CN111777554A - Method for synthesizing cisatracurium besilate - Google Patents
Method for synthesizing cisatracurium besilate Download PDFInfo
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- CN111777554A CN111777554A CN201910268640.3A CN201910268640A CN111777554A CN 111777554 A CN111777554 A CN 111777554A CN 201910268640 A CN201910268640 A CN 201910268640A CN 111777554 A CN111777554 A CN 111777554A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
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- C07D217/20—Aralkyl radicals with oxygen atoms directly attached to the aromatic ring of said aralkyl radical, e.g. papaverine
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- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
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Abstract
The invention discloses a method for synthesizing cisatracurium besilate, which comprises the following steps: reacting a compound shown in a formula I, a compound shown in a formula II and oxalic acid dihydrate to generate a compound shown in a formula III; reacting the obtained compound in the formula III under the catalysis of Pd/C to generate a compound in a formula IV; reacting the compound shown in the formula IV with 1, 5-pentanediol to generate a compound shown in a formula V; reacting the obtained compound shown in the formula V with methyl benzene sulfonate to obtain cis-atracurium besilate; wherein, the compounds shown in formula I, formula II, formula III, formula IV and formula V are respectively as follows:
Description
1. Field of the invention
The invention relates to the technical field of drug synthesis, in particular to a method for synthesizing cisatracurium besilate.
2. Background of the invention
Cisatracurium besilate (cisatracurium besylate) is a latest generation muscle relaxant and is widely applied to the fields of trachea cannula, liver and kidney dysfunction, cardiovascular surgery and the like. Cisatracurium besilate has the characteristics of metabolism through a non-liver and non-kidney pathway and cardiovascular protection, has advantages in similar medicines, and has 3 times stronger muscle relaxation effect than clinical common atracurium besilate. Cisatracurium besilate is mainly suitable for general anesthesia and can be widely applied to tracheal intubation, liver and kidney dysfunction, cardiovascular surgery and elderly and pediatric patients. The medicine has gradually replaced vecuronium bromide and benzsulfamic atracurium since 1996 when first marketed in the uk, and becomes an indispensable muscle relaxant in clinic.
Atracurium besylate has 4 chiral centers, 10 isomers. Cisatracurium besilate is a cis isomer and has the following structural formula:
the cisatracurium besilate belongs to quaternary ammonium salt, is easily soluble in chloroform or ethanol and slightly soluble in water, and has a melting point of 90-93 ℃. The carbon on the benzyl position of the cisatracurium besilate is one of chiral centers, so that the cisatracurium besilate is unstable in chemical property and easy to decompose and rotate, and therefore, the cisatracurium besilate needs to be shielded from light, sealed and stored at 2-8 ℃.
The prior synthesis method of the benzene sulfonic cisatracurium comprises the following steps of mainly dividing 3 types of benzene sulfonic cisatracurine into racemic tetrahydropapaverine as a raw material, and obtaining R-type isomers through resolution and alkalization dissociation. The second method is that the R-tetrahydropapaverine and methyl acrylate are added and then are subjected to exchange reaction with 1, 5-pentanediol ester, methylation reaction is carried out to obtain atracurium besylate, and the atracurium besylate is separated by silica gel column chromatography to obtain the product. And the third method comprises the steps of performing Michel addition reaction on the R-tetrahydropapaverine and methyl acrylate, performing an azomethylation reaction on the product and methyl benzenesulfonate, performing addition reaction on the product and 1, 5-pentanediol, and reacting the product with azomethylated methyl benzenesulfonate to obtain the product.
In the synthesis method, the first method easily generates byproducts to interfere the reaction, but has simple steps, higher purity and low impurity content. The second method avoids the use of 1, 5-pentanediol acrylic acid diester, but also increases the reaction steps. The method III determines a spatial structure in the reaction process, avoids the generation of isomers, but has more complex steps. Moreover, the synthesis methods have the problems of low product yield and low product purity, so that the cost of the medicine cannot be reduced. In addition, atracurium besylate contains multiple isomers, and it is difficult to maintain the chiral center of cisatracurium besylate during synthesis.
3. Summary of the invention
In view of the prior art, the invention aims to provide a method for synthesizing cisatracurium besilate. The synthesis method can obviously improve the yield and the purity of the cisatracurium besilate, and reduce the synthesis cost of the cisatracurium besilate.
