CN113563417B - Continuous flow synthesis method of argatroban intermediate - Google Patents
Continuous flow synthesis method of argatroban intermediate Download PDFInfo
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- 229960003856 argatroban Drugs 0.000 title claims abstract description 33
- 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 30
- 238000001308 synthesis method Methods 0.000 title claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 97
- 239000003054 catalyst Substances 0.000 claims abstract description 33
- 239000000463 material Substances 0.000 claims abstract description 21
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000001257 hydrogen Substances 0.000 claims abstract description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 17
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 17
- 239000002904 solvent Substances 0.000 claims abstract description 17
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims abstract description 15
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 claims abstract description 11
- 239000000203 mixture Substances 0.000 claims abstract description 8
- 230000035484 reaction time Effects 0.000 claims abstract description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 5
- 239000011259 mixed solution Substances 0.000 claims abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 45
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 7
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 3
- 235000019253 formic acid Nutrition 0.000 claims description 3
- 230000002194 synthesizing effect Effects 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims 1
- 229910052751 metal Inorganic materials 0.000 claims 1
- 239000002184 metal Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 19
- 239000007788 liquid Substances 0.000 abstract description 17
- 238000000034 method Methods 0.000 abstract description 16
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 230000003321 amplification Effects 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 230000000694 effects Effects 0.000 abstract description 4
- 238000003199 nucleic acid amplification method Methods 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 2
- -1 (2R, 4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1, 2,3, 4-tetrahydro-3-methyl-8-quinolinyl) sulfonyl ] amino ] pentyl ] -4-methyl-2-piperidinecarboxylic acid Chemical compound 0.000 description 33
- 239000000243 solution Substances 0.000 description 29
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 24
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 19
- 238000002360 preparation method Methods 0.000 description 19
- 239000007789 gas Substances 0.000 description 18
- 239000012535 impurity Substances 0.000 description 13
- 229910052757 nitrogen Inorganic materials 0.000 description 12
- 239000000706 filtrate Substances 0.000 description 10
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 10
- 230000001105 regulatory effect Effects 0.000 description 10
- 238000001291 vacuum drying Methods 0.000 description 10
- 238000005086 pumping Methods 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 238000004811 liquid chromatography Methods 0.000 description 7
- MRAUNPAHJZDYCK-BYPYZUCNSA-N L-nitroarginine Chemical compound OC(=O)[C@@H](N)CCCNC(=N)N[N+]([O-])=O MRAUNPAHJZDYCK-BYPYZUCNSA-N 0.000 description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 235000019441 ethanol Nutrition 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- KXNPVXPOPUZYGB-IOVMHBDKSA-N (2R,4R)-1-[(2S)-5-(diaminomethylideneamino)-2-[(3-methyl-1,2,3,4-tetrahydroquinolin-8-yl)sulfonylamino]-1-oxopentyl]-4-methyl-2-piperidinecarboxylic acid Chemical compound OC(=O)[C@H]1C[C@H](C)CCN1C(=O)[C@H](CCCN=C(N)N)NS(=O)(=O)C1=CC=CC2=C1NCC(C)C2 KXNPVXPOPUZYGB-IOVMHBDKSA-N 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 3
- 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 description 2
- 208000007536 Thrombosis Diseases 0.000 description 2
- 229920000180 alkyd Polymers 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- DNUTZBZXLPWRJG-UHFFFAOYSA-N 1-Piperidine carboxylic acid Chemical compound OC(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-N 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229940033590 argatroban injection Drugs 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 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 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 230000000887 hydrating effect Effects 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 230000016507 interphase Effects 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 206010043554 thrombocytopenia Diseases 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
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/0093—Microreactors, e.g. miniaturised or microfabricated reactors
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Biophysics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
The invention provides a continuous flow synthesis method of an argatroban intermediate, which is characterized in that the argatroban intermediate I is used as a raw material, the argatroban intermediate II is obtained through a palladium-carbon hydrogenation step, and the synthesis process is carried out in a micro-channel reactor. The method comprises the steps of taking a mixed solution of a compound I, a catalyst and a solvent as a first material, taking hydrogen as a second material, and carrying out continuous flow hydrogenation on the mixture to synthesize an intermediate II through a microchannel reactor, wherein the reaction temperature is 80-200 ℃, the reaction time is 84-140 seconds, and the pressure is 5-15 bar. Wherein X represents a hydrogen atom, a methyl group or an ethyl group. Compared with the existing conventional kettle type reactor, the process has the advantages of short reaction time, small reaction holding liquid volume, no amplification effect, no need of a pressurized hydrogenation kettle, improvement of reaction safety, more than 90 percent of target product conversion rate and more than 99 percent of purity, and contribution to industrial production.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a continuous flow synthesis method of an argatroban intermediate.
