CN115650863A - Method for preparing venlafaxine hydrochloride - Google Patents
Method for preparing venlafaxine hydrochloride Download PDFInfo
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- CN115650863A CN115650863A CN202211080833.4A CN202211080833A CN115650863A CN 115650863 A CN115650863 A CN 115650863A CN 202211080833 A CN202211080833 A CN 202211080833A CN 115650863 A CN115650863 A CN 115650863A
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Abstract
The invention relates to the field of venlafaxine synthesis, and discloses a method for preparing venlafaxine hydrochloride. The method comprises the following steps: taking anisole and pyruvate as raw materials, carrying out Friedel-crafts reaction to obtain aryl lactate, then carrying out acid catalysis to eliminate and dehydrate to obtain aryl acrylate, then carrying out addition reaction with dimethylamine, and then carrying out Grignard reaction to obtain venlafaxine hydrochloride.
Description
Technical Field
The invention relates to the field of venlafaxine synthesis, and in particular relates to a method for preparing venlafaxine hydrochloride.
Background
Venlafaxine hydrochloride is a new generation antidepressant developed by Wyeth-Ayerst company, is different from other antidepressants, has unique chemical structure and neuropharmacological action, plays an antidepressant effect by inhibiting reuptake of 5-hydroxytryptamine and norepinephrine, has no inhibiting effect on monoamine oxidase, histamine, alpha 1-NA receptor and the like, and has few adverse reactions.
At present, venlafaxine hydrochloride is synthesized by a strategy of mainly using p-methoxyphenylacetonitrile and cyclohexanone as raw materials for re-reduction. Such as 2-Phenyl-2- (1-hydroxychloroalkyl) ethyl amine derivatives: synthesis and antidepressant activity (John P. Yardley, G.E.Morris Husbands et al, J.Med.chem.1990, 33 (10): 2899-2905) takes p-methoxybenzeneacetonitrile as a raw material, and the raw material and cyclohexanone undergo condensation reaction under the conditions of n-butyl lithium and-78 ℃, and then the venlafaxine hydrochloride is prepared through reduction and methylation reaction, wherein the total yield is 38%. However, this method has a low yield and severe reaction conditions. In addition, US4535186, an Improved and Improved-Free Large-Scale Synthesis of Venlafaxine Hydrochloride (Mohanarangam Saravanann et al, org. ProcesssDev.2011, 15, 1392) and Venlafaxine Hydrochloride Synthesis (Zhao Zhiquan, peng Lizeng, J.Med.Med.Med.Industrial., 2004, 35 (10): 577-578) all disclose methods for synthesizing Venlafaxine Hydrochloride from methoxybenzyl cyanide and cyclohexanone. However, such methods are expensive to produce, the hydrogenation reduction of the cyano group uses a high-pressure hydrogenation kettle for hydrogenation, and the danger of such high-pressure hydrogenation process is high.
Synthesis research of antidepressant drug venlafaxine (Zhou Jinpei, zhang Huibin, etc., chinese university of pharmacy, 1999, 30 (4): 249-250) discloses venlafaxine hydrochloride prepared by taking anisole and chloroacetyl chloride as starting materials and carrying out five steps of reactions such as Friedel-crafts acylation, amination, reduction, bromination, grignard reaction, etc., wherein the total yield is 11%. The method has long route, complex reaction, more impurities generated in the reaction process and low yield, and is not suitable for industrial production.
It can be seen that the disclosed synthesis methods all have the disadvantages of low yield, more impurities or long route, are not beneficial to industrialization, have high production cost and have high danger of the synthesis process. In industrial production, a safer, green and high-yield method for synthesizing venlafaxine hydrochloride needs to be developed.
Disclosure of Invention
The invention aims to solve the problems of low yield, more impurities, long synthesis route, high production cost and high risk of the synthesis process of venlafaxine hydrochloride in the prior art, and provides a synthesis method of venlafaxine hydrochloride.
