CN111217747B - Preparation method of pamaquine - Google Patents
Preparation method of pamaquine Download PDFInfo
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- CN111217747B CN111217747B CN202010188546.XA CN202010188546A CN111217747B CN 111217747 B CN111217747 B CN 111217747B CN 202010188546 A CN202010188546 A CN 202010188546A CN 111217747 B CN111217747 B CN 111217747B
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- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention provides a preparation method of pamaquinone, which comprises the following steps: substituting the amino group on the 8-amino-6-methoxyquinoline with halogen to obtain 8-halogen-6-methoxyquinoline, and then coupling with 5-diethylamino-2-aminopentane to obtain the pamaquiline. The preparation method provided by the invention takes 8-amino-6-methoxyquinoline and 5-diethylamino-2-aminopentane as raw materials, and adopts a two-step synthesis reaction to obtain the product pamaquinone, the raw materials of the preparation method are wide in source, the synthesis route is simple, the reaction conditions are mild and easy to reproduce, the yield and the purity of the pamaquinone prepared by the method are high, the yield of the pamaquinone is 5-57%, and the purity of the pamaquinone is 95-98%.
Description
Technical Field
The invention belongs to the technical field of compound synthesis, and relates to a preparation method of pamaquinone.
Background
Pamaquine (Pamaquine), systematic named 6-methoxy-8- (4 '-diethylamino-1' -methylbutyl) aminoquinoline, has a molecular weight of 315.46. The pamaquinone is yellow or orange yellow powder, odorless, bitter, insoluble in water, and soluble in ethanol and propanol. Pamaquine is an antimalarial drug, is effective in killing erythrocytic exoplasmodium and gametophyte, can reduce recurrence and spread of malaria, and when used with quinine, can radically cure vivax malaria and malaria quartana, but has high toxicity, and the structural formula of pamaquine can be represented by formula I:
currently, pamaquine is mainly prepared by the following two routes:
route one: the 8-amino-6-methoxyquinoline and 5-diethylamino-2-pentanone (A) are reacted to obtain an intermediate B directly, and the intermediate B is subjected to Pt or Ni catalytic hydrogenation to obtain the pamaquine, wherein the route can be represented by the following reaction formula:
the main problem of the first route is that the reaction from A to B takes a particularly long time, the conversion is not high even after a long time, and the yield is extremely low.
And a second route: the ketal C is prepared from 5-diethylamino-2-pentanone (A), the ketal C is subjected to a one-step high-temperature reaction to obtain an intermediate D, the intermediate D is subjected to a reaction with 8-amino-6-methoxyquinoline to generate an intermediate B identical to the first route, and finally, the intermediate B is reduced to obtain the pamaquinone, wherein the first route can be represented by the following reaction formula:
the second route has the main problems that the reaction conditions from A to C are harsh, the requirement on water is high, the reproduction is difficult, the route is long, and the synthesis process is complicated.
In addition, the raw material A used in the above two routes is not easy to obtain, and is generally synthesized by using 5-chloro-2-pentanone as a starting material and diethylamine, and the reaction process can be represented by the following reaction formula:
in addition to the above-mentioned synthetic routes, the other methods for synthesizing pamaquinone have the disadvantages of difficult raw material source and low yield compared with the above two routes.
Therefore, the development of a synthetic route of pamaquinone, which has the advantages of readily available raw materials, simple synthetic route and high yield, is an urgent problem to be solved in the field.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide a preparation method of pamaquinone, which takes 8-amino-6-methoxyquinoline and 5-diethylamino-2-aminopentane as raw materials, is easy to obtain the raw materials, can synthesize the pamaquinone by adopting two steps of reactions, and has the advantages of simple synthetic route and high product yield.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention provides a preparation method of pamaquinone, which comprises the following steps: substituting the amino group on the 8-amino-6-methoxyquinoline with halogen to obtain 8-halogen-6-methoxyquinoline, and then coupling with 5-diethylamino-2-aminopentane to obtain the pamaquiline.