Background
Argatroban, chinese name: (2R, 4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1, 2,3, 4-tetrahydro-3-methyl-8-quinolinyl) sulfonyl ] amino ] pentyl ] -4-methyl-2-piperidinecarboxylic acid having the structural formula:
the drug was synthesized earliest by Mitsubishi chemical institute in Japan, marketed in Japan at month 2 in 1990, approved for the treatment of peripheral thrombosis and acute cerebral apoplexy, and later approved by the United states FDA in 2000 for the treatment and prevention of thrombosis and heparin-induced immune disease-thrombocytopenia (HIT). In 2005, argatroban injection "dabber" from Tianjin pharmaceutical institute was approved by the national food and drug administration for marketing.
The synthesis route of Argatroban in the prior art:
raw material N as described in EP0008746, US4258192, US4201863, JP8115267 G Reaction of (1) nitro-L-arginine with di-tert-butyl pyrocarbonate to give N G -nitro-N 2 -tert-butoxycarbonyl-L-arginine (2), then amide condensation with (2R, 4R) -4-methylpiperidine-2-ethyl formate (3) to generate a compound (4), removal of tert-butoxycarbonyl to generate a compound (5) under acidic conditions, condensation with 3-methyl-8-quinoline sulfonyl chloride (6) to obtain a compound (7), and hydrolysis, hydrogenation and hydration to obtain Argatroban monohydrate; the reaction route is as follows:
the synthetic route is as described in patent EP0823430, CN101348463A, CN101348481A, N G -condensing nitro-L-arginine (1) with 3-methylquinoline-8-sulfonyl chloride (6) to generate a compound (9), condensing with (2R, 4R) -4-methyl-2-piperidinecarboxylic acid ethyl ester (3) to generate a compound (7), hydrolyzing to obtain a compound (I), and then hydrogenating and hydrating to obtain Argatroban monohydrate; the reaction route is as follows:
the inventor discovers that in the existing synthetic route, the compound I is used as a key intermediate of two synthetic routes, argatroban is synthesized by a catalytic hydrogenation process, a traditional batch hydrogenation reaction kettle is used, the process is high in temperature and high in pressure, the time consumption is long, the conversion rate is low, the impurity is more, and the safety risk exists.
Disclosure of Invention
Aiming at the problems, the invention aims to optimize the traditional hydrogenation process, and provides a continuous flow synthesis method of an argatroban intermediate. Compared with the conventional kettle-type catalytic hydrogenation process, the method avoids the problems of high temperature and high pressure in the hydrogenation process, long reaction time and the like, thereby ensuring the safety in the production process; the process has short reaction time, small liquid holding volume and no amplification effect, essentially changes the safety of the reaction, ensures that the conversion rate of the target product is more than 90 percent, ensures that the purity is more than 99 percent, and is beneficial to industrial production.
The invention is realized by adopting the following technical scheme:
a continuous flow synthesis method of an argatroban intermediate comprises the steps of taking a mixed solution of the argatroban intermediate I, a catalyst and a solvent as a first material, taking hydrogen as a second material, reacting by a micro-channel reactor, and synthesizing an argatroban intermediate II by continuous flow hydrogenation under proper conditions; the synthetic route is as follows:
wherein X represents a hydrogen atom, a methyl group or an ethyl group.
Wherein the argatroban intermediate I is a (2R, 4R) -1- [ (2S) -5- [ [ imino (nitroamino) methyl ] amino ] -2- [ [ (3-methyl-8-quinolyl) sulfonyl ] amino ] -1-oxo-pentyl ] -4-methyl-2-piperidinecarboxylic acid compound, wherein X represents a hydrogen atom, methyl and ethyl.
Wherein the argatroban intermediate II is (2R, 4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1, 2,3, 4-tetrahydro-3-methyl-8-quinolinyl) sulfonyl ] amino ] pentyl ] -4-methyl-2-piperidinecarboxylic acid compound, wherein X represents a hydrogen atom, methyl and ethyl.
