CN102718756B - Paroxetine hydrochloride compound and synthetic method thereof - Google Patents
Paroxetine hydrochloride compound and synthetic method thereof Download PDFInfo
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- CN102718756B CN102718756B CN2012102242059A CN201210224205A CN102718756B CN 102718756 B CN102718756 B CN 102718756B CN 2012102242059 A CN2012102242059 A CN 2012102242059A CN 201210224205 A CN201210224205 A CN 201210224205A CN 102718756 B CN102718756 B CN 102718756B
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Abstract
The invention relates to the field of medicine and particularly relates to a paroxetine hydrochloride compound and a synthetic method thereof. The paroxetine hydrochloride compound has the following structural formula. According to the paroxetine hydrochloride compound, ethyl chloroformate for industrial production is used as a demethylation reagent, the reagent is stable, the production condition of demethylation is moderate, the total yield is high and about 75%, and the paroxetine hydrochloride compound accords with the requirement of a 2010 edition of a pharmacopeia and applicable to industrial production.
Description
Technical field
The present invention relates to field of medicaments, relate in particular to paroxetine hydrochloride compound and synthetic method thereof.
Background technology
Paroxetine hydrochloride, chemical name: (-)-(3S, 4R)-4-(fluorophenyl)-3-{ [3,4-(methylene-dioxy) phenoxy group] methyl }-piperidine hydrochlorate semihydrate.Its structural formula is as follows:
；
Be applicable to treat various melancholia.Comprise dysthymia disorders and reactive depression with anxiety, with or without the panic disorder of agoraphobia, and obsession.
In existing paroxetine hydrochloride technique, take p-Fluorobenzenecarboxaldehyde as starting raw material, reaction generates the paroxetine methanesulfonate hydrochloride through five steps, then through demethylating reaction, becomes paroxetine hydrochloride, and concrete route is following as Fig. 1.Take p-Fluorobenzenecarboxaldehyde as starting raw material, reaction generates the paroxetine methanesulfonate hydrochloride through five steps, become paroxetine hydrochloride through demethylating reaction again, company considers for environmental protection now, the intermediate paroxetine methanesulfonate is entrusted to the cooperation production of units, and including the quality assurance system of the said firm in company management, company produces take paroxetine methanesulfonate as starting raw material, through demethylating reaction, generates paroxetine hydrochloride.Use chloroformic acid-α-chloroethene ester to be demethylation reagent in former technique, use the sulfur oxychloride of new distillation during this reagent is synthetic, complicated operation, synthetic chloroformic acid-α-chloroethene ester poor stability, yield is about 67%.
Chinese invention patent application (application number: 200810104136.1 applyings date: the preparation method who 2008-04-16) discloses a kind of paroxetine hydrochloride and intermediate thereof, the method adopts structural formula to prepare the compound of structural formula for (I) for the compound of (II), then prepare paroxetine, relate to multiple organic solvent in the method, be unfavorable for the removal of organic solvent;
（Ⅱ） （Ⅰ）。
Summary of the invention
, in order to solve the above problems, an object of the present invention is to provide a kind of paroxetine hydrochloride compound.Another object of the present invention is to provide the synthetic method of above-mentioned paroxetine hydrochloride compound.It is demethylation reagent that the present invention adopts the Vinyl chloroformate of suitability for industrialized production, and this reagent stability is good, and the demethylating reaction working condition is gentle, total recovery high (approximately 75%), and product meets 2010 editions pharmacopeia requirements, is fit to suitability for industrialized production.
