CN113549126B - Preparation method of ramipril - Google Patents
Preparation method of ramipril Download PDFInfo
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- CN113549126B CN113549126B CN202010328000.XA CN202010328000A CN113549126B CN 113549126 B CN113549126 B CN 113549126B CN 202010328000 A CN202010328000 A CN 202010328000A CN 113549126 B CN113549126 B CN 113549126B
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- phenylpropyl
- alanine
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- HDACQVRGBOVJII-JBDAPHQKSA-N ramipril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](C[C@@H]2CCC[C@@H]21)C(O)=O)CC1=CC=CC=C1 HDACQVRGBOVJII-JBDAPHQKSA-N 0.000 title claims abstract description 23
- 229960003401 ramipril Drugs 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- CEIWXEQZZZHLDM-AAEUAGOBSA-N (2s)-2-[[(2s)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino]propanoic acid Chemical compound CCOC(=O)[C@@H](N[C@@H](C)C(O)=O)CCC1=CC=CC=C1 CEIWXEQZZZHLDM-AAEUAGOBSA-N 0.000 claims abstract description 46
- 238000000034 method Methods 0.000 claims abstract description 19
- DYWSVUBJGFTOQC-UHFFFAOYSA-N xi-2-Ethylheptanoic acid Chemical compound CCCCCC(CC)C(O)=O DYWSVUBJGFTOQC-UHFFFAOYSA-N 0.000 claims abstract description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 78
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 72
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 48
- 238000003756 stirring Methods 0.000 claims description 41
- 238000006243 chemical reaction Methods 0.000 claims description 40
- 239000000706 filtrate Substances 0.000 claims description 28
- 238000001914 filtration Methods 0.000 claims description 28
- 239000012074 organic phase Substances 0.000 claims description 28
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims description 23
- 238000005406 washing Methods 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- 238000002425 crystallisation Methods 0.000 claims description 12
- 230000008025 crystallization Effects 0.000 claims description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 9
- 239000007788 liquid Substances 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 238000004321 preservation Methods 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 abstract description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 abstract description 8
- -1 tert-butoxycarbonyl (Boc) Chemical class 0.000 abstract description 6
- 238000009776 industrial production Methods 0.000 abstract description 4
- 125000006239 protecting group Chemical group 0.000 abstract description 4
- 238000006482 condensation reaction Methods 0.000 abstract description 3
- 238000005984 hydrogenation reaction Methods 0.000 abstract description 3
- 230000007547 defect Effects 0.000 abstract description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 17
- 239000000126 substance Substances 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 229960003767 alanine Drugs 0.000 description 8
- 239000013078 crystal Substances 0.000 description 8
- 239000012065 filter cake Substances 0.000 description 8
- 239000008213 purified water Substances 0.000 description 8
- 238000000967 suction filtration Methods 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 6
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- BAZAXWOYCMUHIX-UHFFFAOYSA-M sodium perchlorate Chemical compound [Na+].[O-]Cl(=O)(=O)=O BAZAXWOYCMUHIX-UHFFFAOYSA-M 0.000 description 4
- 229910001488 sodium perchlorate Inorganic materials 0.000 description 4
- OQOGEOLRYAOSKO-UHFFFAOYSA-N 1,1-dichloro-1-nitroethane Chemical compound CC(Cl)(Cl)[N+]([O-])=O OQOGEOLRYAOSKO-UHFFFAOYSA-N 0.000 description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 239000005541 ACE inhibitor Substances 0.000 description 2
- 101710129690 Angiotensin-converting enzyme inhibitor Proteins 0.000 description 2
- 101710086378 Bradykinin-potentiating and C-type natriuretic peptides Proteins 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005658 halogenation reaction Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 150000003335 secondary amines Chemical class 0.000 description 2
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 1
- CXUJLPNJEHJGPZ-UHFFFAOYSA-N 2-ethylheptanoic acid;hydrochloride Chemical compound Cl.CCCCCC(CC)C(O)=O CXUJLPNJEHJGPZ-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 241000206601 Carnobacterium mobile Species 0.000 description 1
- 208000007530 Essential hypertension Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
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- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- 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)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Peptides Or Proteins (AREA)
Abstract
The invention provides a preparation method of ramipril, which changes the carboxyl on the traditional benzyl protection (S, S, S) -2-azabicyclo [3, 0] octane-3-carboxylate into tert-butoxycarbonyl (Boc) to protect the amino on N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine, obtains a key intermediate of ramipril through condensation reaction, and then removes a protecting group under the action of dilute hydrochloric acid to obtain a ramipril Li Zheyi strategy, thereby solving the technical defect that Pd-C/H 2 with higher danger coefficient has to be used for catalyzing hydrogenation and then removing benzyl finally because the carboxyl on the benzyl protection (S, S, S) -2-azabicyclo [3, 0] octane-3-carboxylate is adopted in the prior art. Meanwhile, the cost is reduced, and the method is more suitable for industrial production.
