A synthetic process for a key intermediate of fluvastatin

Abstract

The present invention discloses a synthesis process for a key intermediate of fluvastatin. The process comprises a simple condensation reaction similar to an aldol condensation reaction, followed by reduction of a nitro derivative and a double bond reaction to obtain an indole ring, and finally, introduction of an isopropyl group, thereby obtaining the key intermediate compound V of fluvastatin. The present invention has the following beneficial effects: the raw materials used in each step of the present invention are readily available and relatively low in price, which can effectively reduce production costs, save production costs, and bring considerable economic benefits; the reagents used in the present invention are less hazardous, generate less waste, and are simple to handle, with less harm, which is beneficial to environmental protection, energy conservation, and emission reduction, conforming to the concept of green chemistry; the reaction route of the present invention is simple to operate, has a high product yield, generates few by-products, has high product purity, good atom economy, and is easy to separate, making it suitable for industrial scale-up production.

Description

Technical Field

[0001] The present invention relates to the technical field related to the synthesis of pharmaceutical intermediates, and in particular to a synthesis process of a key intermediate of fluvastatin. Background Art

[0002] Fluvastatin, chemically named [R*,S*-(E)]-(±)-7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl] 3,5-dihydroxy-6-heptanoate, is a fully synthetic cholesterol-lowering drug and a hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. It acts in the liver, inhibiting endogenous cholesterol synthesis, reducing cholesterol levels in hepatocytes, stimulating the synthesis of low-density lipoprotein (LDL) receptors, increasing LDL particle uptake, and lowering total plasma cholesterol. Since the marketed fluvastatin is a racemic form, the construction of the indole ring is crucial for fluvastatin synthesis. Therefore, indole derivatives are key intermediates in the synthesis of fluvastatin. The following are the main methods for synthesizing indole derivatives of fluvastatin:

[0003] U.S. Patent No. 5,354,772 reports a method for constructing a key intermediate of an indole ring using Fischer-Indole synthesis. The synthetic route is as follows:

[0004] Route 1

[0005]

[0006] This method can construct key intermediates, but the raw materials used are expensive. Key raw materials or intermediates such as phenyldiazonium salt are relatively dangerous and are not suitable for large-scale production. In addition, DIBAL-H is used for ester reduction, which has a high cost.

[0007] The literature (Tetrahedron Letters, 1985, 26, 2155-2158) reported a method for synthesizing key intermediate indole derivatives. The method uses the Vilsmeier reaction to modify the indole ring to construct the key intermediate of the indole ring. The synthetic route is as follows:

[0008] Route 2

[0009]

[0010] This method can synthesize indole compounds with high yields through the Bischler reaction. However, the key step, the Vilsmeier reaction, has poor reaction selectivity due to the large number of active centers on the ring, and the product is difficult to purify and separate, resulting in a very low yield, which is not conducive to industrial production.

[0011] The literature (J.Org.Chem.2010,75,7514–7518) reported a method for asymmetric synthesis of a key intermediate of fluvastatin using chiral ligands. The reaction scheme is shown below:

[0012] Route 3

[0013]

[0014] This method involves first synthesizing an indole ring and then introducing a side chain group through asymmetric synthesis using a chiral ligand. This method can achieve good selectivity in small-scale tests, but the raw materials and ligand catalysts used are expensive and are not suitable for large-scale production.

[0015] Chinese patents CN200510022213 and CN200510093297 also reported the synthesis of key trans-olefin intermediates via the Witting reaction of aldehyde indoles and phosphine ylides. Similar routes involve forming the parent nucleus into a ylide reagent and condensing the side chain, but these also suffer from the disadvantage of a long reaction route. For example, Chinese patent CN103342721B discloses a method for preparing an indole phosphine ylide reagent. This method involves introducing a side chain by hydroxymethylating the indole ring with a halogenating agent, and then directly preparing the ylide reagent. The reaction route is shown below:

[0016] Route 4

[0017]

[0018] The preparation steps of the intermediates synthesized by the above-mentioned witting reaction are long and the overall yield is low, which is not suitable for large-scale production.

[0019] Therefore, in order to solve the problems existing in the prior art, it is necessary to find a practical route for synthesizing the key intermediates of fluvastatin with simple process, low cost, good selectivity, easy separation and suitable for large-scale production. Summary of the Invention

[0020] The present invention aims to overcome the deficiencies in the prior art and provides a synthesis process for a key intermediate of fluvastatin. The process comprises a simple condensation reaction similar to an aldol condensation reaction, a reduction reaction of a nitro derivative and a double bond reaction to obtain an indole ring, and finally an isopropyl group is introduced to obtain a key intermediate compound V of fluvastatin. The method has stable process, low raw material prices, mild reaction conditions, good selectivity, few by-products, simple post-processing operations, easy product separation, and little generation of the three wastes. The method complies with the concept of green chemistry, and the purity and yield of the obtained product are both high. The method provides a new idea and method for the large-scale production of key intermediates of fluvastatin.

