CN113717166B - Synthesis method of pramipexole - Google Patents

Synthesis method of pramipexole Download PDF

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CN113717166B
CN113717166B CN202110272593.7A CN202110272593A CN113717166B CN 113717166 B CN113717166 B CN 113717166B CN 202110272593 A CN202110272593 A CN 202110272593A CN 113717166 B CN113717166 B CN 113717166B
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reaction
chloride
magnesium chloride
pramipexole
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CN113717166A (en
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郑旭春
张一平
吴怡华
付晨晨
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Hangzhou Cheminspire Technologies Co ltd
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

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Abstract

The invention provides a synthetic method of a new product of pramipexole, which comprises the steps of taking 3- (oxazol-2-yl) propyl acyl morpholine compound 1 and 2, 5-dibromopyridine compound 2 as initial raw materials, carrying out strong base bromine pulling on the compound 2, carrying out condensation reaction on the compound 2 and amide compound 1 to obtain compound 3, then reducing carbonyl to obtain compound 4, carrying out ullmann coupling reaction on the compound and 2-amino-2-methylpropanoic acid compound 5 to obtain compound 6, carrying out esterification to obtain compound 7, and carrying out direct one-pot condensation and cyclization on the compound and 3-fluoro-4-isothiocyanato-2- (trifluoromethyl) benzonitrile compound 8 to obtain a product of pramipexole 9; the method is simple to operate, the total yield is high, the purity of the obtained product is high, and the method is suitable for large-scale production.

Description

Synthesis method of pramipexole
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and relates to a method for synthesizing pramipexole amine. Specifically, the invention discloses a chemical synthesis method of an intermediate and a product of an AR antagonist Prussian amine. The method is simple, convenient and efficient, and has good application prospect.
Background
Prussian amine (also known as GT 0918), which is a new generation Androgen Receptor (AR) antagonist developed independently by the development pharmaceutical industry, has a chemical structure which is a novel compound derived from the change of the core structure of the new anti-prostate cancer drug Enzalutamine newly marketed in the United states, and has higher in vitro AR targeting activity compared with Enzalutamine and bicalutamide. The medicine is currently used for treating male prostatic cancer in the phase II clinical stage, a research and development team is exploring the treatment effect of the medicine on the new coronaries pneumonia, and a clinical test of the praecox for treating the COVID-19 is being developed in Brazil. The development pharmaceutical industry published the clinical trial data on day 1, 2021 and 7. The result shows that the praecox can significantly inhibit the conversion of a new male subject from mild to severe, and the safety of short-term administration (15 days of oral administration) is good. The development pharmaceutical industry published mid-term data of its praecox treatment of new coronal female subjects in brazil, day 1, 10, 2021. The mid-term data of the new crown female subject treated by the pramipexole is consistent with the clinical test results of the new crown male subject treated by the pramipexole published before, the conversion from mild symptoms to severe symptoms of the new crown patients can be obviously reduced, and the fact that the therapeutic effect of the new crown patients treated by the pramipexole possibly has no sex difference is proved. At present, the subsequent clinical experiments are still in progress, and if the product can be successfully used for treating the new coronaries, the market prospect of the product is wide.
The chemical name of the praecox is: 4- (4, 4-dimethyl-3- (6- (3- (oxazol-2-yl) propyl) pyridin-3-yl) -5-oxo-2-thioimidazolidin-1-yl) -3-fluoro-2- (trifluoromethyl) benzonitrile, the structure is shown below:
the synthesis method of the Pr-Kluyvernamine reported in PCT patent WO2012119559A is to take 4- (5-nitropyridin-2-yl) butyric acid as a starting raw material, esterify and ammonolyze the 4- (5-nitropyridin-2-yl) butyramide, cyclize the 4- (5-nitropyridin-2-yl) butyramide with 1, 3-dioxolan-2-one under the action of polyphosphoric acid to obtain 2- (3- (5-nitropyridin-2-yl) propyl) oxazole, reduce the nitro by utilizing iron powder, then carry out addition reaction with TMSCN and acetone under the catalysis of zinc chloride to obtain 2-methyl-2- ((6- (3- (oxazol-2-yl) propyl) pyridin-3-yl) amino) propionitrile, and cyclize the 2- (trifluoromethyl) benzonitrile with 3-fluoro-4-isothiocyanato obtain the Pr-Kluyvernamine product. The route is as follows:
the linear steps of the route are overlong, PPA polyphosphoric acid is used in cyclization reaction for forming oxazole, a virulent reagent TMSCN is also used in the route, the process is complicated, three wastes are more, and certain potential safety hazards are provided, and the method for synthesizing the praecox by using the method which is simple in process route, high in yield, low in cost and suitable for industrial production is still needed.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a novel synthesis method of the praecox, which has the advantages of simple process route, low cost and suitability for industrial production.
