CN1876646A - Improved cinepazide maleate preparation method - Google Patents
Improved cinepazide maleate preparation method Download PDFInfo
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- CN1876646A CN1876646A CN 200610103455 CN200610103455A CN1876646A CN 1876646 A CN1876646 A CN 1876646A CN 200610103455 CN200610103455 CN 200610103455 CN 200610103455 A CN200610103455 A CN 200610103455A CN 1876646 A CN1876646 A CN 1876646A
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Abstract
The invention relates the preparing method of maleic acid cinprazole. The method comprises the following steps: preparing chloracetyl pyrrolyl; preparing 1- [(1- pyrrolidine carbonyl) methyl] ethyleneamine; preparing 3, 4, 5- trimethoxyl cinnamomum cassia acyl; preparing 1- [(1- pyrrolidine carbonyl) methyl]-4- 3, 4, 5- trimethoxyl cinnamomum cassia acyl) ethyleneamine; preparing 1-[(1- pyrrolidine carbonyl) methyl]-4- 3, 4, 5- trimethoxyl cinnamomum cassia acyl) ethyleneamine maleate; preparing the purification of maleic acid cinprazole. The invention has the character that the solvent is one of chloroform and acetone. The fusing point of the product is 170-175Deg.C. The product has the advantages of high fusing point and stable crystal shape.
Description
Technical field
The present invention relates to 1-[(1-Pyrrolidine carbonyl) methyl]-preparation method of 4-(3,4,5-trimethoxy cinnamoyl) piperazine maleic acid salt (Cinepazide Maleate).
Background technology
1-[(1-Pyrrolidine carbonyl) methyl]-4-(3,4,5-trimethoxy cinnamoyl) piperazine maleic acid salt has following molecular structure
With molecular formula C
26H
35N
3O
9, general Cinepazide Maleate by name, English Cinepazide Maleate by name is a calcium channel blocker, can stop Ca
2+Stride film intravasation smooth muscle cell and cause smooth muscle loosening, distend the blood vessels, the alleviating vascular spasm descends vascular resistance, and brain and cardiac blood flow increase; Strengthen the effect of adenosine and cAMP; Improve erythrocytic snappiness and distortion by kapillary ability, microcirculation improvement; Blood viscosity lowering has provide protection to the organ of ischemic.Be mainly used in the treatment cardiac and cerebral vascular diseases clinically.
In view of the dosage of Cinepazide Maleate is bigger, be necessary to set up suitable suitability for industrialized production, more complete preparation technology's method.
The present invention relates to the synthesis preparation method of Cinepazide Maleate.At the deficiency that exists in the known Cinepazide Maleate synthesis preparation method, carried out effective improvement, invent the simple and easy to do method for preparing high-melting-point stable crystalline forms product, realize that Cinepazide Maleate is more suitable for the technology of preparing of commercial scale production.
US3634411 discloses a kind of preparation method of Cinepazide Maleate.With 3,4,5-trimethoxy cinnamyl chloride (II) and 1-[(1-Pyrrolidine carbonyl) methyl] piperazine (III), in the presence of the acid-acceptor sodium bicarbonate, dry-out benzene is that solvent carries out condensation reaction generation cinepazide; Chinese Journal of New Drugs [2003,12 (8): 625～626] reported, above-mentioned two reaction raw materials (II and III) are dissolved in methylene dichloride respectively after, charging reaction under the ice-water bath cooling conditions; CN1631877A also discloses a kind of synthetic method of Cinepazide Maleate, in the step 4), still need alkaline medium inhale under acid and the subcooling will (II) solid add in the solution of (III) and react, operation stepss such as sodium hydrogen carbonate solution washing are passed through in aftertreatment:
Be reaction solvent with the bigger benzene of toxicity in the US3634411 synthetic method, benzene in toxic substance, belongs to the material that restriction is used to Genus Homo; US3634411 and CN1631877A all have acid-acceptor to exist down to react, and the solid of compound (II) is lighter, and easily generation is flown upward, and product post-processing operation step is also many; The Chinese Journal of New Drugs reported method, its reaction conditions requires also high.
In the US3634411 synthetic method, after the reaction of cinepazide and toxilic acid generated Cinepazide Maleate, making fusing point with the dehydrated alcohol recrystallization was 135 ℃ product; Also with the dehydrated alcohol recrystallization, make fusing point and be 130～132 ℃ product in the Chinese Journal of New Drugs reported method; The product property instability.In the step 5) of CN1631877A; after cinepazide and toxilic acid reaction generate Cinepazide Maleate; also with the dehydrated alcohol recrystallization; though obtain fusing point and be 171-173 ℃ product; but the solubleness of Cinepazide Maleate in dehydrated alcohol is little; volume is very big during recrystallization, is unfavorable for large-scale production:
In the CA60:9313h document, be preparation 1-[(1-Pyrrolidine carbonyl with the ether) methyl] reaction solvent of piperazine, the ether boiling point is low, the volatile liquid of being advisable, operational hazards; Pass through processing such as ethyl acetate, sherwood oil and alkalization in the step 1) of CN1631877A, complex operation:
The embodiment 2 of CN1631877A) in, behind the reacting generating compound (III), product is handled by the working method of wet distillation, because the usage quantity of raw material piperazine is excessive greatly in the reaction, the actually operating difficulty; In the CN1631877A narration CA51:7436i document synthetic compound (III), the distillation of utilization vacuum decompression is carried out purifying to product, and prolong latch up phenomenon, mass production danger very easily take place in the operation:
Summary of the invention
The invention provides a kind of fusing point height, stable crystal formation, the preparation method of the Cinepazide Maleate of suitable commercial scale production.
The invention provides the improved preparation method of a kind of Cinepazide Maleate, comprise the steps: the preparation of chloracetyl Pyrrolizidine; 1-[(1-Pyrrolidine carbonyl) methyl] preparation of piperazine; 3,4, the preparation of 5-trimethoxy cinnamyl chloride; 1-[(1-tetramethyleneimine carbonyl) methyl]-preparation of 4-(3,4,5-trimethoxy cinnamoyl) piperazine; 1-[(1-tetramethyleneimine carbonyl) methyl]-preparation of 4-(3,4,5-trimethoxy cinnamoyl) piperazine maleic acid salt; The purifying of Cinepazide Maleate and the preparation of stable crystalline forms; It is characterized in that: the solvent that uses in the preparation process of the stable crystalline forms of Cinepazide Maleate is a kind of or its arbitrary combination in chloroform and the acetone.
The solvent that uses in the purification step of described Cinepazide Maleate is a kind of or its arbitrary combination in alcohols or the chloroform.
Described alcohols is a kind of or its arbitrary combination in ethanol or the Virahol.
As prioritization scheme, the solvent that uses in the purification step of described Cinepazide Maleate is 95% ethanol.
As further optimizing, in the preparation process of described Cinepazide Maleate stable crystalline forms, the solvent that uses is acetone.
