CN113845417B - Method for synthesizing (+/-) -naproxen by using continuous flow micro-channel reactor oxidation - Google Patents
Method for synthesizing (+/-) -naproxen by using continuous flow micro-channel reactor oxidation Download PDFInfo
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- CN113845417B CN113845417B CN202111145964.1A CN202111145964A CN113845417B CN 113845417 B CN113845417 B CN 113845417B CN 202111145964 A CN202111145964 A CN 202111145964A CN 113845417 B CN113845417 B CN 113845417B
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- naphthyl
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- 238000000034 method Methods 0.000 title claims abstract description 63
- 238000007254 oxidation reaction Methods 0.000 title claims abstract description 25
- 230000003647 oxidation Effects 0.000 title claims description 16
- 229960002009 naproxen Drugs 0.000 title abstract description 16
- 230000002194 synthesizing effect Effects 0.000 title abstract description 7
- 239000000463 material Substances 0.000 claims abstract description 184
- 238000006243 chemical reaction Methods 0.000 claims abstract description 77
- 239000007800 oxidant agent Substances 0.000 claims abstract description 33
- 230000001590 oxidative effect Effects 0.000 claims abstract description 31
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 claims abstract description 29
- RCGQAPUWWHXBOK-UHFFFAOYSA-N 2-(6-methoxynaphthalen-2-yl)propanal Chemical compound C1=C(C(C)C=O)C=CC2=CC(OC)=CC=C21 RCGQAPUWWHXBOK-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000002904 solvent Substances 0.000 claims abstract description 12
- 238000005086 pumping Methods 0.000 claims abstract description 3
- 239000000243 solution Substances 0.000 claims description 61
- 238000003756 stirring Methods 0.000 claims description 49
- 239000011259 mixed solution Substances 0.000 claims description 47
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 39
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 34
- 235000019345 sodium thiosulphate Nutrition 0.000 claims description 34
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 27
- BKOOMYPCSUNDGP-UHFFFAOYSA-N 2-methylbut-2-ene Chemical compound CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 claims description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 22
- RRHGJUQNOFWUDK-UHFFFAOYSA-N Isoprene Chemical compound CC(=C)C=C RRHGJUQNOFWUDK-UHFFFAOYSA-N 0.000 claims description 21
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 claims description 20
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 18
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims description 18
- 239000007787 solid Substances 0.000 claims description 18
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 14
- 238000010791 quenching Methods 0.000 claims description 14
- 230000000171 quenching effect Effects 0.000 claims description 14
- 239000007788 liquid Substances 0.000 claims description 13
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 12
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 12
- 239000002994 raw material Substances 0.000 claims description 12
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical group [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 12
- 239000004289 sodium hydrogen sulphite Substances 0.000 claims description 10
- MHNNAWXXUZQSNM-UHFFFAOYSA-N 2-methylbut-1-ene Chemical group CCC(C)=C MHNNAWXXUZQSNM-UHFFFAOYSA-N 0.000 claims description 8
- GGWCZBGAIGGTDA-UHFFFAOYSA-N 1-(6-methoxynaphthalen-2-yl)ethanone Chemical compound C1=C(C(C)=O)C=CC2=CC(OC)=CC=C21 GGWCZBGAIGGTDA-UHFFFAOYSA-N 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 7
- 239000003513 alkali Substances 0.000 claims description 7
- 239000007864 aqueous solution Substances 0.000 claims description 7
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 239000000337 buffer salt Substances 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 5
- 238000006114 decarboxylation reaction Methods 0.000 claims description 5
- 230000007062 hydrolysis Effects 0.000 claims description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims description 5
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 4
- 239000012752 auxiliary agent Substances 0.000 claims description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 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
- 238000000926 separation method Methods 0.000 claims description 4
- 238000009833 condensation Methods 0.000 claims description 3
- 230000005494 condensation Effects 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- -1 potassium alkoxide Chemical class 0.000 claims description 3
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 2
- 239000005695 Ammonium acetate Substances 0.000 claims description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 239000004280 Sodium formate Substances 0.000 claims description 2
- 235000019257 ammonium acetate Nutrition 0.000 claims description 2
- 229940043376 ammonium acetate Drugs 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- FOCAUTSVDIKZOP-UHFFFAOYSA-M chloroacetate Chemical compound [O-]C(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-M 0.000 claims description 2
- 229940089960 chloroacetate Drugs 0.000 claims description 2
- 238000007599 discharging Methods 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 235000011056 potassium acetate Nutrition 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- WFIZEGIEIOHZCP-UHFFFAOYSA-M potassium formate Chemical compound [K+].[O-]C=O WFIZEGIEIOHZCP-UHFFFAOYSA-M 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 239000001632 sodium acetate Substances 0.000 claims description 2
- 235000017281 sodium acetate Nutrition 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 claims description 2
- 235000019254 sodium formate Nutrition 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 abstract description 15
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 abstract description 9
- 238000010924 continuous production Methods 0.000 abstract description 3
- 239000000543 intermediate Substances 0.000 abstract description 2
- 230000003321 amplification Effects 0.000 abstract 1
- 239000012456 homogeneous solution Substances 0.000 abstract 1
- 238000003199 nucleic acid amplification method Methods 0.000 abstract 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 33
- 230000001105 regulatory effect Effects 0.000 description 20
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 12
- 239000003651 drinking water Substances 0.000 description 11
- 235000020188 drinking water Nutrition 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 10
- 229910010271 silicon carbide Inorganic materials 0.000 description 10
- 238000000967 suction filtration Methods 0.000 description 10
- 238000001291 vacuum drying Methods 0.000 description 10
- 239000006227 byproduct Substances 0.000 description 9
- 230000001276 controlling effect Effects 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- 239000005457 ice water Substances 0.000 description 9
- 238000006276 transfer reaction Methods 0.000 description 9
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 235000010265 sodium sulphite Nutrition 0.000 description 6
- 230000021736 acetylation Effects 0.000 description 5
- 238000006640 acetylation reaction Methods 0.000 description 5
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 5
- LWIHDJKSTIGBAC-UHFFFAOYSA-K potassium phosphate Substances [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 230000003110 anti-inflammatory effect Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- 238000007086 side reaction Methods 0.000 description 3
- 239000002699 waste material Substances 0.000 description 3
- 230000000202 analgesic effect Effects 0.000 description 2
- MCUHSYTVMNEJFT-UHFFFAOYSA-N butan-2-yl 2-chloroacetate Chemical compound CCC(C)OC(=O)CCl MCUHSYTVMNEJFT-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- OSVXSBDYLRYLIG-UHFFFAOYSA-N dioxidochlorine(.) Chemical compound O=Cl=O OSVXSBDYLRYLIG-UHFFFAOYSA-N 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 238000006146 oximation reaction Methods 0.000 description 2
- 230000006289 propionylation Effects 0.000 description 2
- 238000010515 propionylation reaction Methods 0.000 description 2
