Sacubitril

Sacubitril, AHU 377

NEPRILYSIN INHIBITOR

FOR HEART FAILURE

CAS 149709-62-6

CAS SODIUM SALT 149690-05-1

(2R,4S)-5-(biphenyl-4-yl)-4-((3-carboxypropionyl)amino)-2-methylpentanoic acid ethyl ester

5-(Biphenyl-4-yl)-4(S)-(3-carboxypropionamido)-2(R)-methylbutyric acid ethyl ester

N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2R-methyl butanoic acid ethyl ester

[1,1′-Biphenyl]-4-pentanoic acid, γ-[(3-carboxy-1-oxopropyl)amino]-α-methyl-, α-ethyl ester, (αR,γS)-

• [1,1′-Biphenyl]-4-pentanoic acid, γ-[(3-carboxy-1-oxopropyl)amino]-α-methyl-, ethyl ester, [S-(R*,S*)]-
• (2R,4S)-4-[(3-Carboxy-1-oxopropyl)amino]-4-[(p-phenylphenyl)methyl]-2-methylbutanoic acid ethyl ester
• (2R,4S)-5-(Biphenyl-4-yl)-4-[(3-carboxypropionyl)amino]-2-methylpentanoic acid ethyl ester

• Formula	C24H29NO5
  MW	411.49 g/mol

AHU377; AHU-377; Sacubitril; 149709-62-6; UNII-17ERJ0MKGI; Alpha-ethyl (alphaR,gammaS)-gamma-<(3-carboxy-1-oxopropyl)amino>-alpha-methyl<1,1′-biphenyl>-4-pentanoate

Sacubitril sodium
149690-05-1

Sacubitril is an antihypertensive drug used in combination with valsartan. The combination drug, valsartan/sacubitril, known during trials as LCZ696 and marketed under the brand name, Entresto, is a treatment for heart failure.^[1] It was approved under the FDA’spriority review process for use in heart failure on July 7, 2015.

Mechanism of action

Sacubitril is a prodrug that is activated to LBQ657 by de-ethylation via esterases.^[2] LBQ657 inhibits the enzyme neprilysin,^[3] which is responsible for the degradation of atrial and brain natriuretic peptide, two blood pressure lowering peptides that work mainly by reducing blood volume.^[4]

SYNTHESIS

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SYNTHESIS

WO-2008031567

http://www.google.com/patents/WO2008031567A1?cl=en

the following steps:

and optionally the following additional steps:

Example 1 :

(E)-(R)-5-biphenyl-4-yl-4-fert-butoxycarbonylamino-2-methylpent-2-enoic acid

(E)-(R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpent-2-enoic acid ethyl ester (CAS# 149709-59-1) is hydrolysed using lithium hydroxide in ethanol to yield (£)-(f?)-5-biphenyl-4-yl-4-te/t-butoxycarbonylamino-2-methylpent-2-enoic acid as a white solid. δ_H (400 MHz; DMSO) 1.31 (9H₁ s, (CH₃J₃), 1.59 (3H, s, 1- CH₃), 2.68 (1H, dd, J 6.8, 13.2, 5-H_A), 2.86 (1H, m, 5-H_B), 4.44 (1H, m, 4-H), 6.51 (1H₁ d, J 9.2, 3-H), 7.16 (1H, d, J 8.0, NH), 7.26 (2H, d, J 8.0, Ar-ortho- H(Ph)), 7.31 (1H, t, J 7.6, Ar-(Ph)-para-H), 7.40 (2H, t, J 8.0, Ar-(Ph)-metø-H), 7.54 (2H, d, J 8.0, Ar-mefa-H(Ph), 7.60 (2H, d, J 7.6, Ar-(Ph)-ort/vo-H), 12.26 (1H, s, CO₂H); m/z (+ESI) 404 ([MNa]⁺, 17%), 382 ([MHf, 2), 326 (10), 264 (100), 167 (13).

Example 2:

(2/?,4S)-5-biphenyl-4-yl-4-fert-butoxycarbonylamino-2-methylpentanoic acid in crystalline form [2(i-a)]