As a further illustration of the present invention, wherein the catalyst used for the hydrogenation comprises a palladium on carbon catalyst, the weight ratio of argatroban intermediate I to metallic palladium in the palladium on carbon catalyst is from 1:0.006 to 0.024. Preferably, the catalyst used for the hydrogenation is a 10% wt palladium on carbon catalyst, and the weight ratio of the argatroban intermediate I to the metallic palladium in the palladium on carbon catalyst is between 1:0.006 and 0.02.
As a further explanation of the present invention, the solvent is a mixed solvent of an acid solvent including but not limited to liquid organic acids such as formic acid and acetic acid, and an alcohol solvent including but not limited to methanol, ethanol, isopropanol, ethylene glycol, etc., preferably the volume ratio of the alcohol solvent to the acid solvent is 1ml:2-6ml. Preferably, the volume ratio of the alcohol solvent to the acid solvent is 1ml to 4ml.
As a further explanation of the present invention, the mass to volume ratio of the argatroban intermediate I to the mixed solvent is preferably 1g:10-30ml, more preferably 1g:20ml.
As a further illustration of the present invention, it is preferred that the flow rate of material one is 15 to 30g/min, more preferably 20g/min, and that of material two is 180 to 360ml/min, more preferably 240nl/min, under the standard conditions.
As a further illustration of the present invention, wherein the preferred reaction temperature is from 80 to 200℃and the preferred reaction pressure is from 5 to 15bar. More preferably the reaction temperature is 140℃and still more preferably the reaction pressure is 6-9bar.
As a further illustration of the invention, a reaction time of 60 to 140s is preferred.
Compared with the prior art, the invention has the following beneficial effects:
1) Compared with the conventional pressurized hydrogenation reactor, the continuous flow synthesis of the microchannel reactor has the advantages that the reaction liquid volume is small, the potential safety hazard of hydrogenation reaction is reduced, and the safety of reaction and production is greatly improved. The process has short reaction time, small reaction holding liquid volume, no amplification effect, basically changes the safety of the reaction, ensures that the conversion rate of the target product is more than 90 percent, ensures that the purity of the product in the reaction liquid is more than 80 percent, ensures that the molar yield of the related product obtained by post-treatment steps such as catalyst separation, reduced pressure concentration, pH value adjustment, dissolution and decoloration, recrystallization, drying and the like is more than 65 percent, ensures that the purity of the product is more than 99.0 percent, and is beneficial to industrial production.
2) An alcohol-acid system is adopted as a reaction solvent, and the method is suitable for a glass micro-channel reactor.
3) The reaction time is greatly shortened from 5-24 hours of kettle reaction to 60-140 seconds.
4) The reaction process has no amplification effect, and provides a new continuous flow reaction method for preparing the Argatroban intermediate II from the Argatroban intermediate I.
5) The invention utilizes the efficient and excellent mass and heat transfer performance of the micro-reactor, strengthens the interphase mass transfer and heat transfer capability in the reaction process, can obviously reduce the volume of the reactor, improves the reaction yield and improves the production efficiency and the safety. The method can solve the problems of low production efficiency, poor product purity, high device danger and the like in the hydrogenation kettle process, can realize continuous and automatic operation of the process, and has the advantages of high yield, good safety and the like.
Drawings
The invention is further described below with reference to the accompanying drawings;
figure 1 shows a continuous flow synthesis process flow of argatroban intermediate i.
Detailed Description
For a clearer understanding of the objects, features and advantages of the present invention, the invention is further illustrated below with reference to the attached drawings and specific examples. Unless otherwise indicated, the starting materials are all commercially available; adopting a high-flux microchannel reactor type G1; corning company of the united states.
