CN111471085A - Method for continuously preparing argatroban - Google Patents
Method for continuously preparing argatroban Download PDFInfo
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- CN111471085A CN111471085A CN202010302202.7A CN202010302202A CN111471085A CN 111471085 A CN111471085 A CN 111471085A CN 202010302202 A CN202010302202 A CN 202010302202A CN 111471085 A CN111471085 A CN 111471085A
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- arginine
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- 238000000034 method Methods 0.000 title claims abstract description 56
- KXNPVXPOPUZYGB-XYVMCAHJSA-N argatroban Chemical compound OC(=O)[C@H]1C[C@H](C)CCN1C(=O)[C@H](CCCN=C(N)N)NS(=O)(=O)C1=CC=CC2=C1NC[C@H](C)C2 KXNPVXPOPUZYGB-XYVMCAHJSA-N 0.000 title claims abstract description 38
- 229960003856 argatroban Drugs 0.000 title claims abstract description 38
- 238000006243 chemical reaction Methods 0.000 claims abstract description 58
- MRAUNPAHJZDYCK-BYPYZUCNSA-N L-nitroarginine Chemical compound OC(=O)[C@@H](N)CCCNC(=N)N[N+]([O-])=O MRAUNPAHJZDYCK-BYPYZUCNSA-N 0.000 claims abstract description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 30
- 239000012074 organic phase Substances 0.000 claims abstract description 29
- 239000008346 aqueous phase Substances 0.000 claims abstract description 19
- 239000012071 phase Substances 0.000 claims abstract description 15
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 12
- 239000002904 solvent Substances 0.000 claims abstract description 11
- 239000003444 phase transfer catalyst Substances 0.000 claims abstract description 9
- 238000005694 sulfonylation reaction Methods 0.000 claims abstract description 8
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 6
- 238000007670 refining Methods 0.000 claims abstract description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- 238000003756 stirring Methods 0.000 claims description 31
- 239000007788 liquid Substances 0.000 claims description 29
- 239000003960 organic solvent Substances 0.000 claims description 29
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- 238000001914 filtration Methods 0.000 claims description 18
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 238000001816 cooling Methods 0.000 claims description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 239000003513 alkali Substances 0.000 claims description 12
- 239000000706 filtrate Substances 0.000 claims description 12
- 239000007864 aqueous solution Substances 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 11
- XCMAYGDQKTWICK-UHFFFAOYSA-N 3-methylquinoline-8-sulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC2=CC(C)=CN=C21 XCMAYGDQKTWICK-UHFFFAOYSA-N 0.000 claims description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- MGNCLNQXLYJVJD-UHFFFAOYSA-N cyanuric chloride Chemical compound ClC1=NC(Cl)=NC(Cl)=N1 MGNCLNQXLYJVJD-UHFFFAOYSA-N 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 10
- 238000006722 reduction reaction Methods 0.000 claims description 10
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 9
- 238000002425 crystallisation Methods 0.000 claims description 8
- 230000008025 crystallization Effects 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 8
- 230000035484 reaction time Effects 0.000 claims description 8
- 239000011259 mixed solution Substances 0.000 claims description 7
- 238000004321 preservation Methods 0.000 claims description 7
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical group OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical group CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 5
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 claims description 5
- 238000006482 condensation reaction Methods 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 150000007530 organic bases Chemical class 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- 238000000967 suction filtration Methods 0.000 claims description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 239000000243 solution Substances 0.000 claims description 4
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 3
- VFTFKUDGYRBSAL-UHFFFAOYSA-N 15-crown-5 Chemical compound C1COCCOCCOCCOCCO1 VFTFKUDGYRBSAL-UHFFFAOYSA-N 0.000 claims description 2
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- 239000002274 desiccant Substances 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical group CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 2
- GHBNOCBWSUHAAA-HTQZYQBOSA-N ethyl (2r,4r)-4-methylpiperidine-2-carboxylate Chemical compound CCOC(=O)[C@H]1C[C@H](C)CCN1 GHBNOCBWSUHAAA-HTQZYQBOSA-N 0.000 claims 3
- 239000002585 base Substances 0.000 claims 2
- 150000003990 18-crown-6 derivatives Chemical group 0.000 claims 1
- -1 (2R,4R) -4-methyl-2-ethyl piperidine Chemical compound 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 239000003795 chemical substances by application Substances 0.000 description 10
- 238000009833 condensation Methods 0.000 description 10
- 230000005494 condensation Effects 0.000 description 10
- 239000000543 intermediate Substances 0.000 description 9
- 238000004519 manufacturing process Methods 0.000 description 9
- 229960001701 chloroform Drugs 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000000746 purification Methods 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- ZFSLODLOARCGLH-UHFFFAOYSA-N isocyanuric acid Chemical compound OC1=NC(O)=NC(O)=N1 ZFSLODLOARCGLH-UHFFFAOYSA-N 0.000 description 3
- DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 description 3
- VHXJRLYFEJAIAM-UHFFFAOYSA-N quinoline-2-sulfonyl chloride Chemical compound C1=CC=CC2=NC(S(=O)(=O)Cl)=CC=C21 VHXJRLYFEJAIAM-UHFFFAOYSA-N 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- 239000002699 waste material Substances 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 150000001263 acyl chlorides Chemical class 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 150000001718 carbodiimides Chemical class 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000032798 delamination Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 description 1
- GPIQOFWTZXXOOV-UHFFFAOYSA-N 2-chloro-4,6-dimethoxy-1,3,5-triazine Chemical compound COC1=NC(Cl)=NC(OC)=N1 GPIQOFWTZXXOOV-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
- 239000004475 Arginine Substances 0.000 description 1
- 229940123900 Direct thrombin inhibitor Drugs 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 1
- 229930064664 L-arginine Natural products 0.000 description 1
- 235000014852 L-arginine Nutrition 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 239000004280 Sodium formate Substances 0.000 description 1
- 108090000190 Thrombin Proteins 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229960004676 antithrombotic agent Drugs 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 235000009697 arginine Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 235000017168 chlorine Nutrition 0.000 description 1
- 125000001309 chloro group Chemical class Cl* 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000002485 combustion reaction Methods 0.000 description 1
- 238000010924 continuous production Methods 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 239000000852 hydrogen donor Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 238000003408 phase transfer catalysis Methods 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- WFIZEGIEIOHZCP-UHFFFAOYSA-M potassium formate Chemical compound [K+].[O-]C=O WFIZEGIEIOHZCP-UHFFFAOYSA-M 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 description 1
- 235000019254 sodium formate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000006103 sulfonylation Effects 0.000 description 1
- 229960004072 thrombin Drugs 0.000 description 1
- 239000003868 thrombin inhibitor Substances 0.000 description 1
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
- C07K5/06086—Dipeptides with the first amino acid being basic
- C07K5/06095—Arg-amino acid
Abstract
The invention belongs to the technical field of medicines, and relates to a method for continuously preparing argatroban, which comprises the following specific processes of realizing N-nitro-L-arginine sulfonylation reaction in two phases of water and a solvent through a phase transfer catalyst, directly condensing an organic phase with (2R,4R) -4-methyl-2-ethyl piperidine without concentration after the reaction is finished, carrying out hydrolysis reaction on an aqueous phase under an alkaline condition after the reaction is finished, then carrying out hydrogenation reduction by using a microreactor, and finally refining to obtain the argatroban.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a method for continuously preparing argatroban.
Background
The argatroban is a small-molecule direct thrombin inhibitor derived from L-arginine, has good selectivity, and has a structural formula formed by combining arginine, piperidine and quinoline, and three functional groups in total to form a tripod structure, so that the argatroban has the characteristics of three-dimensional property, rapidity, selectivity and reversibility in combination with a thrombin active site.
Argatroban (Argatroban) was first developed by Mitsubishi chemical research institute of japan as an antithrombotic agent under the trade name of norubicin (novsta), and under the chemical name of (2R,4R) -4-methyl-1- [ N- ((R, S) -3-methyl-1, 2,3, 4-tetrahydro-8-quinolinesulfonyl) -L-arginyl ] -2-piperidinecarboxylic acid.
The structural formula is as follows:
the reported synthesis routes of argatroban all use nitro-L-arginine as a starting material, and the condensation sequences of piperidine carboxylate or quinoline sulfonyl chloride are different to form two main routes.
The first route is that the amino group of nitro-L-arginine is protected by t-butyloxycarbonyl, condensed with piperidine carboxylate, removed of t-butyloxycarbonyl, condensed with quinoline sulfonyl chloride, ester hydrolyzed, and hydrogenated to obtain argatroban (US4258192, US4201863, JP8115267, EP008764A, CN109912570, CN101914133, etc.), the reaction formula is as follows:
the second route is condensation of nitro-L-arginine with quinoline sulfonyl chloride, followed by condensation with piperidine carboxylate, ester hydrolysis, hydrogenation reduction to give argatroban (US4117127, EP823430, CN101348481, CN104059125, CN101348463, etc.), and the reaction formula is as follows:
because the microreactor has the characteristics of ultrahigh mass transfer and heat transfer efficiency, continuous production and the like which are different from the traditional reactor, the microreactor can obviously shorten the reaction time and accurately control the reaction temperature, thereby reducing the generation of byproducts; the effect is more obvious for heterogeneous reaction.