2(i-a) To a suspension of (E)-(f?)-5-biphenyl-4-yl-4-te/t-butoxycarbonylamino-2- methylpent-2-enoic acid [2(ii-a)] (200 g, 524.3 mmol) in degassed ethanol (900 ml) at 40 °C a solution of diiodo(p-cymene)ruthenium(ll) dimer (0.052 g, 0.0524 mmol) and (αf?,αf?)-2,2^>-bis(α-Λ/,Λ/-dimethylaminophenylmethyl)-(S,S)- 1 ,1′-bis[di(3,5-dimethyl-4-methoxyphenyl)phosphine]ferrocene (= Mandyphos SL-M004-1) (0.116 g, 0.110 mmol) is added in degassed ethanol (100 ml). The solution is degassed using vacuum and a pressure of 20 bar hydrogen applied. The mixture is stirred at 40 ⁰C for 6 h. Vessel is then purged with nitrogen. Ethanol (700 ml) is removed by distillation, lsopropyl acetate (600 ml) is added. Solvent (600 ml) is removed by distillation, lsopropyl acetate (600 ml) is added. Solvent (600 ml) is removed by distillation, lsopropyl acetate (300 ml) is added and the solution is heated to reflux. Heptane fraction (1200 ml) is added and the mixture is cooled to room temperature. The solid is collected by filtration and washed with heptane fraction-isopropyl acetate 2 : 1 mixture (360 ml). The solid is dried overnight at 50 ⁰C under 1-50 mbar vacuum to afford the title compound as a white/off-white solid [Ratio 2(i-a) : 2(i-b) 99 : 1, as determined by HPLC analysis]. Mpt 146-147 ⁰C; δ_H (500 MHz; DMSO) 1.07 (3H₁ d, J 7.0, 1-CH₃), 1.34 (9H, s, (CH₃)₃), 1-38 (1H, m, 3-H_A), 1.77 (1H, m, 3-H_B), 2.43 (1H, m, 2-H), 2.70 (2H, d, J 7.0, 5-H)₁ 3.69 (1 H, m, 4-H), 6.74 (1 H, d, J 9.0, NH)₁ 7.27 (2H, d, J 8.0, Ar-ortA;o-H(Ph)), 7.36 (1H, t, J 7.0, Ar-(Ph)-para-H), 7.46 (2H, t, J 7.5, Ar-(Ph)- meta-H), 7.57 (2H, d, J 8.0, Ar-mefa-H(Ph), 7.64 (2H, d, J 7.5, Ar-(Ph)-orfΛo-H), 12.01 (1H, s, CO₂H); δ_c (500 MHz, DMSO) 18.1 (1-CH₃), 28.3 [(CH₃)₃], 35.9 (2- C), 37.9 (3-C), 40.7 (5-C), 50.0 (4-C), 77.4 [(C(CH₃)₃], 126.3, 126.5, 127.2, 128.9, 129.8 (Ar-CH), 137.7 (Ar-/pso-C(Ph)), 138.3 (Ar-para-C(Ph)), 140.1 (Ar- (Ph)-/pso-C), 155.2 (NCO), 177.2 (CO₂H); mlz (+ESI) 406 ([MNa]⁺, 6%), 384 ([MH]⁺, 31 ), 328 (100), 284 (19); Found: [MH]⁺, 384.21691. C₂₃H₃₀NO₄ requires MH 384.21693

PATENT

http://www.google.com/patents/EP0555175A1

Example 1….THE SODIUM SALT

To a solution of N-(3-carbo(t)butoxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2R-methylbutanoic acid ethyl ester (0.80 g) in 15 ml of CH₂CI₂ at room temperature are added 3 ml of trifluoroacetic acid. The mixture is stirred overnight and concentrated. The residue is dissolved in tetrahydrofuran (THF), and 6.5 ml of 1 N NaOH is added. The mixture is concentrated and triturated with ether. The solid can be recrystallized from methylene chloride-hexane to give sodium N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2R-methyl butanoic acid ethyl ester melting at 159-160°C; [a]D20 = – 11.4° (methanol).

• SODIUM SALT

The starting material is prepared as follows:

A solution of a-t-BOC-(R)-tyrosine methyl ester (5.9 g, 20 mmol) and pyridine (8 mL, 100 mmol) in methylene chloride (30 mL) is cooled to 0-5°C. Trifluoromethanesulfonic anhydride (4 mL, 23 mmol) is added at 0-5°C, and the resulting mixture is held for another 30 minutes. The reaction mixture is diluted with water (60 mL) and methylene chloride (100 mL), and washed sequentially with 0.5 N sodium hydroxide solution (1 x 50 mL), water (1 x 60 mL), 10% citric acid solution (2 x 75 mL) and water (1 x 60 mL). The organic phase is dried over MgS0₄ and concentrated to an oil. The oil is purified by column chromatography (silica gel, hexane/ethyl acetate, 2:1 to give methyl(R)-2-(t-butoxycarbonylamino)-3-[4-(trifluoromethylsulfonyloxy)phenyl]-propionate which crystallizes on standing; m.p. 46-48°C; [a]²⁰ _D-36.01⁰ (c=1, CHCI₃).

Nitrogen is passed through a suspension of (R)-2-(t-butoxycarbonylamino)-3-[4-(trifluoromethylsulfonyloxy)-phenyl]-propionate (1.75mmol), phenylboronic acid (3.5 mmol), anhydrous potassium carbonate (2.63 mmol) and toluene (17 mL) for 15 minutes. Tetrakis(triphenyiphosphine)paiiadium(0) is added, and the mixture is heated at 85-90° for 3 hours. The reaction mixture is cooled to 25°C, diluted with ethyl acetate (17 mL) and washed sequentially with saturated sodium bicarbonate (1 x 20 mL), water (1 x 20 mL), 10% citric acid (1 x 20 mL), water (1 x 20 mL) and saturated sodium chloride solution (1 x 20 mL). The organic phase is concentrated, and the residue is purified by column chromatography (silica gel, hexane/ethyl acetate 2:1) to yield methyl (R)-2-(t-butoxycarbonylamino)-3-(p-phenylphenyl)-propionate which can also be called N-(R)-t-butoxycarbonyl-(p-phenylphenyl)-alanine methyl ester.

To a solution of N-(R)-t-butoxycarbonyl-(p-phenylphenyl)-alanine methyl ester (6.8 g) in 60 ml of THF and 20 ml of methanol are added 20 ml of aqueous 1 N sodium hydroxide solution. The mixture is stirred for 1 h at room temperature and then acidified with 21 ml of 1 N hydrochloric acid. The aqueous solution is extracted 3x with ethyl acetate. The combined organic extracts are dried (MgS0₄), filtered and concentrated to give N-(R)-t-butoxycarbonyl-(p-phenylphenyl)-alanine, m.p. 98-99°C; [a]²°_D -18.59° (c=1, methanol).

