CN113980096A - Process for synthesizing ton-grade perindopril tert-butylamine - Google Patents
Process for synthesizing ton-grade perindopril tert-butylamine Download PDFInfo
- Publication number
- CN113980096A CN113980096A CN202111433701.0A CN202111433701A CN113980096A CN 113980096 A CN113980096 A CN 113980096A CN 202111433701 A CN202111433701 A CN 202111433701A CN 113980096 A CN113980096 A CN 113980096A
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- CN
- China
- Prior art keywords
- butylamine
- under reduced
- reduced pressure
- reaction
- perindopril tert
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- 238000000034 method Methods 0.000 title claims abstract description 36
- IYNMDWMQHSMDDE-MHXJNQAMSA-N perindopril erbumine Chemical compound CC(C)(C)N.C1CCC[C@@H]2N(C(=O)[C@H](C)N[C@@H](CCC)C(=O)OCC)[C@H](C(O)=O)C[C@@H]21 IYNMDWMQHSMDDE-MHXJNQAMSA-N 0.000 title claims abstract description 31
- 230000002194 synthesizing effect Effects 0.000 title claims description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- AUVAVXHAOCLQBF-YUMQZZPRSA-N (2s)-2-[[(2s)-1-ethoxy-1-oxopentan-2-yl]azaniumyl]propanoate Chemical compound OC(=O)[C@H](C)N[C@@H](CCC)C(=O)OCC AUVAVXHAOCLQBF-YUMQZZPRSA-N 0.000 claims abstract description 11
- 238000002360 preparation method Methods 0.000 claims abstract description 11
- PTLASYHTXGUCJU-WDTSGDEMSA-N benzyl (2s,3as,7as)-2,3,3a,4,5,6,7,7a-octahydro-1h-indole-2-carboxylate;4-methylbenzenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1.O=C([C@H]1N[C@H]2CCCC[C@H]2C1)OCC1=CC=CC=C1 PTLASYHTXGUCJU-WDTSGDEMSA-N 0.000 claims abstract description 9
- QNRXNRGSOJZINA-QMMMGPOBSA-N (2s)-2,3-dihydro-1h-indole-2-carboxylic acid Chemical compound C1=CC=C2N[C@H](C(=O)O)CC2=C1 QNRXNRGSOJZINA-QMMMGPOBSA-N 0.000 claims abstract description 8
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 8
- SNDPXSYFESPGGJ-BYPYZUCNSA-N L-2-aminopentanoic acid Chemical compound CCC[C@H](N)C(O)=O SNDPXSYFESPGGJ-BYPYZUCNSA-N 0.000 claims abstract description 7
- SNDPXSYFESPGGJ-UHFFFAOYSA-N L-norVal-OH Natural products CCCC(N)C(O)=O SNDPXSYFESPGGJ-UHFFFAOYSA-N 0.000 claims abstract description 4
- 230000002829 reductive effect Effects 0.000 claims description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
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- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 6
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- CQYBNXGHMBNGCG-FXQIFTODSA-N (2s,3as,7as)-2,3,3a,4,5,6,7,7a-octahydro-1h-indol-1-ium-2-carboxylate Chemical compound C1CCC[C@@H]2[NH2+][C@H](C(=O)[O-])C[C@@H]21 CQYBNXGHMBNGCG-FXQIFTODSA-N 0.000 claims description 5
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 5
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- 239000000463 material Substances 0.000 claims description 5
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- 239000000203 mixture Substances 0.000 claims description 4
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 claims description 4
- 239000012071 phase Substances 0.000 claims description 4
- 238000003825 pressing Methods 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- DAEPDZWVDSPTHF-UHFFFAOYSA-M sodium pyruvate Chemical compound [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 0.000 claims description 4
- 238000009987 spinning Methods 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 3
- RPNNPZHFJPXFQS-UHFFFAOYSA-N methane;rhodium Chemical compound C.[Rh] RPNNPZHFJPXFQS-UHFFFAOYSA-N 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 3
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 2
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- 238000006297 dehydration reaction Methods 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
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- 239000012074 organic phase Substances 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 229940054269 sodium pyruvate Drugs 0.000 claims description 2
- 239000003638 chemical reducing agent Substances 0.000 claims 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims 1
- 238000002425 crystallisation Methods 0.000 claims 1
- 230000008025 crystallization Effects 0.000 claims 1
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- 238000011085 pressure filtration Methods 0.000 claims 1
- 238000005406 washing Methods 0.000 claims 1
- 150000003839 salts Chemical class 0.000 abstract description 6
- 238000009903 catalytic hydrogenation reaction Methods 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- 238000009833 condensation Methods 0.000 abstract description 3
