A new method for synthesizing D-N-BOC-biphenylpropanol

Abstract

The present invention discloses a preparation method of a sacubitril intermediate, belonging to the field of pharmaceutical manufacturing. (R)-4-(Hydroxymethyl)oxazolidin-2-one reacts with sulfonyl chloride to generate (S)-(2-oxooxazolidin-4-yl)methyl 4-methylbenzenesulfonate, and the product then reacts with a Grignard reagent to obtain (R)-(2-oxooxazolidin-4-yl)methylbiphenyl, which is then hydrolyzed and BOC is introduced onto the amino group to obtain D-N-BOC-biphenylpropanol. This preparation method has a short route, mild reaction conditions, simple process operation, and is suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to a preparation method of sacubitril intermediate biphenylpropanol, belonging to the technical field of pharmaceutical synthesis. Background Art

[0002] Currently, there are still relatively few drugs available for the treatment of heart failure, and patients still face a high risk of death and poor quality of life. LCZ696 (trade name Entresto) is a dual-action angiotensin receptor neprilysin inhibitor developed by Novartis. It has a unique mode of action, combining Novartis' hypertension drug valsartan and the experimental drug neprilysin inhibitor sacubitril (AHU-377), and is considered to be able to reduce the strain of heart failure. Among them, sacubitril can block the mechanism of action of two polypeptides responsible for lowering blood pressure, and valsartan can improve vasodilation and stimulate the body to excrete sodium and water. Currently, LCZ696 has been approved for the treatment of heart failure patients with reduced ejection fraction, with significant efficacy and low side effects, and has broad market prospects.

[0003] D-N-BOC-biphenylpropanol is the key starting material for the synthesis of sacubitril valsartan sodium. Currently, the synthesis methods reported in the literature have problems such as long synthesis routes, the need for expensive chiral catalysts, or the use of flammable, explosive, and other materials, resulting in high costs and being not conducive to industrial production.

[0004] The literature (J.Med.Chem,1995,38,1689-1700) discloses a preparation method of D-N-BOC-biphenylpropanol, and its synthesis route is as follows:

[0005]

[0006] The raw material D-tyrosine of this route is expensive. The trifluoromethanesulfonic anhydride used in the reaction process is not only expensive but also highly corrosive, requiring high production operation requirements. The palladium catalyst used in the Suzuki coupling reaction step is also expensive. The entire synthesis route is relatively long, with a low overall yield and high costs.

[0007] Patent WO2014032627 discloses a preparation method of a sacubitril intermediate (D-N-BOC-biphenylpropanol), and its synthesis route is as follows:

[0008]

[0009] Although this route is shorter, the Mitsunobu reaction uses triphenylphosphine, and its by-product triphenylphosphine oxide is not easy to remove. Diethyl azodicarboxylate is sensitive to light, heat, and vibration, presenting certain safety risks.

[0010] Patent WO2013026773 discloses a preparation method of sacubitril intermediate (D-N-BOC-biphenylpropanol). First, using biphenylbenzaldehyde and N-benzoyl glycine as raw materials, the intermediate prepared under the condition of acetic anhydride is ring-opened with methanol. The obtained intermediate is catalytically asymmetric hydrogenated and reduced for the double bond by ruthenium catalyst and chiral monophosphorus ligand to obtain the enantiomeric intermediate, and then through catalytic hydrogenation reduction and Boc protection to obtain the final product. The synthetic route is as follows:

[0011]

[0012] This route uses rhodium catalyst and chiral ligand to catalytically reduce and construct the chiral center. This catalyst and chiral ligand are expensive and difficult to obtain, resulting in a relatively high synthesis cost of D-N-BOC-biphenylpropanol. Moreover, this reaction needs to be carried out under anhydrous and anaerobic conditions, and the reaction conditions are harsh, which is difficult to industrialize.

[0013] Patents CN101774941A and CN102482202B disclose that first, the racemate of N-acetylphenylalanine is synthesized, and then (R)-N-acetylphenylalanine is prepared through chiral resolution. This intermediate can be subsequently prepared into tert-butyl N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxy)ethyl]carbamate through a series of chemical reactions. The synthetic route is as follows:

[0014]

[0015] This method uses malonic acid derivative to prepare the racemate of N-acetylphenylalanine through heating decarboxylation reaction, and uses chiral resolving agent (S)-1-phenylethylamine for resolution to prepare (R)-N-acetylphenylalanine. The starting material malonic acid derivative of this process is difficult to prepare, the yield of the resolution reaction is low, and the resolution process usually makes the product of the other configuration unable to be utilized, or unable to be completely racemized and then utilized, resulting in an increase in the raw material cost of this intermediate, which is not suitable for industrial production. Summary of the Invention

[0016] Technical Problem: Aiming at the problems existing in the current prior art synthesis methods, such as long synthetic routes, or the need for expensive chiral catalysts, or the use of flammable and explosive materials, or high costs, which are not conducive to industrial production, or the use of chiral resolving agents resulting in cost increases, etc., the present invention proposes the following technical solutions to solve the problems.