Concretely, the improved preparation method of described Cinepazide Maleate, step is as follows:
The preparation of step 1, chloracetyl Pyrrolizidine
Chloroacetyl chloride is added in the chloroform, cool under stirring, be added dropwise to the solution that Pyrrolidine and triethylamine are dissolved in chloroform, finish, stir and return to room temperature, continue reaction 1 hour, add entry, washing is extracted, and anhydrous sodium sulfate drying steams solvent;
Step 2,1-[(1-Pyrrolidine carbonyl) methyl] preparation of piperazine
Anhydrous potassium carbonate, Piperazine anhydrous are added in the dehydrated alcohol, under the stirring and refluxing, be added dropwise to the chloracetyl Pyrrolizidine, continue stirring reaction, leave standstill to room temperature, reaction mixture is centrifugal, collects solution, steams solvent, adds water, underpressure distillation, repetitive operation, purified product;
Step 3,3,4, the preparation of 5-trimethoxy cinnamyl chloride
With 3,4, the 5-trimethoxy cinnamic acid adds in the chloroform, is added dropwise to sulfur oxychloride under the stirring, and behind the one-tenth homogeneous solution, room temperature is placed and spent the night, and decompression steams solvent to dried, the adding minimum of chloroform, and heating for dissolving, crystallization is separated out in cooling, filters and collects crystallization;
Step 4,1-[(1-tetramethyleneimine carbonyl) methyl]-preparation of 4-(3,4,5-trimethoxy cinnamoyl)-piperazine
With 3,4,5-trimethoxy cinnamyl chloride adds in the methylene dichloride, and stirring and dissolving progressively adds 1-[(1-Pyrrolidine carbonyl again) methyl] piperazine, finish, continue stirring reaction.Add shake well after the entry, leave standstill, divide water-yielding stratum.Add dilute hydrochloric acid solution in the organic layer and extract, set acid, the aqueous solution are added dropwise to the sodium hydroxide solution neutralization, dichloromethane extraction, and the set dichloromethane solution washes dichloromethane solution with water, anhydrous sodium sulfate drying, decompression steams solvent to doing;
Step 5,1-[(1-tetramethyleneimine carbonyl) methyl]-preparation of 4-(3,4,5-trimethoxy cinnamoyl)-piperazine maleic acid salt
With 1-[(1-tetramethyleneimine carbonyl) methyl]-4-(3,4,5-trimethoxy cinnamoyl) piperazine adds in the ethanol, stirs, and adds maleic acid again, stir, and the room temperature standing over night, crystalline solid is separated out, and filters and collects crystallization, makes Cinepazide Maleate;
The purifying of step 6, Cinepazide Maleate and the preparation of stable crystalline forms
Cinepazide Maleate is added in ethanol, Virahol, acetone or the chloroform, stir, heating is left standstill, and crystallisation by cooling filters and collects crystallization, makes Cinepazide Maleate.
As optimization, the improved preparation method of described Cinepazide Maleate, step is as follows:
The preparation of step 1, chloracetyl Pyrrolizidine
700 gram chloroacetyl chlorides are added in 2000 milliliters of chloroforms, cool to-10～-5 ℃ under stirring, slowly be added dropwise to the solution that 440 gram Pyrrolidines and 690 gram triethylamines are dissolved in 2000 milliliters of chloroforms, finish, stir and return to room temperature, continue reaction 1 hour, water with 300 milliliters * 3, washing is extracted, and anhydrous sodium sulfate drying steams solvent;
Step 2,1-[(1-Pyrrolidine carbonyl) methyl] preparation of piperazine
1020 gram Anhydrous potassium carbonates, 1830 gram Piperazine anhydrous are added in 4500 milliliters of dehydrated alcohols, under the stirring and refluxing, be added dropwise to the solution that 630 gram chloracetyl Pyrrolizidines are dissolved in 1600 milliliters of dehydrated alcohols, finish, continued stirring reaction 2.5 hours, and shut down and leave standstill to room temperature the reaction mixture centrifuge dripping, collect solution, steam solvent, add 300 ml waters, underpressure distillation, repetitive operation, purified product;
Step 3,3,4, the preparation of 5-trimethoxy cinnamyl chloride
With 800 grams 3,4, the 5-trimethoxy cinnamic acid adds in 3200 milliliters of chloroforms, is added dropwise to 2504 gram sulfur oxychlorides under stirring, after becoming homogeneous solution, room temperature is placed and is spent the night, and decompression steams solvent to doing, and adds minimum of chloroform, heating for dissolving, crystallization is separated out in cooling, filters and collects crystallization;
Step 4,1-[(1-tetramethyleneimine carbonyl) methyl]-preparation of 4-(3,4,5-trimethoxy cinnamoyl)-piperazine
With 800 grams 3,4,5-trimethoxy cinnamyl chloride adds in 4000 milliliters of methylene dichloride, and stirring and dissolving under 15～20 ℃, progressively adds 562 gram 1-[(1-Pyrrolidine carbonyls again) methyl] piperazine, finish, continued stirring reaction 4 hours.Add 2000 ml water shake wells, leave standstill, divide water-yielding stratum.Adding 2000 milliliter of 5% dilute hydrochloric acid solution in the organic layer extracts, set acid, the aqueous solution, slowly be added dropwise to 20% sodium hydroxide solution, be neutralized to pH8～9,2000 milliliters of dichloromethane extraction three times, the set dichloromethane solution washs dichloromethane solution 2 times with 200 ml waters, anhydrous sodium sulfate drying, decompression steam solvent to doing;
Step 5,1-[(1-tetramethyleneimine carbonyl) methyl]-preparation of 4-(3,4,5-trimethoxy cinnamoyl)-piperazine maleic acid salt
With 900 gram 1-[(1-tetramethyleneimine carbonyls) methyl]-4-(3,4,5-trimethoxy cinnamoyl) piperazine adds in 2500 milliliter of 95% ethanol, stir, be added dropwise to 268 gram maleic acids again and be dissolved in 1500 milliliter of 95% alcoholic acid solution, continue to stir 30 minutes, the room temperature standing over night, crystalline solid is separated out, and filters and collects crystallization, makes Cinepazide Maleate;
The purifying of step 6, Cinepazide Maleate and the preparation of stable crystalline forms
80 gram Cinepazide Maleate are added in 250 milliliter of 95% ethanol, stir, the heating for dissolving clarification is left standstill, and crystallisation by cooling filters and collects crystallization; 80 gram Cinepazide Maleate are added in the solvent of a kind of or its arbitrary combination in 200 milliliters of chloroforms and the acetone, stir, reflux 1 hour leaves standstill cooling, filters and collects crystallization, drying.
The product of the improved preparation method's preparation of described Cinepazide Maleate is that fusing point is 170～175 ℃ a Cinepazide Maleate.
The beneficial effect that the present invention realized is as follows:
Utilize the product of preparation method's preparation of Cinepazide Maleate provided by the present invention, the fusing point height, stable crystal formation is fit to commercial scale production.Utilizing the product of preparation method's preparation of Cinepazide Maleate provided by the present invention is that fusing point is 170～175 ℃ a Cinepazide Maleate, and the melting range of product is ± 0～2 ℃.
Embodiment
Below step be to the describing in further detail of the inventive method, but do not mean that any restriction to the present invention.
Embodiment 1:
The preparation of step 1, chloracetyl Pyrrolizidine
700 gram chloroacetyl chlorides are added in 2000 milliliters of chloroforms, cool to-10～-5 ℃ under stirring, slowly be added dropwise to the solution that 440 gram Pyrrolidines and 690 gram triethylamines are dissolved in 2000 milliliters of chloroforms, finish, stir and return to room temperature, continue reaction 1 hour, the water of adding 300 milliliters * 3, washing is extracted, and anhydrous sodium sulfate drying steams solvent, obtain the light green transparent liquid, room temperature is placed and is solidified, and weighs 732 grams, yield 80.2%.
1HNMR(CDCl
3)：δ1.85(m，2H，-CH
2-)，δ1.96(m，2H，-CH
2-)，δ3.48[m，4H，(-CH
2-N)
2]，δ3.99(s，2H，O＝C-CH
2-Cl)。
Step 2,1-[(1-Pyrrolidine carbonyl) methyl] preparation of piperazine
1020 gram Anhydrous potassium carbonates, 1830 gram Piperazine anhydrous are added in 4500 milliliters of dehydrated alcohols, under the stirring and refluxing, be added dropwise to the solution that 630 gram chloracetyl Pyrrolizidines are dissolved in 1600 milliliters of dehydrated alcohols; finish; continued stirring reaction 2.5 hours, and shut down and leave standstill to room temperature the reaction mixture centrifuge dripping; collect solution; steam solvent, add 300 ml waters, underpressure distillation; repetitive operation, purified product.Obtain brown thick substances, room temperature is placed and is solidified, and makes N-[(1-Pyrrolidine carbonyl) methyl] piperazine 856 grams, yield 100.2%.
