New process for continuously preparing carbamazepine

Abstract

The invention discloses a novel process for continuously preparing carbamazepine, which comprises the following steps: (1) dissolving indole in an organic solvent as a raw material solution I, filling a tubular reactor with a copper catalyst and the like, reacting the raw material solution I in the tubular reactor to obtain a reaction solution, and distilling to obtain 1-phenylindole; (2) respectively dissolving 1-phenylindole and an acid catalyst in an organic solvent to serve as a raw material solution II and a raw material solution III, mixing the raw material solution II and the raw material solution III through a tubular reactor for reaction to obtain a reaction solution, and recrystallizing the reaction solution to obtain iminostilbene; and (3) dissolving iminostilbene and triphosgene in an organic solvent to serve as raw material solutions IV and V, carrying out mixed reaction on the raw material solutions IV and V through a tubular reactor, carrying out mixed reaction with ammonia water again after the reaction is ended, and finally recrystallizing the reaction solution to obtain carbamazepine. The process comprises three steps of reaction, the yield of each step is more than 85%, the reaction speed is high, the side reaction is few, the mass and heat transfer efficiency is high, the safety is high, the three wastes are few, the cost is low, and the post-treatment is convenient.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a new process for continuously preparing carbamazepine. Background Art

[0002] Carbamazepine, whose chemical name is 5H-dibenzo[b,f]azepine-5-carboxamide, is currently used for anti-epileptic, anti-manic-depressive, anti-arrhythmic, treatment of trigeminal neuralgia, diabetes insipidus and depression, and has a wide range of clinical applications.

[0003] There are many methods for preparing carbamazepine. Currently, industrial production mainly adopts the o-nitrotoluene synthesis process (such as reported by Zhou Yiguo et al., Pharmaceutical Industry, 1972 (2): 4-9). The specific synthesis route is as follows: o-nitrotoluene is used as the starting material, coupling is carried out under the action of a strong base, catalytic hydrogenation is used to reduce the nitro group, and then a ring-closing reaction is carried out at an ultra-high temperature to obtain iminodibenzyl, which is then subjected to chlorination, bromination, elimination and amination, and a total of seven steps of reaction to obtain the product carbamazepine. This process has the advantages of mature technology, cheap raw materials and low production cost, but has the disadvantages of long reaction steps, complex post-treatment, more three wastes, and the use of hydrogenation or ultra-high temperature reaction dangerous processes.

[0004]

[0005] CN118459407A provides a continuous preparation method of carbamazepine, wherein iminostilbenecarbonyl chloride and chlorobenzene are mixed to obtain a raw material liquid; the raw material liquid and ammonia water are respectively introduced into a preheating module for mixing and preheating by a constant flow pump, and then introduced into a microchannel device for reaction to obtain a reaction liquid; the reaction liquid is post-treated to obtain a carbamazepine product. This process studies the microchannel continuous process of amination reaction, but uses iminostilbenecarbonyl chloride as the starting raw material, and the raw material is expensive.

[0006] Andrew V. Stachulski's research group (Organic & Biomolecular Chemistry, 2014, 45 (17): 8426-8434.) provides an indole synthesis process, using indole and iodobenzene as raw materials, L-proline as a ligand, cuprous iodide as a catalyst, and DMSO as a solvent, and performing an arylation reaction for 24 hours to obtain 1-phenylindole, and using 40 times the equivalent of polyphosphoric acid to catalyze rearrangement and ring-closing reaction for 36 hours to obtain iminostilbene (the yield of this step is only 67%), and then reacting with phosgene and ammonia in a "one-pot method" to obtain carbamazepine in a total of four steps. This process has the advantages of short reaction steps and relatively mild reaction conditions, but has the disadvantages of expensive raw materials, low yield of key rearrangement reaction, too long reaction time, and too much waste acid generated.

