CN102964301A - Method for synthesizing IOX2 - Google Patents
Method for synthesizing IOX2 Download PDFInfo
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- CN102964301A CN102964301A CN2012104839914A CN201210483991A CN102964301A CN 102964301 A CN102964301 A CN 102964301A CN 2012104839914 A CN2012104839914 A CN 2012104839914A CN 201210483991 A CN201210483991 A CN 201210483991A CN 102964301 A CN102964301 A CN 102964301A
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- dissolved
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- benzyl
- reaction
- iox2
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- 238000000034 method Methods 0.000 title claims abstract description 13
- CAOSCCRYLYQBES-UHFFFAOYSA-N 2-[[[4-hydroxy-2-oxo-1-(phenylmethyl)-3-quinolinyl]-oxomethyl]amino]acetic acid Chemical compound O=C1C(C(=O)NCC(=O)O)=C(O)C2=CC=CC=C2N1CC1=CC=CC=C1 CAOSCCRYLYQBES-UHFFFAOYSA-N 0.000 title claims abstract description 11
- 230000002194 synthesizing effect Effects 0.000 title abstract 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 17
- VYFOAVADNIHPTR-UHFFFAOYSA-N isatoic anhydride Chemical compound NC1=CC=CC=C1CO VYFOAVADNIHPTR-UHFFFAOYSA-N 0.000 claims abstract description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- 150000001875 compounds Chemical class 0.000 claims description 19
- 239000007787 solid Substances 0.000 claims description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 12
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 10
- 239000012312 sodium hydride Substances 0.000 claims description 10
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- WUWHFEHKUQVYLF-UHFFFAOYSA-M sodium;2-aminoacetate Chemical compound [Na+].NCC([O-])=O WUWHFEHKUQVYLF-UHFFFAOYSA-M 0.000 claims description 6
- 238000010189 synthetic method Methods 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 5
- WYACBZDAHNBPPB-UHFFFAOYSA-N diethyl oxalate Chemical compound CCOC(=O)C(=O)OCC WYACBZDAHNBPPB-UHFFFAOYSA-N 0.000 claims description 5
- 238000001953 recrystallisation Methods 0.000 claims description 5
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims description 4
- 206010013786 Dry skin Diseases 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical class BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 claims description 3
- 238000001514 detection method Methods 0.000 claims description 3
- 239000012467 final product Substances 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 150000008065 acid anhydrides Chemical class 0.000 claims description 2
- 150000008064 anhydrides Chemical class 0.000 claims description 2
- 239000013078 crystal Substances 0.000 claims description 2
- 238000003810 ethyl acetate extraction Methods 0.000 claims description 2
- 239000000284 extract Substances 0.000 claims description 2
- AJFDBNQQDYLMJN-UHFFFAOYSA-N n,n-diethylacetamide Chemical compound CCN(CC)C(C)=O AJFDBNQQDYLMJN-UHFFFAOYSA-N 0.000 claims description 2
- 239000012074 organic phase Substances 0.000 claims description 2
- 238000010025 steaming Methods 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- XZNZVRHSHRYPDL-UHFFFAOYSA-N 1-benzyl-3,1-benzoxazine-2,4-dione Chemical compound O=C1OC(=O)C2=CC=CC=C2N1CC1=CC=CC=C1 XZNZVRHSHRYPDL-UHFFFAOYSA-N 0.000 claims 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 2
- 125000004494 ethyl ester group Chemical group 0.000 claims 2
- FHIKZROVIDCMJA-UHFFFAOYSA-N 2-(2,2-diphenylpentanoyloxy)ethyl-diethylazanium;chloride Chemical compound Cl.C=1C=CC=CC=1C(C(=O)OCCN(CC)CC)(CCC)C1=CC=CC=C1 FHIKZROVIDCMJA-UHFFFAOYSA-N 0.000 claims 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims 1
- 239000007810 chemical reaction solvent Substances 0.000 claims 1
- 229940126214 compound 3 Drugs 0.000 claims 1
- 230000035484 reaction time Effects 0.000 claims 1
- -1 sodium hydrides Chemical class 0.000 claims 1
- 239000008096 xylene Substances 0.000 claims 1
- 238000011031 large-scale manufacturing process Methods 0.000 abstract 1
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 102000004079 Prolyl Hydroxylases Human genes 0.000 description 1
- 108010043005 Prolyl Hydroxylases Proteins 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000007805 chemical reaction reactant Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Indole Compounds (AREA)
Abstract
The invention discloses a method for synthesizing IOX2 through utilizing isatoic anhydride. The conventional technology is improved and optimized, the reaction cost and treatment difficulty are lowered, each step of reaction is simple to operate and is controllable, the method is suitable for large scale production, and the reaction yield is increased.
