CN108239085A - A kind of purifying of ziprasidone and preparation method - Google Patents
A kind of purifying of ziprasidone and preparation method Download PDFInfo
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- CN108239085A CN108239085A CN201611218851.9A CN201611218851A CN108239085A CN 108239085 A CN108239085 A CN 108239085A CN 201611218851 A CN201611218851 A CN 201611218851A CN 108239085 A CN108239085 A CN 108239085A
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
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Abstract
The invention discloses a kind of purification process of ziprasidone, include the following steps：(1) ziprasidone crude product is taken, heating is dissolved in the in the mixed solvent of tetrahydrofuran and water composition, adds in activated carbon decolorizing, and solid is precipitated；Wherein, the volume ratio of tetrahydrofuran and water is 15：1‑5；(2) ziprasidone sterling is obtained after taking solid washing dry.The method of the present invention is easy to operate, safety, and yield and purity are higher, to equipment without particular/special requirement, can meet the needs of large-scale industrial production, improve industrial production efficiency, material is greatly saved, reduce industrial production cost.The invention also discloses a kind of preparation methods of the high-purity ziprasidone carried out using purification process of the present invention.
Description
Technical field
The present invention relates to drug fields, and in particular to a kind of purifying of ziprasidone and preparation method.
Background technology
Ziprasidone (Ziprasidone) is the novel atypia wide spectrum antipsychotic drug of Pfizer's exploitation, for controlling
Schizophrenia is treated, molecular structure is as follows：
This product category serotonin and dopamine-receptor antagonist are particularly strong to 5-HTA2/DA D2 receptor affinities.
In September, 2000 lists for the first time in Sweden, enters Chinese market within 2007, at present in the country's listing of more than 50, the world.The medicine pair
The schizophrenia positive and negative symptoms are effective, especially more preferable to the effect of negative symptoms, safe, with the anti-spirit of tradition
Sick medicine phases ratio, the medicine can also improve negative symptoms in addition to it can improve positive symptom, improve cognitive function, and tolerance significantly improves；
Compared with Olanzapine, quinoline Horizon, Risperidone for being widely used etc., this product does not cause to negative symptoms better efficacy or quite
Weight gain and Serum Prolactin In Patients raising, Small side effects are in existing atypical antipsychotic agents.
Existing literature 1 (CN97194243) reports the purifying of Ziprasidone alkali, the preparation of ziprasidone.Specifically
For：
Ziprasidone alkali 46.8kg, 2816.4L tetrahydrofuran is heated to reflux and is kept for 45 minutes, filtering, and filter vacuum is dense
Contracting is cooled to 5 DEG C, stirs 2 hours.Centrifugal filtration, 0-5 DEG C of tetrahydrofuran cleaning are dry.Qi Laxi after upper step purifying
Ketone alkali 1000g, 7500mL sterile water, 4000mL tetrahydrofurans, are protected from light, are stirred and heated to 50 DEG C, by 188mL methanesulfonic acids and
812mL sterile waters mix, and are added in Ziprasidone alkali, are heated to back flow reaction 30 minutes.Cool overnight (18h) is stirred, point
From, and be continuously dried to obtain with 1500mL tetrahydrofurans/sterile water (65/35, v/v) and 1000mL sterile water wash.But this
The impurity content that kind of method is prepared is high, and obtained ziprasidone is pink colour to red, European Pharmacopoeia 8.7
Middle regulation ziprasidone should be white to off-white color, therefore the ziprasidone that such method prepares is not inconsistent
Close the standard of pharmacopeia.
Existing literature 2 (CN101437817) reports the preparation and purification of Ziprasidone alkali, specially：
4- (1,2- benzisothiazole -3- bases) -1- piperazines of 38.4g, 5- (2- bromoethyls) -6- chloro- 1,3- of 21.96g
Dihydro-indole ketone is dissolved in 240mL acetonitriles, boils 4h.Cooling, filtering, 50mL acetonitriles washing, with 240mL distilled water in 85-90
Temperature between DEG C stirs 1 hour, filters, dry.It is flowed back with the tetrahydrofuran containing 7.5% water of 760mL, adds in 2.8g
Charcoal, 2.8g silica gel flow back 30 minutes, and filtering, filtrate is concentrated into 80mL, is stirred 30 minutes in ice water, filter, with the cold tetrahydrochysenes of 20mL
Furans washs, and is dried to obtain.Inventor repeats this experiment, it is found that reaction is not easy that the reaction was complete, low yield.