Description
Technical Field
The invention belongs to the field of organic chemical synthesis, and particularly relates to a preparation method of ramipril.
Background
Ramipril (Ramipril), having the chemical name (2 s,3as,6 as) -1- { (2 s) -2- { [ (1 s) -1- (ethoxycarbonyl) -3-phenylpropyl ] amino } propionyl } -octahydrocyclopenta [ b ] pyrrole-2-carboxylic acid, is a long-acting, potent Angiotensin Converting Enzyme Inhibitor (ACEI) developed by Hoechst, germany, and is suitable for patients with moderate and severe essential hypertension and moderate and malignant congestive heart failure, and has the characteristics of quick drug effect, long action time, high tissue specificity, low toxic and side effects, etc. in 1989, the ramipril is marketed for the first time in French.
There are many reports about the preparation methods of ramipril, but most of the preparation methods basically adopt benzyl to protect carboxyl on (S, S, S) -2-azabicyclo [3, 0] octane-3-carboxylate to obtain (S, S, S) -2-azabicyclo [3, 0] octane-3-carboxylate hydrochloride, then the benzyl hydrochloride is condensed with N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine or analogues thereof to form a key intermediate of ramipril, and then the target product ramipril is obtained by removing the protecting group benzyl through catalytic hydrogenation. For example, european patent EP0079022 (1983) reports a synthesis method of the formula I, which uses benzyl to protect carboxyl on (S, S, S) -2-azabicyclo [3, 0] octane-3-carboxylate, after resolution, the carboxyl is condensed with N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine, and then Pd/C catalytic hydrogenation is used to remove the protecting group to obtain ramipril, wherein Pd/C used for hydrogenation deprotection is inflammable, and the danger coefficient is high in hydrogenation reaction. Therefore, the process has higher requirements on reaction equipment and operation, has high risk coefficient, is not suitable for large-scale industrial production, and has the following reaction route:
Chinese patent CN101326151 reports another preparation method of ramipril, shown in formula ii, which also employs benzyl to protect the carboxyl group on (S, S) -2-azabicyclo [3, 0] octane-3-carboxylate, and Pd/C in the hydrodebenzyl stage. Therefore, the method is also not suitable for large-scale industrial production, and the reaction route is as follows:
Patent CN101855207a reports that ramipril is obtained directly by coupling reaction without any protection of the secondary amine of the reactant, but it is found by analysis that it requires an acyl halogenation reaction to activate the reactant before the coupling reaction is carried out, and it is known that the acyl halogenation reaction does not conform to the concept of green chemistry, and the secondary amine of the reactant is not protected, self-condensed impurities are extremely easy to generate, and in addition, the reaction of this route requires a reaction under extremely low temperature of-40 ℃, so severe reaction conditions are difficult to realize in the scale-up production stage. Therefore, developing a new route which is efficient, mild in reaction conditions, less in generated impurities and suitable for industrial method production has important significance.
