Preparation method of atenol-d7

Abstract

The invention discloses a preparation method of atenol-d7, which comprises the following steps: (1) taking 2-(4-hydroxyphenyl) acetamide as a raw material, and condensing the 2-(4-hydroxyphenyl) acetamide with epoxy chloropropane to obtain 2-[4-(epoxy-2-methoxy) phenyl] acetamide; and (2) carrying out a reaction on the 2-[4-(epoxy-2-yl methoxy) phenyl] acetamide, acetone-d6 and sodium borodeuteride d4, so as to prepare atenol-d7. The atom utilization rate can be remarkably improved, and the production cost is greatly reduced.

Description

Technical Field

[0001] The invention relates to the technical field of deuterated drug synthesis, and in particular to a method for preparing atenolol-d7. Background Art

[0002] Atenolol, with the chemical formula C14H22N2O3, is a selective β1 adrenergic receptor blocker. Atenolol has a selective blocking effect on β1 receptors and has a low affinity for bronchial smooth muscle β2 receptors. A small dose can significantly reduce the animal's heart rate, cardiac contractility and cardiac output, and lower blood pressure. Atenolol has no intrinsic sympathomimetic activity and membrane stabilizing effect, and can reduce plasma renin activity and AGⅡ levels. It has no myocardial inhibitory effect, diffuses into the ciliary epithelium through the ciliary muscle, reduces aqueous humor production, and reduces intraocular pressure.

[0003] Atenolol is mainly used in the clinic to treat hypertension and heart diseases, such as angina pectoris, arrhythmia, myocardial infarction, and can also be used for hypertension, angina pectoris and glaucoma. Oral absorption is about 50%, and small doses can pass the blood-brain barrier. The protein binding rate is 6-10%. The effect reaches its peak 2 to 4 hours after taking it, and the duration of action is relatively long. The half-life is 6 to 7 hours, and it is mainly excreted in the urine in its original form. It can be cleared during hemodialysis.

[0004] The derivative atenolol-d7 obtained by deuterating the isopropyl group of the terminal isopropylamine can be used as an important tool for studying drug metabolism and pharmacokinetics. Its chemical structure is as follows: Its synthesis route has not been reported. If the synthesis method of atenolol is referred to for synthesis, the conventional scheme designed by the inventors in the early stage is: using 4-hydroxyphenylacetamide (also known as 2-(4-hydroxyphenyl)acetamide) as the starting material, atenolol-d7 can be obtained through alkylation and epoxy ring opening: The isopropylamine-d7 used in this synthesis step needs to be greatly excessive (greater than 20 equivalents), the atom utilization rate is low, and the isopropylamine-d7 that can be purchased is all hydrochloride, can not be directly used for reaction, need to be freed in advance, so cause its consumption to further increase. And the price of isopropylamine-d7 hydrochloride is very expensive, and the route cost is too high, need a kind of new method to synthesize atenolol-d7. Summary of the invention

[0005] The object of the present invention is to provide a method for preparing atenolol-d7, which can significantly improve the atomic utilization rate and greatly reduce the production cost.

[0006] The technical solution adopted by the present invention to solve its technical problem is: A preparation method of atenolol-d7 comprises the following steps: (1) 2-(4-hydroxyphenyl)acetamide is used as a raw material and condensed with epichlorohydrin to obtain 2-[4-(epoxy-2-ylmethoxy)phenyl]acetamide; (2) 2-[4-(epoxy-2-ylmethoxy)phenyl]acetamide, acetone-d6 and sodium borodeuteride-d4 are reacted to prepare atenolol-d7.

[0007] Compared with the previous scheme, the present invention uses deuterated acetone and sodium borodeuteride-d4 to synthesize terminal isopropylamine-d7. Compared with the use of isopropylamine-d7 hydrochloride (greater than 20 equivalents), the amount is reduced by about 7 times, and the atomic utilization rate is increased by about 4 times. At the same time, the prices of deuterated acetone and sodium borodeuteride-d4 are much lower than isopropylamine-d7, which significantly reduces the cost. Secondly, each step of the reaction can be purified by pulping, filtration, etc., which simplifies the post-processing, and the obtained product has high purity and is suitable for further scale-up.