The preparation method provided by the invention takes 8-amino-6-methoxyquinoline and 5-diethylamino-2-aminopentane as raw materials, and the 5-diethylamino-2-aminopentane is more widely available compared with 5-diethylamino-2-pentanone in the traditional pamaquinone synthesis route. Therefore, the preparation method has the advantages of simple and easily obtained raw materials, simple synthetic route, higher yield and easy reproduction.
As a preferred technical scheme of the invention, the preparation method comprises the following steps:
(1) mixing copper halide or cuprous halide, diazotization reagent and 8-amino-6-methoxyquinoline, and reacting to obtain 8-halogen-6-methoxyquinoline (E);
(2) mixing 5-diethylamino-2-aminopentane and the 8-halogen-6-methoxyquinoline in a basic environment, and reacting under the catalysis of a catalyst to obtain the pamaquiline.
The reaction process can be represented by the following reaction equation, wherein X represents a halogen:
in the invention, under the action of a diazotization reagent, the 8-amino-6-methoxyquinoline, copper halide or cuprous halide is subjected to one-step Muldmeyer reaction, the amino group on the 8-amino-6-methoxyquinoline is replaced by halogen to prepare an intermediate E (8-halogen-6-methoxyquinoline), and then the intermediate E and 5-diethylamino-2-aminopentane are subjected to one-step Buchwald-Hartwig coupling reaction, and the halogen atom is replaced by the amino group on the 5-diethylamino-2-aminopentane to obtain the product pamaquiline.
As a preferred technical solution of the present invention, the copper halide includes any one of copper bromide, copper chloride or copper iodide or a combination of at least two of them, and is preferably copper bromide.
According to the invention, copper halide is used for replacing 8-amino-6-methoxyquinoline, the effect is optimal when copper bromide is used, and after bromine is used for substitution, the success rate of the next coupling reaction can be improved, and the product yield is improved.
Preferably, the cuprous halide comprises any one of cuprous bromide, cuprous chloride or cuprous iodide or a combination of at least two thereof.
Preferably, the molar ratio of the 8-amino-6-methoxyquinoline to the copper halide or cuprous halide is 1 (0.8-1), and may be, for example, 1:0.8, 1:0.82, 1:0.84, 1:0.85, 1:0.88, 1:0.9, 1:0.92, 1:0.94, 1:0.96, 1:0.98, 1:1, or the like.
In the present invention, if the molar amount of the copper halide and/or cuprous halide is larger than 8-amino-6-methoxyquinoline, the halogen atom may be substituted for the hydrogen atom at other positions on the quinoline ring, which may result in the formation of a byproduct.
As a preferred embodiment of the present invention, the reaction in step (1) is carried out in a first solvent.
Preferably, the first solvent is water or an organic reagent, preferably acetonitrile.
Preferably, the diazotising agent comprises a nitrite or alkyl nitrite.
Preferably, the first solvent is water and the diazotizing agent comprises a nitrite salt.
Preferably, the first solvent is an organic reagent and the diazotizing agent comprises an alkyl nitrite.
Preferably, the molar ratio of the 8-amino-6-methoxyquinoline to the diazotizing agent is 1 (0.8-1), and may be, for example, 1:0.8, 1:0.82, 1:0.84, 1:0.85, 1:0.88, 1:0.9, 1:0.92, 1:0.94, 1:0.96, 1:0.98, 1:1, or the like.
Preferably, the alkyl nitrite comprises any one of isopropyl nitrite, isoamyl nitrite, tert-butyl nitrite, n-butyl nitrite, isobutyl nitrite, methyl nitrite or ethyl nitrite, or a combination of at least two thereof, preferably tert-butyl nitrite.