In order to achieve the purpose, the invention adopts the following technical scheme:
a method for synthesizing cisatracurium besilate, comprising the following steps: reacting a compound shown in a formula I, a compound shown in a formula II and oxalic acid dihydrate to generate a compound shown in a formula III; reacting the obtained compound in the formula III under the catalysis of Pd/C to generate a compound in a formula IV; the compound of formula IV is reacted with 1, 5-pentanediol in CoCl2·6H2Reacting under the catalysis of O to generate a compound shown in the formula V; reacting the obtained compound shown in the formula V with methyl benzene sulfonate to obtain cis-atracurium besilate; wherein, the compounds shown in formula I, formula II, formula III, formula IV and formula V are respectively as follows:
preferably, the compound of formula I is prepared from tetrahydropapaverine hydrochloride and (2S, 3S) -1-methyl-5-oxo-2-phenyltetrahydro-1H-pyrrolidine-3-carboxylic acid in a molar ratio of 1: (1-1.5) reaction.
In the synthesis process of the compound shown in the formula I, (2S, 3S) -1-methyl-5-oxo-2-phenyltetrahydro-1H-pyrrolidine-3-carboxylic acid is selected as a chiral resolving agent, so that the stereoselectivity of the reaction is high, and the ee value of the chiral center of the product is high.
Preferably, the compound of formula II is formed by reacting benzyl chloride and acrylic acid in a molar ratio of 1: 1.
Preferably, the compound of formula I, the compound of formula II and oxalic acid dihydrate are in a molar ratio (1.5-1.6): (1.7-1.8): (1.7-1.8).
Preferably, the compound of formula I and the compound of formula II are reacted at 80 ℃ for 4h, cooled to room temperature, added with oxalic acid dihydrate and stirred for 1 h.
Preferably, the compound of formula III is reacted under Pd/C catalysis to produce a compound of formula IV:
dissolving the compound of formula III in water, adjusting the pH of the solution to 9-10, adding dichloromethane to the solution, stirring the mixture for 10-20 min, separating the organic layer, extracting the aqueous layer with dichloromethane, combining the organic layers, washing with saturated saline, drying with anhydrous magnesium sulfate and evaporating under reduced pressure to obtain an oil; adding anhydrous methanol into the oily substance, stirring to dissolve, adding Pd/C into the solution, and adding H at 1atm2The reaction was stirred under the conditions and after the reaction was completed, the catalyst was removed by filtration.
More preferably, the catalyst is added in an amount of 5 to 8% by weight of the compound of formula III.
More preferably, the conditions of the stirring reaction are as follows: stirring for 2 hours at the temperature of 8-12 ℃.
The invention has the beneficial effects that:
(1) in the invention, a chiral resolving agent is adopted in the reaction process of generating T473-01 by the reaction of T473-00 to form one of the required chiral centers; during the reaction of T473-01 and T473-02 to form T473-1, oxalate is formed, and the post-reaction treatment mode with the highest chiral selectivity is determined through the investigation of various recrystallization methods. In the subsequent reaction process, mild reaction conditions are selected, and the chiral center of the product is maintained in each step of the reaction process. In addition, during the reaction process of synthesizing the key intermediate T473-3, a catalyst CoCl is added2·6H2O, which is extremely beneficial to the maintenance of chiral centers in the reaction product; when synthesizing T473-3, column chromatography purification is used in the post-reaction treatment process, so that the optical purity of the product is further ensured.
(2) The starting materials used in the invention are papaverine and benzyl chloride, which are very easily available starting raw materials, and the cost is low. The synthesis method can obviously improve the yield and the purity of the cis-atracurium besilate, and reduce the synthesis cost of the cis-atracurium besilate.
4. Detailed description of the preferred embodiments
It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.
As described in the background section, atracurium besylate has 4 chiral centers, 10 isomers. Cisatracurium besilate is one of the cis isomers. Therefore, isomers are easily generated in the process of synthesizing the cisatracurium besilate, the separation and purification process is complex, the product yield is low, and the product purity is not high.
Based on the above, the present invention aims to provide a novel method for synthesizing cisatracurium besilate, wherein the synthetic route is as follows:
in the synthesis method, tetrahydropapaverine hydrochloride is used as a starting material, and (2S, 3S) -1-methyl-5-oxo-2-phenyltetrahydro-1H-pyrrolidine-3-carboxylic acid is used as a chiral resolving agent to synthesize T473-01, so that the stereoselectivity of the reaction is high, and the ee value of the chiral center of the product is high. The T473-01 is mainly used for generating a chiral center in a product in the reaction process, and the T473-01 prepared by the method has high chiral selectivity, so that a separation method of column chromatography adopted by the traditional product is avoided.