- 239000002516 radical scavenger Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- NQMUGNMMFTYOHK-UHFFFAOYSA-N 1-methoxynaphthalene Chemical group C1=CC=C2C(OC)=CC=CC2=C1 NQMUGNMMFTYOHK-UHFFFAOYSA-N 0.000 description 1
- QQLIGMASAVJVON-UHFFFAOYSA-N 1-naphthalen-1-ylethanone Chemical compound C1=CC=C2C(C(=O)C)=CC=CC2=C1 QQLIGMASAVJVON-UHFFFAOYSA-N 0.000 description 1
- 101710134784 Agnoprotein Proteins 0.000 description 1
- 239000004155 Chlorine dioxide Substances 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 230000010718 Oxidation Activity Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 235000019398 chlorine dioxide Nutrition 0.000 description 1
- 229910001919 chlorite Inorganic materials 0.000 description 1
- 229910052619 chlorite group Inorganic materials 0.000 description 1
- 150000001879 copper Chemical class 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000002440 industrial waste Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000013021 overheating Methods 0.000 description 1
- 238000010525 oxidative degradation reaction Methods 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- ZUPDNLCLXSWMAE-UHFFFAOYSA-N potassium;butan-2-olate Chemical compound [K+].CCC(C)[O-] ZUPDNLCLXSWMAE-UHFFFAOYSA-N 0.000 description 1
- WQKGAJDYBZOFSR-UHFFFAOYSA-N potassium;propan-2-olate Chemical compound [K+].CC(C)[O-] WQKGAJDYBZOFSR-UHFFFAOYSA-N 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- HBMJWWWQQXIZIP-UHFFFAOYSA-N silicon carbide Chemical group [Si+]#[C-] HBMJWWWQQXIZIP-UHFFFAOYSA-N 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 description 1
- 229960002218 sodium chlorite Drugs 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/16—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation
-
- 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
Abstract
The invention discloses a method for synthesizing naproxen by utilizing a continuous flow micro-channel reactor, belonging to the technical field of medical intermediates. And pumping a homogeneous solution formed by 2- (6-methoxy-2-naphthyl) propanal and a solvent into a microchannel reactor with an oxidant through a metering pump respectively, and carrying out mixed contact in the microchannel to carry out oxidation reaction to obtain (+/-) -2- (6-methoxy-2-naphthyl) propionic acid, namely naproxen. The method solves the problems of long reaction time, high reaction condition requirement, low process safety coefficient, high cost and the like in the prior art, and has the advantages of simple operation, high process safety, short reaction time, high conversion rate and selectivity, high product purity, continuous production, rapid industrialized amplification and the like, and the materials can directly enter post-treatment operation after the reaction is finished, so that the post-treatment is simple, the product yield is more than 95%, and the purity is more than 99%.
Description
Technical Field
The invention belongs to the technical field of medical intermediates, and relates to a method for synthesizing (+/-) -naproxen by oxidation in a continuous flow micro-channel reactor, in particular to a continuous flow synthesis method for synthesizing naproxen by oxidizing 2- (6-methoxy-2-naphthyl) propanal in a micro-channel reactor.
Background
Naproxen (naproxen), chemical name S- (+) -2- (6-methoxy-2-naphthyl) propionic acid, is a non-steroidal anti-inflammatory analgesic (NSIND) developed by syntex company, has the effects of anti-inflammatory, antipyretic and analgesic, has the advantages of complete oral absorption, low toxicity, small side effect and the like, and is an important medicine in the anti-inflammatory and antibacterial fields.
The technology of naproxen is expired in 1993, and in recent years, new synthetic technology routes are endless, and the technology routes reported in literature are as many as more than ten, and can be totally divided into two main categories: firstly, synthesizing racemic naproxen, and then resolving by a chiral resolving agent to obtain S-naproxen with optical activity; and the second is an asymmetric synthesis method, wherein the S-naproxen with a single configuration is directly synthesized by using a chiral auxiliary or a chiral catalyst.
At present, the process for realizing industrial production really comprises an acetylation process and a propionylation process, and the industrial production processes reported in the literature are all first methods, namely, processes of synthesizing racemate and then splitting. Representative of the acetylation process are US4423244B, WO2001049053A1, CN102731295B; the propionylation process is disclosed in patent CN101234963A, CN108530278A, CN109485561A and CN110183323A. However, the existing propionyl process has the disadvantages of long synthetic reaction flow, complex process, multiple high-risk processes, high safety risk and high cost. The general naproxen synthesis and acetylation process is now described as follows:
the acetylation process is to obtain (+/-) -naproxen by condensation, hydrolysis, decarboxylation, oxidation or oximation hydrolysis with acetyl naphthalene methyl ether as the initial raw material, and the synthetic route is as follows:
the acetylation process is divided into two different process paths, the first two steps are basically consistent, the third step is different, the A process is to oxime 2- (6-methoxy-2-naphthyl) propanal firstly, then hydrolyze and acidify to obtain (+/-) -naproxen, patent WO2001049053A1 and CN102731295B already disclose that 6-methoxy-2-acetylnaphthalene is used as a starting material and applied to industrial production through the A synthesis route, but the hydroxylamine is used in the process route, the production cost is increased, the added value of the product is reduced, and a large amount of industrial waste gas, waste water and waste residues are generated in the oximation and hydrolysis process, so that the three waste treatment cost of enterprises is increased, and the concept of green chemistry is not met. The B process directly oxidizes 2- (6-methoxy-2-naphthyl) propanal in one step to obtain (+/-) -naproxen, which is a process route with good atomic utilization rate and higher economic added value, and the common oxidant in the process is KMnO 4 、H 5 IO 6 、CrO 3 、KHSO 5 、AgNO 3 Oxidizing agents such as copper salts, but in the process, decomposition is requiredSolves the three wastes pollution problem of heavy metal salt and the economic problems of expensive oxidant price and the like. Meanwhile, the oxidation reaction belongs to high-risk reaction in the traditional kettle type reactor, and has low safety coefficient and poor controllability; in addition, most of oxidation reactions are exothermic reactions, and the released heat of the reactions is not timely removed from a reaction system, so that the reactions are out of control and even explodes; and the oxidation reaction time in the traditional kettle reactor is long, and the product may have problems of excessive oxidation and oxidative degradation, which lead to the reduction of the product quality.
The pinnic oxidation reaction uses sodium chlorite as an oxidant with medium polarity to oxidize aldehyde to corresponding carboxylic acid, and has high efficiency, high selectivity, cheap and easy operation of the oxidant and convenient operation of reaction conditions, so that the method is widely applied to organic synthesis and total synthesis of natural products. Patent CN105294667B reports that the method of pinmick oxidation oxidizes 2- (6-methoxy-2-naphthyl) propanal to obtain naproxen with a yield up to 91%; journal (New Journal ofChemistry,2018, 42:10414-10420) also reports a pinmick oxidation process with a 90% yield of 2- (6-methoxy-2-naphthyl) propionic acid; there are many reports of this type, but most share common drawbacks: the 2-methyl-2-butene as byproduct hypochlorous acid scavenger (or capturing agent) with the weight of more than 10 times or even tens of equivalent is used, and the cost of the 2-methyl-2-butene is high, meanwhile, the boiling point of the 2-methyl-2-butene is low, the 2-methyl-2-butene is easy to volatilize, the consumption of the byproduct hypochlorous acid is high, and the application of pinnic acid oxidation in industrialization is limited.