Description
Technical field
The synthesis technology that the present invention relates to a kind of IOX2 improves, and belongs to the medicine bioengineering chemical technology field, also relates to some intermediate that obtains by this method.
Background technology
IOX2 has another name called nitrogen-{ [1,2-dihydro-4-hydroxyl-2-oxygen-1-benzyl-3-quinoline] carbonyl } glycine, and it is a kind of white solid, at the selective depressant that medically is hypoxia inducible factor (HIF) prolyl hydroxylase.
The preparation of IOX2 is take isatoic anhydride as raw material, through benzyl on the benzyl bromine, then becomes ester with the diethyl malonate reaction by acid anhydrides, makes with Sodium glycocollate salt formation amino acid more at last.
Summary of the invention
The present invention mainly improves former operational path, makes per step operation controlled easy to operate, is beneficial to amplify to produce, and improves yield.
The invention provides formula (4) compound (IOX2)
The invention provides formula (3) compound
Method with Sodium glycocollate reactant salt preparation (4) compound, the method is (3) compound and glycine sodium salt (equivalence ratio is 1:1.2) in ethylene glycol monomethyl ether solution reflux 2-6 hour, reacting complete rear cooling pours in the frozen water, the hcl acidifying that adds 6N, solid washes out and is target product, purity can get final product the solid that washes out recrystallization in acetic acid if purity requirement is higher about 95%.
The invention provides formula (2) compound
Method with diethyl malonate reaction preparation formula (3) compound, the method is reacted under alkaline condition for (2) compound and diethyl malonate, then acidifying obtains formula (3) compound, this reaction product and reactant polarity are more or less the same, the TLC detection difficult, 120 ℃ of heat-up times are long effective.
The invention provides formula (1) compound
With the method for bromobenzene reaction preparation formula (2) compound, the method is reacted under alkaline condition for (1) compound and bromobenzene, and final product crystallization in toluene makes formula (2) compound.
Embodiment
Embodiment 1
4.5 the gram sodium hydride is dissolved in the tetrahydrofuran (THF) of 50 milliliters of dryings, solution is cooled to 10 ℃.16.3 gram (0.1 mole) isatoic anhydrides are dissolved in 50 milliliters of N, in the N-diethyl acetamide, in the time of 10 ℃, splash in the tetrahydrofuran solution of sodium hydride, stir half an hour, after half an hour the tetrahydrofuran (THF) of 250 milliliters of dryings that are dissolved in 17.1 gram benzyl bromines is splashed in the solution.Room temperature reaction spends the night, and reacts complete and rear solution is poured into water, and uses ethyl acetate extraction, separates dry organic phase, obtains semi-solid dress material after revolving steaming, and this material heating is dissolved in brown needle-like crystals 12.5 grams that recrystallization is behind the toluene, productive rate about 50%.
Embodiment 2
Take sodium hydride 1.2 grams that sherwood oil washed and be dissolved in the N,N-dimethylacetamide, solution is cooled to 5 ℃.Get 4.7 gram diethyl oxalates and be dissolved in the N,N-dimethylacetamide, under 5 ℃, splash in the sodium hydride solution, reacted one hour.React complete after, get 6.0 and digest compound
2Be dissolved in the dry N,N-dimethylacetamide, be added drop-wise in the mentioned solution, be heated to 120 ℃ of reactions 17 hours.React and remove heating after complete, in process of cooling, add 2.0 gram acetic acid, then stir and be cooled to room temperature.Reaction solution is poured into water, extracts with ethyl acetate, ethyl acetate is spin-dried for the semi-solid compound that then obtains and washes with a small amount of ethanol with the salt washing, namely gets good solid, filters and drains to get compound
3Be 4.0 grams, productive rate is about 53%.
Embodiment 3
The compound of obtaining
34.0 gram, glycine sodium salt 1.52 grams are dissolved in the ethylene glycol monomethyl ether solution, and reflux is more than 2 hours, and the complete rear cooling of TLC detection reaction is poured in the frozen water, then uses the hcl acidifying of 6 mol/L, has a large amount of solids to separate out behind the adding hydrochloric acid.Filter and collect the gained solid, drain and obtain white solid
IOX2Be 4.0 grams, productive rate is about 90%.Carry out the recrystallization processing in the acetic acid if require the higher white solid heating that obtains can be dissolved in of purity.