Disclosure of Invention
The invention provides a preparation method of ramipril, which changes the carboxyl on the traditional benzyl protection (S, S, S) -2-azabicyclo [3, 0] octane-3-carboxylate into tert-butoxycarbonyl (Boc) to protect the amino on N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine, obtains a key intermediate of ramipril through condensation reaction, and then removes a protecting group under the action of dilute hydrochloric acid to obtain a ramipril Li Zheyi strategy, thereby solving the technical defect that Pd-C/H2 with higher danger coefficient has to be used for catalytic hydrogenation and then removing benzyl finally because the carboxyl on the benzyl protection (S, S, S) -2-azabicyclo [3, 0] octane-3-carboxylate is adopted in the prior art. Meanwhile, the cost is reduced, and the method is more suitable for industrial production.
The specific technical content of the invention is as follows:
Step 1: dissolving N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine in an organic solvent, adding triethylamine and di-tert-butyl dicarbonate, stirring at room temperature for reaction, concentrating under reduced pressure after the reaction is finished, adding ethyl acetate for dissolving, standing at low temperature for crystallization to obtain white crystalline amino-protected N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine;
step 2: adding the amino-protected N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine, an organic solvent, a condensing agent, hobt and triethylamine obtained in the step 1 into a reaction kettle, slowly adding (S, S, S) -2-azabicyclo [3, 0] octane-3-carboxylate under stirring at the temperature of 10-15 ℃, finishing the addition, carrying out heat preservation and stirring reaction, centrifuging and filtering after the reaction is finished, slowly adding dilute hydrochloric acid into the filtrate at the temperature of 10-15 ℃, carrying out heat preservation and stirring, centrifuging and filtering, separating liquid, collecting an organic phase, washing, concentrating the organic phase under reduced pressure to obtain oily matter, adding ethyl acetate for dissolving, and standing at low temperature for crystallization to obtain ramipril.
Preferably, the organic solvent in step 1 is chloroform, dichloromethane, diethyl ether or toluene, preferably dichloromethane.
Preferably, the mass volume ratio of the N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine to the organic solvent in the step 1 is 50-300: 1, mass in g and volume in L; preferably 100 to 200:1, mass in g and volume in L.
Preferably, the amount of di-tert-butyl dicarbonate used in step 1 is 1 to 2 times, preferably 1.2 to 1.5 times the mass of N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine.
Preferably, the amount of triethylamine described in step 1 is 0.36 to 0.72 times, preferably 0.5 to 0.6 times the mass of N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine.
Preferably, the reaction time in step 1 is 1.5 to 3 hours, preferably 2 to 2.5 hours.
Preferably, the low temperature in step 1 is 0 to 10 ℃, preferably 5 to 10 ℃.
Preferably, the organic solvent in step 2 is chloroform, dichloromethane, diethyl ether or toluene, preferably dichloromethane.
Preferably, the mass volume ratio of the amino-protected N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine to the organic solvent in the step 2 is 50-200: 1, mass in g and volume in L; preferably 50 to 100:1, mass in g and volume in L.
Preferably, the condensing agent in step 2 is DCC (dicyclohexylcarbodiimide), DIC (N, N' -diisopropylcarbodiimide), or EDC (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride); EDC is preferred.
Preferably, the molar ratio of amino-protected N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine to condensing agent, hobt and triethylamine described in step 2 is 1:1.1 to 1.8:1 to 1.7:1.8 to 3.8, preferably 1:1.3 to 1.5:1.1 to 1.4:2.3 to 3.
Preferably, the amount of (S, S, S) -2-azabicyclo [3, 0] octane-3-carboxylate salt described in step2 is 0.3-0.8 times, preferably 0.5 times the mass of the amino-protected N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine.
Preferably, the reaction time described in step 2 is from 5 to 8 hours, preferably from 6 to 7 hours.
Preferably, the low temperature in step 2 is 0 to 10 ℃, preferably 5 to 10 ℃.
Preferably, the time of the heat-preserving stirring in the step2 is 0.5 to 2 hours, preferably 1 hour.
Compared with the prior art, the invention has the technical effects that:
According to the invention, N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine protected by tert-butoxycarbonyl (Boc) is used as an initiator, a key intermediate of ramipril is obtained through condensation reaction, and then a protecting group is removed under the action of dilute hydrochloric acid, so that ramipril can be obtained.