In order to achieve the aim of the invention, the invention adopts the following technical scheme:
one of the purposes of the invention is to provide an intermediate compound 6 of the praecox, which has the structural formula:
the invention also provides a synthesis method of the intermediate compound 6 of the pramipexole, which comprises the following steps:
(1) 2, 5-dibromopyridine compound 2 is subjected to bromine pulling under the action of alkali and then is subjected to condensation reaction with 3- (oxazol-2-yl) propyl acyl morpholine compound 1 to obtain compound 3;
(2) Reducing carbonyl by using a reducing agent under the action of acid to obtain a compound 4;
(3) The compound 4 and the 2-amino-2-methylpropanoic acid 5 are subjected to Ullmann coupling reaction under the catalysis of copper salt to obtain an intermediate compound 6
Further, in the step (1), bromine is directly removed by using n-butyllithium to obtain an aryl lithium reagent or isopropyl magnesium chloride, cyclohexyl magnesium chloride or n-butyl magnesium chloride or a complex of the isopropyl magnesium chloride, cyclohexyl magnesium chloride or n-butyl magnesium chloride and lithium chloride is subjected to Grignard exchange with a compound 2 to obtain an aryl Grignard reagent; selecting catalyst without or zinc chloride or neodymium chloride as catalyst; the reaction solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran, toluene, trifluoromethyl benzene or dichloromethane; the reaction temperature is-75-90 ℃.
Further, in the reduction reaction of the step (2), the reducing agent is selected from lithium borohydride, sodium borohydride, potassium borohydride, triethylsilane or tetramethyl disiloxane; the additive is selected from aluminum trichloride, boron trifluoride diethyl etherate or trifluoroacetic acid; the reaction solvent is selected from dichloromethane, 1, 2-dichloroethane, toluene, acetonitrile, tetrahydrofuran or 2-methyltetrahydrofuran; the reaction temperature is-10 to 110 ℃.
Further, the catalyst selected in the ullmann coupling reaction in the step (3) is cuprous oxide, cuprous chloride, cuprous bromide or cuprous iodide; the base is selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, triethylamine, diisopropylethylamine, DBU or DABCO; no ligand or ligand selected from L-proline, acetylacetone, dibenzoylmethane or N, N' -dimethylethylenediamine; the reaction solvent is selected from N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, toluene, xylene or chlorobenzene. The reaction temperature is 20-180 ℃.
The second purpose of the invention is to provide an intermediate compound 7 of the praecox, which has the structural formula:
wherein R is methyl, ethyl, isopropyl, n-butyl, allyl or benzyl.
The invention also provides a synthesis method of the intermediate compound 7 of the praecox, which comprises the steps that the chemical formula 3 is subjected to esterification reaction to obtain the chemical formula 7;
wherein R is methyl, ethyl, isopropyl, n-butyl, allyl or benzyl.
Further, the esterification reaction can correspondingly select methanol, ethanol, isopropanol, n-butanol, allyl alcohol or benzyl alcohol as a reaction solvent directly; the acylating reagent is thionyl chloride or phosphorus oxychloride; the reaction temperature is 0-100 ℃.
Or the esterifying reagent may be selected from the corresponding bromoalkane, iodoalkane, chloroalkane, triflate alkyl or p-toluenesulfonate alkyl esters as esterifying agent; the base is selected from potassium carbonate, sodium carbonate, triethylamine, diisopropylethylamine, pyridine, DMAP, DBU or DABCO; the reaction solvent is selected from acetone, dichloromethane, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran and 1, 4-dioxane; the reaction temperature is 0-110 ℃.