The traditional process has the following problems:
1. the intermediates of the first route or the second route both need complex post-treatment steps, each high-purity intermediate is obtained after purification, and then subsequent step reaction can be carried out, so that the post-treatment and purification steps are complex, the production working hour is prolonged, and the production efficiency is reduced; in addition, a plurality of solvents or even mixed solvents are required to be used in the reaction process or the post-treatment process in each step, so that the waste liquid treatment pressure is increased, and the development idea of green environmental protection is not met.
2. In the step of synthesizing the compound I in the palladium-carbon hydrogenation step, the reaction is carried out in an organic solvent, the pressure of 5MPa is required for the reaction, the temperature is maintained at 80 ℃, the filtration is required after the reaction is finished, and the organic solvent exists in the filtration process, so that the spontaneous combustion possibility of the palladium-carbon is further increased, and the risk coefficient is increased for the production process. Although CN105837658 uses hydrogen donors (one or more of sodium formate, potassium formate and ammonium formate) instead of hydrogen, high pressure operation is not required, but 10% palladium on carbon with 20-40% of substrate is required, which increases synthesis cost.
3. In the reaction step of synthesizing the compound III by sulfonylation, CN101348463 uses THF as a solvent, sodium carbonate aqueous solution is used for reaction, and dichloromethane, trichloromethane or ethyl acetate is used for extraction after the reaction is finished and concentration is carried out, so that a large amount of solvent is used, and the yield is only about 50%; CN101914133 adopts chloroform as solvent, and triethylamine is as the acid adjuvant and reacts, but need to pass through column chromatography separation after the aftertreatment, is more unsuitable for industrial production.
4. In the step process of synthesizing the compound II by amide condensation, 2.5-3 mol of excessive phosphorus oxychloride is used for condensation in CN104059125, a large amount of alkali liquor is needed for neutralization in the post-treatment, and the yield is only about 86%. In order to reduce the corrosion of the acidic condensing agent to the equipment and increase the condensation conversion rate, CN19519196 and CN103570803 use carbodiimide type condensing agents (DCC, DIC, EDCI, etc.), but such condensing agents require the addition of an acylation catalyst or an active agent, since the addition intermediate of the acid to the carbodiimide in the first stage of the reaction is unstable, and if the addition intermediate is converted into the corresponding active ester or active amide without the acylation catalyst, the addition intermediate itself forms the corresponding stable urea by-product through rearrangement, and neither of these patents uses a catalyst or an active agent. In order to improve the condensing agent again, a phosphate ester condensing agent is used in CN101348481, and a CDMT condensing agent is used in CN109912570, but in order to improve the condensation yield as much as possible, the molar ratio of the carboxylic acid to the condensing agent is at least 0.8-1.2, and the amount of the condensing agent used is increased.
Disclosure of Invention
Aiming at the problems, the invention aims to overcome the defects of the prior art and provide a method for continuously preparing argatroban, which reduces the complicated treatment and purification steps of each intermediate and realizes continuous reaction, thereby improving the production efficiency. In the reaction process, the same solvent is almost adopted in a plurality of steps, so that the solvent is more favorably recovered, and the aim of reducing the waste liquid is fulfilled; in addition, the method selects the microreactor to carry out palladium-carbon hydrogenation reduction, thereby avoiding the problems of high temperature and high pressure, long reaction time and the like in the hydrogenation process and further ensuring the safety in the production process. The preparation method has the advantages of safety, environmental protection, low production cost, convenient operation and the like, and is more suitable for industrial production. The synthetic route of the invention is as follows:
the method specifically comprises the following steps:
(1) sulfonylation reaction
Dissolving N-nitro-L-arginine in an alkaline water solution, adding an organic solvent A to dissolve 3-methyl-8-quinolinesulfonyl chloride, then adding a phase transfer catalyst, stirring and reacting, layering after the reaction is finished, removing an organic phase, adding the solvent A into an aqueous phase again, adjusting the pH to 5-6 with concentrated hydrochloric acid, extracting and layering, drying the organic phase with a drying agent, filtering, and transferring the filtrate to the next procedure;
the method for continuously preparing argatroban is characterized in that in the step (1), the weight ratio of water to N-nitro-L-arginine is 5-8 ml/g, the molar ratio of N-nitro-L-arginine to alkali is 1: 1-1.5, and the alkali is one or more of sodium hydroxide, potassium carbonate and sodium carbonate.
The method for continuously preparing argatroban is characterized in that in the step (1), the organic solvent A is one of trichloromethane or dichloromethane, the volume-to-weight ratio of the amount of the organic solvent A for dissolving 3-methyl-8-quinolinesulfonyl chloride to N-nitro-L-arginine is 3-5 ml/g, the volume-to-weight ratio of the amount of the organic solvent A for extraction to N-nitro-L-arginine is 5-8 ml/g, and the molar ratio of N-nitro-L-arginine to 3-methyl-8-quinolinesulfonyl chloride is 1: 1-1.3.
