CN100491375C - Preparation method of ziprasidone - Google Patents
Preparation method of ziprasidone Download PDFInfo
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- CN100491375C CN100491375C CNB200610125949XA CN200610125949A CN100491375C CN 100491375 C CN100491375 C CN 100491375C CN B200610125949X A CNB200610125949X A CN B200610125949XA CN 200610125949 A CN200610125949 A CN 200610125949A CN 100491375 C CN100491375 C CN 100491375C
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- ziprasidone
- piperazine
- benzisothiazole
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Abstract
The invention discloses a making method of qilaxi ketone with structural formula as formula (I), which is characterized by the following: the chemical name of compound is 5-(2-(4-(1,2-benzo isothiazole-3-base)-piperazine) acetyl)-6-chloride-1, 3-dihydrogen-2H-indole-2-ketone, which is reduced in the organic acid solvent; the solvent is C1-C6 paraffin acid substituted by at least one halogenate atom with carboxyl function group.
Description
(1) technical field
The present invention relates to a kind of preparation method of Ziprasidone.
(2) background technology
Ziprasidone (ziprasidone) is a kind of newer atypical antipsychotic agents, and it is serotonin and dopamine D
2The antagonist of acceptor, it can effectively treat schizophrenia feminine gender and positive symptom, comprise illusion, illusion and initiative shortage etc., develop by U.S. Pfizer company, in September, 2000, in Sweden's listing, the chemical name of Ziprasidone was: 5-(2-(4-(1,2-benzisothiazole-3-yl)-1-piperazinyl) ethyl)-6-chloro-1 first, 3-dihydro-2H-indol-2-one, structural formula is as follows:
U.S. Pat 4831031 discloses the method for preparing Ziprasidone:
This method is to be catalyzer with the sodium iodide, in the presence of yellow soda ash, hexone is a solvent, compound N-(1,2-benzisothiazole-3-yl) piperazine and compound 5-(2-chloroethyl) 6-chloro-indolone back flow reaction is 40 hours, after column chromatography makes Ziprasidone.Total recovery is 20%, and so low yield explanation has a large amount of by products, needs expensive purification procedures, in addition, there are many reports to mention changing solvent and optimize this reaction, but the result who does not all feel quite pleased.
(3) summary of the invention
Prepare for solving Ziprasidone in the prior art that yield is low, complicated operation, long reaction time, deficiency that cost is high, the invention provides the preparation method of a kind of yield height, simple to operate, the reaction times is short, cost is low Ziprasidone.
For reaching goal of the invention the technical solution used in the present invention be:
A kind of preparation method of Ziprasidone; described method is that ((4-(1 for 2-by the compound of structural formula as (I): 5-; 2-benzisothiazole-3-yl)-and piperazine) ethanoyl)-6-chloro-1; 3-dihydro-2H-indol-2-one; reduce with reductive agent in organic acid solvent and make described Ziprasidone, described organic acid solvent is to contain carboxyl functional group and contain the C that a halogen atom replaces at least
1～C
6Alkane acid;
With the Ziprasidone that this method of reducing obtains, aftertreatment is very simple, and purity is very high.
Described reductive agent can be trialkyl silane, and the alkyl of described trialkyl silane is C
1～C
6Alkyl, be preferably trimethyl silane or triethyl silicane.It is one of following that described organic acid solvent is preferably: trichoroacetic acid(TCA) or trifluoroacetic acid or chloropon.
Described reduction reaction was reacted 12～28 hours down at 20～50 ℃, described 5-(2-(4-(1,2-benzisothiazole-3-yl)-piperazine) ethanoyl)-6-chloro-1, and 3-dihydro-2H-indol-2-one is 1:1～6 with the ratio of trialkyl silane amount of substance.
Described 5-(2-(4-(1,2-benzisothiazole-3-yl)-piperazine) ethanoyl)-6-chloro-1,3-dihydro-2H-indol-2-one is obtained by following method:
With structural formula is the compound of formula (II): N-(1,2-benzisothiazole-3-yl) piperazine or its halogen acid salt, and the compound of general formula (III)
In the presence of alkali, make catalyzer with alkaline metal iodide, in the presence of the organic solvent that contains sulfoxide or amide group, carry out condensation reaction and obtain described 5-(2-(4-(1,2-benzisothiazole-3-yl)-piperazine) ethanoyl)-6-chloro-1,3-dihydro-2H-indol-2-one; Wherein, formula (II) L is a leavings group, and described leavings group is one of following: 1. chlorine, 2. bromine, 3. iodine, 4. mesyloxy, 5. tolysulfonyl oxygen base.