1H NMR (DMSO-d
6): δ 1.74 (m, 2H, pyrrolidine-CH
2-), δ 1.85 (m, 2H, pyrrolidine-CH
2-), δ 2.83 (wide s, 4H, piperazine N (CH
2)
2), δ 3.09 (s, 2H ,-CH
2CO), δ 3.26 (t, 2H, pyrrolidine N-CH
2-) δ 3.44 (t, 2H, pyrrolidine N-CH
2-), δ 3.91 (wide s, 5H, piperazine N (CH
2)
2, NH).
Step 3,3,4, the preparation of 5-trimethoxy cinnamyl chloride
With 800 grams 3,4, the 5-trimethoxy cinnamic acid adds in 3200 milliliters of chloroforms, be added dropwise to 2504 gram sulfur oxychlorides under stirring, behind the one-tenth homogeneous solution, room temperature is placed and is spent the night, decompression steams solvent to doing, and adds minimum of chloroform, heating for dissolving, cooling, separate out crystallization, filter and collect crystallization, get faint yellow crystalline solid, weigh 824 grams, yield 95.6%.
1H?NMR(CDCl
3)：δ3.89(s，3H，OCH
3)，δ3.90(s，6H，2×OCH
3)，δ6.37(d，1H，-CH＝)，δ6.79(s，2H，ArH)，δ7.72(d，1H，-CH＝)。
Step 4,1-[(1-tetramethyleneimine carbonyl) methyl]-preparation of 4-(3,4,5-trimethoxy cinnamoyl)-piperazine
With 800 grams 3,4,5-trimethoxy cinnamyl chloride adds in 4000 milliliters of methylene dichloride, and stirring and dissolving under 15～20 ℃, progressively adds 562 gram 1-[(1-Pyrrolidine carbonyls again) methyl] piperazine, finish, continued stirring reaction 4 hours.Add 2000 ml water shake wells, leave standstill, divide water-yielding stratum.Add 2000 milliliter of 5% dilute hydrochloric acid solution in the organic layer and extract, set acid, the aqueous solution slowly are added dropwise to 20% sodium hydroxide solution, after being neutralized to pH 8～9,2000 milliliters of dichloromethane extraction three times, set dichloromethane solution, wash dichloromethane solution 2 times with 200 ml waters, anhydrous sodium sulfate drying, decompression steam solvent to doing, and obtain transparent thick product, self-vulcanizing, weigh 996 grams, 106～109 ℃ ℃ of fusing points, yield 76.5%.
1H NMR (CDCl
3): δ 1.88 (m, 2H, pyrrolidine-CH
2-), δ 1.97 (m, 2H, pyrrolidine-CH
2-), δ 2.66 (wide s, 2H, piperazine N (CH
2)
2), δ 3.19 (s, 2H ,-CH
2CO), δ 3.49[m, 4H, pyrrolidine N (CH
2)
2], δ 3.73 (wide s, 2H, piperazine NCH
2), δ 3.81 (wide s, 2H, piperazine NCH
2), δ 3.88 (s, 3H, OCH
3), δ 3.90 (s, 6H, 2 * OCH
3), δ 6.73 (s, 2H, ArH), δ 6.75 (d, 1H ,-CH=), δ 7.59 (d, 1H ,-CH=).
Step 5,1-[(1-tetramethyleneimine carbonyl) methyl]-preparation of 4-(3,4,5-trimethoxy cinnamoyl)-piperazine maleic acid salt
With 900 gram 1-[(1-tetramethyleneimine carbonyls) methyl]-4-(3,4,5-trimethoxy cinnamoyl) piperazine adds in 2500 milliliter of 95% ethanol; stir; be added dropwise to 268 gram maleic acids again and be dissolved in 1500 milliliter of 95% alcoholic acid solution, continue to stir the room temperature standing over night 30 minutes; crystalline solid is separated out; filter and collect crystallization, make Cinepazide Maleate, weigh 1039 grams; 118～122 ℃ of fusing points, productive rate 90.8%.
1HNMR (CDCl
3): δ 1.89 (m, 2H, pyrrolidine-CH
2-), δ 2.01 (m, 2H, pyrrolidine-CH
2-), δ 3.39 (m, 2H, pyrrolidine N-CH
2-), δ 3.47 (m, 6H, pyrrolidine N-CH
2-, piperazine N (CH
2)
2) δ 3.87[s, 2H ,-CH
2CO], δ 3.88 (s, 3H, OCH
3), δ 3.89 (s, 6H, 2 * OCH
3), δ 4.05 (wide s, 4H, pyrrolidine CON (CH
2)
2), δ 6.30 (s, 2H, maleic acid2 *-CH=), δ 6.75 (d, 1H ,-CH=), δ 6.76 (s, 2H, ArH), δ 7.61 (d, 1H ,-CH=), δ 12.57 (wide s, 2H, maleic acid 2 * COOH).
The purifying of step 6, Cinepazide Maleate and the preparation of stable crystalline forms
80 gram Cinepazide Maleate are added in 250 milliliter of 95% ethanol, stir, the heating for dissolving clarification is left standstill, and crystallisation by cooling filters and collects crystallization, makes Cinepazide Maleate 75 grams, 120～122 ℃ of fusing points, productive rate 93.8%.80 gram Cinepazide Maleate are added in 200 milliliters of acetone, stir, reflux 1 hour leaves standstill cooling, filters and collects crystallization, and drying makes Cinepazide Maleate 78 grams, 174～175 ℃ of fusing points, productive rate 97.5%.
Utilize the product of preparation method's preparation of Cinepazide Maleate provided by the present invention, the fusing point height, stable crystal formation is fit to commercial scale production.Utilizing the product of preparation method's preparation of Cinepazide Maleate provided by the present invention is that fusing point is 170～175 ℃ a Cinepazide Maleate, and the melting range of product is ± 0～2 ℃.
Embodiment 2:
The preparation of step 1, chloracetyl Pyrrolizidine
700 gram chloroacetyl chlorides are added in 2000 milliliters of chloroforms, cool to-10～-5 ℃ under stirring, slowly be added dropwise to the solution that 440 gram Pyrrolidines and 690 gram triethylamines are dissolved in 2000 milliliters of chloroforms, finish, stir and return to room temperature, continue reaction 1 hour, water with 300 milliliters * 3, washing is extracted, and anhydrous sodium sulfate drying steams solvent, obtain the light green transparent liquid, room temperature is placed and is solidified, and weighs 732 grams, yield 80.2%.
1HNMR(CDCl
3)：δ1.85(m，2H，-CH
2-)，δ1.96(m，2H，-CH
2-)，δ3.48[m，4H，(-CH
2-N)
2]，δ3.99(s，2H，O＝C-CH
2-Cl)。
Step 2,1-[(1-Pyrrolidine carbonyl) methyl] preparation of piperazine
1020 gram Anhydrous potassium carbonates, 1830 gram Piperazine anhydrous are added in 4500 milliliters of dehydrated alcohols, under the stirring and refluxing, be added dropwise to the solution that 630 gram chloracetyl Pyrrolizidines are dissolved in 1600 milliliters of dehydrated alcohols; finish; continued stirring reaction 2.5 hours, and shut down and leave standstill to room temperature the reaction mixture centrifuge dripping; collect solution; steam solvent, add 300 ml waters, underpressure distillation; repetitive operation, purified product.Obtain brown thick substances, room temperature is placed and is solidified, and makes N-[(1-Pyrrolidine carbonyl) methyl] piperazine 856 grams, yield 100.2%.