The byproduct hypochlorous acid in the reaction system has the following effects: 1. relative to ClO 2 - The electrode potential of HOCl/Cl-is higher for HOCl redox ion pairs, and the ion pairs with stronger oxidability can bring about a plurality of excessive oxidation side reactions; 2. hypochlorous acid itself further consumes chlorite ions to generate chlorine dioxide with free radical oxidation activity, and brings about a plurality of side reactions; 3. hypochlorous acid reacts with the carbon-carbon double bond of the electron-rich methoxy naphthalene ring to form chlorinated byproducts. The continuous flow micro-channel reaction has the advantages of short reaction time, low reaction condition requirement,the continuous flow micro-channel reactor has the characteristics of simple operation, high safety and the like, so that the continuous flow micro-channel reactor has great technical advantages when being applied to the oxidation synthesis of (+ -) -naproxen: firstly, the safety of the oxidation reaction is high, and secondly, the consumption of the byproduct hypochlorous acid scavenger is greatly reduced due to the short reaction time and continuous reaction; and finally, because the reaction time is short, the generation of byproducts such as excessive oxidation, chlorination and the like is greatly reduced, thereby improving the product yield and the product quality.
Disclosure of Invention
The invention aims to provide a method for preparing (+/-) -2- (6-methoxy-2-naphthyl) propionic acid by oxidation in a continuous flow micro-channel reactor based on the prior art, wherein 2- (6-methoxy-2-naphthyl) propanal is used as a raw material and is prepared by oxidation reaction with an oxidant in the micro-channel reactor, and the method has the advantages of short reaction time, low reaction condition requirement, simple and safe operation, high raw material conversion rate and high product purity, and is suitable for continuous production.
The technological process of the invention is shown in figure 1, and the adopted technical scheme is as follows: a method for preparing (+/-) -2- (6-methoxy-2-naphthyl) propionic acid by oxidation in a continuous flow micro-channel reactor, which comprises the following steps:
(1) Preparing a material A mixed solution: after adding the reaction auxiliary agent into the solution of the material A, stirring and dissolving;
(2) Preparing a material B mixed solution: adjusting the pH value of the oxidant aqueous solution to be 2-6 under the room temperature condition;
(3) Pumping the mixed solution of the material A and the mixed solution of the material B into a microchannel reactor through a metering pump, mixing the two materials in the microchannel reaction, carrying out continuous oxidation reaction at the reaction temperature of 0-100 ℃ and the reaction pressure of 0.15-0.5 MPa, and carrying out quenching reaction on the reacted materials for 1-300 s, thereby obtaining (+/-) -2- (6-methoxy-2-naphthyl) propionic acid after treatment.
Further, in the step (1) of the technical scheme, 6-methoxy-2-acetylnaphthalene and chloroacetate are used as raw materials, potassium alkoxide is used as alkali, and the material A solution is obtained through condensation, hydrolysis, decarboxylation and liquid separation, or the material A solid is dissolved in a reaction solvent to obtain the material A solution.
Further, in the step (1) of the above technical scheme, the reaction auxiliary agent is 2-methyl-1-butene, 2-methyl-2-butene or 2-methyl-1, 3-butadiene; wherein the molar ratio of 2-methyl-1-butene, 2-methyl-2-butene or 2-methyl-1, 3-butadiene to 2- (6-methoxy-2-naphthyl) propanal is 1.0-3.0: 1, preferably 1.1 to 1.8:1.
Further, in the step (1) of the technical scheme, the compound 2- (6-methoxy-2-naphthyl) propanal is firstly dissolved in a solvent, and then 2-methyl-1-butene, 2-methyl-2-butene or 2-methyl-1, 3-butadiene is added for stirring and dissolving to prepare a material A solution; wherein the mass volume ratio of the compound 2- (6-methoxy-2-naphthyl) propanal to the solvent is 1:4-15 g/mL, preferably 1:4-10 g/mL.
Further, in the above-mentioned step (1) of the technical scheme, the solvent used is sec-butanol, tert-butanol, isopropanol or n-butanol, preferably sec-butanol or isopropanol.
Further, in the step (2) of the above embodiment, the oxidizing agent includes NaClO 2 、NaClO、NaNO 2 、KClO 2 、KClO、KNO 2 、KMnO 4 Or H 2 O 2 One or more of them, preferably NaClO 2 。
Further, in the step (2) of the above technical scheme, the pH of the solution is adjusted by using an acid, a base or a buffer salt; the acid comprises one or more of hydrochloric acid, sulfuric acid or acetic acid, preferably acetic acid;
the alkali comprises one or more of sodium hydroxide, potassium carbonate, cesium carbonate, sodium carbonate, potassium bicarbonate or sodium bicarbonate, preferably sodium bicarbonate;
the buffer salt comprises one or more of potassium dihydrogen phosphate, sodium acetate, potassium acetate, ammonium acetate, sodium formate or potassium formate, preferably potassium dihydrogen phosphate.
Further, in the step (2) of the above technical scheme, the oxidant is diluted by adding water to a water solution with a mass fraction of 10-30%, preferably 12-25%; acetic acid or potassium dihydrogen phosphate is added at room temperature to adjust the pH to be 2.0-6.0, preferably 3.0-4.0.
Further, in the step (3) of the technical scheme, the mol ratio of the material A2- (6-methoxy-2-naphthyl) propanal to the material B oxidant is 1:1.1-2.5, and the preferable mol ratio is 1:1.3-2.0.
The research finds that: the reaction molar ratio of the 2- (6-methoxy-2-naphthyl) propanal to the oxidant has great influence on the yield and purity of the target product, and the lower amount of the oxidant leads to incomplete reaction of the raw material 2- (6-methoxy-2-naphthyl) propanal, and leads to low yield and poor quality of the target product; the higher amount of oxidant results in increased side reaction products, increased amounts of quencher and increased costs.
Further, in the step (3) of the above technical scheme, the micro-channel reactor is a micro-reactor or a micro-mixer with double-feeding and single-discharging modules, and single modules or multiple modules are connected in series. The microchannel reactor is a silicon carbide reactor, model CSD1005. The reaction temperature is precisely controlled by an external heat exchanger.
Further, in the above-mentioned step (3) of the technical scheme, the reaction residence time of the micro-channel is 60 to 300 seconds, preferably 80 to 180 seconds.
Further, in the step (3) of the technical scheme, the reacted material is quenched by sodium thiosulfate or sodium bisulfate.
In the prior art, the oxidant is quenched by sodium thiosulfate aqueous solution, after liquid separation, water is added into an organic phase, the pH is regulated to 7-13, after stirring and liquid separation, after the pH is regulated to 2-6 by an aqueous phase, stirring and suction filtration are carried out, and vacuum drying is carried out until the weight is constant, thus obtaining the (+/-) -2- (6-methoxy-2-naphthyl) propionic acid crude product.