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- 239000007858 starting material Substances 0.000 abstract description 2
- 229960002582 perindopril Drugs 0.000 description 15
- IPVQLZZIHOAWMC-QXKUPLGCSA-N perindopril Chemical compound C1CCC[C@H]2C[C@@H](C(O)=O)N(C(=O)[C@H](C)N[C@@H](CCC)C(=O)OCC)[C@H]21 IPVQLZZIHOAWMC-QXKUPLGCSA-N 0.000 description 15
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- -1 Perindopril erbumine salt Chemical class 0.000 description 6
- 229940125904 compound 1 Drugs 0.000 description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
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- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 4
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 2
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- QPAOQVAYDANIBL-RGURZIINSA-N (2s)-2-[ethoxycarbonyl(2-ethoxycarbonylbutyl)amino]propanoic acid Chemical compound CCOC(=O)C(CC)CN([C@@H](C)C(O)=O)C(=O)OCC QPAOQVAYDANIBL-RGURZIINSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Life Sciences & Earth Sciences (AREA)
- Indole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a synthetic process method of ton-grade perindopril tert-butylamine, which comprises the following steps: the (S) -indoline-2-carboxylic acid (2) is subjected to catalytic hydrogenation and condensation to form salt to obtain mother ring (2S,3aS,7aS) -octahydroindole-2-carboxylic acid benzyl ester p-toluenesulfonate (4). The side chain N- [ (S) -1-ethoxycarbonylbutyl ] - (S) -alanine (6) is synthesized in one step by taking L-norvaline (5) as a starting material. 4 and 6 are condensed and hydrogenated to form salt, thus obtaining perindopril tert-butylamine salt (1), and the purity of the product reaches 99.86 percent. The method provided by the invention has the advantages of easily available raw materials, convenience in operation, good reaction selectivity, high yield, low requirements on instruments and equipment, greenness and environmental friendliness, can be used for large-scale preparation of perindopril tert-butylamine compounds, and is applied to the fields of organic synthesis, medicinal chemistry and the like.
Description
Technical Field
The invention relates to organic chemistry and pharmaceutical chemistry, in particular to a synthesis process of perindopril tert-butylamine salt.
Background
Perindopril erbumine salt (Perindopril erbumine salt), which is known aS (2S,3aS,7aS) -1- [ (2S) -2- [ [ (1S) -1- (ethoxycarbonyl) butyl ] amino ] propionyl ] octahydro-1H-indole-2-carboxylic acid tert-butylamine salt, is an angiotensin converting enzyme inhibitor developed by Schweiya (Sernier) of France and marketed in France in 1989.
The product is a third generation Angiotensin Converting Enzyme (ACE) inhibitor with strong and long effect, can provide 24 hr control of blood pressure, and can be widely used for treating cardiovascular system diseases, and can reduce peripheral vascular resistance without change of cardiac output and heart rate. It has effects of dilating and repairing artery blood vessel, relieving left ventricular hypertrophy, correcting myocardial hypertrophy and endomembrane excessive collagen, and reducing perfusion arrhythmia, and can be used for treating hypertension and congestive heart failure.
ACE plays an important role in the pathophysiology of hypertension by providing angiotensin (Ang) I to Ang II, providing vasoconstriction, and stimulating the adrenal cortex to secrete aldosterone. Perindopril, which is the free acid form of perindopril tert-butylamine, is a prodrug that is hydrolyzed mainly in the liver to perindopril base, thereby lowering blood pressure by lowering the activity of plasma Ang II. Many studies have shown that perindopril, besides its effectiveness in terms of its tolerability and tolerability in the treatment of hypertension and congestive heart failure, also reduces the risk of patients with stable coronary heart disease and previous stroke or transient ischemic attacks. The most common Adverse Events (AE) perindopril cause cough, hypotension, gastrointestinal discomfort, visual impairment and dizziness. This occurs in all patients receiving ACEI treatment for cough and hypotension, but the incidence of perindopril is lower compared to other drugs. Perindopril is usually administered in combination with other blood pressure medications in clinical practice to improve its therapeutic efficacy and to improve the cationic compliance of the medication.