To a solution of N-(R)-t-butoxycarbonyl-(p-phenylphenyl)-alanine (4.8 g) in 70 ml of methylene chloride (CH₂CI₂) at 0°C with 1.65 g of N,O-dimethylhydroxylamine HCI, 1.7 g of triethylamine and 2.85 g of hydroxybenzotriazole are added 5.37 g of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride. The mixture is stirred 17 h at room temperature. The mixture is concentrated taken up in ethyl acetate (EtOAc) and washed with saturated sodium bicarbonate, 1N HCI and brine, then dried (MgS0₄), filtered and concentrated to give N-(R)-t-butoxycarbonyl-(p-phenylphenyl)-alanine N,O-dimethyl hydroxylamine amide.

To a 0°C solution of N-(R)-t-butoxycarbonyl-(p-phenylphenyl)-alanine N,O-dimethyl hydroxylamine amide (5.2 g) in 250 ml of diethyl ether are added 0.64 g of lithium aluminum hydride. The reaction is stirred for 30 min. and quenched with aqueous potassium hydrogen sulfate. The mixture is stirred for additional 5 min., poured onto 1N HCI, extracted (3x) with EtOAc, dried (MgS0₄), filtered, and concentrated to give N-(R)-4-t-butoxycarbonyl-(p-phenylphenyl)-alanine carboxaldehyde as a colorless oil.

To a 0°C solution of N-(R)-t-butoxycarbonyl-(p-phenylphenyl)-alanine carboxaldehyde (4.4 g) in 200 ml of CH₂CI₂are added 10 g of carboethoxyethylidene phenyl phosphorane. The mixture is warmed to room temperature, stirred for 1 h, washed with brine, dried (MgS0₄), filtered and concentrated. The residue is chromatographed on silica gel eluting with (1:2) ether:hexane to give N-t-butoxycarbonyl-(4R)-(p-phenylphenylme- thyl)-4-amino-2-methyl-2-butenoic acid ethyl ester.

A solution of N-t-butoxycarbonyl-(4R)-(p-phenylphenylmethyl)-4-amino-2-methyl-2-butenoic acid ethyl ester (4.2 g) in 400 ml of ethanol is suspended with 2.0 g of 5% palladium on charcoal and then is hydrogenated at 50 psi for 6h. The catalyst is removed by filtration and the filtrate is concentrated to give N-t-butoxycarbonyl(4S)-(p-phenylphenylmethyl)-4-amino-2-methylbutanoic acid ethyl ester as a 80:20 mixture of diastereomers.

To the N-t-butoxycarbonyl(4S)-(p-phenylphenylmethyl)-4-amino-2-methylbutanoic acid ethyl ester (4.2 g) in 40 ml of CH₂CI₂ at 0°C is bubbled dry hydrogen chloride gas for 15 min. The mixture is stirred 2 h and concentrated to give (4S)-(p-phenylphenylmethyl)-4-amino-2-methylbutanoic acid ethyl ester hydrochloride as a 80:20 mixture of diastereomers.

To a room temperature solution of the above amine salt (3.12 g) in 15 ml of CH₂CI₂ and 15 ml of pyridine are added 13.5 g of succinic anhydride. The mixture is stirred for 17 h, concentrated, dissolved in ethyl acetate, washed with 1N HCI and brine, and dried (MgS0₄) to give N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenyl- methyl)-4-amino-2-methylbutanoic acid ethyl ester as a 80:20 mixture of diastereomers.

The above N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2-methylbutanoic acid ethyl ester diastereomeric mixture (3.9 g) and N,N-dimethylformamide-di-t-butyl acetal (8.8 ml) are heated at 80°C in 40 ml of toluene for 2 h. The mixture is poured onto ice- 1N HCI, extracted with ether, chromatographed on silica gel eluting with (2:1) toluene:ethyl acetate to give N-(3-carbo(t)butoxy-1-oxopropyl)-(4S)-(p-phenylphe- nylmethyl)-4-amino-2R-methylbutanoic acid ethyl ester as the more polar material and the corresponding (S,S) diastereomer as the less polar material.

Example 2………THE ACID

To a solution of N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester (0.33 g) in 20 ml of (1:1) ethanol:tetrahydrofuran (THF) at room temperature are added 5 ml of 1 N sodium hydroxide solution (NaOH) and stirred for 17 h. The mixture is concentrated, dissolved in water and washed with ether. The aqueous layer is acidified with 1 N hydrochloric acid (HCI), extracted 3x with ethyl acetate (EtOAc), dried over magnesium sulfate (MgS0₄), filtered and concentrated. The residue is triturated with ether to yield N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid melting at 158-164°C, [α]_D ²⁰= -23.5° (methanol).

PATENT

CN 104557600

http://www.google.com/patents/CN104557600A?cl=zh

United States Patent US5217996 and international patent W02008031567, W02010136474 and W02012025501 reported a synthetic route follows to the chiral amino alcohols as raw materials, oxidized to the aldehyde, Victoria ladder tin reaction, chiral hydrogenation and amidation condensation reaction to obtain the objective product.

In addition, the international patent TO2008083967, TO2011088797, TO2012025502 and TO2014198195 reported that another type of preparation. The route through the 2-oxo-proline as raw material, carboxyl activating biphenyl substituted carbonyl reduction, chiral methylation, ring-opening reaction and amide condensation reaction to obtain the objective product.