Existing literature 3 (CN102250083A) reports the preparation of Ziprasidone alkali, specially：
Chloro- 1, the 3- Dihydro-indoles ketone of 5- (2- chloroethyls) -6- and 4- are added in into water-soluble aprotic polar solvent
The hydrochloride of (1,2- benzisothiazole -3- bases) -1- piperazines, and the aqueous solution of inorganic base is added in, it is small to react 3-6 at 60-70 DEG C
Shi Hou is cooled to 30 DEG C, adds in purified water, and 20-30 DEG C is stirred 30-60 minutes, is filtered, washing, dry obtained Ziprasidone.This
Inventor repeats above-mentioned reaction, after reaction time consumption is up to 20 hours, can not the reaction was complete, there are low yield, only 60% is left
The right side, and the Ziprasidone alkali purity being prepared is also low, is 92%.
It is therefore desirable to the preparation routes of one new ziprasidone of exploration discovery, can make the first being prepared
Sulfonic acid Ziprasidone purity is high, and yield is high, and color, to off-white color, meets the quality standard of pharmacopeia to be white.
Invention content
To solve the above problems, the present invention provides a kind of purification process of ziprasidone, include the following steps：
(1) ziprasidone crude product is taken, heating is dissolved in the in the mixed solvent of tetrahydrofuran and water composition, adds in activity
Solid is precipitated in carbon decoloring；Wherein, the volume ratio of tetrahydrofuran and water is 15：1-5；
(2) ziprasidone sterling is obtained after taking solid washing dry.
Further, in step (1), the mass volume ratio of the ziprasidone crude product and mixed solvent is：1:
8-25g/mL。
Further, in step (1), the mass ratio of the activated carbon dosage and crude product ziprasidone is 0.05-
1：1.
Further, in step (2), the washing reagent is esters solvent, ether solvent, ketones solvent or nitrile are molten
Agent.
Further, the washing reagent is ethyl acetate, acetonitrile, tetrahydrofuran, acetone, butanone or ether.
Further, in step (2), the mass volume ratio of ziprasidone crude product and washing reagent is：1:5-
20g/mL。
The present invention also provides a kind of preparation methods of high-purity ziprasidone, it is characterised in that：(A) with 5-
Chloro- 1, the 3- Dihydro-indoles ketone of (2- bromoethyls) -6- and 4- (1,2- benzisothiazole -3- bases) -1- piperazines are raw material, with organic
The mixed solvent of solvent and water reacts in the presence of an inorganic base as solvent；The organic solvent is selected from tetrahydrofuran, diformazan
Base sulfoxide or acetonitrile；The volume ratio of the organic solvent and water is 10：1-10；
(B) reaction solution is filtered, washes, dissolved with tetrahydrofuran, concentrated, added in acetone crystallization at 0-25 DEG C, obtain together
Draw western ketone alkali crude product；
(C) Ziprasidone alkali crude product with Loprazolam is reacted, ziprasidone crude product is prepared；
(D) ziprasidone crude product is purified according to claim 1-6 any one of them purification process, be prepared
The ziprasidone of high-purity.
Further, in step (A), the inorganic base is selected from sodium carbonate or potassium carbonate.
Further, in step (A), 4- (1,2- benzisothiazole -3- bases) -1- piperazines and 5- (2- bromoethyls) -6- are chloro-
The molar ratio of 1,3- Dihydro-indole ketone is 1:1-2, the molar ratio with inorganic base are 1:0.4-2.
Further, the mass volume ratio of chloro- 1, the 3- Dihydro-indoles ketone of 5- (2- the bromoethyls) -6- and mixed solvent
It is 1：6-20g/mL.