The method for continuously preparing argatroban is characterized in that in the step (1), one or more of 18 crown 6, 15 crown 5, polyethylene glycol, TEBA, tetrabutylammonium bromide and tetrabutylammonium chloride are selected as a phase transfer catalyst, preferably TEBA is selected, the dosage of the phase transfer catalyst is 0.5-1% of the weight of N-nitro-L-arginine, the reaction temperature is 30-40 ℃, and the reaction time is 2-3 hours.
In order to simplify the post-treatment steps and remove excessive raw materials, thereby improving the purity of the intermediate, two phases are selected for reaction; meanwhile, in order to improve the reaction rate of the water and organic phase two-phase raw materials, the method adds a phase transfer catalyst. After the reaction is finished, the potassium salt or the sodium salt formed by the compound IIII is dissolved in water, and after delamination, the excessive 3-methyl-8-quinoline sulfonyl chloride is dissolved in an organic phase and is respectively removed. After extraction with alkali, the phase transfer catalyst is removed by dissolving in water.
(2) Condensation reaction
Adding cyanuric chloride, cooling, dropwise adding organic alkali, reacting for 1-2 h under heat preservation after dropwise adding, dropwise adding a mixed solution of an organic solvent A of (2R,4R) -4-methyl-2-ethyl piperidinecarboxylate, and reacting for 0.5-1 h under heat preservation; after the reaction is finished, filtering, adding water into filtrate, layering, and removing an organic phase; adding an organic solvent A into the water phase, adjusting the pH to 6-7 by using a saturated sodium bicarbonate aqueous solution, extracting and layering, removing the water phase, and transferring the organic phase to the next working procedure;
the method for continuously preparing argatroban is characterized in that in the step (2), the molar ratio of N-nitro-L-arginine to cyanuric chloride is 1: 0.4-0.6, the molar ratio of N-nitro-L-arginine to organic base is 1: 1-1.2, the organic base is one or more of triethylamine, N-methylmorpholine and N, N-diisopropylethylamine, and triethylamine is preferably selected, and the dropping temperature is kept at 0-10 ℃;
the method for continuously preparing argatroban is characterized in that in the step (2), the molar ratio of N-nitro-L-arginine to (2R,4R) -4-methyl-2-ethyl piperidinecarboxylate is 1: 1-1.2, the volume-to-weight ratio of the organic solvent A used for dissolving (2R,4R) -4-methyl-2-ethyl piperidinecarboxylate to N-nitro-L-arginine is 2-4 ml/g, and the volume-to-weight ratio of the organic solvent A used for extraction to N-nitro-L-arginine is 5-8 ml/g.
During condensation, cyanuric chloride is selected to contain three active chlorines in the material molecule, and can form active ester with three molecules of carboxylic acid, so that the purposes of generating corrosive acyl chloride and reducing the consumption of a condensing agent are avoided. After the reaction in this step is completed, the filtration step is for the hydrochloride of the organic base. Cyanuric chloride is decomposed with water into cyanuric acid and hydrogen chloride, the cyanuric acid is dissolved in chloroform and dichloromethane, the hydrogen chloride can form hydrochloride with the compound III and is dissolved in water, and after delamination, cyanuric acid and (2R,4R) -4-methyl-2-ethyl piperidinecarboxylate are removed along with an organic phase.
(3) Hydrolysis reaction
Adding an alkaline aqueous solution and an organic solvent B, stirring at room temperature for reaction, removing an organic phase after the reaction is finished, collecting a water phase, and transferring to a working procedure;
the method for continuously preparing argatroban is characterized in that in the step (3), the alkali is sodium hydroxide or potassium hydroxide, the molar ratio of N-nitro-L-arginine to the alkali is 1: 3-5, the concentration of the alkali is 20% -30%, the reaction time is 3-4 h, the organic solvent B is one or more of methanol, ethanol, isopropanol, N-propanol and ethylene glycol, ethanol is preferred, and the volume weight ratio of the organic solvent B to N-nitro-L-arginine in the step is 3-4 ml/g.
After the reaction in the step is finished, the compound II forms sodium salt or potassium salt which is dissolved in water, and the quality of the intermediate is further improved after layering.
(4) Hydrogenation reduction
Adding 10% palladium-carbon into the water phase in the previous process, mixing uniformly, introducing the mixture and hydrogen into a microreactor for reduction reaction, filtering feed liquid, and transferring to the next process;
the method for continuously preparing argatroban is characterized in that in the step (4), the using amount of 10% palladium carbon is 5-10% of the weight of N-nitro-L-arginine, the flow rate of the mixed solution is 10 ml/min-30 ml/min, hydrogen is introduced, the nitrogen back pressure in a microreactor is controlled by 10-20 bar, the flow rate is 800-1000 ml/min, the residence time is 1-5 min, and the reaction temperature is 90-120 ℃.
