CN111320570B - Preparation method of lansoprazole key intermediate - Google Patents
Preparation method of lansoprazole key intermediate Download PDFInfo
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/68—One oxygen atom attached in position 4
Abstract
The invention relates to a preparation method of a lansoprazole key intermediate. The technical scheme of the invention is as follows: firstly, preparing (2,2, 2-trifluoroethoxy) ethylene (compound 7) and 3-amino-4-chloro-2-methylbut-2-enoic acid ethyl ester (compound 9) respectively; then the two react to prepare 6- (chloromethyl) -5-methyl-4- (2,2, 2-trifluoroethoxy) -2,3,4, 5-tetrahydropyridine; finally, 6- (chloromethyl) -5-methyl-4- (2,2, 2-trifluoroethoxy) -2,3,4, 5-tetrahydropyridine (compound 10) is oxidized by hydrogen peroxide under the catalysis of manganese tetraphenylporphyrinoxide (Mn (O) -Salon) to form 2- (chloromethyl) -3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine (compound 5). The technical scheme of the invention reduces the danger and the energy consumption, and is more suitable for large-scale industrial production.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of a lansoprazole key intermediate 2-chloromethyl-3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine.
Background
Lansoprazole (chemical name: 2- ({ [ 3-methyl-4- (2,2, 2-trifluoroethoxy) -2-pyridinyl ] methyl } sulfinyl) -1H-benzimidazole) is the second marketed proton pump inhibitor after omeprazole, developed and developed by Nippon martial arts corporation, and has the following chemical structure:
at present, various synthetic methods for preparing lansoprazole have been reported, wherein the most widely used method in production is that 2-chloromethyl-3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine 2 or hydrochloride 5 thereof is subjected to condensation reaction with mercaptobenzimidazole 3 under the action of alkali to generate a compound 4, and the compound 4 is oxidized by hydrogen peroxide under the action of a catalyst to generate lansoprazole 1 (U.S. Pat. No. 4,4689333). As follows:
the compound 2 or hydrochloride 5 thereof used in the first condensation reaction is an important intermediate for the synthesis of lansoprazole.
The literature reports that the preparation of lansoprazole intermediate 2-chloromethyl-3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine (formula 2) or hydrochloride thereof (formula 5) mainly comprises the following methods:
in the first method, patent CN100355749C reports that lutidine is used as a raw material, and is subjected to N-oxidation under the action of hydrogen peroxide, and then is nitrified to obtain 2, 3-dimethyl-4-nitropyridine-N-oxide, and then is subjected to substitution, rearrangement, hydrolysis and chlorination to obtain the product. The method has the advantages of long route, complex operation, high reaction risk, more three-waste discharge, environmental protection and high cost, needs to use a large amount of oxidants, strong acid, strong alkali and strong corrosive materials, and is not suitable for the current industrial production. The document reports a maximum overall yield of only 46%. The route is as follows:
the second method, Ahn et al [ Bull. Korean chem. Soc. 2002, 23, 4, 626] report that 3-methylpyridine is used as a raw material and is prepared by nitration, cyanidation, substitution, hydrolysis, esterification, reduction and chlorination reaction, the method has longer steps and complicated operation, and a large amount of oxidizing agent, strong acid, strong alkali and strong corrosive materials are needed, and a high-toxicity sodium cyanide reagent is used, so that the method is not suitable for industrial production. The document reports an overall yield of about 49%. The route is as follows:
the third method, reported in patent WO0000474a1, uses 2, 3-dimethyl-4-nitropyridine-N-oxide as raw material, and is prepared by rearrangement, complexation, substitution and chlorination reactions. The method improves the activity of pyridine 4-site substitution reaction by forming a complex under the condition of not retaining N-oxide, but has longer route and no obvious improvement on yield compared with the first method, has no obvious advantages compared with the first method, and is not suitable for industrial production. The route is as follows:
the fourth method, patent WO1997029103A2, reports that the product is obtained by aromatization after direct ring closure of 3- (2,2, 2-trifluoroethoxy) acrolein and 1-chloro-2-butanone. The method has a short route, but the raw material 3- (2,2, 2-trifluoroethoxy) acrolein does not produce an industrialized product, and the reaction yield is low (Liuyanfei and the like [ the synthesis process improvement of lansoprazole, the fine chemical intermediate 2011, 41, 3 and 26] report only 22%), and the method is not suitable for industrial production. The route is as follows:
disclosure of Invention
The invention aims to find a synthetic route of lansoprazole intermediate 2-chloromethyl-3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine, which can improve the yield, reduce the cost, reduce three wastes, is simple and convenient to operate and is suitable for industrial production.
The technical scheme of the invention is as follows: a preparation method of a lansoprazole intermediate 2-chloromethyl-3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine comprises the following steps:
step 1, ethylene oxide and trifluoroethanol react under the catalysis of acid to prepare (2,2, 2-trifluoroethoxy) ethylene (compound 7).
The acid is selected from one of sulfuric acid and hydrochloric acid.
The reaction temperature is-10 to 10 ℃, and the reaction time is 2 to 5 hours.
In this step, trifluoroethanol: ethylene oxide: the feeding molar ratio of the acid is 1 (1.0-2) to 0.02-0.2, preferably 1: 1.2: 0.05.
And 2, carrying out methylation reaction on the 4-chloroacetoacetic acid ethyl ester and a methylation reagent under the catalysis of alkali, evaporating to remove the solvent after the reaction is finished, and further carrying out amination reaction under the condition of ammonia water and ammonium acetate to generate the 3-amino-4-chloro-2-methylbut-2-ethyl enoate (compound 9).
The reaction in this step can be carried out in a one-pot process.
The base is selected from triethylamine, diisopropylethylamine and the like.
The methylating agent is selected from dimethyl sulfate, methyl iodide and the like.
The methylation reaction solvent can be dichloromethane, chloroform, etc.
The methylation reaction temperature is 10-40 ℃, and the reaction time is 2-8 hours. The ammonification reaction temperature is-10 to 40 ℃, and the reaction time is 2 to 12 hours.
In this step, ethyl 4-chloroacetoacetate: alkali: a methylating agent: ammonia water: the molar ratio of ammonium acetate is 1 (1.1-2.0): 1.0-1.6): 1.4-2.5, preferably 1: 1.6: 1.2: 1.1: 1.8.
And 3, performing a trimolecular cyclization reaction on 3-amino-4-chloro-2-methylbut-2-enoic acid ethyl ester (compound 9), the (2,2, 2-trifluoroethoxy) ethylene (compound 7) and paraformaldehyde under the catalytic action of acid, and directly adding hydrochloric acid to perform catalytic decarboxylation reaction to generate 6- (chloromethyl) -5-methyl-4- (2,2, 2-trifluoroethoxy) -2,3,4, 5-tetrahydropyridine (compound 10) after the reaction is finished.
The step is a one-pot reaction. Can save the use of reagents, save energy and reduce the discharge of waste solvents.
The acid is selected from acetic acid, benzenesulfonic acid, methanesulfonic acid and the like, and the reaction solvent can be water.
The cyclization reaction temperature is 10-50 ℃, and the reaction time is 1-5 hours. The decarboxylation reaction temperature is 10-50 ℃, and the reaction time is 2-6 hours.
In this step, compound 9: compound 7: paraformaldehyde: the molar ratio of the acid is 1 (1-1.2) to 2-5 (0.05-0.2), preferably 1: 1.05: 3: 0.1.
Step 4, 6- (chloromethyl) -5-methyl-4- (2,2, 2-trifluoroethoxy) -2,3,4, 5-tetrahydropyridine (compound 10) is oxidized by hydrogen peroxide under the catalysis of manganese tetraphenylporphyrinoxide (Mn (O) -Salon) to form 2- (chloromethyl) -3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine (compound 5).
The Mn (O) -Salon used in the reaction was as follows: mn (o) -Salon 1 (R = R ' = H), mn (o) -Salon 2 (R = R ' = OMe), mn (o) -Salon 3 (R = OMe, R ' = H), mn (o) -Salon 4 (R = R ' = Me), mn (o) -Salon 5 (R = Me, R ' = H), and the like.
The reaction solvent can be selected from methanol, ethanol, isopropanol, etc.
The reaction temperature in the step is 10-50 ℃, and the reaction time is 3-7 hours.
In this step, compound 10: hydrogen peroxide: the molar ratio of Mn (O) -Salon is 1 (2-4) to (0.01-0.05), preferably 1: 3: 0.02.