Benzyl is adopted as a protecting group in the reaction process of the T473-1, and the protecting group is easier to remove after the reaction; in the subsequent deprotection process, the protective group can be removed only by recording catalytic amount of Pd/C under mild reaction conditions; and the catalyst is directly filtered and removed after the reaction, the filtrate is concentrated, the reaction condition is mild, the treatment after the reaction is simple, and the chiral center is favorably maintained. Racemization of a chiral center caused by using acid or alkali in the process of removing methyl as a protecting group is avoided; compared with the methyl as a protecting group, the method does not need complicated steps such as pH regulation, extraction, drying, concentration and the like after the benzyl protecting group is removed, only needs simple filtration and concentration, and has simple reaction and easy operation.
In the reaction process of synthesizing the key intermediate T473-3, a catalyst CoCl is added2·6H2O, is extremely beneficial to the maintenance of chiral centers in reaction products, the reaction conditions are very mild, and the catalyst can be recycled.
The synthesis method can keep the chiral center of the product in the reaction process of each step, avoids the generation of isomers, and does not need to adopt a column chromatography method to separate the product.
In order to make the technical solutions of the present application more clearly understood by those skilled in the art, the technical solutions of the present application will be described in detail below with reference to specific embodiments.
The test materials used in the examples of the present invention, which were not specifically described, were all those conventional in the art and commercially available.
Example 1: synthesis of cisatracurium besilate
(1) Synthesis of Compound T473-02:
a round bottom flask was charged with anhydrous DMF (0.6L) and acrylic acid (129.7g, 1.8mol) and potassium carbonate (273.6g, 1.98mol) was added in portions, controlling the temperature below 45 ℃. T473-02A (227.9g, 1.8mol) was then added and, after the addition was complete, the mixture was stirred at 100 ℃ for 3 hours. After completion of the reaction, the reaction solution was cooled to room temperature, and 1.0L of pentane was added. The organic layer was washed with water (3X 300mL) and saturated brine (1X 300 mL). The organic layer was collected, dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure to give 288.1g of a colorless oil, i.e., T473-02, in 98.8% yield.
1H NMR(CDCl3，300Hz)：7.36-7.28(m，5H)，6.43(dd，J1＝5.4Hz，J2＝10.8Hz，1H)，6.13(dd，J1＝4.2Hz，J2＝11.1Hz，1H)，5.81(dd，J1＝4.8Hz，J2＝8.1Hz，1H)，5.31(s，2H).
MS(GC-MS)：m/z 162(M+).
(2) Synthesis of Compound T473-01:
sodium borohydride (283.7g, 7.5mol) was added to a solution of anhydrous tetrahydrofuran (2.5L) under argon, then (2S, 3S) -1-methyl-5-oxo-2-phenyltetrahydro-1H-pyrrolidine-3-carboxylic acid (500g, 2.3mmol) was added to the suspension and the reaction mixture was stirred at room temperature for 4 hours, then zinc chloride (110g, 0.8mol) was added and stirred at room temperature for an additional 1 hour. T473-00(755.7g, 2mol) was dissolved in 1L of anhydrous tetrahydrofuran and after the addition was complete, the mixture was stirred for 16h and finally refluxed for 1 h. After the reaction, the reaction solution was cooled to room temperature, 0.5L of 30% sodium hydroxide solution was added, and the mixture was stirred for 10 min. The aqueous layer was then extracted with dichloromethane (1L X3), the organic layers were combined, washed with saturated brine (1L X1), dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure to give a yellow oil, and the residue was chromatographed on silica gel to give T473-01 as a pale yellow oil in 95.8% yield.
1H NMR(CDCl3，300Hz)：6.75(m，1H)，6.63(d，J＝6.48Hz，1H)，6.50(d，J＝4.38Hz，1H)，6.37(m，2H)，4.35(m，1H)，3.98(m，2H)，3.82(m，1H)，3.75(s，6H)，3.68(s，3H)，3.42(s，3H)，3.19(m，2H)，2.98(m，1H).
ESI+MS(m/z)：344.2[MH+].
[α]D＝-37.4°(c＝0.26，CHCl3).
