Preparation method of impurities in key intermediate of alendronate sodium

Abstract

The invention discloses a preparation method of impurities in an alendronate sodium key intermediate, other derivative impurities, the impurities in the intermediate and the derivative impurities thereof can be generated in the alendronate sodium synthesis process, and the impurities and the derivative impurities thereof are difficult to remove in the reaction post-treatment process, so that research, preparation and control are necessary. The preparation method of the impurity in the intermediate comprises the following steps: adding a polar reagent as a solvent into a reactor containing gamma-4-aminobutyric acid, selecting organic alkali, and selecting R1-as a compound A protecting group and R2-as a compound B protecting group; and after the reaction of the compound A and the compound B is completed, removing the protecting group through strong acid, removing the solvent, and crystallizing and purifying through methanol / water to obtain the impurities in the alendronate sodium intermediate. The impurity provided by the invention is a necessity for quality research and control of an alendronate sodium intermediate and a finished product, and can be used as a reference substance of related substances in analysis method development and daily detection, and quantitative detection of the impurity has important significance for process optimization.

Description

TECHNICAL FIELD

[0002] The application belongs to the field of chemical pharmacy, and particularly relates to a preparation method of an impurity in a key intermediate of alendronate sodium. BACKGROUND

[0004] 4-aminobutyric acid is a key intermediate for synthesizing alendronate sodium. Alendronate sodium is developed by Merck & Co. and is the first bisphosphonate drug approved by FDA for treating postmenopausal osteoporosis and the first drug approved by FDA for treating male osteoporosis. Alendronate sodium tablets were first marketed on FDA on September 29, 1995, and the trade name is Fosamax + , (US5019651A) alendronate sodium synthesis route as follows:

[0005]

[0006] Currently, 4-aminobutyric acid is mainly produced in two ways: 1) biological fermentation; and 2) 2-pyrrolidone synthesis. The second method is adopted to synthesize 4-aminobutyric acid, and it is found in experiments that an impurity exists. The theoretical molecular weight of the target impurity is 188.23, and the compound prepared in experiments is detected by LC-MS, as shown in the figure. In the spectrum, [M-1] = 187.13, the signal response is strong, and it is confirmed that it is the target impurity. The impurity compound ii has similar chemical properties to compound i, so in the process of synthesizing alendronate sodium from compound i, compound ii will also produce new stubborn impurities, which are very difficult to remove.

[0007] STRUCTURE INFORMATION

[0008]

[0009] The above compound i and compound ii are similar in structure, and it is difficult to separate and purify them. In addition, the subsequent research of the impurity brings difficulties. Finally, the impurity compound ii produces stubborn impurities that are difficult to remove in the synthesis of alendronate sodium. Therefore, it is necessary to research, prepare and control the impurity compound ii. SUMMARY

[0011] The purpose of the present application is to provide a preparation method of an impurity in a key intermediate of alendronate sodium to solve the problems in the background art.

[0012] A preparation method of an impurity in a key intermediate of alendronate sodium, wherein the impurity is 4-(4-aminobutyramide) butyric acid, i.e. the above compound ii, and the preparation method is as follows

[0013] 1) 4-aminobutyric acid as raw material, in a polar organic reagent with R1 protecting group to get compound A

[0014] 2) 4-aminobutyric acid as raw material, in a polar organic reagent with R2 protecting group to get compound B

[0015] 3) compound A as raw material, in a polar solvent with compound B

[0016] 4) through strong acid to remove R1 protection, R2 protection to get compound ii

[0017] The above four-step reaction process is as follows:

[0018]

[0019] The present application in the synthesis of compound ii, no other impurities, no need for subsequent separation, improve the product yield.

[0020] The present application provides the impurity is alendronate sodium intermediate and finished product quality research and control of the necessary, in the analysis method development and daily testing can be used as the reference substance of related substances, its quantitative detection has important significance for process optimization. BRIEF DESCRIPTION OF DRAWINGS

[0022] Figure 1 The HPLC spectrum of the impurity compound ii;

[0023] Figure 2 The MS spectrum of the impurity compound ii produced in the synthesis of 2-pyrrolidone 4-aminobutyric acid. DETAILED DESCRIPTION

[0025] The present application is further described below in conjunction with specific examples

[0026] In order to make the technical means, creative characteristics, achieve the purpose of the invention easy to understand, the following through specific examples of the technical scheme of the present application is further described, but not limited the scope of the present application. For the convenience of description, the following examples omit the necessary conventional technical conditions, such as feeding mode, material weighing. Omit the technical conditions are conventional or technical personnel easy to know.