As a preferred embodiment of the present invention, the temperature of the reaction in the step (1) is 55 to 65 ℃ and may be, for example, 55 ℃, 56 ℃, 57 ℃, 58 ℃, 59 ℃, 60 ℃, 61 ℃, 62 ℃, 63 ℃, 64 ℃ or 65 ℃.
In the invention, if the reaction temperature is higher than 65 ℃, the side products generated by bromination on the quinoline ring are obviously increased; if the temperature is lower than 55 ℃, the reaction rate is obviously reduced, and a large amount of the raw material 8-amino-6-methoxyquinoline remains.
Preferably, the reaction time in step (1) is 1.5-2.5h, such as 1.5h, 1.6h, 1.7h, 1.8h, 1.9h, 2h, 2.1h, 2.2h, 2.3h, 2.4h or 2.5 h.
Preferably, the reaction of step (1) is carried out under stirring conditions.
Preferably, a separation operation is also performed after the reaction in the step (1) is finished.
Preferably, the separating operation comprises filtration, rotary evaporation and column chromatography.
In a preferred embodiment of the present invention, the alkaline environment in step (2) has a pH of 11 to 12, which may be, for example, 11, 11.2, 11.4, 11.5, 11.6, 11.8 or 12.
Preferably, step (2) obtains the alkaline environment by adding an alkali metal carbonate.
Preferably, the alkali metal carbonate comprises any one of cesium carbonate, lithium carbonate, sodium carbonate, potassium carbonate or rubidium carbonate or a combination of at least two thereof, preferably cesium carbonate.
Preferably, the molar ratio of the 8-halogen-6-methoxyquinoline to the alkali metal carbonate is 1 (1-3), and may be, for example, 1:1, 1:1.2, 1:1.5, 1:1.8, 1:2, 1:2.2, 1:2.5, 1:2.8, 1:3, or the like.
As a preferred embodiment of the present invention, the molar ratio of 8-halo-6-methoxyquinoline to 5-diethylamino-2-aminopentane in step (2) is 1 (1-1.2), and may be, for example, 1:1, 1:1.02, 1:1.04, 1:1.05, 1:1.06, 1:1.08, 1:1.1, 1:1.12, 1:1.14, 1:1.15, 1:1.18 or 1: 1.2.
Preferably, the reaction temperature in step (2) is 100-120 ℃, for example, 100 ℃, 102 ℃, 104 ℃, 106 ℃, 108 ℃, 110 ℃, 112 ℃, 114 ℃, 116 ℃, 118 ℃ or 120 ℃ and the like.
In the invention, if the reaction temperature is higher than 120 ℃, more 8-halogen-6-methoxyquinoline dehalogenation byproducts can be generated; if the temperature is lower than 100 ℃, the reaction is slow, and a large amount of both substrates remains.
Preferably, the reaction time in step (2) is 12-16h, such as 12h, 12.5h, 13h, 13.5h, 14h, 14.5h, 15h, 15.5h or 16 h.
Preferably, the reaction of step (2) is carried out in a second solvent.
Preferably, the second solvent comprises dioxane.
As a preferred technical scheme of the invention, the catalyst comprises 1,1 '-binaphthyl-2, 2' -bis-diphenylphosphine and tris (dibenzylideneacetone) dipalladium. The palladium catalyst and the phosphine ligand must be used simultaneously to achieve the catalytic effect.
Preferably, the molar ratio of the 8-halogen-6-methoxyquinoline to the 1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine is 1 (0.05-0.1), and may be, for example, 1:0.05, 1:0.055, 1:0.06, 1:0.065, 1:0.07, 1:0.075, 1:0.08, 1:0.085, 1:0.09, 1:0.095, 1:0.1, or the like.
Preferably, the molar ratio of the 8-halogen-6-methoxyquinoline to tris (dibenzylideneacetone) dipalladium is 1 (0.02-0.05), and may be, for example, 1:0.02, 1:0.025, 1:0.028, 1:0.03, 1:0.035, 1:0.038, 1:0.04, 1:0.042, 1:0.045, 1:0.048, or 1: 0.05.
