CN113264841A - Method for continuously preparing (3S) -3-aminomethyl-5-methylhexanoic acid - Google Patents
Method for continuously preparing (3S) -3-aminomethyl-5-methylhexanoic acid Download PDFInfo
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- CN113264841A CN113264841A CN202110522616.5A CN202110522616A CN113264841A CN 113264841 A CN113264841 A CN 113264841A CN 202110522616 A CN202110522616 A CN 202110522616A CN 113264841 A CN113264841 A CN 113264841A
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- aminomethyl
- methylhexanoic acid
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- AYXYPKUFHZROOJ-ZETCQYMHSA-N pregabalin Chemical compound CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 title claims abstract description 33
- 238000000034 method Methods 0.000 title claims abstract description 21
- 238000002156 mixing Methods 0.000 claims description 20
- 238000006243 chemical reaction Methods 0.000 claims description 14
- NPDKTSLVWGFPQG-SSDOTTSWSA-N (3r)-3-(2-amino-2-oxoethyl)-5-methylhexanoic acid Chemical compound CC(C)C[C@H](CC(N)=O)CC(O)=O NPDKTSLVWGFPQG-SSDOTTSWSA-N 0.000 claims description 10
- 239000005708 Sodium hypochlorite Substances 0.000 claims description 9
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 239000007788 liquid Substances 0.000 claims description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 239000003638 chemical reducing agent Substances 0.000 claims description 6
- 238000002425 crystallisation Methods 0.000 claims description 6
- 230000008025 crystallization Effects 0.000 claims description 6
- 230000003068 static effect Effects 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- 239000012528 membrane Substances 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 238000003860 storage Methods 0.000 claims description 4
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 claims description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 2
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 claims description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 claims description 2
- 239000002585 base Substances 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 3
- 229960001233 pregabalin Drugs 0.000 description 13
- 238000002360 preparation method Methods 0.000 description 8
- 238000004321 preservation Methods 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 6
- 230000035484 reaction time Effects 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 235000010265 sodium sulphite Nutrition 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 206010036376 Postherpetic Neuralgia Diseases 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- JGJLWPGRMCADHB-UHFFFAOYSA-N hypobromite Chemical compound Br[O-] JGJLWPGRMCADHB-UHFFFAOYSA-N 0.000 description 2
- WQYVRQLZKVEZGA-UHFFFAOYSA-N hypochlorite Chemical compound Cl[O-] WQYVRQLZKVEZGA-UHFFFAOYSA-N 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 235000011121 sodium hydroxide Nutrition 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 1
- 238000007167 Hofmann rearrangement reaction Methods 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 101150026239 PDPN gene Proteins 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 229910000435 bromine oxide Inorganic materials 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 1
- 238000007602 hot air drying Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 229940009697 lyrica Drugs 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000010888 waste organic solvent Substances 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/38—Separation; Purification; Stabilisation; Use of additives
- C07C227/40—Separation; Purification
- C07C227/42—Crystallisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Crystallography & Structural Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the field of chemical pharmacy, and particularly relates to a method for continuously preparing (3S) -3-aminomethyl-5-methylhexanoic acid.
Description
Technical Field
The invention relates to the field of chemical pharmacy, in particular to a method for continuously preparing (3S) -3-aminomethyl-5-methylhexanoic acid.
Technical Field
Pregabalin (Pregabalin) is a gamma-aminobutyric acid (GABA) analog developed by the company picui, chemical name (3S) -3-aminomethyl-5-methylhexanoic acid (structural formula below), and commercial name of Lyrica. Approval to market in the european union in 7 months 2004 and in the united states in 6 months 2005. Pregabalin is used as an anticonvulsant, and is mainly used for treating adult partial seizure, diabetic neuralgia (pDPN), postherpetic neuralgia (PHN) and anxiety disorder.
