Preparation method of cinacalcet hydrochloride crystal form I

Abstract

The invention relates to the technical field of medicine preparation, and particularly discloses a preparation method of cinacalcet hydrochloride crystal form I. The preparation method comprises the following steps: taking 3-(3-trifluoromethylphenyl) propyl alcohol as a raw material, and synthesizing 3-(3-trifluoromethylphenyl) propionaldehyde by using an oxidizing agent through oxidation; the method comprises the following steps: catalyzing 3-(3-trifluoromethylphenyl) propionaldehyde by using a catalyst to carry out reductive amination reaction to generate cinacalcet; the preparation method comprises the following steps: synthesizing and preparing cinacalcet hydrochloride through a cinacalcet salt forming reaction; the cinacalcet hydrochloride crystal form I is prepared by mixing cinacalcet hydrochloride with a crystal transformation solvent, heating to reflux, cooling, filtering and drying. The method for preparing the cinacalcet hydrochloride crystal form I has the advantages of simple operation steps, low environmental pollution, few product impurities and high yield.

Description

Technical Field

[0001] The present invention relates to the technical field of drug preparation, and more specifically, to a method for preparing Cinacalcet hydrochloride crystal form I. Background Art

[0002] Cinacalcet hydrochloride (CINA) is the first calcium-sensitive receptor agonist approved by the U.S. Food and Drug Administration. It is mainly used to treat secondary hyperparathyroidism in patients with chronic kidney disease (CKD) undergoing maintenance dialysis. It acts on calcium receptors on the surface of parathyroid cells to inhibit the secretion of parathyroid hormone, thereby reducing the concentration of parathyroid hormone in serum and achieving the therapeutic purpose.

[0003] International Patent Publication No. WO2006 / 127933 characterizes the crystalline cinacalcet hydrochloride currently sold on the market as SensiparR as Form I (named Form I).

[0004] At present, there are four main methods for synthesizing Cinacalcet hydrochloride:

[0005] 1. (3-trifluoromethylphenyl) acrylic acid is used as a starting material, first reacted with ethyl chloroformate to generate an active ester, the active ester is then condensed with (R)-α-1-naphthylethylamine, and then subjected to Pd-C hydrogenation, borane reduction, and salt formation to obtain Cinacalcet hydrochloride. This method uses highly toxic and highly polluting ethyl chloroformate as an activator, and in the amide reduction process, a BH3-THF solution with high toxicity, poor stability, and high price is used, which is not suitable for industrial production.

[0006] 2. Using (3-trifluoromethylphenyl) acrolein and (R)-α-1-naphthylethylamine as starting materials, Cinacalcet hydrochloride is obtained by reduction amination, hydrogenation, and salt formation. The starting material (3-trifluoromethylphenyl) acrolein of this method has poor stability and is difficult to purify and preserve. In addition, the highly toxic sodium cyanoborohydride is used in the reduction amination process, which is not suitable for industrial production.

[0007] 3. Using 3-trifluoromethyl iodobenzene as the starting material, the intermediate (3-trifluoromethylphenyl) propargyl alcohol is obtained by Heck reaction, which is then activated by hydroxyl and condensed with (R)-α-1-naphthylethylamine, and then reduced and salified to obtain Cinacalcet hydrochloride. The raw materials and catalyst Pd(OAc)2 of this method are expensive, and there are many side reactions during the Heck reaction, which is difficult to separate and purify, and is not conducive to industrial production.

[0008] 4. Using (3-trifluoromethylphenyl) propionic acid as the starting material, after carboxyl activation, condensation with (R)-α-1-naphthylethylamine, and then reduction with borane, salification to obtain Cinacalcet hydrochloride. This method uses borane as a strong reducing agent, which may cause a violent reaction during the reduction process and requires strict control of the reaction conditions. In addition, borane is highly toxic and has high safety requirements for the production environment and operators, and is also not suitable for industrial production.