[0007] In summary, the first process and the third process are both intermittent production processes. The first process has disadvantages such as long reaction steps and complex post-processing, so it is not worth studying as a continuous process; the third process is also difficult to achieve tubular continuous reaction due to disadvantages such as long reaction time and low yield of key reactions; the second process is only a continuous process for the last step of amination in the synthesis of carbamazepine, and the raw materials are expensive. In the intermittent synthesis process reported in the literature, the last two steps of acyl chlorination and amination are often carried out in a "one-pot" process, so the practical value of this continuous process is not great. Summary of the invention

[0008] In view of this, in view of the above technical problems, the present invention has creatively studied the third process and provided a new process for preparing carbamazepine in a tubular continuous manner, which overcomes the shortcomings of the existing process and achieves the advantages of high yield, low cost, short reaction steps, short reaction time, simple post-treatment, less three wastes and process safety, and is a green, safe and efficient new process. This new process has not been reported in the literature and has innovativeness and industrial production value.

[0009] The specific process route of the present invention is as follows:

[0010]

[0011] The specific process of the present invention is as follows: indole and halobenzene are used as starting materials, a copper / base catalytic system is filled in a centimeter-level tubular fixed-bed catalytic reactor, and the reaction is carried out for several minutes to obtain 1-phenylindole; the intermediate and the acid are respectively dissolved in a solvent, and the reaction is carried out for several minutes through a centimeter-level tubular liquid phase reactor to obtain iminostilbene; the intermediate, solid phosgene and ammonia water are respectively dissolved in a solvent, and the reaction is carried out twice through a centimeter-level tubular liquid phase reactor, and the reaction is carried out for several minutes respectively, so as to carry out a "one-pot" reaction and obtain the product carbamazepine.

[0012] The technical solution adopted by the present invention to solve its technical problem is:

[0013] A new process for continuously preparing carbamazepine, the steps are as follows:

[0014] Step 1: continuously preparing 1-phenylindole; dissolving indole in an organic solvent which is also a reactant, heating and dissolving to obtain a raw material solution I; mixing a copper catalyst and an acid binding agent evenly and filling them into a tubular reactor; introducing the raw material solution I, entering a preheater for mixing and preheating, and then entering a tubular reactor for reaction to obtain a reaction solution ①; the reaction solution ① is distilled to obtain 1-phenylindole.

[0015] Step 2: continuously prepare iminostilbene; dissolve 1-phenylindole in an organic solvent to obtain a raw material solution II; dissolve an acid catalyst in an organic solvent to obtain a raw material solution III; introduce the raw material solutions II and III into a preheater for mixing and preheating, and then into a tubular reactor for reaction to obtain a reaction solution ②; the reaction solution ② is subjected to desolventization and recrystallization to obtain iminostilbene.

[0016] Step 3: Continuously prepare carbamazepine; dissolve iminostilbene in an organic solvent to obtain a raw material liquid IV; dissolve triphosgene in an organic solvent to obtain a raw material liquid V; introduce raw material liquids IV and V into a preheater for mixing and preheating, and then introduce them into a tubular reactor for reaction to obtain a reaction liquid ③; introduce reaction liquid ③ and ammonia water into a preheater for mixing and preheating, respectively, and then introduce them into a tubular reactor for reaction to obtain a reaction liquid ④; the reaction liquid ④ is subjected to desolventization and recrystallization to obtain carbamazepine.

[0017] Furthermore, in step 1, the tubular reactor is made of a stainless steel hollow column with an inner diameter ranging from 0.1 to 1.5 cm and a length ranging from 1 to 20 cm; in steps 2 and 3, the tubular reactor has an inner diameter ranging from 0.1 to 1.0 cm and a length ranging from 0.5 to 5 m.

[0018] Further, in step 1, the copper catalyst is one of cupric oxide, cuprous oxide, cuprous chloride, cupric chloride dihydrate, cupric iodide, cuprous iodide, cupric bromide, and cuprous bromide, preferably cuprous iodide; the acid binding agent is one of sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium methoxide, potassium carbonate, potassium bicarbonate, potassium hydroxide and triethylamine, preferably potassium carbonate; the organic solvent is one of fluorobenzene, chlorobenzene, bromobenzene and iodobenzene, preferably bromobenzene.

[0019] Furthermore, in step 1, the preheating and reactor temperature are 120-160° C.; and the reaction time is 1-5 minutes.

[0020] Furthermore, in step 1, the mass ratio of indole to the organic solvent, the acid binding agent, and the copper catalyst is 1:(5-15):(1.5-3.5):(0.01-0.2), and the preferred mass ratio is 1:10:2.5:0.1.