Further, in the step (3) of the technical scheme, when the quenching reaction is carried out, the mass ratio of the oxidant to the sodium thiosulfate or the sodium bisulphite is 1:0.3-4.5; preferably 1:0.5 to 3.0; the mass volume ratio of sodium thiosulfate to water in the sodium thiosulfate solution is 1:4-30 g/mL, preferably 1:8-20 g/mL; the mass volume ratio of the sodium bisulphite to the water in the sodium bisulphite solution is 1:4-30 g/mL, preferably 1:8-1:20 g/mL.
Further, in the step (3) of the technical scheme, the flow rate of the mixed solution of the conveying material A is 5-60 mL/min; the flow rate of the mixed solution of the conveying material B is 5-80 mL/min.
The invention adopts the micro-channel reactor to carry out continuous flow type reaction, the materials remained in the micro-channel reactor are few, the materials are fully mixed, the reaction time is short, the reaction time and the reaction temperature can be accurately controlled, a great amount of byproducts generated by excessive oxidation due to local overheating or prolonged reaction time are avoided, and the problems of long reaction time, more byproducts, complex post-treatment operation and low yield and purity in the prior art are avoided; the preparation method can accurately control the feeding proportion of the reaction materials, greatly shortens the reaction time, has high safety, low cost, simple post-treatment, high product yield of more than 95 percent and high purity of more than 99 percent, and is particularly suitable for industrialized mass production.
The invention adopts the micro-channel reactor to produce the target product (+/-) -2- (6-methoxy-2-naphthyl) propionic acid, can precisely control the proportion of the feed, precisely control the pH value, the reaction temperature and the reaction time of a reaction system, basically has no new impurity, can save raw materials, save cost, greatly shorten the reaction time and improve the safety of the process.
The invention has the beneficial effects that:
compared with the existing synthesis method, the method for preparing 2- (6-methoxy-2-naphthyl) propionic acid by oxidizing 2- (6-methoxy-2-naphthyl) propanal by adopting the microchannel reactor adopts continuous flow type reaction, has the advantages of less material remained in the microchannel reactor, accurate feeding proportion of each reaction material, full reaction mixing, accurate control of pH, reaction temperature and time of the reaction material, reduction of byproduct generation, raw material saving, cost reduction, great shortening of reaction time and high safety.
The preparation method provided by the invention can realize continuous production, the materials after the reaction can directly enter post-treatment operation, the post-treatment is simple, the yield of the product is more than 95%, the purity is more than 99%, and the preparation method is particularly suitable for industrial mass production, so that the production is more economical and environment-friendly.
The microchannel reactor adopted by the invention is acid and alkali resistant, can be used for assembling and disassembling each module conveniently, and can be adjusted according to actual needs.
Drawings
FIG. 1 is a process flow diagram of the preparation method of the present invention.
Detailed Description
The method of preparing (+ -) -2- (6-methoxy-2-naphthyl) propionic acid by oxidation of the present invention is further illustrated by the following examples, which are not intended to limit the present invention in any way.
Example 1:
microchannel reactor model-silicon carbide reactor model CSD1005
(1) Preparing a material A mixed solution: 50.1g (0.234 mol) of 2- (6-methoxy-2-naphthyl) propanal (solid) is dissolved by 300ml of sec-butyl alcohol (mass volume ratio is 1:6.0), 26.1ml of 2-methyl-1, 3-butadiene (1.1 eq) is added and placed in a material tank A (the bottom of the material tank is connected with a corresponding feed pipeline of a micro-channel through a valve), and the material tank A is stirred, dissolved and placed at a low temperature for standby;
(2) Preparing a material B mixed solution: naClO is processed by 2 23.3g (0.258 mol, mol ratio 1:1.1), and 170.9g of water were added thereto and stirred to dilute the mixture to prepare 12% NaClO by mass 2 The pH=3.0-4.0 is adjusted by adding monopotassium phosphate under the condition of room temperature, and the total volume of the solution is 187mL. Placing in a material tank B (the bottom of the material tank is connected with a corresponding feeding pipeline of the micro-channel through a valve), stirring and dissolving, and then placing at a low temperature for standby;
(3) 20.3g of sodium thiosulfate (the mass ratio of the oxidant to the sodium thiosulfate is 1:0.9) was dissolved in 163mL of water (the mass volume ratio of the sodium thiosulfate to the water is 1:8) and placed at the outlet of the microchannel reactor and stirred continuously.
(4) And (3) opening a valve at the bottom of a material tank, respectively conveying a material A mixed solution in the material tank A and a material B mixed solution in the material tank B through a digital display metering pump for 6 minutes, setting the flow rate of the material tank A to 55mL/min through the metering pump, conveying the two materials into a micro-channel reactor through a feeding pump according to the set flow rate for reaction, keeping the reaction in the channel for 60 seconds, controlling the temperature of the micro-channel reactor to be 0-30 ℃ through an ice water heat exchanger outside, adjusting the pressure to be 0.15-0.3 Mpa, and introducing the reacted materials into a sodium thiosulfate solution in a stirring state for quenching reaction. Introducing the quenched material into a transfer reaction container, standing and separating liquid; separating after 0.5h, adding 200mL of drinking water into an organic phase after separating, regulating the pH value of the solution to be 9-10 by potassium hydroxide, stirring for 1 h, standing for separating, regulating the pH value to be 3-4 by 2.0mol/L hydrochloric acid after 0.5h, stirring for 1 h, carrying out suction filtration, and carrying out vacuum drying until the weight is constant, thereby obtaining 52.7g of (+/-) -2- (6-methoxy-2-naphthyl) propionic acid solid, wherein the yield is 98.0%, and the purity is 99.31% by high performance liquid chromatography.
Example 2:
microchannel reactor model-silicon carbide reactor model CSD1005
(1) Preparing a material A mixed solution: 50.1g (0.234 mol) of 2- (6-methoxy-2-naphthyl) propanal (solid) is dissolved by 300mL of isopropanol (the mass volume ratio is 1:6.0), 25.6mL of 2-methyl-1, 3-butadiene (1.5 eq) is added and placed in a material tank A (the bottom of the material tank is connected with a corresponding feed pipeline of a micro-channel through a valve), and the material tank A is stirred, dissolved and placed at a low temperature for standby;
(2) Preparing a material B mixed solution: naClO is processed by 2 27.5g (0.304 mol, mol ratio 1:1.3), and 110.0g of water were added thereto and stirred to dilute the mixture to prepare 20% NaClO by mass 2 And adding acetic acid into the aqueous solution at room temperature to adjust the pH=3.0-4.0, wherein the total volume of the solution is 136mL. Placing in a material tank B (the bottom of the material tank is connected with a corresponding feeding pipeline of the micro-channel through a valve), stirring and dissolving, and then placing at a low temperature for standby;
(3) 50.1g of sodium thiosulfate (the mass ratio of the oxidant to the sodium thiosulfate is 1:1.8) was dissolved in 701.4mL of water (the mass-to-volume ratio of the sodium thiosulfate to the water is 1:14) and placed at the outlet of the microchannel reactor and stirred continuously.