Detailed Description
The invention is further illustrated by the following examples, with the understanding that: the examples of the present invention are intended to be illustrative of the invention and not limiting thereof, so that simple modifications of the invention based on the method of the invention are within the scope of the invention as claimed.
The product prepared by the method can be measured according to the Chinese pharmacopoeia standard, and the specific method is as follows:
According to high performance liquid chromatography (China general pharmacopoeia 0512), octadecylsilane chemically bonded silica is used as filler (NucleosilC column, 4.0mm×250mm,3 μm or column with equivalent efficacy), and the column temperature is 65deg.C. Mobile phase a sodium perchlorate buffer (2.0 g sodium perchlorate, 0.5ml triethylamine, 800ml water were added and dissolved, pH was adjusted to 3.6) with phosphoric acid) -acetonitrile (800:200). Mobile phase B sodium perchlorate buffer (sodium perchlorate 2.0g, triethylamine 0.5ml, water 300ml, pH 2.6 adjusted with phosphoric acid) -acetonitrile (300:700) was dissolved, and gradient eluted according to the following table, detection wavelength 210nm.
Example 1
N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine (279 g) was dissolved in methylene chloride (2L), triethylamine (139.5 g) and di-tert-butyl dicarbonate (362 g) were added under stirring, stirring was carried out at room temperature for 2 hours after completion of the addition, ethyl acetate (1L) was added after the reaction was completed, the reaction mixture was concentrated under reduced pressure at 35 to 45℃and allowed to stand still at 5℃for crystallization for 24 hours, suction filtration was carried out, and the filter cake was washed with N-heptane (80 mL) to give a white crystal with a yield of 94.6% (based on N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine) and an HPLC purity of 99.7%, MS-ESI M/z:379.16 (M+H) +.
Adding the obtained amino-protected N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine (300 g), methylene dichloride (4L), EDC (250 g), hobt (120 g) and triethylamine (180 g) into a reaction kettle, controlling the temperature to be 10-15 ℃, slowly adding (S, S, S) -2-azabicyclo [3, 0] octane-3-carboxylate (150 g) under stirring, finishing the addition, keeping the reaction for 6H, centrifuging and filtering to obtain filtrate, controlling the temperature to be 10-15 ℃, slowly adding 2M dilute hydrochloric acid (1L) into the filtrate, finishing the addition, keeping the temperature and stirring for 1H, centrifuging and filtering to obtain filtrate, separating liquid, collecting an organic phase, washing the organic phase once by 1L saturated sodium bicarbonate solution, washing three times by purified water (1L each time), concentrating the organic phase at 35-45 ℃ under reduced pressure to obtain oily substance, then adding ethyl acetate (1.2L), standing and crystallizing at 5 ℃ for 24H, centrifuging and filtering to obtain the ethide, wherein the yield of the ethide is 93.5% (3.5M (3-S-3M) and the amino-protected by the method is calculated by the method of (39M-3-HPLC/99M).
Example 2
N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine (279 g) was dissolved in methylene chloride (2L), triethylamine (167 g) and di-tert-butyl dicarbonate (418 g) were added under stirring, stirring was carried out at room temperature for 2.5 hours after the completion of the reaction, ethyl acetate (1L) was added after the concentration of the reaction solution at 35 to 45℃under reduced pressure, standing still and crystallization were carried out at 10℃for 24 hours, suction filtration was carried out, and the filter cake was washed with N-heptane (80 mL) to obtain white crystals with a yield of 92.5% (based on N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine), an HPLC purity of 99.5%, and MS-ESI M/z:379.16 (M+H) +.