In order to realize above-mentioned purpose, the present invention has adopted following technical scheme:
The paroxetine hydrochloride compound, it has following structural formula:
Above-mentioned paroxetine hydrochloride compound adopts following method to prepare:
1) the N-paroxetine methanesulfonate is added in toluene, the add-on of toluene is 10-20 times of N-paroxetine methanesulfonate weight,
Stir, drip the Vinyl chloroformate toluene mixture liquid under room temperature, the mol ratio of Vinyl chloroformate and N-paroxetine methanesulfonate is after 1:1.10-1.50 adds, stir 20-40 minute, be warming up to 60-70 ℃, insulated and stirred 4-6 hour, the TLC detection reaction is complete, and chemical equation is as follows:
Organic layer is water and sodium bicarbonate aqueous solution washing respectively, branch vibration layer, and concentrating under reduced pressure removes toluene, obtains thick thing;
2) residue adds ethanol, adds potassium hydroxide, the add-on of ethanol is 30-50 times of N-paroxetine methanesulfonate weight, the add-on of potassium hydroxide is 2.50-4.50 times of N-paroxetine methanesulfonate weight, intensification 70-90 ℃ of backflow 20-25 hour, the TLC detection reaction is complete, and chemical equation is as follows:
;
After reacting completely, concentrate and remove ethanol, stir the cooling methylbenzene extraction that adds, water layer is used methylbenzene extraction again, merge organic layer, organic layer washes with water, discards water layer, and at organic layer, drops into Medicinal Charcoal, stir 20-40 minute, after filtering decarbonization, obtain the paroxetine toluene solution;
3) add concentrated hydrochloric acid to transfer pH to 1-3 in organic layer, after having a large amount of crystal to separate out, 0-5 ℃, insulation 0.8-1.5 hour, filter, and can obtain the paroxetine hydrochloride crude product, and chemical equation is as follows:
；
4) Virahol is added in reactor the crude product weight in wet base: Virahol weight=1:3-5, Heating temperature is below 80 ℃, to dissolution of solid, press filtration to crystallization kettle, is cooled to 5-10 ℃, be incubated approximately 1-2 hour, filter, use washed with isopropyl alcohol, filter, 60-70 ℃ of drying under reduced pressure obtains anhydride, anhydride purified water hydration 5-6h, dry, be dried to moisture 2.0-3.0%, obtain finished product, chemical equation is as follows:
。
It is demethylation reagent that the present invention adopts the Vinyl chloroformate of suitability for industrialized production, and this reagent stability is good, and the demethylating reaction working condition is gentle, total recovery high (approximately 75%), and product meets 2010 editions pharmacopeia requirements, is fit to suitability for industrialized production.
Description of drawings
Fig. 1 is existing paroxetine hydrochloride process flow sheet.
Fig. 2 is paroxetine base toluene solution preparation technology skeleton diagram of the present invention.
Fig. 3 is paroxetine hydrochloride production technique skeleton diagram of the present invention.
Embodiment
Embodiment 1
The synthesis technique of paroxetine hydrochloride, process for purification
1) preparation of paroxetine hydrochloride crude product:
As shown in Figure 2,20 kg N-paroxetine methanesulfonates are added in 290kg toluene, stir, drip the Vinyl chloroformate toluene mixture liquid under room temperature, after adding, stirred 30 minutes, be warming up to 60-70 ℃, (the TLC detection reaction was complete in insulated and stirred 4-6 hour, sherwood oil: ethyl acetate=3:1), organic layer is water and sodium bicarbonate aqueous solution washing respectively, branch vibration layer, concentrating under reduced pressure removes toluene, obtains thick thing.
The N-paroxetine methanesulfonate, source: the Golden Bridge chemical plant of bordering on the sea
Residue adds ethanol 700kg, adds potassium hydroxide 70.0Kg, temperature rising reflux 20-25 hour (80 ℃ of left and right) (the TLC detection reaction be complete, as reacts slowly and can add potassium hydroxide).After reacting completely, concentrate and remove ethanol, stir the cooling 200L methylbenzene extraction that adds, water layer is used the 200L methylbenzene extraction again, merge organic layer, which floor has use the 200kg*4 water washing, discard water layer, organic layer drops into the 1.5kg Medicinal Charcoal, stirred 30 minutes, and after filtering decarbonization, obtained the paroxetine toluene solution.
2) as shown in Figure 3, add concentrated hydrochloric acid to transfer pH to 1 ~ 3 in organic layer, after having a large amount of crystal to separate out, 0-5 ℃, be incubated 1 hour, filters, and approximately 30kg(is wet can to obtain the paroxetine hydrochloride crude product).