(4) And (3) opening a valve at the bottom of a material tank, respectively conveying a material A mixed solution in the material tank A and a material B mixed solution in the material tank B through a digital display metering pump, setting the flow rate of the material tank A to 40mL/min and the flow rate of the material tank B to 17mL/min through the metering pumps, conveying the two materials into a micro-channel reactor by using a feed pump according to the set flow rate to react, keeping the reaction in the channel for 120 seconds, controlling the temperature of the micro-channel reactor to be 10-50 ℃ outside through an ice water heat exchanger, adjusting the pressure to be 0.15-0.3 Mpa, and introducing the reacted materials into a sodium thiosulfate solution in a stirring state to perform quenching reaction. Introducing the quenched material into a transfer reaction container, standing and separating liquid; separating after 0.5h, adding 200ml of drinking water into an organic phase after separating, regulating the pH value of the solution to be 9-10 by using 2.0mol/L potassium hydroxide, stirring for 1 h, standing for separating, separating the solution after 0.5h, regulating the pH value to be 3-4 by using 2.0mol/L hydrochloric acid, stirring for 1 h, carrying out suction filtration, and carrying out vacuum drying to constant weight to obtain 52.3g of (+/-) -2- (6-methoxy-2-naphthyl) propionic acid solid, wherein the yield is 97.2%, and the purity is 99.17% by high performance liquid chromatography.
Example 3:
microchannel reactor model-silicon carbide reactor model CSD1005
(1) Preparing a material A mixed solution: 100.3g (0.469 mol) of 2- (6-methoxy-2-naphthyl) propanal (solid) is dissolved with 400mL of sec-butyl alcohol (mass volume ratio is 1:4.0), 52.2mL of 2-methyl-1, 3-butadiene (1.1 eq) is added and placed in a material tank A (the bottom of the material tank is connected with a corresponding feed pipeline of a micro-channel through a valve), and the material tank A is stirred, dissolved and placed at a low temperature for standby;
(2) Preparing a material B solution: naClO is processed by 2 63.58g (0.703 mol, mol ratio 1:1.5), 466.2g of water was added thereto and stirred and diluted to prepare 12% NaClO by mass fraction 2 The pH=3.0-4.0 is adjusted by adding monopotassium phosphate under the condition of room temperature, and the total volume of the solution is 514mL. Placing in a material tank B (the bottom of the material tank is connected with a corresponding feeding pipeline of the micro-channel through a valve), stirring and dissolving, and then placing at a low temperature for standby;
(3) 44.5g of sodium bisulfite (mass ratio of oxidizer to sodium bisulfite is 1:0.7) is dissolved with 445mL of water (mass volume ratio of sodium bisulfite to water is 1:10) and placed at the outlet of the microchannel reactor with continuous stirring.
(4) And (3) opening a valve at the bottom of a material tank, respectively conveying a material A mixed solution in the material tank A and a material B mixed solution in the material tank B through a digital display metering pump for 8 minutes, setting the flow rate of the material tank A to 55mL/min through the metering pump, conveying the two materials into a micro-channel reactor through a feeding pump according to the set flow rate for reaction, keeping the reaction in the channel for 100 seconds, controlling the temperature of the micro-channel reactor to be 30-50 ℃ through an ice water heat exchanger outside, adjusting the pressure to be 0.15-0.3 Mpa, and introducing the reacted materials into sodium bisulfite solution under the stirring state for quenching reaction. Introducing the quenched material into a transfer reaction container, standing and separating liquid; separating after 0.5h, adding 400mL of drinking water into an organic phase after separating, regulating the pH value of the solution to be 9-10 by using 2.0mol/L potassium hydroxide, stirring for 1 h, standing for separating, separating the solution after 0.5h, regulating the pH value to be 3-4 by using 2.0mol/L hydrochloric acid, stirring for 1 h, carrying out suction filtration, and carrying out vacuum drying to constant weight to obtain 106.3g of (+/-) -2- (6-methoxy-2-naphthyl) propionic acid solid, wherein the yield is 98.6%, and the purity is 99.41% by high performance liquid chromatography.
Example 4:
microchannel reactor model-silicon carbide reactor model CSD1005
(1) Preparing a material A mixed solution: 100.1g (0.467 mol) of 2- (6-methoxy-2-naphthyl) propanal (solid) is dissolved by 1000mL of sec-butyl alcohol (mass volume ratio is 1:10), 50.4mL of 2-methyl-2-butene (1.2 eq) is added and placed in a material tank A (the bottom of the material tank is connected with a corresponding feed pipeline of a micro-channel through a valve), and the material tank A is stirred and dissolved and then placed at a low temperature for standby;
(2) Preparing a material B mixed solution: naClO is processed by 2 71.8g (0.794 mol, mol ratio 1:1.7), and 406.9g of water were added thereto and stirred to dilute the mixture to prepare 15% NaClO by mass 2 The pH=3.0-4.0 is adjusted by adding monopotassium phosphate under the condition of room temperature, and the total volume of the solution is 509mL. Placing in a material tank B (the bottom of the material tank is connected with a corresponding feeding pipeline of the micro-channel through a valve), stirring and dissolving, and then placing at a low temperature for standby;
(3) 28.7g of sodium bisulfite (mass ratio of oxidizer to sodium bisulfite of 1:0.4) was dissolved in 229mL of water (mass volume ratio of sodium bisulfite to water of 1:8) and placed at the outlet of the microchannel reactor with constant stirring.
(4) And (3) opening a valve at the bottom of a material tank, respectively conveying a material A mixed solution in the material tank A and a material B mixed solution in the material tank B through a digital display metering pump for 18 minutes, setting a flow rate of 60mL/min of the material tank A and a flow rate of 29mL/min of the material tank B through the metering pumps, conveying the two materials into a micro-channel reactor through a feeding pump according to the set flow rate for reaction, keeping the reaction in the channel for 80 seconds, controlling the temperature of the micro-channel reactor to be 20-40 ℃ through an ice water heat exchanger outside, adjusting the pressure to be 0.15-0.3 Mpa, and introducing the reacted materials into sodium bisulfite solution under a stirring state for quenching reaction. Introducing the quenched material into a transfer reaction container, standing and separating liquid; separating after 0.5h, adding 400mL of drinking water into an organic phase after separating, regulating the pH value of the solution to be 9-10 by using 2.0mol/L potassium hydroxide, stirring for 1 h, standing for separating, separating the solution after 0.5h, regulating the pH value to be 3-4 by using 2.0mol/L hydrochloric acid, stirring for 1 h, carrying out suction filtration, and carrying out vacuum drying to constant weight to obtain 105.0g of (+/-) -2- (6-methoxy-2-naphthyl) propionic acid solid, wherein the yield is 97.60%, and the purity is 99.08% by high performance liquid chromatography.