The present invention provides a kind of purifying of new ziprasidone and preparation method methods.The method of the present invention can
Low yield of the existing technology is effectively solved, product purity is low, and product colour is unqualified, is unsatisfactory for regulation of pharmacopeia etc. and asks
Topic, the ziprasidone bulk pharmaceutical chemicals to synthesize cheap and good quality provide an effective solution route.
The method of the present invention can make to prepare the yield of Ziprasidone alkali up to more than 90%, chemical purity relative to the prior art
Up to more than 99.5%, making the purifying yield of ziprasidone, purity reaches more than 99.8%, and solves up to more than 85%
The color problem of ziprasidone, the ziprasidone being prepared are white, make ziprasidone
Color meet the regulation of pharmacopeia, improve the quality of product.
Also, the method for the present invention is easy to operate, safety, and yield and purity are higher, to equipment without particular/special requirement, Ke Yiman
The demand of sufficient large-scale industrial production, improves industrial production efficiency, and material is greatly saved, and reduces industrial production cost.
Obviously, the above according to the present invention according to the ordinary technical knowledge and customary means of this field, is not departing from
Under the premise of the above-mentioned basic fundamental thought of the present invention, the modification, replacement or change of other diversified forms can also be made.
The specific embodiment of form by the following examples remakes further specifically the above of the present invention
It is bright.But the range that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to following example.It is all to be based on the above of the present invention
The technology realized all belongs to the scope of the present invention.
Specific embodiment
The preparation of 1 Ziprasidone alkali of embodiment
Weigh chloro- 1, the 3- Dihydro-indoles ketone of 5- (2- bromoethyls) -6- of 70g, 4- (1, the 2- benzisothiazole -3- of 84g
Base) -1- piperazines, 13.5g sodium carbonate, add in 700mL acetonitriles, 140mL water is passed through nitrogen protection, and back flow reaction is to the reaction was complete.
It is cooled to room temperature, filters, wash filter cake.It is flowed back with the 2170mL tetrahydrofurans for containing 7.5% water, adds in 7g activated carbons and 7g silicon
Glue, reflux decoloration, filtrate are concentrated into 245mL, add in 245mL acetone, and 10 DEG C of crystallizations filter, dry pink Ziprasidone
Alkali 97.5g, it is that survey its purity be 99.51% to 92.6%, HPLC to calculate its yield.
The preparation of 2 Ziprasidone alkali of embodiment
Weigh chloro- 1, the 3- Dihydro-indoles ketone of 5- (2- bromoethyls) -6- of 70g, 4- (1, the 2- benzisothiazole -3- of 56g
Base) -1- piperazines, 11g sodium carbonate, add in 382mL tetrahydrofurans, 38mL water is passed through nitrogen protection, and back flow reaction is to having reacted
Entirely.It is cooled to room temperature, filters, wash filter cake.With 2170mL contain 7.5% water tetrahydrofuran flow back, add in 7g activated carbons and
7g silica gel, reflux decoloration, filtrate are concentrated into 245mL, add in 245mL tetrahydrofurans, and 20 DEG C of crystallizations filter, pinkly dry
Ziprasidone alkali 96.2g, it is that survey its purity be 99.50% to 91.3%, HPLC to calculate its yield.
The preparation of 3 Ziprasidone alkali of embodiment
Weigh chloro- 1, the 3- Dihydro-indoles ketone of 5- (2- bromoethyls) -6- of 70g, 4- (1, the 2- benzisothiazole -3- of 63g
Base) -1- piperazines, 16g sodium carbonate, add in 327mL dimethyl sulfoxide (DMSO)s, 163mL water, be passed through nitrogen protection, back flow reaction to react
Completely.It is cooled to room temperature, filters, wash filter cake.It is flowed back with the 2170mL tetrahydrofurans for containing 7.5% water, adds in 7g activated carbons
With 7g silica gel, reflux decoloration, filtrate is concentrated into 245mL, adds in 245mL acetonitriles, 25 DEG C of crystallizations, filters dry pink neat drawing
Western ketone alkali 96.8g, it is that survey its purity be 99.52% to 91.9%, HPLC to calculate its yield.