Claims (4)
1.IOX2 synthetic method, to adopt isatoic anhydride and benzyl bromine benzyl on the position at the nitrogen of isatoic anhydride under the effect of sodium hydride, obtain N-benzyl isatoic anhydride, N-benzyl isatoic anhydride becomes 1-benzyl-4-hydroxyl-2-oxygen-1 with the rear acidifying of diethyl oxalate reaction by acid anhydrides under the effect of sodium hydride, 2-dihydroquinoline-3-carboxylic acid, ethyl ester obtains final product with glycine sodium salt in ethylene glycol monomethyl ether backflow acidifying at last again.
2. the synthetic method of IOX2 as described in requiring such as right 1 is characterized in that: process isatoic anhydride and diethyl oxalate with sodium hydride, reaction solvent includes but not limited to benzene,toluene,xylene, tetrahydrofuran (THF) and N,N-dimethylacetamide.
3. the synthetic method of IOX2 as described in requiring such as right 1, it is characterized in that: become 1-benzyl-4-hydroxyl-2-oxygen-1 by N-benzyl isatoic anhydride and diethyl oxalate reaction, during 2-dihydroquinoline-3-carboxylic acid, ethyl ester, temperature of reaction comprises 100 ℃ to 140 ℃, 10 hours to 24 hours reaction times.
4. the synthetic method of proadifen hydrochloride as described in requiring such as right 1, it is characterized in that: described IOX2 synthetic method makes: 4.5 gram sodium hydrides are dissolved in the tetrahydrofuran (THF) of 50 milliliters of dryings, solution is cooled to 10 ℃, 16.3 gram (0.1 mole) isatoic anhydrides are dissolved in 50 milliliters of N, in the N-diethyl acetamide, in the time of 10 ℃, splash in the tetrahydrofuran solution of sodium hydride, stir half an hour, after half an hour the tetrahydrofuran (THF) of 250 milliliters of dryings that are dissolved in 17.1 gram benzyl bromines is splashed in the solution, room temperature reaction spends the night, reacting complete is poured into water solution afterwards, use ethyl acetate extraction, separate dry organic phase, revolve and obtain semi-solid dress material after the steaming, the heating of this material is dissolved in the brown needle-like crystals that recrystallization is behind the toluene, take sodium hydride 1.2 grams that sherwood oil washed and be dissolved in the N,N-dimethylacetamide, solution is cooled to 5 ℃, get 4.7 gram diethyl oxalates and be dissolved in N, in the N-N,N-DIMETHYLACETAMIDE, under 5 ℃, splash in the sodium hydride solution, reacted one hour, react complete after, get 6.0 and digest compound
2Be dissolved in the dry N,N-dimethylacetamide, be added drop-wise in the mentioned solution, be heated to 120 ℃ of reactions 17 hours, react and remove heating after complete, in process of cooling, add 2.0 gram acetic acid, then stir and be cooled to room temperature, reaction solution is poured into water, extract with ethyl acetate, ethyl acetate is spin-dried for the semi-solid compound that then obtains and washes with a small amount of ethanol with the salt washing, namely get good solid, filter and drain to get compound
3, the compound of obtaining
34.0 gram, glycine sodium salt 1.52 grams are dissolved in the ethylene glycol monomethyl ether solution, and reflux is more than 2 hours, the complete rear cooling of TLC detection reaction is poured in the frozen water, then uses the hcl acidifying of 6 mol/L, has a large amount of solids to separate out behind the adding hydrochloric acid, filter and collect the gained solid, drain and obtain white solid
IOX2Be 4.0 grams, productive rate is about 90%, if require higher can being dissolved in the white solid heating that obtains of purity to carry out the recrystallization processing in the acetic acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012104839914A CN102964301A (en) | 2012-11-26 | 2012-11-26 | Method for synthesizing IOX2 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012104839914A CN102964301A (en) | 2012-11-26 | 2012-11-26 | Method for synthesizing IOX2 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102964301A true CN102964301A (en) | 2013-03-13 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2012104839914A Pending CN102964301A (en) | 2012-11-26 | 2012-11-26 | Method for synthesizing IOX2 |
Country Status (1)
| Country | Link |
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| CN (1) | CN102964301A (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007038571A2 (en) * | 2005-09-26 | 2007-04-05 | Smithkline Beecham Corporation | Prolyl hydroxylase antagonists |
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- 2012-11-26 CN CN2012104839914A patent/CN102964301A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007038571A2 (en) * | 2005-09-26 | 2007-04-05 | Smithkline Beecham Corporation | Prolyl hydroxylase antagonists |
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| PB01 | Publication | ||
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| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
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Application publication date: 20130313 |