The invention further provides a synthesis method of the Prussian amine product, which comprises the steps of condensing the compound 7 and the compound 8 into a ring by a one-pot method under the action of alkali to obtain a final product Prussian amine compound 9;
wherein R is methyl, ethyl, isopropyl, n-butyl, allyl or benzyl;
further, the cyclization reaction base is selected from sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium carbonate, sodium carbonate, triethylamine, diisopropylethylamine, pyridine, DMAP, DBU or DABCO; the reaction solvent is selected from acetone, dichloromethane, 1, 2-dichloroethane, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, toluene, xylene or chlorobenzene. The reaction temperature is 20-180 ℃.
The invention aims at providing a method for synthesizing a new product of the prasugrel, which comprises the steps of taking 3- (oxazol-2-yl) propyl acyl morpholine compound 1 and 2, 5-dibromopyridine compound 2 as starting materials, carrying out strong base bromine pulling on the compound 2, carrying out condensation reaction on the compound 2 and amide compound 1 to obtain compound 3, then reducing carbonyl to obtain compound 4, carrying out ullmann coupling reaction on the compound and 2-amino-2-methylpropanoic acid compound 5 to obtain compound 6, carrying out esterification to obtain compound 7, and carrying out direct one-pot condensation and cyclization on the compound and 3-fluoro-4-isothiocyanato-2- (trifluoromethyl) benzonitrile compound 8 to obtain a prasugrel product compound 9; the route is as follows:
the method for synthesizing the pramipexole has the advantages of greatly shortening the route steps, improving the route efficiency, avoiding the use of noble metal catalysts, reducing the process cost, reducing the generation of byproducts and being beneficial to improving the purity of the final finished product. In general, the route is simple to operate, the total yield is high, the purity of the obtained product is high, and the method is suitable for large-scale production.
The specific embodiment is as follows:
the following describes in detail the examples of the present invention, which are implemented on the premise of the technical solution of the present invention, and detailed embodiments and specific operation procedures are given, but the scope of protection of the present invention is not limited to the following examples.
Example 1
Adding compound 2 (23.69 g,100 mmol) and tetrahydrofuran (115 mL) into a three-neck flask, stirring and dissolving, switching nitrogen in vacuum for 3 times, cooling to 0-5 ℃ in an ice bath, dropwise adding 1.0M isopropyl magnesium chloride lithium chloride complex tetrahydrofuran solution (105 mmol,105 mL) under nitrogen protection, reacting for 0.5 hours at 0-5 ℃, then dropwise adding compound 1 (23.13 g,110mmol, dissolving in 115mL tetrahydrofuran), reacting for 5-6 hours after the completion of dropwise adding until the room temperature is reached, adding saturated ammonium chloride (115 mL) after the completion of the reaction, quenching the reaction, extracting the mixed solution with ethyl acetate (115 mL) for 3 times, merging organic phase water (58 mL) for 2 times, concentrating, recrystallizing with an ethyl acetate petroleum ether mixed solvent to obtain an intermediate 3 (22.80 g, 81.1%)
MS(ESI)m/z＝280.1,283.1[M+H] + .
The lithium chloride complex of isopropyl magnesium chloride in example 1 may be replaced by cyclohexyl magnesium chloride or n-butyl magnesium chloride, or may be replaced by a complex of cyclohexyl magnesium chloride or n-butyl magnesium chloride and lithium chloride; zinc chloride or neodymium chloride can be added into the reaction system as a catalyst, and the solvent tetrahydrofuran can be replaced by 2-methyltetrahydrofuran, toluene, trifluoromethyl benzene or dichloromethane.