Adding the obtained amino-protected N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine (300 g), dichloromethane (4L), EDC (287 g), hobt (150 g) and triethylamine (240 g) into a reaction kettle, controlling the temperature to be 10-15 ℃, slowly adding (S, S, S) -2-azabicyclo [3, 0] octane-3-carboxylate (150 g) under stirring, finishing the addition, keeping the temperature and stirring for 7H, centrifuging and filtering after the reaction is finished to obtain filtrate, controlling the temperature to be 10-15 ℃, slowly adding 2M dilute hydrochloric acid (1L) into the filtrate, finishing the addition, keeping the temperature and stirring for 1H, centrifuging and filtering to obtain filtrate, separating liquid, collecting an organic phase, washing the organic phase once by 1L of saturated sodium bicarbonate solution, washing three times by purified water (1L each time), concentrating the organic phase at 35-45 ℃ under reduced pressure to obtain oily substance, then adding ethyl acetate (1.2L), standing and crystallizing at 10 ℃ for 24H, centrifuging and filtering to obtain the ethyl acetate, wherein the yield of the ethyl acetate is 92.7% (based on the amino-protected N- [1- (S) -3-phenylpropyl ] -3-alanine) in percentage by HPLC/99 z:416.46 (M+H) +.
Example 3
N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine (279 g) was dissolved in methylene chloride (1.4L), triethylamine (100 g) and di-tert-butyl dicarbonate (279 g) were added under stirring, stirring was carried out at room temperature for 2.5 hours after completion of the addition, after completion of the reaction, the reaction mixture was concentrated under reduced pressure at 35 to 45℃and then ethyl acetate (0.5L) was added, and after standing crystallization at 5℃for 24 hours, suction filtration was carried out, the filter cake was washed with N-heptane (80 mL) to give white crystals with a yield of 92.3% (based on N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine) and an HPLC purity of 99.1%, MS-ESI M/z:379.16 (M+H) +.
Adding the obtained amino-protected N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine (300 g), dichloromethane (3L), EDC (210 g), hobt (105 g) and triethylamine (150 g) into a reaction kettle, controlling the temperature to be 10-15 ℃, slowly adding (S, S, S) -2-azabicyclo [3, 0] octane-3-carboxylate (90 g) under stirring, keeping the temperature for 6.5H after the addition is finished, centrifuging and filtering to obtain filtrate, controlling the temperature to be 10-15 ℃, slowly adding 2M dilute hydrochloric acid (1L) into the filtrate, keeping the temperature for 1H after the addition, centrifuging and filtering to obtain filtrate, separating liquid, collecting an organic phase, washing the organic phase once by 1L saturated sodium bicarbonate solution, washing three times by purified water (1L each time), concentrating the organic phase at 35-45 ℃ under reduced pressure to obtain oily substance, adding ethyl acetate (1.2L) for dissolving, standing at 5 ℃ for 24H, centrifuging and filtering to obtain the filtrate, and standing until the yield of the 2M dilute hydrochloric acid (1L) is higher than that the amino-protected by 2M (3-3M) is 5M (95-phenylpropyl) and the yield is higher than 99.95-3M (95M-3H/99Z) of the amino-protected amino-3-phenylpropyl-alanine, wherein the yield is calculated by HPLC.
Example 4
N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine (279 g) was dissolved in methylene chloride (2.8L), triethylamine (200.8 g) and di-tert-butyl dicarbonate (558 g) were added under stirring, stirring was carried out at room temperature for 2 hours after completion of the addition, after completion of the reaction, the reaction mixture was concentrated under reduced pressure at 35 to 45℃and then ethyl acetate (1L) was added, and after standing crystallization at 10℃for 24 hours, suction filtration was carried out, and the filter cake was washed with N-heptane (80 mL) to give white crystals with a yield of 92.6% (based on N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine) and an HPLC purity of 99.2%, MS-ESI M/z:379.16 (M+H) +.