[0017] Technical Solution

[0018] The synthesis method of D-N-BOC-biphenylpropanol of the present invention is as follows:

[0019] (R)-4-(Hydroxymethyl)oxazolidin-2-one reacts with p-toluenesulfonyl chloride to form (S)-(2-oxooxazolidin-4-yl)methyl 4-methylbenzenesulfonate;

[0020] ii The product of step i reacts with magnesium biphenyl bromide to obtain (R)-(2-oxooxazolidin-4-yl)methylbiphenyl;

[0021] iii The product of step ii is then hydrolyzed, and BOC is introduced onto the amino group to obtain D-N-BOC-biphenylpropanol;

[0022] This preparation method has a short route, mild reaction conditions, simple process operation, and is suitable for industrial production.

[0023]

[0024] Furthermore, in the first-step reaction of the reaction between (R)-4-(hydroxymethyl)oxazolidin-2-one and p-toluenesulfonyl chloride, the basic reagents DMAP and TEA are added;

[0025] Furthermore, the preparation method of magnesium biphenyl bromide is to heat the THF solution of magnesium powder to no more than 60 °C under nitrogen protection, add the THF solution of 4-bromobiphenyl, and after the reaction is initiated, add the remaining THF solution of 4-bromobiphenyl for reaction;

[0026] Even further, iodine is added to the reaction system when the reaction is initiated.

[0027] Furthermore, in the second-step reaction, the THF solution of (S)-(2-oxooxazolidin-4-yl)methyl 4-methylbenzenesulfonate is added to the THF solution of magnesium biphenyl bromide;

[0028] Even further, the reaction is carried out under low-temperature conditions, and the reaction temperature is -10 to -20 °C;

[0029] Even further, copper(I) iodide is added to the reaction system.

[0030] Furthermore, in the third-step reaction, the product obtained in the second step is dissolved in ethanol, and then hydrochloric acid is added for reflux. Subsequently, the system is cooled to room temperature, and NaOH solution and BOC anhydride are added;

[0031] Even further, after adding NaOH solution and BOC anhydride, the system is heated to 35 - 45 °C for heat preservation, then water is added and kept at 40 - 45 °C for heat preservation, and then cooled to 20 - 25 °C for heat preservation.

[0032] Technical effect: The sacubitril intermediate biphenylpropanol obtained by the technical solution of the present invention has a simple route, mild conditions, does not use strongly corrosive reagents, and does not use a chiral resolving agent in the synthesis of chiral intermediates. The yield of the final product reaches more than 90%, and no enantiomers are detected in the final product, saving costs, optimizing the process, and being suitable for industrial production. Embodiment

[0033] Abbreviation description of solvents used

[0034] DCM Dichloromethane; DMAP 4-Dimethylaminopyridine; MTBE Methyl tert-butyl ether

[0035] THF Tetrahydrofuran; Boc tert-Butyloxycarbonyl; (Boc)2O Di-tert-butyl dicarbonate

[0036] Step 1: Synthesis of (S)-(2-oxooxazolidin-4-yl)methyl 4-methylbenzenesulfonate

[0037] Add 25 g (R)-4-(hydroxymethyl)oxazolidin-2-one (0.21 mol) and 42.7 g p-toluenesulfonyl chloride (0.22 mol, 1.05 eq) to 500 mL DCM, add DMAP (1.3 g, 10.5 mmol, 0.05 eq) and TEA (19.2 g, 0.19 mol, 1.1 eq). Heat the reaction mixture to room temperature and stir overnight. Quench the reaction with water and extract twice with 150 mL DCM. Wash the organic layer twice with 1 N hydrochloric acid and concentrate the organic phase to dryness of DCM. Crystallize the residue with MTBE, filter and dry in vacuo to obtain 55.3 g of a white solid. Yield 97%, purity 99.6%.

[0038] Step 2: Synthesis of (R)-(2-oxooxazolidin-4-yl)methylbiphenyl Example

[0039] Add 100 ml of THF and 5.2 g (1.2 eq) of magnesium powder to a three-necked flask. At the same time, dissolve 49.0 g of p-bromobiphenyl in 100 ml of THF. Under nitrogen protection, heat the magnesium powder system to 35 - 50 °C. Add a small amount of iodine and 30 ml of the THF solution of 4-bromobiphenyl at 35 - 50 °C. After the reaction is initiated, add the remaining THF solution of 4-bromobiphenyl at 35 - 50 °C. After addition, keep the temperature for 4 h. Then cool the system to room temperature and add 4.2 g of copper(I) iodide. Then cool the system to -10 - -20 °C and add 200 ml of the THF solution containing 50.0 g of (S)-(2-oxooxazolidin-4-yl)methyl 4-methylbenzenesulfonate (0.18 mol). After addition, keep the temperature for 2 h. Pour the reaction system into 150.0 g of 4 M hydrochloric acid, stir, let stand, and separate the layers. Keep the organic phase. Concentrate the solvent of the organic phase under reduced pressure at 30 - 40 °C to obtain an off-white solid, which is directly used for the next step. Example