Described organic solvent is: dimethyl formamide or dimethyl sulfoxide (DMSO) or N,N-DIMETHYLACETAMIDE or dimethyl formamide or dimethyl sulfoxide (DMSO) or N,N-DIMETHYLACETAMIDE separately with the mixing of the arbitrary proportion of one of following solvent: alcohols, ketone, ethers or water.
Described alkali is organic bases or mineral alkali, and described organic bases is triethylamine or diethylamine; Described mineral alkali is alkali-metal carbonate, alkali-metal supercarbonate or alkali-metal oxyhydroxide.
Described alkali is preferably yellow soda ash, salt of wormwood, sodium bicarbonate or saleratus.Described alkaline metal iodide is preferably sodium iodide or potassiumiodide.
The ratio of described compound (II) or its salt and compound (III) amount of substance is 1～2:1, and temperature of reaction is 25～150 ℃ in the described condensation reaction, and the reaction times is 1～24 hour.
Concrete, described method is as follows:
(1) with structural formula be compound N-(1,2-benzisothiazole-3-yl) piperazine or its halogen acid salt of formula (II), and the compound of general formula (III)
In the presence of alkali yellow soda ash, salt of wormwood, sodium bicarbonate or saleratus, make catalyzer with sodium iodide or potassiumiodide, organic solvent dimethyl formamide or dimethyl sulfoxide (DMSO) or N,N-DIMETHYLACETAMIDE or dimethyl formamide or dimethyl sulfoxide (DMSO) or N,N-DIMETHYLACETAMIDE separately with the miscible solution of water in the presence of, under 70～100 ℃ of conditions, carry out condensation reaction in 2～7 hours, ((4-(1 for 2-to obtain described 5-through separation and purification, 2-benzisothiazole-3-yl)-and piperazine) ethanoyl)-6-chloro-1,3-dihydro-2H-indol-2-one; Wherein, L is a chlorine in the formula (II);
(2) ((4-(1 for 2-with 5-; 2-benzisothiazole-3-yl)-and piperazine) ethanoyl)-6-chloro-1; 3-dihydro-2H-indol-2-one; in organic acid solvent trichoroacetic acid(TCA) or trifluoroacetic acid or chloropon; reacted 12～28 hours down at 20～50 ℃ with trimethyl silane or triethyl silicane; make described Ziprasidone; ((4-(1 for 2-for described 5-; 2-benzisothiazole-3-yl)-and piperazine) ethanoyl)-6-chloro-1,3-dihydro-2H-indol-2-one is 1:1～6 with the ratio of trialkyl silane amount of substance.
The preparation method of compound (II) is referring to European patent EP 741129, and the preparation method of compound (III) is referring to periodical J.Med.Chem.1996,39,143-148.
The beneficial effect of the new Preparation Method And Their Intermediate of Ziprasidone of the present invention is mainly reflected in: the yield height, can reach more than 85%, and simple to operate, reaction times is short, greatly reduce cost, and only need regulate the pH value and just can obtain the very high product of purity, be beneficial to suitability for industrialized production.
(4) embodiment
The present invention is described further below in conjunction with specific embodiment, but protection scope of the present invention is not limited in this:
Embodiment 1 (Comparative Examples):
0.73g (3.20mmol) 5-(2-chloroethyl) 6-chloro-indolone, 0.70g (3.2mmol) N-(1,2-benzisothiazole-3-yl) piperazine, 0.68g (.40mmol) yellow soda ash, 2mg sodium iodide, the 30ml hexone, join in the 125ml round-bottomed flask that nitrogen inlet and condenser are housed reaction backflow 40hr, cooling, filter distillation.Distillment is through column chromatography purification, with 11 eluent ethyl acetate byproducts, with the ethyl acetate 1.51 wash-out products that contain 4% methyl alcohol, distill washing the product that comes, distillment is joined in the methylene dichloride, add ether again, logical hydrogen chloride gas makes it saturated, produces precipitation, filters, wash with ether, filter, filter cake is used washing with acetone again, filters, obtain the Ziprasidone hydrochloride, yield is 20%.
