CN110903212A - Method for synthesizing cinacalcet intermediate - Google Patents
Method for synthesizing cinacalcet intermediate Download PDFInfo
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- CN110903212A CN110903212A CN201911350377.9A CN201911350377A CN110903212A CN 110903212 A CN110903212 A CN 110903212A CN 201911350377 A CN201911350377 A CN 201911350377A CN 110903212 A CN110903212 A CN 110903212A
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Abstract
The invention particularly discloses a preparation method of a cinacalcet hydrochloride intermediate (R) -N- (1- (naphthalene-1-yl) ethyl-3- (trifluoromethyl) phenyl) propionamide. The 3- (3-trifluoromethylphenyl) propionic acid is used as a raw material, is condensed with N, N-Carbonyldiimidazole (CDI) to obtain an intermediate state, and is condensed with (R) -1- (1-naphthyl) ethylamine to obtain a final product cinacalcet intermediate, so that an acyl halide reagent is avoided, no acid gas is generated, the method is environment-friendly, low in equipment requirement, mild in reaction temperature, high in product yield, few in impurities and high in purity, and is suitable for large-scale production.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a preparation method of a cinacalcet hydrochloride intermediate (R) -N- (1- (naphthalene-1-yl) ethyl-3- (trifluoromethyl) phenyl) propionamide.
Background
The chemical name of cinacalcet hydrochloride is: n- ((1R) -1- (1-naphthyl) ethyl) -3- (3- (trifluoromethyl) phenyl) propyl-1-amine hydrochloride, the structure of which is represented by the following formula (IV):
（Ⅳ）
cinacalcet hydrochloride is a calcimimetic developed by NPS Pharmaceuticals, usa
(calcimetics). It activates the calcium receptor in the parathyroid gland, thereby reducing parathyroid hormone (PTH) secretion, regulating parathyroid calcium receptor behavior, and reducing parathyroid hormone, calcium, phosphorus and calcium-phosphorus complex levels by enhancing receptor sensitivity to calcium levels in the bloodstream. Is mainly used for treating secondary hyperparathyroidism of Chronic Kidney Disease (CKD) patients undergoing dialysis and hypercalcemia of parathyroid cancer patients. In 2004, cinacalcet hydrochloride manufactured by Amgen corporation was approved by FDA in the united states and marketed under the trade name sensipa, and in 2007, cinacalcet hydrochloride manufactured by kylin pharmaceutical corporation was marketed in japan under the trade name regpar, and has been widely used in clinical practice. Wherein (R) -N- (1- (naphthalene-1-yl) ethyl-3- (trifluoromethyl) phenyl) propionamide is an important intermediate for synthesizing cinacalcet hydrochloride.
At present, patent documents US200725964A1 and WO2007127445A2 report that 3- (3-trifluoromethylphenyl) propionic acid of formula (II) and its derivatives (mixed acid anhydride and acid halide) and (R) -1- (1-naphthyl) ethylamine of formula (I) are subjected to condensation reaction to obtain the cinacalcet intermediate of formula (III). The method uses acyl halide reagent with strong corrosivity and toxicity, has large corrosion to reaction equipment, releases a large amount of acid gas in the operation process, causes inconvenient production and operation, and pollutes the production environment.
In patent CN106831441A, m-trifluoromethyl propenone and (R) -1- (1-naphthyl) ethylamine of formula (I) are directly condensed under acidic condition to obtain formula (III). The m-trifluoromethyl acrylketone is complex to synthesize, cannot be supplied in large batch on the market, and cannot be produced in large scale.
In patent CN104926665A, 3- (3-trifluoromethylphenyl) propionic acid of formula (II) and (R) -1- (1-naphthyl) ethylamine of formula (I) are coupled in a one-pot method to obtain a cinacalcet product, an expensive catalyst, namely tris (pentafluorophenyl) borane is used, and impurities are more in the one-pot method, a chromatographic column is used for post-treatment, so that the separation is difficult, the yield is low, and the scale-up production is difficult.
Disclosure of Invention
The invention aims to solve the problems and provide a synthesis method of (R) -N- (1- (naphthalene-1-yl) ethyl-3- (trifluoromethyl) phenyl) propionamide, which is a cinacalcet hydrochloride intermediate, and is safe, environment-friendly, convenient to operate, high in yield and suitable for industrial production.