Example 2
A three-necked flask was charged with compound of formula 2 (23.69 g,100 mmol) and tetrahydrofuran (115 mL), the solution was stirred and dissolved, then the nitrogen was switched in vacuo for 3 times, dry ice acetone was cooled to-70-75℃under nitrogen, 2.5M n-butyllithium tetrahydrofuran solution (105 mmol,42 mL) was added dropwise, the reaction was carried out at-70-75℃for 0.5 hours, anhydrous zinc chloride in tetrahydrofuran (13.63 g,100mmol, dissolved in 115mL of tetrahydrofuran) was added dropwise, then 1 (23.13 g,110mmol, dissolved in 115mL of tetrahydrofuran) was added dropwise, the reaction was carried out at room temperature for 5-6 hours after the completion of the dropwise, saturated ammonium chloride (115 mL) was added to quench the reaction, the mixture was extracted 3 times with ethyl acetate (115 mL), the organic phase water (58 mL) was combined and washed 2 times, and after the concentration, the mixture was recrystallized with ethyl acetate petroleum ether mixed solvent to obtain intermediate 3 (26.00 g, 92.5%).
In example 2, zinc chloride may be replaced by neodymium chloride, or zinc chloride may not be added in the reaction, and the solvent tetrahydrofuran may be replaced by 2-methyltetrahydrofuran, toluene, trifluoromethylbenzene or dichloromethane.
Example 3
Into a three-necked flask, compound 3 (28.11 g,100 mmol) and tetrahydrofuran (140 mL) were charged, and after stirring uniformly, trifluoroacetic acid (34.21 g,300 mmol) was added, and the mixture was heated to 50-55℃and sodium borohydride (5.67 g,150 mmol) was added in portions, and after the addition was completed, the mixture was heated to reflux for reaction overnight. After the completion of the reaction, the reaction was quenched by adding water (280 mL) to the cooled reaction mixture, the aqueous phase was extracted 3 times with ethyl acetate (140 mL), and the mixture was washed with water (70 mL) 2 times, concentrated, and crystallized from ethyl acetate/petroleum ether mixture to give intermediate 4 (23.32 g, 87.3%).
MS(ESI)m/z＝267.1,269.1[M+H] + .
In example 3, trifluoroacetic acid can be replaced with aluminum trichloride or boron trifluoride etherate; the solvent tetrahydrofuran may be replaced by dichloromethane, 1, 2-dichloroethane, toluene or 2-methyltetrahydrofuran; sodium borohydride may be replaced by lithium borohydride, potassium borohydride, triethylsilane or tetramethyldisiloxane.
Example 4
3 (28.11 g,100 mmol) and acetonitrile (140 mL) were added to a three-necked flask, and after stirring, trifluoroacetic acid (34.21 g,300 mmol) was added thereto, and after heating to 50-55℃triethylsilane (17.44 g,150 mmol) was slowly added dropwise thereto, and after the addition was completed, the mixture was heated again to reflux for reaction overnight. After the completion of the reaction, the reaction was quenched by adding water (280 mL) to the cooled reaction mixture, the aqueous phase was extracted 3 times with ethyl acetate (140 mL), and the mixture was washed with water (70 mL) 2 times, concentrated, and crystallized from ethyl acetate/petroleum ether mixture to give intermediate 4 (24.58 g, 92.0%).
In example 4, trifluoroacetic acid can be replaced with aluminum trichloride or boron trifluoride etherate; the solvent acetonitrile may be replaced by tetrahydrofuran, dichloromethane, 1, 2-dichloroethane, toluene or 2-methyltetrahydrofuran; triethylsilane may be replaced with sodium borohydride, lithium borohydride, potassium borohydride, or tetramethyldisiloxane.
Example 5
Into a three-necked flask, compound 4 (26.71 g,100 mmol), 2-amino-2-methylpropanoic acid compound 5 (12.37 g,120 mmol) and N, N-dimethylacetamide (134 mL) were charged, and cuprous iodide (1.90 g,10 mmol), dibenzoylmethane (2.24 g,10 mmol) and potassium carbonate (27.64 g,200 mmol) were added under nitrogen protection, and the mixture was heated to 100-105℃to react overnight after stirring. Water (267 mL) was added after the reaction, extraction was performed 3 times with ethyl acetate (134 mL), the mixture was stirred and separated, the aqueous phase was collected and pH was adjusted to 4-5 with 2N hydrochloric acid, a large amount of solids were precipitated, and compound 6 (25.63 g, 88.6%) was obtained by filtration and drying. MS (ESI) m/z=288.2 [ m-H] - .