The reaction formula of the invention is as follows:
has the advantages that:
the invention provides a preparation method of lansoprazole intermediate 2-chloromethyl-3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine, which has the following advantages compared with the prior art:
compared with the linear synthesis of other routes, the method has the advantages that the unreported brand-new synthesis route is used, the convergent synthesis mode of synthesizing two fragments first and then closing the rings is adopted, the yield and the synthesis efficiency are improved, the one-pot method is used for combining with the multi-step reaction, the process steps are further shortened, the operation is simplified, the aftertreatment loss is reduced, and the discharge of three wastes is reduced. Compared with the most commonly adopted route I, the route reduces 2 operation steps, the production period is shortened from 7 days to 4 days, and the total yield is improved to more than 70 percent from the highest 46 percent reported in the literature. The whole route has no dangerous nitration reaction and high-temperature reaction, reduces the danger and the energy consumption, and is more suitable for large-scale industrial production.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The following examples are intended to further illustrate the invention, but not to limit the scope of the invention.
Example 1
Step 1 preparation of (2,2, 2-trifluoroethoxy) ethylene (Compound 7)
200.0 g (2.00 mol) of trifluoroethanol and 20.0 g (0.200 mol) of sulfuric acid are added into a 1L reaction bottle, the temperature is reduced to-20 ℃, 105.7 g (2.40 mol) of ethylene oxide is slowly added under the protection of nitrogen, and the temperature is controlled at 0 ℃ for reaction for 3 hours. After the reaction is finished, distillation is carried out, and fractions at 31-33 ℃ are collected to obtain 234.8 g of (2,2, 2-trifluoroethoxy) ethylene, wherein the yield is 93.2% and the GC purity is 99.03%.
Step 2. preparation of 3-amino-4-chloro-2-methylbut-2-enoic acid ethyl ester (Compound 9)
Into a 2L reaction flask were charged 330.0 g (2.00 mol) of ethyl 4-chloroacetoacetate, 660.0 g of dichloromethane, 222.6 g (2.20 mol) of triethylamine, stirred at 25 ℃ for 1 hour, and slowly added dropwise 252.3 g (2.00 mol) of dimethyl sulfate, and the temperature was controlled at 40 ℃ to react for 3 hours. After the reaction, the solvent is removed by concentration under reduced pressure. The temperature is reduced to 0 ℃, 149.9 g (2.20 mol) of 25% ammonia water and 277.5 g (3.60 mol) of ammonium acetate are added, and the temperature is controlled to 0 ℃ for reaction for 8 h. Filtering, eluting with 330.0 g of ice water, and drying to obtain 336.48 g of 3-amino-4-chloro-2-methylbut-2-enoic acid ethyl ester, wherein the yield is 94.6% and the HPLC purity is 95.23%.
Step 3 preparation of 6- (chloromethyl) -5-methyl-4- (2,2, 2-trifluoroethoxy) -2,3,4, 5-tetrahydropyridine (Compound 10)
A4L reaction flask was charged with 900.0 g of water and 152.3 g (5.07 mol) of paraformaldehyde, and heated until the paraformaldehyde was completely dissolved. 300.0 g (1.69 mol) of ethyl 3-amino-4-chloro-2-methylbut-2-enoate, 20.3 g (0.338 mol) of acetic acid, 223.7 g (1.77 mol) of (2,2, 2-trifluoroethoxy) ethylene were added and the reaction was carried out for 3 hours at a temperature of 30 ℃. Concentrated hydrochloric acid was added to adjust pH =1, and the reaction was carried out at 40 ℃ for 3 h. Adjusting the pH value to be 8-9 by using 6 mol/L sodium hydroxide aqueous solution, and performing suction filtration to obtain 384.2 g of 6- (chloromethyl) -5-methyl-4- (2,2, 2-trifluoroethoxy) -2,3,4, 5-tetrahydropyridine, wherein the yield is 93.4 percent, and the HPLC purity is 99.28 percent.
Step 4. preparation of lansoprazole intermediate 2-chloromethyl-3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine (Compound 2)
A2L reaction flask was charged with 450.0 g of absolute ethanol, 300.0 g (1.23 mol) of 6- (chloromethyl) -5-methyl-4- (2,2, 2-trifluoroethoxy) -2,3,4, 5-tetrahydropyridine, 9.48 g (24.6 mmol) of Mn (O) -Salon 1, temperature controlled at 30 ℃ and 418.3 g (3.69 mol) of 30% hydrogen peroxide dropwise. After dropping, the reaction was continued at this temperature for 5 hours. After the reaction, ethanol is removed by concentration under reduced pressure, 600.0 g of water is added, after stirring for 1 hour, 284.1 g of lansoprazole intermediate 2-chloromethyl-3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine is obtained by suction filtration, the yield is 96.3%, and the HPLC purity is 99.84%. The total yield was 79.3%.
Example 2
Step 1 preparation of (2,2, 2-trifluoroethoxy) ethylene (Compound 7)
210.0 g (2.10 mol) of trifluoroethanol and 10.5 g (0.105 mol) of sulfuric acid are added into a 1L reaction bottle, the temperature is reduced to-20 ℃, 92.5 g (2.10 mol) of ethylene oxide is slowly added under the protection of nitrogen, and the temperature is controlled at 0 ℃ for reaction for 4 hours. After the reaction is finished, distilling, and collecting fractions at 31-33 ℃ to obtain 247.58 g of (2,2, 2-trifluoroethoxy) ethylene, wherein the yield is 88.2 percent and the GC purity is 98.35 percent.
Step 2. preparation of 3-amino-4-chloro-2-methylbut-2-enoic acid ethyl ester (Compound 9)
Into a 2L reaction flask were charged 330.0 g (2.00 mol) of ethyl 4-chloroacetoacetate, 660.0 g of dichloromethane, 263.1 g (2.60 mol) of triethylamine, stirred at 25 ℃ for 1 hour, 277.5 g (2.20 mol) of dimethyl sulfate was slowly added dropwise, and the temperature was controlled at 25 ℃ to react for 6 hours. After the reaction, the solvent is removed by concentration under reduced pressure. The temperature is reduced to 0 ℃, 149.9 g (2.20 mol) of 25% ammonia water and 277.5 g (3.60 mol) of ammonium acetate are added, and the temperature is controlled to 0 ℃ for reaction for 8 h. Filtering, eluting with 330.0 g of ice water, and drying to obtain 331.2 g of 3-amino-4-chloro-2-methylbut-2-enoic acid ethyl ester, wherein the yield is 93.02% and the HPLC purity is 99.65%.
Step 3 preparation of 6- (chloromethyl) -5-methyl-4- (2,2, 2-trifluoroethoxy) -2,3,4, 5-tetrahydropyridine (Compound 10)
A4L reaction flask was charged with 900.0 g of water and 152.3 g (5.07 mol) of paraformaldehyde, and heated until the paraformaldehyde was completely dissolved. 300.0 g (1.69 mol) of ethyl 3-amino-4-chloro-2-methylbut-2-enoate, 16.2 g (0.169 mol) of methanesulfonic acid, 223.7 g (1.77 mol) of (2,2, 2-trifluoroethoxy) ethylene were added and the reaction was carried out for 3 h at 30 ℃. Concentrated hydrochloric acid was added to adjust pH =1, and the reaction was carried out at 40 ℃ for 3 h. Adjusting the pH value to be 8-9 by using 6 mol/L sodium hydroxide aqueous solution, and performing suction filtration to obtain 384.6 g of 6- (chloromethyl) -5-methyl-4- (2,2, 2-trifluoroethoxy) -2,3,4, 5-tetrahydropyridine, wherein the yield is 93.5 percent, and the HPLC purity is 99.47 percent.
Step 4. preparation of lansoprazole intermediate 2-chloromethyl-3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine (Compound 2)
A2L reaction flask was charged with 450.0 g of absolute ethanol, 300.0 g (1.23 mol) of 6- (chloromethyl) -5-methyl-4- (2,2, 2-trifluoroethoxy) -2,3,4, 5-tetrahydropyridine, 12.43 g (24.6 mmol) of Mn (O) -Salon 2, temperature controlled at 30 ℃ and 418.3 g (3.69 mol) of 30% hydrogen peroxide dropwise. After dropping, the reaction was continued at this temperature for 5 hours. After the reaction, ethanol is removed by concentration under reduced pressure, 600.0 g of water is added, the mixture is stirred for 1 hour and then is filtered by suction to obtain 280.0 g of lansoprazole intermediate 2-chloromethyl-3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine, the yield is 94.9 percent, and the HPLC purity is 99.57 percent. The total yield is 72.80%.