At present, a plurality of related documents and patents at home and abroad report a preparation method for preparing (3S) -3-aminomethyl-5-methylhexanoic acid by Hofmann rearrangement by using hypobromite or hypochlorite. WO2008137512A2 discloses a preparation method of (3S) -3-aminomethyl-5-methylhexanoic acid, wherein bromine is used in sample 4, sample 5 and sample 6, and the preparation method is high in volatility, corrosiveness, high in price, low in economical efficiency and high in pollution from the perspective of green chemistry. US5616793 discloses a process for the preparation of (3S) -3-aminomethyl-5-methylhexanoic acid which uses large amounts of bromine and sodium hydroxide, is uneconomically environmentally friendly, gives low yields, and gives a single step yield of only 66.7% based on the disclosed mass of pregabalin prepared. CN109678737A discloses a preparation method of pregabalin, which claim 1 discloses a method for obtaining high-purity pregabalin by extraction in acid-organic solvent after huffman rearrangement of substrate and sodium hypochlorite, wherein the method uses a large amount of organic solvent and performs multiple extraction operations, and the increase of operation steps in the industrial production process can greatly prolong the production cycle and affect the productivity, although the yield and purity of the obtained product are high; in addition, the waste organic solvent requires additional treatment, increasing the production cost. CN106748850A discloses a method for preparing pregabalin, wherein hydrogenation of palladium on carbon is used, the price of palladium on carbon is high, which increases the production cost, and the introduction of palladium on carbon and hydrogen is unfavorable for intrinsic safety, meanwhile, the paragraph [0038] of the specification discloses that the reduction time is 5-48 hours, the catalytic reduction time disclosed in the embodiment is 10-30 hours, the reaction period is long, and the production efficiency is low.
Disclosure of Invention
In order to enable the preparation of the pregabalin to be more efficient, rapid and continuous, the cost is low, three wastes are less, and the prepared pregabalin has high yield and high purity, the invention provides a method for continuously preparing the pregabalin.
The invention provides a method for continuously preparing (3S) -3-aminomethyl-5-methylhexanoic acid, which specifically comprises the following steps:
a) preparing an ionic membrane liquid alkali solution containing (R) -3- (2-amino-2-oxoethyl) -5-methylhexanoic acid, and naming the solution as a solution A;
b) placing the sodium hypochlorite solution in a container for later use, namely the solution B, wherein the container is not particularly limited and can be a reaction kettle, a storage tank or other storage containers;
c) preparing a reducing agent into a solution, namely a solution C;
d) introducing the solution A and the solution B into a mixer for mixing reaction, and naming an effluent as a solution AB;
e) introducing the solution C and the solution AB into another mixer for mixing reaction, and naming as solution ABC;
f) introducing the solution ABC into a crystallization kettle, and stirring for crystallization;
g) slowly adding acid dropwise to adjust the pH value, filtering and drying to obtain (3S) -3-aminomethyl-5-methylhexanoic acid.
In a preferred embodiment of the present invention, the weight ratio of (R) -3- (2-amino-2-oxoethyl) -5-methylhexanoic acid to caustic soda liquid in the solution A is (30-50 g)/100 g.
As a preferred technical scheme of the invention, the preparation temperature of the solution A is-10-20 ℃.
As a preferable technical scheme of the invention, the effective chlorine mass concentration of the solution B is 10-15% (g/L), and the storage temperature is-10-20 ℃.
The preferable technical scheme of the invention is that the reducing agent in the step c) is sulfite or bisulfite, and the concentration of the solution of the reducing agent is 0.20-0.30 g/ml.
As a preferred embodiment of the present invention, wherein the mixer in steps d) and e) is one of a microchannel mixer, a static mixer or a tubular reactor.
As a preferred technical scheme of the invention, the mixing time of the mixing reaction in the step d) is 30-180 s, the mixing pressure is from normal pressure to 0.6Mpa, and the mixing temperature is-10-45 ℃.
As a preferred technical scheme, the mixing time of the mixing reaction in the step e) is 1-360 s, the mixing pressure is from normal pressure to 0.6Mpa, and the mixing temperature is-10-25 ℃.
As a preferable technical scheme of the invention, the stirring crystallization time in the step f) is 20-240 min, and the stirring temperature is controlled at 0-30 ℃.