Perindopril is absorbed quickly after oral administration, the bioavailability can reach 65-95%, and the bioavailability of peripheral Endolaprilat is about 16-19%. As food intake affects the bioavailability of perindopril a and perindopril should be taken before meals to perindopril a, perindopril. Previous studies found maximum plasma concentration (C) max) Perindopril is reached within 1 hour after oral administration, and CmaxPerindopril is reached after 3-4 hours. It has also been reported that plasma protein binding rate of perindopril is reduced by some 10-20% compared to perindopril, about 60%. National half-life (t) for the elimination of perindopril1/2) About 1 hour, while t is free1/2PerindoprilatMuch longer (about 30-120 hours). This single-center, open label, randomized, crossover, bioequivalence study was conducted to evaluate the test envelope bioequivalence ondol tert-butylamine tablets (Sichuan sea Cisco pharmaceutical Co., Ltd.) Ltd, Chinese Chengdu) and reference perindopril tert-butylamine tablets (Acertil @, Schuyvera (Tianjin) pharmaceutical Co., Ltd., Tianjin, China) healthy Chinese subjects under fasting conditions (crossover at stage 2) and extended feeding (crossover at stage 4) conditions due to increased variability in absorption in the presence of food. Pharmacokinetic (PK) characterization of 4 mg tolerability perindopril tert-butylamine tablets was also assessed.
At present, there are mainly 4 methods for synthesizing compound 1 reported. First, the diastereomer method: the (2S,3aS,7aS) -octahydroindole-2-carboxylic acid ethyl ester and L-alanine protected by amino are condensed, hydrolyzed and deprotected to obtain (2S) -1- [ (S) -propylaminoyl ] -2-octahydroindole-2-carboxylic acid ethyl ester, and then the ethyl ester and ethyl pyruvate are subjected to reductive amination to obtain a mixture of 2 diastereomers, and finally the mixture is subjected to resolution and salt formation to obtain a compound 1 with a total yield of 17%. Trifluoroacetic acid used in the method has strong corrosivity, and the final resolution process is immature, so that the material loss is large.
The second lactone anhydride method: n- (2-ethoxycarbonylbutyl) alanine is condensed with phosgene to form a five-membered cyclic anhydride compound, and then condensed with (2S,3aS,7aS) -octahydroindole-2-carboxylic acid (3) to form a salt to obtain a compound 1, wherein the total yield is 64%. The method has short route and stable process, but uses the highly toxic phosgene as a reaction reagent, so that the industrial production has high risk.
The third acyl chloride method: reacting N- (2-ethoxycarbonylbutyl) alanine with ethyl chloroformate to protect amino to obtain N- (2-ethoxycarbonylbutyl) -N-ethoxycarbonylalanine, reacting with thionyl chloride to generate acyl chloride, condensing with a compound 3, deprotecting and salifying to obtain a compound 1 with a total yield of 45%. The synthetic route is stable and suitable for industrial production, but the total yield is low.
Fourth active ester method: condensing L-norvaline ethyl ester and pyruvic acid, carrying out asymmetric catalytic hydrogenation to generate N- [ (S) -1-ethoxycarbonylbutyl ] - (S) -alanine (6), and carrying out condensation, catalytic hydrogenation and deprotection on the N- [ (S) -1-ethoxycarbonylbutyl ] - (S) -alanine and a compound 3 protected by ethyl ester or benzyl ester to obtain a compound 1, wherein the total yield is 55%.
The above reported processes all have the problem that the yield cannot be improved in mass production, so we have improved the process for perindopril tert-butylamine which is industrially produced in ton grade.
Disclosure of Invention
The invention aims to overcome the technical defects, provides a synthesis method, provides a simple technological method for synthesizing perindopril tert-butylamine with industrial yield, improves the low stability of the existing perindopril tert-butylamine salt tablets, screens a perindopril technological formula, and improves the stability under the condition of reaction damp heat.