The preparation of 4 Ziprasidone alkali of embodiment
Weigh chloro- 1, the 3- Dihydro-indoles ketone of 5- (2- bromoethyls) -6- of 70g, -4- (1, the 2- benzisothiazole -3- of 70g
Base) -1- piperazines, 20g potassium carbonate, add in 280mL acetonitriles, 280mL water is passed through nitrogen v protections, and back flow reaction is to the reaction was complete.
It is cooled to room temperature, filters, wash filter cake.It is flowed back with the 2170mL tetrahydrofurans for containing 7.5% water, adds in 7g activated carbons and 7g silicon
Glue, reflux decoloration, filtrate are concentrated into 245mL, add in 100mL dimethyl sulfoxides, and 0 DEG C of crystallization filters, dry pink Qi Laxi
Ketone alkali 97.2g, it is that survey its purity be 99.51% to 92.3%, HPLC to calculate its yield.
The preparation of 5 Ziprasidone alkali of embodiment
Weigh chloro- 1, the 3- Dihydro-indoles ketone of 5- (2- bromoethyls) -6- of 70g, 4- (1, the 2- benzisothiazole -3- of 112g
Base) -1- piperazines, 25g potassium carbonate, add in 525mL tetrahydrofurans, 105mL water is passed through nitrogen protection, and back flow reaction is to having reacted
Entirely.It is cooled to room temperature, filters, wash filter cake.With 2170mL contain 7.5% water tetrahydrofuran flow back, add in 7g activated carbons and
7g silica gel, reflux decoloration, filtrate are concentrated into 245mL, add in 245mL acetone, 10 DEG C of crystallizations, filter dry pink Qi Laxi
Ketone alkali 95.5g, it is that survey its purity be 99.53% to 90.7%, HPLC to calculate its yield.
The preparation of 6 Ziprasidone alkali of embodiment
Weigh chloro- 1, the 3- Dihydro-indoles ketone of 5- (2- bromoethyls) -6- of 70g, 4- (1, the 2- benzisothiazole -3- of 91g
Base) -1- piperazines, 30g sodium carbonate, add in 636mL dimethyl sulfoxide (DMSO)s, 64mL water is passed through nitrogen protection, and back flow reaction is to having reacted
Entirely.It is cooled to room temperature, filters, wash filter cake.With 2170mL contain 7.5% water tetrahydrofuran flow back, add in 7g activated carbons and
7g silica gel, reflux decoloration, filtrate are concentrated into 245mL, add in 245mL acetonitriles, 20 DEG C of crystallizations, filter dry pink Qi Laxi
Ketone alkali 95.0g, it is that survey its purity be 99.56% to 90.2%, HPLC to calculate its yield.
The preparation of 7 Ziprasidone alkali of embodiment
Weigh chloro- 1, the 3- Dihydro-indoles ketone of 5- (2- bromoethyls) -6- of 70g, 4- (1, the 2- benzisothiazole -3- of 96g
Base) -1- piperazines, 40g sodium carbonate, add in 606mL acetonitriles, 304mL water is passed through nitrogen protection, and back flow reaction is to the reaction was complete.It is cold
But to room temperature, filter cake is washed in filtering.It is flowed back with the 2170mL tetrahydrofurans for containing 7.5% water, adds in 7g activated carbons and 7g silicon
Glue, reflux decoloration, filtrate are concentrated into 245mL, add in 100mL dimethyl sulfoxides, and 5 DEG C of crystallizations filter, dry pink Qi Laxi
Ketone alkali 96.6g, it is that survey its purity be 99.50% to 91.7%, HPLC to calculate its yield.
The preparation of 8 Ziprasidone alkali of embodiment
Weigh chloro- 1, the 3- Dihydro-indoles ketone of 5- (2- bromoethyls) -6- of 70g, 4- (1, the 2- benzisothiazole -3- of 100g
Base) -1- piperazines, 54g sodium carbonate, add in 525mL tetrahydrofurans, 525mL water is passed through nitrogen protection, and back flow reaction is to having reacted
Entirely.It is cooled to room temperature, filters, wash filter cake.With 2170mL contain 7.5% water tetrahydrofuran flow back, add in 7g activated carbons and
7g silica gel, reflux decoloration, filtrate are concentrated into 245mL, add in 245mL acetone, and 15 DEG C of crystallizations filter, dry pink neat drawing
Western ketone alkali 97.0g, it is that survey its purity be 99.60% to 92.1%, HPLC to calculate its yield.