As a preferred technical scheme of the invention, the reaction in the step (2) is carried out under a protective atmosphere.
Preferably, the protective atmosphere is a nitrogen atmosphere.
Preferably, a separation operation is also performed after the reaction in the step (2) is finished.
As a preferred technical scheme of the invention, the preparation method comprises the following steps:
(1) dispersing 8-amino-6-methoxyquinoline in acetonitrile, adding copper bromide at 23-28 ℃, wherein the molar ratio of the 8-amino-6-methoxyquinoline to the copper bromide is 1 (0.8-1), stirring for 20-40min, adding tert-butyl nitrite, continuing stirring for 5-15min, then heating to 55-65 ℃, reacting for 1.5-2.5h, filtering, carrying out rotary evaporation on the filtrate, and carrying out column chromatography to obtain 8-halogen-6-methoxyquinoline, wherein the process can be represented by the following reaction formula:
(2) mixing the 8-halogen-6-methoxyquinoline, 1 '-binaphthyl-2, 2' -bisdiphenylphosphine, cesium carbonate, tris (dibenzylideneacetone) dipalladium and 5-diethylamino-2-aminopentane, the molar ratio of the 8-halogen-6-methoxyquinoline to the cesium carbonate is 1: (1-3), the molar ratio of the 8-halogen-6-methoxyquinoline to the 5-diethylamino-2-aminopentane is 1: (1-1.2), replacing air in the reaction system with nitrogen, adding dioxane, replacing air in the reaction system with nitrogen again, reacting at the temperature of 100-120 ℃ for 12-16h, filtering, performing rotary evaporation on the filtrate and performing column chromatography to obtain the pamaquinone, wherein the process can be represented by the following reaction formula:
the recitation of numerical ranges herein includes not only the above-recited numerical values, but also any numerical values between non-recited numerical ranges, and is not intended to be exhaustive or to limit the invention to the precise numerical values encompassed within the range for brevity and clarity.
Compared with the prior art, the invention has the beneficial effects that:
the preparation method of the pamaquine uses 8-amino-6-methoxyquinoline and 5-diethylamino-2-aminopentane as raw materials, and obtains the product pamaquine through two-step reactions of Muldmeyer reaction and Buchwald-Hartwig coupling reaction, and the preparation method has the advantages of wide raw material source, simplicity and easiness in obtaining, simple synthetic route, fewer steps, no requirement of harsh reaction conditions and easiness in repeating; meanwhile, the pamaquine can be prepared by the preparation method provided by the invention, the yield is 5-57%, the yield can reach 31-57% under better conditions, the highest yield can reach 57%, the purity is 95-98%, the product yield is higher, the product quality is better, and the preparation method is suitable for industrial application.
Drawings
FIG. 1 is a NMR spectrum of the product obtained in example 1.
Detailed Description
The technical solution of the present invention is further explained by the following embodiments. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention.
In the following examples, 8-amino-6-methoxyquinoline, 5-diethylamino-2-aminopentane and the remaining reagents were purchased from conventional reagent manufacturers;
in the following examples, the room temperature is 25 ℃;
in the following examples, the eluent used in the column chromatography in step (1) comprises petroleum ether, dichloromethane and ethyl acetate, and the volume ratio of the petroleum ether, the dichloromethane and the ethyl acetate is 1:1: 0.05-1: 1: 0.15; an eluent used in the column chromatography in the step (2) comprises petroleum ether, ethyl acetate and ammonia water, and the volume ratio of the petroleum ether to the ethyl acetate to the ammonia water is 3:1: 0.003-1: 3: 0.003;
in the following examples, the compounds were characterized using Shimadzu, LC-2010AHT liquid chromatograph, Agilent, model 1260/6120B LC MS, and Walian, 400-MR NMR spectrometer.