In order to achieve the technical purpose, the invention adopts the following technical scheme based on an active ester method, and specifically comprises the following steps:
compared with the prior art, the beneficial effects are as follows:
the invention provides a process method of ton-grade perindopril tert-butylamine, which takes (S) -indoline-2-carboxylic acid (2) aS a raw material, and obtains mother ring (2S,3aS,7aS) -octahydroindole-2-carboxylic acid benzyl ester p-toluenesulfonate (4) through catalytic hydrogenation and condensation salt formation. The side chain N- [ (S) -1-ethoxycarbonylbutyl ] - (S) -alanine (6) is synthesized in one step by taking L-norvaline (5) as a starting material. 4 and 6 are condensed and hydrogenated to form salt, thus obtaining perindopril tert-butylamine salt (1). In the 2 hydrogenation, palladium or rhodium carbon is used for catalysis, the hydrogenation pressure is reduced from 5MPa to 2.5MPa, the hydrogenation time is shortened from 40 h to about 6h, and the yield is 81%. In the final step of synthesis, a proper amount of water is added into a hydrogenation solvent, and a hydrogenation and salification one-pot method is adopted, so that the generation of impurities (S) -2- [ (3S,5aS,9aS,10aS) -3-methyl-1, 4-dioxydecahydropyrazino [1,2-a ] indole-2 (1H) -yl ] ethyl valerate (7) can be inhibited, and the purity of the product reaches 99.86%. The purity is very high, no further purification measures are needed, the yield is not lower than that of the existing perindopril tert-butylamine preparation process, the purity is higher than that of the existing process, the cost is lower, and the industrial popularization is easy. The method provided by the invention has the advantages of easily available raw materials, convenience in operation, good reaction selectivity, high yield, low requirements on instruments and equipment, greenness and environmental friendliness, can be used for large-scale preparation of perindopril tert-butylamine compounds, and is applied to the fields of organic synthesis, medicinal chemistry and the like.
Detailed Description
The following examples further illustrate the technical solutions of the present invention, but should not be construed as limiting the scope of the present invention.
The embodiment of the invention provides a process method of ton-grade perindopril tert-butylamine, which comprises the following steps:
example 1: preparation of (2S,3aS,7aS) -octahydroindole-2-carboxylic acid (3).
(S) -indoline-2-carboxylic acid (2, Shanghai Bidi medical science and technology Co., Ltd., purity 99.1%, 180kg, 1104mol), methanol (1080kg) and 5% rhodium carbon (19.2kg) or 7% palladium carbon were added to a hydrogenation reactor, the temperature was controlled at 50 ℃ and the pressure was controlled at 2.5MPa, and the reaction was carried out for 6 hours, but the reaction time was shortened or prolonged by several hours. After the hydrogenation was completed, the reaction mixture was cooled to 35 ℃ and press-filtered, the filter cake was washed with water (40kg), and the filtrate was concentrated to dryness under reduced pressure at 60 ℃. Adding dioxane (1900kg) and water (180 kg) into the residue, heating to 85 ℃, stirring until the solid is dissolved clearly, cooling and crystallizing for 2-3 h, performing filter spinning, drying the filter cake at 45-55 ℃ under reduced pressure for 2h, heating to 85 ℃ and drying under reduced pressure for about 14h to obtain a white solid 3(151kg, 81%), the purity is 98.48%, and the content of isomers is 0.90% [ HPLC peak area normalization method chromatographic column Y: MC-Triart PFP column (4.6mm × 250mm,5 μm); mobile phase A is 1% trifluoroacetic acid solution, B is acetonitrile, gradient elution (0-8 min: A85%, 8-15 min: A85% -40%, 15-18 min: A40%, 18-18.1 min: A40% -85%, 18.1-23 min: A85%); the column temperature is 35 ℃; the flow rate is 1.0 ml/min; detector electrospray detector (CAD); retention time 37.5 min, 88.5 min]。1 H NMR(400MHz, CD3OD)δ:4.32(brs,1H),3.90～3.95(m,1H),3.59(brs,1H),2.21～2.36(m,2H),1.86～2.09(m,1H),1.61～1.84(m,2H),1.50～1.61(m,2H),1.27～1.50(m,4H) ；13C NMR(100 MHz,CD 3 OD)δ:173.42,59.53,59.42,58.69,37.36,32.76,25.47,24.94,24.91,21.53, 21.49；ESI-TOF+-HRMS(m/z): 170.117 2[M+H]+。
Example 2: preparation of benzyl (2S,3aS,7aS) -octahydroindole-2-carboxylate p-toluenesulfonate (4).