In order to achieve the above object, the present invention provides a method for preparing venlafaxine hydrochloride, wherein the method comprises:
(1) In the presence of Lewis acid, performing Friedel-crafts reaction on anisole and pyruvate to obtain a compound I;
(2) Dehydrating the compound I in the presence of an acid to obtain a compound II;
(3) Performing addition reaction on the compound II and dimethylamine to obtain a compound III;
(4) Performing Grignard reaction on the compound III and a double Grignard reagent of 1,5-dihalogenopentane to obtain venlafaxine hydrochloride shown as a compound IV;
wherein R is selected from methyl or ethyl.
According to the technical scheme, the method provided by the invention takes anisole and pyruvate ester as raw materials to carry out Friedel-crafts reaction, dehydration, dimethylamine addition and Grignard reaction, and solves the technical problem of low synthesis yield by taking anisole as a raw material in the prior art. The total molar yield of the venlafaxine hydrochloride prepared according to the technical scheme of the invention can reach 67 percent, and the product purity is more than 99 weight percent. The method provided by the invention only relates to 4 steps, and the reaction process is easy to industrialize.
Detailed Description
The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value, and such ranges or values should be understood to encompass values close to those ranges or values. For ranges of values, between the endpoints of each of the ranges and the individual points, and between the individual points may be combined with each other to give one or more new ranges of values, and these ranges of values should be considered as specifically disclosed herein.
The invention provides a method for preparing venlafaxine hydrochloride, which comprises the following steps:
(1) In the presence of Lewis acid, performing Friedel-crafts reaction on anisole and pyruvate to obtain a compound I;
(2) Dehydrating the compound I in the presence of an acid to obtain a compound II;
(3) Performing addition reaction on the compound II and dimethylamine to obtain a compound III;
(4) Carrying out Grignard reaction on the compound III and a double Grignard reagent of 1,5-dihalogenopentane to obtain venlafaxine hydrochloride shown as a compound IV;
wherein R is selected from methyl or ethyl.
The synthetic scheme involved in the method is as follows:
wherein R is selected from methyl or ethyl; x is selected from chlorine or bromine.
Step 1: under the existence of Lewis acid, performing Friedel-crafts reaction on anisole and pyruvate to obtain a compound I, wherein R is selected from methyl or ethyl;
according to the process of the invention, the friedel-crafts reaction is carried out in the presence of a first solvent selected from 1,2-dichloroethane and/or dichloromethane. The first solvent selected by the invention has better solubility to various raw materials and auxiliary materials, and increases the yield of the target product compound I so as to improve the yield of venlafaxine hydrochloride.
According to the process of the present invention, the lewis acid is selected from the group consisting of aluminum trichloride, aluminum tribromide, boron trifluoride etherate, titanium tetrachloride, ferric trichloride or zinc chloride, preferably aluminum trichloride; the pyruvate is methyl pyruvate or ethyl pyruvate.
According to the process of the invention, the Friedel-crafts reaction temperature is between-20 ℃ and 40 ℃, preferably the reaction temperature is between 0 ℃ and 5 ℃. The Friedel-crafts reaction pressure can be 0.05-0.15MPa; the Friedel-crafts reaction time is 2-4h.
According to the method of the invention, the molar ratio of the anisole, the pyruvate and the Lewis acid is 1: 1-1.5.
Step 2: dehydrating the compound I in the presence of acid to obtain a compound II, wherein R is selected from methyl or ethyl;
according to the method of the present invention, the acid is selected from at least one of hydrochloric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid, taurine, preferably p-toluenesulfonic acid. The molar ratio of the acid to the compound I is 0.01-0.2:1. The acid selected by the invention has more advantages in the aspects of proper solubility and acid strength, and can accelerate the dehydration rate and improve the yield of the compound II so as to improve the yield of venlafaxine hydrochloride.
