AU2018102140A4

AU2018102140A4 - Method for preparing sacubitril intermediate

Info

Publication number: AU2018102140A4
Application number: AU2018102140A
Authority: AU
Inventors: Shuang HUANG; Weisi LI; Siqing WU; Qiang Xu; Yi XUE; Jian Yang
Original assignee: JIANGSU ZHONGBANG PHARMACEUTICAL CO Ltd
Current assignee: Jiangsu Zhongbang Pharmaceutical Co ltd
Priority date: 2017-07-27
Filing date: 2018-05-31
Publication date: 2019-10-03
Anticipated expiration: 2026-05-31
Also published as: AU2018305416A1; CN107382779B; CN107382779A; WO2019019795A1

Abstract

Abstract The present invention discloses a synthetic method of an Entresto intermediate and belongs to the 5 field of chemical pharmacy. The synthetic method includes the following steps: reacting a starting material of glycine, with diterbutyl dicarbonate ester under an alkaline condition, performing dehydrogenation and amino protection, and performing substitution, deprotection and salt formation with a compound of a formula II in the presence of a chiral catalyst by virtue of a "one-pot process" to obtain a compound of a formula III having a chiral intermediate; reducing the 10 compound of the formula III, refining and salifying to obtain a compound of a formula IV, and performing amino protection on the compound of the formula IV and the diterbutyl dicarbonate ester, thereby obtaining a target product of a formula I, that is, (R)-tert-butyl-(1-([1,1'-biphenyl]-4-yl)-3-hydroxyl propane-2-yl) carbamate. According to the synthetic method of the Entresto intermediate provided by the present invention, needed raw 15 materials and reagents are readily available, reaction conditions are mild, total yield is high, cost is low, the refining involves only two salt processes, after-treatment operation is simple, and product quality is reliable and stable. The whole process is very suitable for industrial production.

Description

The present invention belongs to the field of chemical pharmacy, and particularly relates to a intermediate preparation process of an Entresto which is a key component in an anti-heart-failure drug of an Entresto combination drug.

Background Art

Entresto (formerly known as LCZ696) is a chronic heart failure drug researched and developed by Novartis, a Swiss pharmaceutical giant. The Entresto is used for treating NYHA II-IV level patients with heart failure, and acts on a neuroendocrine system of the heart in multiple manners. The drug is a remarkable breakthrough in the field of heart failure treatment over the past 25 years, and is expected to successfully shake an overall heart failure treatment framework unmodified over the past 10 years. The Entresto has been approved by FDA on July 23, 2015. At present, the Entresto is being reviewed by health management organizations all over the world including Canada, Switzerland and European Union. Once the Entresto is approved to be used for treating heart failure with low ejection fraction by the global health management organizations, sales volume of the Entresto is estimated to be expected to break through 5 billion dollars. A structural formula of the Entresto is as follows:

Patents for synthesis of a key intermediate (R)-tert-butyl-(l-([l,l'-biphenyl]-4-yl)-3-hydroxyl propane-2-yl) carbamate involved in a preparation process of Entresto mainly include a patent

2018102140 31 May 2018

WO2014032627 and a patent EP1903027. The synthetic method of the (R) -tert-butyl-(l-([l,l'-biphenyl]-4-yl)-3-hydroxyl propane-2-yl) carbamate disclosed in the patents WO2014032627 and EP1903027 mainly includes the following steps: taking 4-bromobiphenyl as a starting material, preparing the material into a Grignard reagent, and carrying out a condensation reaction with a raw material (S)-epoxy chloropropane or (S) -epoxy-tert-butyl ether to obtain a corresponding hydroxyl compound; carrying out a

