised in that: the mol ratio of described alkaline matter and 1-cyclopentyl-1-phenyl ethylene oxide is: 1.2:1.
4. a kind of method being applicable to prepare 1-cyclopentyl-2-methoxyl group-1-phenylethyl alcohol according to claim 1, it is characterized in that: described purification was that post is purified, the eluent selected comprises sherwood oil and ethyl acetate, counts in mass ratio, sherwood oil: ethyl acetate=(3��30): 1.
5. a kind of method being applicable to prepare 1-cyclopentyl-2-methoxyl group-1-phenylethyl alcohol according to claim 4, it is characterised in that: described sherwood oil and the mass ratio of ethyl acetate are (3��6): 1.
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