Example 1: preparation of (2R, 4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1, 2,3, 4-tetrahydro-3-methyl-8-quinolinyl) sulfonyl ] amino ] pentyl ] -4-methyl-2-piperidinecarboxylic acid
1. The device comprises: a continuous flow micro-channel reactor, a micro-channel connection mode is determined by referring to fig. 1, a mixed reaction module is determined according to the flow rate and the reaction residence time, and a heat exchange medium is heat conduction oil;
2. as shown in fig. 1, the first flow path: preparing a feed liquid, namely preparing 15.0g of compound (I), 3.0g of 10wt% palladium-carbon catalyst, 300ml of acetic acid and 150ml of absolute ethyl alcohol, stirring, pumping the mixture into a microchannel reactor through a feed pump, and setting the flow rate to be 30g/min through a metering module;
3. and a second flow path: the material hydrogen is passed through the gas circuit controller, and the gas flow rate is set to 260ml/min;
4. pipeline pressure control: the pressure of the nitrogen preparation pipeline is 10bar;
5. the system was set at a circulation temperature of 140℃and after 89 seconds of reaction in 8 reaction modules (68 ml volume) of the continuous flow reactor, the reaction solution was collected. The purity of (2R, 4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1, 2,3, 4-tetrahydro-3-methyl-8-quinolinyl) sulfonyl ] amino ] pentyl ] -4-methyl-2-piperidinecarboxylic acid in the reaction solution was 86.19%. The reaction solution was filtered to recover the catalyst. The filtrate is concentrated under reduced pressure, diluted, pH value is regulated to 8-9, activated carbon is decolorized after methanol is dissolved, methanol-water is recrystallized, and vacuum drying is carried out, thus obtaining (2R, 4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1, 2,3, 4-tetrahydrochysene-3-methyl-8-quinolyl) sulfonyl ] amino ] amyl ] -4-methyl-2-piperidinecarboxylic acid, the liquid chromatography purity is 99.24%, the maximum single impurity is 0.28%, and the molar yield is 68.1%.
Example 2: preparation of (2R, 4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1, 2,3, 4-tetrahydro-3-methyl-8-quinolinyl) sulfonyl ] amino ] pentyl ] -4-methyl-2-piperidinecarboxylic acid
1. The device comprises: a continuous flow micro-channel reactor, a micro-channel connection mode is determined by referring to fig. 1, a mixed reaction module is determined according to the flow rate and the reaction residence time, and a heat exchange medium is heat conduction oil;
2. as shown in fig. 1, the first flow path: preparing a feed liquid, namely preparing 15.0g of compound (I), 7.5g of 10wt% palladium-carbon catalyst, 200ml of acetic acid and 100ml of absolute ethyl alcohol, stirring, pumping into a microchannel reactor through a feed pump, and setting the flow rate to be 20g/min through a metering module;
3. and a second flow path: the material hydrogen is passed through the gas circuit controller, and the gas flow rate is set to 240ml/min;
4. pipeline pressure control: the pressure of the nitrogen preparation pressure pipeline is 6.0bar;
5. the system was set at a circulation temperature of 100℃and after 102 seconds of reaction in 8 reaction modules (68 ml volume) of the continuous flow reactor, the reaction solution was collected. The purity of (2R, 4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1, 2,3, 4-tetrahydro-3-methyl-8-quinolinyl) sulfonyl ] amino ] pentyl ] -4-methyl-2-piperidinecarboxylic acid in the reaction solution was 91.60%. The reaction solution was filtered to recover the catalyst. The filtrate is concentrated under reduced pressure, diluted, pH value is regulated to 8-9, activated carbon is decolorized after methanol is dissolved, methanol-water is recrystallized, and vacuum drying is carried out, thus obtaining (2R, 4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1, 2,3, 4-tetrahydrochysene-3-methyl-8-quinolyl) sulfonyl ] amino ] amyl ] -4-methyl-2-piperidinecarboxylic acid, the purity of liquid chromatography is 99.47 percent, the maximum single impurity is 0.217 percent, and the molar yield is 72.3 percent.
Comparative test example 1: preparation of (2R, 4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1, 2,3, 4-tetrahydro-3-methyl-8-quinolinyl) sulfonyl ] amino ] pentyl ] -4-methyl-2-piperidinecarboxylic acid
15.0g of compound (I), 3.0g of 10wt% palladium-carbon catalyst, 300ml of acetic acid and 150ml of absolute ethyl alcohol are added into a high-pressure hydrogenation kettle, after the addition, the air in the kettle is replaced by nitrogen for three times, the nitrogen in the kettle is replaced by hydrogen for three times, the pressure of the hydrogen is increased to 10bar, the temperature is increased to 140 ℃ for reaction, and the temperature is kept for hydrogenation reaction for 24 hours.
After the completion of the reaction, the purity of (2R, 4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1, 2,3, 4-tetrahydro-3-methyl-8-quinolinyl) sulfonyl ] amino ] pentyl ] -4-methyl-2-piperidinecarboxylic acid in the reaction solution was 80.47%. The reaction solution was filtered to recover the catalyst. The filtrate is concentrated under reduced pressure, diluted, pH value is regulated to 8-9, activated carbon is decolorized after methanol is dissolved, methanol-water is recrystallized, and vacuum drying is carried out, thus obtaining (2R, 4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1, 2,3, 4-tetrahydro-3-methyl-8-quinolyl) sulfonyl ] amino ] amyl ] -4-methyl-2-piperidinecarboxylic acid, the liquid chromatographic purity is 98.60 percent, the maximum single impurity is 0.67 percent, and the molar yield is 52.6 percent.
