WO2023029235A1

WO2023029235A1 - Method for preparing sacubitril intermediate

Info

Publication number: WO2023029235A1
Application number: PCT/CN2021/132938
Authority: WO
Inventors: 马保德; 郑勇鹏; 余弘毅; 赵金辉; 肖烨
Original assignee: 凯特立斯（深圳）科技有限公司
Priority date: 2021-09-03
Filing date: 2021-11-25
Publication date: 2023-03-09
Also published as: CN115745841A; CN115745841B

Abstract

The present invention belongs to the technical field of chemical synthesis and discloses a method for preparing a sacubitril intermediate. A key aza-tricyclic compound 5 is generated by using starting materials, chloramine-T trihydrate (formula 1) and an epoxypropane compound as shown in formula 2 which are simply and easily obtained, by means of a three-step reaction, then biphenyl is introduced by means of a Grignard reaction, then Ts on nitrogen is converted into a Boc group, and the preparation of the N-Boc amino alcohol compound of formula I can be completed. The whole method is simple to operate, safe and pollution-free, has no special requirements for equipment, has a low production cost, is suitable for industrial production, and has notable progress in comparison with the prior art.

Description

A kind of preparation method of sacubitril intermediate

technical field

The invention belongs to the field of medicinal chemical synthesis, and in particular relates to a preparation method of a sacubitril intermediate. The method has short steps, simple operation, low cost and great industrial application value.

Background technique

Sacubitril (AHU-377) is one of the main components of LCZ696 (CAS: 936623-90-4), an anti-heart failure drug developed by Novartis. The drug is a supramolecular complex (complex) formed by non-covalent bonding of valsartan and AHU-377, which has dual effects of angiotensin receptor blocking and neutral endopeptidase inhibition, and reduces cardiovascular The risk of disease, mainly used to treat heart failure, can also be used for high blood pressure.

Sacubitril (AHU-377) usually needs to be prepared through the key intermediate N-Boc amino alcohol (I). The chemical name of this intermediate is: N-[(1R)-2-[1,1'-biphenyl ]-4-yl-1-(hydroxymethyl)ethyl]tert-butyl carbamate; CAS: 1426129-50-1; Molecular formula: C20H25NO3; Molecular weight: 327.42; Structural formula:

In the prior art, there are many patent literature reports about the synthetic method of sacubitril intermediate N-Boc amino alcohol (I), but most of the reported methods have long synthetic routes, expensive reagents, and low enantiomeric ratios. , harsh process conditions, unfriendly environment, high preparation cost and other issues.

Patent WO2014032627 and patent EP1903027 disclose the preparation method of N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate tert-butyl ester, synthesis The route looks like this:

The main problems of this method are: using triphenylphosphine, a large amount of triphenoxyphosphine compounds are generated after the reaction, which makes separation and purification difficult; azodicarboxylate compounds are also used, and these compounds are sensitive to light, heat and vibration. Sensitive and potentially explosive when heated. These problems will lead to an increase in the overall production cost, as well as an increase in waste.

Similarly, Chinese patent CN 105985225 discloses a preparation method of an intermediate of Shakubiqu, which is as follows

This method is similar to the methods disclosed in patent WO2014/032627 and patent EP1903027, the main change is that the hydroxyl protecting agent is used instead of epichlorohydrin, the reaction process is basically similar, and the same reaction type uses basically the same reagents, the last step, due to The hydroxyl group is protected with a benzyl group, and additional palladium-catalyzed hydrogenolysis is required to remove the protecting group. Although the patent claims that the yield of N-Boc aminoalcohol has been improved, considering the cost of reagents, adding the noble metal catalytic hydrogenolysis step does not show obvious advantages in terms of cost.

Chinese patent CN 105884656 discloses a preparation method of Shakubiqu intermediate, as follows:

In this method, benzylmagnesium bromide is used as a raw material to react with monomethyl oxalyl chloride to generate the required methyl ketoate; then under the action of a brominating reagent, the 4-position of the benzene ring is brominated; Copper-catalyzed coupling with phenylboronic acid to obtain biphenone ester; in the system of glucose, NADP ⁺ and reductase CGKR2 and GDH, catalyzed asymmetric reductive amination of keto ester to obtain chiral amino acid methyl ester; After Boc protects the amino group, under the action of sodium borohydride and Lewis acid, the methyl carboxylate is reduced to alcohol to obtain the key intermediate N-Boc amino alcohol

The above-mentioned method, firstly, has the problem of a relatively long synthetic route, and secondly, it is inconvenient to use acid chloride and bromine reagent, and copper-catalyzed coupling and asymmetric reductive amination steps require the use of more metal copper and reductase; in addition, the patent The enantiomeric excess of the product after reductive amination is not indicated. Moreover, enzymes are expensive and have high requirements for reactions, so they are not suitable for industrial production.