Example 3
Step 1 preparation of (2,2, 2-trifluoroethoxy) ethylene (Compound 7)
200.0 g (2.00 mol) of trifluoroethanol and 4.0 g (0.040 mol) of sulfuric acid are added into a 1L reaction bottle, the temperature is reduced to-20 ℃, 105.7 g (2.40 mol) of ethylene oxide is slowly added under the protection of nitrogen, and the temperature is controlled at 0 ℃ for reaction for 4 hours. After the reaction is finished, distilling, and collecting fractions at 31-33 ℃ to obtain 237.84 g of (2,2, 2-trifluoroethoxy) ethylene, wherein the yield is 94.32% and the GC purity is 95.33%.
Step 2. preparation of 3-amino-4-chloro-2-methylbut-2-enoic acid ethyl ester (Compound 9)
A2L reaction flask was charged with 330.0 g (2.00 mol) of ethyl 4-chloroacetoacetate, 660.0 g of dichloromethane, 323.8 g (3.20 mol) of triethylamine, stirred at 25 ℃ for 1 hour, and slowly added dropwise with 302.7 g (2.40 mol) of dimethyl sulfate, and reacted at 25 ℃ for 4 hours while controlling the temperature. After the reaction, the solvent is removed by concentration under reduced pressure. The temperature is reduced to 0 ℃, 149.9 g (2.20 mol) of 25% ammonia water and 277.5 g (3.60 mol) of ammonium acetate are added, and the temperature is controlled to 0 ℃ for reaction for 8 h. Filtering, rinsing with 330.0 g of ice water, and drying to obtain 335.7 g of 3-amino-4-chloro-2-methylbut-2-enoic acid ethyl ester, wherein the yield is 94.3 percent, and the HPLC purity is 99.12 percent.
Step 3 preparation of 6- (chloromethyl) -5-methyl-4- (2,2, 2-trifluoroethoxy) -2,3,4, 5-tetrahydropyridine (Compound 10)
A4L reaction flask was charged with 900.0 g of water and 101.5 g (3.38 mol) of paraformaldehyde, and heated until the paraformaldehyde was completely dissolved. 300.0 g (1.69 mol) of ethyl 3-amino-4-chloro-2-methylbut-2-enoate, 26.7 g (0.169 mol) of benzenesulfonic acid, 223.7 g (1.77 mol) of (2,2, 2-trifluoroethoxy) ethylene were added and the temperature was controlled at 30 ℃ for reaction for 3 hours. Concentrated hydrochloric acid was added to adjust pH =1, and the reaction was carried out at 40 ℃ for 3 h. Adjusting the pH value to be 8-9 by using 6 mol/L sodium hydroxide aqueous solution, and performing suction filtration to obtain 375.9 g of 6- (chloromethyl) -5-methyl-4- (2,2, 2-trifluoroethoxy) -2,3,4, 5-tetrahydropyridine, wherein the yield is 91.3 percent, and the HPLC purity is 99.23 percent.
Step 4. preparation of lansoprazole intermediate 2-chloromethyl-3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine (Compound 2)
A2L reaction flask was charged with 450.0 g of absolute ethanol, 300.0 g (1.23 mol) of 6- (chloromethyl) -5-methyl-4- (2,2, 2-trifluoroethoxy) -2,3,4, 5-tetrahydropyridine, 10.86 g (24.6 mmol) of Mn (O) -Salon 4, temperature controlled at 30 ℃ and 418.3 g (3.69 mol) of 30% hydrogen peroxide dropwise. After dropping, the reaction was continued at this temperature for 5 hours. After the reaction, ethanol was removed by concentration under reduced pressure, 600.0 g of water was added, and after stirring for 1 hour, 281.2 g of lansoprazole intermediate 2-chloromethyl-3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine was obtained by suction filtration, with a yield of 95.3% and an HPLC purity of 99.72%. The total yield is 77.39%.
Example 4
Step 1 preparation of (2,2, 2-trifluoroethoxy) ethylene (Compound 7)
200.0 g (2.00 mol) of trifluoroethanol and 10.0 g (0.100 mol) of sulfuric acid are added into a 1L reaction bottle, the temperature is reduced to minus 20 ℃, 141.0 g (3.20 mol) of ethylene oxide is slowly added under the protection of nitrogen, and the temperature is controlled at 0 ℃ for reaction for 2 hours. After the reaction is finished, distilling, and collecting the fraction at 31-33 ℃ to obtain 230.0 g of (2,2, 2-trifluoroethoxy) ethylene, wherein the yield is 91.2 percent and the GC purity is 98.98 percent.
Step 2. preparation of 3-amino-4-chloro-2-methylbut-2-enoic acid ethyl ester (Compound 9)
A2L reaction flask was charged with 330.0 g (2.00 mol) of ethyl 4-chloroacetoacetate, 660.0 g of dichloromethane, 364.3 g (3.60 mol) of triethylamine, stirred at 25 ℃ for 1 hour, 353.2 g (2.80 mol) of dimethyl sulfate was slowly added dropwise thereto, and the temperature was controlled at 25 ℃ to react for 2 hours. After the reaction, the solvent is removed by concentration under reduced pressure. The temperature is reduced to 0 ℃, 149.9 g (2.20 mol) of 25% ammonia water and 277.5 g (3.60 mol) of ammonium acetate are added, and the temperature is controlled to 0 ℃ for reaction for 8 h. Filtering, eluting with 330.0 g of ice water, and drying to obtain 329.3 g of 3-amino-4-chloro-2-methylbut-2-enoic acid ethyl ester, wherein the yield is 92.5% and the HPLC purity is 98.70%.
Step 3 preparation of 6- (chloromethyl) -5-methyl-4- (2,2, 2-trifluoroethoxy) -2,3,4, 5-tetrahydropyridine (Compound 10)
A4L reaction flask was charged with 900.0 g of water and 253.8 g (8.45 mol) of paraformaldehyde, and heated until the paraformaldehyde was completely dissolved. 300.0 g (1.69 mol) of ethyl 3-amino-4-chloro-2-methylbut-2-enoate, 13.4 g (0.084 mol) of benzenesulfonic acid, 223.7 g (1.77 mol) of (2,2, 2-trifluoroethoxy) ethylene were added and the temperature was controlled at 50 ℃ for reaction for 3 hours. Concentrated hydrochloric acid was added to adjust pH =1, and the reaction was carried out at 50 ℃ for 2 h. Adjusting the pH value to be 8-9 by using 6 mol/L sodium hydroxide aqueous solution, and performing suction filtration to obtain 391.55 g of 6- (chloromethyl) -5-methyl-4- (2,2, 2-trifluoroethoxy) -2,3,4, 5-tetrahydropyridine, wherein the yield is 95.2 percent, and the HPLC purity is 99.79 percent.
Step 4. preparation of lansoprazole intermediate 2-chloromethyl-3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine (Compound 2)
A2L reaction flask was charged with 450.0 g of methanol, 300.0 g (1.23 mol) of 6- (chloromethyl) -5-methyl-4- (2,2, 2-trifluoroethoxy) -2,3,4, 5-tetrahydropyridine, 10.96 g (24.6 mmol) of Mn (O) -Salon 3, temperature controlled at 30 ℃ and 418.3 g (3.69 mol) of 30% hydrogen peroxide dropwise. After dropping, the reaction was continued at this temperature for 5 hours. After the reaction, ethanol was removed by concentration under reduced pressure, 600.0 g of water was added, and after stirring for 1 hour, 285.60 g of lansoprazole intermediate 2-chloromethyl-3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine was obtained by suction filtration, with a yield of 96.8% and an HPLC purity of 99.69%. The total yield was 77.74%.
Example 5
Step 1 preparation of (2,2, 2-trifluoroethoxy) ethylene (Compound 7)
200.0 g (2.00 mol) of trifluoroethanol and 39.4 g (0.400 mol) of hydrochloric acid are added into a 1L reaction bottle, the temperature is reduced to-20 ℃, 105.7 g (2.40 mol) of ethylene oxide is slowly added under the protection of nitrogen, and the temperature is controlled at 10 ℃ for reaction for 5 hours. After the reaction is finished, distilling, and collecting fractions at 31-33 ℃ to obtain 226.7 g of (2,2, 2-trifluoroethoxy) ethylene, wherein the yield is 89.9% and the GC purity is 95.72%.