3(90kg, 533mol), p-toluenesulfonic acid monohydrate (112kg, 589mol), benzyl alcohol (144kg, 1333 mol) and toluene (840L) are added into a reaction kettle, the temperature is increased to 110 ℃, and reflux reaction is carried out for about 14 hours. After the reaction was completed, the reaction mixture was cooled to about 60 ℃ and concentrated to dryness under reduced pressure. Ethyl acetate (900L) was added, the temperature was reduced to about 5 ℃, the crystals were crystallized for 2h, filtered by shaking, the filter cake was dried at room temperature under reduced pressure for 2h, then heated to 65 ℃ and dried under reduced pressure for 20h to give a white solid 4(218kg, 95%) with a purity of 98.40% [ HPLC peak area normalization: a chromatographic column Shimpack CLC-ODS column (6.0 mm. times.150 mm,5 μm); mobile phase A is buffer solution (1.38 g sodium dihydrogen phosphate is dissolved in 1000ml water, and the pH is adjusted to 2.7 by concentrated phosphoric acid), B is acetonitrile, gradient elution (0-15 min: A70%, 15-20 min: A70% -30%, 20-35 min: A30%, 35-40 min: A30% -70%, 40-45 min: A70%); the column temperature is 35 ℃; the flow rate is 1.0 ml/min; the detection wavelength is 215 nm; retention time 10.8min]。mp 161～162 ℃；1H NMR(400MHz, DMSO-d6)δ:7.47(t,J=6.6 Hz,2H),7.30～7.43(m,5H),7.06～7.13(m, 2H),5.21(t,J=8.5 Hz,2H),4.49(dd,J=12.0、5.5 Hz,1H),3.54～3.60(m,1H),2.23～2.33(m,5H),1.97～2.06(m,1H),1.76～1.84(m,1H),1.56(dd,J=23.8、15.6Hz,3H),1.27(t,J=29.8Hz,4H) ；13C NMR(100MHz,DMSO-d6)δ:169.94,145.82,138.23,135.51,128.93, 128.88,128.74,128.53,125.91,68.01,58.95,57.81,36.55,30.64,24.85,24.37,22.54, 21.21,20.17；ESI-TOF+-HRMS(m/z):260.163 0[M–TsOH+H] +。
Example 3: preparation of N- [ (S) -1-ethoxycarbonylbutyl ] - (S) -alanine (6).
Adding L-norvaline (5, 150 kg, 1282 mol) and absolute ethyl alcohol (1200L) into a reaction kettle, controlling the temperature to be 5 ℃, slowly and dropwise adding thionyl chloride (190 kg, 1597 mol), and finishing dropping for about 9 hours. Raising the temperature to 60 ℃, and keeping the temperature for reaction for about 4 hours. After the reaction is finished, concentrating the mixture to be dry at 45-55 ℃ under reduced pressure. Adding into the concentrate in sequenceAdding water (800L), absolute ethyl alcohol (900L), sodium pyruvate (160 kg, 1455 mol) and 7% palladium carbon (11.5 kg), and carrying out hydrogenation reaction at room temperature and 0.4MPa for about 16 h. And after the hydrogenation is finished, performing filter pressing, and adjusting the pH value of the filtrate to 3.5-4.0 by using concentrated hydrochloric acid (5-15L). Controlling the temperature to be not higher than 60 ℃, distilling the solvent under reduced pressure until a large amount of solids are separated out from the materials, cooling to about 0 ℃, crystallizing for about 3 hours, and performing filter spinning. Adding the filter cake into a reaction kettle, adding water (600L) and absolute ethyl alcohol (600L), stirring and heating to 45 ℃, and dissolving to be clear. Controlling the temperature to be not higher than 60 ℃, distilling under reduced pressure until a large amount of solid is separated out from the material, cooling to about 0 ℃, crystallizing for about 3 hours, filtering by throwing, drying the filter cake at 35 ℃ under reduced pressure for 2 hours, then heating to about 70 ℃ and drying under reduced pressure for 20 hours to obtain white solid 6 (125 kg, 45 percent), the purity of 99.32 percent, and the isomer N- [ (R) -1-ethoxycarbonyl butyl) s]Content of- (S) -alanine 0.58% [ HPLC peak area normalization: the chromatographic conditions are the same as 3; retention time 9.5 min, isomer 10.6 min]。mp 158～159 ℃。1H NMR(400 MHz, DMSO-d6 )δ: 4.05(dd, J=14.1、7.0 Hz, 2H), 3.22(dt, J=6.6、1.8 Hz, 1H), 3.10～3.16(m, 1H), 1.47(dt, J=12.7、6.4 Hz, 2H), 1.27(dd, J=15.0、7.5 Hz, 2H), 1.10～1.21(m, 6H), 0.82(t, J=7.3 Hz, 3H) ；13C NMR(100 MHz,DMSO-d6 )δ: 175.92, 174.50, 60.46, 59.14, 54.79,35.16, 19.18, 18.85, 14.55, 14.09 ；ESI-TOF + -HRMS(m/z): 218.135 5[M+H] +。