The preparation of 9 Ziprasidone alkali of embodiment
Weigh chloro- 1, the 3- Dihydro-indoles ketone of 5- (2- bromoethyls) -6- of 70g, 4- (1, the 2- benzisothiazole -3- of 105g
Base) -1- piperazines, 35g potassium carbonate, add in 1000mL dimethyl sulfoxide (DMSO)s, 200mL water, be passed through nitrogen protection, back flow reaction to react
Completely.It is cooled to room temperature, filters, wash filter cake.It is flowed back with the 2170mL tetrahydrofurans for containing 7.5% water, adds in 7g activated carbons
With 7g silica gel, reflux decoloration, filtrate is concentrated into 245mL, adds in 245mL tetrahydrofurans, and 10 DEG C of crystallizations filter, pinkly dry
Color Ziprasidone alkali 97.4g, it is that survey its purity be 99.59% to 92.5%, HPLC to calculate its yield.
The preparation of 10 Ziprasidone alkali of embodiment
Weigh chloro- 1, the 3- Dihydro-indoles ketone of 5- (2- bromoethyls) -6- of 70g, 4- (1, the 2- benzisothiazole -3- of 77g
Base) -1- piperazines, 15g sodium carbonate, add in 1273mL acetonitriles, 127mL water is passed through nitrogen protection, and back flow reaction is to the reaction was complete.
It is cooled to room temperature, filters, wash filter cake.It is flowed back with the 2170mL tetrahydrofurans for containing 7.5% water, adds in 7g activated carbons and 7g silicon
Glue, reflux decoloration, filtrate are concentrated into 245mL, add in 245mL acetone, and 15 DEG C of crystallizations filter, dry pink Ziprasidone
Alkali 97.9g, it is that survey its purity be 99.54% to 92.9%, HPLC to calculate its yield.
The preparation of 11 ziprasidone crude product of embodiment
It weighs Ziprasidone alkali 80g, tetrahydrofuran 320mL, purified water 600g that embodiment 1 is prepared and is passed through nitrogen
It protects and is protected from light, 50 DEG C are warming up under stirring, Loprazolam aqueous solution 86.3g (Loprazolam 22.3g, water 64g) is slowly added dropwise,
It is added dropwise, is warming up to back flow reaction 30min；After completion of the reaction, stirring and crystallizing is overnight, filters, dry pink solid first
Sulfonic acid Ziprasidone crude product 94g, yield 95%, purity 95.2%.
The purifying of 12 ziprasidone crude product of embodiment
Ziprasidone crude product 90g, tetrahydrofuran 675mL, purified water 45g that embodiment 11 is prepared are weighed,
It is passed through nitrogen to protect and be protected from light, reflux dissolved clarification is warming up under stirring, add in medicinal carbon 4.5g, be stirred at reflux decoloration, rapidly
Heat filter, filtrate decompression are concentrated to dryness to obtain solid, add in ethyl acetate 450mL, stir, and filter, dry white solid methylsulphur
Sour Ziprasidone sterling 78.0g, yield 86.6%, it is 99.80% that HPLC, which surveys its purity,.
The purifying of 13 ziprasidone crude product of embodiment
Commercially available red ziprasidone crude product 90g, tetrahydrofuran 708mL, the purified water 142g being commercially available is weighed,
It is passed through nitrogen to protect and be protected from light, reflux dissolved clarification is warming up under stirring, add in medicinal carbon 9g, be stirred at reflux decoloration, rapid heat
Filter, filtrate decompression are concentrated to dryness to obtain solid, add in acetonitrile 450mL, stir, filter, dry that white solid methanesulfonic acid is drawn together
Western ketone sterling 76.5g, yield 85.0%, it is 99.81% that HPLC, which surveys its purity,.