Example 5:
microchannel reactor model-silicon carbide reactor model CSD1005
(1) Preparing a material A mixed solution (one-pot method): 100.4g (0.501 mol) of 6-methoxy-2-acetylnaphthalene is added with 82.7g of sec-butyl chloroacetate (1.1 eq) and stirred uniformly, 400mL of sec-butyl alcohol and 112.2g of potassium sec-butoxide are added for reaction at room temperature for 2 hours, 294.59g of 40% KOH aqueous solution is dropwise added for reaction at 40 ℃ for 2 hours, 400mL of drinking water is added, the temperature is raised to reflux, decarboxylation is carried out, the solvent is removed by evaporation while the solvent is removed by evaporation, and the temperature is reduced to room temperature; the total volume of the solution is about 500ml, 97.1ml of 2-methyl-1-butene (1.8 eq, calculated by 6-methoxy-2-acetylnaphthalene) is added into a raw material tank A (the bottom of the raw material tank is connected with a corresponding feeding pipeline of a micro-channel through a valve), and the mixture is stirred and dissolved and then placed at a low temperature for standby;
(2) Preparing a material B mixed solution: 90.18g (1.002 mol, molar ratio: 1:2.0) of NaClO was diluted with 510.0g of water under stirring to give 15% NaClO 2 The pH=5.0-6.0 is adjusted by adding monopotassium phosphate under the condition of room temperature, and the total volume of the solution is 576mL.Placing in a material tank B (the bottom of the material tank is connected with a corresponding feeding pipeline of the micro-channel through a valve), stirring and dissolving, and then placing at a low temperature for standby;
(3) 90.18g of sodium sulfite (1:1 mass ratio of oxidant to sodium sulfite) was dissolved in 901.8mL of water (1:10 mass/volume ratio of sodium sulfite to water) and placed at the outlet of the microchannel reactor with constant stirring.
(4) And (3) opening a valve at the bottom of a material tank, respectively conveying a material A mixed solution in the material tank A and a material B mixed solution in the material tank B through a digital display metering pump, setting the flow rate of the material tank A to be 55mL/min and the flow rate of the material tank B to be 58mL/min through the metering pump after the material is fed for 10 minutes, conveying the two materials into a micro-channel reactor by a feeding pump according to the set flow rate for reaction, keeping the reaction in the channel for 180 seconds, controlling the temperature of the micro-channel reactor to be 30-60 ℃ outside through an ice water heat exchanger, adjusting the pressure to be 0.15-0.3 Mpa, and introducing the reacted materials into a sodium thiosulfate solution in a stirring state for quenching reaction. Introducing the quenched material into a transfer reaction container, standing and separating liquid; separating after 0.5h, adding 400mL of drinking water into an organic phase after separating, regulating the pH value of the solution to be 9-10 by using 2.0mol/L potassium hydroxide, stirring for 1 h, standing for separating, separating the solution after 0.5h, regulating the pH value to be 3-4 by using 2.0mol/L hydrochloric acid, stirring for 1 h, carrying out suction filtration, and carrying out vacuum drying to constant weight to obtain 102.9g of (+/-) -2- (6-methoxy-2-naphthyl) propionic acid solid, wherein the yield is 95.4%, and the purity is 99.07% by high performance liquid chromatography.
Example 6:
microchannel reactor model-silicon carbide reactor model CSD1005
(1) Preparing a material A mixed solution (one-pot method): 100.4g (0.501 mol) of 6-methoxy-2-acetylnaphthalene is added with 82.7g of sec-butyl chloroacetate (1.1 eq) and stirred uniformly, 400mL of isopropanol and 98.20g of potassium isopropoxide are added for reaction at room temperature for 2 hours, 294.59g of 40% KOH aqueous solution with mass fraction is dropwise added for reaction at 40 ℃ for 2 hours, 400mL of drinking water is added, the temperature is raised to reflux, decarboxylation is carried out, the solvent is removed by evaporation at the same time, and the temperature is reduced to room temperature; the total volume of the solution is about 500ml, 50.4ml of 2-methyl-2-butene (1.2 eq, calculated by 6-methoxy-2-acetylnaphthalene) is added into a raw material tank A (the bottom of the raw material tank is connected with a corresponding feeding pipeline of a micro-channel through a valve), and the mixture is stirred and dissolved and then placed at a low temperature for standby;
(2) Preparing a material B mixed solution: 67.94g (0.751 mol, mol ratio: 1:1.5) of water was added thereto and 205.0g of water was stirred and diluted to prepare 25% NaClO by mass 2 The pH=5.0-6.0 is adjusted by adding potassium dihydrogen phosphate under the condition of room temperature, and the total volume of the solution is 257mL. Placing in a material tank B (the bottom of the material tank is connected with a corresponding feeding pipeline of the micro-channel through a valve), stirring and dissolving, and then placing at a low temperature for standby;
(3) 135.88g of sodium sulfite (mass ratio of oxidant to sodium sulfite 1:2.0) was dissolved in 1087.1mL of water (mass volume ratio of sodium sulfite to water 1:8.0) and placed at the outlet of the microchannel reactor with constant stirring.
(4) And (3) opening a valve at the bottom of a material tank, respectively conveying a material A mixed solution in the material tank A and a material B mixed solution in the material tank B through a digital display metering pump, setting the flow rate of the material tank A to 55mL/min and the flow rate of the material tank B to 26mL/min through the metering pumps, conveying the two materials into a micro-channel reactor by using a feed pump according to the set flow rate to react, keeping the reaction in the channel for 240 seconds, controlling the temperature of the micro-channel reactor to be 40-80 ℃ outside through an ice water heat exchanger, adjusting the pressure to be 0.15-0.3 Mpa, and introducing the reacted materials into a sodium thiosulfate solution in a stirring state to perform quenching reaction. Introducing the quenched material into a transfer reaction container, standing and separating liquid; separating after 0.5h, adding 400mL of drinking water into an organic phase after separating, regulating the pH value of the solution to be 9-10 by using 2.0mol/L potassium hydroxide, stirring for 1 h, standing for separating, separating the solution after 0.5h, regulating the pH value to be 3-4 by using 2.0mol/L hydrochloric acid, stirring for 1 h, carrying out suction filtration, and carrying out vacuum drying to constant weight to obtain 102.6g of (+/-) -2- (6-methoxy-2-naphthyl) propionic acid solid, wherein the yield is 95.1%, and the purity is 99.24% by high performance liquid chromatography.
Comparative example 1:
microchannel reactor model-silicon carbide reactor model CSD1005
(1) Preparing a material A mixed solution: 50.3g (0.235 mol) of 2- (6-methoxy-2-naphthyl) propanal (solid) is dissolved by 300mL of sec-butyl alcohol (the mass volume ratio is 1:6.0), and the mixture is placed in a material tank A (the bottom of the material tank is connected with a corresponding feed pipeline of a micro-channel through a valve), stirred and dissolved, and then placed at a low temperature for standby;
(2) Preparing a material B mixed solution: the mass fraction is 30% H 2 O 2 20.0g (0.586 mol, mol ratio 1:2.5), 30mL of water was added and the mixture was diluted with stirring to prepare 12% H by mass fraction 2 O 2 And adding acetic acid into the aqueous solution at room temperature to adjust the pH=4.0-5.0, wherein the total volume of the solution is 50mL. Placing in a material tank B (the bottom of the material tank is connected with a corresponding feeding pipeline of the micro-channel through a valve), stirring and dissolving, and then placing at a low temperature for standby;
(3) 22.0g of sodium thiosulfate (the mass ratio of the oxidant to the sodium thiosulfate is 1:1.1) is dissolved in 176mL of water (the mass volume ratio of the sodium thiosulfate to the water is 1:8) and placed at the outlet of the microchannel reactor and stirred continuously.