Example 4: preparation of perindopril tert-butylamine salt (1)
Sodium bicarbonate (60 kg, 714 mol), water (1000L) and 4 (200 kg, 464 mol) were added to the reaction kettle and stirred at room temperature for about 1 h. Dichloromethane (700L) was added for extraction, the layers were separated and the aqueous layer was extracted with dichloromethane (300L). After the organic phases are combined, 6 (105 kg, 483 mol) and 1-hydroxybenzotriazole [ HOBT, 17.6 kg, 130 mol are added in turn, wherein hydrazine hydrate (less than or equal to 500X 10) is a potential genotoxic impurity–6) And ortho-nitrochlorobenzene (less than or equal to 93X 10)–6) Uniform lighting established index control]Triethylamine (8 kg, 79 mol) and dicyclohexylcarbodiimide (DCC, 98 kg, 476 mol) were reacted at 30 ℃ for 4 h. Filter pressing after the reaction (mainly removing the side product of DCC reaction)The product dicyclohexylurea), the filtrate was washed with 3% sodium bicarbonate solution (600L × 2) (mainly to remove HOBT and excess 6), then with water (600L), and concentrated to dryness at 30-50 deg.C under reduced pressure. Then, ethyl acetate (1100L), 7% palladium on charcoal (12 kg), water (55 kg) and tert-butylamine (40kg, 546 mol) were added, and hydrogenation was carried out at room temperature and under a hydrogen pressure of 0.3 to 0.5 MPa, preferably 0.4MPa, for 4 to 6 hours, followed by TLC [ developing solvent: methylene chloride methanol (10: 1)]Monitoring until the reaction is complete. And (2) after hydrogenation, performing filter pressing, controlling the temperature to be less than or equal to 40 ℃, performing reflux dehydration under reduced pressure until the moisture content of the materials in the kettle is less than or equal to 1.5%, adding ethyl acetate (900L), heating to 75 ℃, stirring, dissolving, slowly cooling to 0 ℃, crystallizing for 1-2 h, performing filter spinning, drying a filter cake under reduced pressure at room temperature for 2h, heating to 40-50 ℃, preferably 45 ℃, and drying under reduced pressure for 12h to obtain a white solid 1(174 kg, 85%), the purity is 99.86%, and the content of an impurity 7 is 0.03% [ HPLC peak area normalization method: an Inertsil C8 column (4.0 mm. times.150 mm,5 μm) was used as a chromatographic column; mobile phase A is water (adjusted to pH 2.5 with perchloric acid), B is acetonitrile solution containing 0.03% perchloric acid, gradient elution (0-5 min: A95%, 5-60 min: A95% -40%, 60-65 min: A40% -95%, 65-75 min: A95%); the column temperature is 60 ℃; the flow rate is 1.0 ml/min; the detection wavelength is 215 nm; retention time 124.5 min, 738.6 min]. Optical purity 99.96%, isomer (2S,3aS,7aS) -1- [ (2S) -2- [ [ (1R) -1- (ethoxycarbonyl) butyl)]Amino group]Propionyl group]Content of octahydro-1H-indole-2-carboxylic acid<0.02％。
As can be seen from the above examples, the method of the present invention has the advantages of mild reaction conditions, wide application range, tolerance to functional groups, simple operation, low requirements for instruments and equipment, high yield, and simple and easily available raw materials.
The above-described embodiments of the present invention should not be construed as limiting the scope of the present invention. Any other corresponding changes and modifications made according to the technical idea of the present invention should be included in the protection scope of the claims of the present invention.