Step 2. preparation of 3-amino-4-chloro-2-methylbut-2-enoic acid ethyl ester (Compound 9)
Into a 2L reaction flask were charged 330.0 g (2.00 mol) of ethyl 4-chloroacetoacetate, 660.0 g of dichloromethane, 404.8 g (4.00 mol) of triethylamine, stirred at 10 ℃ for 1 hour, 403.6 g (3.20 mol) of dimethyl sulfate was slowly added dropwise, and the temperature was controlled at 10 ℃ to react for 8 hours. After the reaction, the solvent is removed by concentration under reduced pressure. The temperature is reduced to 0 ℃, 149.9 g (2.20 mol) of 25% ammonia water and 277.5 g (3.60 mol) of ammonium acetate are added, and the temperature is controlled to 0 ℃ for reaction for 8 h. Filtering, eluting with 330.0 g of ice water, and drying to obtain 332.5 g of 3-amino-4-chloro-2-methylbut-2-enoic acid ethyl ester, wherein the yield is 93.4% and the HPLC purity is 94.04%.
Step 3 preparation of 6- (chloromethyl) -5-methyl-4- (2,2, 2-trifluoroethoxy) -2,3,4, 5-tetrahydropyridine (Compound 10)
A4L reaction flask was charged with 900.0 g of water and 152.3 g (5.07 mol) of paraformaldehyde, and heated until the paraformaldehyde was completely dissolved. 300.0 g (1.69 mol) of ethyl 3-amino-4-chloro-2-methylbut-2-enoate, 26.7 g (0.169 mol) of benzenesulfonic acid and 213.1 g (1.69 mol) of (2,2, 2-trifluoroethoxy) ethylene were added and the temperature was controlled at 40 ℃ for 4 hours. Concentrated hydrochloric acid was added to adjust pH =1, and the reaction was carried out at 40 ℃ for 3 h. Adjusting the pH value to be 8-9 by using 6 mol/L sodium hydroxide aqueous solution, and performing suction filtration to obtain 364.4 g of 6- (chloromethyl) -5-methyl-4- (2,2, 2-trifluoroethoxy) -2,3,4, 5-tetrahydropyridine, wherein the yield is 88.6 percent, and the HPLC purity is 99.52 percent.
Step 4. preparation of lansoprazole intermediate 2-chloromethyl-3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine (Compound 2)
A2L reaction flask was charged with 450.0 g of isopropanol, 300.0 g (1.23 mol) of 6- (chloromethyl) -5-methyl-4- (2,2, 2-trifluoroethoxy) -2,3,4, 5-tetrahydropyridine, 10.96 g (24.6 mmol) of Mn (O) -Salon 3, controlled at 30 ℃ and 418.3 g (3.69 mol) of 30% hydrogen peroxide was added dropwise. After dropping, the reaction was continued at this temperature for 5 hours. After the reaction, ethanol was removed by concentration under reduced pressure, 600.0 g of water was added, and after stirring for 1 hour, 281.2 g of lansoprazole intermediate 2-chloromethyl-3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine was obtained by suction filtration, with a yield of 95.3% and an HPLC purity of 99.32%. The total yield is 70.9%.
Example 6
Step 1 preparation of (2,2, 2-trifluoroethoxy) ethylene (Compound 7)
200.0 g (2.00 mol) of trifluoroethanol and 10.0 g (0.100 mol) of sulfuric acid are added into a 1L reaction bottle, the temperature is reduced to minus 20 ℃, 123.3 g (2.80 mol) of ethylene oxide is slowly added under the protection of nitrogen, and the temperature is controlled at 0 ℃ for reaction for 3 hours. After the reaction is finished, distillation is carried out, and fractions at 31-33 ℃ are collected to obtain 235.8 g of (2,2, 2-trifluoroethoxy) ethylene, wherein the yield is 93.5% and the GC purity is 98.82%.
Step 2. preparation of 3-amino-4-chloro-2-methylbut-2-enoic acid ethyl ester (Compound 9)
A2L reaction flask was charged with 330.0 g (2.00 mol) of ethyl 4-chloroacetoacetate, 660.0 g of dichloromethane, 323.8 g (3.20 mol) of triethylamine, stirred at 25 ℃ for 1 hour, and slowly added dropwise with 302.7 g (2.40 mol) of dimethyl sulfate, and reacted at 25 ℃ for 4 hours while controlling the temperature. After the reaction, the solvent is removed by concentration under reduced pressure. Cooling to-10 ℃, adding 136.2 g (2.00 mol) of 25% ammonia water and 385.4 g (5.00 mol) of ammonium acetate, controlling the temperature to-10 ℃ and reacting for 12 h. Filtering, eluting with 330.0 g of ice water, and drying to obtain 335.74 g of 3-amino-4-chloro-2-methylbut-2-enoic acid ethyl ester, wherein the yield is 94.3%, and the HPLC purity is 98.96%.
Step 3 preparation of 6- (chloromethyl) -5-methyl-4- (2,2, 2-trifluoroethoxy) -2,3,4, 5-tetrahydropyridine (Compound 10)
A4L reaction flask was charged with 900.0 g of water and 152.3 g (5.07 mol) of paraformaldehyde, and heated until the paraformaldehyde was completely dissolved. 300.0 g (1.69 mol) of ethyl 3-amino-4-chloro-2-methylbut-2-enoate, 26.7 g (0.169 mol) of benzenesulfonic acid, 234.4 g (1.86 mol) of (2,2, 2-trifluoroethoxy) ethylene were added and the temperature was controlled at 30 ℃ for reaction for 3 hours. Concentrated hydrochloric acid was added to adjust pH =1, and the reaction was carried out at 40 ℃ for 3 h. Adjusting the pH value to be 8-9 by using 6 mol/L sodium hydroxide aqueous solution, and performing suction filtration to obtain 392.0 g of 6- (chloromethyl) -5-methyl-4- (2,2, 2-trifluoroethoxy) -2,3,4, 5-tetrahydropyridine, wherein the yield is 95.3 percent, and the HPLC purity is 98.76 percent.
Step 4. preparation of lansoprazole intermediate 2-chloromethyl-3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine (Compound 2)
A2L reaction flask was charged with 450.0 g of anhydrous ethanol, 300.0 g (1.23 mol) of 6- (chloromethyl) -5-methyl-4- (2,2, 2-trifluoroethoxy) -2,3,4, 5-tetrahydropyridine, 10.96 g (24.6 mmol) of Mn (O) -Salon 3, temperature controlled at 30 ℃ and 278.9 g (2.46 mol) of 30% hydrogen peroxide dropwise. After dropping, the reaction was continued at this temperature for 7 hours. After the reaction, ethanol was removed by concentration under reduced pressure, 600.0 g of water was added, and after stirring for 1 hour, 280.86 g of lansoprazole intermediate 2-chloromethyl-3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine was obtained by suction filtration, with a yield of 95.2% and an HPLC purity of 99.66%. The total yield is 79.99%.
Example 7
Step 1 preparation of (2,2, 2-trifluoroethoxy) ethylene (Compound 7)
230.0 g (2.30 mol) of trifluoroethanol and 11.5 g (0.115 mol) of sulfuric acid are added into a 1L reaction bottle, the temperature is reduced to minus 20 ℃, 202.6 g (4.60 mol) of ethylene oxide is slowly added under the protection of nitrogen, and the temperature is controlled to minus 10 ℃ for reaction for 2 hours. After the reaction is finished, distilling, and collecting fractions at 31-33 ℃ to obtain 259.5 g of (2,2, 2-trifluoroethoxy) ethylene, wherein the yield is 89.5% and the GC purity is 95.21%.
Step 2. preparation of 3-amino-4-chloro-2-methylbut-2-enoic acid ethyl ester (Compound 9)
A2L reaction flask was charged with 330.0 g (2.00 mol) of ethyl 4-chloroacetoacetate, 660.0 g of chloroform, 413.6 g (3.20 mol) of diisopropylethylamine, stirred at 25 ℃ for 1 hour, and slowly added dropwise with 302.7 g (2.40 mol) of dimethyl sulfate, and the temperature was controlled at 25 ℃ for reaction for 3 hours. After the reaction, the solvent is removed by concentration under reduced pressure. The temperature is reduced to 0 ℃, 149.9 g (2.20 mol) of 25% ammonia water and 277.5 g (3.60 mol) of ammonium acetate are added, and the temperature is controlled to 0 ℃ for reaction for 8 h. Filtering, eluting with 330.0 g of ice water, and drying to obtain 333.9 g of 3-amino-4-chloro-2-methylbut-2-enoic acid ethyl ester, wherein the yield is 93.8% and the HPLC purity is 98.60%.