[0021] The synthetic route of the present invention is as follows:

[0022]

[0023] The technical solution of the present invention is as follows:

[0024] A process for synthesizing a key intermediate of fluvastatin comprises the following steps:

[0025] In the first step, compound I is dissolved in an organic solvent, an alkali reagent is added, and compound II N,N-dimethylaminoethyl acetate is added, and the mixture is heated under reflux for reaction. After the reaction is completed, the product is separated to obtain compound III;

[0026] In the second step, the product of the first step, compound III, is dissolved in an organic solvent, a catalyst is added, hydrogen is introduced until hydrogen absorption stops, and the product is separated to obtain compound IV;

[0027] In the third step, the compound IV obtained in the second step is dissolved in an organic solvent, 2-chloropropane is added, an organic base reagent is added, and the mixture is heated under reflux to obtain the target compound V.

[0028] Furthermore, the solvent used in the first step reaction is a mixed solution of THF and ethanol, and the molar ratio of ethanol to THF in the solvent is 1:2 to 4, preferably 1:3.

[0029] Furthermore, the alkaline reagent used in the first step reaction is sodium ethoxide, and the amount of sodium ethoxide used is 1.5 to 2.5 eq of reactant I, preferably 2 eq.

[0030] Furthermore, the solvent used in the second step reaction is ethanol, and the ethanol is anhydrous ethanol.

[0031] Furthermore, the catalyst for the second step reaction is W-2 type Raney nickel (Raney Ni W-2 type).

[0032] Furthermore, the amount of catalyst used in the second step reaction is 3 to 9% wt of compound III, preferably 5% wt.

[0033] Furthermore, in the first step reaction, the molar ratio of compound I to compound II is 1:1 to 1.2, preferably 1:1.

[0034] Furthermore, the solvent used in the third step reaction is THF.

[0035] Furthermore, in the third step reaction, the molar ratio of the reactant compound IV to 2-chloropropane is 1:1.0-1.2, preferably 1:1.1.

[0036] Furthermore, the base reagent used in the third step reaction is triethylamine, and the amount of the catalyst used is 1 to 1.2 eq of compound IV, preferably 1.1 eq.

[0037] The beneficial effects of the present invention are as follows: the raw materials used in each step of the present invention are easily available and relatively low in price, which can effectively reduce production costs, save production costs, and bring considerable economic benefits; the hazards of the reagents used in the present invention are reduced, less waste is generated, the product treatment is simple, the hazards are small, it is beneficial to protect the environment, save energy and reduce emissions, and is in line with the concept of green chemistry; the reaction route of the present invention is simple to operate, the product yield is high, the generation of by-products is small, the product purity is high, the atom economy is good, the product is easy to separate, and it is suitable for industrial scale-up production. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 Schematic diagram of the synthesis route reaction flow of the present invention;

[0039] Figure 2 This is a schematic diagram of the reaction flow of Route 1 of the present invention;

[0040] Figure 3 This is a schematic diagram of the reaction flow of Route 2 of the present invention;

[0041] Figure 4 This is a schematic diagram of the reaction flow of Route 3 of the present invention;

[0042] Figure 5 Schematic diagram of the reaction flow of route 4 of the present invention. DETAILED DESCRIPTION

[0043] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the embodiments of the present invention and the accompanying drawings. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0044] Example 1

[0045] In the first step, 12.3 g (0.05 mol) of compound I was dissolved in 200 ml of a mixed solution of ethanol:THF (1:3), and 6.8 g (0.1 mol) of sodium ethoxide as an alkaline reagent was added, followed by 13.1 g (0.05 mol) of N,N-dimethylaminoethyl acetic acid. The mixture was heated with stirring and refluxed at 60-70°C for 6-8 hours. After the reaction was completed, dilute hydrochloric acid was added to neutralize the mixture until it was neutral. The solvent was evaporated, and 50 ml of saturated brine and 50 ml of toluene were added. The organic phase was separated and crystallized by evaporation. The product was washed with deionized water 2-3 times, and then recrystallized with 50 ml of toluene to obtain 15.8 g of compound III with a yield of 87.9% and a purity of 97.9%.