3) (the crude product weight in wet base: Virahol weigh=1:4) adds in reactor, is heated to dissolution of solid (below 80 ℃), adds in case of necessity gac with the 120kg Virahol, press filtration to crystallization kettle, is cooled to 5-10 ℃, and insulation is 1-2 hour approximately, filter, use washed with isopropyl alcohol, filter, 60-70 ℃ of drying under reduced pressure obtains anhydride, anhydride purified water hydration 5-6h, dry, be dried to moisture 2.0-3.0%, obtain approximately 18kg of finished product.
4) three wastes are processed
Acid gas in the paroxetine hydrochloride production process adopts buck to absorb, decompose; Main organic solvent such as the recoveries such as toluene, Virahol; Residual liquid waste material and solid waste adopt burning disposal; Contain organic waste water, discharge after active sludge treatment reaches emission standard.
The study on the stability situation of test example 1 sample
Again after related substance, toxic impurities, isomer methodology being carried out corresponding research, three batch samples 100401,100402, the 100403 room temperatures placements related substance of 18 months that original technique three batch samples 091201,091202,091203 room temperature placement 24 months, embodiment 1 produce are analyzed, result show sample permanent stability that production technique is produced before changing afterwards investigate in related substance without considerable change, the related substance situation is basically identical.
The isomer that original technique three batch samples 091201,091202,091203 room temperature placement 26 months, embodiment 1 three batch samples 100401,100402,100403 room temperatures were placed 18 months detects, 6 batch samples all do not detect isomer, and are consistent with the situation of 0 month.
The steadiness of embodiment 1 three batch samples is as follows:
Study on the stability project: select according to the high spot reviews project of above-mentioned governing principle regulation and the character of this kind, mainly contain outward appearance, pH, moisture, related substance, content.
Check foundation: press 2010 editions standards of pharmacopoeia regulations of paroxetine hydrochloride
Three batches 100401,100402,100403 of producing of sample: embodiment 1.
Accelerated test
Test method: get this product simulation listing drug packaging, put 40 ℃ ± 2
oPlaced 6 months under the condition of C relative humidity RH75% ± 5%.By 0,1,2,3 and sampling in 6 months, to measure indices and 0 o'clock sample and compare, test-results is in Table 1.
Accelerated test is investigated 6 months, and test-results shows, this product appearance luster does not have considerable change, and related substance is without obvious increase, and other indices and 0 o'clock sample compare does not have considerable change.
Table 1 paroxetine hydrochloride accelerated test result
2.2 test of long duration
Get this product listing drug packaging three batches (100401,100402,100403 batches) in room temperature 25
oC ± 2
oPlace under C relative humidity RH60% ± 10% condition,, by 0,3 and sampling in 6 months, measure indices and 0 o'clock sample and compare, the results are shown in Table 2.
Room temperature is investigated 18 months, and sampling is in required time measured indices and compared with 0 o'clock sample, and appearance luster is variation not, and related substance, content etc. are without considerable change, other indices and relatively there is no considerable change at 0 o'clock.
Table 2 paroxetine hydrochloride bulk drug long-term test results
Conclusion: this product, by the listing drug packaging, is preserved at ambient temperature, and character is more stable, will continue this product is investigated.
The stability test conclusion
This product after changing three batch samples 100401,100402,100403 through accelerating 6 months and long-term investigation 18 months, indices, without considerable change,, with first three batch sample 091201,091202,091203 of change, is investigated no significant difference as a result.
The residual inspection of test example 2 related substances
Vinyl chloroformate:The vapor-phase chromatography of the Vinyl chloroformate of the methodology checking of process system, in detection intermediate product paroxetine crude product, Vinyl chloroformate is residual, and assay shows, is showed no the residual of Vinyl chloroformate.Company checks the Vinyl chloroformate in the paroxetine crude product is residual, and limit is 1ppm, and the Vinyl chloroformate that can effectively control in finished product is residual.
Impurity 1-methyl-4-(p-fluorophenyl)-1,2,3, it is assorted that 6-tetrahydropyridine(is called for short poison, European Pharmacopoeia impurity D):With the assorted liquid phase chromatography of poison through the checking of the methodology of system, detect 100401,100402,100,403 3 batches of paroxetine hydrochlorides that embodiment 1 produces poisoning assorted residual, assay shows, embodiment 1 three batch samples are showed no assorted the detecting of poison.Embodiment 1 sample is placed and is approximately carried out the toxic impurities inspection after 20 months, and sample is detectable toxicity impurity not, shows in the sample storage process and has no the assorted generation of poison.