According to the method of the invention, the dehydration is carried out in the presence of a second solvent, wherein the second solvent is selected from at least one of benzene, toluene, dichloromethane, 1,2-dichloroethane, preferably toluene. The dehydration temperature is 40-120 ℃, and the preferable temperature is 90-110 ℃; the dehydration pressure is 0.05-0.15MPa. In the temperature range of the invention, the azeotropic property of the second solvent and water is utilized, which is beneficial to the dehydration of the compound I to achieve the effect of high yield.
And step 3: performing addition reaction on the compound II and dimethylamine to obtain a compound III, wherein R is selected from methyl or ethyl;
according to the method, the temperature of the addition reaction is 10-50 ℃, and the pressure of the addition reaction is 0-1MPa.
And 4, step 4: carrying out Grignard reaction on the compound III and a double Grignard reagent of 1,5-dihalogenopentane to obtain venlafaxine shown as a compound IV; wherein R is selected from methyl or ethyl; x is selected from chlorine or bromine.
According to the process of the invention, the 1,5-dihalopentane is selected from 1,5-dichloropentane or 1,5-dibromopentane.
According to the process of the invention, the molar ratio of compound III to the bis-Grignard reagent 5363-dihalopentane of 1,5 is 1: 1.05-2.
According to the method of the present invention, the grignard reaction is carried out in the presence of a third solvent; the third solvent is at least one selected from tetrahydrofuran, methyltetrahydrofuran, methyl tert-butyl ether, methyl cyclopentyl ether and toluene, and is preferably methyltetrahydrofuran; preferably, the Grignard reaction temperature is 0-50 ℃, the reaction pressure is 0.05-0.15MPa, the reaction time is 30-300min, and the preferred reaction temperature is 0-10 ℃.
According to the method, after the reaction is finished and the solvent is recovered, acid water is used for quenching, the solvent is extracted, and the product venlafaxine hydrochloride is obtained by recrystallization with hydrogen chloride; specifically, the acid water may be hydrochloric acid, dilute sulfuric acid, or the like. In particular, recrystallization may be carried out in isopropanol.
According to a particularly preferred embodiment of the present invention, there is provided a process for the preparation of venlafaxine hydrochloride comprising the steps of:
(1) Adding methyl pyruvate into the solution in the presence of 1,2-dichloroethane and Lewis acid aluminum trichloride, dropwise adding anisole at 0-5 ℃, after dropwise adding for 2 hours, preserving heat at 0-5 ℃ for reacting for 1 hour. Adding water, stirring for 1 hour, layering, washing the oil phase with water for 2 times, and concentrating under reduced pressure to obtain aryl lactate (compound I) (R = Me);
(2) Adding the aryl lactate (R = Me) and p-toluenesulfonic acid which are the products obtained in the step (1) into a toluene solution, dehydrating at 90-110 ℃, cooling the solution to 20-30 ℃ after the reaction is finished, and washing twice with a sodium hydroxide solution to obtain a toluene solution of aryl acrylate (compound II) (R = Me);
(3) Introducing dimethylamine gas into the toluene solution of the aryl acrylate in the step (2) at 40-50 ℃, and after the reaction is finished, carrying out reduced pressure distillation to recover the toluene solvent to obtain dimethylamine ester (compound III) (R = Me);
(4) Adding magnesium into dry methyltetrahydrofuran, stirring and heating to reflux, dropwise adding a 1,5-dichloropentane methyltetrahydrofuran solution, and keeping reflux for 2 hours after dropwise adding. And under the protection of nitrogen, cooling to the internal temperature of 0-10 ℃ to obtain a mixed solution. Dropwise adding the methyl tetrahydrofuran solution of the dimethyl amine ester (compound III) (R = Me) in the step (3) into the mixed solution, dropwise adding for about 60-80 minutes, and after the addition is finished, keeping the temperature at 0-10 ℃ for reaction for 60 minutes; then cooling to the internal temperature of 0-10 ℃, adding dimethylbenzene, dropwise adding dilute hydrochloric acid while stirring, stirring for 30 minutes after the addition is finished, carrying out phase separation, and washing an oil phase with hydrochloric acid, a sodium bicarbonate solution and water in sequence; then decompressing, concentrating and recovering the solvent, and recrystallizing in isopropanol by using hydrogen chloride to obtain white crystal venlafaxine hydrochloride;
the present invention will be described in detail below by way of examples. In the following examples, the room temperature is about 20-30 ℃.