1H NMR (DMSO-d
6): δ 1.74 (m, 2H, pyrrolidine-CH
2-), δ 1.85:(m, 2H, pyrrolidine-CH
2-), δ 2.83 (wide s, 4H, piperazine N (CH
2)
2), δ 3.09 (s, 2H ,-CH
2CO), δ 3.26 (t, 2H, pyrrolidine N-CH
2-) δ 3.44 (t, 2H, pyrrolidine N-CH
2-), δ 3.91 (wide s, 5H, piperazine N (CH
2)
2, NH).
Step 3,3,4, the preparation of 5-trimethoxy cinnamyl chloride
With 800 grams 3,4, the 5-trimethoxy cinnamic acid adds in 3200 milliliters of chloroforms, be added dropwise to 2504 gram sulfur oxychlorides under stirring, behind the one-tenth homogeneous solution, room temperature is placed and is spent the night, decompression steams solvent to doing, and adds minimum of chloroform, heating for dissolving, cooling, separate out crystallization, filter and collect crystallization, get faint yellow crystalline solid, weigh 824 grams, yield 95.6%.
1H?NMR(CDCl
3)：δ3.89(s，3H，OCH
3)，δ3.90(s，6H，2×OCH
3)，δ6.37(d，1H，-CH＝)，δ6.79(s，2H，ArH)，δ7.72(d，1H，-CH＝)。
Step 4,1-[(1-tetramethyleneimine carbonyl) methyl] preparation of 4-(3,4,5-trimethoxy cinnamoyl)-piperazine
With 800 grams 3,4,5-trimethoxy cinnamyl chloride adds in 4000 milliliters of methylene dichloride, and stirring and dissolving under 15～20 ℃, progressively adds 562 gram 1-[(1-Pyrrolidine carbonyls again) methyl] piperazine, finish, continued stirring reaction 4 hours.Add 2000 ml water shake wells, leave standstill, divide water-yielding stratum.Add 2000 milliliter of 5% dilute hydrochloric acid solution in the organic layer and extract, set acid, the aqueous solution slowly are added dropwise to 20% sodium hydroxide solution, after being neutralized to pH8～9,2000 milliliters of dichloromethane extraction three times, set dichloromethane solution, wash dichloromethane solution 2 times with 200 ml waters, anhydrous sodium sulfate drying, decompression steam solvent to doing, and obtain transparent thick product, self-vulcanizing, weigh 996 grams, 106～109 ℃ of fusing points, yield 76.5%.
1H NMR (CDCl
3): δ 1.88 (m, 2H, pyrrolidine-CH
2-), δ 1.97 (m, 2H, pyrrolidine-CH
2-), δ 2.66 (wide s, 2H, piperazine N (CH
2)
2), δ 3.19 (s, 2H ,-CH
2CO), δ 3.49[m, 4H, pyrrolidine N (CH
2)
2], δ 3.73 (wide s, 2H, piperazine NCH
2), δ 3.81 (wide s, 2H, piperazine NCH
2), δ 3.88 (s, 3H, OCH
3), δ 3.90 (s, 6H, 2 * 0CH
3), δ 6.73 (s, 2H, ArH), δ 6.75 (d, 1H ,-CH=), δ 7.59 (d, 1H ,-CH=).
Step 5,1-[(1-tetramethyleneimine carbonyl) methyl]-preparation of 4-(3,4,5-trimethoxy cinnamoyl)-piperazine maleic acid salt
With 900 gram 1-[(1-tetramethyleneimine carbonyls) methyl]-4-(3; 4,5-trimethoxy cinnamoyl) piperazine adds in 2500 milliliter of 95% ethanol, stirs; be added dropwise to 268 gram maleic acids again and be dissolved in 1500 milliliter of 95% alcoholic acid solution; continue to stir 30 minutes, the room temperature standing over night, crystalline solid is separated out; filter and collect crystallization; make Cinepazide Maleate 1039 grams, 118～122 ℃ of fusing points, productive rate 90.8%.
1H NMR (CDCl
3): δ 1.89 (m, 2H, pyrrolidine-CH
2-), δ 2.01 (m, 2H, pyrrolidine-CH
2-), δ 3.39 (m, 2H, pyrrolidine N-CH
2-), δ 3.47 (m, 6H, pyrrolidine N-CH
2-, piperazineN (CH
2)
2) δ 3.87[s, 2H ,-CH
2CO], δ 3.88 (s, 3H, OCH
3), δ 3.89 (s, 6H, 2 * OCH
3), δ 4.05 (wide s, 4H, pyrrolidine CON (CH
2)
2), δ 6.30 (s, 2H, maleic acid 2 *-CH=), δ 6.75 (d, 1H ,-CH=), δ 6.76 (s, 2H, ArH), δ 7.61 (d, 1H ,-CH=), δ 12.57 (wide s, 2H, maleic acid 2 * COOH).
The purifying of step 6, Cinepazide Maleate and the preparation of stable crystalline forms
80 gram Cinepazide Maleate are added in 480 milliliters of Virahols, and heating for dissolving leaves standstill, and crystallisation by cooling filters and collects crystallization, makes Cinepazide Maleate 74.6 grams, 119～121 ℃ of fusing points, productive rate 93.3%.80 gram Cinepazide Maleate are added in 200 milliliters of acetone, stir, reflux 1 hour leaves standstill cooling, filters and collects crystallization, and drying makes Cinepazide Maleate 77.8 grams, 174～175 ℃ of fusing points, productive rate 97.3%.
Utilize the product of preparation method's preparation of Cinepazide Maleate provided by the present invention, the fusing point height, stable crystal formation is fit to commercial scale production.Utilizing the product of preparation method's preparation of Cinepazide Maleate provided by the present invention is that fusing point is 170～175 ℃ a Cinepazide Maleate, and the melting range of product is ± 0～2 ℃.
Embodiment 3:
The preparation of step 1, chloracetyl Pyrrolizidine
700 gram chloroacetyl chlorides are added in 2000 milliliters of chloroforms, cool to-10～-5 ℃ under stirring, slowly be added dropwise to the solution that 440 gram Pyrrolidines and 690 gram triethylamines are dissolved in 2000 milliliters of chloroforms, finish, stir and return to room temperature, continue reaction 1 hour, water with 300 milliliters * 3, washing is extracted, and anhydrous sodium sulfate drying steams solvent, obtain the light green transparent liquid, room temperature is placed and is solidified, and weighs 732 grams, yield 80.2%.
1HNMR(CDCl
3)：δ1.85(m，2H，-CH
2-)，δ1.96(m，2H，-CH
2-)，δ3.48[m，4H，(-CH
2-N)
2]，δ3.99(s，2H，O＝C-CH
2-Cl)。
Step 2,1-[(1-Pyrrolidine carbonyl) methyl] preparation of piperazine
1020 gram Anhydrous potassium carbonates, 1830 gram Piperazine anhydrous are added in 4500 milliliters of dehydrated alcohols, under the stirring and refluxing, be added dropwise to the solution that 630 gram chloracetyl Pyrrolizidines are dissolved in 1600 milliliters of dehydrated alcohols; finish; continued stirring reaction 2.5 hours, and shut down and leave standstill to room temperature the reaction mixture centrifuge dripping; collect solution; steam solvent, add 300 ml waters, underpressure distillation; repetitive operation, purified product.Obtain brown thick substances, room temperature is placed and is solidified, and makes N-[(1-Pyrrolidine carbonyl) methyl] piperazine 856 grams, yield 100.2%.