The purifying of 14 ziprasidone crude product of embodiment
Ziprasidone crude product 90g, tetrahydrofuran 675mL, purified water 225g that embodiment 11 is prepared are weighed,
It is passed through nitrogen to protect and be protected from light, reflux dissolved clarification is warming up under stirring, add in medicinal carbon 13.5g, be stirred at reflux decoloration, rapidly
Heat filter, filtrate decompression are concentrated to dryness to obtain solid, add in acetone 1100mL, stir, filter, dry that white solid methanesulfonic acid is neat
Western ketone sterling 76.9g, yield 85.4% are drawn, it is 99.83% that HPLC, which surveys its purity,.
The purifying of 15 ziprasidone crude product of embodiment
Ziprasidone crude product 90g, tetrahydrofuran 652mL, purified water 348g that embodiment 11 is prepared are weighed,
It is passed through nitrogen to protect and be protected from light, reflux dissolved clarification is warming up under stirring, add in medicinal carbon 18g, be stirred at reflux decoloration, rapid heat
Filter is concentrated under reduced pressure into 300mL, adds in 300mL acetone crystallizations, and filtering is dry that yellow filter cake, addition tetrahydrofuran 600mL are stirred
It mixes, filters, it is dry that white solid ziprasidone sterling 76.7g, yield 85.2%, HPLC survey its purity and be
99.80%.
The purifying of 16 ziprasidone crude product of embodiment
Ziprasidone crude product 90g, tetrahydrofuran 720mL, purified water 480g that embodiment 11 is prepared are weighed,
It is passed through nitrogen to protect and be protected from light, reflux dissolved clarification is warming up under stirring, add in medicinal carbon 25g, be stirred at reflux decoloration, rapid heat
Filter is concentrated under reduced pressure into 300mL, adds in 300mL acetonitrile crystallizations, and filtering is dry that yellow filter cake, addition ethyl acetate 700mL are stirred
It mixes, filters, it is dry that white solid ziprasidone sterling 77.3g, yield 85.9%, HPLC survey its purity and be
99.80%.
The purifying of 17 ziprasidone crude product of embodiment
The ziprasidone crude product 90g for weighing that embodiment 11 is prepared, tetrahydrofuran 1250mL, purified water
1000g is passed through nitrogen and protects and be protected from light, and reflux dissolved clarification is warming up under stirring, adds in medicinal carbon 35g, is stirred at reflux decoloration,
Rapid heat filter, is concentrated under reduced pressure into 300mL, adds in 300mL acetone crystallizations, filtering, and dry yellow filter cake adds in ether
1200mL is stirred, and is filtered, and dry white solid ziprasidone sterling 77.0g, yield 85.6%, it is pure that HPLC surveys its
Spend is 99.81%.
The purifying of 18 ziprasidone crude product of embodiment
The ziprasidone crude product 90g for weighing that embodiment 11 is prepared, tetrahydrofuran 1050mL, purified water
1050g is passed through nitrogen and protects and be protected from light, and reflux dissolved clarification is warming up under stirring, adds in medicinal carbon 90g, is stirred at reflux decoloration,
Rapid heat filter, is concentrated under reduced pressure into 300mL, adds in 300mL tetrahydrofuran crystallizations, filtering, and dry yellow filter cake adds in tetrahydrochysene furan
Mutter 1500mL, stirs, and filters, and dry white solid ziprasidone sterling 77.1g, yield 85.7%, HPLC surveys it
Purity is 99.84%.
The purifying of 19 ziprasidone crude product of embodiment
The ziprasidone crude product 90g for weighing that embodiment 11 is prepared, tetrahydrofuran 1080mL, purified water
270g is passed through nitrogen and protects and be protected from light, and reflux dissolved clarification is warming up under stirring, adds in medicinal carbon 50g, is stirred at reflux decoloration,
Rapid heat filter, is concentrated under reduced pressure into 300mL, adds in 100mL dimethyl sulfoxide crystallizations, filtering, and dry yellow filter cake adds in acetonitrile
900mL is stirred, and is filtered, dry that white solid ziprasidone sterling 76.5g, yield 85.0%, HPLC survey its purity
It is 99.82%.