(4) And (3) opening a valve at the bottom of a material tank, respectively conveying a material A mixed solution in the material tank A and a material B mixed solution in the material tank B through a digital display metering pump for 6 minutes, setting the flow rate of the material tank A to be 50mL/min through the metering pump, conveying the two materials into a micro-channel reactor through a feeding pump at the same time according to the set flow rate for reaction, keeping the reaction in the channel for 60 seconds, controlling the temperature of the micro-channel reactor to be 0-30 ℃ through an ice water heat exchanger outside, adjusting the pressure to be 0.15-0.3 Mpa, and introducing the reacted materials into a sodium thiosulfate solution in a stirring state for quenching reaction. Introducing the quenched material into a transfer reaction container, standing and separating liquid; separating after 0.5h, adding 200mL of drinking water into an organic phase after separating, regulating the pH value of the solution to be 9-10 by using 2.0mol/L potassium hydroxide, stirring for 1 h, standing for separating, separating the solution after 0.5h, regulating the pH value to be 3-4 by using 2.0mol/L hydrochloric acid, stirring for 1 h, carrying out suction filtration, and carrying out vacuum drying to constant weight to obtain 27.5g of (+/-) -2- (6-methoxy-2-naphthyl) propionic acid solid, wherein the yield is 50.86%, and the purity is 89.31% by high performance liquid chromatography.
Comparative example 2:
microchannel reactor model-silicon carbide reactor model CSD1005
(1) Preparing a material A mixed solution, namely dissolving 50.5g (0.236 mol) of 2- (6-methoxy-2-naphthyl) propanal (solid) with 300ml of isopropanol (the mass volume ratio is 1:6.0), placing the solution in a material tank A (the bottom of the material tank is connected with a corresponding feed pipeline of a micro-channel through a valve), stirring and dissolving the solution, and placing the solution at a low temperature for later use;
(2) Preparing a material B mixed solution: 41.01g KMnO 4 (0.259 mol, mol ratio of 1:1.1), 300.0g of water was added thereto and stirred and diluted to prepare KMnO having a mass fraction of 12% 4 The pH=5.0-6.0 is adjusted by adding monopotassium phosphate under the condition of room temperature, and the total volume of the solution is 350ml. Placing in a material tank B (the bottom of the material tank is connected with a corresponding feeding pipeline of the micro-channel through a valve), stirring and dissolving, and then placing at a low temperature for standby;
(3) 45.1g of sodium thiosulfate (the mass ratio of the oxidant to the sodium thiosulfate is 1:1.1) is dissolved in 450mL of water (the mass volume ratio of the sodium thiosulfate to the water is 1:10) and is placed at the outlet of the microchannel reactor and stirred continuously.
(4) And (3) opening a valve at the bottom of a material tank, respectively conveying a material A mixed solution in the material tank A and a material B mixed solution in the material tank B through a digital display metering pump, setting the flow rate of the material tank A to be 37mL/min and the flow rate of the material tank B to be 44mL/min through the metering pumps, conveying the two materials into a micro-channel reactor by using a feed pump according to the set flow rate to react, keeping the reaction in the channel for 100 seconds, controlling the temperature of the micro-channel reactor to be 10-50 ℃ outside through an ice water heat exchanger, adjusting the pressure to be 0.15-0.3 Mpa, and introducing the reacted materials into a sodium thiosulfate solution in a stirring state to perform quenching reaction. Introducing the quenched material into a transfer reaction container, standing and separating liquid; separating after 0.5h, adding 200mL of drinking water into an organic phase after separating, regulating the pH value of the solution to be 9-10 by using 2.0mol/L potassium hydroxide, stirring for 1 h, standing for separating, separating the solution after 0.5h, regulating the pH value to be 3-4 by using 2.0mol/L hydrochloric acid, stirring for 1 h, carrying out suction filtration, and carrying out vacuum drying to constant weight to obtain 42.3g of (+/-) -2- (6-methoxy-2-naphthyl) propionic acid solid, wherein the yield is 78.25%, and the purity is 90.71% by high performance liquid chromatography.
Comparative example 3:
microchannel reactor model-silicon carbide reactor model CSD1005
(1) Preparing a material A mixed solution: 50.1g (0.234 mol) of 2- (6-methoxy-2-naphthyl) propanal (solid) is dissolved by 300mL of sec-butyl alcohol (the mass volume ratio is 1:6.0), and the mixture is placed in a material tank A (the bottom of the material tank is connected with a corresponding feed pipeline of a micro-channel through a valve), stirred and dissolved, and then placed at a low temperature for standby;
(2) Preparing a material B mixed solution: naClO22.63g (0.304 mol, molar ratio 1:1.3) was diluted by adding water 166.1g and stirred to prepare a 12% aqueous NaClO solution, and acetic acid was added at room temperature to adjust pH=4.0 to 5.0, the total volume of the solution being 187mL. Placing in a material tank B (the bottom of the material tank is connected with a corresponding feeding pipeline of the micro-channel through a valve), stirring and dissolving, and then placing at a low temperature for standby;
(3) 33.94g of sodium thiosulfate (the mass ratio of the oxidant to the sodium thiosulfate is 1:1.5) is dissolved in 271.5mL of water (the mass volume ratio of the sodium thiosulfate to the water is 1:8) and placed at the outlet of the microchannel reactor and stirred continuously.
(4) And (3) opening a valve at the bottom of a material tank, respectively conveying a material A mixed solution in the material tank A and a material B mixed solution in the material tank B through a digital display metering pump, setting the flow rate of the material tank A to be 37mL/min and the flow rate of the material tank B to be 24mL/min through the metering pumps, conveying the two materials into a micro-channel reactor by using a feed pump according to the set flow rate to react, keeping the reaction in the channel for 120 seconds, controlling the temperature of the micro-channel reactor to be 10-50 ℃ outside through an ice water heat exchanger, adjusting the pressure to be 0.15-0.3 Mpa, and introducing the reacted materials into a sodium thiosulfate solution in a stirring state to perform quenching reaction. Introducing the quenched material into a transfer reaction container, standing and separating liquid; separating after 0.5h, adding 200mL of drinking water into an organic phase after separating, regulating the pH value of the solution to be 9-10 by using 2.0mol/L potassium hydroxide, stirring for 1 h, standing for separating, separating the solution after 0.5h, regulating the pH value to be 3-4 by using 2.0mol/L hydrochloric acid, stirring for 1 h, carrying out suction filtration, and carrying out vacuum drying to constant weight to obtain 35.3g of (+/-) -2- (6-methoxy-2-naphthyl) propionic acid solid, wherein the yield is 65.30%, and the purity is 81.71% by high performance liquid chromatography.