[0027] It should be noted that the present application relates to the substance cas number information as follows:

[0028] DCM: 75-09-2

[0029] DMF: 68-12-2

[0030] THF: 203-726-8

[0031] TEA:121-44-8

[0032] DBU:6674-22-2

[0033] DIPEA:7087-68-5

[0034] Boc2O:246-240-1

[0035] FmocCl:249-313-6

[0036] CbzCl:501-53-1

[0037] PMBCl:212-540-6

[0038] TBDPSCl:261-282-0

[0039] TBSCl:18162-48-6

[0040] Tol:108-88-3

[0041] HCl:7647-01-0

[0042] HBr: 10035-10-6

[0043] Example 1

[0044] The synthesis route is as follows:

[0045] Synthesis of compound A: 5.00 g (48.49 mmol, 1.0 eq) of 4-aminobutyric acid was added to 25 ml (5V) of DCM. The mixture was stirred until it was evenly dispersed. The temperature was controlled at 20-30℃. 5.29 g (24.25 mmol, 0.5 eq) of Boc2O and 4.90 g (48.49 mmol, 1.0 eq) of TEA were added. The mixture was heated to reflux and reacted for 4-12 h. After the reaction was completed, 25 ml of water was added. The mixture was separated and the organic phase was concentrated to obtain 7.97 g of off-white powder solid compound A, with a yield of 81% and an HPLC purity of 98.17%.

[0046] Synthesis of Compound B: 5.00 g (48.49 mmol, 1.0 eq) of 4-aminobutyric acid was added to 25 ml (5V) of methanol. The mixture was stirred until it was evenly dispersed. The mixture was heated to reflux for 4-12 h. After the reaction was completed, the mixture was filtered and the filtrate was concentrated to obtain 4.48 g of Compound B, with a yield of 79% and an HPLC purity of 97.43%.

[0047] Synthesis of impurity compound ii: take 5.00 g (24.63 mmol, 1.0 eq) of compound A, take 2.88 g (24.63 mmol, 1.0 eq) of compound B, add 25 ml of purified water, uniformly disperse the system, reflux reaction stirring for 12-16 h, cool to room temperature, add 5.61 g (49.26 mmol, 2.0 eq) of trifluoroacetic acid, stir at room temperature for 2-4 h, the reaction is completed, concentrate, and crystallize with methanol / water to obtain 3.47 g of impurity compound ii, with a yield of 75% and a purity of 99.10%.

[0048] Example 2

[0049] The synthesis route is as follows:

[0050] Synthesis of compound A: take 4-aminobutyric acid 5.00 g (48.49 mmol, 1.0 eq), add DCM 25 ml (5V), stir until the system is uniformly dispersed, control the temperature at 20-30°C, add PMBCl 7.59 g 48.49 mmol, 1.0 eq), add DIPEA 6.26 g (48.49 mmol, 1.0 eq), warm up to reflux reaction for 4-12 h, the reaction is completed, add 25 ml of water, separate the liquid, and the organic phase is concentrated to obtain 8.99 g of white powder solid compound A, with a yield of 83% and an HPLC purity of 98.32%.

[0051] Synthesis of compound B: take 4-aminobutyric acid 5.00 g (48.49 mmol, 1.0 eq), add methanol 25 ml (5V), stir until the system is uniformly dispersed, warm up to reflux reaction for 4-12 h, the reaction is completed, filter, and concentrate the filtrate to obtain 4.48 g of compound B, with a yield of 79% and an HPLC purity of 97.43%.

[0052] Synthesis of impurity compound ii: take 5.00 g (24.63 mmol, 1.0 eq) of compound A, take 2.88 g (24.63 mmol, 1.0 eq) of compound B, add 25 ml of purified water, uniformly disperse the system, reflux reaction stirring for 12-16 h, cool to room temperature, add 5.61 g (49.26 mmol, 2.0 eq) of trifluoroacetic acid, stir at room temperature for 2-4 h, the reaction is completed, concentrate, and crystallize with methanol / water to obtain 3.47 g of impurity compound ii, with a yield of 75% and a purity of 99.10%.

[0053] Example 3

[0054] The synthesis route is as follows:

[0055] Synthesis of compound A: Take 4-aminobutyric acid 5.00 g (48.49 mmol, 1.0 eq), add DCM 25 ml (5V), stir until the system is uniformly dispersed, control the temperature at 20-30°C, add Boc2O 5.29 g (24.25 mmol, 0.5 eq), add DIPEA 6.26 g (48.49 mmol, 1.0 eq), warm up to reflux for 4-12 h, the reaction is completed, add 25 ml water, separate the liquid, and the organic phase is concentrated to obtain 8.17 g of white powder solid compound A with a yield of 83% and an HPLC purity of 98.08%.

[0056] Synthesis of compound B: Take 4-aminobutyric acid 5.00 g (48.49 mmol, 1.0 eq), add THF 25 ml (5V), stir until the system is uniformly dispersed, add TBSCl 7.31 g (48.49 mmol, 1.0 eq), warm up to reflux for 4-12 h, the reaction is completed, filter, and the filtrate is concentrated to obtain 8.85 g of compound B with a yield of 84% and an HPLC purity of 98.24%.

[0057] Synthesis of impurity compound ii: Take 5.00 g (24.63 mmol, 1.0 eq) of compound A, take 5.35 g (24.63 mmol, 1.0 eq) of compound B, add THF 25 ml, disperse the system uniformly, reflux and stir for 12-16 h, cool to room temperature, add concentrated hydrochloric acid 5.66 g (24.63 mmol, 2.3 eq), stir at room temperature for 2-4 h, the reaction is completed, concentrate, and crystallize with methanol / water to obtain 3.41 g of impurity compound ii with a yield of 81% and a purity of 98.61%.