Example Eight:

in the reaction flask was added (2R, 4S) -2- methyl-4-amino -5- (l, P- biphenyl-4-yl) – pentanoic acid ethyl ester (VII) (1.55g, 5mmol ), Jie of pyridine (1.2g, 15mmol) and dichloromethane burning 25mL, stirring to dissolve, butyric anhydride (1.0g, 10mmol), was heated to 4〇-45 ° C, the reaction was stirred for 6 hours. Fill Gaudin anhydride (0. 5g, 5mmol), the reaction was continued for 4 hours and the end of the reaction by TLC. Concentrated under reduced pressure, the residue was recrystallized from ethyl acetate and n-hexane to give an off-white solid sand sacubitril Kubica song (I) L 6g, a yield of 77.9%;

1H NMR (CDCl3) S 7.51 (d, 2H), 7.46 ( d, 2H), 7.36 (m, 2H), 7. 27 (m, 1H), 7. 17 (d, 2H), 5. 72 (d, 1H), 4. 19 (brs, 1H), 4. 06 (q, 2H), 2. 87-2. 72 (m, 2H), 2. 62-2. 54 (m, 2H), 2. 49 (brs, 1H), 2. 43-2. 33 ( m, 2H), I 88 (m 1H), I 54-1 43 (m, 1H), I. 18 (t, 3H), l 10 (d, 3H);…..

FAB-MSm / z : 412 [M + H] +.

PATENT

http://www.google.com/patents/WO2014198195A1?cl=en

Example 7

(2 Standby

Acetyl chloride (1 mL) 0 ° C was added ethanol (10 mL), and at room temperature for 0.5 hours, the compound (3R, 5S) -5- biphenyl-4-methyl-1- (2,2- methyl-propionyl) -3-methyl pyrrolidone (520 mg, 1.49 mmol), the reaction was refluxed for 3 days. After cooling to room temperature, and concentrated. The reaction mixture was dissolved in 8 mL of dichloromethane and pyridine 1: 1 mixed solution, and then butyryl anhydride (223 mg, 2.23 mmol). 30 ° C overnight. LC-MS detection, a small amount of starting material remaining, fill Gading anhydride (75 mg, 0.74 mmol), continue to reflect four hours. Concentrated and reverse phase column chromatography to give a white foam solid (2R, 4S) -5- biphenyl-4-yl-4- (3-carboxy – propionylamino) -2-methyl – acetic acid ester a (355 mg, 58%) and white solid (2R, 4S) -5- biphenyl-4-yl-4- (3-carboxy – propionylamino) -2-methyl – pentanoic acid b ( 13 mg, 2.3%).

a: 1H MR (400 MHz, CDCl ₃ ) [delta] 7.51 (d, = 7.8 Hz, 2H), 7.46 (d, = 7.8 Hz, 2H), 7.36 (t, J = 7.6 Hz, 2H), 7.27 (t, J = 7.2 Hz, IH), 7.17 (d, J = 7.9 Hz, 2H), 5.72 (d, J = 8.1 Hz, IH), 4.19 (brs, IH), 4.06 (q, J = 7.0 Hz, 2H) , 2.87-2.72 (m, 2H), 2.62-2.54 (m, 2H), 2.49 (brs, IH), 2.43-2.33 (m, 2H), 1.88 (ddd, = 13.2, 9.5, 3.9 Hz, IH), 1.54-1.43 (m, IH), 1.18 (t, = 7.0 Hz, 3H), 1.10 (d, = 7.2 Hz, 3H).

LC-MS: t _R = 3.43 min; [M + H] +: 412.0.

……………………

Paper

JOURNAL OF MEDICINAL CHEMISTRY, vol. 38, no. 10, 1995, pages 1689-1700,

http://pubs.acs.org/doi/pdf/10.1021/jm00010a014

NOTE———–DIACID

(aR,yS)-y-[ (3-Carbo-1-oxopropyl)aminol-a-methyl- [l,l’-biphenyllpentanoic Acid (21a).

To the sodium salt of 19a (0.73 g, 1.68 mM) in 20 mL of THF:EtOH was added 1 N NaOH (5.0 mL, 5.0 “01). The reaction mixture was stirred overnight and then washed with ether. The aqueous layer was acidified with 1 N HCI, re-extracted with EtOAc (3 x 10 mL), dried (MgSO& and evaporated to dryness. The solid was recrystallized from ethanol to yield 435 mg of 21a DIACID OF SACUBITRIL

melting at 165-167 “C:

[a] D25~ -28.73 (c = 10.1 in MeOH);

‘H NMR, DMSOD6

PPM 12.0, (s, 2H), 7.75 (d, 1H), 7.62 (d, 2H), 7.55 (d, 2H), 7.45 (t, 2H), 7.32 (t, lH), 7.25 (d, 2H), 4.92 (m, lH), 2.70 (d, 2H), 2.35 (t, 3H), 2.25 (m, 2H), 1.75 (m, lH), 1.32 (m, lH), 1.03 (d, 3H).

Anal. (C22H25N05) C,H,N

Note diacid is sacubitrilat (LBQ657)

NMR PREDICT

 1H NMR PREDICT

13C NMR PREDICT

COSY PREDICT

…………….

NMR…..http://www.chemietek.com/Files/Line3/CHEMIETEK,%20AHU-377%20,%20Lot%2001,%20NMR-MeOD,%201.1.pdf

Mol. Formula:C₂₄H₂₉NO₅ ∙ C₄H₁₁NO₃

MW:532.6

HPLC………http://www.chemietek.com/Files/Line2/CHEMIETEK,%20AHU-377%20,%20Lot%2001,%20HPLC.pdf

update………

PATENT

WO2016180275

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016180275&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=FullText

However, the second step of the synthetic route use succinimide nitrogen atoms introduced by Mitsunobu reaction with hydrochloric acid hydrolysis to remove, then converted to Boc protected at the end of the synthesis process AHU377 Boc will have to take off protection, then any connection with succinic anhydride reaction product introduced into the structure of succinic acid portion, so that this method of atom economy and the economy of the steps are low.