[0009] Based on the above statements, the present invention provides a method for preparing Cinacalcet Hydrochloride Form I. Summary of the invention

[0010] In order to solve the problems encountered in the current synthesis process of Cinacalcet Hydrochloride Form I, such as expensive materials, high toxicity, many side reactions, and difficulty in product separation and purification, the present invention provides a method for preparing Cinacalcet Hydrochloride Form I.

[0011] The present invention provides a method for preparing Cinacalcet Hydrochloride Form I, which adopts the following technical scheme:

[0012] A method for preparing Cinacalcet hydrochloride crystal form I comprises the following steps:

[0013] S1, using 3-(3-trifluoromethylphenyl)propanol as a raw material, using an oxidant to oxidize and synthesize 3-(3-trifluoromethylphenyl)propanal;

[0014] S2, using a catalyst to catalyze the reductive amination reaction of 3-(3-trifluoromethylphenyl)propanal to generate cinacalcet;

[0015] S3, synthesizing and preparing Cinacalcet hydrochloride through a Cinacalcet salt-forming reaction;

[0016] S4. Mix Cinacalcet hydrochloride with a crystal conversion solvent, raise the temperature to reflux, cool, filter, and dry to obtain Cinacalcet hydrochloride Form I.

[0017] Preferably, the oxidant in step S1 is a TEMPO / NaClO combination.

[0018] Preferably, the catalyst in step S2 is a NaBH4 / Fe(OTf)3 combination.

[0019] Preferably, the crystallization solvent in step S4 is isopropyl ether.

[0020] Preferably, the specific method of step S1 is: in an ice-water bath, dissolve 1 part of 3-(3-trifluoromethylphenyl)propanol in 15-25 parts of dichloromethane, add 0.5-1 parts of TEMPO and 1-2 parts of NaClO, stir and react for 20-40 minutes, add 0.5-1 parts of triethylamine, stir for 1-3 hours, add 3-8 parts of 5% HCl solution, separate the organic layer, wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate to obtain colorless oily 3-(3-trifluoromethylphenyl)propanal.

[0021] Preferably, the specific method of step S2 is: dissolving 1 part of 3-(3-trifluoromethylphenyl)propanal in 24-32 parts of dichloromethane, adding 0.5-1 parts of (R)-1-naphthylethylamine, 0.1-0.3 parts of NaBH4 and 0.01-0.03 parts of Fe(OTf)3, stirring at room temperature for 5-15 minutes, and then adding 13-18 parts of methanol. After the reaction is complete, the solvent is evaporated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a light yellow oily substance, Cinacalcet.

[0022] Preferably, the specific method of step S3 is: dissolving 1 part of cinacalcet in 2-3 parts of isopropanol, adding 4-12 parts of concentrated hydrochloric acid, heating under reflux and stirring for 1-3 hours, stopping heating, cooling to 40-50°C, adding 60-100 parts of water under stirring, stirring for 1-3 hours, filtering, washing the filter cake with water, and drying at 80-100°C for 4-6 hours to obtain cinacalcet hydrochloride.

[0023] Preferably, the specific method of step S4 is: 1 part of cinacalcet hydrochloride and 8-12 parts of isopropyl ether are heated to reflux, maintained for 4-6 hours, cooled to room temperature, filtered, the filter cake is washed with 0.3-0.6 parts of isopropyl ether, and vacuum dried at 40-60° C. to constant weight to obtain cinacalcet hydrochloride form I.

[0024] In summary, the present invention has the following beneficial effects:

[0025] 1. In the prior art, the oxidant used in the process of oxidizing 3-(3-trifluoromethylphenyl)propanol to 3-(3-trifluoromethylphenyl)propanal has the disadvantages of harsh reaction conditions, slow reaction speed, low product yield, etc., while the present invention uses a TEMPO / NaClO combination as an oxidant, with mild reaction conditions, fast reaction speed and high yield.

[0026] 2. Compared with the prior art, the present invention simplifies the operation steps, reduces the use of toxic reagents in the synthesis process, and does not produce toxic gases during the preparation process, thereby reducing environmental pollution. The product has a low impurity content, a high product yield, and is easy to purify. DETAILED DESCRIPTION

[0027] The present invention is further described in detail below with reference to the embodiments.