Embodiment 2:5-(2-(4-(1,2-benzisothiazole-3-yl)-piperazine) ethanoyl)-6-chloro-1, the preparation of 3-dihydro-2H-indol-2-one:
N-(1,2-benzisothiazole-3-yl) piperazine hydrochloride 7.9g (31mmol) is added in the 250ml there-necked flask, add 40ml DMF (dimethyl formamide), stir.Add 5-(2-chloracetyl) 6-chloro-indolone 4.88g (20mmol), potassiumiodide 6g, salt of wormwood 10g; begin to warm to 70 ℃; be incubated after 4 hours, underpressure distillation adds 40ml water; add 6N hydrochloric acid; transfer PH=3～4, filter, the washing filter cake is to neutral; 55 ℃ of dry 7.21g product, yields: 82.5% of getting.5-(2-(4-(1,2-benzisothiazole-3-yl)-piperazine) ethanoyl)-6-chloro-1, the physical parameter of 3-dihydro-2H-indol-2-one:
MS(％)M
+1?426+1
NMR(d，CDCl
3)：3.2-3.6(m，8H)，7.4-7.7(m，2H)，7.8(d，1H)，7.87(d，1H)，2.7(s，2H)，6.9(s，1H)，10.8(s，1H)，3.8(s，2H)，7.7(s，1H)
Embodiment 3:5-(2-(4-(1,2-benzisothiazole-3-yl)-piperazine) ethanoyl)-6-chloro-1, the preparation of 3-dihydro-2H-indol-2-one:
N-(1,2-benzisothiazole-3-yl) piperazine 6.8g (31mmol) is added in the 250ml there-necked flask, add 30ml DMF (dimethyl formamide), stir.Add 5-(2-acetyl bromide) 6-chloro-indolone 4.88g (20mmol), sodium iodide 7g, sodium bicarbonate 11g; begin to warm to 50 ℃; be incubated after 12 hours, underpressure distillation adds 40ml water; add 6N hydrochloric acid; transfer PH=3～4, filter, the washing filter cake is to neutral; 55 ℃ of dry 6.02g product, yields: 68.9% of getting.
Embodiment 4:5-(2-(4-(1,2-benzisothiazole-3-yl)-piperazine) ethanoyl)-6-chloro-1, the preparation of 3-dihydro-2H-indol-2-one:
N-(1,2-benzisothiazole-3-yl) piperazine hydrochloride 17.3g (67.6mmol) is added in the 250ml there-necked flask, add 60ml DMSO (dimethyl sulfoxide (DMSO)), stir.Add 5-(2-mesyloxy-ethanoyl) 6-chloro-indolone 15.1g (50mmol), potassiumiodide 7g, potassium hydroxide 22g; begin to warm to 60 ℃; be incubated after 8 hours, add the 200ml frozen water, separate out solid; leave standstill; filter, the washing filter cake gets red solid to neutral; dry 13.4g product, the yield: 69.5% of getting.
Embodiment 5:5-(2-(4-(1,2-benzisothiazole-3-yl)-piperazine) ethanoyl)-6-chloro-1, the preparation of 3-dihydro-2H-indol-2-one:
N-(1,2-benzisothiazole-3-yl) piperazine hydrochloride 20g (78.3mmol) is added in the 250ml there-necked flask, add 60ml DMAC (N,N-DIMETHYLACETAMIDE), stir.Add 5-(2-iodoacetyl) 6-chloro-indolone 11g (45mmol), sodium iodide 8g, yellow soda ash 26g begins to warm to 120 ℃; be incubated after 2 hours, add the 200ml frozen water, separate out solid, leave standstill; filter the extremely neutral red solid that gets of washing filter cake, dry 15g product, the yield: 77.6% of getting.
Embodiment 6: the preparation of Ziprasidone:
With 7.21g (8.6mmol) 5-(2-(4-(1,2-benzisothiazole-3-yl)-piperazine) ethanoyl)-6-chloro-1,3-dihydro-2H-indol-2-one drops into the 250ml there-necked flask; add the 60ml trifluoroacetic acid, 3.5ml (21.5mmol) triethyl silicane is warming up to 30 ℃ of reactions 23 hours; underpressure distillation; be cooled to 0 ℃, add saturated sodium bicarbonate solution and transfer PH=7, be chilled to 0 ℃ of filtration; get the garnet solid; dry about 50 ℃, get the 6.4g dark red solid, yield: 92.1%.5-(2-(4-(1,2-benzisothiazole-3-yl)-piperazine) ethanoyl)-6-chloro-1, the equivalence ratio of 3-dihydro-2H-indol-2-one and triethyl silicane is 1:2.5.