In the following examples, reaction monitoring was performed by GC (gas chromatography); HPCL (liquid chromatography) detects the content of the product; the pure molar yield for each step was calculated as actual/theoretical yield 100%. The total molar yield is calculated as the product of the pure molar yields of the individual steps.
The starting materials, acids, bases, solvents, etc., used in the following examples were all obtained commercially. The double Grignard reagent of 1,5-dihalogen pentane can be obtained commercially or prepared by self, and the specific preparation method can refer to the specific embodiment of the invention.
GC (gas chromatography): SHIMADZU GC-2014
HPCL (liquid chromatography): SHIMADZU LC-20AT
Infrared spectroscopy instrument: SHIMADZU AIM-9000
Nuclear magnetic resonance apparatus: bruker 400MHz
Example 1
Step 1: preparation of Compound I
35g (0.343 mol) of methyl pyruvate and 47.9g (0.359 mol) of aluminum trichloride were added to 400mL of 1,2-dichloroethane, and the mixed solution was cooled to 0 ℃. Slowly dripping 35g (0.324 mol) of anisole, keeping the temperature at 5 ℃ for 1 hour after dripping for 2 hours, slowly adding 200mL of water, stirring for 1 hour, demixing, washing an oil phase with 200mL of water for 2 times, and then concentrating under reduced pressure to obtain 66g (the purity is 95.0wt%, the purity is 0.297 mol) of the product aryl lactate (compound I) (R = Me), wherein the purity molar yield is 91.6%. Directly entering the next reaction without purification. Characterization data for compound I (R = Me) are as follows:
IR(neat)v3516，2959，1729，1255cm -1 ； 1 H NMR(CDCl 3 )δ1.76(s，3H)， 3.75(s，3H)，3.78(s，3H)，6.87(d，2H)，7.45(d，2H)；MS(EI)m/e：211(M+1)。
step 2: preparation of Compound II
65.6g (0.297 mol) of the aryl lactate (R = Me) was added to 200mL of toluene, 2g of p-toluenesulfonic acid was then added, the mixed solution was heated to 100 ℃ for refluxing and water separation, and the reaction was followed by gas chromatography until the reaction was completed until the starting material was less than 1%. The reacted solution was cooled to room temperature and washed twice with 40mL of 5% sodium hydroxide solution to give a toluene solution of aryl acrylate (Compound II).
And step 3: preparation of Compound III (R = Me)
The toluene solution of the aryl acrylate was heated to 45 ℃ and then 16g (0.355 mol) of dimethylamine gas was added, the reaction was followed by gas chromatography until the aryl acrylate (R = Me) was less than 1.5%, the gas addition was stopped and stirring was continued for 30 minutes. Thereafter, the toluene solvent was recovered by distillation under the reduced pressure to obtain 65.8g (purity 97% by weight, purity 0.268 mol) of dimethyl amide (compound III) (R = Me) and 90.2% in the two-step reaction of step 2 and step 3. The obtained compound III was detected by an infrared spectrometer, a nuclear magnetic resonance spectrometer and a mass spectrometer, respectively. The detection data are as follows:
IR(neat)v3499，3356，3018，2978，1727，1611，1512，1249，1216，1178， 758cm -1 ； 1 H NMR(CDCl 3 )δ2.35(s，6H)，2.55(dd，1H)，3.23(dd，1H)，3.69(s，3H)， 3.79(s，3H)，3.89(dd，1H)，6.88(d，2H)，7.27(d，2H)；MS(EI)m/e：238(M+1)。
and 4, step 4: preparation of venlafaxine hydrochloride
