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A technology of AHU377 and synthesis method, applied in the directions of organic chemistry methods, chemical instruments and methods, preparation of organic compounds, etc., can solve the problems such as the unreported synthesis of AHU377 calcium salt route, etc., and achieves low comprehensive cost, mild reaction conditions, and yield. high effect
Inactive Publication Date: 2018-07-20
NANJING REDWOOD FINE CHEM CO LTD
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[0003] There is currently no reported
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Embodiment 1
[0027] Embodiment 1 A kind of synthetic method of AHU377 calcium salt, comprises the steps:
[0028] 1) Add 500g of 4-bromo-D-phenylalanine and 2.5L of methanol into the reaction flask, add 217.7ml of thionyl chloride dropwise, after the addition is complete, raise the temperature to 65°C, keep the reaction for 1 hour, concentrate and crystallize under reduced pressure at 40°C Obtain 482g 4-bromo-D-phenylalanine methyl ester hydrochloride;
[0029] 2) Dissolve 482g of 4-bromo-D-phenylalanine methyl ester hydrochloride in 4.8L of dichloromethane, add 392.9g of BOC anhydride and 938mLkg of triethylamine, keep the reaction at 20-25°C for 3 hours, and the reaction is over Afterwards, concentrated crystallization obtains 469g Boc-4-bromo-D-phenylalanine methyl ester (80% yield);
[0030] 3) Mix 284.5g phenylmagnesium bromide and 469g Boc-4-bromo-D-phenylalanine methyl ester, -15 ～ Reaction at -20°C for 2 hours, the reaction was completed, raised to room temperature, concentrated ...
Embodiment 2
[0037] Embodiment 2 A kind of synthetic method of AHU377 calcium salt, comprises the steps:
[0038] 1) Add 250g of 4-bromo-D-phenylalanine and 1.25L of methanol into the reaction flask, add 108.85ml of thionyl chloride dropwise, after the addition is complete, raise the temperature to 65°C, keep the temperature for 1 hour, and crystallize under reduced pressure at 40°C to obtain 241g 4-bromo-D-phenylalanine methyl ester hydrochloride;
[0039] 2) Dissolve 241g of 4-bromo-D-phenylalanine methyl ester hydrochloride in 2.4L of dichloromethane, add 196.5g of BOC anhydride and 469mLkg of triethylamine, keep the reaction at 20-25°C for 3 hours, and the reaction is over Afterwards, concentrated and crystallized to obtain 234.5g Boc-4-bromo-D-phenylalanine methyl ester (80% yield);
[0040] 3) Mix 142.3g phenylmagnesium bromide and 234.5g Boc-4-bromo-D-phenylalanine methyl ester, -15 ～ -20 DEG C reacted for 2 hours, the reaction was finished, rose to room temperature, concentrated ...
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Abstract
The invention discloses a method for synthesizing an AHU377 calcium salt. The method comprises the following steps: reacting 4-bromo-D-phenylalanine with thionyl chloride, reacting obtained methyl 4-bromo-D-phenylalaninate hydrochloride with BOC acid anhydride, reacting the obtained reaction product with phenylmagnesium bromide to obtain N-tert-butyloxycarbonyl-amino-4,4-biphenyl-R-alanine methylester, reacting the N-tert-butyloxycarbonyl-amino-4,4-biphenyl-R-alanine methyl ester with sodium borohydride, reacting the obtained reaction product with ethyl 2-(triphenylphosphoranylidene)propionate to obtain ethyl (4R)-5-[1,1'-biphenyl]-4-yl-4-[[tert-butoxycarbonyl]amino]-2-methyl-2-pentenoate, reacting the ethyl (4R)-5-[1,1'-biphenyl]-4-yl-4-[[tert-butoxycarbonyl]amino]-2-methyl-2-pentenoatewith lithium hydroxide, performing catalytic hydrogenation, reacting the obtained catalytic hydrogenation product with thionyl chloride to obtain ethyl (2R, 4S)-5- ([1,1-biphenyl)-4-amino-2-methylpentenoate hydrochloride, and stirring and reacting the ethyl (2R, 4S)-5- ([1,1-biphenyl)-4-amino-2-methylpentenoate hydrochloride, calcium chloride and succinic anhydride to obtain the target product.The method has the advantages of simple steps, mild reaction conditions, high purity and high yield.
Description
technical field [0001] The invention belongs to the technical field of chemical synthesis, and in particular relates to a synthesis method of AHU377 calcium salt. Background technique [0002] Calcium salt of AHU-377 ((2R,4S)-5-(biphenyl-4-yl)-4-(amino)-5-(3-carboxy-propionylamino)-2methyl-pentanoic acid ethyl ester calcium Salt) is a prodrug that can convert the active form of the enzyme cleavage LBQ657 ethyl ester, which forms LCZ696 with angiotensin IIAT1 receptor antagonist valsartan in a 1:1 molar ratio, and LCZ696 belongs to angiotensin II (AT2) receptor and neprilysin (Neprilysin) receptor dual inhibitor, its antihypertensive effect is better than standard antihypertensive drugs, is a new type of drug for the treatment of heart failure, the efficacy and safety of the drug milestone III The drug enalapril, which surpasses the clinical standard drug, was used in a clinical trial for mild to moderate hypertension in patients with a double-blind phase II trial. Sartan, ...
Claims
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