Mitsunobu reaction on hydroxyl condensate and succinimide in the presence of diethyl azodicarboxylate/triphenylphosphine to perform configuration inversion so as to obtain an intermediate pyrrolidine-2,5-diketone; further removing amino protection groups of the intermediate in a concentrated acid, and performing nucleophilic substitution under an alkaline condition to obtain (R)-3-([l,l'-biphenyl]-4-yl)-2-aminopropyl-l-ol hydrochloride; and finally, performing amino protection on the salt and Boc anhydride, thereby obtaining the key intermediate (R)-tert-butyl-(l-([1,1'-biphenyl]-4-yl)-3-hydroxyl propane-2-yl) carbamate. The route is complicated in synthesis steps, a Grignard reaction is involved in the first reaction step, and since a reaction is suddenly initiated in an amplification process, the reaction is violent, and risk of scouring easily occurs. In addition, the triphenylphosphine is used in the second step; a large amount of phosphorus triphenyl oxide is produced in the system after reaction completion and is difficult to be removed, thereby influencing measurement in the next step, causing that usage of the Boc is difficult to be determined during amino protection and causing poor product quality of unreacted Boc anhydride in a residual part of the product. A specific synthetic route is as follows:

Summary of the Invention

The present invention overcomes defects in the prior art. By virtue of a novel process, a reaction route is shortened by adopting a “one-pot” process, after-treatment is simplified, total yield is high, and quality of a prepared product is excellent. The problem that the above method cannot be completely used for industrialization is solved.

2018102140 31 May 2018

Another purpose of the present invention provides a novel route of preparing (R)-tert-butyl-(l-([l,l'-biphenyl]-4-yl)-3-hydroxyl propane-2-yl) carbamate. The process includes the following steps:

HOOC

Note: Y is sulfate radical or halogen (1) reacting a starting material of glycine with diterbutyl dicarbonate ester under an alkaline condition, performing dehydrogenation and amino protection, performing substitution with a compound of a formula II in the presence of a chiral catalyst by virtue of a “one-pot process”, and performing deprotection with an acid to obtain a compound of a formula III having a chiral intermediate;

(2) reducing the compound of the formula III in presence of a reducing agent, refining and salifying in presence of a protonic acid to obtain a compound of a formula IV;

(3) performing amino protection on the compound of the formula IV and the diterbutyl dicarbonate ester at low temperature, thereby obtaining a target product of a formula I, that is, (R)-tert-butyl-(l-([l,l'-biphenyl]-4-yl)-3-hydroxyl propane-2-yl) carbamate.

HOOC

Note: Y is sulfate radical or halogen (1) reacting a starting material of glycine, with diterbutyl dicarbonate ester in a polar solvent under an alkaline condition, performing dehydrogenation and amino protection, performing substitution with a compound of a formula II in the presence of a chiral catalyst by virtue of a “one-pot process”, and performing deprotection to get the salt formatior under an acid condition to obtain a compound of a formula III after substitution, wherein the chiral catalyst is a compound

2018102140 31 May 2018

R-2-amino-2'-hydroxyl-1,1'-dinaphthalene of a formula V;

Ri isHorCl-C3 alkyl

V (2) reducing the compound of the formula III in presence of a reducing agent, refining and 5 salifying in presence of a strong protonic acid to obtain a compound of a formula IV;

(3) performing amino protection on the compound of the formula IV and the diterbutyl dicarbonate ester at a low temperature, thereby obtaining a target product, that is, [1,1 '-biphenyl]-4-yl)-1 -(hydroxymethyl)ethyl] tert-butyl carbamate.

In the step (1), the alkaline condition is selected from one of metal sodium, sodium hydroxide, 10 potassium hydroxide, sodium methylate, sodium ethoxide, sodium hydride, potassium tert-butoxide and sodium tert-butoxide.

In the step (1), the polar solvent is selected from one of methanol, ethanol, isopropanol, 1,4-dioxane and tetrahydrofuran.

In the step (1), Ri is one of hydrogen, methyl, ethyl, propyl and isopropyl.

In the step (1), a molar ratio of the chiral catalyst to the compound of the formula II is 0.3%-0.7%.

In the step (1), the acid is selected from one of hydrochloric acid (or gas), hydrobromic acid (or gas) and sulfuric acid for performing acid treatment, preferably hydrochloric acid.

In the step (2), the reducing agent is one of sodium borohydride, potassium borohydride and lithium aluminum tetrahydride.