1H NMR (DMSO-d
6): δ 1.74 (m, 2H, pyrrolidine-CH
2-), δ 1.85 (m, 2H, pyrrolidine-CH
2-), δ 2.83 (wide s, 4H, piperazine N (CH
2)
2), δ 3.09 (s, 2H ,-CH
2CO), δ 3.26 (t, 2H, pyrrolidine N-CH
2-) δ 3.44 (t, 2H, pyrrolidine N-CH
2-), δ 3.91 (wide s, 5H, piperazine N (CH
2)
2, NH).
Step 3,3,4, the preparation of 5-trimethoxy cinnamyl chloride
With 800 grams 3,4, the 5-trimethoxy cinnamic acid adds in 3200 milliliters of chloroforms, be added dropwise to 2504 gram sulfur oxychlorides under stirring, behind the one-tenth homogeneous solution, room temperature is placed and is spent the night, decompression steams solvent to doing, and adds minimum of chloroform, heating for dissolving, cooling, separate out crystallization, filter and collect crystallization, get faint yellow crystalline solid, weigh 824 grams, yield 95.6%.
1H?NMR(CDCl
3)：δ3.89(s，3H，OCH
3)，δ3.90(s，6H，2×OCH
3)，δ6.37(d，1H，-CH＝)，δ6.79(s，2H，ArH)，δ7.72(d，1H，-CH＝)。
Step 4,1-[(1-tetramethyleneimine carbonyl) methyl]-preparation of 4-(3,4,5-trimethoxy cinnamoyl)-piperazine
With 800 grams 3,4,5-trimethoxy cinnamyl chloride adds in 4000 milliliters of methylene dichloride, and stirring and dissolving under 15～20 ℃, progressively adds 562 gram 1-[(1-Pyrrolidine carbonyls again) methyl] piperazine, finish, continued stirring reaction 4 hours.Add 2000 ml water shake wells, leave standstill, divide water-yielding stratum.Add 2000 milliliter of 5% dilute hydrochloric acid solution in the organic layer and extract, set acid, the aqueous solution slowly are added dropwise to 20% sodium hydroxide solution, after being neutralized to pH8～9,2000 milliliters of dichloromethane extraction three times, set dichloromethane solution, wash dichloromethane solution 2 times with 200 ml waters, anhydrous sodium sulfate drying, decompression steam solvent to doing, and obtain transparent thick product, self-vulcanizing, weigh 996 grams, 106～109 ℃ of fusing points, yield 76.5%.
1HNMR (CDCl
3): δ 1.88 (m, 2H, pyrrolidine-CH
2-), δ 1.97 (m, 2H, pyrrolidine-CH
2-), δ 2.66 (wide s, 2H, piperazine N (CH
2)
2), δ 3.19 (s, 2H ,-CH
2CO), δ 3.49[m, 4H, pyrrolidine N (CH
2)
2], δ 3.73 (wide s, 2H, piperazine NCH
2), δ 3.81 (wide s, 2H, piperazine NCH
2), δ 3.88 (s, 3H, OCH
3), δ 3.90 (s, 6H, 2 * OCH
3), δ 6.73 (s, 2H, ArH), δ 6.75 (d, 1H ,-CH=), δ 7.59 (d, 1H ,-CH=).
Step 5,1-[(1-tetramethyleneimine carbonyl) methyl]-preparation of 4-(3,4,5-trimethoxy cinnamoyl)-piperazine maleic acid salt
With 900 gram 1-[(1-tetramethyleneimine carbonyls) methyl]-4-(3; 4,5-trimethoxy cinnamoyl) piperazine adds in 2500 milliliter of 95% ethanol, stirs; be added dropwise to 268 gram maleic acids again and be dissolved in 1500 milliliter of 95% alcoholic acid solution; continue to stir 30 minutes, the room temperature standing over night, crystalline solid is separated out; filter and collect crystallization; make Cinepazide Maleate 1039 grams, 118～122 ℃ of fusing points, productive rate 90.8%.
1H NMR (CDCl
3): δ 1.89 (m, 2H, pyrrolidine-CH
2-), δ 2.01 (m, 2H, pyrrolidine-CH
2-), δ 3.39 (m, 2H, pyrrolidine N-CH
2-), δ 3.47 (m, 6H, pyrrolidine N-CH
2-, piperazineN (CH
2)
2) δ 3.87[s, 2H ,-CH
2CO], δ 3.88 (s, 3H, OCH
3), δ 3.89 (s, 6H, 2 * OCH
3), δ 4.05 (wide s, 4H, pyrrolidine CON (CH
2)
2), δ 6.30 (s, 2H, maleic acid 2 *-CH=), δ 6.75 (d, 1H ,-CH=), δ 6.76 (s, 2H, ArH), δ 7.61 (d, 1H ,-CH=), δ 12.57 (wide s, 2H, maleic acid 2 * COOH).
The preparation of step 6, Cinepazide Maleate purifying and stable crystalline forms
80 gram Cinepazide Maleate are added in 560 milliliters of chloroforms, and heating for dissolving leaves standstill, and crystallisation by cooling filters and collects crystallization, makes Cinepazide Maleate 60.2 grams, 170～172 ℃ of fusing points, productive rate 75.3%.
Utilize the product of preparation method's preparation of Cinepazide Maleate provided by the present invention, the fusing point height, stable crystal formation is fit to commercial scale production.Utilizing the product of preparation method's preparation of Cinepazide Maleate provided by the present invention is that fusing point is 170～175 ℃ a Cinepazide Maleate, and the melting range of product is ± 0～2 ℃.
Embodiment 4:
The preparation of step 1, chloracetyl Pyrrolizidine
700 gram chloroacetyl chlorides are added in 2000 milliliters of chloroforms, cool to-10～-5 ℃ under stirring, slowly be added dropwise to the solution that 440 gram Pyrrolidines and 690 gram triethylamines are dissolved in 2000 milliliters of chloroforms, finish, stir and return to room temperature, continue reaction 1 hour, water with 300 milliliters * 3, washing is extracted, and anhydrous sodium sulfate drying steams solvent, obtain the light green transparent liquid, room temperature is placed and is solidified, and weighs 732 grams, yield 80.2%.
1HNMR(CDCl
3)：δ1.85(m，2H，-CH
2-)，δ1.96(m，2H，-CH
2-)，δ3.48[m，4H，(～CH
2-N)
2]，δ3.99(s，2H，O＝C-CH
2-Cl)。
Step 2,1-[(1-Pyrrolidine carbonyl) methyl] preparation of piperazine
1020 gram Anhydrous potassium carbonates, 1830 gram Piperazine anhydrous are added in 4500 milliliters of dehydrated alcohols, under the stirring and refluxing, be added dropwise to the solution that 630 gram chloracetyl Pyrrolizidines are dissolved in 1600 milliliters of dehydrated alcohols; finish; continued stirring reaction 2.5 hours, and shut down and leave standstill to room temperature the reaction mixture centrifuge dripping; collect solution; steam solvent, add 300 ml waters, underpressure distillation; repetitive operation, purified product.Obtain brown thick substances, room temperature is placed and is solidified, and makes N-[(1-Pyrrolidine carbonyl) methyl] piperazine, weigh 856 grams, yield 100.2%.
1HNMR (DMSO-d
6): δ 1.74 (m, 2H, pyrrolidine-CH
2-), δ 1.85 (m, 2H, pyrrolidine-CH
2-), δ 2.83 (wide s, 4H, piperazine N (CH
2)
2), δ 3.09 (s, 2H ,-CH
2CO), δ 3.26 (t, 2H, pyrrolidine N-CH
2-) δ 3.44 (t, 2H, pyrrolidine N-CH
2-), δ 3.91 (wide s, 5H, piperazine N (CH
2)
2, NH).