(5) Refining
Adding an organic solvent B into the filtrate, heating for refluxing, then adjusting the pH value with acetic acid, cooling for crystallization, carrying out suction filtration, and drying to obtain the high-purity argatroban.
The method for continuously preparing argatroban is characterized in that in the step (5), the volume-weight ratio of the using amount of the organic solvent B to the N-nitro-L-arginine is 1-4 ml/g, the pH value of the solution is adjusted to 6-7, the crystallization temperature is 0-10 ℃, and the crystallization temperature is 1-2 hours.
The invention has the beneficial effects that:
1. the preparation method reduces the complicated treatment and purification steps of each intermediate, realizes continuous reaction, and improves the production efficiency;
2. in the reaction process, the same solvent is almost adopted in a plurality of steps, so that the solvent is more favorably recovered, and the aim of reducing the waste liquid is fulfilled;
3. in order to simplify the post-treatment step, the method adopts a two-phase reaction; meanwhile, in order to improve the efficiency and the conversion rate of the sulfonylation reaction, phase transfer catalysis is added;
4. in order to further reduce the production cost, cyanuric chloride is adopted in the condensation step, so that the aims of generating corrosive acyl chloride and reducing the consumption of a condensation agent are fulfilled;
5. according to the method, the microreactor is selected for hydrogenation reduction of palladium-carbon, so that the problems of high temperature and high pressure, long reaction time and the like in the hydrogenation process are solved, the reaction time can be obviously shortened, and the reaction temperature can be accurately controlled, so that the generation of byproducts is reduced, and the potential safety hazard in the production process is reduced. Meanwhile, water is used as a reaction solvent, so that an organic solvent is completely avoided, and the safety of the reaction is further ensured.
Detailed Description
The present invention will be described in further detail with reference to the following examples. However, it should be understood that the above description of the present invention is not limited to the following examples.
In the examples, the chiral purity detection method used is referred to CN103936821, i.e. chromatographic column: ChiralDaicel-AGP column (250mm × 6mm, 5 μm), mobile phase: acetonitrile-water (60:40), detection wavelength: 254nm, flow rate: 1.5ml/min, column temperature: 25 deg.C, sample introduction: 10 μ l.
In the embodiment, the microreactor is a G1 glass reactor produced by corning corporation and is formed by connecting twelve glass modules in series (wherein the glass modules are sequentially called as a first reaction module, a second reaction module and the like), feed liquid can be fully and uniformly mixed after entering the modules, the foremost end of each module is fed by a high-pressure pump, and the rearmost end of each module is provided with a gas-liquid separator for back pressure and gas-liquid separation, and the reactor is resistant to high temperature and high pressure.
Example 1 Process for the continuous preparation of argatroban
(1) Sulfonylation reaction
Adding 25.8g (0.645mol) of sodium hydroxide and 400ml of water into a 1000m L three-necked flask, stirring to dissolve, adding 50g (0.43mol) of N-nitro-L-arginine, stirring to dissolve at room temperature, adding 135.1g (0.559mol) of 3-methyl-8-quinoline sulfonyl chloride and 250ml of chloroform into another 500ml three-necked flask, stirring to dissolve, transferring into the 1000ml three-necked flask, adding 0.5g of TEBA after the transfer is finished, heating to 40 ℃ for reaction for 2h, standing for layering, discarding an organic phase, adding 400ml of chloroform into an aqueous phase, adjusting the pH to 6.0 with concentrated hydrochloric acid, stirring, layering, discarding an aqueous phase, adding 40g of anhydrous sodium sulfate into the organic phase, drying for 30min, filtering, transferring the filtrate into a 1000ml three-necked flask, and transferring to the next process.
(2) Condensation reaction
Adding 47.6g of cyanuric chloride (0.258mol) into the 1000m L three-necked bottle, stirring, cooling to 10 ℃, dropwise adding 72ml (0.516mol) of triethylamine, controlling the dropwise adding temperature to be within the range of 0-10 ℃, controlling the temperature to be within the range of 0-10 ℃ after dropwise adding, carrying out heat preservation reaction for 1h, dropwise adding a mixed solution of 100ml of chloroform and 88.4g (0.516mol) of (2R,4R) -4-methyl-2-ethyl piperidinecarboxylate, controlling the dropwise adding temperature to be within the range of 0-10 ℃, reacting for 0.5h after dropwise adding, filtering after the reaction is finished, adding 500ml of water into the filtrate, standing for layering, discarding the organic phase, collecting the aqueous phase, transferring the aqueous phase into a 2000ml three-necked bottle, adding 400ml of chloroform, adjusting the pH value to 7.0 by using a saturated sodium bicarbonate aqueous solution, layering, discarding the aqueous phase, and transferring the organic phase into the 2000ml three-necked bottle for the next process.