In the step (2), the strong protonic acid is selected from one of hydrochloric acid, hydrobromic acid and sulfuric acid.

In the step (3), the reaction temperature of the compound of the formula IV and the diterbutyl dicarbonate ester is -10-10°C, preferably -5-5°C.

In the step (3), the reaction temperature of the compound of the formula IV and the diterbutyl 25 dicarbonate ester is -5-5 °C.

Beneficial Effects:

According to the synthetic method of an Entresto intermediate, that is, (R)-tert-butyl-(l-([l,l'-biphenyl]-4-yl)-3-hydroxyl propane-2-yl) carbamate provided by the present invention, needed raw materials and reagents are readily available, cost is relatively low, reaction steps are fewer, reaction conditions are mild, the refining involves only two salt processes, after-treatment operation is simple, and product quality is reliable and stable.

2018102140 31 May 2018

Compared with the prior art, the present invention has the advantages as follows: glycine and 4-bromomethylbiphenyl are subjected to chiral substitution by virtue of a chiral catalyst and then reduced, and an intermediate (R)-3-([l,l'-biphenyl]-4-yl)-2-aminopropyl-l-ol hydrochloride may be obtained in two steps; a conversion rate is high, total yield is 70%-80%, and complicated operation and low yield caused by too long route are avoided; and according to the salifying and refining methods of the obtained intermediate, the target product with stable quality may be obtained without refining, and the product is very suitable for industrial production of Entresto.

Brief Description of the Drawings

Figure 1 is a nuclear magnetism map of a compound I;

Figure 2 is a mass spectrum of the compound I; and Figure 3 is a map of related substances of the compound I.

Detailed Description of the Invention

Example 1

Preparation of (R)-3-([l,l'-biphenyl])-2-aminopropionic acid hydrochloride (III)

1000 g of methanol and 40.0 g of (l.Omol) sodium hydroxide were added into 3F of reaction flask, stirred at room temperature and dissolved to be clarified, then 37.6 g of (0.5mol) glycine and 109.2 g of (0.5mol) diterbutyl dicarbonate ester were added, the reflux time 3h at 65-75°C; the system was cooled down to a room temperature after completion of the reaction, 0.43 g of (1.5 mmol) (R)-(-)-2-amino-2'-hydroxy-l,l'-biphenyl was added, and a solution prepared from 123.6 g of (0.5mol) 4-bromomethylbiphenyl and 500 g of methanol was dropped while stirring; the solution was stirred at the room temperature for 2 h after dropping completion, and after completion of the reaction, as monitored by TEC ; the system was filtered, and the filtrate was filled into a clean reaction flask, HC1 gas was introduced into the system while stirring until pH of the system is 1.0-2.0, introduction of the hydrochloric acid gas was stopped, the system was continuously stirred at the room temperature for 1 -2 h, filtering was perfomed to get the filter cake, and a filter cake was dried, thereby obtaining 121.2 g of a white solid, wherein a value ee is 99.0%, HPEC = 99.0%, and molar yield is 87.3%.

Preparation of (R)-3-([l,l'-biphenyl])-2-aminopropanol hydrochloride (IV)

55.6 g of (0.2mol) (R)-3-([l,l'-biphenyl])-2-aminopropionic acid hydrochloride and 2E of tetrahydro furan were added into 3E of reaction flask, 20.3 g of (0.2mol) triethylamine was dropped at a room temperature, the system was stirred until the solid was completely dissolved to be clarified, cooled down to 0°C, stirred for 30 min and filtered, filtrate was cooled down to 0°C again under nitrogen protection, 11.4 g of (0.3mol) lithium aluminum tetrahydride was added in

2018102140 31 May 2018 batches after the temperature was stabilized, the system was heated to reflux after adding completion, the temperature was maintained and the system was reacted for 24 h, and after completion of the reaction, as monitored by TLC ; the system was cooled down to 0°C again, a solution prepared from 4 g of sodium hydroxide and 10 g of water was dropped after the temperature was stabilized, 10 g of water was added again after dropping completion, the system was heated to the room temperature, stirred for 1 h and filtered, the filtered was concentrated under reduced pressure to provide a residue, concentrated hydrochloric acid was added into the system to regulate a pH value to 1-2, the system was stirred at 5-10°C for 2-4 h and filtered, the filter cake was rinsed with a small amount of ethyl acetate and dried, thereby obtaining 46.7 g of a white solid, wherein HPLC = 99.0%, and yield is 88.5%.