[0008] Step (1) specifically comprises: taking the raw materials 2-(4-hydroxyphenyl)acetamide, epichlorohydrin, and alkaline substances, adding them to a solvent, heating to 40-70° C., reacting for 4-8 hours, and obtaining 2-[4-(epoxy-2-ylmethoxy)phenyl]acetamide after separation and purification. Specifically, separation and purification, for example, comprises: pouring the reaction solution into water, stirring to precipitate a solid, filtering it, and washing it with water for 2-3 times to obtain a solid, beating it with ethanol, and drying it to obtain purified 2-[4-(epoxy-2-ylmethoxy)phenyl]acetamide.

[0009] Preferably, the molar ratio of 2-(4-hydroxyphenyl)acetamide:epichlorohydrin:alkaline substance is 1:2-4:2-3.

[0010] Preferably, the alkaline substance is at least one of potassium carbonate and cesium carbonate.

[0011] Preferably, the solvent is at least one of N,N-dimethylformamide, acetone and acetonitrile.

[0012] Step (2) is specifically as follows: S21: dispersing 2-[4-(epoxy-2-ylmethoxy)phenyl]acetamide in an ammonia methanol solution, stirring for 15-18 hours, and separating and purifying to obtain an intermediate product; separation and purification, for example, includes concentration, ethanol slurrying, filtering solids, and drying to obtain 2-[4-(3-amino-2-hydroxypropoxy)phenyl]acetamide; S22: pretreating the intermediate product with deuterated methanol-d4; the purpose of the pretreatment is to increase the deuteration degree of the reaction product; S23: dissolving the pretreated intermediate product and acetone-d6 in deuterated methanol-d4, heating to 50-80° C. and stirring for 2-6 hours, then cooling the reaction solution to 0-5° C., adding sodium borodeuteride-d4, and reacting at room temperature for 1-3 hours; S24: quench the reaction, separate and purify to obtain atenolol-d7. The reaction solution can be quenched with heavy water, and the separation and purification includes, for example, concentrating the organic solvent, adding water to filter to remove the solid, extracting the mother liquor with dichloromethane / isopropanol, drying, and concentrating to obtain atenolol-d7.

[0013] Deuterated methanol-d4 is used as a solvent in S22 and S23 to increase the deuteration degree of the reaction product.

[0014] Preferably, the concentration of ammonia in the methanol solution is 7 mol / L. 15-30 L of ammonia methanol solution is added to 1 mol of 2-[4-(epoxy-2-ylmethoxy)phenyl]acetamide.

[0015] The pretreatment in S22 includes: dispersing the intermediate product in deuterated methanol-d4, heating to 60-80° C., stirring for 2-4 hours, and evaporating the solvent deuterated methanol-d4 by a rotary evaporator.

[0016] Preferably, the molar ratio of intermediate product: acetone-d6: sodium borodeuteride-d4 is 1:2-4:3-6.

[0017] The invention has the beneficial effects of significantly improving the atomic utilization rate and greatly reducing the production cost. According to the test, the purity of atenolol-d7 is greater than 99% and the deuteration degree is greater than 98%. DETAILED DESCRIPTION

[0018] The technical solution of the present invention is further described in detail below through specific embodiments.

[0019] In the present invention, unless otherwise specified, the raw materials and equipment used can be purchased from the market or are commonly used in the art. The methods in the following embodiments, unless otherwise specified, are all conventional methods in the art.

[0020] Example 1 A preparation method of atenolol-d7 comprises the following steps: S11: 2-(4-hydroxyphenyl)acetamide (purchased from Titan Corporation, ) (35 g, 231.54 mmol, 1.0 eq) was dissolved in N, N-dimethylformamide (240 mL), and epichlorohydrin (64.27 g, 694.62 mmol, 3.0 eq) and potassium carbonate (64 g, 463.08 mmol, 2.0 eq) were added. The reaction solution was heated to 60°C and stirred for 6 hours. The reaction was detected by LCMS and TLC, and the starting material disappeared.