Adding 11.2g (0.467 mol) of magnesium chips into a dry 1000mL four-necked bottle, adding 40mL of dry methyl tetrahydrofuran, heating to reflux under stirring, dropwise adding 250mL of methyl tetrahydrofuran solution of 30.8g of 1, 5-dichloropentane under reflux, adding a small particle of iodine, dropwise adding 10% of 1,5-dichloropentane methyl tetrahydrofuran solution to initiate violent reflux, continuously dropwise adding the rest 90% of 1,5-dichloropentane methyl tetrahydrofuran solution, dropwise adding for about 60 minutes, and adding heat generated by human materials to maintain the reflux of the system under the condition that the heating steam amount is kept unchanged in the process of dropwise adding speed, and maintaining the reflux for 2 hours after the addition. Under the protection of nitrogen, cooling the mixture to room temperature, transferring the mixture into a freezing bath under the protection of nitrogen, cooling the mixture to an internal temperature of 0 ℃, controlling the temperature to be 10 ℃, dissolving 50g of 97% (0.204 mol) of dimethylamine ester (compound III) (R = Me) obtained in the step 3 into 250mL of methyltetrahydrofuran, dropwise adding the mixed solution into the system for about 80 minutes, and keeping the temperature at 10 ℃ for reaction for 60 minutes after the dropwise adding is finished; then, the mixture was cooled to an internal temperature of 5 ℃ and 200mL of xylene was added, and a diluted hydrochloric acid solution prepared from 40mL of concentrated hydrochloric acid (36%) and 100mL of water was slowly added dropwise with stirring, and after the completion of the addition, the mixture was stirred for 30 minutes, and the phases were separated, and the oil phase was washed with 50mL of 5% hydrochloric acid, 50mL of 5% sodium bicarbonate solution, and 100mL of water in this order. After the solvent was recovered by concentration under reduced pressure, the solvent was recrystallized from isopropanol with hydrogen chloride to obtain 52.5g (0.167 mol) of white crystals, and the white crystals were examined by an infrared spectrometer, a nuclear magnetic resonance spectrometer and a mass spectrometer, respectively, and the examination data were as follows:
Mp：213-216℃。IR(KBr)v3350，2944，2989，1589，1520cm -1 ； 1 H NMR(CDCl 3 )δ0.89-1.74(m，10H)，2.63(d，3H)，2.83(d，3H)，3.15(m，1H)， 3.38(dd，1H)，3.81(s，3H)，4.05(dd，1H)，6.88(d，2H)，7.15(d，2H)，11.7(s，1H)； MS(FAB)m/e：278(M+1)。
the data are compared with the data of 2-Phenyl-2- (1-hydroxychloroalkyl) ethyl amine derivatives: alignment of the data in synthesis and antidepressant activity (John P. Yardley, G.E.Morris Husbands et al, J.Med.chem.1990, 33 (10): 2899-2905) demonstrated that the white crystals were venlafaxine hydrochloride.
Purity 99.7wt%, pure molar yield of venlafaxine hydrochloride in step 4 is about 82%. From anisole to venlafaxine hydrochloride, the overall molar yield of venlafaxine hydrochloride during this process was 67.7%.
Example 2
Following the procedure of example 1, except that in the preparation of compound I, dichloroethane was used as the first solvent, 65.4g (purity 95.5wt%, purity 0.296 mol) of the product aryl lactate (compound I) (R = Me) was obtained, with a pure molar yield of about 91.5% in step 1. Finally, white crystals are obtained.
According to the same detection method as in example 1, the finally obtained white crystal is venlafaxine hydrochloride.
Purity 99.8wt%, pure molar yield of venlafaxine hydrochloride in step 4 was about 80.7%.
The total molar yield from anisole to venlafaxine hydrochloride was 65.2%.