Example 1
The embodiment provides a preparation method of pamaquinone, which comprises the following specific operation steps:
(1) acetonitrile (500mL), 8-amino-6-methoxyquinoline (48g, 0.28mol, 1eq) was added to a 1L three-necked flask, and copper bromide (55g, 0.25mol, 0.9eq) was added in one portion at room temperature. After stirring the reaction system at room temperature for 30min, slowly adding tert-butyl nitrite (29g, 0.28mol, 1eq), stirring for 10min after adding the tert-butyl nitrite, and heating to 60 ℃ for reaction for two hours;
and after the LCMS detection reaction is finished, cooling, sucking and filtering by using kieselguhr as a pad, leaching a filter cake by using 100mL of acetonitrile, spin-drying a filtrate to obtain a brown oily crude product, and performing column chromatography to obtain a light yellow solid E, namely 46g of 8-bromo-6-methoxyquinoline.
(2) A three-neck flask is charged with intermediate E (41g, 0.17mol, 1eq), 1,1 '-binaphthyl-2, 2' -bis-diphenylphosphine (7.4g, 12mmol, 0.07eq), cesium carbonate (83g, 0.26mol, 1.5eq), tris (dibenzylideneacetone) dipalladium (3.4g, 6mmol, 0.035eq), 5-diethylamino-2-aminopentane (30g, 0.19mol, 1.1eq), nitrogen was replaced three times, dioxane 600mL was added, nitrogen was replaced three times, the temperature was raised to 110 ℃ for reaction for 12h, and TLC detected that the starting material E was completely reacted.
Cooling the system to room temperature, filtering with diatomite, spin-drying the filtrate, and performing column chromatography to obtain red oily substance 44g with a yield of 57%; the purity was 98%.
Mass spectrogram of product [ M + 1%]+＝316.3；
The nuclear magnetic resonance hydrogen spectrum of the product is shown in figure 1, and the spectrogram data is as follows:1H NMR(400MHz,CDCl3) δ 8.52(dd, J ═ 4.2,1.6Hz,1H),7.91(dd, J ═ 8.2,1.6Hz,1H),7.29(dd, J ═ 8.2,4.2Hz,1H),6.32(d, J ═ 2.5Hz,1H),6.29(d, J ═ 2.5Hz,1H),6.03(d, J ═ 8.0Hz,1H),3.88(s,3H), 3.67-3.56 (m,1H),2.53(q, J ═ 7.2Hz,4H),2.46(t, J ═ 7.2Hz,2H), 1.81-1.49 (m,4H),1.30(d, J ═ 6.3Hz,3H),1.01(t, J ═ 7.2Hz, 6H); the nuclear magnetic resonance hydrogen spectrum data of the pamaquiline standard product are consistent.
Example 2
The embodiment provides a preparation method of pamaquinone, which comprises the following specific operation steps:
(1) acetonitrile (500mL), 8-amino-6-methoxyquinoline (48g, 0.28mol, 1eq) was added to a 1L three-necked flask, and copper bromide (50g, 0.224mol, 0.8eq) was added in one portion at room temperature. After the reaction system is stirred for 20min at room temperature, tert-butyl nitrite (29g, 0.28mol, 1eq) is slowly added, the mixture is stirred for 5min at room temperature, and then the mixture is heated to 55 ℃ for reaction for 1.5 h;
and (3) detecting the residual 20% of the 8-amino-6-methoxyquinoline by LCMS, cooling, filtering by using kieselguhr, leaching a filter cake by using 100mL of acetonitrile, drying a filtrate by spinning to obtain a brown oily crude product, and performing column chromatography to obtain a light yellow solid E, namely 32g of 8-bromo-6-methoxyquinoline.