[0021] S12: Pour the reaction solution into water (1.5 L), stir for 1 hour, filter the suspension, rinse the filter cake twice with water, and drain. Slurry the solid with ethanol (700 mL) for 30 minutes, filter the solid, and dry it to obtain the product 2-[4-(epoxy-2-ylmethoxy)phenyl]acetamide (28g, yield 58.35%).

[0022] 1 H NMR (400MHz, DMSO) δ7.38(s,1H),7.17(d,J=8.6Hz,2H),688(d,J=8.6Hz,2H),6.82(s,1H),4.27(dd,J=11.4,2.6Hz,1H),3. 79(dd,J=11.4,6.5Hz,1H),3.34–3.24(m,3H),2.83(t,J=4.8Hz,1H),2.69(dd,J=5.1,2.7Hz,1H).MS(ESI):m / z=207.9[M+H] + .

[0023] S21: Suspend 2-[4-(epoxy-2-ylmethoxy)phenyl]acetamide (3.7 g, 17.85 mmol, 1.0 eq) in 7 M ammonia methanol solution (400 mL) and stir for 15 h. Concentrate the reaction solution to dryness (water pump decompression, temperature 40 ° C, rotary evaporator to evaporate the solvent), slurry with ethanol (100 mL), and filter to obtain a solid. The solid is dried to obtain the product 2-[4-(3-amino-2-hydroxypropoxy)phenyl]acetamide (3.92 g, yield 98%).

[0024] 1 H NMR (400MHz, DMSO) δ7.39 (s, 1H), 7.15 (d, J = 8.4Hz, 2H), 6.89–6.77 (m, 3H), 3.92–3.87 (m, 1H), 3.85–3.80 (m, 1H), 3. 76–3.64(m,1H),3.28(s,2H),2.69(dd,J=12.6,4.4Hz,1H),2.57(dd,J=12.7,6.4Hz,1H).MS(ESI):m / z=224.9[M+H]+ .

[0025] S22: Dissolve 2-[4-(3-amino-2-hydroxypropoxy)phenyl]acetamide (0.7 g, 3.12 mmol, 1.0 eq) in deuterated methanol-d4 (30 mL), heat to 70°C, stir for 3 h, and then concentrate to dryness (evaporate the solvent on a rotary evaporator).

[0026] S23: Dissolve the pretreated 2-[4-(3-amino-2-hydroxypropoxy)phenyl]acetamide and acetone-d6 (0.60 g, 9.36 mmol, 3.0 eq) in deuterated methanol-d4 (26 mL) and stir at room temperature overnight. Then heat the reaction solution to 60°C and stir for 4 hours until the Schiff base is formed. Finally, cool the reaction solution to 4°C and add sodium borodeuteride-d4 (0.65 g, 15.60 mmol, 5.0 eq). The reaction solution is gradually heated to room temperature and reacted for 2 hours.

[0027] S24: The reaction solution was quenched with heavy water (1 mL), concentrated to remove methanol-d4, water (10 mL) was added, and the solid was removed by filtration. The filtrate was extracted with dichloromethane / isopropanol (dichloromethane / isopropanol = 10:1 volume ratio) (20 mL*3), dried over anhydrous sodium sulfate, and then concentrated on a rotary evaporator to obtain atenolol-d7 (480 mg, yield 56.5%) with a purity of >99% and a deuteration degree of >98%.

[0028] 1 H NMR(400MHz,MeOD)δ7.21(d,J=8.4Hz,2H),6.90(d,J=8.4Hz,2H),4.06(m,1H),3.95(d,J=5.2Hz,2H) ,3.43(s,2H),2.90(dd,J=12.1,3.4Hz,1H),2.72(dd,J=12.0,8.7Hz,1H).MS(ESI):m / z=274.2[M+H] + .

[0029] Embodiment 2-5 The present embodiment provides a method for preparing atenolol-d7. The preparation process thereof is as shown in Example 1, except that the amount of reactants and the control of various parameters are specifically shown in Table 1.

[0030] Table 1

[0031] Example 6 The difference between this embodiment and embodiment 1 is that 463.08 mmol of cesium carbonate replaces potassium carbonate in S11. The rest is the same as embodiment 1. Finally, atenolol-d7 is obtained with a purity of >99% and a deuteration degree of >98%.