[0028] Example 1-3 provides a method for preparing Cinacalcet Hydrochloride Form I.

[0029] Example 1

[0030] A method for preparing Cinacalcet hydrochloride crystal form I comprises the following steps:

[0031] S1: Under an ice-water bath, dissolve 1 part of 3-(3-trifluoromethylphenyl)propanol in 15 parts of dichloromethane, add 0.5 parts of TEMPO and 1 part of NaClO, stir and react for 20 minutes, add 0.5 parts of triethylamine, stir for 1 hour, then add 3 parts of 5% HCl solution, separate the organic layer, wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate to obtain colorless oily 3-(3-trifluoromethylphenyl)propanal.

[0032] S2: Dissolve 1 part of 3-(3-trifluoromethylphenyl)propanal in 24 parts of dichloromethane, add 0.5 parts of (R)-1-naphthylethylamine, 0.1 parts of NaBH4 and 0.01 parts of Fe(OTf)3, stir at room temperature for 5 minutes, then add 13 parts of methanol. After the reaction is complete, evaporate the solvent, wash with saturated brine, dry with anhydrous sodium sulfate, filter and concentrate to obtain Cinacalcet as a light yellow oil.

[0033] S3: Dissolve 1 part of cinacalcet in 2 parts of isopropanol, add 4 parts of concentrated hydrochloric acid, heat under reflux and stir for 1 hour, then stop heating, cool to 40°C, add 60 parts of water with stirring, stir for 1 hour, filter, rinse the filter cake with water, and dry at 80°C for 4 hours to obtain cinacalcet hydrochloride.

[0034] S4: 1 part of Cinacalcet hydrochloride and 8 parts of isopropyl ether were heated to reflux, maintained for 4 hours, cooled to room temperature, filtered, the filter cake was washed with 0.3 parts of isopropyl ether, and vacuum dried at 40° C. to constant weight to obtain Cinacalcet hydrochloride Form I.

[0035] Example 2

[0036] A method for preparing Cinacalcet hydrochloride crystal form I comprises the following steps:

[0037] S1: Under an ice-water bath, dissolve 1 part of 3-(3-trifluoromethylphenyl)propanol in 20 parts of dichloromethane, add 0.75 parts of TEMPO and 1.5 parts of NaClO, stir and react for 30 minutes, add 0.75 parts of triethylamine, stir for 2 hours, then add 5.5 parts of 5% HCl solution, separate the organic layer, wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate to obtain colorless oily 3-(3-trifluoromethylphenyl)propanal.

[0038] S2: Dissolve 1 part of 3-(3-trifluoromethylphenyl)propanal in 28 parts of dichloromethane, add 0.75 parts of (R)-1-naphthylethylamine, 0.2 parts of NaBH4 and 0.02 parts of Fe(OTf)3, stir at room temperature for 10 minutes, then add 16 parts of methanol. After the reaction is complete, evaporate the solvent, wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate to obtain Cinacalcet as a light yellow oil.

[0039] S3: Dissolve 1 part of cinacalcet in 2.5 parts of isopropanol, add 8 parts of concentrated hydrochloric acid, heat under reflux and stir for 2 hours, then stop heating, cool to 45°C, add 80 parts of water with stirring, stir for 2 hours, filter, rinse the filter cake with water, and dry at 90°C for 5 hours to obtain cinacalcet hydrochloride.

[0040] S4: 1 part of Cinacalcet hydrochloride and 10 parts of isopropyl ether were heated to reflux, maintained for 5 hours, cooled to room temperature, filtered, the filter cake was washed with 0.45 parts of isopropyl ether, and vacuum dried at 50° C. to constant weight to obtain Cinacalcet hydrochloride Form I.

[0041] Example 3

[0042] A method for preparing Cinacalcet hydrochloride crystal form I comprises the following steps:

[0043] S1: Under an ice-water bath, dissolve 1 part of 3-(3-trifluoromethylphenyl)propanol in 25 parts of dichloromethane, add 1 part of TEMPO and 2 parts of NaClO, stir and react for 40 minutes, add 1 part of triethylamine, stir for 3 hours, add 8 parts of 5% HCl solution, separate the organic layer, wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate to obtain colorless oily 3-(3-trifluoromethylphenyl)propanal.