Comparative test example 2: preparation of (2R, 4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1, 2,3, 4-tetrahydro-3-methyl-8-quinolinyl) sulfonyl ] amino ] pentyl ] -4-methyl-2-piperidinecarboxylic acid
1. The device comprises: a continuous flow micro-channel reactor, a micro-channel connection mode is determined by referring to fig. 1, a mixed reaction module is determined according to the flow rate and the reaction residence time, and a heat exchange medium is heat conduction oil;
2. as shown in fig. 1, the first flow path: preparing a feed liquid, namely preparing 15.0g of a compound I, 3.0g of a 10wt% palladium-carbon catalyst and 450ml of water, stirring, pumping the mixture into a microchannel reactor through a feed pump, and setting the flow rate to be 30g/min through a metering module;
3. and a second flow path: the material hydrogen is passed through the gas circuit controller, and the gas flow rate is set to 260ml/min;
4. pipeline pressure control: the pressure of the nitrogen preparation pipeline is 10bar;
5. the system was set at a circulation temperature of 140℃and after reacting for 90 seconds in 8 reaction modules (68 ml volume) of the continuous flow reactor, the reaction solution was collected. The purity of (2R, 4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1, 2,3, 4-tetrahydro-3-methyl-8-quinolinyl) sulfonyl ] amino ] pentyl ] -4-methyl-2-piperidinecarboxylic acid in the reaction solution was 71.45%. The reaction solution was filtered to recover the catalyst. The filtrate is concentrated under reduced pressure, diluted, pH value is regulated to 8-9, activated carbon is decolorized after methanol is dissolved, methanol-water is recrystallized, and vacuum drying is carried out, thus obtaining (2R, 4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1, 2,3, 4-tetrahydrochysene-3-methyl-8-quinolyl) sulfonyl ] amino ] amyl ] -4-methyl-2-piperidinecarboxylic acid, the liquid chromatography purity is 96.55 percent, the maximum mono-impurity is 1.23 percent, and the molar yield is 40.3 percent.
The results show that the alkyd system is adopted to be compared with the water system, and the reaction stability and the repeatability are good; the reaction parameters are adjusted, and repeated experiments prove that the alkyd system has remarkable advantages.
In patent CN111471085a, a micro-reactor technology is selected to perform catalytic hydrogenation reaction of compound I, the reaction solvent is an alkaline aqueous solution, the substrate (argatroban piperidine carboxylic acid intermediate) is insoluble in water, the solubility in alkaline water is improved, but the stability is poor, alkali degradation impurities are easily generated in the reaction process, the argatroban intermediate I piperidine formic acid compound is easy to generate degradation impurities in the alkaline aqueous solution, and the related piperidine formic acid compound is also unstable under the process conditions. Meanwhile, the reaction conditions are high temperature and high pressure, but most of reaction modules of the microreactor are made of glass materials, irreversible loss can be caused by long-time application of the conditions, the application of the conditions in the microreactor is limited, and the microreactor made of glass materials is easy to damage after multiple times of use. The reaction system of the invention is different from the reaction system, and the hydrogen consumption is much smaller.
The hydrogenation reduction conditions of CN111471085a are: adding 10% palladium-carbon into the water phase of the previous step, uniformly mixing, introducing the mixture and hydrogen into a microreactor to perform reduction reaction, filtering the feed liquid, and transferring to the next step; the use 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 to be 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 ℃.