(2) A three-necked flask was charged with intermediate E (41g, 0.17mol, 1eq), 1,1 '-binaphthyl-2, 2' -bis-diphenylphosphine (5.3g, 8.5mmol, 0.05eq), cesium carbonate (72g, 0.22mol, 1.3eq), tris (dibenzylideneacetone) dipalladium (3.1g, 3.4mmol, 0.02eq), 5-diethylamino-2-aminopentane (26.9g, 0.17mol, 1eq), replaced with nitrogen three times, charged with dioxane 600mL, replaced with nitrogen three times, and warmed to 100 ℃ for 15 h. LCMS check intermediate E for 15% remaining.
Cooling the system to room temperature, filtering with diatomite, spin-drying the filtrate, and performing column chromatography to obtain 31g of red oily matter with a yield of 28%; the purity was 96%.
Example 3
The embodiment provides a preparation method of pamaquinone, which comprises the following specific operation steps:
(1) acetonitrile (500mL), 8-amino-6-methoxyquinoline (48g, 0.28mol, 1eq) was added to a 1L three-necked flask, and copper bromide (62g, 0.28mol, 1eq) was added in one portion at room temperature. After the reaction system is stirred for 40min at room temperature, tert-butyl nitrite (29g, 0.28mol, 1eq) is slowly added, stirred for 15min at room temperature after the addition is finished, and then heated to 65 ℃ for reaction for 2.5 h;
and after the LCMS detection reaction is finished, cooling, sucking and filtering by using kieselguhr as a pad, leaching a filter cake by using 100mL of acetonitrile, spin-drying a filtrate to obtain a brown oily crude product, and performing column chromatography to obtain a light yellow solid E, namely 13g of 8-bromo-6-methoxyquinoline.
(2) A three-necked flask was charged with intermediate E (41g, 0.17mol, 1eq), 1,1 '-binaphthyl-2, 2' -bis-diphenylphosphine (8.46g, 13.6mmol, 0.08eq), cesium carbonate (88.4g, 0.27mol, 1.6eq), tris (dibenzylideneacetone) dipalladium (7.78g, 8.5mmol, 0.05eq), 5-diethylamino-2-aminopentane (31.6g, 0.20mol, 1.2eq), replaced with nitrogen three times, charged with dioxane 600mL, replaced with nitrogen three times, and warmed to 120 ℃ for 10 h. The reaction was complete by TLC.
Cooling the system to room temperature, filtering with diatomite, and performing rotary column chromatography on the filtrate to obtain 41g of red oily matter with the yield of 15%; the purity was 97%.
Example 4
The difference from example 1 is that in this example copper bromide was replaced by cuprous bromide (0.9 eq); the rest of the procedure and reaction conditions were the same as in example 1.
Example 5
The difference from example 1 is that in this example copper bromide was replaced by copper chloride (0.9 eq); the rest of the procedure and reaction conditions were the same as in example 1.
Example 6
The difference from example 1 is that in this example the amount of copper bromide was increased to 1.2eq, the ratio of 8-amino-6-methoxyquinoline to copper bromide was 1: 1.2; the rest of the procedure and reaction conditions were the same as in example 1.
Example 7
The difference from example 1 is that in this example the amount of copper bromide was reduced to 0.7eq, the ratio of 8-amino-6-methoxyquinoline to copper bromide was 1: 0.7; the rest of the procedure and reaction conditions were the same as in example 1.
Example 8
The difference from example 1 is that tert-butyl nitrite was replaced with an equimolar amount of isoamyl nitrite in this example; the rest of the procedure and reaction conditions were the same as in example 1.
Example 9
The difference from example 1 is that in this example, acetonitrile was replaced with 40% aqueous HBr solution of the same volume, and tert-butyl nitrite was replaced with sodium nitrite of the same molar amount, and the solution was dropped into the reaction system at 0 ℃; the rest of the procedure and reaction conditions were the same as in example 1.
Example 10
The difference from example 1 is that cesium carbonate is replaced by an equimolar amount of sodium carbonate in this example; the rest of the procedure and reaction conditions were the same as in example 1.