[0044] S2: Dissolve 1 part of 3-(3-trifluoromethylphenyl)propanal in 32 parts of dichloromethane, add 1 part of (R)-1-naphthylethylamine, 0.3 parts of NaBH4 and 0.03 parts of Fe(OTf)3, stir at room temperature for 15 minutes, then add 18 parts of methanol. After the reaction is complete, evaporate the solvent, wash with saturated brine, dry with anhydrous sodium sulfate, filter and concentrate to obtain Cinacalcet as a light yellow oil.

[0045] S3: Dissolve 1 part of cinacalcet in 3 parts of isopropanol, add 12 parts of concentrated hydrochloric acid, heat under reflux and stir for 3 hours, then stop heating, cool to 50°C, add 100 parts of water with stirring, stir for 3 hours, filter, rinse the filter cake with water, and dry at 100°C for 6 hours to obtain cinacalcet hydrochloride.

[0046] S4: 1 part of Cinacalcet hydrochloride and 12 parts of isopropyl ether were heated to reflux, maintained for 6 hours, cooled to room temperature, filtered, the filter cake was washed with 0.6 parts of isopropyl ether, and vacuum dried at 60° C. to constant weight to obtain Cinacalcet hydrochloride Form I.

[0047] In order to verify the comprehensive performance of the preparation method of Cinacalcet Hydrochloride Form I prepared in Examples 1-3 of the present invention, the applicant set up Comparative Examples 1-3, which are as follows:

[0048] Comparative Example 1

[0049] A method for preparing Cinacalcet hydrochloride crystal form I comprises the following steps:

[0050] S1: Dissolve 1 part of DMSO in 20 parts of dichloromethane solution to obtain solution A, dissolve 0.8 parts of oxalyl chloride in 20 parts of dichloromethane solution to obtain solution B, and dissolve 1 part of 3-(3-trifluoromethylphenyl)propanol in 20 parts of dichloromethane solution to obtain solution C. Under -78°C, add solution A dropwise to solution B, stir the reaction for 0.5h, then add solution C dropwise, and continue stirring the reaction for 2h. Add 0.5 parts of triethylamine, stir for 0.5h, slowly warm to room temperature, add water dropwise, and quench the reaction. After separating the organic layer, wash with saturated sodium chloride solution and dry with sodium sulfate. Filter and concentrate to obtain colorless oily 3-(3-trifluoromethylphenyl)propanal.

[0051] S2: Dissolve 1 part of 3-(3-trifluoromethylphenyl)propanal in 24 parts of dichloromethane, add 0.5 parts of (R)-1-naphthylethylamine, 0.1 parts of NaBH4 and 0.01 parts of Fe(OTf)3, stir at room temperature for 5 minutes, then add 13 parts of methanol. After the reaction is complete, evaporate the solvent, wash with saturated brine, dry with anhydrous sodium sulfate, filter and concentrate to obtain Cinacalcet as a light yellow oil.

[0052] S3: Dissolve 1 part of cinacalcet in 2 parts of isopropanol, add 4 parts of concentrated hydrochloric acid, heat under reflux and stir for 1 hour, then stop heating, cool to 40°C, add 60 parts of water with stirring, stir for 1 hour, filter, rinse the filter cake with water, and dry at 80°C for 4 hours to obtain cinacalcet hydrochloride.

[0053] S4: 1 part of Cinacalcet hydrochloride and 8 parts of isopropyl ether were heated to reflux, maintained for 4 hours, cooled to room temperature, filtered, the filter cake was washed with 0.3 parts of isopropyl ether, and vacuum dried at 40° C. to constant weight to obtain Cinacalcet hydrochloride Form I.

[0054] Comparative Example 2

[0055] A method for preparing Cinacalcet hydrochloride crystal form I comprises the following steps:

[0056] S1: Under room temperature, 1 part of 3-(3-trifluoromethylphenyl)propanol was dissolved in 15 parts of dichloromethane, 2 parts of PCC were added, and the mixture was stirred for 8 hours. The mixture was filtered through diatomaceous earth, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain colorless oily 3-(3-trifluoromethylphenyl)propanal.