Embodiment 7: the preparation of Ziprasidone:
Get 17g (20.3mmol) 5-(2-(4-(1,2-benzisothiazole-3-yl)-piperazine) ethanoyl)-6-chloro-1,3-dihydro-2H-indol-2-one drops into the 250ml there-necked flask; add the 80ml trichoroacetic acid(TCA), 2.03ml (27.4mmol) trimethyl silane is warming up to 50 ℃ of reactions 16 hours; underpressure distillation; be cooled to 0 ℃, add saturated sodium bicarbonate solution and transfer PH=7, be chilled to 0 ℃ of filtration; get the garnet solid; dry about 50 ℃, get the 13.9g dark red solid, yield: 84.5%.5-(2-(4-(1,2-benzisothiazole-3-yl)-piperazine) ethanoyl)-6-chloro-1, the equivalence ratio of 3-dihydro-2H-indol-2-one and trimethyl silane is 1:1.35.
The physical data of Ziprasidone is as follows: mp〉300 ℃ of .1H-NMR (δ, DMSO-d6): 3.15-3.60 (m, 10H), 3.72 (d, 2H), 4.10 (d, 2H), 6.88 (s, 1H), 7.28 (s, 1H), 7.48 (t, 1H), 7.60 (t, 1H), 8.14 (dd, 2H), 10.6 (s, 1H), 11.4 (bs, 1H) .MS (m/e, %): 412 (M+, 0.4), 233 (18), 232 (100), 177 (19) .IR (KBr, cm-1) 1708,1628,1489.
Implement 8: the preparation of Ziprasidone
Get 17g (20.3mmol) 5-(2-(4-(1,2-benzisothiazole-3-yl)-piperazine) ethanoyl)-6-chloro-1,3-dihydro-2H-indol-2-one drops into the 250ml there-necked flask; add the 100ml chloropon, 3.3ml (20.3mmol) triethyl silicane is warming up to 50 ℃ of reactions 20 hours; underpressure distillation; be cooled to 0 ℃, add saturated sodium bicarbonate solution and transfer PH=7, be chilled to 0 ℃ of filtration; get the garnet solid; dry about 50 ℃, get the 13.1g dark red solid, yield: 79.5%.5-(2-(4-(1,2-benzisothiazole-3-yl)-piperazine) ethanoyl)-6-chloro-1, the equivalence ratio of 3-dihydro-2H-indol-2-one and triethyl silicane is 1:1.
Claims (9)
1. the preparation method of a Ziprasidone; it is characterized in that described method is that ((4-(1 for 2-by the compound of structural formula as (I): 5-; 2-benzisothiazole-3-yl)-and piperazine) ethanoyl)-6-chloro-1; 3-dihydro-2H-indol-2-one; reduce with trialkyl silane in organic acid solvent and make described Ziprasidone, described organic acid solvent is to contain carboxyl functional group and contain the C that a halogen atom replaces at least
1～C
6Alkane acid; The alkyl of described trialkyl silane is the alkyl of C1～C6;
2. the preparation method of Ziprasidone as claimed in claim 1 is characterized in that described trialkyl silane is trimethyl silane or triethyl silicane.
3. the preparation method of Ziprasidone as claimed in claim 1 is characterized in that described organic acid solvent is one of following: trichoroacetic acid(TCA), trifluoroacetic acid, chloropon.
4. the preparation method of Ziprasidone as claimed in claim 1; it is characterized in that described reduction reaction was 20～50 ℃ of following reactions 12～28 hours; ((4-(1 for 2-for described 5-; 2-benzisothiazole-3-yl)-and piperazine) ethanoyl)-6-chloro-1,3-dihydro-2H-indol-2-one is 1:1～6 with the ratio of trialkyl silane amount of substance.
5. as the preparation method of the described Ziprasidone of one of claim 1～4, it is characterized in that described 5-(2-(4-(1,2-benzisothiazole-3-yl)-piperazine) ethanoyl)-6-chloro-1,3-dihydro-2H-indol-2-one is obtained by following method:
With structural formula is the compound of formula (II): N-(1,2-benzisothiazole-3-yl) piperazine or its halogen acid salt, and the compound of general formula (III)
In the presence of alkali, make catalyzer with alkaline metal iodide, in the presence of the organic solvent that contains sulfoxide or amide group, carry out condensation reaction and obtain described 5-(2-(4-(1,2-benzisothiazole-3-yl)-piperazine) ethanoyl)-6-chloro-1,3-dihydro-2H-indol-2-one; Wherein, L is a leavings group in the formula (III), and described leavings group is one of following: 1. chlorine, 2. bromine, 3. iodine, 4. mesyloxy, 5. tolysulfonyl oxygen base; Described alkali is organic bases or mineral alkali, and described organic bases is triethylamine or diethylamine; Described mineral alkali is alkali-metal carbonate, alkali-metal supercarbonate or alkali-metal oxyhydroxide.