Adding the obtained amino-protected N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine (300 g), methylene dichloride (6L), DIC (227 g), hobt (180 g) and triethylamine (300 g) into a reaction kettle, controlling the temperature to be 10-15 ℃, slowly adding (S, S, S) -2-azabicyclo [3, 0] octane-3-carboxylate (240 g) under stirring, finishing the addition, keeping the reaction for 6H, centrifuging and filtering to obtain filtrate, controlling the temperature to be 10-15 ℃, slowly adding 2M dilute hydrochloric acid (1L) into the filtrate, finishing the addition, keeping the temperature and stirring for 1H, centrifuging and filtering to obtain filtrate, separating liquid, collecting an organic phase, washing the organic phase once by 1L saturated sodium bicarbonate solution, washing three times by purified water (1L each time), concentrating the organic phase at 35-45 ℃ under reduced pressure to obtain oily substance, adding ethyl acetate (1.2L), standing and dissolving crystalline ramide at 10 ℃ for 24H, centrifuging and filtering to obtain the crystalline ramide at 10-15 ℃, wherein the yield of the amino-protected N- [1- (S-3-phenylpropyl) -2M (99.53M) is calculated by the purity of the amino-3-phenylpropyl) -L-alanine, and the yield of the amino-protected amino-3-phenylpropyl ] -L-alanine is calculated by HPLC.
Example 5
N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine (279 g) was dissolved in methylene chloride (2L), triethylamine (139.5 g) and di-tert-butyl dicarbonate (362 g) were added under stirring, stirring was carried out at room temperature for 2 hours after completion of the addition, ethyl acetate (1L) was added after the reaction was concentrated under reduced pressure at 35 to 45℃and allowed to stand still at 0℃for crystallization for 24 hours, suction filtration was carried out, and the filter cake was washed with N-heptane (80 mL) to give a white crystal with a yield of 91.3% (based on N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine), an HPLC purity of 98.5%, and MS-ESI M/z:379.16 (M+H) +.
Adding the obtained amino-protected N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine (300 g), methylene dichloride (4L), DCC (268 g), hobt (120 g) and triethylamine (180 g) into a reaction kettle, controlling the temperature to be 10-15 ℃, slowly adding (S, S, S) -2-azabicyclo [3, 0] octane-3-carboxylate (150 g) under stirring, finishing the addition, keeping the reaction for 6H, centrifuging and filtering to obtain filtrate, controlling the temperature to be 10-15 ℃, slowly adding 2M dilute hydrochloric acid (1L) into the filtrate, finishing the addition, keeping the temperature and stirring for 1H, centrifuging and filtering to obtain filtrate, separating liquid, collecting an organic phase, washing the organic phase once by 1L saturated sodium bicarbonate solution, washing three times by purified water (1L each time), concentrating the organic phase at 35-45 ℃ under reduced pressure to obtain oily substance, then adding ethyl acetate (1.2L), standing and crystallizing at 0 ℃ for 24H, centrifuging and filtering to obtain the ethyl acetate with the yield of 91.4% (1M-7M (1M) of the amino-3-phenylpropyl) -L-alanine, wherein the yield is calculated by ESZ-39M-7.96-7% of the amino-protected amino-3-phenylpropyl-L-alanine.
Example 6
N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine (279 g) was dissolved in methylene chloride (2L), triethylamine (139.5 g) and di-tert-butyl dicarbonate (362 g) were added under stirring, stirring was carried out at room temperature for 2 hours after completion of the addition, ethyl acetate (1L) was added after the reaction was completed, the reaction mixture was concentrated under reduced pressure at 35 to 45℃and allowed to stand still at 15℃for crystallization for 24 hours, suction filtration was carried out, and the filter cake was washed with N-heptane (80 mL) to give white crystals with a yield of 82.5% (based on N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine) and an HPLC purity of 99.0%, MS-ESI M/z:379.16 (M+H) +.
Adding the obtained amino-protected N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine (300 g), dichloromethane (4L), EDC (250 g), hobt (120 g) and triethylamine (180 g) into a reaction kettle, controlling the temperature to be 10-15 ℃, slowly adding (S, S, S) -2-azabicyclo [3, 0] octane-3-carboxylate (150 g) under stirring, finishing the addition, carrying out heat preservation for 6H, centrifuging and filtering to obtain filtrate, controlling the temperature to be 10-15 ℃, slowly adding 2M dilute hydrochloric acid (1L) into the filtrate, finishing the addition, carrying out heat preservation and stirring for 1H, centrifuging and filtering to obtain filtrate, separating liquid, collecting an organic phase, washing the organic phase once by 1L saturated sodium bicarbonate solution, washing three times by purified water (1L each time), concentrating the organic phase at 35-45 ℃ under reduced pressure to obtain oily substance, then adding ethyl acetate (1.2L), standing and crystallizing at 15 ℃ for 24H, centrifuging and filtering to obtain the ethyl acetate, and obtaining the ethyl-3.3% (by the method of which accounts for 3.3% of the amino-protected amino-3- (S-3-phenylpropyl) -L-alanine) with the purity of which is calculated by HPLC (3-HPLC): 416.46 (M+H) +.