Example 3
The procedure is as in example 1, except that in the preparation of compound I, 68.0g (0.360 mol) of titanium tetrachloride are used as Lewis acid and the Friedel-crafts reaction temperature is 5 ℃. The obtained product, aryl lactate (compound I) (R = Me), was 61.9g (purity 94.1wt%, pure amount of 0.276 mol), and the pure molar yield of step 1 was about 85.2%. Finally, white crystals are obtained.
According to the same detection method as in example 1, the finally obtained white crystal is venlafaxine hydrochloride.
Purity 99.6wt%, pure molar yield of venlafaxine hydrochloride in step 4 was about 80.3%.
The total molar yield from anisole to venlafaxine hydrochloride was 62.1%.
Example 4
The procedure is as in example 1, except that in the preparation of compound III from compound I, the acid used for dehydration is 2g of phosphoric acid, the second solvent is benzene, and the dehydration temperature is 80 ℃. The obtained dimethyl amine ester (compound III) (R = Me) 60.5g (purity 97wt%, pure amount of 0.247 mol), and pure molar yield of both reactions of dehydration and dimethylamine addition were 84.6%. Finally, white crystals are obtained.
According to the same detection method as in example 1, the finally obtained white crystal is venlafaxine hydrochloride.
Purity 99.6wt%, pure molar yield of venlafaxine hydrochloride in step 4 was about 81.6%.
The total molar yield from anisole to venlafaxine hydrochloride was 63.4%.
Example 5
The procedure of example 1 was followed except that in the preparation of venlafaxine hydrochloride in step 4, tetrahydrofuran was used as the reaction solvent; the reaction temperature was 20 ℃. White crystals were obtained.
According to the same detection method as in example 1, the finally obtained white crystal is venlafaxine hydrochloride.
Purity 99.7wt%, pure molar yield of venlafaxine hydrochloride in step 4 was about 75.1%.
The total molar yield from anisole to venlafaxine hydrochloride was 58.3%.
Example 6
The procedure of example 2 was followed except that in the preparation of venlafaxine hydrochloride in step 4, the reaction solvent used was methyl tert-butyl ether; the 1,5-dihalopentane used is 1,5-dibromopentane; the reaction temperature was 30 ℃. White crystals were obtained.
According to the same detection method as in example 1, the finally obtained white crystal is venlafaxine hydrochloride.
Purity 99.8wt%, pure molar yield of venlafaxine hydrochloride in step 4 was about 71.9%.
The total molar yield from anisole to venlafaxine hydrochloride was 57.5%.
The results show that the total yield of the venlafaxine hydrochloride prepared by the method can reach 67.7 percent, and the purity of the venlafaxine hydrochloride is more than 99.5 percent by weight.
The preferred embodiments of the present invention have been described above in detail, but the present invention is not limited thereto. Within the scope of the technical idea of the invention, many simple modifications can be made to the technical solution of the invention, including combinations of various technical features in any other suitable way, and these simple modifications and combinations should also be regarded as the disclosure of the invention, and all fall within the scope of the invention.
Claims (10)
1. A process for preparing venlafaxine hydrochloride, said process comprising:
(1) Under the existence of Lewis acid, performing Friedel-crafts reaction on anisole and pyruvate to obtain a compound I;
(2) Dehydrating the compound I in the presence of an acid to obtain a compound II;
(3) Performing addition reaction on the compound II and dimethylamine to obtain a compound III;
(4) Carrying out Grignard reaction on the compound III and a double Grignard reagent of 1,5-dihalogenopentane to obtain venlafaxine hydrochloride shown as a compound IV;
wherein R is selected from methyl or ethyl.
2. The process according to claim 1, wherein in step (1), the Lewis acid is selected from the group consisting of aluminum trichloride, aluminum tribromide, boron trifluoride etherate, titanium tetrachloride, ferric trichloride, and zinc chloride, preferably aluminum trichloride;
the pyruvate ester is methyl pyruvate or ethyl pyruvate.