The purifying of 20 ziprasidone crude product of embodiment
The ziprasidone crude product 90g for weighing that embodiment 11 is prepared, tetrahydrofuran 1000mL, purified water
500g is passed through nitrogen and protects and be protected from light, and reflux dissolved clarification is warming up under stirring, adds in medicinal carbon 70g, is stirred at reflux decoloration,
Rapid heat filter, is concentrated under reduced pressure into 300mL, adds in 300mL acetone crystallizations, filtering, and dry yellow filter cake adds in acetone
1800mL is stirred, and is filtered, and dry white solid ziprasidone sterling 76.8g, yield 85.3%, it is pure that HPLC surveys its
Spend is 99.80%.
The purifying of 21 ziprasidone crude product of embodiment
The ziprasidone crude product 90g for weighing that embodiment 11 is prepared, tetrahydrofuran 1543mL, purified water
257g is passed through nitrogen and protects and be protected from light, and reflux dissolved clarification is warming up under stirring, adds in medicinal carbon 60g, is stirred at reflux decoloration,
Rapid heat filter, is concentrated under reduced pressure into 300mL, adds in 300mL acetonitrile crystallizations, filtering, and dry yellow filter cake adds in ether 450mL,
Stirring filters, dry that white solid ziprasidone sterling 77.5g, yield 86.1%, HPLC survey its purity and be
99.85%.
The purifying of 22 ziprasidone crude product of embodiment
Ziprasidone crude product 90g, tetrahydrofuran 652mL, purified water 348g that embodiment 11 is prepared are weighed,
It is passed through nitrogen to protect and be protected from light, reflux dissolved clarification is warming up under stirring, add in medicinal carbon 18g, be stirred at reflux decoloration, rapid heat
Filter is concentrated under reduced pressure into 300mL, adds in 300mL acetone crystallizations, and filtering is dry that yellow filter cake, addition butanone 600mL are stirred,
It filters, dry white solid ziprasidone sterling 76.7g, yield 85.2%, it is 99.81% that HPLC, which surveys its purity,.
Further to prove the advantageous effect of the method for the present invention, comparative experimental example is provided below.
Comparative experimental example 1
According to existing literature 3 (CN102250083A)：
Tetrahydrofuran 210mL is added in into 500mL there-necked flasks, opens stirring, chloro- 1, the 3- bis- of input 5- (2- chloroethyls) -6-
Hydrogen-indoles -2- (2H) -one 15.0g (65.2mmol), 3- (1- piperazinyls) -1,2- benzisothia triazole hydrochlorides 17.0g
(66.5mmol) adds 90mL 20%Na2CO3Aqueous solution is warming up to 60-70 DEG C, and insulation reaction 5 hours, TLC detections are reacted
After be cooled to 30 DEG C, add in purified water 225mL, cooling finishes insulated and stirred 45 minutes, filters, and purifies water wash with 30mL
Filter cake.Solid material is put into drying 4 hours in 60 DEG C of vacuum drying chambers, obtains red Ziprasidone 16.7g, yield
62.1%, HPLC detect purity 92.5%.
In conclusion the method for the present invention is easy to operate, safety, yield and purity are higher, can to equipment without particular/special requirement
To meet the needs of large-scale industrial production, improve industrial production efficiency, material be greatly saved, reduce industrial production into
This.
Claims (10)
1. a kind of purification process of ziprasidone, it is characterised in that：Include the following steps：
(1) ziprasidone crude product is taken, heating is dissolved in the in the mixed solvent of tetrahydrofuran and water composition, adds in activated carbon and takes off
Solid is precipitated in color；Wherein, the volume ratio of tetrahydrofuran and water is 15：1-5；
(2) ziprasidone sterling is obtained after taking solid washing dry.
2. purification process according to claim 1, it is characterised in that：In step (1), the ziprasidone crude product
Mass volume ratio with mixed solvent is：1:8-25g/mL.