Example 7
N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine (279 g) was dissolved in chloroform (2L), triethylamine (223.2 g) and di-tert-butyl dicarbonate (474 g) were added under stirring, stirring was carried out at room temperature for 2 hours after completion of the addition, ethyl acetate (1L) was added after the reaction was completed, the reaction mixture was concentrated under reduced pressure at 35 to 45℃and allowed to stand still at 10℃for crystallization for 24 hours, suction filtration was carried out, and the filter cake was washed with N-heptane (80 mL) to give white crystals with a yield of 88.6% (based on N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine), an HPLC purity of 98.2%, and MS-ESI M/z:379.16 (M+H) +.
Adding the obtained amino-protected N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine (300 g), chloroform (4L), DIC (252 g), hobt (240 g) and triethylamine (360 g) into a reaction kettle, controlling the temperature to be 10-15 ℃, slowly adding (S, S, S) -2-azabicyclo [3, 0] octane-3-carboxylate (150 g) under stirring, finishing the addition, keeping the reaction for 6H, centrifuging and filtering to obtain a filtrate, controlling the temperature to be 10-15 ℃, slowly adding 2M dilute hydrochloric acid (1L) into the filtrate, finishing the addition, keeping the temperature and stirring for 1H, centrifuging and filtering to obtain a filtrate, separating the filtrate, collecting an organic phase, washing the organic phase once by 1L saturated sodium bicarbonate solution, washing three times by purified water (1L each time), concentrating the organic phase at 35-45 ℃ under reduced pressure to obtain an oily substance, adding ethyl acetate (1.2L), standing and dissolving the oily substance at 10 ℃, centrifuging and filtering to obtain crystalline ramide at the temperature of 24H, wherein the yield of 86.2% (2M-phenylalanine is calculated by the method of (1-39M-3M) and the purity of the amino-protected amino-3- (S-3-phenylpropyl) -1-alanine, wherein the yield is calculated by the method is (39M-5-3H).
Example 8
N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine (279 g) was dissolved in toluene (2L), triethylamine (83.7 g) and di-tert-butyl dicarbonate (220 g) were added under stirring, stirring was carried out at room temperature for 2 hours after completion of the addition, ethyl acetate (1L) was added after the reaction was completed, the reaction mixture was concentrated under reduced pressure at 35 to 45℃and allowed to stand still at 5℃for crystallization for 24 hours, suction filtration was carried out, and the filter cake was washed with N-heptane (80 mL) to give a white crystal with a yield of 82.6% (based on N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine), HPLC purity of 99.0%, MS-ESI M/z:379.16 (M+H) +.
Adding the obtained amino-protected N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine (300 g), toluene (4L), DCC (206 g), hobt (90 g) and triethylamine (120 g) into a reaction kettle, controlling the temperature to be 10-15 ℃, slowly adding (S, S, S) -2-azabicyclo [3, 0] octane-3-carboxylate (150 g) under stirring, finishing the addition, keeping the reaction for 6H, centrifuging and filtering to obtain filtrate, controlling the temperature to be 10-15 ℃, slowly adding 2M dilute hydrochloric acid (1L) into the filtrate, finishing the addition, keeping the temperature and stirring for 1H, centrifuging and filtering to obtain filtrate, separating liquid, collecting an organic phase, washing the organic phase once by 1L saturated sodium bicarbonate solution, washing three times by purified water (1L each time), concentrating the organic phase at 35-45 ℃ under reduced pressure to obtain oily substance, then adding ethyl acetate (1.2L), standing and crystallizing at 5 ℃ for 24H, centrifuging and filtering to obtain the ethide with the yield of 83.5% (3.5% of the amino-protected N- [1- (S) -3-phenylpropyl ] -L-alanine (39M), wherein the yield is calculated by the method is 1-39M-3-HPLC (HPLC).