Preparation of N-Noc-(R)-3-([l,l'-biphenyl])-2-aminopropanol (I)

1. 39.6 g of (0.15mol) (R)-3-([l,l'-biphenyl])-2-aminopropanol hydrochloride and a solution prepared from 9.0 g of (0.23mol) sodium hydroxide and 100 g of water were added into IL of reaction flask, the materials were stirred until the solid was white flocculus, the system was stirred for about 25 min, and cooled; a solution prepared from 36.0 g of (0.17mol) diterbutyl dicarbonate ester and lOOg of a di chloromethane solution was dropped at 0-5 °C; after dropping completion, react for 4h at a room temperature , after completion of the reaction, as monitored by TLC; the solution was separated,the dichloromethane layer was separated out, the water layer was extracted with 100 g of dichloromethane again, and the organic layer was merged; steaming was performed to remove lOOg of the organic layer under a reduced pressure, 100 g of n-heptane was added, stirred and crystallized at 0 °C, suction filtration was performed, the filter cake was rinsed with the n-heptane, and dried, thereby obtaining 45.7 g of a white solid, wherein a value ee is 99.7%, HPLC = 99.0%, and yield is 93.1%.

Example 2

500 g of ethanol and 34.0 g of (0.5mol) sodium ethoxide were added into 2L of reaction flask, and stirred at room temperature, 18.8 g of (0.25 mol) glycine and 54.6 g of (0.25 mol) diterbutyl dicarbonate ester were added, this mixture was heated to reflux for 3 hour at 75-85°C ;cooled down to after completion of the reaction,cool down to room temperature, 0.37 g of (1.25 mmol) (R)-(-)-2-aminomethyl-2'-hydroxy-l,l'-biphenyl was added, and a solution prepared from 61.8 g of (0.25 mol) 4-bromomethylbiphenyl and 200 g of ethanol was dropped while stirring; stirring was performed at the room temperature for 2 h after dropping completion, and after completion of the reaction, as monitored by TLC ; the system was filtered, and the filtrate was filled into a clean reaction flask, concentrated hydrochloric acid was introduced into the system while stirring until pH of the reaction solution was 1.0-2.0, the system was continuously stirred at the room temperature for 1-2 h, and filtered, and a filter cake was dried, thereby obtaining 62.8 g of a white

2018102140 31 May 2018 solid, wherein a value ee is 99.2%, HPLC = 99.0%, and molar yield is 90.5%.

Preparation of (R)-3-([l,l'-biphenyl])-2-aminopropanol sulfate (IV)

41.7 g of (0.15mol) (R)-3-([l,l'-biphenyl])-2-aminopropionic acid hydrochloride and 1.5L of tetrahydro furan were added into 2L of reaction flask, 15.2 g of (0.15mol) triethylamine was dropped at room temperature, stirring was performed until the solid was completely dissolved to be clarified, the system was cooled down to 0°C, stirred for 30 min and filtered, filtrate was cooled down to 0°C again under nitrogen protection, 8.5 g of (0.23mol) lithium aluminum tetrahydride was added in batches after the temperature was stabilized, the system was heated to reflux after adding completion, the temperature was maintained andreacted for 24h, and monitored by TLC until the raw materials are completely reacted; the system was cooled down to 0°C again, a solution prepared from 3.0 g of sodium hydroxide and 8 g of water was dropped after the temperature is stabilized, 8 g of water was added again after dropping completion, the system was heated to the room temperature, stirred for 1 h and filtered, rotary evaporation was performed on the filtrate under a reduced pressure to be dry, 50% of a sulfuric acid solution was added into the system, the PH was regulated to 1-2, the system was stirred at 5-10°C for 2-4 h and filtered, a filter cake was pulped with 100 g of water, and the filter cake was rinsed with a small amount of ethyl acetate after filtering, and dried, thereby obtaining 45.5 g of a white solid, wherein HPLC = 99.0%, and yield is 93.2%.