Step 3,3,4, the preparation of 5-trimethoxy cinnamyl chloride
With 800 grams 3,4, the 5-trimethoxy cinnamic acid adds in 3200 milliliters of chloroforms, be added dropwise to 2504 gram sulfur oxychlorides under stirring, behind the one-tenth homogeneous solution, room temperature is placed and is spent the night, decompression steams solvent to doing, and adds minimum of chloroform, heating for dissolving, cooling, separate out crystallization, filter and collect crystallization, get faint yellow crystalline solid, weigh 824 grams, yield 95.6%.
1H?NMR(CDCl
3)：δ3.89(s，3H，OCH
3)，δ3.90(s，6H，2×OCH
3)，δ6.37(d，1H，-CH＝)，δ6.79(s，2H，ArH)，δ7.72(d，1H，-CH＝)。
Step 4,1-[(1-tetramethyleneimine carbonyl) methyl]-preparation of 4-(3,4,5-trimethoxy cinnamoyl)-piperazine
With 800 grams 3,4,5-trimethoxy cinnamyl chloride adds in 4000 milliliters of methylene dichloride, and stirring and dissolving under 15～20 ℃, progressively adds 562 gram 1-[(1-Pyrrolidine carbonyls again) methyl] piperazine, finish, continued stirring reaction 4 hours.Add shake well behind 2000 ml waters, leave standstill, divide water-yielding stratum.Add 2000 milliliter of 5% dilute hydrochloric acid solution in the organic layer and extract, set acid, the aqueous solution slowly are added dropwise to 20% sodium hydroxide solution, after being neutralized to pH8～9,2000 milliliters of dichloromethane extraction three times, set dichloromethane solution, wash dichloromethane solution 2 times with 200 ml waters, anhydrous sodium sulfate drying, decompression steam solvent to doing, and obtain transparent thick product, self-vulcanizing, weigh 996 grams, 106～109 ℃ of fusing points, yield 76.5%.
1H NMR (CDCl
3): δ 1.88 (m, 2H, pyrrolidine-CH
2-), δ 1.97 (m, 2H, pyrrolidine-CH
2-), δ 2.66 (wide s, 2H, piperazine N (CH
2)
2), δ 3.19 (s, 2H ,-CH
2CO), δ 3.49[m, 4H, pyrrolidine N (CH
2)
2], δ 3.73 (wide s, 2H, piperazine NCH
2), δ 3.81 (wide s, 2H, piperazine NCH
2), δ 3.88 (s, 3H, OCH
3), δ 3.90 (s, 6H, 2 * OCH
3), δ 6.73 (s, 2H, ArH), δ 6.75 (d, 1H ,-CH=), δ 7.59 (d, 1H ,-CH=).
Step 5,1-[(1-tetramethyleneimine carbonyl) methyl] preparation of 4-(3,4,5-trimethoxy cinnamoyl)-piperazine maleic acid salt
With 900 gram 1-[(1-tetramethyleneimine carbonyls) methyl]-4-(3,4,5-trimethoxy cinnamoyl) piperazine adds in 2500 milliliter of 95% ethanol; stir; be added dropwise to 268 gram maleic acids again and be dissolved in 1500 milliliter of 95% alcoholic acid solution, continue to stir the room temperature standing over night 30 minutes; crystalline solid is separated out; filter and collect crystallization, make Cinepazide Maleate, weigh 1039 grams; 118～122 ℃ of fusing points, productive rate 90.8%.
1HNMR (CDCl
3): δ 1.89 (m, 2H, pyrrolidine-CH
2-), δ 2.01 (m, 2H, pyrrolidine-CH
2-), δ 3.39 (m, 2H, pyrrolidine N-CH
2-), δ 3.47 (m, 6H, pyrrolidine N-CH
2-, piperazine N (CH
2)
2) δ 3.87[s, 2H ,-CH
2CO], δ 3.88 (s, 3H, OCH
3), δ 3.89 (s, 6H, 2 * OCH
3), δ 4.05 (wide s, 4H, pyrrolidine CON (CH
2)
2), δ 6.30 (s, 2H, maleic acid2 *-CH=), δ 6.75 (d, 1H ,-CH=), δ 6.76 (s, 2H, ArH), δ 7.61 (d, 1H ,-CH=), δ 12.57 (wide s, 2H, maleic acid 2 * COOH).
The preparation of step 6, Cinepazide Maleate stable crystalline forms
80 gram Cinepazide Maleate are mixed with 80 milliliters of acetone, stir, leave standstill, filter and collect crystallization, drying makes Cinepazide Maleate 78.2 grams, 171～173 ℃ of fusing points, productive rate 97.8%.
Utilize the product of preparation method's preparation of Cinepazide Maleate provided by the present invention, the fusing point height, stable crystal formation is fit to commercial scale production.Utilizing the product of preparation method's preparation of Cinepazide Maleate provided by the present invention is that fusing point is 170～175 ℃ a Cinepazide Maleate, and the melting range of product is ± 0～2 ℃.
Embodiment 5:
The preparation of step 1, chloracetyl Pyrrolizidine
700 gram chloroacetyl chlorides are added in 2000 milliliters of chloroforms, cool to-10～-5 ℃ under stirring, slowly be added dropwise to the solution that 440 gram Pyrrolidines and 690 gram triethylamines are dissolved in 2000 milliliters of chloroforms, finish, stir and return to room temperature, continue reaction 1 hour, water with 300 milliliters * 3, washing is extracted, and anhydrous sodium sulfate drying steams solvent, obtain the light green transparent liquid, room temperature is placed and is solidified, and weighs 732 grams, yield 80.2%.
1HNMR(CDCl
3)：δ1.85(m，2H，-CH
2-)，δ1.96(m，2H，-CH
2-)，δ3.48[m，4H，(-CH
2-N)
2]，δ3.99(s，2H，O＝C-CH
2-Cl)。
Step 2,1-[(1-Pyrrolidine carbonyl) methyl] preparation of piperazine
1020 gram Anhydrous potassium carbonates, 1830 gram Piperazine anhydrous are added in 4500 milliliters of dehydrated alcohols, under the stirring and refluxing, be added dropwise to the solution that 630 gram chloracetyl Pyrrolizidines are dissolved in 1600 milliliters of dehydrated alcohols; finish; continued stirring reaction 2.5 hours, and shut down and leave standstill to room temperature the reaction mixture centrifuge dripping; collect solution; steam solvent, add 300 ml waters, underpressure distillation; repetitive operation, purified product.Obtain brown thick substances, room temperature is placed and is solidified, and makes N-[(1-Pyrrolidine carbonyl) methyl] piperazine, weigh 856 grams, yield 100.2%.
1HNMR (DMSO-d
6): δ 1.74 (m, 2H, pyrrolidine-CH
2-), δ 1.85 (m, 2H, pyrrolidine-CH
2-), δ 2.83 (wide s, 4H, piperazine N (CH
2)
2), δ 3.09 (s, 2H ,-CH
2CO), δ 3.26 (t, 2H, pyrrolidine N-CH
2-) δ 3.44 (t, 2H, pyrrolidine N-CH
2-), δ 3.91 (wide s, 5H, piperazine N (CH
2)
2, NH).
Step 3,3,4, the preparation of 5-trimethoxy cinnamyl chloride
With 800 grams 3,4, the 5-trimethoxy cinnamic acid adds in 3200 milliliters of chloroforms, be added dropwise to 2504 gram sulfur oxychlorides under stirring, behind the one-tenth homogeneous solution, room temperature is placed and is spent the night, decompression steams solvent to doing, and adds minimum of chloroform, heating for dissolving, cooling, separate out crystallization, filter and collect crystallization, get faint yellow crystalline solid, weigh 824 grams, yield 95.6%.