Claims (9)
1. The preparation method of ramipril is characterized by comprising the following specific preparation steps:
Step 1: dissolving N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine in an organic solvent, adding triethylamine and di-tert-butyl dicarbonate, stirring at room temperature for reaction, concentrating under reduced pressure after the reaction is finished, adding ethyl acetate for dissolving, standing at low temperature for crystallization to obtain white crystalline amino-protected N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine;
Step 2: adding the amino-protected N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine, an organic solvent, a condensing agent, hobt and triethylamine obtained in the step 1 into a reaction kettle, slowly adding (S, S, S) -2-azabicyclo [3, 0] octane-3-carboxylate under stirring at the temperature of 10-15 ℃, finishing the addition, carrying out heat preservation and stirring reaction, centrifuging and filtering after the reaction is finished, controlling the temperature to 10-15 ℃, slowly adding dilute hydrochloric acid into the filtrate, carrying out heat preservation and stirring, centrifuging and filtering, separating liquid, collecting an organic phase, washing, concentrating the organic phase under reduced pressure to obtain oily matter, adding ethyl acetate for dissolving, and standing at low temperature for crystallization to obtain ramipril;
。
2. The preparation method of claim 1, wherein the mass-volume ratio of the N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine to the organic solvent in the step 1 is 50-300: 1, mg/ml.
3. The process according to claim 1, wherein the amount of di-t-butyl dicarbonate used in the step 1 is 1 to 2 times the mass of N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine.
4. The process according to claim 1, wherein the amount of triethylamine used in the step 1 is 0.36 to 0.72 times the mass of N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine.
5. The process according to claim 1, wherein the organic solvent in step 2 is chloroform, methylene chloride, diethyl ether or toluene.
6. The method of claim 1, wherein the condensing agent in step 2 is DCC, DIC, or EDC.
7. The preparation method according to claim 1, wherein the mass ratio of the amino-protected N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine to the condensing agent, hobt and triethylamine in the step 2 is 1:0.6 to 1:0.35 to 0.6:0.5 to 1.
8. The process according to claim 1, wherein the amount of (S, S, S) -2-azabicyclo [3, 0] octane-3-carboxylate salt used in step 2 is 0.5 times the mass of the amino-protected N- [1- (S) -ethoxycarbonyl-3-phenylpropyl ] -L-alanine.
9. The process according to claim 1, wherein the low temperature in step 2 is 0 to 10 ℃.
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| CN101855207A (en) * | 2007-11-13 | 2010-10-06 | 帝斯曼知识产权资产管理有限公司 | Improved ramipril synthesis |
| CN104513292A (en) * | 2013-09-29 | 2015-04-15 | 山东新时代药业有限公司 | Preparation method of ramipril |
| CN105777611A (en) * | 2016-03-17 | 2016-07-20 | 浙江工业大学 | Synthesizing method using serine to prepare Ramipril key intermediate |
| CN106748966A (en) * | 2016-12-14 | 2017-05-31 | 浙江工业大学 | A kind of synthetic method of Ramipril key intermediate |
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| CN101855207A (en) * | 2007-11-13 | 2010-10-06 | 帝斯曼知识产权资产管理有限公司 | Improved ramipril synthesis |
| CN104513292A (en) * | 2013-09-29 | 2015-04-15 | 山东新时代药业有限公司 | Preparation method of ramipril |
| CN105777611A (en) * | 2016-03-17 | 2016-07-20 | 浙江工业大学 | Synthesizing method using serine to prepare Ramipril key intermediate |
| CN106748966A (en) * | 2016-12-14 | 2017-05-31 | 浙江工业大学 | A kind of synthetic method of Ramipril key intermediate |
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