[0057] S2: Dissolve 1 part of 3-(3-trifluoromethylphenyl)propanal in 24 parts of dichloromethane, add 0.5 parts of (R)-1-naphthylethylamine, 0.1 parts of NaBH4 and 0.01 parts of Fe(OTf)3, stir at room temperature for 5 minutes, then add 13 parts of methanol. After the reaction is complete, evaporate the solvent, wash with saturated brine, dry with anhydrous sodium sulfate, filter and concentrate to obtain Cinacalcet as a light yellow oil.

[0058] S3: Dissolve 1 part of cinacalcet in 2 parts of isopropanol, add 4 parts of concentrated hydrochloric acid, heat under reflux and stir for 1 hour, then stop heating, cool to 40°C, add 60 parts of water with stirring, stir for 1 hour, filter, rinse the filter cake with water, and dry at 80°C for 4 hours to obtain cinacalcet hydrochloride.

[0059] S4: 1 part of Cinacalcet hydrochloride and 8 parts of isopropyl ether were heated to reflux, maintained for 4 hours, cooled to room temperature, filtered, the filter cake was washed with 0.3 parts of isopropyl ether, and vacuum dried at 40° C. to constant weight to obtain Cinacalcet hydrochloride Form I.

[0060] Comparative Example 3

[0061] A method for preparing Cinacalcet hydrochloride crystal form I comprises the following steps:

[0062] S1: Under room temperature, dissolve 1 part of 3-(3-trifluoromethylphenyl)propanol in 15 parts of dichloromethane, add 4 parts of Dess-Martin oxidant, stir and react for 6 hours, add 3 parts of 5% HCl solution, separate the organic layer, wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate to obtain colorless oily 3-(3-trifluoromethylphenyl)propanal.

[0063] S2: Dissolve 1 part of 3-(3-trifluoromethylphenyl)propanal in 24 parts of dichloromethane, add 0.5 parts of (R)-1-naphthylethylamine, 0.1 parts of NaBH4 and 0.01 parts of Fe(OTf)3, stir at room temperature for 5 minutes, then add 13 parts of methanol. After the reaction is complete, evaporate the solvent, wash with saturated brine, dry with anhydrous sodium sulfate, filter and concentrate to obtain Cinacalcet as a light yellow oil.

[0064] S3: Dissolve 1 part of cinacalcet in 2 parts of isopropanol, add 4 parts of concentrated hydrochloric acid, heat under reflux and stir for 1 hour, then stop heating, cool to 40°C, add 60 parts of water with stirring, stir for 1 hour, filter, rinse the filter cake with water, and dry at 80°C for 4 hours to obtain cinacalcet hydrochloride.

[0065] S4: 1 part of Cinacalcet hydrochloride and 8 parts of isopropyl ether were heated to reflux, maintained for 4 hours, cooled to room temperature, filtered, the filter cake was washed with 0.3 parts of isopropyl ether, and vacuum dried at 40° C. to constant weight to obtain Cinacalcet hydrochloride Form I.

[0066] Performance Testing

[0067] The comprehensive properties of Cinacalcet Hydrochloride Form I prepared in Examples 1-3 of the present invention and Comparative Examples 1-3 were tested respectively.

[0068] Oxidants Reaction temperature Reaction time Yield Comparative Example 1 DMSO / oxalyl chloride -78℃ 2.5h 85％ Comparative Example 2 PCC Room temperature 8h 38％ Comparative Example 3 Dess-Martin Room temperature 6h 57％ Example 2 TEMPO / NaClO Ice water bath 0.5h 97％

[0069] In the prior art, Swen oxidation (DMSO / oxalyl chloride), PCC oxidation, and Martin oxidation are generally used. The yield of Swen oxidation (DMSO / oxalyl chloride) is high, but the reaction conditions are harsh and require low temperature conditions, which is not suitable for industrial production; the yield of PCC oxidation is low and is not environmentally friendly; the yield of Martin oxidation is average, but the reagent price is high and the production cost is high. The present invention uses a TEMPO / NaClO combination as an oxidant to oxidize 3-(3-trifluoromethylphenyl)propanol to 3-(3-trifluoromethylphenyl)propanal. The reaction conditions are mild, the reaction rate is fastest, and the yield is highest.