(3) Synthesis of Compound T473-1:
t472-01(542.6g, 1.58mol) was dissolved in 2.0L of toluene, and then T473-02(285g, 1.75mol) and glacial acetic acid (36.5g, 0.83mol) were added to the solution. The mixture was heated at 80 ℃ for 4 hours. Subsequently, the mixture was cooled to ambient temperature and a solution of oxalic acid dihydrate (220.6g, 1.75mol) in acetone (1.0L) was added. The mixture was stirred for 1 hour, and the precipitate was filtered and washed with 0.2L of ethyl acetate. The solid was collected. 4.0L of methanol was added and the mixture was heated to reflux to give a solution which was filtered hot. The filtrate was cooled to ambient temperature and held at that temperature for 2 hours. The precipitate was collected by filtration, washed with ethyl acetate (1.0L. times.3) and dried at 60 ℃ to give T473-1 as a white solid in 86.0% yield.
1H NMR(CDCl3，300Hz)：7.31-7.27(m，5H)，6.61(d，J＝8.63Hz，1H)，6.57(s，1H)，6.52(d，J＝5.73Hz，1H)，6.45(m，2H)，5.34(s，2H)，4.67(m，1H)，4.15(m，2H)，3.78(m，1H)，3.73(s，6H)，3.62(s，3H)，3.45(s，3H)，3.39(m，2H)，3.24(m，2H)，3.11(m，1H)，2.86(m，2H).
[α]D＝-59.0°(c＝1.00，DMSO).
ESI+MS(m/z)：506.3[MH+]
(4) Synthesis of Compound T473-2:
t473-1(655.2g, 1.1mol) dissolved in 4.0L water, 20% sodium hydroxide solution added to make the solution pH between 9-10, then add 3.0L dichloromethane to the solution, stir the mixture at room temperature for 15 minutes, separate the organic layer, the aqueous layer was extracted twice with dichloromethane (2 × 2.0.0L), the combined organic layer, saturated saline (1 × 2.0.0L) washed, anhydrous magnesium sulfate dried and evaporated under reduced pressure to give an oil, add 3.0L anhydrous methanol to the oil, stir to make it dissolve, then add Pd/C (40g) to the solution, after the addition was complete, H at 1atm2The reaction mixture was stirred at 8 ℃ to 12 ℃ for 2 hours. After the reaction was completed, the mixture was filtered to remove the catalyst, and the filtrate was collected and reduced in pressureDistillation gave 429.2g of T473-2 as an oil in 93.9% yield.
1H NMR(CDCl3，300Hz)：6.67(d，J＝9.26Hz，1H)，6.57(s，1H)，6.50(d，J＝2.95Hz，1H)，6.45(m，1H)，6.12(s，1H)，4.82(m，1H)，4.37(m，2H)，3.93(m，1H)，3.75(s，6H)，3.59(s，3H)，3.53(m，2H)，3.39(s，3H)，3.18(m，2H)，3.16(m，1H)，2.96(m，2H).
ESI+MS(m/z)：416.5[MH+]
(5) Synthesis of Compound T473-3:
t473-2(415.5g, 1mol) was dissolved in 2L acetonitrile and 1, 5-pentanediol (104.2g, 1mol) and glacial acetic acid (120g, 2mol) and CoCl were added to the solution2·6H2O (11.9g, 0.05mol), the reaction was left at 60 ℃ for 12h, after completion of the reaction, acetonitrile was removed under reduced pressure to obtain a viscous oily liquid, then 500ml of water and 1.0L of dichloromethane were added to the reaction solution, stirred for 10min, and left to stand for separation, the aqueous layer was extracted with dichloromethane (500ml of × 2), the organic layers were combined, washed with saturated brine (500ml of × 2), dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain a yellow solid substance, and the solid substance was subjected to silica gel column chromatography (dichloromethane: methanol 5: 1), and the eluate was distilled under reduced pressure to obtain 816.4g as a white solid, with a yield of 90.8%.
Collecting a water layer after extraction, and concentrating the water layer under reduced pressure to obtain a catalyst CoCl2·6H2And O, drying and then repeatedly using.
1H NMR(CDCl3)：6.72(d，J＝8.38Hz，2H)，6.61(s，2H)，6.52(d，J＝2.12Hz，2H)，6.48(dd，J1＝2.28Hz，J2＝8.64Hz，2H)，5.96(s，2H)，4.95(dd，J1＝3.12Hz，J2＝8.86Hz，2H)，4.26(m，8H)，3.91(m，2H)，3.80(s，12H)，3.68(s，6H)，3.58(m，4H)，3.35(s，6H)，3.29(m，4H)，3.21(m，2H)，2.85(m，4H)，1.64(m，6H).