As a preferred technical scheme of the invention, the acid in the step g) is sulfuric acid or hydrochloric acid, and the pH value is adjusted to be 6.5-7.5.
The innovation point of the invention is that the operation process is simplified through continuous reaction, and the reaction time is shortened; the invention has the advantages that the obtained target product (3S) -3-aminomethyl-5-methylhexanoic acid has short reaction time, less three wastes, high conversion rate, high yield and small amplification effect, and is very suitable for industrial production.
Drawings
FIG. 1 is a reaction scheme of examples 1 and 2.
FIG. 2 is a reaction scheme of example 3.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The following specific preparation examples are intended to illustrate the invention in detail, and the examples are intended to be illustrative in more detail only, and not to limit the invention in any way.
Example 1
651g of 30% ionic membrane liquid alkali and 70g of purified water are weighed and added into a container, the mixture is stirred and mixed uniformly, then the temperature is reduced to minus 10 ℃, 240g of (R) -3- (2-amino-2-oxoethyl) -5-methylhexanoic acid is slowly added in batches to dissolve the mixture, and the mixture is placed at minus 10 ℃ for heat preservation for later use. 870g of sodium hypochlorite solution with the mass concentration of 10 percent of available chlorine is weighed and placed at minus 10 ℃ for heat preservation for standby. Respectively enabling the (R) -3- (2-amino-2-oxoethyl) -5-methylhexanoic acid solution and sodium hypochlorite to pass through a microchannel reactor 1 under the heat preservation state of-10 ℃, enabling an effluent to pass through a second microchannel reactor 2, enabling 33.3ml of 0.3g/ml sodium bisulfite solution to flow into the second microchannel reactor 2 at the same time, enabling the total reaction time of a microchannel plate to be 60s, collecting the effluent into a crystallizer, slowly dropwise adding sulfuric acid to adjust the pH value to be 6.5-7.5, filtering, and drying with hot air at 50 ℃ for 3h to obtain 198.5g of pregabalin with the purity of 99.9% and the yield of 97.3%.
Example 2
390g of 30% ionic membrane liquid alkali and 331g of purified water are weighed and added into a container, stirred and mixed uniformly, then cooled to 20 ℃, and then 240g of (R) -3- (2-amino-2-oxoethyl) -5-methylhexanoic acid is slowly added in batches to be dissolved and then placed at 20 ℃ for heat preservation for later use. 638g of sodium hypochlorite solution with 15% available chlorine mass concentration is weighed and placed at-10 ℃ for heat preservation for later use. And (R) -3- (2-amino-2-oxoethyl) -5-methylhexanoic acid solution and sodium hypochlorite simultaneously pass through a microchannel reactor 1 under the condition of heat preservation at 20 ℃, effluent passes through the microchannel reactor 2, 50ml of 0.20g/ml sodium sulfite solution simultaneously flows into a second microchannel reactor 2, the total reaction time of a microchannel plate is 120s, the effluent is collected into a crystallizer, refined hydrochloric acid is slowly dripped to adjust the pH to be 6.5-7.5, filtering is carried out, and hot air drying is carried out at 50 ℃ for 3h to obtain 198.3g of pregabalin with the purity of 99.9% and the yield of 97.2%.
Example 3
83kg of 30% ionic membrane liquid alkali and 33kg of purified water are weighed into a 20L container, stirred, mixed uniformly and cooled to 20 ℃, 40kg of (R) -3- (2-amino-2-oxoethyl) -5-methylhexanoic acid is added into the container, dissolved and then kept at 0 ℃ for later use. 14.5kg of a sodium hypochlorite solution with the mass concentration of 10% of available chlorine is weighed and placed at 0 ℃ for heat preservation for later use. Passing the (R) -3- (2-amino-2-oxoethyl) -5-methylhexanoic acid solution and sodium hypochlorite through a static mixer 1 and a tubular reactor 1 at the same time in a heat preservation state at 0 ℃, passing the effluent through the static mixer 2, simultaneously passing 0.4L0.25g/ml of sodium sulfite solution (0.1kg of sodium sulfite dissolved in 0.48L of water) into the static mixer 2, passing the effluent through the tubular reactor 2, collecting the total reaction time of the static mixer and the tubular reactor for 360s, slowly dropwise adding 3.34kg of 37% hydrochloric acid into a crystallizer to adjust the pH value to 6.5-7.5, cooling to 0-10 ℃, filtering, and drying by hot air at 50 ℃ for 3h to obtain 33.5kg of pregabalin with the purity of 99.9% and the yield of 98.5%.