Step 3 preparation of 6- (chloromethyl) -5-methyl-4- (2,2, 2-trifluoroethoxy) -2,3,4, 5-tetrahydropyridine (Compound 10)
A4L reaction flask was charged with 900.0 g of water and 152.3 g (5.07 mol) of paraformaldehyde, and heated until the paraformaldehyde was completely dissolved. 300.0 g (1.69 mol) of ethyl 3-amino-4-chloro-2-methylbut-2-enoate, 26.7 g (0.169 mol) of benzenesulfonic acid, 255.7 g (2.03 mol) of (2,2, 2-trifluoroethoxy) ethylene were added and the temperature was controlled at 10 ℃ for reaction for 5 hours. Concentrated hydrochloric acid was added to adjust pH =1, and the reaction was carried out at 10 ℃ for 6 h. Adjusting the pH value to be 8-9 by using 6 mol/L sodium hydroxide aqueous solution, and performing suction filtration to obtain 395.7 g of 6- (chloromethyl) -5-methyl-4- (2,2, 2-trifluoroethoxy) -2,3,4, 5-tetrahydropyridine, wherein the yield is 96.2 percent, and the HPLC purity is 96.35 percent.
Step 4. preparation of lansoprazole intermediate 2-chloromethyl-3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine (Compound 2)
A2L reaction flask was charged with 450.0 g of anhydrous ethanol, 300.0 g (1.23 mol) of 6- (chloromethyl) -5-methyl-4- (2,2, 2-trifluoroethoxy) -2,3,4, 5-tetrahydropyridine, 10.96 g (24.6 mmol) of Mn (O) -Salon 3, temperature-controlled at 10 ℃ and 557.8 g (4.92 mol) of 30% hydrogen peroxide were added dropwise. After dropping, the reaction was continued at this temperature for 7 hours. After the reaction, ethanol was removed by concentration under reduced pressure, 600.0 g of water was added, and after stirring for 1 hour, 269.1 g of lansoprazole intermediate 2-chloromethyl-3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine was obtained by suction filtration, with a yield of 91.2% and an HPLC purity of 99.65%. The total yield was 73.7%.
Example 8
Step 1 preparation of (2,2, 2-trifluoroethoxy) ethylene (Compound 7)
200.0 g (2.00 mol) of trifluoroethanol and 10.0 g (0.100 mol) of sulfuric acid are added into a 1L reaction bottle, the temperature is reduced to-20 ℃, 105.7 g (2.40 mol) of ethylene oxide is slowly added under the protection of nitrogen, and the temperature is controlled at 0 ℃ for reaction for 3 hours. After the reaction is finished, distilling, and collecting fractions at 31-33 ℃ to obtain 233.0 g of (2,2, 2-trifluoroethoxy) ethylene, wherein the yield is 92.4% and the GC purity is 98.49%.
Step 2. preparation of 3-amino-4-chloro-2-methylbut-2-enoic acid ethyl ester (Compound 9)
A2L reaction flask was charged with 330.0 g (2.00 mol) of ethyl 4-chloroacetoacetate, 660.0 g of dichloromethane, 323.8 g (3.20 mol) of triethylamine, stirred at 10 ℃ for 1 hour, and slowly added dropwise with 340.7 g (2.40 mol) of methyl iodide, and the temperature was controlled at 10 ℃ to react for 4 hours. After the reaction, the solvent is removed by concentration under reduced pressure. The temperature is reduced to 0 ℃, 149.9 g (2.20 mol) of 25% ammonia water and 277.5 g (3.60 mol) of ammonium acetate are added, and the temperature is controlled to 0 ℃ for reaction for 8 h. Filtering, eluting with 330.0 g of ice water, and drying to obtain 335.4 g of 3-amino-4-chloro-2-methylbut-2-enoic acid ethyl ester, wherein the yield is 94.2% and the HPLC purity is 99.44%.
Step 3 preparation of 6- (chloromethyl) -5-methyl-4- (2,2, 2-trifluoroethoxy) -2,3,4, 5-tetrahydropyridine (Compound 10)
A4L reaction flask was charged with 900.0 g of water and 203.0 g (6.76 mol) of paraformaldehyde, and heated until the paraformaldehyde was completely dissolved. 300.0 g (1.69 mol) of ethyl 3-amino-4-chloro-2-methylbut-2-enoate, 26.7 g (0.169 mol) of benzenesulfonic acid, 223.7 g (1.77 mol) of (2,2, 2-trifluoroethoxy) ethylene were added and the temperature was controlled at 30 ℃ for reaction for 3 hours. Concentrated hydrochloric acid was added to adjust pH =1, and the reaction was carried out at 40 ℃ for 3 h. Adjusting the pH value to be 8-9 by using 6 mol/L sodium hydroxide aqueous solution, and performing suction filtration to obtain 388.3 g of 6- (chloromethyl) -5-methyl-4- (2,2, 2-trifluoroethoxy) -2,3,4, 5-tetrahydropyridine, wherein the yield is 94.4 percent, and the HPLC purity is 99.90 percent.
Step 4. preparation of lansoprazole intermediate 2-chloromethyl-3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine (Compound 2)
A2L reaction flask was charged with 450.0 g of absolute ethanol, 300.0 g (1.23 mol) of 6- (chloromethyl) -5-methyl-4- (2,2, 2-trifluoroethoxy) -2,3,4, 5-tetrahydropyridine, 10.96 g (24.6 mmol) of Mn (O) -Salon 3, temperature controlled at 30 ℃ and 418.3 g (3.69 mol) of 30% hydrogen peroxide dropwise. After the dripping is finished, the temperature is controlled to be 50 ℃ to continue the reaction for 3 hours. After the reaction, ethanol was removed by concentration under reduced pressure, 600.0 g of water was added, and after stirring for 1 hour, 281.97 g of lansoprazole intermediate 2-chloromethyl-3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine was obtained by suction filtration, with a yield of 95.58% and an HPLC purity of 99.93%. The total yield was 78.5%.
Example 9
Step 1 preparation of (2,2, 2-trifluoroethoxy) ethylene (Compound 7)
200.0 g (2.00 mol) of trifluoroethanol and 10.0 g (0.100 mol) of sulfuric acid are added into a 1L reaction bottle, the temperature is reduced to-20 ℃, 105.7 g (2.40 mol) of ethylene oxide is slowly added under the protection of nitrogen, and the temperature is controlled at 0 ℃ for reaction for 3 hours. After the reaction is finished, distilling, and collecting the fraction at 31-33 ℃ to obtain 234.5 g of (2,2, 2-trifluoroethoxy) ethylene, wherein the yield is 93.0 percent and the GC purity is 98.50 percent.
Step 2. preparation of 3-amino-4-chloro-2-methylbut-2-enoic acid ethyl ester (Compound 9)
A2L reaction flask was charged with 330.0 g (2.00 mol) of ethyl 4-chloroacetoacetate, 660.0 g of dichloromethane, 323.8 g (3.20 mol) of triethylamine, stirred at 25 ℃ for 1 hour, and slowly added dropwise with 302.7 g (2.40 mol) of dimethyl sulfate, and reacted at 25 ℃ for 4 hours while controlling the temperature. After the reaction, the solvent is removed by concentration under reduced pressure. The temperature is reduced to 0 ℃, 177.1 g (2.60 mol) of 25% ammonia water and 246.7 g (3.20 mol) of ammonium acetate are added, and the temperature is controlled to 0 ℃ for reaction for 8 h. Filtering, eluting with 330.0 g of ice water, and drying to obtain 320.8 g of 3-amino-4-chloro-2-methylbut-2-enoic acid ethyl ester, wherein the yield is 90.1% and the HPLC purity is 98.50%.
Step 3 preparation of 6- (chloromethyl) -5-methyl-4- (2,2, 2-trifluoroethoxy) -2,3,4, 5-tetrahydropyridine (Compound 10)
A4L reaction flask was charged with 900.0 g of water and 152.3 g (5.07 mol) of paraformaldehyde, and heated until the paraformaldehyde was completely dissolved. 300.0 g (1.69 mol) of ethyl 3-amino-4-chloro-2-methylbut-2-enoate, 40.1 g (0.254 mol) of benzenesulfonic acid, 223.7 g (1.77 mol) of (2,2, 2-trifluoroethoxy) ethylene were added and the temperature was controlled at 30 ℃ for reaction for 2 hours. Concentrated hydrochloric acid was added to adjust pH =1, and the reaction was carried out at 40 ℃ for 3 h. Adjusting the pH value to be 8-9 by using 6 mol/L sodium hydroxide aqueous solution, and performing suction filtration to obtain 390.8 g of 6- (chloromethyl) -5-methyl-4- (2,2, 2-trifluoroethoxy) -2,3,4, 5-tetrahydropyridine, wherein the yield is 95.0 percent, and the HPLC purity is 99.04 percent.