Example 3: preparation of methyl (2R, 4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1, 2,3, 4-tetrahydro-3-methyl-8-quinolinyl) sulfonyl ] amino ] pentyl ] -4-methyl-2-piperidinecarboxylate
1. The device comprises: a continuous flow micro-channel reactor, a micro-channel connection mode is determined by referring to fig. 1, a mixed reaction module is determined according to the flow rate and the reaction residence time, and a heat exchange medium is heat conduction oil;
2. flow path one: preparing a feed liquid, namely preparing 15.0g of compound (I), 3.0g of 10wt% palladium-carbon catalyst, 200ml of formic acid and 100ml of methanol, stirring, pumping into a microchannel reactor through a feed pump, and setting the flow rate to be 20g/min through a metering module;
3. and a second flow path: the material hydrogen is passed through the gas circuit controller, and the gas flow rate is set to be 180ml/min;
4. pipeline pressure control: the pressure of the nitrogen preparation pressure pipeline is 5.0bar;
5. the system was set at a circulation temperature of 80℃and after 103 seconds of reaction in 8 reaction modules (68 ml volume) of the continuous flow reactor, the reaction solution was collected. The purity of (2R, 4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1, 2,3, 4-tetrahydro-3-methyl-8-quinolinyl) sulfonyl ] amino ] pentyl ] -4-methyl-2-piperidinecarboxylic acid methyl ester in the reaction solution was 82.34%. The reaction solution was filtered to recover the catalyst. The filtrate is concentrated under reduced pressure, diluted, pH value is regulated to 8-9, activated carbon is decolorized after methanol is dissolved, methanol-water is recrystallized, and vacuum drying is carried out, thus obtaining (2R, 4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1, 2,3, 4-tetrahydro-3-methyl-8-quinolyl) sulfonyl ] amino ] amyl ] -4-methyl-2-piperidinecarboxylic acid methyl ester, the liquid chromatographic purity is 99.08%, the maximum mono-impurity is 0.53%, and the molar yield is 67.9%.
Example 4: preparation of methyl (2R, 4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1, 2,3, 4-tetrahydro-3-methyl-8-quinolinyl) sulfonyl ] amino ] pentyl ] -4-methyl-2-piperidinecarboxylate
1. The device comprises: a continuous flow micro-channel reactor, a micro-channel connection mode is determined by referring to fig. 1, a mixed reaction module is determined according to the flow rate and the reaction residence time, and a heat exchange medium is heat conduction oil;
2. flow path one: preparing a feed liquid, namely preparing 15.0g of compound (I), 7.5g of 10wt% palladium-carbon catalyst, 375ml of acetic acid and 75ml of methanol, stirring, pumping the mixture into a microchannel reactor through a feed pump, and setting the flow rate to be 30g/min through a metering module;
3. and a second flow path: the material hydrogen is passed through the gas circuit controller, and the gas flow rate is set to 360ml/min;
4. pipeline pressure control: the pressure of the nitrogen preparation pipeline is 9.0bar;
5. the system was set at a circulation temperature of 200℃and after 70 seconds of reaction by 8 reaction modules (68 ml volume) of the continuous flow reactor, the reaction solution was collected. The purity of (2 r,4 r) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1, 2,3, 4-tetrahydro-3-methyl-8-quinolinyl) sulfonyl ] amino ] pentyl ] -4-methyl-2-piperidinecarboxylic acid methyl ester in the reaction solution was 86.12%. The reaction solution was filtered to recover the catalyst. The filtrate is concentrated under reduced pressure, diluted, pH value is regulated to 8-9, activated carbon is decolorized after methanol is dissolved, methanol-water is recrystallized, and vacuum drying is carried out, thus obtaining (2R, 4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1, 2,3, 4-tetrahydro-3-methyl-8-quinolyl) sulfonyl ] amino ] amyl ] -4-methyl-2-piperidinecarboxylic acid methyl ester, the liquid chromatographic purity is 99.12 percent, the maximum mono-impurity is 0.48 percent, and the molar yield is 69.2 percent.
Example 5: preparation of ethyl (2R, 4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1, 2,3, 4-tetrahydro-3-methyl-8-quinolinyl) sulfonyl ] amino ] pentyl ] -4-methyl-2-piperidinecarboxylate
1. The device comprises: a continuous flow micro-channel reactor, a micro-channel connection mode is determined by referring to fig. 1, a mixed reaction module is determined according to the flow rate and the reaction residence time, and a heat exchange medium is heat conduction oil;
2. flow path one: preparing a feed liquid, namely preparing 15.0g of compound (I), 3.0g of 10wt% palladium-carbon catalyst, 200ml of acetic acid and 100ml of absolute ethyl alcohol, stirring, pumping into a microchannel reactor through a feed pump, and setting the flow rate to be 15g/min through a metering module;
3. and a second flow path: the material hydrogen is passed through the gas circuit controller, and the gas flow rate is set to be 180ml/min;
4. pipeline pressure control: the pressure of the nitrogen preparation pipeline is 10bar;
5. the system was set at a circulation temperature of 125℃and reacted in 8 reaction modules (68 ml volume) of a continuous flow reactor for 140 seconds, followed by collecting the reaction solution. The purity of (2R, 4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1, 2,3, 4-tetrahydro-3-methyl-8-quinolinyl) sulfonyl ] amino ] pentyl ] -4-methyl-2-piperidinecarboxylic acid methyl ester in the reaction solution was 87.64%. The reaction solution was filtered to recover the catalyst. The filtrate is concentrated under reduced pressure, diluted, pH value is regulated to 8-9, active carbon is decolorized after methanol is dissolved, methanol-water is recrystallized, and vacuum drying is carried out, thus obtaining (2R, 4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1, 2,3, 4-tetrahydro-3-methyl-8-quinolyl) sulfonyl ] amino ] amyl ] -4-methyl-2-piperidinecarboxylic acid ethyl ester, the liquid chromatography purity is 99.31 percent, the maximum single impurity is 0.44 percent, and the molar yield is 70.1 percent.