1H?NMR(CDCl
3)：δ3.89(s，3H，OCH
3)，δ3.90(s，6H，2×OCH
3)，δ6.37(d，1H，-CH＝)，δ6.79(s，2H，ArH)，δ7.72(d，1H，-CH＝)。
Step 4,1-[(1-tetramethyleneimine carbonyl) methyl]-preparation of 4-(3,4,5-trimethoxy cinnamoyl)-piperazine
With 800 grams 3,4,5-trimethoxy cinnamyl chloride adds in 4000 milliliters of methylene dichloride, and stirring and dissolving under 15～20 ℃, progressively adds 562 gram 1-[(1-Pyrrolidine carbonyls again) methyl] piperazine, finish, continued stirring reaction 4 hours.Add shake well behind 2000 ml waters, leave standstill, divide water-yielding stratum.Add 2000 milliliter of 5% dilute hydrochloric acid solution in the organic layer and extract, set acid, the aqueous solution slowly are added dropwise to 20% sodium hydroxide solution, after being neutralized to pH8～9,2000 milliliters of dichloromethane extraction three times, set dichloromethane solution, wash dichloromethane solution 2 times with 200 ml waters, anhydrous sodium sulfate drying, decompression steam solvent to doing, and obtain transparent thick product, self-vulcanizing, weigh 996 grams, 106～109 ℃ of fusing points, yield 76.5%.
1H NMR (CDCl
3): δ 1.88 (m, 2H, pyrrolidine-CH
2-), δ 1.97 (m, 2H, pyrrolidine-CH
2-), δ 2.66 (wide s, 2H, piperazine N (CH
2)
2), δ 3.19 (s, 2H ,-CH
2CO), δ 3.49[m, 4H, pyrrolidine N (CH
2)
2], δ 3.73 (wide s, 2H, piperazine NCH
2), δ 3.81 (wide s, 2H, piperazine NCH
2), δ 3.88 (s, 3H, OCH
3), δ 3.90 (s, 6H, 2 * OCH
3), δ 6.73 (s, 2H, ArH), δ 6.75 (d, 1H ,-CH=), δ 7.59 (d, 1H ,-CH=).
Step 5,1-[(1-tetramethyleneimine carbonyl) methyl]-preparation of 4-(3,4,5-trimethoxy cinnamoyl)-piperazine maleic acid salt
With 900 gram 1-[(1-tetramethyleneimine carbonyls) methyl] 4-(3,4,5-trimethoxy cinnamoyl) piperazine adds in 2500 milliliter of 95% ethanol; stir; be added dropwise to 268 gram maleic acids again and be dissolved in 1500 milliliter of 95% alcoholic acid solution, continue to stir the room temperature standing over night 30 minutes; crystalline solid is separated out; filter and collect crystallization, make Cinepazide Maleate, weigh 1039 grams; 118～122 ℃ of fusing points, productive rate 90.8%.
1HNMR (CDCl
3): δ 1.89 (m, 2H, pyrrolidine-CH
2-), δ 2.01 (m, 2H, pyrrolidine-CH
2-), δ 3.39 (m, 2H, pyrrolidine N-CH
2-), δ 3.47 (m, 6H, pyrrolidine N-CH
2-, piperazine N (CH
2)
2) δ 3.87[s, 2H ,-CH
2CO], δ 3.88 (s, 3H, OCH
3), δ 3.89 (s, 6H, 2 * OCH
3), δ 4.05 (wide s, 4H, pyrrolidine CON (CH
2)
2), δ 6.30 (s, 2H, maleic acid2 *-CH=), δ 6.75 (d, 1H ,-CH=), δ 6.76 (s, 2H, ArH), δ 7.61 (d, 1H ,-CH=), δ 12.57 (wide s, 2H, maleic acid 2 * COOH).
The preparation of step 6, Cinepazide Maleate stable crystalline forms
80 gram Cinepazide Maleate are added in 200 milliliters of acetone, stir, reflux 1 hour leaves standstill cooling, filters and collects crystallization, and drying makes Cinepazide Maleate 78 grams, 173～175 ℃ of fusing points, productive rate 97.5%.
Utilize the product of preparation method's preparation of Cinepazide Maleate provided by the present invention, the fusing point height, stable crystal formation is fit to commercial scale production.Utilizing the product of preparation method's preparation of Cinepazide Maleate provided by the present invention is that fusing point is 170～175 ℃ a Cinepazide Maleate, and the melting range of product is ± 0～2 ℃.
Claims (8)
1. the improved preparation method of Cinepazide Maleate comprises the steps: the preparation of chloracetyl Pyrrolizidine; 1-[(1-Pyrrolidine carbonyl) methyl] preparation of piperazine; 3,4, the preparation of 5-trimethoxy cinnamyl chloride; 1-[(1-tetramethyleneimine carbonyl) methyl]-preparation of 4-(3,4,5-trimethoxy cinnamoyl) piperazine; 1-[(1-tetramethyleneimine carbonyl) methyl]-preparation of 4-(3,4,5-trimethoxy cinnamoyl) piperazine maleic acid salt; The purifying of Cinepazide Maleate and the preparation of stable crystalline forms; It is characterized in that: the solvent that uses in the preparation process of the stable crystalline forms of Cinepazide Maleate is a kind of or its arbitrary combination in chloroform and the acetone.
2. the improved preparation method of Cinepazide Maleate according to claim 1 is characterized in that, the solvent that uses in the purification step of described Cinepazide Maleate is a kind of or its arbitrary combination in alcohols or the chloroform.
3. the improved preparation method of Cinepazide Maleate according to claim 2 is characterized in that, described alcohols is a kind of or its arbitrary combination in ethanol or the Virahol.
4. the improved preparation method of Cinepazide Maleate according to claim 3 is characterized in that the solvent that uses in the purification step of described Cinepazide Maleate is 95% ethanol.
5. the improved preparation method of Cinepazide Maleate according to claim 1 is characterized in that in the preparation process of described Cinepazide Maleate stable crystalline forms, the solvent that uses is acetone.