Claims (10)
1. A method for continuously preparing (3S) -3-aminomethyl-5-methylhexanoic acid specifically comprises the following steps:
a) preparing an ionic membrane liquid alkali solution containing (R) -3- (2-amino-2-oxoethyl) -5-methylhexanoic acid, and naming the solution as a solution A;
b) placing the sodium hypochlorite solution in a container for later use, and naming the solution as solution B;
c) preparing a reducing agent into a solution, namely a solution C;
d) introducing the solution A and the solution B into a mixer for mixing reaction, and naming an effluent as a solution AB;
e) introducing the solution C and the solution AB into another mixer for mixing reaction, and naming as solution ABC;
f) introducing the solution ABC into a crystallization kettle, and stirring for crystallization;
g) slowly adding acid dropwise to adjust the pH value, filtering and drying to obtain (3S) -3-aminomethyl-5-methylhexanoic acid.
2. The method for continuously preparing (3S) -3-aminomethyl-5-methylhexanoic acid according to claim 1, wherein the weight ratio of (R) -3- (2-amino-2-oxoethyl) -5-methylhexanoic acid to liquid base in solution A is (30-50 g)/100 g.
3. The method for continuously preparing (3S) -3-aminomethyl-5-methylhexanoic acid according to claim 1, wherein solution A is prepared at a temperature of-10 to 20 ℃.
4. The method for continuously preparing (3S) -3-aminomethyl-5-methylhexanoic acid according to claim 1, wherein solution B has an available chlorine mass concentration of 10-15% in g/L and a storage temperature of-10-20 ℃.
5. The method for continuously preparing (3S) -3-aminomethyl-5-methylhexanoic acid according to claim 1, wherein the reducing agent in step c) is a sulfite or bisulfite, and the concentration of the reducing agent in the solution is 0.20 to 0.30 g/ml.
6. The process of claim 1, wherein the mixer in steps d) and e) is one of a microchannel mixer, a static mixer or a tubular reactor.
7. The method of claim 1, wherein the mixing time of the mixing reaction in the step d) is 30-180S, the mixing pressure is from normal pressure to 0.6MPa, and the mixing temperature is-10-45 ℃.
8. The method of claim 1, wherein the mixing time of the mixing reaction in step e) is 1-360S, the mixing pressure is from normal pressure to 0.6MPa, and the mixing temperature is-10-25 ℃.
9. The method for continuously preparing (3S) -3-aminomethyl-5-methylhexanoic acid according to claim 1, wherein the stirring crystallization time in step f) is 20-240 min, and the stirring temperature is controlled to be 0-30 ℃.
10. The process for continuously preparing (3S) -3-aminomethyl-5-methylhexanoic acid according to claim 1, characterized in that the acid used in step g) is sulfuric acid or hydrochloric acid, adjusted to a pH of 6.5 to 7.5.
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| CN202110522616.5A CN113264841A (en) | 2021-05-13 | 2021-05-13 | Method for continuously preparing (3S) -3-aminomethyl-5-methylhexanoic acid |
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| CN202110522616.5A CN113264841A (en) | 2021-05-13 | 2021-05-13 | Method for continuously preparing (3S) -3-aminomethyl-5-methylhexanoic acid |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023071011A1 (en) * | 2021-10-26 | 2023-05-04 | 浙江华海药业股份有限公司 | Method for purifying pregabalin |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023071011A1 (en) * | 2021-10-26 | 2023-05-04 | 浙江华海药业股份有限公司 | Method for purifying pregabalin |
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