(3) Hydrolysis reaction
Adding 200ml ethanol into the 2000m L three-necked bottle, stirring, adding 430ml 20% sodium hydroxide aqueous solution, stirring at room temperature, reacting for 4h, standing for layering, discarding the organic phase, collecting the aqueous phase, and transferring to the next process.
(4) Hydrogenation reduction
Adding 5g of 10% palladium-carbon into the feed liquid obtained in the step (3), stirring and mixing uniformly, introducing the mixed liquid into a first reaction module in a microreactor, preheating to 120 ℃, controlling the flow rate of the mixed liquid to be 30ml/min, introducing the mixed liquid into a second reaction module, and introducing hydrogen at the same time, wherein the nitrogen in the microreactor has back pressure, the system pressure is controlled to be 10bar, and the hydrogen flow rate is 800 ml/min; fully mixing the gas and the feed liquid in the module, and reacting for 1min at 120 ℃; filtering the obtained reaction liquid, cooling to room temperature, and transferring to the next working procedure.
(5) Refining
And (3) transferring the feed liquid obtained in the step (4) into a 2000ml three-necked bottle, adding 200ml ethanol, heating to reflux, adjusting the pH of the feed liquid to 7.0 by using acetic acid, then cooling to 10 ℃, stirring for crystallization for 2h, performing suction filtration, and drying a filter cake for 4h at 50 ℃ to obtain 135g of fine argatroban with the molar yield of 61.72%. The chemical purity is 99.2%, and the chiral purity is 99.6%.
Example 2 Process for the continuous preparation of argatroban
(1) Sulfonylation reaction
Adding 24.2g (0.43mol) of potassium hydroxide and 250ml of water into a 1000m L three-necked bottle, stirring to dissolve, adding 50g (0.43mol) of N-nitro-L-arginine, stirring to dissolve at room temperature, adding 103.9g (0.43mol) of 3-methyl-8-quinoline sulfonyl chloride and 150ml of dichloromethane into another 500ml three-necked bottle, stirring to dissolve, transferring into the 1000ml three-necked bottle, adding 0.25g of tetrabutylammonium bromide after transferring, heating to 30 ℃, reacting for 3h, standing to stratify, discarding an organic phase, adding 250ml of dichloromethane into an aqueous phase, adjusting the pH to 5.0 with concentrated hydrochloric acid, stirring, stratifying, discarding the aqueous phase, adding 30g of anhydrous magnesium sulfate into the organic phase, drying for 30min, filtering, transferring the filtrate into a 1000ml three-necked bottle, and transferring to the next process.
(2) Condensation reaction
Adding 31.7g of cyanuric chloride (0.172mol) into the 1000m L three-mouth bottle, cooling to 0 ℃ after stirring and clearing, dropwise adding 47ml (0.43mol) of N-methylmorpholine, controlling the dropwise adding temperature to be within the range of 0-10 ℃, controlling the temperature to be within the range of 0-10 ℃ after dropwise adding, carrying out heat preservation reaction for 2h, dropwise adding a mixed solution of 120ml of dichloromethane and 73.6g (0.43mol) of (2R,4R) -4-methyl-2-ethyl piperidoate, controlling the dropwise adding temperature to be within the range of 0-10 ℃, reacting for 1h after dropwise adding, filtering after finishing the reaction, adding 500ml of water into filtrate, standing for layering, discarding the organic phase, collecting the aqueous phase, transferring the aqueous phase into a 2000ml three-mouth bottle, adding 250ml of dichloromethane, adjusting the pH value to 6.0 by using a saturated sodium bicarbonate aqueous solution, layering, discarding the aqueous phase, transferring the organic phase into the 2000ml three-mouth bottle, and transferring into the next process.
(3) Hydrolysis reaction
Adding 150ml of methanol into the 2000m L three-necked bottle, stirring, adding 241ml of 30% potassium hydroxide aqueous solution, stirring and reacting for 3 hours at room temperature, standing and layering after the reaction is finished, removing an organic phase, collecting a water phase, and transferring to the next procedure.
(4) Hydrogenation reduction
Adding 2.5g of 10% palladium-carbon into the feed liquid obtained in the step (3), stirring and mixing uniformly, introducing the mixed liquid into a first reaction module in a microreactor, preheating to 90 ℃, then controlling the flow rate of the mixed liquid to be 10ml/min, introducing the mixed liquid into a second reaction module, and introducing hydrogen at the same time, wherein the nitrogen back pressure in the microreactor, the system pressure is controlled to be 20bar, and the hydrogen flow rate is 1000 ml/min; fully mixing the gas and the feed liquid in the module, and reacting for 5min at 90 ℃; filtering the obtained reaction liquid, cooling to room temperature, and transferring to the next working procedure.