Example 11
The difference from example 1 is that 1,1 '-binaphthyl-2, 2' -bis-diphenylphosphine was not used in this example, but 2-dicyclohexylphosphonium-2, 4, 6-triisopropylbiphenyl was used in place of it in an equimolar amount; the rest of the procedure and reaction conditions were the same as in example 1.
Example 12
The difference from example 1 is that tris (dibenzylideneacetone) dipalladium is not used in this example, but instead an equimolar amount of tetrakis (triphenylphosphine) palladium; the rest of the procedure and reaction conditions were the same as in example 1.
Example 13
The difference from example 1 is that dioxane is replaced by toluene in this example; the rest of the procedure and reaction conditions were the same as in example 1.
The yield, yield and purity of the pamaquine product prepared in examples 1-13 are shown in table 1:
TABLE 1
As can be seen from the above table, the method for preparing pamaquinone has the advantages of wide sources of raw materials, simplicity, easy obtainment, simple synthetic route, fewer steps, no requirement of harsh reaction conditions, and easy repetition; as is clear from comparison of example 1 with examples 4 and 5, the yield of the product obtained by substitution with copper bromide was higher than that of cuprous bromide and cupric chloride; as is clear from comparison of example 1 with examples 6 and 7, when the molar amount of 8-amino-6-methoxyquinoline and copper bromide is out of the range of 1 (0.8-1), the yield of the obtained product is low; as is clear from comparison between example 1 and example 9, the yield is low when 40% aqueous HBr is used as a solvent in step (1) of the present invention; as is clear from comparison of example 1 with examples 11 and 12, a combination of 1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine and tris (dibenzylideneacetone) dipalladium as a ligand and a catalyst can achieve a higher yield.
In summary, in the preparation method of pamaquinone, when appropriate raw materials, appropriate raw material ratios, reaction temperatures, solvents and catalysts are adopted, the yield of pamaquinone can reach 57%, the purity is 98%, the product yield is high, the quality is good, and the preparation method is suitable for industrial application.
The applicant declares that the present invention illustrates the detailed structural features of the present invention through the above embodiments, but the present invention is not limited to the above detailed structural features, that is, it does not mean that the present invention must be implemented depending on the above detailed structural features. It should be understood by those skilled in the art that any modifications of the present invention, equivalent substitutions of selected components of the present invention, additions of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.
Claims (22)
1. The preparation method of pamaquine is characterized by comprising the following steps:
(1) mixing copper halide or cuprous halide, diazotization reagent and 8-amino-6-methoxyquinoline, and reacting at 55-65 ℃ for 1.5-2.5h to obtain 8-halogen-6-methoxyquinoline;
the copper halide is copper bromide, the cuprous halide is cuprous bromide, and the reaction is carried out in acetonitrile;
the molar ratio of the 8-amino-6-methoxyquinoline to the copper halide or cuprous halide is 1 (0.8-1);
(2) mixing 5-diethylamino-2-aminopentane and the 8-halogen-6-methoxyquinoline in an alkaline environment, and reacting at the temperature of 100-120 ℃ for 12-16h under the catalysis of a catalyst to obtain the pamaquiline;
the catalyst comprises 1,1 '-binaphthyl-2, 2' -bis-diphenylphosphine and tris (dibenzylideneacetone) dipalladium.
2. The method according to claim 1, wherein the molar ratio of the 8-amino-6-methoxyquinoline to the diazotizing agent is 1 (0.8-1).
3. The method according to claim 1, wherein the diazotizing agent is an alkyl nitrite.
4. The method according to claim 3, wherein the alkyl nitrite is selected from any one of isopropyl nitrite, isoamyl nitrite, tert-butyl nitrite, n-butyl nitrite, isobutyl nitrite, methyl nitrite, and ethyl nitrite, or a combination of at least two thereof.