1 HNMR(400MHz,CDCl 3 )8.10-8.25(m,1H),7.56(s,1H),7.19-7.24(m,1H),7.00-7.10(m,2H),2.95-3.05(m,2H),2.85-2.95(m,2H),2.24-2.36(m,2H),1.42-1.63(m,6H).
In example 5, cuprous iodide may be replaced with cuprous oxide, cuprous chloride, or cuprous bromide; the potassium carbonate may be replaced with sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, triethylamine, diisopropylethylamine, DBU or DABCO; the dibenzoylmethane can be replaced by L-proline, acetylacetone or N, N' -dimethylethylenediamine, or can be added; n, N-dimethylacetamide can be replaced by N, N-dimethylformamide, N-methylpyrrolidone, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, toluene, xylene or chlorobenzene. The reaction temperature is 20-180 ℃.
Example 6
Into a three-necked flask, compound 4 (26.71 g,100 mmol), 2-amino-2-methylpropanoic acid Compound 5 (12.37 g,120 mmol) and NMP (134 mL) were charged, and cuprous iodide (1.90 g,10 mmol), N' -dimethylethylenediamine (0.88 g,10 mmol) and DBU (30.45 g,200 mmol) were added under nitrogen protection, and after stirring, the mixture was heated to 100-105℃and reacted overnight. Water (267 mL) was added after the reaction, ethyl acetate (134 mL) was added for extraction 3 times, the mixture was stirred and separated, the pH of the aqueous phase was adjusted to 4-5 with 2N hydrochloric acid, a large amount of solids were precipitated, and compound 6 (22.39 g, 77.4%) was obtained by filtration and drying. MS (ESI) m/z=288.2 [ m-H] - .
1 HNMR(400MHz,CDCl 3 )8.10-8.25(m,1H),7.56(s,1H),7.19-7.24(m,1H),7.00-7.10(m,2H),2.95-3.05(m,2H),2.85-2.95(m,2H),2.24-2.36(m,2H),1.42-1.63(m,6H).
In example 6, cuprous iodide may be replaced with cuprous oxide, cuprous chloride, or cuprous bromide; DBU may be replaced with potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, triethylamine, diisopropylethylamine or DABCO; n, N' -dimethyl ethylenediamine can be replaced by dibenzoylmethane with L-proline or acetylacetone, or can be added; n-methylpyrrolidone NMP may be replaced by N, N-dimethylacetamide, N-dimethylformamide, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, toluene, xylene or chlorobenzene. The reaction temperature is 20-180 ℃.
Example 7
Into a three-necked flask, compound 6 (28.93 g,100 mmol) and methanol (145 mL) were added, the mixture was stirred uniformly, cooled to 0-5℃and thionyl chloride (17.85 g,150 mmol) was slowly added, followed by heating to room temperature and reaction for 4-6 hours. And (3) rotating part of methanol at the end of the reaction, slowly adding 5% sodium bicarbonate to adjust the pH to 9-10, pulping, filtering, pulping the crude product with methanol and water, filtering and drying to obtain the compound 7a (28.36 g, 93.5%).
MS(ESI)m/z＝304.1[M+H] + .
1 HNMR(400MHz,CDCl 3 )8.08-8.24(m,1H),7.55(s,1H),7.16-7.23(m,1H),6.98-7.11(m,2H),3.60-3.78(m,3H),2.92-3.03(m,2H),2.83-2.94(m,2H),2.23-2.37(m,2H),1.38-1.58(m,6H).
In example 7, thionyl chloride can be replaced with phosphorus oxychloride. When the benzyl alcohol is used as the reaction solvent instead of the methanol, the corresponding obtained compound is benzyl ester; when the methanol is changed to allyl alcohol as a reaction solvent, the corresponding obtained compound is allyl ester; when the methanol is changed to n-butanol as a reaction solvent, the corresponding obtained compound is n-butyl ester; when isopropanol is used instead of methanol as the reaction solvent, the corresponding compound is isopropyl ester.
Example 8
Into a three-necked flask, compound 6 (28.93 g,100 mmol), ethanol (145 mL) was added, the mixture was stirred uniformly, cooled to 0-5℃and phosphorus oxychloride (23.00 g,150 mmol) was slowly added, followed by heating to room temperature and reacting for 4-6 hours. And (3) rotating part of ethanol at the end of the reaction, slowly adding 5% sodium bicarbonate to adjust the pH to 9-10, pulping, filtering, pulping the crude product with ethanol and water, filtering and drying to obtain the compound 7b (28.15 g, 88.7%).