ESI+MS(m/z)：900.1[MH+]
(6) Synthesis of Compound T473 (cisatracurium besilate)
T473-2(801.0g, 0.89mol) was added to the oil 1.0L of dichloromethane, methyl benzenesulfonate (281.2g, 1.8mol) and 20ml of DMSO, and the mixture was stirred at room temperature for 24 h. After the reaction, the reaction mixture was distilled under reduced pressure to remove methylene chloride, thereby obtaining a yellow oil. To the oil was added diethyl ether (2.0L), followed by stirring at room temperature for 30 minutes. Filtration, collection of the filtrate, and evaporation of the solvent to dryness gave a yellow oil. 1.5L of tetrahydrofuran was added to the oil, dissolved and then left to stir at room temperature for 1 h. Subsequently, the mixture was cooled to-20 ℃ overnight and a solid material precipitated. Filtration and washing of the filter cake with tetrahydrofuran collected the filter cake which was dried to give 945.2g of T473 as a white solid in 85.4% yield and 99.5% purity.
1H NMR(CDCl3)：7.83(m，4H)，7.29(m，6H)，6.64(d，J＝8.21，2H)，6.53(s，2H)，6.47(d，J＝1.83Hz，2H)，6.42(dd，J1＝1.83Hz，J2＝8.16Hz，2H)，5.92(s，2H)，4.92(dd，J1＝3.26Hz，J2＝8.93Hz，2H)，4.14(m，8H)，3.88(m，2H)，3.79(s，12H)，3.63(s，6H)，3.54(m，4H)，3.39(s，6H)，3.32(m，4H)，3.25(s，6H)，3.18(m，2H)，2.89(m，4H)，1.68(m，4H)，1.56(m，2H).
The above description is only a preferred embodiment of the present application and is not intended to limit the present application, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, improvement and the like made within the spirit and principle of the present application shall be included in the protection scope of the present application.
Claims (8)
1. The method for synthesizing cisatracurium besilate is characterized by comprising the following steps: a compound of formula I, a compound of formula II andreacting oxalic acid dihydrate to generate a compound shown in a formula III; reacting the obtained compound in the formula III under the catalysis of Pd/C to generate a compound in a formula IV; the compound of formula IV is reacted with 1, 5-pentanediol in CoCl2·6H2Reacting under the catalysis of O to generate a compound shown in the formula V; reacting the obtained compound shown in the formula V with methyl benzene sulfonate to obtain cis-atracurium besilate; wherein, the compounds shown in formula I, formula II, formula III, formula IV and formula V are respectively as follows:
2. the method of claim 1, wherein the compound of formula I is prepared from tetrahydropapaverine hydrochloride and (2S, 3S) -1-methyl-5-oxo-2-phenyltetrahydro-1H-pyrrolidine-3-carboxylic acid in a molar ratio of 1: (1-1.5) reaction.
3. The process of claim 1, wherein the compound of formula II is formed by reacting benzyl chloride and acrylic acid in a 1:1 molar ratio.
4. The method according to claim 1, wherein the compound of formula I, the compound of formula II and the oxalic acid dihydrate are present in a molar ratio (1.5-1.6): (1.7-1.8): (1.7-1.8).
5. The method as claimed in claim 4, wherein the compound of formula I and the compound of formula II are reacted at 80 ℃ for 4h, cooled to room temperature, added with oxalic acid dihydrate and stirred for 1 h.
6. The process according to claim 1, wherein the compound of formula III is reacted under Pd/C catalysis to produce a compound of formula IV:
dissolving the compound of formula III in water, adjusting pH to 9-10, adding dichloromethane, stirring for 10-20 min, separating organic layer, extracting water layer with dichloromethane, combining organic layers, and saturatingWashing with brine, drying over anhydrous magnesium sulfate and evaporating under reduced pressure to obtain an oily substance; adding anhydrous methanol into the oily substance, stirring to dissolve, adding Pd/C into the solution, and adding H at 1atm2The reaction was stirred under the conditions and after the reaction was completed, the catalyst was removed by filtration.
7. The process of claim 6, wherein the catalyst is added in an amount of 5-8% by weight of the compound of formula III.
8. The method according to claim 6, wherein the conditions of the stirring reaction are as follows: stirring for 2 hours at the temperature of 8-12 ℃.
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| CN107056699A (en) * | 2017-01-17 | 2017-08-18 | 连云港贵科药业有限公司 | A kind of preparation method of high-purity Cisatracurium besylate |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112778200A (en) * | 2021-01-20 | 2021-05-11 | 江苏诚信药业有限公司 | Preparation method and application of cisatracurium besilate |
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