5. The method according to claim 4, wherein the alkyl nitrite is tert-butyl nitrite.
6. The method according to claim 1, wherein the reaction in step (1) is carried out under stirring.
7. The process according to claim 1, wherein a separation operation is further performed after the reaction in the step (1) is completed.
8. The method of claim 7, wherein the separating comprises filtering, rotary evaporation and column chromatography.
9. The method of claim 1, wherein the alkaline environment of step (2) has a pH of 11 to 12.
10. The process according to claim 1, wherein step (2) is carried out by adding an alkali metal carbonate to obtain the alkaline environment.
11. The production method according to claim 10, wherein the alkali metal carbonate is selected from any one of cesium carbonate, lithium carbonate, sodium carbonate, potassium carbonate, or rubidium carbonate, or a combination of at least two of them.
12. The process according to claim 11, wherein the alkali metal carbonate is cesium carbonate.
13. The process according to claim 10, wherein the molar ratio of 8-halo-6-methoxyquinoline to alkali metal carbonate is 1 (1-3).
14. The process according to claim 1, wherein the molar ratio of 8-halo-6-methoxyquinoline to 5-diethylamino-2-aminopentane in step (2) is 1 (1-1.2).
15. The method according to claim 1, wherein the reaction in step (2) is carried out in a second solvent.
16. The method of claim 15, wherein the second solvent comprises dioxane.
17. The preparation method according to claim 1, wherein the molar ratio of the 8-halogen-6-methoxyquinoline to the 1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine is 1 (0.05-0.1).
18. The method according to claim 1, wherein the molar ratio of 8-halo-6-methoxyquinoline to tris (dibenzylideneacetone) dipalladium is 1 (0.02-0.05).
19. The method according to claim 1, wherein the reaction of step (2) is carried out under a protective atmosphere.
20. The method of claim 19, wherein the protective atmosphere is a nitrogen atmosphere.
21. The method according to claim 1, wherein a separation operation is further performed after the reaction in the step (2) is completed.
22. The method of claim 1, comprising the steps of:
(1) dispersing 8-amino-6-methoxyquinoline in acetonitrile, adding copper bromide at 23-28 ℃, wherein the molar ratio of the 8-amino-6-methoxyquinoline to the copper bromide is 1 (0.8-1), stirring for 20-40min, adding tert-butyl nitrite, continuing stirring for 5-15min, heating to 55-65 ℃, reacting for 1.5-2.5h, filtering, carrying out rotary evaporation on the filtrate, and carrying out column chromatography to obtain 8-halogen-6-methoxyquinoline;
(2) mixing the 8-halogen-6-methoxyquinoline, 1 '-binaphthyl-2, 2' -bisdiphenylphosphine, cesium carbonate, tris (dibenzylideneacetone) dipalladium and 5-diethylamino-2-aminopentane, the molar ratio of the 8-halogen-6-methoxyquinoline to the cesium carbonate is 1: (1-3), the molar ratio of the 8-halogen-6-methoxyquinoline to the 5-diethylamino-2-aminopentane is 1: (1-1.2), replacing air in the reaction system with nitrogen, adding dioxane, replacing air in the reaction system with nitrogen again, reacting at 100-120 deg.C for 12-16h, filtering, rotary evaporating the filtrate, and performing column chromatography to obtain pamaquinoline.
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| CN100408575C (en) * | 2001-05-25 | 2008-08-06 | 惠氏公司 | Aryl-8-azabicyclo[3,2,1]octanes for treating depression |
| WO2012068335A2 (en) * | 2010-11-18 | 2012-05-24 | Dalhousie University | Novel catalysts |
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| CN100408575C (en) * | 2001-05-25 | 2008-08-06 | 惠氏公司 | Aryl-8-azabicyclo[3,2,1]octanes for treating depression |
| WO2012068335A2 (en) * | 2010-11-18 | 2012-05-24 | Dalhousie University | Novel catalysts |
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