[0046] In the second step, under nitrogen protection, 17.9 g (0.05 mol of the product of the first step reaction) of compound III was dissolved in 200 ml of organic solvent ethanol, and 0.90 g of W-2 type Raney nickel catalyst was added. The solution was heated to 40-50°C, hydrogen was introduced into the solution, and the reaction was stirred until the absorption of hydrogen stopped. The solvent was evaporated, 50 ml each of water and tetrahydrofuran were added, extraction was carried out, the organic phase was separated, and the crystallization was evaporated. The product was washed with deionized water and dried. The product was recrystallized from 50 ml of toluene to obtain 13.8 g of compound IV with a yield of 97.5% and a purity of 98.5%.

[0047] In the third step, under nitrogen protection, 14.16 g (0.05 mol) of compound IV obtained in the second step was dissolved in 150 ml of organic solvent THF, 4.3 g (0.055 mol) of 2-chloropropane and 0.055 mol of organic base reagent triethylamine were added, and the mixture was heated under reflux at 35-40°C for 5-6 hours. The mixture was cooled to room temperature and neutralized to neutrality by adding dilute hydrochloric acid. The organic phase was separated, the solvent and 2-chloropropane were evaporated, and the product was recrystallized from 50 ml of toluene to obtain 15.8 g of target compound V with a yield of 96.9% and a purity of 98.0%.

[0048] Example 2

[0049] In the first step, the ratio of the ethanol to THF mixed solution in Example 1 was adjusted to 1:2, and the other operations remained unchanged to obtain 15.2 g of compound III with a yield of 84.6% and a purity of 97.5%.

[0050] Example 3

[0051] In the first step, the ratio of the ethanol to THF mixed solution in Example 1 was adjusted to 1:4, and the other operations remained unchanged to obtain 15.4 g of compound III with a yield of 85.7% and a purity of 97.6%.

[0052] Example 4

[0053] In the first step, the amount of sodium ethoxide in Example 1 was adjusted to 1.5 eq, and the other operations remained unchanged to obtain 15.0 g of compound III with a yield of 83.4% and a purity of 97.5%.

[0054] Example 5

[0055] In the first step, the amount of sodium ethoxide in Example 1 was adjusted to 2.5 eq, and the other operations remained unchanged to obtain 15.7 g of compound III with a yield of 87.3% and a purity of 97.6%.

[0056] Example 6

[0057] In the first step, the amount of compound II in Example 1 was adjusted to 7.9 g (0.06 mol), and the other operations remained unchanged to obtain 15.9 g of compound III with a yield of 88.4% and a purity of 97.6%.

[0058] Example 7

[0059] In the second step, the amount of catalyst in Example 1 was adjusted to 0.54 g (3% wt), and the other operations remained unchanged to obtain 13.4 g of compound IV with a yield of 94.7% and a purity of 98.0%.

[0060] Example 8

[0061] In the second step, the amount of the organic base reagent in Example 1 was adjusted to 1.61 g (9% wt), and the other operations remained unchanged to obtain 13.8 g of compound IV with a yield of 97.5% and a purity of 98.0%.

[0062] Example 9

[0063] In the third step, the amount of 2-chloropropane was adjusted to 0.05 mol, and the other operations remained unchanged to obtain 15.5 g of compound IV with a yield of 95.0% and a purity of 97.5%.

[0064] Example 10

[0065] In the third step, the amount of 2-chloropropane was adjusted to 0.06 mol, and the other operations remained unchanged to obtain 15.8 g of compound IV with a yield of 96.9% and a purity of 97.8%.

[0066] Example 11

[0067] In the third step, the amount of the organic base reagent was adjusted to 0.05 mol, and the other operations remained unchanged to obtain 15.5 g of compound IV with a yield of 95.0% and a purity of 97.8%.

[0068] Example 12

[0069] In the third step, the amount of the organic base reagent was adjusted to 0.06 mol, and the other operations remained unchanged to obtain 15.7 g of compound IV with a yield of 96.3% and a purity of 98.0%.

[0070] Reference document example (CN103342721B)

[0071] Example 1

[0072] (1) Halogenation reaction: Control the temperature at 25±5°C and add 504.0 kg (5 mL / g) of 1,2-dichloroethane, 80 kg (315.8 mol, 1.0 equiv.) of the main raw material 3-(4-fluorophenyl)-1-isopropyl-1H-indole, and 67.5 kg (379.0 mol, 1.2 equiv.) of N-bromosuccinimide to a 2000 L reactor. Heat the system to reflux for reaction and monitor the reaction by HPLC until the reaction is complete. Pour the system into 480.0 kg (5 mL / g) of saturated sodium bisulfite aqueous solution to terminate the reaction. Allow the mixture to stand, separate the liquids, concentrate the organic phase, and add 126.4 kg (2 mL / g) of ethanol for recrystallization to obtain 89.2 kg of the halogenated product 2-bromo-3-(4-fluorophenyl)-1-isopropyl-1H-indole. The liquid phase purity is 96.0% and the yield is 85.0%.