The document J.Med.Chem.1995, 38, 1689-1700 reported a method for preparing an intermediate of sacubitril using D-tyrosine as a raw material. The synthetic route is as follows:

The D-tyrosine used in this method is a non-natural amino acid, which is expensive; the reaction process also uses an expensive trifluoromethanesulfonic anhydride reagent, and this reagent is very active and corrosive, and has high requirements for production equipment and operation. Good for industrial applications.

Chinese patent CN103764624 discloses a method for preparing sacubitril intermediate amino alcohol by using p-phenylbenzaldehyde as a raw material, and its synthetic route is as follows:

This method uses the precious metals Rh and Pd, resulting in high production costs; and the operation of lithium aluminum hydride is potentially dangerous

In summary, in the existing preparation methods, the preparation of chiral amino alcohol, the key intermediate of sacubitril, is limited by raw materials, reaction reagents, post-treatment processes, etc. Problems such as low enantiomer ratio and unfriendly environment lead to high production cost, cumbersome operation, and are not conducive to industrialization.

Therefore, the development of a simple, economical and industrialized production route is conducive to improving the industrialization of Shakubiqu.

Contents of the invention

Aiming at the problems existing in the prior art, the present invention aims to provide a simple and efficient method for preparing the intermediate of sacubitril. The method has the characteristics of low cost, easy operation, environmental friendliness and the like, and is suitable for industrialized production and the like.

In order to realize the purpose of the foregoing invention, the present invention implements through the following technical solutions:

A preparation method of a sacubitril intermediate, which relates to a preparation method of a sacubitril intermediate N-Boc amino alcohol (I), including steps a to f in the synthetic route:

In compound 2, X is a halogen, hydroxyl or protected hydroxyl; the activated reagent of hydroxyl is acid chloride, sulfonyl chloride, chlorosilane, etc.; the base (Base) is selected from sodium salt and potassium salt, and the acid (acid) is an inorganic acid.

Among them, the compound of formula 7, the compound of formula 8 and the compound of formula I are the intermediates of sacubitril required by the present invention.

The compound of formula 5 can be prepared by a step-by-step method, and can also be synthesized by a one-pot method.

As a preferred solution, the step a is to prepare the corresponding N-Ts amino alcohol (formula 3) from chloramine-T trihydrate (formula 1) and propylene oxide derivatives (formula 2) in a solvent.

As a further preferred solution, in step a, the X group in the propylene oxide derivative (Formula 2) is selected from chlorine, bromine, hydroxyl, siloxy, alkoxy, acyloxy, more preferably chlorine, hydroxyl , acyloxy and siloxy.

As a further preferred solution, in step a, the molar ratio of the propylene oxide derivative (Formula 2) to chloramine-T trihydrate (Formula 1) is 1-2:1, more preferably 1-1.2:1 .

As a further preferred solution, in step a, the reaction solvent is selected from tetrahydrofuran, dichloromethane, toluene, acetonitrile, N,N-dimethylformamide or solvent-free conditions, more preferably acetonitrile or solvent-free.

As a further preferred solution, in step a, the reaction temperature is selected from 0-100°C, more preferably 20-50°C, and still more preferably 25-37°C.

As a preferred solution, the step b is to use an activated reagent to activate the secondary alcohol on the N-Ts amino alcohol (Formula 3) in the presence of a base.

As a further preferred solution, in step b, the activated reagent is selected from sulfuryl chloride, chlorosilane and acid chloride, more preferably sulfuryl chloride, and even more preferably MsCl, TsCl and NsCl.

As a further preferred solution, in step b, the molar ratio of the activated reagent to the N-Ts amino alcohol (Formula 3) is 1 to 2:1, more preferably 1.0 to 1.2:1, and even more preferably 1.05- 1.15:1.

As a further preferred solution, in step b, the base is selected from triethylamine, trimethylamine, tri-n-butylamine, N,N-diethylpropylamine, N,N-diethylmethylamine, 2-ethoxy Any of ethylamine, N-isopropylethylenediamine, pyridine, piperidine, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert-butoxide One, more preferably triethylamine, N,N-diethylpropylamine, sodium hydroxide, potassium tert-butoxide, more preferably triethylamine, sodium hydroxide.