(5) Refining
And (3) transferring the feed liquid obtained in the step (4) into a 2000ml three-necked bottle, adding 50ml of methanol, heating to reflux, adjusting the pH of the feed liquid to 6.0 by using acetic acid, then cooling to 0 ℃, stirring and crystallizing for 1h, performing suction filtration, and drying a filter cake for 4h at 50 ℃ to obtain 120g of fine argatroban with the molar yield of 54.87%. The chemical purity is 99.0%, and the chiral purity is 99.3%.
Example 3 Process for the continuous preparation of argatroban
(1) Sulfonylation reaction
Adding 31.6g (0.559mol) of potassium hydroxide and 300ml of water into a 1000m L three-necked bottle, stirring to dissolve, adding 50g (0.43mol) of N-nitro-L-arginine, stirring to dissolve at room temperature, adding 124.7g (0.516mol) of 3-methyl-8-quinoline sulfonyl chloride and 200ml of dichloromethane into another 500ml three-necked bottle, stirring to dissolve, transferring into the 1000ml three-necked bottle, adding 0.4g of TEBA after the transfer is finished, heating to 40 ℃, reacting for 2 hours, standing for layering, discarding an organic phase, adding 300ml of dichloromethane into an aqueous phase, adjusting the pH to 5.4 with concentrated hydrochloric acid, stirring, layering, discarding the aqueous phase, adding 35g of anhydrous magnesium sulfate into the organic phase, drying for 30 minutes, filtering, transferring the filtrate into a 1000ml three-necked bottle, and transferring to the next process.
(2) Condensation reaction
Adding 39.7g of cyanuric chloride (0.215mol) into the 1000m L three-necked bottle, cooling to 5 ℃ after stirring and clearing, dropwise adding 66ml (0.473mol) of triethylamine, controlling the dropwise adding temperature to be within the range of 0-10 ℃, controlling the temperature to be within the range of 0-10 ℃ after dropwise adding, carrying out heat preservation reaction for 1.5h, dropwise adding a mixed solution of 150ml of dichloromethane and 81g (0.473mol) (2R,4R) -4-methyl-2-ethyl piperidinecarboxylate, controlling the dropwise adding temperature to be within the range of 0-10 ℃, reacting for 1h after dropwise adding, filtering after the reaction is finished, adding 500ml of water into filtrate, standing for layering, discarding an organic phase, collecting an aqueous phase, transferring the aqueous phase into a 2000ml three-necked bottle, adding 300ml of dichloromethane, adjusting the pH value to 6.5 with a saturated sodium bicarbonate aqueous solution, layering, discarding the aqueous phase, and transferring the organic phase into the next procedure from the 2000ml three-necked bottle.
(3) Hydrolysis reaction
Adding 130ml of isopropanol into the 2000m L three-necked bottle, stirring, adding 480ml of 20% potassium hydroxide aqueous solution, stirring and reacting for 3.5h at room temperature, standing and layering after the reaction is finished, removing an organic phase, collecting a water phase, and transferring to the next procedure.
(4) Hydrogenation reduction
Adding 4g of 10% palladium-carbon into the feed liquid obtained in the step (3), stirring and mixing uniformly, introducing the mixed liquid into a first reaction module in a microreactor, preheating to 100 ℃, controlling the flow rate of the mixed liquid to be 20ml/min, introducing the mixed liquid into a second reaction module, and introducing hydrogen at the same time, wherein the nitrogen back pressure in the microreactor is controlled to be 15bar, and the hydrogen flow rate is 900 ml/min; fully mixing the gas and the feed liquid in the module, and reacting for 3min at 100 ℃; filtering the obtained reaction liquid, cooling to room temperature, and transferring to the next working procedure.
(5) Refining
And (3) transferring the feed liquid obtained in the step (4) into a 2000ml three-necked bottle, adding 150ml ethanol, heating to reflux, adjusting the pH of the feed liquid to 6.8 by using acetic acid, then cooling to 5 ℃, stirring for crystallization for 1.5h, performing suction filtration, and drying a filter cake for 4h at 50 ℃ to obtain 144g of fine argatroban with the molar yield of 65.84%. The chemical purity is 99.4%, and the chiral purity is 99.5%.