[0070] This specific embodiment is merely an explanation of the present invention and is not a limitation of the present invention. After reading this specification, those skilled in the art may make non-creative modifications to the present embodiment as needed. However, as long as they are within the scope of the claims of the present invention, they are protected by the patent law.

Claims

1. A method for preparing Cinacalcet Hydrochloride Form I, characterized in that: The steps include: S1, using 3-(3-trifluoromethylphenyl)propanol as a raw material, using an oxidant to oxidize and synthesize 3-(3-trifluoromethylphenyl)propanal; S2, using a catalyst to catalyze the reductive amination reaction of 3-(3-trifluoromethylphenyl)propanal to generate cinacalcet; S3, synthesizing and preparing Cinacalcet hydrochloride through a Cinacalcet salt-forming reaction; S4. Mix Cinacalcet hydrochloride with a crystal conversion solvent, raise the temperature to reflux, cool, filter, and dry to obtain Cinacalcet hydrochloride Form I.

2. The method for preparing Cinacalcet Hydrochloride Form I according to claim 1, characterized in that: In step S1, the oxidant is a TEMPO / NaClO combination.

3. The method for preparing Cinacalcet Hydrochloride Form I according to claim 1, characterized in that: The catalyst in step S2 is a NaBH4 / Fe(OTf)3 combination.

4. The method for preparing Cinacalcet Hydrochloride Form I according to claim 1, characterized in that: The crystallization solvent in step S4 is isopropyl ether.

5. The method for preparing Cinacalcet Hydrochloride Form I according to claim 1, characterized in that: The specific method of step S1 is as follows: in an ice-water bath, dissolve 1 part of 3-(3-trifluoromethylphenyl)propanol in 15-25 parts of dichloromethane, add 0.5-1 parts of TEMPO and 1-2 parts of NaClO, stir and react for 20-40 minutes, add 0.5-1 parts of triethylamine, stir for 1-3 hours, add 3-8 parts of 5% HCl solution, separate the organic layer, wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate to obtain colorless oily 3-(3-trifluoromethylphenyl)propanal.

6. The method for preparing Cinacalcet Hydrochloride Form I according to claim 1, characterized in that: The specific method of step S2 is: dissolving 1 part of 3-(3-trifluoromethylphenyl)propanal in 24-32 parts of dichloromethane, adding 0.5-1 parts of (R)-1-naphthylethylamine, 0.1-0.3 parts of NaBH4 and 0.01-0.03 parts of Fe(OTf)3, stirring at room temperature for 5-15 minutes, and then adding 13-18 parts of methanol. After the reaction is complete, the solvent is evaporated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a light yellow oily substance, Cinacalcet.

7. The method for preparing Cinacalcet Hydrochloride Form I according to claim 1, characterized in that: The specific method of step S3 is: dissolving 1 part of cinacalcet in 2-3 parts of isopropanol, adding 4-12 parts of concentrated hydrochloric acid, heating under reflux and stirring for 1-3 hours, stopping heating, cooling to 40-50° C., adding 60-100 parts of water under stirring, stirring for 1-3 hours, filtering, washing the filter cake with water, and drying at 80-100° C. for 4-6 hours to obtain cinacalcet hydrochloride.

8. The method for preparing Cinacalcet Hydrochloride Form I according to claim 1, characterized in that: The specific method of step S4 is: 1 part of cinacalcet hydrochloride and 8-12 parts of isopropyl ether are heated to reflux, maintained for 4-6 hours, cooled to room temperature, filtered, the filter cake is washed with 0.3-0.6 parts of isopropyl ether, and vacuum dried at 40-60℃ to constant weight to obtain cinacalcet hydrochloride form I.