The reaction equation is as follows
（Ⅱ） (Ⅰ) (Ⅲ)
The above purpose of the invention is realized by adopting the following technical scheme:
the intermediate product (III) cinacalcet intermediate is prepared by using 3- (3-trifluoromethylphenyl) propionic acid as a raw material, condensing with N, N-Carbonyldiimidazole (CDI) to obtain an intermediate state, and condensing with (R) -1- (1-naphthyl) ethylamine.
The molar ratio of said N, N-Carbonyldiimidazole (CDI) to formula (II) is from 1.0 to 3.0, more preferably 2.0
If the by-product (V) is produced in excess
（Ⅴ）
The reaction solvent is at least one of toluene, acetonitrile, tetrahydrofuran and dichloromethane, and is preferably a dichloromethane solvent.
The molar ratio of the formula (I) to the formula (II) is 1.0 to 2.0, preferably 1.5. If excessive, by-products (V) are produced
（Ⅴ）
The reaction temperature is 5-35 ℃, and more preferably 5-15 ℃;
the reaction time in the above is 2 to 7 hours, more preferably 4 to 5 hours.
Compared with the prior art, the method has the following technical advantages:
(1) the method avoids using acyl halide reagent, does not generate acid gas, is environment-friendly and has lower requirement on equipment;
(2) high-temperature reaction is avoided, and the reaction temperature is mild;
(3) the invention has the advantages of high product yield, less impurities, high purity, suitability for large-scale production and higher economic value.
Description of the drawings:
FIG. 1 is a mass spectrum of the cinacalcet hydrochloride intermediate prepared in example 10;
FIG. 2 is an H-NMR spectrum of a cinacalcet hydrochloride intermediate prepared in example 10;
FIG. 3 is a C-NMR spectrum of cinacalcet hydrochloride intermediate prepared in example 10.
The present invention will be described in further detail below by way of examples, but it should not be construed that the scope of the subject matter of the present invention is limited to the following examples. Such alterations and modifications are intended to be included herein by the scope of this disclosure, and such modifications are intended to be within the meaning of those skilled in the art.
Example 1:
adding 10g of '3- (3-trifluoromethylphenyl) propionic acid' into a 250ml three-necked bottle, adding 60ml of toluene, protecting with nitrogen, dropwise adding 6g of thionyl chloride, adding 50mg of DMF as a catalyst, heating to 47 +/-3 ℃ after the addition, reacting for 2h, decompressing the reaction system, carrying out rotary evaporation on the toluene and the redundant thionyl chloride to obtain 11g of '3- (3-trifluoromethylphenyl) propionyl chloride', dissolving the obtained '3- (3-trifluoromethylphenyl) propionyl chloride' into the 250ml three-necked bottle by using 45ml of acetonitrile, adding 7.8g of '(R) -1- (1-naphthyl) ethylamine' and 6.4g of anhydrous potassium carbonate, heating and refluxing for 22h after the addition, filtering the reaction system, and distilling the filtrate under reduced pressure until the filtrate is dry to obtain 18g of solid. The solid was dissolved in 130ml of toluene, 37ml of 32% hydrochloric acid was added, the system pH = 0.5. + -. 0.5 was adjusted, the organic layer was washed 3 times with 37ml of clear water, and the solvent was evaporated off by rotary evaporation under reduced pressure to give 13.52g of a tan solid.
The experiment summary: the product yield was 79.5% and the purity was 96.72% by HPLC at 220nm, as measured by area normalization. A large amount of irritant acid gas escapes in the experimental distillation process.
Example 2:
adding 10g of '3- (3-trifluoromethylphenyl) propionic acid' into a 250ml three-necked bottle, adding 60ml of toluene, protecting with nitrogen, dropwise adding 6g of thionyl chloride, adding 50mg of DMF as a catalyst, heating to 48 +/-3 ℃ after the addition, reacting for 2h, decompressing the reaction system, carrying out rotary evaporation on the toluene and the redundant thionyl chloride to obtain 11g of '3- (3-trifluoromethylphenyl) propionyl chloride', dissolving the obtained '3- (3-trifluoromethylphenyl) propionyl chloride' into the 250ml three-necked bottle by using 45ml of acetonitrile, adding 7.8g of '(R) -1- (1-naphthyl) ethylamine' and 6.4g of anhydrous potassium carbonate, heating and refluxing for 22h after the addition, filtering the reaction system, and distilling the filtrate under reduced pressure until the filtrate is dry to obtain 18g of solid. The solid was dissolved in 130ml of toluene, 37ml of 32% hydrochloric acid was added, the system pH = 0.6. + -. 0.4 was adjusted, the organic layer was washed 3 times with 37ml of clear water, and the solvent was evaporated off by rotary evaporation under reduced pressure to give 13.64g of a tan solid.