6. the improved preparation method of Cinepazide Maleate according to claim 1 is characterized in that, the improved preparation method of described Cinepazide Maleate, and step is as follows:
The preparation of step 1, chloracetyl Pyrrolizidine
Chloroacetyl chloride is added in the chloroform, cool under stirring, be added dropwise to the solution that Pyrrolidine and triethylamine are dissolved in chloroform, finish, stir and return to room temperature, continue reaction 1 hour, add entry, washing is extracted, and anhydrous sodium sulfate drying steams solvent;
Step 2,1-[(1-Pyrrolidine carbonyl) methyl] preparation of piperazine
Anhydrous potassium carbonate, Piperazine anhydrous are added in the dehydrated alcohol, under the stirring and refluxing, be added dropwise to the chloracetyl Pyrrolizidine, continue stirring reaction, leave standstill to room temperature, reaction mixture is centrifugal, collects solution, steams solvent, adds water, underpressure distillation, repetitive operation, purified product;
Step 3,3,4, the preparation of 5-trimethoxy cinnamyl chloride
With 3,4, the 5-trimethoxy cinnamic acid adds in the chloroform, is added dropwise to sulfur oxychloride under the stirring, and behind the one-tenth homogeneous solution, room temperature is placed and spent the night, and decompression steams solvent to dried, the adding minimum of chloroform, and heating for dissolving, crystallization is separated out in cooling, filters and collects crystallization;
Step 4,1-[(1-tetramethyleneimine carbonyl) methyl]-preparation of 4-(3,4,5-trimethoxy cinnamoyl)-piperazine
With 3,4,5-trimethoxy cinnamyl chloride adds in the methylene dichloride, and stirring and dissolving progressively adds 1-[(1-Pyrrolidine carbonyl again) methyl] piperazine, finish, continue stirring reaction.Add shake well after the entry, leave standstill, divide water-yielding stratum.Add dilute hydrochloric acid solution in the organic layer and extract, set acid, the aqueous solution are added dropwise to the sodium hydroxide solution neutralization, dichloromethane extraction, and the set dichloromethane solution washes dichloromethane solution with water, anhydrous sodium sulfate drying, decompression steams solvent to doing;
Step 5,1-[(1-tetramethyleneimine carbonyl) methyl]-preparation of 4-(3,4,5-trimethoxy cinnamoyl)-piperazine maleic acid salt
With 1-[(1-tetramethyleneimine carbonyl) methyl]-4-(3,4,5-trimethoxy cinnamoyl) piperazine adds in the ethanol, stirs, and adds maleic acid again, stir, and the room temperature standing over night, crystalline solid is separated out, and filters and collects crystallization, makes Cinepazide Maleate;
The purifying of step 6, Cinepazide Maleate and the preparation of stable crystalline forms
Cinepazide Maleate is added in ethanol, Virahol, acetone or the chloroform, stir, heating is left standstill, and crystallisation by cooling filters and collects crystallization, makes Cinepazide Maleate.
7. the improved preparation method of Cinepazide Maleate according to claim 6 is characterized in that, the improved preparation method of described Cinepazide Maleate, and step is as follows:
The preparation of step 1, chloracetyl Pyrrolizidine
700 gram chloroacetyl chlorides are added in 2000 milliliters of chloroforms, cool to-10～-5 ℃ under stirring, slowly be added dropwise to the solution that 440 gram Pyrrolidines and 690 gram triethylamines are dissolved in 2000 milliliters of chloroforms, finish, stir and return to room temperature, continue reaction 1 hour, water with 300 milliliters * 3, washing is extracted, and anhydrous sodium sulfate drying steams solvent;
Step 2,1-[(1-Pyrrolidine carbonyl) methyl] preparation of piperazine
1020 gram Anhydrous potassium carbonates, 1830 gram Piperazine anhydrous are added in 4500 milliliters of dehydrated alcohols, under the stirring and refluxing, be added dropwise to the solution that 630 gram chloracetyl Pyrrolizidines are dissolved in 1600 milliliters of dehydrated alcohols, finish, continued stirring reaction 2.5 hours, and shut down and leave standstill to room temperature the reaction mixture centrifuge dripping, collect solution, steam solvent, add 300 ml waters, underpressure distillation, repetitive operation, purified product;
Step 3,3,4, the preparation of 5-trimethoxy cinnamyl chloride
With 800 grams 3,4, the 5-trimethoxy cinnamic acid adds in 3200 milliliters of chloroforms, is added dropwise to 2504 gram sulfur oxychlorides under stirring, after becoming homogeneous solution, room temperature is placed and is spent the night, and decompression steams solvent to doing, and adds minimum of chloroform, heating for dissolving, crystallization is separated out in cooling, filters and collects crystallization;
Step 4,1-[(1-tetramethyleneimine carbonyl) methyl]-preparation of 4-(3,4,5-trimethoxy cinnamoyl)-piperazine
With 800 grams 3,4,5-trimethoxy cinnamyl chloride adds in 4000 milliliters of methylene dichloride, and stirring and dissolving under 15～20 ℃, progressively adds 562 gram 1-[(1-Pyrrolidine carbonyls again) methyl] piperazine, finish, continued stirring reaction 4 hours.Add 2000 ml water shake wells, leave standstill, divide water-yielding stratum.Adding 2000 milliliter of 5% dilute hydrochloric acid solution in the organic layer extracts, set acid, the aqueous solution, slowly be added dropwise to 20% sodium hydroxide solution, be neutralized to pH8～9,2000 milliliters of dichloromethane extraction three times, the set dichloromethane solution washs dichloromethane solution 2 times with 200 ml waters, anhydrous sodium sulfate drying, decompression steam solvent to doing;
Step 5,1-[(1-tetramethyleneimine carbonyl) methyl]-preparation of 4-(3,4,5-trimethoxy cinnamoyl)-piperazine maleic acid salt
With 900 gram 1-[(1-tetramethyleneimine carbonyls) methyl]-4-(3,4,5-trimethoxy cinnamoyl) piperazine adds in 2500 milliliter of 95% ethanol, stir, be added dropwise to 268 gram maleic acids again and be dissolved in 1500 milliliter of 95% alcoholic acid solution, continue to stir 30 minutes, the room temperature standing over night, crystalline solid is separated out, and filters and collects crystallization, makes Cinepazide Maleate;
The purifying of step 6, Cinepazide Maleate and the preparation of stable crystalline forms
80 gram Cinepazide Maleate are added in 250 milliliter of 95% ethanol, stir, the heating for dissolving clarification is left standstill, and crystallisation by cooling filters and collects crystallization; 80 gram Cinepazide Maleate are added in the solvent of a kind of or its arbitrary combination in 200 milliliters of chloroforms and the acetone, stir, reflux 1 hour leaves standstill cooling, filters and collects crystallization, drying.
8. according to the product of the improved preparation method's preparation of any described Cinepazide Maleate of claim 1-7, it is characterized in that described product is that fusing point is 170～175 ℃ a Cinepazide Maleate.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101973965A (en) * | 2010-09-20 | 2011-02-16 | 北京琥珀光华医药科技开发有限公司 | Preparation method of maleic acid cinepazide |
| CN101260092B (en) * | 2008-04-14 | 2011-07-20 | 罗军 | Method for preparing cinepazide maleate |
| CN101723918B (en) * | 2008-10-24 | 2011-08-31 | 重庆医科大学医药研究所 | Process for preparing cinepazide maleate |
| CN101531643B (en) * | 2009-04-13 | 2012-11-14 | 上海理奥生物医药科技有限责任公司 | Synthesis method for improved cinepazide maleate |
| CN101955472B (en) * | 2009-03-06 | 2012-11-14 | 王颖 | Preparation method of cinepazide maleate |
| CN112028856A (en) * | 2019-06-03 | 2020-12-04 | 康普药业股份有限公司 | Preparation method of cinepazide maleate intermediate |
-
2006
- 2006-07-21 CN CNB2006101034551A patent/CN100572378C/en active Active
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101260092B (en) * | 2008-04-14 | 2011-07-20 | 罗军 | Method for preparing cinepazide maleate |
| CN101723918B (en) * | 2008-10-24 | 2011-08-31 | 重庆医科大学医药研究所 | Process for preparing cinepazide maleate |
| CN101955472B (en) * | 2009-03-06 | 2012-11-14 | 王颖 | Preparation method of cinepazide maleate |
| CN101531643B (en) * | 2009-04-13 | 2012-11-14 | 上海理奥生物医药科技有限责任公司 | Synthesis method for improved cinepazide maleate |
| CN101973965A (en) * | 2010-09-20 | 2011-02-16 | 北京琥珀光华医药科技开发有限公司 | Preparation method of maleic acid cinepazide |
| CN112028856A (en) * | 2019-06-03 | 2020-12-04 | 康普药业股份有限公司 | Preparation method of cinepazide maleate intermediate |
| CN112028856B (en) * | 2019-06-03 | 2024-03-26 | 康普药业股份有限公司 | Preparation method of cinepazide maleate intermediate |
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| CN100572378C (en) | 2009-12-23 |
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