Example 1

Synthesis of Compound 2

In inert atmosphere, a solution of three 500mL flask was added compound 1 (10g, 1eq), dissolved after 90mL THF, was added CuI (4.814g, 0.1eq), the system moves to the low temperature in the cooling bath to -20 ℃ when, biphenyl magnesium bromide dropwise addition, the internal temperature was controlled not higher than -10 ℃. Bi closed refrigeration drop, return to room temperature overnight. Completion of the reaction, the reaction solution was poured into saturated the NH ₄ of Cl (10vol, 100 mL) was stirred at room temperature for 0.5h. Suction filtered, the filter cake was rinsed with a small amount of EA, and the filtrate was transferred to a separatory funnel carved, and the aqueous phase was extracted with EA (10vol × 2,100mL × 2) and the combined organic phases with saturated NaHC [theta] ₃ , the NH ₄ of Cl, each Brine 150mL (15vol) washed once, dried over anhydrous over MgSO ₄ dried, suction filtered, and concentrated to give a white solid. Product obtained was purified by column 15.2g, yield 78%.

NMR data for the product are as follows:

¹ the H NMR (400MHz, CDCl ₃ ) [delta] 7.57 (D, J = 7.6Hz, 2H), 7.52 (D, J = 8.1Hz, 2H), 7.42 (T, J = 7.6Hz, 2H), 7.38-7.25 (m, 8H), 4.62-4.47 ( m, 2H), 4.09 (dd, J = 6.7,3.5Hz, 1H), 3.54 (dd, J = 9.5,3.5Hz, 1H), 3.43 (dd, J = 9.4 , 6.9Hz, 1H), 2.84 ( d, J = 6.6Hz, 2H), 2.38 (s, 1H).

Example 2

Synthesis of Compound 3

In an inert gas, at room temperature was added to the flask 500mL three Ph3P (18.54g, 2eq), 240mL DCM dissolution, butyryl diimide (of 6.44 g), compound 2 (15g), an ice-water bath cooling to 0 ℃ or so, was added dropwise DIAD (14mL) was complete, the reaction go to room temperature.Starting material the reaction was complete, the system was added to water (100 mL) quenched the reaction was stirred for 10min; liquid separation, the aqueous phase was extracted with DCM (100mL × 2), the combined organic phases with saturated Brine 100mL × 2), dried over anhydrous over MgSO ₄ dried , filtration, spin dry to give a white solid; product was purified by column 15.4g, yield 82%.

NMR data for the product are as follows:

¹ the H NMR (400MHz, CDCl ₃ ) [delta] 7.56 (D, J = 7.4Hz, 2H), 7.49 (D, J = 8.0Hz, 2H), 7.42 (T, J = 7.6Hz, 2H), 7.37-7.30 (m, 3H), 7.27 ( d, J = 6.7Hz, 3H), 7.22 (d, J = 8.0Hz, 2H), 4.75 (s, 1H), 4.56 (d, J = 12.0Hz, 1H), 4.45 (d, J = 12.0Hz, 1H ), 4.06 (t, J = 9.6Hz, 1H), 3.70 (dd, J = 10.0,5.2Hz, 1H), 3.23 (dd, J = 13.8,10.3Hz, 1H) , 3.14-3.00 (m, 1H), 2.48 (d, J = 4.0Hz.4H).

Example 3

Synthesis of Compound 4

Protection of inert gas, at room temperature was added to the flask 1L three compound 3 (18.81g), 470mL EtOH was dissolved, was added Pd / C, replaced the H ₂ three times, move heated on an oil bath at 60 ℃ reaction. Raw reaction was complete, the system was removed from the oil bath, the reaction solution was suction filtered through Celite and concentrated to give the crude product. It was purified by column pure 11.8g, a yield of 81.2%.

NMR data for the product are as follows:

₁ the H NMR (400MHz, CDCl ₃ ) [delta] 7.57 (D, J = 7.8Hz, 2H), 7.51 (D, J = 7.8Hz, 2H), 7.42 (T, J = 7.5Hz, 2H), 7.33 (T , J = 7.2Hz, 1H), 7.26 (d, J = 7.2Hz, 2H), 4.55 (d, J = 5.2Hz, 1H), 4.06-3.97 (m, 1H), 3.86 (dd, J = 12.0, 3.1Hz, 1H), 3.16 (dd , J = 8.1,2.9Hz, 2H), 2.58 (t, J = 7.0Hz, 4H), 1.26 (s, 2H).

Example 4

Synthesis of Compound 7

Protection of inert gas, at room temperature to a 25mL flask was added three Dess-Martin oxidant (767.7mg), 10mL DCM was dissolved, the system was cooled down to -10 deg.] C, was added 4 (500mg). Starting material the reaction was complete, to the system was added saturated NaHCO3 and Na2S2O3 each 5mL, quench the reaction stirred for 10min; aqueous phase was extracted with DCM (10mL × 3) and the combined organic phases with saturated NaHCO3, Brine 30mL each wash, dried over anhydrous MgSO4, filtration, spin dried to give the crude product used directly in the next reaction cast.

Example 5

Synthesis of Compound 8

Inert gas, at room temperature for three to 500mL flask 7 (497.5mg), 10mL DCM to dissolve an ice water bath to cool, added phosphorus ylide reagent (880.6mg), the system was removed from the ice water bath at room temperature. The reaction material completely stop the reaction, the system was added to water (5mL) to quench the reaction. Liquid separation, the aqueous phase was extracted with DCM (10mL × 2), organic phases were combined, washed with saturated Brine 20mL × 2, dried over anhydrous MgSO4, filtration, spin crude done. Product obtained was purified by column 563mg, 90% yield.