The experiment summary: the yield of the product is 80.23%, and the purity is 95.33% by adopting an HPLC method and detecting at 220nm according to area normalization. A large amount of irritant acid gas escapes in the experimental distillation process.
Example 3:
adding 10g of '3- (3-trifluoromethylphenyl) propionic acid' into a 250ml three-necked bottle, adding 60ml of toluene, protecting with nitrogen, dropwise adding 6g of thionyl chloride, adding 50mg of DMF as a catalyst, heating to 46 +/-3 ℃ after the addition, reacting for 2h, decompressing the reaction system, carrying out rotary evaporation on the toluene and the redundant thionyl chloride to obtain 11g of '3- (3-trifluoromethylphenyl) propionyl chloride', dissolving the obtained '3- (3-trifluoromethylphenyl) propionyl chloride' into the 250ml three-necked bottle by using 45ml of acetonitrile, adding 7.8g of '(R) -1- (1-naphthyl) ethylamine' and 6.4g of anhydrous potassium carbonate, heating and refluxing for 22h after the addition, filtering the reaction system, and distilling the filtrate under reduced pressure until the filtrate is dry to obtain 18g of solid. The solid was dissolved in 130ml of toluene, 37ml of 32% hydrochloric acid was added, the system pH = 0.4. + -. 0.4 was adjusted, the organic layer was washed 3 times with 37ml of clear water, and the solvent was evaporated off by rotary evaporation under reduced pressure to give 14.12g of a tan solid.
The experiment summary: the yield of the product was 14.12g, and the purity was determined by HPLC at 220nm and was 96.43% by area normalization. A large amount of irritant acid gas escapes in the experimental distillation process.
In conclusion, by adopting the methods of example 1, example 2 and example 3, a large amount of irritant acidic gas escapes during the distillation treatment process, the environment is polluted, the generated sulfur dioxide and hydrogen chloride gas have strong corrosivity, and operators need to be equipped with special protective articles, so that the method is not beneficial to large-scale industrial production.
Example 4:
adding 450ml of ethyl acetate, 45.0g of m-bromotrifluoromethylbenzene, 4.8g of magnesium powder and 0.5g of iodine particles into a 1000ml reaction bottle, slowly heating to 55 +/-3 ℃, keeping the temperature and stirring for 8 hours, stopping heating, slowly cooling to 5 +/-3 ℃, slowly adding 18.2g of acryloyl chloride dropwise, finishing dropwise adding for 60 minutes, stirring overnight at 5 +/-3 ℃, slowly adding 180ml of ice-water mixture, stirring for 30 minutes, transferring the reaction solution into a 1000ml separating funnel, discarding the solid which is not completely dissolved, standing the mixed solution for 15 minutes, separating, and discarding the lower aqueous phase. Adding 180ml purified water into the organic layer, shaking, standing for 15min, and removing the water phase. The organic layer was dried over 15g of sodium sulfate for 6h, filtered with suction and concentrated at 45. + -. 5 ℃ under reduced pressure to give 27.7g of an oily liquid, i.e.m-trifluoromethylpropenone, in 76.94% yield. The resulting trifluoromethylacrylketone was added to 400ml of ethyl acetate, 29.4g of "(R) -1- (1-naphthyl) ethylamine", 1.8g of sulfuric acid, stirred at room temperature for 6 hours, then 100ml of purified water was added to the reaction solution, the pH of the solution was adjusted to 12 with 10% sodium hydroxide, the mixture was transferred to a 1000ml separatory funnel, the layers were separated, the organic phase was washed with 200ml of purified water, dried over 20g of sodium sulfate for 6 hours, filtered with suction, and the filtrate was concentrated until no solvent ethyl acetate flowed out, to give 32.3g of a yellow oil in 63% yield.
The experiment summary: in example 4, naturally occuring magnesium powder, volatile iodine, and pungent acryloyl chloride were used in a 63% yield and a purity of 93.27% by area normalization using HPLC at 220 nm.