As a further preferred solution, in step b, the molar ratio of the base to the activated reagent (activated reagent) is 1-2:1, more preferably 1.05-1.3:1, still more preferably 1.1-1.2:1.

As a further preferred solution, in step b, the reaction temperature is selected from -20-60°C, more preferably -10-35°C, still more preferably -5-30°C.

As a further preferred solution, in step b, the reaction solvent is selected from tetrahydrofuran, dichloromethane, toluene, acetonitrile, N,N-dimethylformamide or solvent-free conditions, more preferably acetonitrile or solvent-free.

As a preferred scheme, the step c is to cyclize the compound of formula 4 under the action of a base to generate the compound of acridine formula 5.

As a further preferred version, in step c, the base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert-butoxide, bis(trimethyl Any one of silicon-based) lithium amide (LiHMDS), bis(trimethylsilyl) potassium amide (KHMDS), and lithium diisopropylamide (LDA), more preferably bis(trimethylsilyl) Any one of potassium amide (KHMDS), more preferably sodium hydroxide, potassium hydroxide or cesium carbonate.

As a further preferred solution, in step c, the molar ratio of the amount of base to the compound of formula 4 is 1-2:1, more preferably 1.0-1.2:1, and still more preferably 1.05-1.15:1.

As a further preferred solution, in step c, the reaction temperature is selected from -20-60°C, more preferably -10-35°C, still more preferably -5-30°C.

As a further preferred solution, in step c, the reaction solvent is selected from tetrahydrofuran, dichloromethane, toluene, acetonitrile, N,N-dimethylformamide or solvent-free conditions, more preferably acetonitrile or solvent-free.

As a preferred solution, in the step d, the compound of the formula 6 of the Grignard reagent performs nucleophilic addition to the compound of the formula 5 of the acridine to generate the compound of the formula 7.

As a further preferred solution, in step d, the molar ratio of the Grignard reagent formula 6 compound to the formula 5 compound is 1-2:1, more preferably 1-1.5:1, further preferably 1.05-1.20:1.

As a further preferred solution, in step d, the reaction temperature is selected from -20-100°C, more preferably -10-75°C, still more preferably -5-60°C.

As a further preferred solution, in step d, the reaction solvent is selected from any one of tetrahydrofuran, dichloromethane, toluene, acetonitrile, and N,N-dimethylformamide, more preferably tetrahydrofuran or toluene.

The base (Base) described in step c is selected from sodium hydroxide or potassium hydroxide.

As a further preferred solution, the solvent used in step d is THF, and the temperature is -30-10°C.

As a further preferred solution, the additive used in step d is cuprous iodide, and the added mass is 5%-25%.

As a preferred scheme, in the step e, the compound of formula 7 is removed from the Ts protecting group on the nitrogen under the action of acid to generate the compound of formula 8 amino alcohol.

As a further preferred version, in step e, the acid is selected from any one of hydrochloric acid, sulfuric acid, hydrobromic acid, nitric acid, phosphoric acid, acetic acid, perchloric acid, nitrous acid, hypochlorous acid, lactic acid, propionic acid, further Hydrochloric acid, sulfuric acid, hydrobromic acid are preferred.

As a further preferred solution, in step e, the amount of acid used is preferably 1-10 equivalents, more preferably 1-5 equivalents.

As a further preferred solution, in step e, the reaction is performed under heating reflux, ultrasonic or microwave conditions, more preferably heating reflux or microwave.

As a further preferred solution, in step e, the reaction solvent is selected from methanol, ethanol, isopropanol, toluene, acetonitrile, tetrahydrofuran, DMF, 1,4-dioxane or water, more preferably 1,4-dioxane ring or water.

As a preferred solution, in the step f, the amino alcohol compound of formula 8 reacts with Boc ₂ O in a base and a solvent to generate the N-Boc amino alcohol compound of formula I.

As a further preferred solution, in step f, the base is selected from any one of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide and lithium hydroxide, more preferably sodium hydroxide and potassium hydroxide.

As a further preferred solution, in step f, the molar ratio of Boc ₂ O to the compound of amino alcohol formula 8 is 1-2:1, more preferably 1.05-1.5:1, and even more preferably 1.05-1.15:1.

As a further preferred solution, in step f, the molar ratio of alkali to Boc ₂ O is 1-2:1, more preferably 1.05-1.20:1, and even more preferably 1.05-1.10:1.

As a further preferred solution, in step f, the reaction solvent is selected from methanol, ethanol, isopropanol, toluene, acetonitrile, tetrahydrofuran, DMF, 1,4-dioxane or water, more preferably methanol, 1,4-dioxane Oxyhexane, tetrahydrofuran

As a further preferred solution, in step f, the reaction temperature is selected from -20-55°C, more preferably -10-45°C, still more preferably -5-35°C.