[0021] Further, in step 2, the acid catalyst is a protonic acid or sulfonamide compound, wherein the protonic acid is selected from one of trifluoromethanesulfonic acid, fluorosulfonic acid, chlorosulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, p-nitrobenzenesulfonic acid, and polyphosphoric acid; wherein the sulfonamide is selected from one of bistrifluoromethanesulfonimide, bisfluorosulfonimide, bisbenzenesulfonimide, and trifluoromethanesulfonamide, and the preferred acid catalyst is trifluoromethanesulfonic acid; the organic solvent is one of toluene, chlorobenzene, bromobenzene, acetonitrile, dichloroethane, n-heptane, N,N-dimethylformamide and dimethyl sulfoxide, preferably chlorobenzene.

[0022] Furthermore, in step 2, the mass ratio of 1-phenylindole to the organic solvent and the acid catalyst is 1:(5-15):(1-4), and the preferred mass ratio is 1:12:2; in step 2, the preheating and reactor temperature is 80-120° C., and the reaction time is 5-10 minutes.

[0023] Furthermore, in step three, the organic solvent is one of toluene, chlorobenzene, fluorobenzene, iodobenzene, bromobenzene, acetonitrile and n-butanol, preferably chlorobenzene, and the ammonia water is 20-50% ammonia water by mass.

[0024] Furthermore, in step three, the first set of preheating and reactor temperature is 100-130°C, the reaction time is 2-10 minutes, and the second set of preheating and reactor temperature is 60-90°C, the reaction time is 1-8 minutes.

[0025] Furthermore, in step three, the mass ratio of the iminostilbene to triphosgene, organic solvent and aqueous ammonia is 1:(0.5-1.5):(5-15):(1.5-4.5), and the preferred mass ratio is 1:0.7:10:2.5.

[0026] The novel process for continuously preparing carbamazepine of the present invention adopts a coupling of a high-efficiency catalytic system and a centimeter-level tubular reactor. The high-activity catalyst system exists in a molecular state or a nanometer state. The centimeter-level tubular reactor has excellent mass transfer and heat transfer effects, and the reaction parameters of each step are optimized to obtain low pressure and medium temperature. These factors ensure high-efficiency reaction, achieve high yield, extremely short reaction time, few side reactions, and simple post-treatment. The yield of the key reaction reaches 85%, and the catalyst and the solvent can be recovered and reused. DETAILED DESCRIPTION

[0027] The present invention is further described below in conjunction with embodiments, but the protection scope of the present invention is not limited thereto.

[0028] Example 1

[0029] Step 1: Weigh 10 g of indole, 100 g of bromobenzene, 1.5 g of cuprous iodide, and 25 g of potassium carbonate respectively; dissolve indole in solvent bromobenzene, which is also a reactant, and heat to dissolve to obtain raw material solution I; mix cuprous iodide and potassium carbonate evenly and fill them into a tubular reactor (with an inner diameter of 1.0 cm and a length of 10 cm); heat the preheater and the tubular reactor to 155° C.; pass the raw material solution I into the preheater for preheating, and then enter the tubular reactor for reaction, control the reaction time to 3 minutes, and obtain reaction solution ①; after the reaction solution ① is cooled, dismantle the tubular reactor, take out the mixed solid therein, separate the cuprous iodide, and recover it for reuse; the reaction solution ① is subjected to reduced pressure distillation, and the solvent bromobenzene is recovered to obtain the product, which is a light yellow oily liquid 1-phenylindole 15.68 g, with a yield of 95.06% and a purity of 99.9%.

[0030] Example 2

[0031] The copper catalyst cuprous iodide in step 1 of Example 1 was replaced by cuprous oxide, and the rest was the same as Example 1, and finally 15.26 g of 1-phenylindole was obtained with a yield of 92.47% and a purity of 99.9%.

[0032] Example 3

[0033] The copper catalyst cuprous iodide in step 1 of Example 1 was replaced by cuprous bromide, and the rest was the same as Example 1, and finally 14.09 g of 1-phenylindole was obtained with a yield of 85.42% and a purity of 99.9%.

[0034] Example 4

[0035] The acid-binding agent potassium carbonate in step 1 of Example 1 was replaced by potassium hydroxide, and the other conditions were the same as in Example 1. Finally, 14.77 g of 1-phenylindole was obtained with a yield of 89.51% and a purity of 99.9%.