[0073] (2) Hydroxymethylation reaction: Control the temperature at 25±5°C and add 118.4 kg (2 mL / g) of methyl tert-butyl ether and 80 kg (240.8 mol, 1.0 equiv.) of the main raw material 2-bromo-3-(4-fluorophenyl)-1-isopropyl-1H-indole to the reactor. Cool the system to -78°C and then dropwise add 105.2 kg (361.2 mol, 1.5 equiv., 22% w / w) of the metal reagent sec-butyl lithium. After the addition, keep the system at this temperature for 2 h, then add 43.4 kg (481.6 mol, 2.0 equiv.) of paraformaldehyde and continue to keep the temperature until the reaction is complete as detected by HPLC. After the reaction, 460 kg (5 mL / g) of saturated aqueous ammonium chloride solution was added to terminate the reaction, the mixture was allowed to stand, the liquids were separated, the organic phase was concentrated, and 105.6 kg (2 mL / g) of n-hexane was added for recrystallization to obtain 40.9 kg of (3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)methanol (Compound 3) with a liquid phase purity of 95% and a yield of 60%.

[0074] (3) Phosphate esterification reaction: 504.0 kg (5 mL / g) of 1,2-dichloroethane, 80 kg (282.3 mol, 1.0 equiv.) of the main raw material (3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)methanol, 68.6 kg (423.5 mol, 1.5 equiv.) of ferric chloride, and 70.4 kg (423.5 mol, 1.5 equiv.) of triethyl phosphite were added to the reactor in sequence at a temperature of 25 ± 5 °C. After the addition, the system was reacted at this temperature until the reaction was complete as determined by HPLC. The reaction was then terminated by adding 440.0 kg (5 mL / g) of saturated sodium bicarbonate aqueous solution. The mixture was allowed to stand for separation, and the organic phase was concentrated. 264.0 kg (5 mL / g) of n-hexane was added for recrystallization to obtain 91.1 kg of dimethyl (3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl) methyl diethyl phosphonate with a purity of 97% and a yield of 80%.

[0075] In summary, the technical solution adopted by the present invention has the advantages of stable process, low raw material price, mild reaction conditions, good selectivity, fewer by-products, simple post-processing operation, easy separation of products, and less generation of three wastes. Compared with the existing technology, it has substantial characteristics and significant progress.

[0076] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above and that the invention can be embodied in other specific forms without departing from the spirit or essential characteristics of the invention. Therefore, the embodiments should be considered in all respects as illustrative and non-restrictive, and the scope of the invention is defined by the appended claims, not the foregoing description, and all variations within the meaning and range of equivalents of the claims are intended to be included therein. Any reference sign in a claim should not be construed as limiting the claim to which it relates.

[0077] In addition, it should be understood that although this specification is described in terms of implementation methods, not every implementation method contains only one independent technical solution. This narrative method of the specification is only for the sake of clarity. Those skilled in the art should regard the specification as a whole. The technical solutions in each embodiment can also be appropriately combined to form other implementation methods that can be understood by those skilled in the art.

Claims

1. A synthesis process for a key intermediate of fluvastatin, characterized in that The following steps are involved: In the first step, compound I is dissolved in an organic solvent, sodium ethoxide is added as an alkaline reagent, and N,N-dimethylaminoethyl acetate of compound II is added, and the mixture is heated under reflux for reaction. After the reaction is completed, the product is separated to obtain compound III; In the second step, the product of the first step, compound III, is dissolved in an organic solvent, ethanol, a catalyst, type W-2 Raney nickel, is added, hydrogen is introduced until hydrogen absorption stops, and the product is separated to obtain compound IV; In the third step, the compound IV obtained in the second step is dissolved in an organic solvent, THF, 2-chloropropane is added, and an organic base reagent, triethylamine, is added, and the mixture is heated under reflux to obtain the target compound V; The solvent used in the first step reaction is a mixed solution of THF and ethanol, and the molar ratio of ethanol to THF in the solvent is 1:2-3; The amount of sodium ethoxide used is 1.5 to 2.5 eq of reactant I; The amount of catalyst used in the second step reaction is 3-9%wt of compound III; In the first step reaction, the molar ratio of compound I to compound II is 1:1-1.2; In the third step reaction, the molar ratio of the reactant compound IV to 2-chloropropane is 1:1.0-1.2; The amount of the organic base reagent used in the third step reaction is 1 to 1.2 eq of compound IV.

Images