NMR data for the product are as follows:

¹ the H NMR (400MHz, CDCl ₃ ) δ7.60-7.53 (m, 2H), 7.51 (D, J = 8.1Hz, 2H), 7.42 (T, J = 7.6Hz, 2H), 7.33 (D, J = 7.3Hz, 1H), 7.23 (d , J = 8.1Hz, 2H), 7.13 (dd, J = 9.2,1.5Hz, 1H), 5.26 (td, J = 9.5,6.9Hz, 1H), 4.25-4.05 ( m, 2H), 3.40 (dd , J = 13.7,9.7Hz, 1H), 3.13 (dd, J = 13.8,6.7Hz, 1H), 2.53 (d, J = 2.2Hz, 4H), 1.85 (d, J = 1.4Hz, 3H), 1.30 ( t, J = 7.1Hz, 3H).

Example 6

Synthesis of Compound 9

Protection of inert gas, at room temperature to a 50mL flask was added three 8 (365mg, 1eq), 9mL of ethanol and stirred to dissolve, the system was replaced with hydrogen three times, was added Pd / C (25% w / w) at room temperature. The reaction material completely stop the reaction, the system was added to water (5mL) to quench the reaction. The reaction mixture was suction filtered through Celite and concentrated to give the crude product. Product was purified by column, yield 80.2%, purity 97.2%.

Example 7

Synthesis of Compound 10

Equipped with Compound 9 (100mg) acetic acid A reaction flask (9mL), hydrochloric acid (1mL). The reaction was heated oil bath at 80 deg.] C. The reaction material completely stop the reaction, the system was added to water (5mL) to quench the reaction. After saturated NaHCO3 and extracted with EA and concentrated to give crude product. Product obtained was purified by column 90mg, yield 84%.

NMR data for the product are as follows:

¹ the H NMR (400MHz, CDCl ₃ ) δ7.61-7.54 (m, 2H), 7.53-7.48 (m, 2H), 7.41 (dd, J = 10.5,4.9Hz, 2H), 7.31 (dd, J = 8.3 , 6.4Hz, 1H), 7.22 ( d, J = 8.2Hz, 2H), 5.93 (t, J = 9.7Hz, 1H), 4.34-4.00 (m, 3H), 2.91-2.71 (m, 2H), 2.68 -2.57 (m, 2H), 2.55 (ddd, J = 9.4,7.0,4.3Hz, 1H), 2.42 (dt, J = 13.3,6.8Hz, 2H), 1.97-1.74 (m, 1H), 1.64-1.46 (m, 1H), 1.23 ( td, J = 7.1,3.3Hz, 3H), 1.14 (dd, J = 7.1,3.9Hz, 3H)

Example 8

Synthesis of Compound 5

Example 8-1: The reaction flask was added compound 4 (1eq) was added water (2VOL), concentrated hydrochloric acid (2VOL), 110 ℃ reaction was heated in an oil bath overnight, complete conversion of starting material, the HPLC peak area 97%. 10% NaOH solution was added to adjust the pH to about 10, filtration products. Yield 85%.

Example 8-2: The reaction flask was added compound 4 (1eq) was added ethanol (5 vol), water (5 vol), potassium hydroxide (8 eq), was heated in an oil bath overnight at 110 ℃ reaction, complete conversion of the starting material, the HPLC peak area 99%. Water was added (5Vol), filtered to obtain the product. Yield 95%. Product was dissolved in toluene, was added ethanolic hydrochloric acid, the precipitated hydrochloride Compound 5.

NMR data for the product are as follows:

¹ the H NMR (400MHz, of DMSO) [delta] 8.31 (S, 3H), 7.70-7.61 (m, 4H), 7.47 (T, J = 7.6Hz, 2H), 7.42-7.31 (m, 3H), 4.09 (the dq- , J = 42.6,7.1Hz, 1H), 3.62-3.51 (m, 1H), 3.50-3.41 (m, 1H), 3.11-3.00 (m, 1H), 2.95-2.84 (m, 1H), 1.30-1.10 (m, 1H).

EXAMPLE 9

Synthesis of Compound 6

To the reactor was added compound 5, was added absolute ethanol (3vol). Temperature of the outer set 30 ℃ heating, stirring was continued after the temperature reached 25 ℃ 20min. Was added 30% NaOH aqueous solution (1.1eq). External temperature 65 ℃ heating provided, after the internal temperature reached 60 deg.] C was slowly added (of Boc) ₂ O (1.1 eq). Stirring 0.5h, reaction monitoring. After completion of the reaction, water was added slowly dropwise (8vol), turn off the heating and natural cooling. The system temperature was lowered to 25 deg.] C and continue stirring for 2h. Filter cake at 50 ℃ blast oven drying to obtain the product.

NMR data of the product are as follows:

¹ the H NMR (400MHz, CDCl ₃ ) δ7.61-7.50 (m, 4H), 7.61-7.50 (m, 4H), 7.46-7.39 (m, 2H), 7.48-7.38 (m, 2H), 7.38-7.23 (m, 3H), 7.37-7.26 ( m, 3H), 4.82 (d, J = 7.9Hz, 1H), 4.82 (d, J = 7.9Hz, 1H), 3.91 (s, 1H), 3.70 (d, J = 11.0Hz, 1H), 3.77-3.54 (m, 2H), 3.65-3.47 (m, 1H), 2.88 (d, J = 7.0Hz, 2H), 2.88 (d, J = 7.0Hz, 2H), 2.51 (s, 1H), 2.51 (s, 1H), 1.42 (s, 9H), 1.42 (s, 9H).