Claims (9)
1. A process for synthesizing perindopril tert-butylamine with large yield is characterized by comprising the following steps:
(1) adding (S) -indoline-2-carboxylic acid (2), methanol and a reducing agent into a hydrogenation kettle to obtain white solid (2S,3aS,7aS) -octahydroindole-2-carboxylic acid (3);
(2) adding (2S,3aS,7aS) -octahydroindole-2-carboxylic acid, p-toluenesulfonic acid monohydrate, benzyl alcohol and toluene into a reaction kettle to obtain a white solid (2S,3aS,7aS) -octahydroindole-2-carboxylic acid benzyl ester p-toluenesulfonic acid salt (4);
(3) adding L-norvaline (5) and absolute ethanol into a reaction kettle to obtain white solid N- [ (S) -1-ethoxycarbonylbutyl ] - (S) -alanine (6);
(4) adding sodium bicarbonate, water and (2S,3aS,7aS) -octahydroindole-2-carboxylic acid benzyl ester p-toluenesulfonate into a reaction kettle, and stirring at room temperature for about 1 h; adding dichloromethane for extraction, separating liquid, and extracting the water phase with dichloromethane; after the organic phases are combined, N- [ (S) -1-ethoxycarbonylbutyl ] - (S) -alanine (6), 1-hydroxybenzotriazole, triethylamine and DCC are added in sequence, and the mixture reacts for 4 hours at the temperature of 30 ℃ to obtain perindopril tert-butylamine salt after treatment.
2. A process for the synthesis of perindopril tert-butylamine according to claim 1, characterized in that said reducing agent can be rhodium carbon.
3. A process according to claim 1, wherein said reducing agent is palladium on carbon.
4. A process according to claim 1, wherein the temperature during the concentration under reduced pressure is preferably 45-55 ℃.
5. A process according to any one of claims 2-4, wherein the hydrogenation temperature of (S) -indoline-2-carboxylic acid is controlled preferably at 50 ℃, the pressure is 2.5MPa, and the reaction time is preferably 6 h; after the hydrogenation is finished, cooling to 35 ℃, performing filter pressing, washing, and concentrating the filtrate under reduced pressure to be dry; adding dioxane and water into the residue, heating to 85 deg.C, stirring until the solid is dissolved, cooling, crystallizing for 2.5 h, filtering, drying the filter cake at 50 deg.C under reduced pressure for 2h, heating to 85 deg.C, and drying under reduced pressure for 14 h.
6. A process for the synthesis of perindopril tert-butylamine according to any one of claims 2-4, characterized in that: heating to 110 ℃ in the preparation process of (2S,3aS,7aS) -octahydroindole-2-carboxylic acid benzyl ester p-toluenesulfonate (4), and carrying out reflux reaction for 14 h; after the reaction is finished, cooling to 60 ℃, and concentrating under reduced pressure to be dry; adding ethyl acetate, cooling to 5 deg.C, crystallizing for 2 hr, filtering, drying the filter cake at room temperature under reduced pressure for 2 hr, and heating to 65 deg.C for 20 hr.
7. A process for synthesizing perindopril tert-butylamine according to any one of claims 2 to 4, wherein the temperature is controlled at 5 ℃ in the preparation process of N- [ (S) -1-ethoxycarbonylbutyl ] - (S) -alanine (6), thionyl chloride is slowly added dropwise, the temperature is raised to 60 ℃, the temperature is kept for reaction for 4h, and after the reaction is finished, the reaction is concentrated under reduced pressure to be dry; adding water, absolute ethyl alcohol, sodium pyruvate and 7% palladium carbon into the concentrate in sequence, and carrying out hydrogenation reaction for 16 h at the room temperature of 25 ℃ and the pressure of 0.4 MPa; multiple aftertreatment and drying under reduced pressure.
8. A process for the synthesis of perindopril tert-butylamine according to any one of claims 2 to 4, characterized in that the preparation reaction of perindopril tert-butylamine is completed and then filter-pressed, the filtrate is washed with 3% sodium bicarbonate solution, then washed with water and concentrated to dryness under reduced pressure; then adding ethyl acetate, 7% palladium-carbon, water and tert-butylamine, and carrying out hydrogenation reaction for 5 hours at the room temperature under the hydrogen pressure of 0.4MPa until the reaction is complete; and (3) after hydrogenation, performing pressure filtration, controlling the temperature to be not higher than 40 ℃, performing reflux dehydration under reduced pressure until the moisture content of the materials in the kettle is not more than 1.5%, adding ethyl acetate, heating to 75 ℃, stirring for dissolving, slowly cooling to 0 ℃, performing crystallization, performing filter spinning, drying the filter cake at room temperature under reduced pressure for 2 hours, heating to 45 ℃, and drying under reduced pressure for 12 hours.
9. A process for the synthesis of perindopril tert-butylamine according to any one of claims 2 to 4, characterized in that the yield of perindopril tert-butylamine salt preparation is 85%
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Application publication date: 20220128 |