[0040] Add 100 ml of THF and 5.6 g (1.3 eq) of magnesium powder to a three-necked flask. At the same time, dissolve 49.0 g of p-bromobiphenyl in 100 ml of THF. Under nitrogen protection, heat the magnesium powder system to 50 - 60 °C. Add a small amount of iodine and 30 ml of the THF solution of 4-bromobiphenyl at 50 - 60 °C. After the reaction is initiated, add the remaining THF solution of 4-bromobiphenyl at 50 - 60 °C. After addition, keep the temperature for 4 h. Then cool the system to room temperature and add 5.1 g of copper(I) iodide. Then cool the system to -10 - -20 °C and add 200 ml of the THF solution containing 50.0 g of (S)-(2-oxooxazolidin-4-yl)methyl 4-methylbenzenesulfonate (0.18 mol). After addition, keep the temperature for 2 h. Pour the reaction system into 150.0 g of 4 M hydrochloric acid, stir, let stand, and separate the layers. Keep the organic phase. Concentrate the solvent of the organic phase under reduced pressure at 40 - 50 °C to obtain an off-white solid, which is directly used for the next step. Example

[0041] Add 100 ml of THF and 5.6 g (1.2 eq) of magnesium powder to a three-necked flask. At the same time, dissolve 49.0 g of p-bromobiphenyl in 100 ml of THF. Under nitrogen protection, heat the magnesium powder system to 45 - 55 °C. Add a small amount of iodine and 30 ml of the THF solution of 4-bromobiphenyl at 45 - 55 °C. After the reaction is initiated, add the remaining THF solution of 4-bromobiphenyl at 45 - 55 °C. After addition, keep the temperature for 4 h. Then cool the system to room temperature and add 4.8 g of copper(I) iodide. Cool the system to -20 - -30 °C again, and add 200 ml of the THF solution containing 50.0 g of (S)-(2-oxooxazolidin-4-yl)methyl 4-methylbenzenesulfonate (0.18 mol). After addition, keep the reaction at a constant temperature for 2 h. Pour the reaction system into 150.0 g of 4 M hydrochloric acid, stir, let it stand, and separate the layers. Retain the organic phase. Concentrate the solvent of the organic phase under reduced pressure at 40 - 50 °C to obtain an off-white solid, which is directly used in the next step.

[0042] Step 3: Synthesis of D-N-BOC-biphenylpropanol

[0043] Add 200 mL of ethanol to the product obtained in the second step, stir to dissolve, and then add 53.0 g of hydrochloric acid (0.45 mol). Heat the mixture to reflux for 4 h. Cool the system to room temperature. Dissolve 21.6 g of NaOH (0.54 mol) in 100.0 ml of water and add it to the system. Then dissolve 41.3 g of BOC anhydride (0.19 mol) in 100.0 ml of ethanol and add it to the system. Heat the system to 35 - 45 °C and keep the temperature for 2 h. Then add 300.0 ml of water and keep the temperature at 40 - 45 °C for 1 h, and then cool to 20 - 25 °C and keep the temperature for 1 h. Filter, and dry the solid at 60 - 70 °C to obtain 56.6 g of a white solid with a yield of 96%, an HPLC purity of 99.8%, and no enantiomers detected.

Claims

1. A preparation method of a sacubitril intermediate, characterized in that: i (R)-4-(Hydroxymethyl)oxazolidin-2-one reacts with p-toluenesulfonyl chloride to form (S)-(2-oxooxazolidin-4-yl)methyl 4-methylbenzenesulfonate; ii The product of step i reacts with magnesium biphenyl bromide to obtain (R)-(2-oxooxazolidin-4-yl)methylbiphenyl; iii The product of step ii is further hydrolyzed with hydrochloric acid, and BOC is introduced onto the amino group to obtain D-N-BOC-biphenylpropanol; 。 2. The preparation method according to claim 1, characterized in that The reaction temperature of step ii is -10~-20 °C.

3. The preparation method according to claim 1, characterized in that A THF solution of (S)-(2-oxooxazolidin-4-yl)methyl 4-methylbenzenesulfonate is added to a THF solution of magnesium biphenyl bromide for reaction.

4. The preparation method according to claim 3, wherein Copper(I) iodide is added to the reaction.

5. The preparation method according to claim 1, characterized in that In step iii, the product of step ii is dissolved in ethanol, hydrochloric acid is added and refluxed to obtain a hydrolysis product.

6. The preparation method according to claim 5, wherein The hydrolysis product is added to a NaOH solution and reacted with BOC anhydride.

7. The preparation method according to claim 6, characterized in that The reaction temperature is maintained at 35~45 °C for 2 h, water is added, and it is maintained at 40~45 °C for 1 h, and then cooled to 20~25 °C and maintained for 1 h.

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