Preparation of N-Noc-(R)-3-([l,l'-biphenyl])-2-aminopropanol (I)

2. 32.5 g of (O.lmol) (R)-3-([l,l'-biphenyl])-2-aminopropanol sulfate and a solution prepared from 6.0 g of (0.15mol) sodium hydroxide and 70 g of water were added into IL of reaction flask, and stirred until the solid was white flocculus, the system was stirred for about 25 min, and cooled; a solution prepared from 24.0 g of (O.llmol) diterbutyl dicarbonate ester and 70g of a dichloromethane solution was dropped at 0-5°C; a reaction was carried out at room temperature for 4 h after dropping completion, after completion of the reaction, as monitored by TLC; the solution was separated, a dichloromethane layer was separated out, a water layer was extracted with 70 g of dichloromethane again, and the organic layer was merged;70g organic solvent was produced by vacuum distillation, 70 g of n-heptane was added, stirred and crystallized at 0 °C, suction filtration was performed, and the filter cake was rinsed with the n-heptane, and dried, thereby obtaining 30.3 g of a white solid, wherein a value ee is 99.7%,

HPLC 99.0%, and yield is 92.5%.

Example 3

Preparation of (R)-3-([l,l'-biphenyl])-2-aminopropionic acid sulfate (III)

600 g of tetrahydrofuran subjected to non-aqueous treatment and 36.0 g of (0.38 mol) sodium tert-butoxide were added into 2L of reaction flask, and stirred at room temperature, 18.8 g of (0.25 mol) glycine and 54.6 g of (0.25 mol) diterbutyl dicarbonate ester were added, the reflux time 1.5h at 65-75°C; the system was cooled down to a room temperature after reaction completion, 0.5 g of (1.75 mmol) (R)-(-)-2-amino-2'-hydroxy-l,l'-biphenyl was added, and a solution prepared from

2018102140 31 May 2018

61.8 g of (0.25 mol) 4-bromomethylbiphenyl and 200 g of ethanol was dropped while stirring; stirring was performed at the room temperature for 1.5 h after dropping completion, and after completion of the reaction, as monitored by TLC ; the system was filtered, and the filtrate was filled into a clean reaction flask, concentrated hydrochloric acid was introduced into the system while stirring until pH of the reaction solution was 1.0-2.0, the system was continuously stirred at the room temperature for 1-2 h, and filtered, and a filter cake was dried, thereby obtaining 79.9 g of a white solid, wherein a value ee is 99.5%, HPLC = 99.0%, and molar yield is 94.1 %. Preparation of (R)-3-([l,l'-biphenyl])-2-aminopropanol bromate (IV)

50.9 g of (0.15mol) (R)-3-([l,l'-biphenyl])-2-aminopropionic acid hydrochloride and 1.5L of 10 tetrahydro furan were added into a 2L of reaction flask, 15.2 g of (0.15mol) triethylamine was dropped at a room temperature, stirring was performed until the solid was completely dissolved to be clarified, the system was cooled down to 0°C, stirred for 30 min, and filtered, filtrate was cooled down to 0°C again under nitrogen protection, 12.4 g of (0.23mol) potassium borohydride was added in batches after the temperature was stabilized, the system was heated to reflux after adding completion, the temperature was maintained and a reaction was carried out for 24 h, and after completion of the reaction, as monitored by TLC ; the system was cooled down to 0°C again, a solution prepared from 3.0 g of (0.08 mol) sodium hydroxide and 8 g of water was dropped after the temperature was stabilized, 8 g of water was added again after dropping completion, the system was heated to the room temperature, stirred for 1 h, and filtered, rotary evaporation was performed on the filtrate under a reduced pressure to be dry, hydrogen bromide gas was introduced into the system, the PH was regulated to 1-2, the system was stirred at 5-10°C for 2-4 h, and filtered, and the filter cake was rinsed with a small amount of ethyl acetate, and dried, thereby obtaining 43.1 g of a light yellow solid, wherein HPLC = 99.0%, and yield is 93.2%.