[0036] Example 5

[0037] The temperature of the preheater and the tubular reactor in step 1 of Example 1 was replaced with 150° C., and the rest was the same as in Example 1. Finally, 15.07 g of 1-phenylindole was obtained with a yield of 91.31% and a purity of 99.9%.

[0038] Example 6

[0039] The temperature of the preheater and the tubular reactor in step 1 of Example 1 was replaced with 140° C., and the rest was the same as in Example 1. Finally, 13.66 g of 1-phenylindole was obtained with a yield of 82.76% and a purity of 99.9%.

[0040] Example 7

[0041] The solvent bromobenzene in step 1 of Example 1 was replaced by iodobenzene, and the other conditions were the same as those of Example 1. Finally, 15.67 g of 1-phenylindole was obtained with a yield of 94.98% and a purity of 99.9%.

[0042] Example 8

[0043] The inner diameter of the tubular reactor in step 1 of Example 1 was adjusted to 1.5 cm, and the rest was the same as in Example 1. Finally, 13.98 g of 1-phenylindole was obtained with a yield of 84.71% and a purity of 99.9%.

[0044] Example 9

[0045] The reaction time in step 1 of Example 1 was adjusted to 2 minutes, and the other conditions were the same as in Example 1. Finally, 14.61 g of 1-phenylindole was obtained with a yield of 88.53% and a purity of 99.9%.

[0046] Example 10

[0047] Step 2: Weigh 10 g of 1-phenylindole obtained in Example 1 and 20 g of trifluoromethanesulfonic acid, dissolve 1-phenylindole in 120 g of chlorobenzene to obtain raw material liquid II; dissolve trifluoromethanesulfonic acid in 120 g of chlorobenzene to obtain raw material liquid III; the temperature of the preheater and the tubular reactor is 105° C., feed raw material liquids II and III, enter the preheater for mixing and preheating, and then enter the tubular reactor (with an inner diameter of 8 mm and a length of 3 m) for reaction, control the reaction time to 8 minutes, and obtain reaction liquid ②; after the reaction liquid ② is cooled, it is subjected to reduced pressure distillation, the solvent chlorobenzene is recovered, and the solid is recrystallized to obtain 8.531 g of yellow crystal iminostilbene, with a yield of 85.31% and a purity of 99.8%.

[0048] Embodiment 11

[0049] The acid catalyst trifluoromethanesulfonic acid in step 2 of Example 10 was replaced by bistrifluoromethanesulfonyl imide, and the rest was the same as Example 10, and finally 8.027 g of iminostilbene was obtained with a yield of 80.27% and a purity of 99.8%.

[0050] Example 12

[0051] The acid catalyst trifluoromethanesulfonic acid in step 2 of Example 10 was replaced by bis(fluorosulfonyl)imide, and the rest was the same as Example 10, and finally 7.327 g of iminostilbene was obtained with a yield of 73.27% and a purity of 99.8%.

[0052] Embodiment 13

[0053] The temperature of the preheater and the tubular reactor in step 2 of Example 10 was replaced with 100° C., and the rest was the same as Example 10. Finally, 8.344 g of iminostilbene was obtained with a yield of 83.44% and a purity of 99.8%.

[0054] Embodiment 14

[0055] The preheater and the tubular reactor in step 2 of Example 10 were replaced with 95° C., and the other conditions were the same as in Example 10. Finally, 7.887 g of iminostilbene was obtained with a yield of 78.87% and a purity of 99.8%.

[0056] Embodiment 15

[0057] The solvent chlorobenzene in step 2 of Example 10 was replaced by bromobenzene, and the other conditions were the same as those of Example 10. Finally, 8.107 g of iminostilbene was obtained with a yield of 81.07% and a purity of 99.8%.

[0058] Example 16

[0059] The inner diameter of the tubular reactor in step 2 of Example 10 was adjusted to 10 mm, and the rest was the same as Example 10. Finally, 7.67 g of iminostilbene was obtained with a yield of 76.83% and a purity of 99.8%.