The present invention also provides a novel intermediate compound: a compound 7 whose chemical structural formula is:

Wherein, X is halogen, hydroxyl or protected hydroxyl, preferably X is chlorine, bromine, hydroxyl, siloxy, alkoxy, acyloxy;

Further, preferably

Compared with the prior art, the present invention has the following advantageous effects:

In the present invention, the starting material chloramine-T trihydrate (formula 1) and the compound of propylene oxide formula 2 are easily and easily obtained, and the key aza three-membered ring compound 5 is generated through a three-step reaction, and then biphenyl is introduced through the Grignard reaction group, and then change the Ts on the nitrogen into a Boc group to complete the preparation of the N-Boc aminoalcohol formula I compound. The entire route is simple to operate, safe and pollution-free, has no special requirements for equipment, and has low production costs. It is suitable for industrial production and has significant progress compared with the existing technology.

Description of drawings

Fig. 1 is a schematic diagram of the synthetic route of the present invention;

Fig. 2 is the proton NMR spectrum collection of compounds 5a;

Fig. 3 is the proton NMR spectrum collection of compounds 7a;

Figure 4 is the H NMR spectrum of compound I.

Detailed ways

The technical solutions of the present invention will be described in further detail below according to the embodiments and drawings, but the present invention is not limited thereto.

With reference to the synthetic route of Fig. 1:

Embodiment 1: (R)-N-(3-chloro-2-hydroxypropyl)-4-methylbenzenesulfonamide (R)-N-(3-chloro-2-hydroxypropyl)-4-methylbenzenesulfonamide (formula 3a) Preparation

Compound 1 (14.1 g), (S)-epichlorohydrin 2 (4.32 mL), and acetonitrile (30 mL) were added to a round bottom flask (100 mL), heated to 50° C., and stirred for 24 hours. Cool to room temperature, add saturated aqueous sodium thiosulfate solution, extract with ethyl acetate (100mL), wash once with saturated sodium chloride, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain compound 3a with sufficient purity. The crude yield 98%

Example 2: (R)-1-chloro-3-((4-methylphenyl)sulfonylamino)propyl-2-yl methanesulfonate (R)-1-chloro-3-((4 -methylphenyl)sulfonamido)propan-2-yl methanesulfonate (formula 4a) preparation

Add 3a (10.6g), dichloromethane (30mL), and triethylamine (8.9mL) into a round bottom flask (100mL), cool to 0°C, add methanesulfonyl chloride (4.64mL) dropwise, and continue stirring for 10 hours. Add saturated aqueous sodium bicarbonate solution, dichloromethane (70mL), wash with saturated sodium chloride, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain compound 4a with sufficient purity. The crude yield is 97%.

Example 3: Preparation of (R)-2-(chloromethyl)-1-tosylaziridine (R)-2-(chloromethyl)-1-tosylaziridine (Formula 5a)

Add 4a (13.6g) and dichloromethane (50mL) to a round bottom flask (200mL), cool to 0°C, then add sodium hydroxide (2.6g), and continue stirring for 5 hours. Add water, dichloromethane (100 mL), wash with saturated sodium chloride, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain compound 5a with sufficient purity. The crude yield is 96%.

Tested: ¹ H NMR (400MHz, CDCl ₃ ) δ (ppm) 7.84 (d, J = 8Hz, ArH, 2H), 7.35 (d, J = 8Hz, ArH, 2H), 3.47 (ddd, J = 5.6, 7.6, 17.2, CH ₂ , 2H), 3.06 (ddd, J＝4.4, 6.4, 10.8, CH, 1H), 2.6 (d, J＝6.8Hz, CHH, 1H), 2.45 (s, CH ₃ , 3H) , 2.55 (d, J = 6.8 Hz, CHH, 1H).

The H NMR spectrum of compound 5a is shown in Figure 2.

Example 4: (R)-N-(1-([1,1'-biphenyl]-4-yl)-3-chloropropan-2-yl)-4-methylbenzenesulfonamide (R)- Preparation of N-(1-([1,1'-biphenyl]-4-yl)-3-chloropropan-2-yl)-4-methylbenzenesulfonamide (Formula 7a)

Add 4-phenylphenylmagnesium bromide (11.1g, formula 6) in tetrahydrofuran solution (60mL) in the round bottom flask (200mL), add 0.78g cuprous iodide, add formula 5a compound (10.0g) dropwise at room temperature A solution of tetrahydrofuran (20 mL) was added dropwise, the temperature was raised to 60° C., and stirring was continued for 5 hours. After cooling to room temperature, dilute hydrochloric acid was slowly added dropwise, followed by ethyl acetate (100 mL), washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 7a. Subsequently, purified by column chromatography, the pure product 7a could be obtained with a total yield of 70% in three steps.