MS(ESI)m/z＝318.2[M+H] + .
1 HNMR(400MHz,CDCl 3 )8.08-8.24(m,1H),7.56(s,1H),7.16-7.23(m,1H),6.97-7.12(m,2H),3.75-3.97(m,2H),2.91-3.04(m,2H),2.82-2.93(m,2H),2.21-2.35(m,2H),1.35-1.56(m,6H),0.97-1.21(m,3H).
In example 8, phosphorus oxychloride can be replaced with thionyl chloride. When the benzyl alcohol is used as the reaction solvent instead of the ethanol, the corresponding obtained compound is benzyl ester; when the ethanol is changed to allyl alcohol as a reaction solvent, the corresponding obtained compound is allyl ester; when ethanol is changed to n-butanol as a reaction solvent, the corresponding obtained compound is n-butyl ester; when ethanol is changed to isopropanol as a reaction solvent, the corresponding obtained compound is isopropyl ester.
Example 9
Into a three-necked flask, compound 6 (28.93 g,100 mmol) and DMF (145 mL) were added, and after stirring well, potassium carbonate (27.64 g,200 mmol) was added, isopropyl bromide (14.76 g,120 mmol) was added, and then the temperature was raised to 40-45℃for reaction for 4-6 hours. And slowly adding water after the reaction is finished, pulping, filtering, pulping the crude product by using isopropanol and water, filtering and drying to obtain the compound 7c (30.06 g, 90.7%).
MS(ESI)m/z＝332.1[M+H] + .
1 HNMR(400MHz,CDCl 3 )8.11-8.23(m,1H),7.54(s,1H),7.20-7.27(m,1H),6.90-7.05(m,2H),4.93-5.02(m,1H),2.93-3.04(m,2H),2.84-2.97(m,2H),2.22-2.31(m,2H),1.32-1.58(m,12H).
N, N-dimethylformamide DMF in example 9 can be replaced with acetone, dichloromethane, N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane; the potassium carbonate can be replaced by sodium carbonate, triethylamine, diisopropylethylamine, pyridine, DMAP, DBU or DABCO; isopropyl bromide may be replaced with isopropyl triflate or isopropyl p-toluenesulfonate.
When the isopropyl bromide is changed into methyl bromide, methyl iodide or methyl chloride, methyl ester 7a is correspondingly obtained; when the isopropyl bromide is changed into bromoethane or iodoethane or chloroethane, methyl ester 7b is correspondingly obtained; when the isopropyl bromide is changed into n-butyl bromide, n-butyl iodide or n-butyl chloride, the n-butyl ester is correspondingly obtained; when isopropyl bromide is changed into p-toluenesulfonic acid benzyl ester or trifluoro methanesulfonic acid benzyl ester, benzyl ester is obtained correspondingly; when the isopropyl bromide is changed into the allyl tosylate or the allyl triflate, the allyl ester is obtained correspondingly.
Example 10
Into a three-necked flask, compound 7a (30.34 g,100 mmol), compound 8 (27.08 g,110 mmol) and tetrahydrofuran (303 mL) were charged, DIPEA (12.97 g,100 mmol) was added, and the mixture was heated to 55-60℃to react for 6-8 hours. At the end of the reaction, part of the solvent was removed by spinning, water (303 mL) was added, filtration was carried out, the crude product was slurried with a mixed solvent of ethanol and water, filtration was carried out, and drying was carried out to obtain the final product 9 (46.82 g,90.3%, purity 99.8%).
In example 10, diisopropylethylamine DIPEA can be replaced with sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium carbonate, sodium carbonate, triethylamine, pyridine, DMAP, DBU or DABCO; the reaction solvent tetrahydrofuran may be replaced by acetone, methylene chloride, 1, 2-dichloroethane, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, methanol, ethanol, isopropanol, acetonitrile, 2-methyltetrahydrofuran, 1, 4-dioxane, toluene, xylene or chlorobenzene.