Example 5:
adding 450ml of ethyl acetate, 45.0g of m-bromotrifluoromethylbenzene, 4.8g of magnesium powder and 0.5g of iodine particles into a 1000ml reaction bottle, slowly heating to 55 +/-3 ℃, keeping the temperature and stirring for 8 hours, stopping heating, slowly cooling to 5 +/-3 ℃, slowly adding 18.2g of acryloyl chloride dropwise, finishing dropwise adding for 60 minutes, stirring overnight at 5 +/-3 ℃, slowly adding 180ml of ice-water mixture, stirring for 30 minutes, transferring the reaction solution into a 1000ml separating funnel, discarding the solid which is not completely dissolved, standing the mixed solution for 15 minutes, separating, and discarding the lower aqueous phase. Adding 180ml purified water into the organic layer, shaking, standing for 15min, and removing the water phase. The organic layer was dried over 15g of sodium sulfate for 6h, filtered with suction and concentrated at 45. + -. 5 ℃ under reduced pressure to give 27.7g of an oily liquid, i.e.m-trifluoromethylpropenone, in 76.94% yield. The resulting trifluoromethylacrylketone was added to 400ml of ethyl acetate, 29.4g of "(R) -1- (1-naphthyl) ethylamine", 1.8g of sulfuric acid, stirred at room temperature for 6 hours, then 100ml of purified water was added to the reaction solution, the pH of the solution was adjusted to 12 with 10% sodium hydroxide, the mixture was transferred to a 1000ml separatory funnel, the layers were separated, the organic phase was washed with 200ml of purified water, dried over 20g of sodium sulfate for 6 hours, filtered with suction, and the filtrate was concentrated until no solvent ethyl acetate flowed out, to obtain 25.65g of a yellow oily substance with a yield of 50.1%.
The experiment summary: in example 5, the easily natural magnesium powder, the volatile iodine and the acrylyl chloride with pungent odor were used, the yield was 50.1%, and the purity was 94.57% by area normalization by HPLC at 220 nm.
Example 6:
adding 450ml of ethyl acetate, 45.0g of m-bromotrifluoromethylbenzene, 4.8g of magnesium powder and 0.5g of iodine particles into a 1000ml reaction bottle, slowly heating to 55 +/-3 ℃, keeping the temperature and stirring for 8 hours, stopping heating, slowly cooling to 5 +/-3 ℃, slowly adding 18.2g of acryloyl chloride dropwise, finishing dropwise adding for 60 minutes, stirring overnight at 5 +/-3 ℃, slowly adding 180ml of ice-water mixture, stirring for 30 minutes, transferring the reaction solution into a 1000ml separating funnel, discarding the solid which is not completely dissolved, standing the mixed solution for 15 minutes, separating, and discarding the lower aqueous phase. Adding 180ml purified water into the organic layer, shaking, standing for 15min, and removing the water phase. The organic layer was dried over 15g of sodium sulfate for 6h, filtered with suction and concentrated at 45. + -. 5 ℃ under reduced pressure to give 27.7g of an oily liquid, i.e.m-trifluoromethylpropenone, in 76.94% yield. The resulting trifluoromethylacrylketone was added to 400ml of ethyl acetate, 29.4g of "(R) -1- (1-naphthyl) ethylamine", 1.8g of sulfuric acid, stirred at room temperature for 6 hours, then 100ml of purified water was added to the reaction solution, the pH of the solution was adjusted to 12 with 10% sodium hydroxide, the mixture was transferred to a 1000ml separatory funnel, the layers were separated, the organic phase was washed with 200ml of purified water, dried over 20g of sodium sulfate for 6 hours, filtered with suction, and the filtrate was concentrated until no solvent ethyl acetate flowed out, to obtain 29.24g of a yellow oil, with a yield of 57%.
The experiment summary: in example 6, the natural magnesium powder, the volatile iodine and the pungent acryloyl chloride were used in a yield of 57% and a purity of 92.19% by area normalization using HPLC at 220 nm.
In conclusion, in examples 4, 5 and 6, because the magnesium powder is solid, the solid/liquid reaction is not uniformly mixed, the yield is easy to be unstable, and the magnesium powder is a strong reducing agent, so the magnesium powder is easy to spontaneously combust in the air, and the explosion risk is easy to occur in the operation process. The intermediate, m-trifluoromethyl propenone, is unstable in property and difficult to store. Because of the above disadvantages, examples 4, 5 and 6 have long reaction time, complicated reaction process, unstable yield and many impurities.