6. the preparation method of Ziprasidone as claimed in claim 5, it is characterized in that described organic solvent is: dimethyl formamide, dimethyl sulfoxide (DMSO) or N,N-DIMETHYLACETAMIDE, perhaps dimethyl formamide, dimethyl sulfoxide (DMSO) or N,N-DIMETHYLACETAMIDE separately with the mixing of the arbitrary proportion of one of following solvent: alcohols, ketone, ethers, water.
7. the preparation method of Ziprasidone as claimed in claim 5 is characterized in that described alkali is yellow soda ash, salt of wormwood, sodium bicarbonate or saleratus, and described alkaline metal iodide is sodium iodide or potassiumiodide.
8. the preparation method of Ziprasidone as claimed in claim 5, the ratio that it is characterized in that described compound (II) or its halogen acid salt and compound (III) amount of substance is 1～2:1, temperature of reaction is 25～150 ℃ in the described condensation reaction, and the reaction times is 1～24 hour.
9. the preparation method of Ziprasidone as claimed in claim 5 is characterized in that described method is as follows:
(1) with structural formula be compound N-(1,2-benzisothiazole-3-yl) piperazine or its halogen acid salt of formula (II), and the compound of general formula (III)
In the presence of yellow soda ash, salt of wormwood, sodium bicarbonate or saleratus, make catalyzer with sodium iodide or potassiumiodide, at dimethyl formamide, dimethyl sulfoxide (DMSO) or N,N-DIMETHYLACETAMIDE, perhaps dimethyl formamide, dimethyl sulfoxide (DMSO) or N,N-DIMETHYLACETAMIDE separately with the existence of the miscible solution of water under, under 70～100 ℃ of conditions, carry out condensation reaction in 2～7 hours, ((4-(1 for 2-to obtain described 5-through separation and purification, 2-benzisothiazole-3-yl)-and piperazine) ethanoyl)-6-chloro-1,3-dihydro-2H-indol-2-one; Wherein, L is a chlorine in the formula (III);
(2) ((4-(1 for 2-with 5-; 2-benzisothiazole-3-yl)-and piperazine) ethanoyl)-6-chloro-1; 3-dihydro-2H-indol-2-one; in trichoroacetic acid(TCA), trifluoroacetic acid or chloropon; reacted 12～28 hours down at 20～50 ℃ with trimethyl silane or triethyl silicane; make described Ziprasidone; ((4-(1 for 2-for described 5-; 2-benzisothiazole-3-yl)-and piperazine) ethanoyl)-6-chloro-1,3-dihydro-2H-indol-2-one is 1:1～6 with the ratio of trimethyl silane or triethyl silicane amount of substance.
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| CN101450946B (en) * | 2007-12-06 | 2010-12-15 | 浙江海正药业股份有限公司 | Synthetic method of ziprasidone |
| CN102250083B (en) * | 2011-08-03 | 2013-09-04 | 齐鲁天和惠世制药有限公司 | Method for preparing ziprasidone |
| CN102432522B (en) * | 2011-11-01 | 2014-04-02 | 中国人民解放军第二军医大学 | Method for preparing substituted 2-indolinone compound |
| CN108239085A (en) * | 2016-12-26 | 2018-07-03 | 四川科瑞德凯华制药有限公司 | A kind of purifying of ziprasidone and preparation method |
| CN112724066B (en) * | 2021-02-04 | 2022-10-21 | 海南鑫开源医药科技有限公司 | Dihalogen impurity in ziprasidone hydrochloride intermediate and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003070246A1 (en) * | 2002-02-20 | 2003-08-28 | Pfizer Products Inc. | Controlled synthesis of ziprasidone and compositions thereof |
| WO2004100957A1 (en) * | 2003-05-16 | 2004-11-25 | Pfizer Products Inc. | Treatment of bipolar disorders and associated symptoms |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2003070246A1 (en) * | 2002-02-20 | 2003-08-28 | Pfizer Products Inc. | Controlled synthesis of ziprasidone and compositions thereof |
| WO2004100957A1 (en) * | 2003-05-16 | 2004-11-25 | Pfizer Products Inc. | Treatment of bipolar disorders and associated symptoms |
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