Synthesis of Intermediate Compound 6 to Compound 10, i.e., the AHU-377, a synthetic route in the background of the present invention, the cited patent application WO2014032627A1 loaded in detail, not in this repeat.

Example 10

Synthesis of Compound 2

Benzyl glycidyl ether preparation (50g) in THF (200mL) was added. Under inert gas protection, the biphenyl magnesium bromide (365mmol) was added to THF (1020mL) was added the reaction flask is placed in a low temperature bath -40 ℃ cooling. Cuprous iodide (O.leq) when the internal temperature dropped to -9 ℃. Continued to decrease the temperature of -23 ℃ dropwise addition of benzyl glycidyl ether in THF was added dropwise to control the internal temperature process of not higher than -15 deg.] C, 47 min when used, the addition was completed the cooling off the reaction was stirred overnight. The cooling system to -20 ℃ quenched with 1N HCl aqueous solution, <10 ℃ Go stirred 30min at room temperature. Liquid separation, the aqueous phase was extracted with THF, the combined THF phases. Respectively saturated ammonium chloride (250mL), saturated brine (250mL) washed. Rotary evaporation to remove THF, and water (200 mL) Continue rotary evaporation 1h, cool to precipitate a solid. Suction crude. Crude n-heptane was added 2Vol beating, suction filtration to obtain the product in a yield of 90 ~ 95%, HPLC peak area 94%. In another column purification was pure, columned yield 88.6%, HPLC 99.1%.

Example 11

Synthesis of Compound 3

Preparation Example 9, said compound taking the embodiment 2 (5g) added to the reaction flask, the reaction flask was added toluene (80mL), phthalimide (2.55 g of) and triphenylphosphine (5.35g of), the nitrogen was replaced protection. An ice-salt bath cooling to -5 deg.] C, was added dropwise DIAD (4.12g), dropwise addition was exothermic, the temperature was raised to 5 ℃. The reaction was continued 1h sampling HPLC test material substantially complete reaction. Join 12g silica spin column done to collect the product (including DIEA derivative).

Example 12

Synthesis of Compound 11

Compound 3 (3g) was added to the reaction flask embodiment taken in Preparation Example 10, was added ethanol (30 mL), with stirring. Was added hydrazine hydrate (2g) was heated in an oil bath reflux 1h, when supplemented with 20mL ethanol was stirred difficulties, the reaction was continued to 2.5h, HPLC showed the starting material the reaction was complete. Add EA / H2O 100mL each liquid separation, the EA phase was washed with water (100mL) and the combined organic phases were washed with water (100mL) and saturated brine (100mL) washed. Anhydrous magnesium sulfate and filtered spin column was done product 1.88g, yield 88%, HPLC 94%.

NMR data of the product are as follows:

¹ the H NMR (400MHz, of DMSO) [delta] 7.64 (D, J = 7.2Hz, 2H), 7.57 (D, J = 8.1Hz, 2H), 7.45 (T, J = 7.6Hz, 2H), 7.39-7.32 ( m, 5H), 7.29 (d , J = 8.1Hz, 3H), 4.55-4.43 (m, 2H), 3.38-3.23 (m, 3H), 3.18-3.10 (m, 1H), 2.82-2.74 (m, 1H), 2.61-2.52 (m, 1H ).

Example 13

Synthesis of Compound 11

To the toluene solution of the compound 2 was added phthalimide (1.1 eq), triphenylphosphine (1.3 eq) with stirring. External bath set -10 ℃, to cool the system, the internal temperature dropped to 0 ~ 5 ℃, start dropping DIAD (1.3eq), control the internal temperature -5 ~ 5 ℃. Completion of the dropwise addition, the cooling bath was turned off outside the reaction was stirred at room temperature. The reaction was stirred for 1 to 4 hours. The reaction solution to give compound 3, administered directly in the next reaction. To the above reaction mixture was added hydrazine hydrate (6 eq), heated to 70 ~ 80 ℃, to complete the reaction, filtered hot, the filtrate. Aqueous sodium hydroxide solution (20vol 10%) was stirred for 0.5h, allowed to stand for liquid separation from toluene phase. Water was added (20vol) was stirred for 0.5h, allowed to stand for liquid separation from toluene phase. The toluene phase was added hydrochloric acid (20vol, 3N), stirred for 0.5h, to form a solid precipitate. Filtration and drying to obtain a product, i.e. compound 11, the hydrochloride salt, yield 60% in two steps.

NMR data of the product are as follows:

¹ the H NMR (400MHz, of DMSO) [delta] 8.46 (S, 3H), 7.63 (dd, J = 16.4,7.7Hz, 4H), 7.47 (T, J = 7.6Hz, 2H), 7.42-7.22 (m, 8H ), 4.56 (d, J = 12.1Hz, 1H), 4.48 (d, J = 12.1Hz, 1H), 3.58 (d, J = 7.9Hz, 2H), 3.47 (dd, J = 10.9,6.3Hz, 1H ), 3.11 (dd, J = 13.5,4.9Hz, 1H), 2.92 (dd, J = 13.4,9.1Hz, 1H).

Example 14

Synthesis of Compound 12

Weigh Compound 11 (1.38g) was added to the reaction flask. To the reaction flask plus DCM (14ml) and Et3N (462mg, 0.73ml). Weighed (of Boc) ₂O (1.23 g of) was added to DCM (5ml) was dissolved. Room temperature (8 ℃), a solution (of Boc) ₂ DCM solution O was added dropwise to the reaction, (2ml) rinsed with DCM. The reaction mixture was stirred at room temperature, detected by HPLC, the reaction ends 4h. Reaction mixture was washed (15ml) 3 times with Brine (15ml) The reaction solution was washed 1 times. Inorganic sulfate, concentrated and purified by column PE:EA = 15:1 give product 560mg, yield 30.8%, HPLC 99.92%.