Example 6: preparation of ethyl (2R, 4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1, 2,3, 4-tetrahydro-3-methyl-8-quinolinyl) sulfonyl ] amino ] pentyl ] -4-methyl-2-piperidinecarboxylate
1. The device comprises: a continuous flow micro-channel reactor, a micro-channel connection mode is determined by referring to fig. 1, a mixed reaction module is determined according to the flow rate and the reaction residence time, and a heat exchange medium is heat conduction oil;
2. flow path one: preparing a feed liquid, namely preparing 15.0g of compound (I), 7.5g of 10wt% palladium-carbon catalyst, 360ml of acetic acid and 60ml of absolute ethyl alcohol, stirring, pumping into a microchannel reactor through a feed pump, and setting the flow rate to be 20g/min through a metering module;
3. and a second flow path: the material hydrogen is passed through the gas circuit controller, and the gas flow rate is set to be 180ml/min;
4. pipeline pressure control: the pressure of the nitrogen preparation pressure pipeline is 6.5bar;
5. the system was set at a circulation temperature of 150℃and after reacting for 90 seconds in 8 reaction modules (68 ml volume) of the continuous flow reactor, the reaction solution was collected. The purity of (2 r,4 r) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1, 2,3, 4-tetrahydro-3-methyl-8-quinolinyl) sulfonyl ] amino ] pentyl ] -4-methyl-2-piperidinecarboxylic acid methyl ester in the reaction solution was 83.78%. The reaction solution was filtered to recover the catalyst. The filtrate is concentrated under reduced pressure, diluted, pH value is regulated to 8-9, activated carbon is decolorized after methanol is dissolved, methanol-water is recrystallized, and vacuum drying is carried out, thus obtaining (2R, 4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1, 2,3, 4-tetrahydro-3-methyl-8-quinolyl) sulfonyl ] amino ] amyl ] -4-methyl-2-piperidinecarboxylic acid ethyl ester, the liquid chromatography purity is 99.17 percent, the maximum single impurity is 0.58 percent, and the molar yield is 68.1 percent.
Example 7: preparation of ethyl (2R, 4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1, 2,3, 4-tetrahydro-3-methyl-8-quinolinyl) sulfonyl ] amino ] pentyl ] -4-methyl-2-piperidinecarboxylate
1. The device comprises: a continuous flow micro-channel reactor, a micro-channel connection mode is determined by referring to fig. 1, a mixed reaction module is determined according to the flow rate and the reaction residence time, and a heat exchange medium is heat conduction oil;
2. flow path one: preparing a feed liquid, namely preparing 15.0g of a compound (I), 5g of a 10wt% palladium-carbon catalyst, 120ml of acetic acid and 30ml of absolute ethyl alcohol, stirring, pumping the mixture into a microchannel reactor through a feed pump, and setting the flow rate to be 15g/min through a metering module;
3. and a second flow path: the material hydrogen is passed through the gas circuit controller, and the gas flow rate is set to be 180ml/min;
4. pipeline pressure control: the pressure of the nitrogen preparation pipeline is 5bar;
5. the system was set at 180℃for a circulation temperature, and after 120 seconds of reaction in 8 reaction modules (68 ml volume) of the continuous flow reactor, the reaction solution was collected. The purity of (2R, 4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1, 2,3, 4-tetrahydro-3-methyl-8-quinolinyl) sulfonyl ] amino ] pentyl ] -4-methyl-2-piperidinecarboxylic acid methyl ester in the reaction solution was 87.25%. The reaction solution was filtered to recover the catalyst. The filtrate is concentrated under reduced pressure, diluted, pH value is regulated to 8-9, activated carbon is decolorized after methanol is dissolved, methanol-water is recrystallized, and vacuum drying is carried out, thus obtaining (2R, 4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1, 2,3, 4-tetrahydro-3-methyl-8-quinolyl) sulfonyl ] amino ] amyl ] -4-methyl-2-piperidinecarboxylic acid ethyl ester, the liquid chromatography purity is 99.24%, the maximum single impurity is 0.41%, and the molar yield is 69.6%.