[0032] Example 7 This embodiment is different from embodiment 1 in that acetone replaces N,N-dimethylformamide in S11. The rest is the same as embodiment 1. Finally, atenolol-d7 is obtained with a purity of >99% and a deuteration degree of >98%.

[0033] Example 8 The difference between this embodiment and embodiment 1 is that acetonitrile replaces N,N-dimethylformamide in S11. The rest is the same as embodiment 1. Finally, atenolol-d7 is obtained with a purity of >99% and a deuteration degree of >98%.

[0034] Example 9 The difference between this embodiment and embodiment 1 is that 15 L of ammonia methanol solution is added to 1 mol of 2-[4-(epoxy-2-ylmethoxy)phenyl]acetamide in S21. The rest is the same as embodiment 1. Finally, atenolol-d7 is obtained with a purity of >99% and a deuteration degree of >98%.

[0035] Example 10 The difference between this embodiment and embodiment 1 is that 30 L of ammonia methanol solution is added to 1 mol of 2-[4-(epoxy-2-ylmethoxy)phenyl]acetamide in S21. The rest is the same as embodiment 1. Finally, atenolol-d7 is obtained with a purity of >99% and a deuteration degree of >98%.

[0036] Comparative Example 1 The difference between this embodiment and embodiment 1 is that methanol is used instead of deuterated methanol-d4 in S22 and S23, and the rest is the same as embodiment 1. Finally, atenolol-d7 is obtained with a purity of >99% and a deuterated degree of about 65%.

[0037] The above-described embodiment is only a preferred solution of the present invention and does not limit the present invention in any form. There are other variations and modifications without exceeding the technical solution described in the claims.

Claims

1. A method for preparing atenolol-d7, characterized in that, The following steps are involved: (1) 2-(4-hydroxyphenyl)acetamide is used as a raw material and condensed with epichlorohydrin to obtain 2-[4-(epoxy-2-ylmethoxy)phenyl]acetamide; (2) 2-[4-(epoxy-2-ylmethoxy)phenyl]acetamide, acetone-d6 and sodium borodeuteride-d4 are reacted to prepare atenolol-d7.

2. The preparation method according to claim 1, characterized in that: Step (1) is specifically as follows: taking the raw materials 2-(4-hydroxyphenyl)acetamide, epichlorohydrin, and alkaline substances, adding them to a solvent, heating to 40-70° C., reacting for 4-8 hours, and separating and purifying to obtain 2-[4-(epoxy-2-ylmethoxy)phenyl]acetamide.

3. The preparation method according to claim 2, characterized in that: The molar ratio of 2-(4-hydroxyphenyl)acetamide:epichlorohydrin:alkaline substance=1:2-4:2-3.

4. The preparation method according to claim 2, characterized in that: The alkaline substance is at least one of potassium carbonate and cesium carbonate.

5. The preparation method according to claim 2, characterized in that: The solvent is at least one of N,N-dimethylformamide, acetone and acetonitrile.

6. The preparation method according to claim 1, characterized in that: Step (2) is specifically as follows: S21: dispersing 2-[4-(epoxy-2-ylmethoxy)phenyl]acetamide in an ammonia methanol solution, stirring for 15-18 hours, and separating and purifying to obtain an intermediate product; S22: pretreating the intermediate product using deuterated methanol-d4; S23: dissolving the intermediate product after pretreatment and acetone-d6 in deuterated methanol-d4, heating to 50-80°C and stirring for 2-6h, then cooling the reaction solution to 0-5°C, adding sodium borodeuteride-d4, and reacting at room temperature for 1-3h; S24: quench the reaction, separate and purify to obtain atenolol-d7.

7. The preparation method according to claim 6, characterized in that: In the ammonia methanol solution, the concentration of ammonia is 7 mol / L.

8. The preparation method according to claim 6, characterized in that: The pretreatment in S22 includes: dispersing the intermediate product in deuterated methanol-d4, heating to 60-80° C., stirring for 2-4 hours, and evaporating the solvent deuterated methanol-d4 by a rotary evaporator.

9. The preparation method according to claim 6, characterized in that: The molar ratio of intermediate product: acetone-d6: sodium borodeuteride-d4 = 1:2-4:3-6.

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