[0058] Example 4

[0059] The synthesis route is as follows:

[0060] Synthesis of compound A: Take 4-aminobutyric acid 5.00 g (48.49 mmol, 1.0 eq), add DCM 25 ml (5V), stir until the system is uniformly dispersed, control the temperature at 20-30°C, add Boc2O 5.29 g (24.25 mmol, 0.5 eq), add DBU 7.38 g (48.49 mmol, 1.0 eq), warm up to reflux for 4-12 h, the reaction is completed, add 25 ml water, separate the liquid, and the organic phase is concentrated to obtain 8.46 g of white powder solid compound A with a yield of 86% and an HPLC purity of 98.27%.

[0061] Synthesis of compound B: take 4-amino butyric acid 5.00g (48.49mmol, 1.0eq), add THF 25ml (5V), stir until the system is uniformly dispersed, add TBDPSCl 13.33g (48.49mmol, 1.0eq), warm to reflux for 4-12h, filter after the reaction is completed, concentrate the filtrate to obtain 8.20g of compound B, the yield is 84%, the HPLC purity is 98.16%.

[0062] Synthesis of impurity compound ii: take 5.00g (24.63mmol, 1.0eq) of compound A, take 8.41g (24.63mmol, 1.0eq) of compound B, add THF 25ml, uniformly disperse the system, reflux and stir for 12-16h, cool to room temperature, add concentrated hydrochloric acid 6.99g (68.96mmol, 2.8eq), stir at room temperature for 2h-4h, the reaction is completed, concentrate, crystallize with methanol / water to obtain 3.70g of impurity compound ii, the yield is 88%, the purity is 98.54%.

[0063] The present application solves the problems of difficult purification and separation of compound ii when synthesizing impurity compound ii, and provides convenience for impurity research. Finally, through research, preparation and control of compound ii, the derived impurities in the synthesis of alendronate sodium are easy to research, prepare and control.

[0064] The present application has been described by specific examples. Those skilled in the art can change the feeding ratio and other process conditions according to the content of the present application to achieve corresponding other purposes. The related changes do not deviate from the content of the present application, all the similar replacements and changes are obvious to those skilled in the art, and are considered to be included in the scope of the present application.

Claims

1. A method for preparing impurities in sodium alendronate key intermediate, the structural formula of the impurities is shown as formula II, characterized in that: comprising the following steps: adding a polar reagent as a solvent to a reactor containing γ-4-aminobutyric acid, adding an organic base; selecting R1- as a protective group of compound A and R2- as a protective group of compound B; after mixing all raw materials, performing a heating stirring reaction, and after the reaction is completed, removing the protective groups by a strong acid or hydrogen, and removing the solvent to obtain a product; subjecting the product obtained in step (3) to crystallization, and then to a drying step to obtain refined impurities 1 in sodium alendronate key intermediate. The polar solvent in step 1) is selected from DCM (dichloromethane), DMF (N,N-dimethylformamide), ACN (acetonitrile), and THF (tetrahydrofuran).

2. A process for the preparation of impurities in sodium alendronate key intermediates as claimed in claim 1, wherein: The organic base in step 1) is TEA, DBU, or DIPEA.

3. A process for the preparation of impurities in sodium alendronate key intermediates as claimed in claim 1, wherein: In step 2), R1- as a protective group is Boc2O, Fmoc-Cl, Cbz-Cl, or PMB-Cl.

4. A process for the preparation of impurities in sodium alendronate key intermediates as claimed in claim 1, wherein: In step 2), R2- as a protective group is CH3OH, TBDPSCl, or TBSCl.

5. A process for the preparation of impurities in sodium alendronate key intermediates as claimed in claim 1, wherein the process comprises: In step 3), the strong acid for removing the protective groups is HBr (hydrobromic acid), HCl (concentrated hydrochloric acid), or TFA (trifluoroacetic acid).

6. A process for the preparation of impurities in sodium alendronate key intermediates as claimed in claim 1, wherein the process comprises: The crystallization solvent is methanol / water, ethanol / water, or isopropanol / water.

7. A process for the preparation of impurities in sodium alendronate key intermediates as claimed in claim 1, wherein the process comprises: The volume ratio of the solvent to the raw materials in step 1) is 1:1 to 10:

1.

8. A process for the preparation of impurities in sodium alendronate key intermediates as claimed in claim 1, wherein the process comprises: In step 3), the parameters are as follows: the heating temperature is 40-100°C; the stirring time is 2-4h; and the equivalent of the strong acid is 1.0-5.0 eq.

9. A process for the preparation of sodium alendronate key intermediate according to claim 1, characterized by:

10. Use of the impurities in sodium alendronate key intermediate obtained by the preparation method in any one of claims 1-9 as a control for related substances of sodium alendronate key intermediate and finished products. ​

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