Tested: ¹ H NMR (400MHz, CDCl ₃ ) δ (ppm) 7.05-7.65 (m, ArH, 15H), 4.86 (d, J = 8.4Hz, NH, 1H), 3.65-3.80 (m, CH, 1H ), 3.53 (ddd, J=5.2, 11.6, 16.4, CH ₂ , 2H), 2.94 (dd, J=7.2, 14.0Hz, CHH, 1H), 2.79 (dd, J=6.8, 14.0Hz, CHH, 1H ), 2.31 (s, CH ₃ , 3H).

The H NMR spectrum of compound 7a is shown in Figure 3.

Example 5: (R)-3-([1,1'-biphenyl]-4-yl)-2-aminopropan-1-ol (R)-3-([1,1'-biphenyl]- Preparation of 4-yl)-2-aminopropan-1-ol (Formula 8a)

Add compound 7a (10g) and hydrochloric acid (6M, 20mL) into a round bottom flask (100mL), heat to reflux overnight, use 1M sodium hydroxide solution to adjust the pH of the aqueous phase to 8-10, then extract with ethyl acetate and wash with saturated brine Once, dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain compound 8a with a yield of 90%

Example 6: tert-butyl(R)-(1-([1,1'-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamate tert-butyl(R)-(1 -([1,1'-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamate (formula I) preparation

Compound 8a (6.14g), tetrahydrofuran (20mL), sodium hydroxide (1.35g) were added to a round bottom flask (200mL), Boc ₂ O (6.78g) was added dropwise, and reacted overnight at room temperature. Extracted with ethyl acetate, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain compound 9 with a yield of 93%

Tested: ¹ H NMR (400MHz, CDCl ₃ ) δ (ppm) 7.0-7.8 (m, ArH, 9H), 4.8 (d, J = 6.4Hz, 1H), 3.5-3.7 (m, 2H), 2.88 ( d,J=6.0Hz,1H),2.40-2.45(br,OH,1H),1.42(s,9H).

The H NMR spectrum of compound I is shown in Figure 4.

Finally, it should be pointed out that: the above are only some preferred embodiments of the present invention, and should not be interpreted as limiting the protection scope of the present invention. After reading the above content of the present invention, those skilled in the art Some non-essential improvements and adjustments all belong to the protection scope of the present invention.

Claims

A method for preparing a Shakubiqu intermediate, characterized in that it comprises steps a to f:

Wherein, in compound 2, X is a halogen, hydroxyl or protected hydroxyl; the activated reagent of hydroxyl is acid chloride, sulfonyl chloride, chlorosilane, etc.; the base (Base) is selected from sodium salt and potassium salt, and the acid (acid) is an inorganic acid.
The preparation method according to claim 1, characterized in that X is chlorine, bromine, hydroxyl, siloxy, alkoxy, acyloxy, more preferably chlorine, hydroxyl, acyloxy and siloxy.
The preparation method according to claim 1, characterized in that the solvent used in step a is acetonitrile, tetrahydrofuran, N,N-dimethylformamide, preferably acetonitrile.
The preparation method according to claim 1, characterized in that the raw material 2 used in step a is preferably epichlorohydrin.
The preparation method according to claim 1, characterized in that, in step b, the hydroxyl activated reagent (activated reagent) is a sulfonyl chloride, selected from methanesulfonyl chloride, p-toluenesulfonyl chloride or p-nitrobenzenesulfonyl chloride.
The preparation method according to claim 1, wherein the base (Base) in step c is selected from sodium hydroxide or potassium hydroxide.
The preparation method according to claim 1, characterized in that the solvent used in step d is THF, and the temperature is -30-10°C.
The preparation method according to claim 1, characterized in that the additive used in step d is cuprous iodide, and the added mass is 5%-25%.
The preparation method according to claim 1, wherein the acid described in step e is hydrochloric acid, sulfuric acid, phosphoric acid, etc., preferably hydrochloric acid.
A compound 7, characterized in that the chemical structural formula is:

Wherein, X is halogen, hydroxyl or protected hydroxyl, preferably X is chlorine, bromine, hydroxyl, siloxy, alkoxy, acyloxy;

Further, preferably