Step 4. preparation of lansoprazole intermediate 2-chloromethyl-3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine (Compound 2)
A2L reaction flask was charged with 450.0 g of absolute ethanol, 300.0 g (1.23 mol) of 6- (chloromethyl) -5-methyl-4- (2,2, 2-trifluoroethoxy) -2,3,4, 5-tetrahydropyridine, 5.48 g (12.3 mmol) of Mn (O) -Salon 3, temperature controlled at 30 ℃ and 418.3 g (3.69 mol) of 30% hydrogen peroxide dropwise. After dropping, the reaction was continued at this temperature for 7 hours. After the reaction, ethanol is removed by concentration under reduced pressure, 600.0 g of water is added, after stirring for 1 hour, 276.8 g of lansoprazole intermediate 2-chloromethyl-3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine is obtained by suction filtration, the yield is 93.8%, and the HPLC purity is 99.74%. The total yield was 74.7%.
Example 10
Step 1 preparation of (2,2, 2-trifluoroethoxy) ethylene (Compound 7)
200.0 g (2.00 mol) of trifluoroethanol and 10.0 g (0.100 mol) of sulfuric acid are added into a 1L reaction bottle, the temperature is reduced to minus 20 ℃, 105.7 g (2.40 mol) of ethylene oxide is slowly added under the protection of nitrogen, and the temperature is controlled to minus 10 ℃ for reaction for 5 hours. After the reaction is finished, distillation is carried out, and a fraction at 31-33 ℃ is collected to obtain 233.8 g of (2,2, 2-trifluoroethoxy) ethylene, wherein the yield is 92.8% and the GC purity is 98.52%.
Step 2. preparation of 3-amino-4-chloro-2-methylbut-2-enoic acid ethyl ester (Compound 9)
A2L reaction flask was charged with 330.0 g (2.00 mol) of ethyl 4-chloroacetoacetate, 660.0 g of dichloromethane, 323.8 g (3.20 mol) of triethylamine, stirred at 25 ℃ for 1 hour, and slowly added dropwise with 302.7 g (2.40 mol) of dimethyl sulfate, and reacted at 25 ℃ for 4 hours while controlling the temperature. After the reaction, the solvent is removed by concentration under reduced pressure. The temperature is reduced to 0 ℃, 149.9 g (2.20 mol) of 25% ammonia water and 277.5 g (3.60 mol) of ammonium acetate are added, and the temperature is controlled to be 20 ℃ for reaction for 4 hours. Filtering, eluting with 330.0 g of ice water, and drying to obtain 328.6 g of 3-amino-4-chloro-2-methylbut-2-enoic acid ethyl ester, wherein the yield is 92.3% and the HPLC purity is 98.12%.
Step 3 preparation of 6- (chloromethyl) -5-methyl-4- (2,2, 2-trifluoroethoxy) -2,3,4, 5-tetrahydropyridine (Compound 10)
A4L reaction flask was charged with 900.0 g of water and 152.3 g (5.07 mol) of paraformaldehyde, and heated until the paraformaldehyde was completely dissolved. 300.0 g (1.69 mol) of ethyl 3-amino-4-chloro-2-methylbut-2-enoate, 26.7 g (0.169 mol) of benzenesulfonic acid, 223.7 g (1.77 mol) of (2,2, 2-trifluoroethoxy) ethylene were added and the temperature was controlled at 50 ℃ for 1 hour. Concentrated hydrochloric acid was added to adjust pH =1, and the reaction was carried out at 50 ℃ for 2 h. Adjusting the pH value to be 8-9 by using 6 mol/L sodium hydroxide aqueous solution, and performing suction filtration to obtain 380.5 g of 6- (chloromethyl) -5-methyl-4- (2,2, 2-trifluoroethoxy) -2,3,4, 5-tetrahydropyridine, wherein the yield is 92.5 percent, and the HPLC purity is 98.61 percent.
Step 4. preparation of lansoprazole intermediate 2-chloromethyl-3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine (Compound 2)
A2L reaction flask was charged with 450.0 g of absolute ethanol, 300.0 g (1.23 mol) of 6- (chloromethyl) -5-methyl-4- (2,2, 2-trifluoroethoxy) -2,3,4, 5-tetrahydropyridine, 27.39 g (61.5 mmol) of Mn (O) -Salon 3, temperature controlled at 30 ℃ and 418.3 g (3.69 mol) of 30% hydrogen peroxide dropwise. After dropping, the reaction was continued at this temperature for 3 hours. After the reaction, ethanol was removed by concentration under reduced pressure, 600.0 g of water was added, and after stirring for 1 hour, 281.2 g of lansoprazole intermediate 2-chloromethyl-3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine was obtained by suction filtration, with a yield of 95.3% and an HPLC purity of 99.81%. The total yield was 75.5%.
Example 11
Step 1 preparation of (2,2, 2-trifluoroethoxy) ethylene (Compound 7)
200.0 g (2.00 mol) of trifluoroethanol and 10.0 g (0.100 mol) of sulfuric acid are added into a 1L reaction bottle, the temperature is reduced to-20 ℃, 105.7 g (2.40 mol) of ethylene oxide is slowly added under the protection of nitrogen, and the temperature is controlled at 0 ℃ for reaction for 3 hours. After the reaction is finished, distilling, and collecting the fraction at 31-33 ℃ to obtain 239.0 g of (2,2, 2-trifluoroethoxy) ethylene, wherein the yield is 94.8 percent and the GC purity is 99.19 percent.
Step 2. preparation of 3-amino-4-chloro-2-methylbut-2-enoic acid ethyl ester (Compound 9)
A2L reaction flask was charged with 330.0 g (2.00 mol) of ethyl 4-chloroacetoacetate, 660.0 g of dichloromethane, 323.8 g (3.20 mol) of triethylamine, stirred at 25 ℃ for 1 hour, and slowly added dropwise with 302.7 g (2.40 mol) of dimethyl sulfate, and reacted at 25 ℃ for 4 hours while controlling the temperature. After the reaction, the solvent is removed by concentration under reduced pressure. The temperature is reduced to 0 ℃, 149.9 g (2.20 mol) of 25% ammonia water and 277.5 g (3.60 mol) of ammonium acetate are added, and the temperature is controlled to 0 ℃ for reaction for 8 h. Filtering, eluting with 330.0 g of ice water, and drying to obtain 337.1 g of 3-amino-4-chloro-2-methylbut-2-enoic acid ethyl ester, with the yield of 94.7% and the HPLC purity of 98.92%.
Step 3 preparation of 6- (chloromethyl) -5-methyl-4- (2,2, 2-trifluoroethoxy) -2,3,4, 5-tetrahydropyridine (Compound 10)
A4L reaction flask was charged with 900.0 g of water and 152.3 g (5.07 mol) of paraformaldehyde, and heated until the paraformaldehyde was completely dissolved. 300.0 g (1.69 mol) of ethyl 3-amino-4-chloro-2-methylbut-2-enoate, 26.7 g (0.169 mol) of benzenesulfonic acid, 223.7 g (1.77 mol) of (2,2, 2-trifluoroethoxy) ethylene were added and the temperature was controlled at 30 ℃ for reaction for 3 hours. Concentrated hydrochloric acid was added to adjust pH =1, and the reaction was carried out at 40 ℃ for 3 h. Adjusting the pH value to be 8-9 by using 6 mol/L sodium hydroxide aqueous solution, and performing suction filtration to obtain 392.8 g of 6- (chloromethyl) -5-methyl-4- (2,2, 2-trifluoroethoxy) -2,3,4, 5-tetrahydropyridine, wherein the yield is 95.5 percent, and the HPLC purity is 99.13 percent.
Step 4. preparation of lansoprazole intermediate 2-chloromethyl-3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine (Compound 2)
A2L reaction flask was charged with 450.0 g of absolute ethanol, 300.0 g (1.23 mol) of 6- (chloromethyl) -5-methyl-4- (2,2, 2-trifluoroethoxy) -2,3,4, 5-tetrahydropyridine, 10.96 g (24.6 mmol) of Mn (O) -Salon 3, temperature controlled at 30 ℃ and 418.3 g (3.69 mol) of 30% hydrogen peroxide dropwise. After dropping, the reaction was continued at this temperature for 5 hours. After the reaction, ethanol is removed by concentration under reduced pressure, 600.0 g of water is added, after stirring for 1 hour, 284.1 g of lansoprazole intermediate 2-chloromethyl-3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine is obtained by suction filtration, the yield is 96.3%, and the HPLC purity is 99.73%. The total yield is 82.6%.