Example 7:
a10 ml reaction vessel was charged with 0.005mol of tris (pentafluorophenyl) borane under nitrogen protection, 1.5ml of n-butyl ether, 2.0mmol of phenylsilane, followed by 0.5mmol of (R) -1- (1-naphthyl) ethylamine and 1.0mmol of
3- (3-trifluoromethylphenyl) propionic acid, heating and reacting at 120 ℃ for 10h, cooling to room temperature, quenching with sodium hydroxide solution (3M; 3 ml), adding ethyl acetate (3 ml), stirring at room temperature for 3h, extracting with ethyl acetate (2 mlx 3), drying the organic phase with anhydrous sodium sulfate, filtering, evaporating the solvent by a rotary evaporation evaporator, and eluting with a chromatographic column to obtain a white economic product with the yield of 50%.
The experiment summary: the product of example 7 was purified using column chromatography elution with a yield of 50% and a purity of 96.54% by HPLC at 220nm, normalized by area. .
Example 8:
a50 ml reaction vessel was charged with 0.025mol of tris (pentafluorophenyl) borane under nitrogen, 7.5ml of n-butyl ether, 10mmol of phenylsilane, 2.5mmol of (R) -1- (1-naphthyl) ethylamine and 5.0mmol of phenylsilane
3- (3-trifluoromethylphenyl) propionic acid, heating and reacting at 120 ℃ for 10h, cooling to room temperature, quenching with sodium hydroxide solution (3M; 15 ml), adding ethyl acetate (15 ml), stirring at room temperature for 3h, extracting with ethyl acetate (10 mlx 3), drying the organic phase with anhydrous sodium sulfate, filtering, evaporating the solvent by a rotary evaporation evaporator, and eluting with a chromatographic column to obtain a white economic product with the yield of 53%.
The experiment summary: the product was purified in example 8 using column chromatography elution, 53% yield. The purity was 95.04% by HPLC at 220nm, normalized by area.
Example 9:
a50 ml reaction vessel was charged with 0.025mol of tris (pentafluorophenyl) borane under nitrogen, 7.5ml of n-butyl ether, 10mmol of phenylsilane, 2.5mmol of (R) -1- (1-naphthyl) ethylamine and 5.0mmol of phenylsilane
3- (3-trifluoromethylphenyl) propionic acid, heating and reacting at 120 ℃ for 10h, cooling to room temperature, quenching with sodium hydroxide solution (3M; 15 ml), adding ethyl acetate (15 ml), stirring at room temperature for 3h, extracting with ethyl acetate (10 mlx 3), drying the organic phase with anhydrous sodium sulfate, filtering, evaporating the solvent by a rotary evaporation evaporator, and eluting with a chromatographic column to obtain a white economic product with the yield of 51%.
The experiment summary: the product was purified in example 9 using column chromatography elution with a yield of 51%. The purity was 97.71% by HPLC at 220nm, normalized by area.
In conclusion, the tris (pentafluorophenyl) borane catalysts used in examples 7, 8 and 9 are expensive, toxic and require special precautions for human handling. The post-treatment uses column chromatography, uses a large amount of eluent, and has large solvent recovery amount, difficult recovery, high cost and low yield.
Example 10:
the preparation of (R) -N- (1- (naphthalen-1-yl) ethyl-3- (trifluoromethyl) phenyl) propanamide of this example is as follows:
adding 5.0g of 3- (3-trifluoromethylphenyl) propionic acid into a 250ml three-necked bottle, adding 15ml of dichloromethane, stirring to dissolve, adding 7.43g (2.0 eq) of N, N-Carbonyldiimidazole (CDI) in batches, stirring for 1h after adding, beginning to dropwise add 5.9g of (R) -1- (1-naphthyl) ethylamine at 5-15 ℃, reacting for 4-5h, monitoring the reaction of the raw materials by TLC, adding clear water into a reaction system, stirring for 30min, layering, washing an organic phase to be neutral by using clear water, and concentrating under reduced pressure to be dry to obtain 6.98g of a product with the yield of 82%. The purity was measured by HPLC at 220nm and was 99.61% by area normalization.