Example 11
Into a three-necked flask, compound 7b (31.74 g,100 mmol), compound 8 (27.08 g,110 mmol) and DMF (317 mL) were charged, DBU (15.22 g,200 mmol) was added, and the mixture was heated to 55-60℃to react for 6-8 hours. Water (317 mL) is added after the reaction, the mixture is filtered, the crude product is pulped by using a mixed solvent of isopropyl alcohol and water, the filtration and the drying are carried out, and the final product 9 (45.88 g,88.3% and the purity is 99.6%) is obtained.
In example 11, DBU can be replaced with diisopropylethylamine DIPEA, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium carbonate, sodium carbonate, triethylamine, pyridine, DMAP or DABCO; the reaction solvent DMF may be replaced by acetone, dichloromethane, 1, 2-dichloroethane, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, toluene, xylene or chlorobenzene.
Example 12
Into a three-necked flask, compound 7c (33.14 g,100 mmol), compound 8 (27.08 g,110 mmol) and ethanol (280 mL) were charged, and sodium ethoxide (15.22 g,200 mmol) was added and heated to 55-60℃to react for 6-8 hours. At the end of the reaction, part of the solvent was removed by spinning, water (280 mL) was added, filtration was carried out, and the crude product was slurried with a mixed solvent of ethyl acetate and n-heptane, filtration and drying to give the final product 9 (41.23 g,79.2%, purity 99.4%).
In example 12, sodium ethoxide may be replaced with diisopropylethylamine DIPEA, sodium methoxide, sodium tert-butoxide, potassium carbonate, sodium carbonate, triethylamine, pyridine, DBU, DMAP or DABCO; the ethanol as reaction solvent may be replaced by acetone, dichloromethane, 1, 2-dichloroethane, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, methanol, isopropanol, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, toluene, xylene or chlorobenzene.

Claims (3)

1. The synthesis method of the intermediate compound 6 of the pramipexole is characterized by comprising the following steps of:
(1) Directly removing bromine from 2, 5-dibromopyridine compound 2 by using n-butyllithium to obtain an aryl lithium reagent or adopting isopropyl magnesium chloride, cyclohexyl magnesium chloride or n-butyl magnesium chloride or complexes of the isopropyl magnesium chloride, the cyclohexyl magnesium chloride or the n-butyl magnesium chloride and lithium chloride to carry out Grignard exchange with compound 2 to obtain an aryl Grignard reagent, and carrying out condensation reaction on the aryl Grignard reagent and 3- (oxazol-2-yl) propyl acyl morpholine compound 1 to obtain a compound 3;
(2) Reducing carbonyl by using a reducing agent and an additive under the action of acid to obtain a compound 4;
(3) Carrying out an ullmann coupling reaction on the compound 4 and 2-amino-2-methylpropanoic acid 5 under the catalysis of copper salt and the presence of alkali to obtain an intermediate formula 6;
2. the method for synthesizing the intermediate compound 6 of pramipexole according to claim 1, wherein no catalyst or zinc chloride or neodymium chloride is selected as the catalyst in the step (1); the solvent for the reaction is selected from tetrahydrofuran, 2-methyltetrahydrofuran, toluene, trifluoromethylbenzene or dichloromethane; the reducing agent in the step (2) is selected from lithium borohydride, sodium borohydride, potassium borohydride, triethylsilane or tetramethyl disiloxane; the additive is selected from aluminum trichloride, boron trifluoride diethyl etherate or trifluoroacetic acid; the solvent for the reaction is selected from dichloromethane, 1, 2-dichloroethane, toluene, acetonitrile, tetrahydrofuran or 2-methyltetrahydrofuran.
3. The method for synthesizing the intermediate compound 6 of pramipexole as claimed in claim 1, wherein the catalyst selected in the ullmann coupling reaction in the step (3) is cuprous oxide, cuprous chloride, cuprous bromide or cuprous iodide; the base is selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, triethylamine, diisopropylethylamine, DBU or DABCO; no ligand or ligand selected from L-proline, acetylacetone, dibenzoylmethane or N, N' -dimethylethylenediamine; the solvent for the reaction is selected from N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, toluene, xylene or chlorobenzene.
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