Example 12
Step 1 preparation of (2,2, 2-trifluoroethoxy) ethylene (Compound 7)
200.0 g (2.00 mol) of trifluoroethanol and 10.0 g (0.100 mol) of sulfuric acid are added into a 1L reaction bottle, the temperature is reduced to minus 20 ℃, 105.7 g (2.40 mol) of ethylene oxide is slowly added under the protection of nitrogen, and the temperature is controlled to minus 10 ℃ for reaction for 5 hours. After the reaction is finished, distilling, and collecting fractions at 31-33 ℃ to obtain 229.0 g of (2,2, 2-trifluoroethoxy) ethylene, wherein the yield is 90.9% and the GC purity is 97.63%.
Step 2. preparation of 3-amino-4-chloro-2-methylbut-2-enoic acid ethyl ester (Compound 9)
A2L reaction flask was charged with 330.0 g (2.00 mol) of ethyl 4-chloroacetoacetate, 660.0 g of dichloromethane, 323.8 g (3.20 mol) of triethylamine, stirred at 25 ℃ for 1 hour, and slowly added dropwise with 302.7 g (2.40 mol) of dimethyl sulfate, and reacted at 25 ℃ for 4 hours while controlling the temperature. After the reaction, the solvent is removed by concentration under reduced pressure. The temperature is reduced to 0 ℃, 218.0 g (3.20 mol) of 25% ammonia water and 215.8 g (2.80 mol) of ammonium acetate are added, and the temperature is controlled to 40 ℃ for reaction for 2 h. Filtering, eluting with 330.0 g of ice water, and drying to obtain 321.5 g of 3-amino-4-chloro-2-methylbut-2-enoic acid ethyl ester, wherein the yield is 90.3% and the HPLC purity is 98.44%.
Step 3 preparation of 6- (chloromethyl) -5-methyl-4- (2,2, 2-trifluoroethoxy) -2,3,4, 5-tetrahydropyridine (Compound 10)
A4L reaction flask was charged with 900.0 g of water and 152.3 g (5.07 mol) of paraformaldehyde, and heated until the paraformaldehyde was completely dissolved. 300.0 g (1.69 mol) of ethyl 3-amino-4-chloro-2-methylbut-2-enoate, 26.7 g (0.169 mol) of benzenesulfonic acid, 223.7 g (1.77 mol) of (2,2, 2-trifluoroethoxy) ethylene were added and the temperature was controlled at 30 ℃ for reaction for 3 hours. Concentrated hydrochloric acid was added to adjust pH =1, and the reaction was carried out at 30 ℃ for 4 h. Adjusting the pH to 8-9 with 6 mol/L sodium hydroxide aqueous solution, and performing suction filtration to obtain 390.4 g of 6- (chloromethyl) -5-methyl-4- (2,2, 2-trifluoroethoxy) -2,3,4, 5-tetrahydropyridine, wherein the yield is 94.9% and the HPLC purity is 99.62%.
Step 4. preparation of lansoprazole intermediate 2-chloromethyl-3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine (Compound 2)
A2L reaction flask was charged with 450.0 g of absolute ethanol, 300.0 g (1.23 mol) of 6- (chloromethyl) -5-methyl-4- (2,2, 2-trifluoroethoxy) -2,3,4, 5-tetrahydropyridine, 10.17 g (24.6 mmol) of Mn (O) -Salon 5, temperature controlled at 30 ℃ and 418.3 g (3.69 mol) of 30% hydrogen peroxide dropwise. After dropping, the reaction was continued at this temperature for 5 hours. After the reaction, ethanol was removed by concentration under reduced pressure, 600.0 g of water was added, and after stirring for 1 hour, 281.8 g of lansoprazole intermediate 2-chloromethyl-3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine was obtained by suction filtration, with a yield of 95.5% and an HPLC purity of 99.69%. The total yield was 74.4%.
Example 13
Step 1 preparation of (2,2, 2-trifluoroethoxy) ethylene (Compound 7)
4.00 kg (40.0 mol) of trifluoroethanol and 200 g (2.00 mol) of sulfuric acid are added into a 25L reaction kettle, the temperature is reduced to-20 ℃, 2.11 kg (48.0 mol) of ethylene oxide is slowly added under the protection of nitrogen, and the temperature is controlled at 0 ℃ for reaction for 3 hours. After the reaction is finished, distilling, and collecting the fraction at 31-33 ℃ to obtain 4.79 kg of (2,2, 2-trifluoroethoxy) ethylene, wherein the yield is 95.0 percent and the GC purity is 99.44 percent.
Step 2. preparation of 3-amino-4-chloro-2-methylbut-2-enoic acid ethyl ester (Compound 9)
6.50 kg (39.5 mol) of ethyl 4-chloroacetoacetate, 13.00 kg of dichloromethane and 6.40 kg (63.2 mol) of triethylamine are added into a 50L reaction kettle, stirred for 1h at 25 ℃, 5.98 kg (47.4 mol) of dimethyl sulfate is slowly added dropwise, and the temperature is controlled at 25 ℃ to react for 4 h. After the reaction, the solvent is removed by concentration under reduced pressure. The temperature is reduced to 0 ℃, 2.96 kg (43.4 mol) of 25% ammonia water and 5.48 kg (71.1 mol) of ammonium acetate are added, and the temperature is controlled to 0 ℃ for reaction for 8 hours. Centrifuging, rinsing with 6.50 kg of ice water, and drying to obtain 66.50 kg of 3-amino-4-chloro-2-methylbut-2-enoic acid ethyl ester, wherein the yield is 94.8 percent, and the HPLC purity is 98.85 percent.
Step 3 preparation of 6- (chloromethyl) -5-methyl-4- (2,2, 2-trifluoroethoxy) -2,3,4, 5-tetrahydropyridine (Compound 10)
18.00 kg of water and 3.05 kg (101 mol) of paraformaldehyde are charged into a 100L reactor and heated until the paraformaldehyde is completely dissolved. 6.00 kg (33.8 mol) of ethyl 3-amino-4-chloro-2-methylbut-2-enoate, 0.53 kg (3.38 mol) of benzenesulfonic acid and 4.47 kg (35.5 mol) of (2,2, 2-trifluoroethoxy) ethylene were added and the temperature was controlled at 30 ℃ for reaction for 3 hours. Concentrated hydrochloric acid was added to adjust pH =1, and the reaction was carried out at 40 ℃ for 3 h. Adjusting the pH value to 8-9 with 6 mol/L sodium hydroxide aqueous solution, and centrifuging to obtain 7.86 kg of 6- (chloromethyl) -5-methyl-4- (2,2, 2-trifluoroethoxy) -2,3,4, 5-tetrahydropyridine, wherein the yield is 95.5% and the HPLC purity is 99.48%.
Step 4. preparation of lansoprazole intermediate 2-chloromethyl-3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine (Compound 2)
Into a 50L reactor were charged 11.70 kg of anhydrous ethanol, 7.80 kg (1.23 mol) of 6- (chloromethyl) -5-methyl-4- (2,2, 2-trifluoroethoxy) -2,3,4, 5-tetrahydropyridine, 285 g (640 mmol) of Mn (O) -Salon 3, controlled at 30 ℃ and 10.88 kg (96.0 mol) of 30% hydrogen peroxide were added dropwise. After dropping, the reaction was continued at this temperature for 5 hours. After the reaction, ethanol is removed by concentration under reduced pressure, 15.60 kg of water is added, the mixture is stirred for 1 hour and then centrifuged to obtain 7.35 kg of lansoprazole intermediate 2-chloromethyl-3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine, the yield is 95.8 percent, and the HPLC purity is 99.88 percent. The total yield was 82.4%.
Example 14
Step 1 preparation of (2,2, 2-trifluoroethoxy) ethylene (Compound 7)
Adding 20.00 kg (200 mol) of trifluoroethanol and 1.00 kg (10.0 mol) of sulfuric acid into a 100L reaction kettle, cooling to-20 ℃, slowly adding 10.57 kg (240 mol) of ethylene oxide under the protection of nitrogen, and controlling the temperature to be 0 ℃ for reaction for 3 hours. After the reaction is finished, distilling, and collecting fractions at 31-33 ℃ to obtain 24.01 kg of (2,2, 2-trifluoroethoxy) ethylene, wherein the yield is 95.3% and the GC purity is 99.35%.