[0060] Embodiment 17

[0061] The reaction time in step 2 of Example 10 was adjusted to 6 minutes, and the other reaction conditions were the same as those of Example 10. Finally, 8.142 g of iminostilbene was obtained with a yield of 81.42% and a purity of 99.8%.

[0062] Embodiment 18

[0063] Step 3: Weigh 10 g of iminostilbene obtained in Example 10, 7 g of triphosgene, and 25 g of 25% ammonia water; dissolve iminostilbene in 100 g of chlorobenzene to obtain raw material liquid IV; dissolve triphosgene in 100 g of chlorobenzene to obtain raw material liquid V; the temperature of the first set of preheaters and tubular reactors is 120°C, and raw material liquids IV and V are introduced into the preheater for mixing and preheating, and then enter the tubular reactor (inner diameter 8 mm, length 3 m) for reaction, and the reaction time is controlled to 5 minutes to obtain reaction liquid ③. After the temperature of the reaction liquid ③ drops to 80°C, the temperature of the second preheater and the tubular reactor is 80°C, the reaction liquid ③ and ammonia water are introduced, and the mixture enters the second set of preheaters for mixing and preheating, and then enters the tubular reactor (with an inner diameter of 8 mm and a length of 3 m) for reaction. The reaction time is controlled to be 3 minutes to obtain a reaction liquid ④; after the reaction liquid ④ is cooled, it is washed with water, separated, dried, filtered, and the organic phase is distilled under reduced pressure to recover the solvent chlorobenzene, and recrystallized to obtain 11.15 g of white powder carbamazepine with a yield of 91.2% and a purity of 99.8%.

[0064] Embodiment 19

[0065] The solvent chlorobenzene in step 3 of Example 18 was replaced by bromobenzene, and the rest was the same as Example 18, and finally 10.80 g of carbamazepine was obtained with a yield of 88.35% and a purity of 99.8%.

[0066] Embodiment 20

[0067] The temperature of the first set of preheaters and tubular reactors in step 3 of Example 18 was replaced with 115°C, and the rest was the same as Example 18. Finally, 10.87 g of carbamazepine was obtained with a yield of 88.87% and a purity of 99.8%.

[0068] Embodiment 21

[0069] The temperature of the second set of preheaters and tubular reactors in step 3 of Example 18 was replaced with 75°C, and the rest was the same as Example 18. Finally, 10.97 g of carbamazepine was obtained with a yield of 89.72% and a purity of 99.8%.

[0070] Embodiment 22

[0071] The inner diameter of the tubular reactor in step 3 of Example 18 was uniformly adjusted to 10 mm, and the rest was the same as Example 18, and finally 10.57 g of carbamazepine was obtained with a yield of 86.43% and a purity of 99.8%.

[0072] Embodiment 23

[0073] In step 3 of Example 18, the reaction time of the first tubular reactor was adjusted to 4 minutes, and the rest was the same as Example 18, and finally 10.68 g of carbamazepine was obtained with a yield of 87.31% and a purity of 99.8%.

[0074] Embodiment 24

[0075] In step 3 of Example 18, the reaction time of the second tubular reactor was adjusted to 2 minutes. The rest was the same as Example 18. Finally, 10.43 g of carbamazepine was obtained with a yield of 85.31% and a purity of 99.8%.

[0076] The above is only a specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Any person skilled in the art can easily think of changes or substitutions within the technical scope disclosed by the present invention, which should be included in the protection scope of the present invention. Therefore, the protection scope of the present invention should be based on the protection scope of the claims.

Claims

1. A new process for continuously preparing carbamazepine, characterized in that: Here are the steps: Step 1, continuously preparing 1-phenylindole; dissolving indole in an organic solvent, heating to dissolve, and obtaining a raw material solution I; mixing a copper catalyst and an acid binding agent uniformly and filling them into a tubular reactor; introducing the raw material solution I, entering a preheater for mixing and preheating, and then entering a tubular reactor for reaction to obtain a reaction solution ①; the reaction solution ① is distilled to obtain 1-phenylindole; Step 2, continuously preparing iminostilbene; dissolving 1-phenylindole in an organic solvent to obtain a raw material solution II; dissolving an acid catalyst in an organic solvent to obtain a raw material solution III; introducing raw material solutions II and III into a preheater for mixing and preheating, and then into a tubular reactor for reaction to obtain a reaction solution ②; the reaction solution ② is subjected to desolventization and recrystallization to obtain iminostilbene; Step three, continuously preparing carbamazepine; dissolving iminostilbene in an organic solvent to obtain a raw material liquid IV; dissolving triphosgene in an organic solvent to obtain a raw material liquid V; introducing raw material liquids IV and V into a preheater for mixing and preheating, and then entering a tubular reactor for reaction to obtain a reaction liquid ③; introducing reaction liquid ③ and ammonia water into a preheater for mixing and preheating, respectively, and then entering a tubular reactor for reaction to obtain a reaction liquid ④; the reaction liquid ④ is subjected to desolventizing and recrystallization to obtain carbamazepine.