Example 11:
adding 5.0g of 3- (3-trifluoromethylphenyl) propionic acid into a 250ml three-necked bottle, adding 15ml of dichloromethane, stirring to dissolve, adding 3.71g (1.0 eq) of N, N-Carbonyldiimidazole (CDI) in batches, stirring for 1h after adding, beginning to dropwise add 5.9g of (R) -1- (1-naphthyl) ethylamine at 5-15 ℃, reacting for 4-5h, monitoring the reaction of the raw materials by TLC, adding clear water into a reaction system, stirring for 30min, layering, washing an organic phase to be neutral by using clear water, and concentrating to be dry under reduced pressure to obtain 5.21g of a product, wherein the yield is 61.22%. The purity was determined by HPLC at 220nm and was 96.1% by area normalization.
Example 12:
adding 5.0g of 3- (3-trifluoromethylphenyl) propionic acid into a 250ml three-necked bottle, adding 15ml of dichloromethane, stirring to dissolve, adding 11.15g (3.0 eq) of N, N-Carbonyldiimidazole (CDI) in batches, stirring for 1h after adding, beginning to dropwise add 5.9g of (R) -1- (1-naphthyl) ethylamine at 5-15 ℃, reacting for 4-5h, monitoring the reaction of the raw materials by TLC, adding clear water into a reaction system, stirring for 30min, layering, washing an organic phase to be neutral by using clear water, and concentrating to be dry under reduced pressure to obtain 6.80g of a product with the yield of 79.91%. The purity was determined by HPLC at 220nm and was 97.15% by area normalization.
Examples 10 to 12, the results of the experiments are shown in Table 1.
Table 1: molar ratio of N, N-Carbonyldiimidazole (CDI) to 3- (3-trifluoromethylphenyl) propionic acid
Example 13:
adding 5.0g of 3- (3-trifluoromethylphenyl) propionic acid into a 250ml three-necked bottle, adding 15ml of toluene, stirring for dissolving, adding 7.43g (2.0 eq) of N, N-Carbonyldiimidazole (CDI) in batches, stirring for 1h after adding, beginning to dropwise add 5.9g of (R) -1- (1-naphthyl) ethylamine at 5-15 ℃, reacting for 4-5h, monitoring the reaction of raw materials by TLC, adding clear water into a reaction system, stirring for 30min, layering, washing an organic phase to be neutral by using clear water, and concentrating under reduced pressure to be dry to obtain 6.02g of a product, wherein the yield is 70.74%. The purity was measured by HPLC at 220nm and was 99.52% by area normalization.
Example 14:
adding 5.0g of 3- (3-trifluoromethylphenyl) propionic acid into a 250ml three-necked bottle, adding 15ml of acetonitrile, stirring for dissolving, adding 7.43g (2.0 eq) of N, N-Carbonyldiimidazole (CDI) in batches, stirring for 1h after adding, beginning to dropwise add 5.9g of (R) -1- (1-naphthyl) ethylamine at 5-15 ℃, reacting for 4-5h, monitoring the reaction of raw materials by TLC, adding clear water into a reaction system, stirring for 30min, layering, washing an organic phase to be neutral by using clear water, and concentrating under reduced pressure to be dry to obtain 5.83g of a product with the yield of 68.51%. The purity was measured by HPLC at 220nm and was 99.57% by area normalization.
Example 15:
adding 5.0g of 3- (3-trifluoromethylphenyl) propionic acid into a 250ml three-necked bottle, adding 15ml of tetrahydrofuran, stirring to dissolve, adding 7.43g (2.0 eq) of N, N-Carbonyldiimidazole (CDI) in batches, stirring for 1h after adding, beginning to dropwise add 5.9g of (R) -1- (1-naphthyl) ethylamine at 5-15 ℃, reacting for 4-5h, monitoring the reaction completion of raw materials by TLC, adding clear water into a reaction system, stirring for 30min, layering, washing an organic phase to be neutral by using clear water, and concentrating to be dry under reduced pressure to obtain 5.96g of a product with the yield of 70.04%. The purity was measured by HPLC at 220nm and calculated as 99.60% by area normalization.
Examples 13 to 15, results of the experiments are shown in Table 2.