Step 2. preparation of 3-amino-4-chloro-2-methylbut-2-enoic acid ethyl ester (Compound 9)
33.00 kg (200 mol) of ethyl 4-chloroacetoacetate, 66.00 kg of dichloromethane and 32.38 kg (320 mol) of triethylamine are added into a 200L reaction kettle, stirred for 1h at 25 ℃, 30.27 kg (240 mol) of dimethyl sulfate is slowly added dropwise, and the temperature is controlled at 25 ℃ to react for 4 h. After the reaction, the solvent is removed by concentration under reduced pressure. The temperature is reduced to 0 ℃, 14.99 kg (220 mol) of 25% ammonia water and 27.75 kg (360 mol) of ammonium acetate are added, and the temperature is controlled at 0 ℃ for reaction for 8 hours. Centrifuging, rinsing with 33.00 kg of ice water, and drying to obtain 33.86 kg of 3-amino-4-chloro-2-methylbut-2-enoic acid ethyl ester, wherein the yield is 95.1% and the HPLC purity is 98.82%.
Step 3 preparation of 6- (chloromethyl) -5-methyl-4- (2,2, 2-trifluoroethoxy) -2,3,4, 5-tetrahydropyridine (Compound 10)
90.00 kg of water and 15.23 g (507 mol) of paraformaldehyde are charged into a 400L reactor, and heated until the paraformaldehyde is completely dissolved. 30.00 kg (169 mol) of ethyl 3-amino-4-chloro-2-methylbut-2-enoate, 2.67 kg (16.9 mol) of benzenesulfonic acid, 22.37 g (177 mol) of (2,2, 2-trifluoroethoxy) ethylene were added and the reaction was carried out at 30 ℃ for 3 hours. Concentrated hydrochloric acid was added to adjust pH =1, and the reaction was carried out at 40 ℃ for 3 h. Adjusting the pH value to 8-9 with 6 mol/L sodium hydroxide aqueous solution, and centrifuging to obtain 39.61 kg of 6- (chloromethyl) -5-methyl-4- (2,2, 2-trifluoroethoxy) -2,3,4, 5-tetrahydropyridine, wherein the yield is 96.3% and the HPLC purity is 99.40%.
Step 4. preparation of lansoprazole intermediate 2-chloromethyl-3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine (Compound 2)
59.4 kg of absolute ethanol, 39.6 kg (163 mol) of 6- (chloromethyl) -5-methyl-4- (2,2, 2-trifluoroethoxy) -2,3,4, 5-tetrahydropyridine and 1.45 kg (3.26 mol) of Mn (O) -Salon 3 were charged into a 200L reactor, the temperature was controlled at 30 ℃ and 55.44 kg (489 mol) of 30% hydrogen peroxide were added dropwise. After dropping, the reaction was continued at this temperature for 5 hours. After the reaction, ethanol was removed by concentration under reduced pressure, 79.20 kg of water was added, and after stirring for 1 hour, 37.73 kg of lansoprazole intermediate 2-chloromethyl-3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine was obtained by centrifugation, with a yield of 96.9% and a HPLC purity of 99.87%. The total yield is 84.6%.
Claims (10)
1. A preparation method of a lansoprazole intermediate 2-chloromethyl-3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine is characterized by comprising the following steps:
step 1, ethylene oxide and trifluoroethanol react under the catalysis of acid to prepare a compound 7, namely (2,2, 2-trifluoroethoxy) ethylene, wherein the acid is selected from one of sulfuric acid and hydrochloric acid, and the reaction temperature is-10 ℃;
step 2.4-ethyl chloroacetoacetate is subjected to methylation reaction with a methylation reagent under the catalysis of alkali, the solvent is evaporated after the reaction is finished, and further the amination reaction is carried out under the condition of ammonia water and ammonium acetate to generate a compound 9, namely 3-amino-4-chloro-2-methylbut-2-ethyl enoate, wherein the alkali is selected from triethylamine and diisopropylethylamine, and the methylation reagent is selected from dimethyl sulfate and methyl iodide;
step 3, performing a three-molecule cyclization reaction on a compound 9, namely 3-amino-4-chloro-2-methylbut-2-enoic acid ethyl ester, a compound 7, namely (2,2, 2-trifluoroethoxy) ethylene and paraformaldehyde under the catalytic action of acid, and directly adding hydrochloric acid to perform catalytic decarboxylation reaction to prepare a compound 10, namely 6- (chloromethyl) -5-methyl-4- (2,2, 2-trifluoroethoxy) -2,3,4, 5-tetrahydropyridine after the reaction is finished, wherein the acid is selected from acetic acid, benzenesulfonic acid and methanesulfonic acid;
and 4, oxidizing the compound 10, namely 6- (chloromethyl) -5-methyl-4- (2,2, 2-trifluoroethoxy) -2,3,4, 5-tetrahydropyridine by hydrogen peroxide under the catalysis of tetraphenylporphyrinoxide manganese to generate the compound 5, namely 2-chloromethyl-3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine.
2. The preparation method of lansoprazole intermediate 2-chloromethyl-3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine according to claim 1, characterized in that in step 1, the feeding molar ratio is: trifluoroethanol: ethylene oxide: the acid is in the range of 1: 1.0-2: 0.02-0.2.
3. The preparation method of lansoprazole intermediate 2-chloromethyl-3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine according to claim 1, characterized in that in step 1, the feeding molar ratio is: trifluoroethanol: ethylene oxide: the acid was 1: 1.2: 0.05.
4. The preparation method of lansoprazole intermediate 2-chloromethyl-3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine according to claim 1, characterized in that in step 2, the methylation reaction temperature is 10-40 ℃.
5. The preparation method of lansoprazole intermediate 2-chloromethyl-3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine according to claim 1, wherein in step 2, the amination temperature is-10 to 40 ℃.
6. The preparation method of lansoprazole intermediate 2-chloromethyl-3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine according to claim 1, characterized in that in step 2, the feeding molar ratio is: ethyl 4-chloroacetoacetate: alkali: a methylating agent: ammonia water: the ammonium acetate is in the range of 1: 1.1-2.0: 1.0-1.6: 1.4-2.5.
7. The preparation method of lansoprazole intermediate 2-chloromethyl-3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine according to claim 1, characterized in that the molar ratio of the materials fed in step 2 is: ethyl 4-chloroacetoacetate: alkali: a methylating agent: ammonia water: ammonium acetate is 1: 1.6: 1.2: 1.1: 1.8.
8. The preparation method of lansoprazole intermediate 2-chloromethyl-3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine according to claim 1, characterized in that in step 3, the cyclization reaction temperature is 10-50 ℃.
9. The preparation method of lansoprazole intermediate 2-chloromethyl-3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine according to claim 1, characterized in that in step 3, the decarboxylation reaction temperature is 10-50 ℃.
10. The preparation method of lansoprazole intermediate 2-chloromethyl-3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine according to claim 1, characterized in that in step 3, the feeding molar ratio is: compound 9: compound 7: paraformaldehyde: the acid is in the range of 1: 1-1.2: 2-5: 0.05-0.2.
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| CN102225909A (en) * | 2011-05-05 | 2011-10-26 | 埃斯特维华义制药有限公司 | Preparation method of lansoprazole intermediate |
| CN102838537A (en) * | 2012-09-18 | 2012-12-26 | 寿光富康制药有限公司 | Preparation method of lansoprazole intermediate |
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| WO2017012922A1 (en) * | 2015-07-17 | 2017-01-26 | Bayer Cropscience Aktiengesellschaft | Substituted cyclic aryl and heteroaryl carboxylic acid hydrazides or salts thereof and use thereof to increase stress tolerance in plants |
| CN106543146A (en) * | 2016-11-10 | 2017-03-29 | 石家庄市度智医药科技有限公司 | A kind of preparation method of R-lansoprazole |
| WO2017164813A1 (en) * | 2016-03-22 | 2017-09-28 | Nanyang Technological University | Ion pair catalysis of tungstate and molybdate |
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| CN102225909A (en) * | 2011-05-05 | 2011-10-26 | 埃斯特维华义制药有限公司 | Preparation method of lansoprazole intermediate |
| CN102838537A (en) * | 2012-09-18 | 2012-12-26 | 寿光富康制药有限公司 | Preparation method of lansoprazole intermediate |
| CN103664885A (en) * | 2013-12-12 | 2014-03-26 | 武汉工程大学 | Preparation method of benzimidazole proton pump inhibitor intermediate |
| WO2017012922A1 (en) * | 2015-07-17 | 2017-01-26 | Bayer Cropscience Aktiengesellschaft | Substituted cyclic aryl and heteroaryl carboxylic acid hydrazides or salts thereof and use thereof to increase stress tolerance in plants |
| WO2017164813A1 (en) * | 2016-03-22 | 2017-09-28 | Nanyang Technological University | Ion pair catalysis of tungstate and molybdate |
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