NMR data of the product are as follows:

¹ the H NMR (400MHz, CDCl ₃ ) [delta] 7.57 (D, J = 7.6Hz, 2H), 7.49 (D, J = 7.4Hz, 2H), 7.43 (T, J = 7.3Hz, 2H), 7.39-7.28 (m, 5H), 7.24 ( d, J = 9.0Hz, 3H), 5.00-4.80 (br, 1H), 4.51 (q, J = 11.8Hz, 2H), 4.08-3.85 (br, 1H), 3.43 ( d, J = 2.9Hz, 2H) , 3.02-2.77 (m, 2H), 1.42 (s, 9H).

Example 15

Synthesis of Compound 6

Weigh Compound 12 (250mg) and methanol (9ml) was added to the reaction flask. Added Pd / C (138mg, 1 / 4w / w, water content 55%). The H ₂replaced 3 times, 50 ℃ stirred and heated. HPLC detection reaction, the reaction end 30h. Filtered off Pd / C, 40 ℃ concentrated under reduced pressure to remove methanol. PE:EA = 3:1 florisil column to give the product 196mg, 100% yield, 99.34% purity.

NMR data of the product are as follows:

¹ the H NMR (400MHz, CDCl ₃ ) δ7.61-7.50 (m, 4H), 7.61-7.50 (m, 4H), 7.46-7.39 (m, 2H), 7.48-7.38 (m, 2H), 7.38-7.23 (m, 3H), 7.37-7.26 ( m, 3H), 4.82 (d, J = 7.9Hz, 1H), 4.82 (d, J = 7.9Hz, 1H), 3.91 (s, 1H), 3.70 (d, J = 11.0Hz, 1H), 3.77-3.54 (m, 2H), 3.65-3.47 (m, 1H), 2.88 (d, J = 7.0Hz, 2H), 2.88 (d, J = 7.0Hz, 2H), 2.51 (s, 1H), 2.51 (s, 1H), 1.42 (s, 9H), 1.42 (s, 9H).

Method for preparing the AHU-377, characterized by comprising the steps of: (a) Compound (1) S- benzyl glycidyl ether and biphenyl Grignard reagent produced by the reaction of the compound (2) in an organic solvent; ( b) compound (2) with a succinimide or phthalimide Mitsunobu reaction occurs in an organic solvent to form a compound (3); (C) compound (3) in an organic solvent in the role of a catalyst under removal debenzylation protected form compound (4); (D) compound (4) with an oxidizing agent oxidation reaction occurs in an organic solvent to form a compound (7); (E) compound (7) with a phosphorus ylide reagent in an organic solvent to give the compound (8); (F.) compound (8) in an organic solvent in the selective catalytic hydrogenation of the compound (9); and (g) of the compound (9) in an organic solvent in the hydrolysis reaction of the amide compound occurs in the presence of an acid ( 10), i.e., AHU-377;

References

Patent	Submitted	Granted
ORGANIC COMPOUNDS [US2009156585]	2009-06-18
METHODS OF TREATMENT AND PHARMACEUTICAL COMPOSITION [US8101659]	2008-10-23	2012-01-24
Substituted Aminobutyric Derivatives as Neprilysin Inhibitors [US2010305145]	2010-12-02
PROCESS FOR PREPARING BIARYL SUBSTITUTED 4-AMINO-BUTYRIC ACID OR DERIVATIVES THEREOF AND THEIR USE IN THE PRODUCTION OF NEP INHIBITORS [US2009326066]	2009-12-31
Process for preparing 5-biphenyl-4-amino-2-methyl pentanoic acid [US8115016]	2010-05-06	2012-02-14
Methods of treatment and pharmaceutical composition [US7468390]	2003-07-31	2008-12-23
Process for Preparing 5-biphenyl-4-amino-2-methyl Pentanoic Acid [US2014249320]	2014-03-25	2014-09-04
Substituted Aminobutyric Derivatives as Neprilysin Inhibitors [US2012252830]	2012-06-07	2012-10-04
Process for preparing 5-biphenyl-4-amino-2-methyl pentanoic acid [US8716495]	2011-12-21	2014-05-06

 

Sacubitril

Systematic (IUPAC) name
4-{[(2S,4R)-1-(4-Biphenylyl)-5-ethoxy-4-methyl-5-oxo-2-pentanyl]amino}-4-oxobutanoic acid
Clinical data
Legal status	Investigational
Identifiers
CAS Registry Number	149709-62-6
ATC code	None
PubChem	CID: 9811834
ChemSpider	7987587
Synonyms	AHU-377; AHU377
Chemical data
Formula	C24H29NO5
Molecular mass	411.49 g/mol

Sacubitril

Systematic (IUPAC) name
4-{[(2S,4R)-1-(4-Biphenylyl)-5-ethoxy-4-methyl-5-oxo-2-pentanyl]amino}-4-oxobutanoic acid
Identifiers
CAS Number	149709-62-6
ATC code	None
PubChem	CID: 9811834
ChemSpider	7987587
Synonyms	AHU-377; AHU377
Chemical data
Formula	C24H29NO5
Molecular mass	411.49 g/mol
SMILES[hide] CCOC(=O)[C@H](C)C[C@@H](CC1=CC=C(C=C1)C2=CC=CC=C2)NC(=O)CCC(=O)O

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