The above embodiments are only for illustrating the technical solution of the present invention, and are not limiting; although the invention has been described in detail with reference to the foregoing embodiments, those skilled in the art will understand that modifications and substitutions of some of the technical features described in the foregoing embodiments are possible without departing from the spirit and scope of the technical aspects of the embodiments.
Claims (21)
1. The method for preparing (+ -) -2- (6-methoxy-2-naphthyl) propionic acid by continuous flow micro-channel reaction oxidation is characterized by comprising the following steps:
(1) Preparing a material A mixed solution: after adding the reaction auxiliary agent into the solution of the material A, stirring and dissolving; the reaction auxiliary agent is 2-methyl-1-butene, 2-methyl-2-butene or 2-methyl-1, 3-butadiene;
(2) Preparing a material B mixed solution: adjusting the pH value of the oxidant aqueous solution to be 2-6 under the room temperature condition; the oxidant is NaClO 2 ；
(3) Pumping the mixed solution of the material A and the mixed solution of the material B into a microchannel reactor through a metering pump, mixing the two materials in the microchannel reaction, carrying out continuous oxidation reaction at the reaction temperature of 0-100 ℃ and the reaction pressure of 0.15-0.5 MPa, and carrying out quenching reaction on the reacted materials for 1-300 s, thereby obtaining (+/-) -2- (6-methoxy-2-naphthyl) propionic acid after treatment.
2. The method according to claim 1, characterized in that: in the step (1), 6-methoxy-2-acetylnaphthalene and chloroacetate are used as raw materials, potassium alkoxide is used as alkali, and a material A solution is obtained through condensation, hydrolysis, decarboxylation and liquid separation, or a material A solid is dissolved in a reaction solvent to obtain the material A solution.
3. The method according to claim 1, characterized in that: in the step (1), the molar ratio of 2-methyl-1-butene, 2-methyl-2-butene or 2-methyl-1, 3-butadiene to 2- (6-methoxy-2-naphthyl) propanal is 1.0-3.0:1.
4. The method according to claim 1, characterized in that: in the step (1), the molar ratio of 2-methyl-1-butene, 2-methyl-2-butene or 2-methyl-1, 3-butadiene to 2- (6-methoxy-2-naphthyl) propanal is 1.1-1.8:1.
5. A method according to claim 3 or 4, characterized in that: in the step (1), a compound 2- (6-methoxy-2-naphthyl) propanal is firstly dissolved in a solvent, and then 2-methyl-1-butene, 2-methyl-2-butene or 2-methyl-1, 3-butadiene is added for stirring and dissolving to prepare a material A solution; wherein the mass volume ratio of the compound 2- (6-methoxy-2-naphthyl) propanal to the solvent is 1:4-15 g/mL.
6. The method according to claim 5, wherein: in the step (1), the mass volume ratio of the compound 2- (6-methoxy-2-naphthyl) propanal to the solvent is 1:4-10 g/mL.
7. The method according to claim 5, wherein: in the step (1), the solvent used is sec-butanol, tert-butanol, isopropanol or n-butanol.
8. The method according to claim 7, wherein: in the step (1), the solvent used is sec-butanol or isopropanol.
9. The method according to claim 1, characterized in that: in the step (2), acid, alkali or buffer salt is adopted to adjust the pH value of the solution; the acid comprises one or more of hydrochloric acid, sulfuric acid or acetic acid; the alkali comprises one or more of sodium hydroxide, potassium carbonate, cesium carbonate, sodium carbonate, potassium bicarbonate or sodium bicarbonate; the buffer salt comprises one or more of potassium dihydrogen phosphate, sodium acetate, potassium acetate, ammonium acetate, sodium formate or potassium formate.
10. The method according to claim 9, wherein: in the step (2), the acid is acetic acid, the alkali is sodium bicarbonate, and the buffer salt is potassium dihydrogen phosphate.
11. The method according to claim 9 or 10, characterized in that: in the step (2), adding water into an oxidant to dilute the oxidant to a water solution with the mass fraction of 10-30%; acetic acid or potassium dihydrogen phosphate is added at room temperature to adjust the pH to be 2.0-6.0.
12. The method according to claim 11, wherein: in the step (2), the mass fraction is 12-25%; ph=3.0 to 4.0.
13. The method according to claim 1, characterized in that: in the step (3), the mol ratio of the material A2- (6-methoxy-2-naphthyl) propanal to the material B oxidant is 1:1.1-2.5.
14. The method according to claim 13, wherein: in the step (3), the mol ratio of the material A2- (6-methoxy-2-naphthyl) propanal to the material B oxidant is 1:1.3-2.0.
15. The method according to claim 1, characterized in that: in the step (3), the micro-channel reactor is a micro-reactor or a micro-mixer with double feeding and single discharging modules, and single modules or multiple modules are connected in series.
16. The method according to claim 1, characterized in that: in the step (3), the reaction residence time of the micro-channel is 60-300 s.
17. The method according to claim 16, wherein: in the step (3), the reaction residence time of the micro-channel is 80-180 s.
18. The method according to claim 1, characterized in that: in the step (3), the materials after the reaction are quenched by sodium thiosulfate or sodium bisulphite.
19. The method according to claim 18, wherein: in the step (3), when quenching reaction is carried out, the mass ratio of the oxidant to the sodium thiosulfate or the sodium bisulphite is 1:0.3-4.5; the mass volume ratio of sodium thiosulfate to water in the sodium thiosulfate solution is 1:4-30 g/mL; the mass volume ratio of the sodium bisulphite to the water in the sodium bisulphite solution is 1:4-30 g/mL.
20. The method according to claim 19, wherein: in the step (3), when quenching reaction is carried out, the mass ratio of the oxidant to the sodium thiosulfate or the sodium bisulphite is 1:0.5-3.0; the mass volume ratio of sodium thiosulfate to water in the sodium thiosulfate solution is 1:8-20 g/mL; the mass volume ratio of the sodium bisulphite to the water in the sodium bisulphite solution is 1:8-20 g/mL.
21. The method according to claim 1, characterized in that: in the step (3), the flow rate of the mixed solution of the conveying material A is 5-60 mL/min; the flow rate of the mixed solution of the conveying material B is 5-80 mL/min.
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| CN104292098A (en) * | 2014-09-28 | 2015-01-21 | 威海迪嘉制药有限公司 | Preparation method of 2-phenylpropionic acid |
| CN105294667A (en) * | 2014-07-28 | 2016-02-03 | 中国科学院上海有机化学研究所 | NNN ligand, metal complexes thereof, preparation methods and application |
| CN113200841A (en) * | 2021-04-21 | 2021-08-03 | 嘉兴学院 | Novel process for synthesizing racemic naproxen based on Heck coupling |
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| CN105294667A (en) * | 2014-07-28 | 2016-02-03 | 中国科学院上海有机化学研究所 | NNN ligand, metal complexes thereof, preparation methods and application |
| CN104292098A (en) * | 2014-09-28 | 2015-01-21 | 威海迪嘉制药有限公司 | Preparation method of 2-phenylpropionic acid |
| CN113200841A (en) * | 2021-04-21 | 2021-08-03 | 嘉兴学院 | Novel process for synthesizing racemic naproxen based on Heck coupling |
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