Table 2: screening of solvents
Example 16:
adding 5.0g of 3- (3-trifluoromethylphenyl) propionic acid into a 250ml three-necked bottle, adding 15ml of dichloromethane, stirring to dissolve, adding 7.43g (2.0 eq) of N, N-Carbonyldiimidazole (CDI) in batches, stirring for 1h after adding, beginning to dropwise add 3.92g (1.0 eq) (R) -1- (1-naphthyl) ethylamine at 5-15 ℃, reacting for 4-5h, monitoring the reaction of raw materials by TLC, adding clear water into a reaction system, stirring for 30min, layering, washing an organic phase to be neutral by using clear water, and concentrating under reduced pressure to be dry to obtain 6.14g of a product with the yield of 75.33%. The purity was determined by HPLC at 220nm and was 98.72% by area normalization.
Example 17:
adding 5.0g of 3- (3-trifluoromethylphenyl) propionic acid into a 250ml three-necked bottle, adding 15ml of dichloromethane, stirring to dissolve, adding 7.43g (2.0 eq) of N, N-Carbonyldiimidazole (CDI) in batches, stirring for 1h after adding, beginning to dropwise add 7.84g (2.0 eq) (R) -1- (1-naphthyl) ethylamine at 5-15 ℃, reacting for 4-5h, monitoring the reaction of raw materials by TLC, adding clear water into a reaction system, stirring for 30min, layering, washing an organic phase to be neutral by using clear water, and concentrating under reduced pressure to be dry to obtain 6.68g of a product, wherein the yield is 81.96%. The purity was measured by HPLC at 220nm and was 99.57% by area normalization.
Examples 16 to 17, results of the experiments are shown in Table 3.
Table 3: (R) -1- (1-naphthyl) ethylamine in a molar ratio
Example 18:
adding 5.0g of 3- (3-trifluoromethylphenyl) propionic acid into a 250ml three-necked bottle, adding 15ml of dichloromethane, stirring to dissolve, adding 7.43g (2.0 eq) of N, N-Carbonyldiimidazole (CDI) in batches, stirring for 1h after adding, beginning to dropwise add 5.9g of (R) -1- (1-naphthyl) ethylamine at 15-25 ℃, reacting for 4-5h, monitoring the reaction of raw materials by TLC, adding clear water into a reaction system, stirring for 30min, layering, washing an organic phase to be neutral by using clear water, and concentrating to be dry under reduced pressure to obtain 6.55g of a product, wherein the yield is 80.37%. The purity was determined by HPLC at 220nm and was 98.23% by area normalization.
Example 19:
adding 5.0g of 3- (3-trifluoromethylphenyl) propionic acid into a 250ml three-necked bottle, adding 15ml of dichloromethane, stirring to dissolve, adding 7.43g (2.0 eq) of N, N-Carbonyldiimidazole (CDI) in batches, stirring for 1h after adding, beginning to dropwise add 5.9g of (R) -1- (1-naphthyl) ethylamine at 25-35 ℃, reacting for 4-5h, monitoring the reaction of raw materials by TLC, adding clear water into a reaction system, stirring for 30min, layering, washing an organic phase to be neutral by using clear water, and concentrating to be dry under reduced pressure to obtain 6.76g of a product, wherein the yield is 82.94%. The purity was 94.84% by HPLC at 220nm, normalized by area.
Examples 18 to 19, results of the experiments are shown in Table 4.
Table 4: temperature screening
Example 20:
adding 5.0g of 3- (3-trifluoromethylphenyl) propionic acid into a 250ml three-necked bottle, adding 15ml of dichloromethane, stirring to dissolve, adding 7.43g (2.0 eq) of N, N-Carbonyldiimidazole (CDI) in batches, stirring for 1h after adding, beginning to dropwise add 5.9g of (R) -1- (1-naphthyl) ethylamine at 25-35 ℃, reacting for 2-3h, monitoring the reaction of raw materials by TLC, adding clear water into a reaction system, stirring for 30min, layering, washing an organic phase to be neutral by using clear water, and concentrating to be dry under reduced pressure to obtain 6.78g of a product with the yield of 79.67%. The purity was 96.84% by HPLC at 220nm, normalized by area.
Example 21:
adding 5.0g of 3- (3-trifluoromethylphenyl) propionic acid into a 250ml three-necked bottle, adding 15ml of dichloromethane, stirring to dissolve, adding 7.43g (2.0 eq) of N, N-Carbonyldiimidazole (CDI) in batches, stirring for 1h after adding, beginning to dropwise add 5.9g of (R) -1- (1-naphthyl) ethylamine at 25-35 ℃, reacting for 6-7h, monitoring the reaction of raw materials by TLC, adding clear water into a reaction system, stirring for 30min, layering, washing an organic phase to be neutral by using clear water, and concentrating to be dry under reduced pressure to obtain 6.82g of a product, wherein the yield is 80.14%. The purity was 96.02% by HPLC at 220nm, normalized by area.