Preparation of N-Noc-(R)-3-([l,l'-biphenyl])-2-aminopropanol (I)

3. 30.8 g of (O.lmol) (R)-3-([l,l'-biphenyl])-2-aminopropanol bromate and a solution prepared from 6.0 g of (0.15mol) sodium hydroxide and 70 g of water were added into a IL of reaction flask, and stirred until the solid was white flocculus, the system was stirred for about 25 min, and cooled; a solution prepared from 24.0 g of (O.llmol) diterbutyl dicarbonate ester and 70g of a dichloromethane solution was dropped at 0-5 °C; after dropping completion, react for 4h at a room temperature, after completion of the reaction, as monitored by TLC; the solution was separated, a di chloromethane layer was separated out, a water layer was extracted with 70 g of dichloromethane again, and the organic layer was merged; 70g organic solvent was produced by vacuum distillation, 70 g of n-heptane was added, stirred and crystallized at 0°C, suction filtration was performed, and the filter cake was rinsed with the n-heptane, and dried, thereby obtaining 29.3 g of a white solid, wherein a value ee is 99.8%, HPLC = 99.0%, and yield is 89.5%.

Claims

(1) reacting a starting material of glycine, with diterbutyl dicarbonate ester in a polar solvent under an alkaline condition, performing dehydrogenation and amino protection, performing substitution with a compound of a formula II in the presence of a chiral catalyst by virtue of a “one-pot process”, and performing deprotection and salt formation under an acid condition to obtain a compound of a formula III after substitution, wherein the chiral catalyst is a compound Ri-2-amino-2'-hydroxyl-l,l'-dinaphthalene of a formula V, and Ri is alkane of H or C1-C3;
2. The preparation method as recited in claim 1, wherein in the step (1), the alkaline condition is selected from one of metal sodium, sodium hydroxide, potassium hydroxide, sodium methylate, sodium ethoxide, sodium hydride, potassium tert-butoxide and sodium tert-butoxide.

20 3. The preparation method as recited in claim 1, wherein in the step (1), the polar solvent is selected from one of methanol, ethanol, isopropanol, 1,4-dioxane and tetrahydro furan.

(2) reducing the compound of the formula III in presence of a reducing agent, refining and salifying in presence of a strong protonic acid to obtain a compound of a formula IV;
(3) performing amino protection on the compound of the formula IV and the diterbutyl

15 dicarbonate ester at a low temperature, thereby obtaining a target product, that is, [l,r-biphenyl]-4-yl-l-(hydroxymethyl)ethyl] tert-butyl carbamate.
4. The preparation method according to claim 1, wherein in the step (1), Ri is one of hydrogen,

2018102140 31 May 2018 methyl, ethyl, propyl and isopropyl.
5 one of hydrochloric acid, hydrobromic acid and sulfuric acid for performing acid treatment.

5. The preparation method as recited in claim 1, wherein in the step (1), a molar ratio of the chiral catalyst to the compound of the formula II is 0.3%-0.7%.
6. The preparation method as recited in claim 1, wherein in the step (1), the acid is selected from
7. The preparation method as recited in claim 1, wherein in the step (2), the reducing agent is one of sodium borohydride, potassium borohydride and lithium aluminum tetrahydride.
8. The preparation method as recited in claim 11, wherein in the step (2), the strong protonic acid is selected from one of hydrochloric acid, hydrobromic acid and sulfuric acid.

10
9. The preparation method as recited in claim 1, wherein in the step (3), the reaction temperature of the compound of the formula IV and the diterbutyl dicarbonate ester is -10-10 °C.
10. The preparation method as recited in claim 9, wherein in the step (3), the reaction temperature of the compound of the formula IV and the diterbutyl dicarbonate ester is -5-5 °C.