Example 8: preparation of methyl (2R, 4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1, 2,3, 4-tetrahydro-3-methyl-8-quinolinyl) sulfonyl ] amino ] pentyl ] -4-methyl-2-piperidinecarboxylate
1. The device comprises: a continuous flow micro-channel reactor, a micro-channel connection mode is determined by referring to fig. 1, a mixed reaction module is determined according to the flow rate and the reaction residence time, and a heat exchange medium is heat conduction oil;
2. flow path one: preparing a feed liquid, namely preparing 15.0g of a compound (I), 4g of a 10wt% palladium-carbon catalyst, 300ml of acetic acid and 50ml of methanol, stirring, pumping the mixture into a microchannel reactor through a feed pump, and setting the flow rate to be 25g/min through a metering module;
3. and a second flow path: the material hydrogen is passed through the gas circuit controller, and the gas flow rate is set to 270ml/min;
4. pipeline pressure control: the pressure of the nitrogen preparation pipeline is 9.0bar;
5. the system was set at 130℃for circulation, and after 140 seconds of reaction in 8 reaction modules (68 ml volume) of the continuous flow reactor, the reaction solution was collected. The purity of (2R, 4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1, 2,3, 4-tetrahydro-3-methyl-8-quinolinyl) sulfonyl ] amino ] pentyl ] -4-methyl-2-piperidinecarboxylic acid methyl ester in the reaction solution was 89.12%. The reaction solution was filtered to recover the catalyst. The filtrate is concentrated under reduced pressure, diluted, pH value is regulated to 8-9, activated carbon is decolorized after methanol is dissolved, methanol-water is recrystallized, and vacuum drying is carried out, thus obtaining (2R, 4R) -1- [5- [ (aminoiminomethyl) amino ] -1-oxo-2- [ [ (1, 2,3, 4-tetrahydro-3-methyl-8-quinolyl) sulfonyl ] amino ] amyl ] -4-methyl-2-piperidinecarboxylic acid methyl ester, the liquid chromatography purity is 99.13 percent, the maximum mono-impurity is 0.48 percent, and the molar yield is 70.22 percent.
The foregoing is illustrative of embodiments of the present invention and is not to be construed as limiting the invention in any way. The present invention is not limited by the above embodiments, but is capable of being modified or equivalent to the above embodiments according to the technical principles of the present invention.
Claims (3)
1. A continuous flow synthesis method of an argatroban intermediate is characterized in that: taking a mixed solution of the argatroban intermediate I, a catalyst and a solvent as a material I, taking hydrogen as a material II, reacting by a micro-channel reactor, and synthesizing an argatroban intermediate II by continuous flow hydrogenation under proper conditions; the synthetic route is as follows:
wherein X represents a hydrogen atom, a methyl group or an ethyl group;
the catalyst is a palladium-carbon catalyst with a palladium load of 10wt%, and the mass ratio of the argatroban intermediate I to the metal palladium in the palladium-carbon catalyst is 1:0.006 to 0.024; the solvent is a mixed solvent of an alcohol solvent and an acid solvent, wherein the alcohol solvent comprises methanol, ethanol, isopropanol and glycol, the acid solvent comprises formic acid and acetic acid, and the volume ratio of the alcohol solvent to the acid solvent is 1:2-6; the flow rate of the first material is 15-30g/min, and the flow rate of the second material is 180-360ml/min under the standard condition; the reaction temperature is 80 to 200 ℃, and the reaction pressure is 5 to 9bar; the reaction time is 60 to 90s.
2. The continuous flow synthesis method of argatroban intermediate according to claim 1, characterized in that: the argatroban intermediate II comprises diastereoisomeric mixture in any proportion.
3. The continuous flow synthesis method of argatroban intermediate according to claim 1, characterized in that: the mass volume ratio of the argatroban intermediate I to the mixed solvent is 1g:10-30ml.
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