Claims (9)
1. A method for continuously preparing argatroban is characterized by comprising the following steps:
(1) sulfonylation reaction
Dissolving N-nitro-L-arginine in an alkaline water solution, adding an organic solvent A to dissolve 3-methyl-8-quinolinesulfonyl chloride, then adding a phase transfer catalyst, stirring and reacting, layering after the reaction is finished, removing an organic phase, adding the solvent A into an aqueous phase again, adjusting the pH to 5-6 with concentrated hydrochloric acid, extracting and layering, drying the organic phase with a drying agent, filtering, and transferring the filtrate to the next procedure;
(2) condensation reaction
Adding cyanuric chloride, cooling, dropwise adding organic alkali, reacting for 1-2 h under heat preservation after dropwise adding, dropwise adding a mixed solution of an organic solvent A of (2R,4R) -4-methyl-2-ethyl piperidinecarboxylate, and reacting for 0.5-1 h under heat preservation; after the reaction is finished, filtering, adding water into filtrate, layering, and removing an organic phase; adding an organic solvent A into the water phase, adjusting the pH to 6-7 by using a saturated sodium bicarbonate aqueous solution, extracting and layering, removing the water phase, and transferring the organic phase to the next working procedure;
(3) hydrolysis reaction
Adding an alkaline aqueous solution and an organic solvent B, stirring at room temperature for reaction, removing an organic phase after the reaction is finished, collecting a water phase, and transferring to a working procedure;
(4) hydrogenation reduction
Adding 10% palladium-carbon into the water phase in the previous process, mixing uniformly, introducing the mixture and hydrogen into a microreactor for reduction reaction, filtering feed liquid, and transferring to the next process;
(5) refining
Adding an organic solvent B into the filtrate, heating for refluxing, then adjusting the pH value with acetic acid, cooling for crystallization, carrying out suction filtration, and drying to obtain the high-purity argatroban.
2. The method for continuously preparing argatroban according to claim 1, wherein in the step (1), the weight ratio of water to N-nitro-L-arginine is 5-8 ml/g, the molar ratio of N-nitro-L-arginine to a base is 1: 1-1.5, and the base is sodium hydroxide, potassium carbonate or sodium carbonate.
3. The method for continuously preparing argatroban according to claim 1, wherein in step (1), the organic solvent A is chloroform or dichloromethane, the volume-to-weight ratio of the amount of the organic solvent A for dissolving 3-methyl-8-quinolinesulfonyl chloride to N-nitro-L-arginine is 3-5 ml/g, the volume-to-weight ratio of the amount of the organic solvent A for extraction to N-nitro-L-arginine is 5-8 ml/g, and the molar ratio of N-nitro-L-arginine to 3-methyl-8-quinolinesulfonyl chloride is 1: 1-1.3.
4. The method for continuously preparing argatroban according to claim 1, wherein in the step (1), the phase transfer catalyst is 18 crown 6 or 15 crown 5 or polyethylene glycol or TEBA or tetrabutylammonium bromide or tetrabutylammonium chloride, the dosage of the phase transfer catalyst is 0.5-1% of the weight of N-nitro-L-arginine, the reaction temperature is 30-40 ℃, and the reaction time is 2-3 h.
5. A method for continuously preparing argatroban according to claim 1, wherein in the step (2), the molar ratio of the N-nitro-L-arginine to the cyanuric chloride is 1: 0.4-0.6, the molar ratio of the N-nitro-L-arginine to the organic base is 1: 1-1.2, the organic base is triethylamine or N-methylmorpholine or N, N-diisopropylethylamine, and the dropping temperature is maintained at 0-10 ℃.
6. The method for continuously preparing argatroban according to claim 1, wherein in the step (2), the molar ratio of the N-nitro-L-arginine to the ethyl (2R,4R) -4-methyl-2-piperidinecarboxylate is 1: 0.8-1.2, the volume weight ratio of the organic solvent A used for dissolving the ethyl (2R,4R) -4-methyl-2-piperidinecarboxylate to the N-nitro-L-arginine is 2-4 ml/g, and the volume weight ratio of the extraction organic solvent A used for dissolving the ethyl (2R,4R) -4-methyl-2-piperidinecarboxylate to the N-nitro-L-arginine is 5-8 ml/g.
7. The method for continuously preparing argatroban according to claim 1, wherein in the step (3), the alkali is sodium hydroxide or potassium hydroxide, the molar ratio of the N-nitro-L-arginine to the alkali is 1: 3-5, the concentration of the alkali is 20% -30%, the reaction time is 3-4 h, the organic solvent B is methanol or ethanol or isopropanol or N-propanol or ethylene glycol, and the volume-weight ratio of the amount of the organic solvent B to the N-nitro-L-arginine is 3-4 ml/g.
8. The method for continuously preparing argatroban according to claim 1, wherein in the step (4), the amount of 10% palladium-carbon is 5-10% of the weight of N-nitro-L-arginine, the flow rate of the mixed solution is 10 ml/min-30 ml/min, hydrogen is introduced, the nitrogen back pressure in the microreactor is controlled by 10-20 bar, the flow rate is 800-1000 ml/min, the residence time is 1-5 min, and the reaction temperature is 90-120 ℃.
9. The method for continuously preparing argatroban according to claim 1, wherein in the step (5), the volume-to-weight ratio of the organic solvent B to the N-nitro-L-arginine is 1-4 ml/g, the pH of the solution is adjusted to 6-7, the crystallization temperature is 0-10 ℃, and the crystallization temperature is 1-2 h.
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Application publication date: 20200731 |