2. A novel process for continuously preparing carbamazepine according to claim 1, characterized in that: In step 1, the tubular reactor is made of a stainless steel hollow column with an inner diameter ranging from 0.1 to 1.5 cm and a length ranging from 1 to 20 cm; in steps 2 and 3, the tubular reactor has an inner diameter ranging from 0.1 to 1.0 cm and a length ranging from 0.5 to 5 m.

3. A novel process for continuously preparing carbamazepine according to claim 1, characterized in that: In step 1, the copper catalyst is one of copper oxide, cuprous oxide, cuprous chloride, cupric chloride dihydrate, copper iodide, cuprous iodide, cupric bromide, and cuprous bromide, preferably cuprous iodide; the acid binding agent is one of sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium methoxide, potassium carbonate, potassium bicarbonate, potassium hydroxide and triethylamine, preferably potassium carbonate; the organic solvent is one of fluorobenzene, chlorobenzene, bromobenzene and iodobenzene, preferably bromobenzene.

4. A novel process for continuously preparing carbamazepine according to claim 1, characterized in that: In step 1, the preheating and reactor temperature are 120-160° C.; and the reaction time is 1-5 minutes.

5. A novel process for continuously preparing carbamazepine according to claim 1, characterized in that: In step 1, the mass ratio of indole to organic solvent, acid binding agent and copper catalyst is 1:(5-15):(1.5-3.5):(0.01-0.2), and the preferred mass ratio is 1:10:2.5:0.

1.

6. A novel process for continuously preparing carbamazepine according to claim 1, characterized in that: In step 2, the acid catalyst is a protonic acid or sulfonamide compound, wherein the protonic acid is selected from one of trifluoromethanesulfonic acid, fluorosulfonic acid, chlorosulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, p-nitrobenzenesulfonic acid, and polyphosphoric acid; wherein the sulfonamide is selected from one of bistrifluoromethanesulfonimide, bisfluorosulfonimide, bisbenzenesulfonimide, and trifluoromethanesulfonamide, and the preferred acid catalyst is trifluoromethanesulfonic acid; the organic solvent is one of toluene, chlorobenzene, bromobenzene, acetonitrile, dichloroethane, n-heptane, N,N-dimethylformamide and dimethyl sulfoxide, preferably chlorobenzene.

7. A novel process for continuously preparing carbamazepine according to claim 1, characterized in that: In step 2, the mass ratio of 1-phenylindole to the organic solvent and the acid catalyst is 1:(5-15):(1-4), and the preferred mass ratio is 1:12:2; in step 2, the preheating and reactor temperature is 80-120° C., and the reaction time is 5-10 minutes.

8. The novel process for continuously preparing carbamazepine according to claim 1, characterized in that: In step 3, the organic solvent is one of toluene, chlorobenzene, fluorobenzene, iodobenzene, bromobenzene, acetonitrile and n-butanol, preferably chlorobenzene, and the ammonia water is 20-50% by mass.

9. The novel process for continuously preparing carbamazepine according to claim 1, characterized in that: In step three, the first set of preheating and reactor temperature is 100-130°C, the reaction time is 2-10 minutes, the second set of preheating and reactor temperature is 60-90°C, the reaction time is 1-8 minutes.

10. The novel process for continuously preparing carbamazepine according to claim 1, characterized in that: In step 3, the mass ratio of the iminostilbene to triphosgene, organic solvent and aqueous ammonia is 1:(0.5-1.5):(5-15):(1.5-4.5), and the preferred mass ratio is 1:0.7:10:2.5.

Images