Enantiomer (isomer European Pharmacopoeia impurity D):The Chiral liquid chromatography method of the isomer of the methodology checking of process system, isomer in 6 batches of paroxetines that the detection production technique is produced before changing afterwards, assay shows, be showed no detecting of isomer, embodiment 1 three batch samples 100401,100402,100403 permanent stability are investigated 18 months and are not detected isomer.
Related substance:Record 7 kinds of known impurities in 2010 editions paroxetine hydrochloride quality standards of British Pharmacopoeia, recorded 10 kinds of known impurities in 6.0 editions paroxetine hydrochloride quality standards of European Pharmacopoeia.European Pharmacopoeia is consistent with the impurity structural formula of same sequence number in British Pharmacopoeia paroxetine hydrochloride quality standard, is same impurity.Except the above poison that makes a search separately is assorted and cis isomerism is external, according to the actual production technique of our product and the collection situation of impurity, we have collected the synthetic intermediate 1,2,3,4 of impurity A, C, H and paroxetine hydrochloride, carried out the examination and test of products after before changing of the methodological study of system and production technique, wherein intermediate 1,2,3 is monitored in starting material N-paroxetine methanesulfonate.Test-results shows that 6 batches of products do not detect greater than 0.1% assorted peak, and always assorted limit is significantly less than the limit requirement (0.5%) of 2010 editions paroxetine hydrochloride related substances of Chinese Pharmacopoeia.
Relative retention time in, isomer assorted according to our poison, related substance test-results and European Pharmacopoeia 6.0, gather the list of impurity situation as follows.
Table paroxetine hydrochloride impurity situation gathers
Claims (1)
1. the synthetic method of a paroxetine hydrochloride compound, is characterized in that the method comprises the following steps:
1) the N-paroxetine methanesulfonate is added in toluene, the add-on of toluene is 10-20 times of N-paroxetine methanesulfonate weight, stir, drip the Vinyl chloroformate toluene mixture liquid under room temperature, the mol ratio of Vinyl chloroformate and N-paroxetine methanesulfonate is after 1:1.10-1.50 adds, and stirs 20-40 minute, be warming up to 60-70 ℃, insulated and stirred 4-6 hour, the TLC detection reaction is complete, and chemical equation is as follows:
；
Organic layer is water and sodium bicarbonate aqueous solution washing respectively, branch vibration layer, and concentrating under reduced pressure removes toluene, obtains thick thing;
2) residue adds ethanol, adds potassium hydroxide, the add-on of ethanol is 30-50 times of N-paroxetine methanesulfonate weight, the add-on of potassium hydroxide is 2.50-4.50 times of N-paroxetine methanesulfonate weight, intensification 70-90 ℃ of backflow 20-25 hour, the TLC detection reaction is complete, and chemical equation is as follows:
After reacting completely, concentrate and remove ethanol, stir the cooling methylbenzene extraction that adds, water layer is used methylbenzene extraction again, merge organic layer, organic layer washes with water, discards water layer, and at organic layer, drops into Medicinal Charcoal, stir 20-40 minute, after filtering decarbonization, obtain the paroxetine toluene solution;
3) add concentrated hydrochloric acid to transfer pH to 1-3 in organic layer, after having a large amount of crystal to separate out, 0-5 ℃, insulation 0.8-1.5 hour, filter, and can obtain the paroxetine hydrochloride crude product, and chemical equation is as follows:
；
4) Virahol is added in reactor the crude product weight in wet base: Virahol weight=1:3-5, Heating temperature is below 80 ℃, to dissolution of solid, press filtration to crystallization kettle, is cooled to 5-10 ℃, be incubated approximately 1-2 hour, filter, use washed with isopropyl alcohol, filter, 60-70 ℃ of drying under reduced pressure obtains anhydride, anhydride purified water hydration 5-6h, dry, be dried to moisture 2.0-3.0%, obtain finished product, chemical equation is as follows:
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