3. The process according to claim 1 or 2, wherein in step (1), the Friedel-crafts reaction is carried out in the presence of a first solvent selected from 1,2-dichloroethane and/or dichloromethane;
wherein the Friedel-crafts reaction temperature is between-20 ℃ and 40 ℃, and the preferred Friedel-crafts reaction temperature is between 0 and 5 ℃; the Friedel-crafts reaction pressure is 0.05-0.15MPa, and the Friedel-crafts reaction time is 2-4h.
4. The process according to any one of claims 1 to 3, wherein in step (1), the molar ratio of anisole, pyruvate and the Lewis acid is 1:1-1.5:1-1.5.
5. The method according to any one of claims 1 to 4, wherein in step (2), the acid is selected from at least one of hydrochloric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid, taurine, preferably p-toluenesulfonic acid.
6. The process according to any one of claims 1 to 5, wherein in step (2), the molar ratio of the acid to compound I is from 0.01 to 0.2.
7. The process according to any one of claims 1 to 6, wherein the dehydration is carried out in the presence of a second solvent, wherein the second solvent is selected from at least one of benzene, toluene, dichloromethane, 1,2-dichloroethane, preferably toluene;
preferably, the dehydration temperature is 40-120 ℃, preferably 90-110 ℃; the dehydration pressure is 0.05-0.15MPa.
8. The method of any one of claims 1 to 7, wherein in step (4), the 1,5-dihalopentane is selected from 1,5-dichloropentane or 1,5-dibromopentane.
9. The method according to any one of claims 1 to 8, wherein in step (4), the molar ratio of the compound III to the double grignard reagent of 1,5-dihalopentane is 1:1-2.
10. The method according to any one of claims 1 to 9, wherein in step (4), the grignard reaction is carried out in the presence of a third solvent, wherein the third solvent is selected from at least one of tetrahydrofuran, methyltetrahydrofuran, methyl tert-butyl ether, methyl cyclopentyl ether and toluene, preferably methyltetrahydrofuran;
preferably, the reaction temperature is 0-50 ℃, the Grignard reaction pressure is 0.05-0.15MPa, and the Grignard reaction time is 30-300min; the reaction temperature is preferably 0 to 10 ℃.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1244863A (en) * | 1996-12-13 | 2000-02-16 | C&C新药研究所 | Novel benzopyran derivatives |
| EP1213279A1 (en) * | 1999-07-27 | 2002-06-12 | Medichem S.A. | Venlafaxine production process |
| CN1706802A (en) * | 2005-05-27 | 2005-12-14 | 中国科学院上海有机化学研究所 | Prepn process of 2-ary lactate, naprosyn and ibuprofen |
| CN103483210A (en) * | 2012-06-13 | 2014-01-01 | 成都弘达药业有限公司 | New compound and preparation method thereof |
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- 2022-09-05 CN CN202211080833.4A patent/CN115650863A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1244863A (en) * | 1996-12-13 | 2000-02-16 | C&C新药研究所 | Novel benzopyran derivatives |
| EP1213279A1 (en) * | 1999-07-27 | 2002-06-12 | Medichem S.A. | Venlafaxine production process |
| CN1706802A (en) * | 2005-05-27 | 2005-12-14 | 中国科学院上海有机化学研究所 | Prepn process of 2-ary lactate, naprosyn and ibuprofen |
| CN103483210A (en) * | 2012-06-13 | 2014-01-01 | 成都弘达药业有限公司 | New compound and preparation method thereof |
Non-Patent Citations (2)
| Title |
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| DING LIU等: "Room-temperature Pd-catalyzed methoxycarbonylation of terminal alkynes with high branched selectivity enabled by bisphosphine-picolinamide ligand", CHEMCOMM, vol. 58, no. 7, pages 1044 * |
| YU-GUI SI等: "Highly Regioselective Friedel–Crafts Reactions of Electron-Rich Aromatic Compounds with Pyruvate Catalyzed by Lewis Acid-Base: Efficient Synthesis of Pesticide Cycloprothrin", ADV. SYNTH. CATAL, vol. 348, pages 1 - 2 * |
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