3. purification process according to claim 1, it is characterised in that：In step (1), the activated carbon dosage and crude product first
The mass ratio of sulfonic acid Ziprasidone is 0.05-1：1.
4. according to claim 1-3 any one of them purification process, it is characterised in that：In step (2), the washing reagent is
Esters solvent, ether solvent, ketones solvent or nitrile solvents.
5. according to the method described in claim 4, it is characterized in that：The washing reagent is ethyl acetate, acetonitrile, tetrahydrochysene furan
It mutters, acetone, butanone or ether.
6. according to the purification process described in right 5, it is characterised in that：In step (2), ziprasidone crude product is tried with washing
The mass volume ratio of agent is：1:5-20g/mL.
7. a kind of preparation method of high-purity ziprasidone, it is characterised in that：Include the following steps：
(A) it is with chloro- 1, the 3- Dihydro-indoles ketone of 5- (2- bromoethyls) -6- and 4- (1,2- benzisothiazole -3- bases) -1- piperazines
Raw material using the mixed solvent of organic solvent and water as solvent, reacts in the presence of an inorganic base；The organic solvent is selected from four
Hydrogen furans, dimethyl sulfoxide (DMSO) or acetonitrile；The volume ratio of the organic solvent and water is 10：1-10；
(B) reaction solution is filtered, washes, dissolved with tetrahydrofuran, concentrated, add in acetone crystallization, get Qi Laxi at 0-25 DEG C
Ketone alkali crude product；
(C) Ziprasidone alkali crude product with Loprazolam is reacted, ziprasidone crude product is prepared；
(D) ziprasidone crude product is purified according to claim 1-6 any one of them purification process, be prepared high-purity
The ziprasidone of degree.
8. preparation method according to claim 7, it is characterised in that：In step (A), the inorganic base be selected from sodium carbonate or
Potassium carbonate.
9. preparation method according to claim 8, it is characterised in that：In step (A), 4- (1,2- benzisothiazole -3-
Base) molar ratio of -1- piperazines and chloro- 1, the 3- Dihydro-indoles ketone of 5- (2- bromoethyls) -6- is 1:1-2, the molar ratio with inorganic base
It is 1:0.4-2.
10. according to claim 7-9 any one of them preparation methods, it is characterised in that：5- (2- the bromoethyls) -6- is chloro-
The mass volume ratio of 1,3- Dihydro-indole ketone and mixed solvent is 1：6-20g/mL.
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| CN1635892A (en) * | 2002-02-20 | 2005-07-06 | 辉瑞产品公司 | Ziprasidone composition and synthetic controls |
| CN1895252A (en) * | 2005-07-15 | 2007-01-17 | 重庆圣华曦药业有限公司 | Zirasitone mesylate soluble medicinal preparation |
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| CN1995038A (en) * | 2006-07-01 | 2007-07-11 | 杭州盛美医药科技开发有限公司 | Preparation method of ziprasidone |
| CN101437817A (en) * | 2006-05-02 | 2009-05-20 | 吉瑞工厂 | Novel process for production of 5-{2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-ethyl}-6-chloro-1,3-dihydro-2H-indol-2-one (ziprasidone) |
| CN102250083A (en) * | 2011-08-03 | 2011-11-23 | 齐鲁天和惠世制药有限公司 | Method for preparing ziprasidone |
| CN104370850A (en) * | 2013-08-14 | 2015-02-25 | 上海天慈生物谷生物工程有限公司 | Ziprasidone key intermediate preparation method |
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| CN1635892A (en) * | 2002-02-20 | 2005-07-06 | 辉瑞产品公司 | Ziprasidone composition and synthetic controls |
| CN1934108A (en) * | 2003-12-18 | 2007-03-21 | 特瓦制药工业有限公司 | Polymorphic form B2 of ziprasidone base |
| CN1895252A (en) * | 2005-07-15 | 2007-01-17 | 重庆圣华曦药业有限公司 | Zirasitone mesylate soluble medicinal preparation |
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| CN104370850A (en) * | 2013-08-14 | 2015-02-25 | 上海天慈生物谷生物工程有限公司 | Ziprasidone key intermediate preparation method |
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