Examples 20 to 21, results of the experiments are shown in Table 4.
Table 5: time screening
The method for synthesizing the cinacalcet intermediate provided by the invention is described in detail above. The principles and embodiments of the present invention are described herein using specific examples, which are presented to aid in understanding the methods and core concepts of the present invention.
Claims (11)
1. A method for synthesizing a cinacalcet intermediate is characterized by comprising the following specific steps:
the cinacalcet intermediate (III) is obtained by condensing (R) -1- (1-naphthyl) ethylamine (I) and 3- (3-trifluoromethylphenyl) propionic acid (II) in an organic solvent by using N, N-Carbonyldiimidazole (CDI) as a condensing agent.
2. The process for the synthesis of cinacalcet intermediate (iii) according to claim 1, characterized in that the molar ratio of N, N-Carbonyldiimidazole (CDI) to formula (ii) is 1.0-3.0.
3. The process for synthesizing cinacalcet intermediate (iii) according to claim 1, wherein the organic solvent is at least one of toluene, acetonitrile, tetrahydrofuran, and dichloromethane.
4. A process for the synthesis of cinacalcet intermediate (iii) according to claim 1, characterized in that the molar ratio of formula (i) and formula (ii) is 1.0-2.0.
5. The process for the synthesis of cinacalcet intermediate (iii) according to claim 4, characterized in that the reaction temperature is 5-35 ℃.
6. The process for the synthesis of cinacalcet intermediate (iii) according to claim 4, characterized in that the reaction time is 4-7 h.
7. A process for the synthesis of cinacalcet intermediate (iii) according to claim 1, characterized in that the optimum ratio of the molar ratio of N, N-Carbonyldiimidazole (CDI) to formula (ii) is 2.0.
8. A process for the synthesis of cinacalcet intermediate (iii) according to claim 1, characterized in that the organic solvent is at least one of toluene, acetonitrile, tetrahydrofuran, dichloromethane, most preferably dichloromethane.
9. A process for the synthesis of cinacalcet intermediate (iii) according to claim 1, characterized in that the molar ratio of formula (i) and formula (ii) is 1.0-2.0, most preferably 1.5.
10. The method for synthesizing cinacalcet intermediate (iii) according to claim 4, characterized in that the reaction temperature is 5-35 ℃ and the time is 2-7h, and the optimal temperature is: 5-15 ℃.
11. The process for the synthesis of cinacalcet intermediate (iii) according to claim 4, characterized in that the reaction time is 2-7h, the most preferred time being: 4-5 h.
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| CN102718662A (en) * | 2012-07-12 | 2012-10-10 | 杭州新博思生物医药有限公司 | Method for preparing cinacalcet hydrochloride |
| CN106810452A (en) * | 2017-01-13 | 2017-06-09 | 华北水利水电大学 | A kind of preparation method of cinacalcet hydrochloride |
| CN106831441A (en) * | 2017-01-23 | 2017-06-13 | 江苏康思尔医药科技有限公司 | A kind of preparation method of cinacalcet hydrochloride |
| CN109096119A (en) * | 2018-10-29 | 2018-12-28 | 江苏永安制药有限公司 | A method of preparing cinacalcet hydrochloride |
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| CN102718662A (en) * | 2012-07-12 | 2012-10-10 | 杭州新博思生物医药有限公司 | Method for preparing cinacalcet hydrochloride |
| CN106810452A (en) * | 2017-01-13 | 2017-06-09 | 华北水利水电大学 | A kind of preparation method of cinacalcet hydrochloride |
| CN106831441A (en) * | 2017-01-23 | 2017-06-13 | 江苏康思尔医药科技有限公司 | A kind of preparation method of cinacalcet hydrochloride |
| CN109096119A (en) * | 2018-10-29 | 2018-12-28 | 江苏永安制药有限公司 | A method of preparing cinacalcet hydrochloride |
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| CN111704551A (en) * | 2020-08-20 | 2020-09-25 | 天津汉一医药科技有限公司 | Preparation method of cinacalcet hydrochloride |
| CN111704551B (en) * | 2020-08-20 | 2020-11-20 | 天津汉一医药科技有限公司 | Preparation method of cinacalcet hydrochloride |
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