CN112441975B - Preparation method of important intermediate of roflumilast - Google Patents
Preparation method of important intermediate of roflumilast Download PDFInfo
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- CN112441975B CN112441975B CN201910825689.4A CN201910825689A CN112441975B CN 112441975 B CN112441975 B CN 112441975B CN 201910825689 A CN201910825689 A CN 201910825689A CN 112441975 B CN112441975 B CN 112441975B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- MNDBXUUTURYVHR-UHFFFAOYSA-N roflumilast Chemical compound FC(F)OC1=CC=C(C(=O)NC=2C(=CN=CC=2Cl)Cl)C=C1OCC1CC1 MNDBXUUTURYVHR-UHFFFAOYSA-N 0.000 title claims abstract description 7
- 229960002586 roflumilast Drugs 0.000 title claims abstract description 7
- 239000002994 raw material Substances 0.000 claims abstract description 26
- 150000001875 compounds Chemical class 0.000 claims abstract description 18
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims abstract description 13
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000002904 solvent Substances 0.000 claims abstract description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 10
- 239000001257 hydrogen Substances 0.000 claims abstract description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 9
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 claims abstract description 8
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims abstract description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 claims abstract description 6
- 235000019253 formic acid Nutrition 0.000 claims abstract description 6
- 238000000034 method Methods 0.000 claims abstract description 5
- 239000007858 starting material Substances 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 150000001412 amines Chemical group 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 6
- 239000007868 Raney catalyst Substances 0.000 abstract description 5
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 abstract description 5
- 229910000564 Raney nickel Inorganic materials 0.000 abstract description 5
- 239000012450 pharmaceutical intermediate Substances 0.000 abstract description 2
- 238000013341 scale-up Methods 0.000 abstract description 2
- 239000000706 filtrate Substances 0.000 description 10
- 238000001914 filtration Methods 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000012467 final product Substances 0.000 description 4
- 238000004537 pulping Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 3
- 239000000852 hydrogen donor Substances 0.000 description 3
- -1 4-hydroxy-1-methyl-7-phenoxy-3-isoquinolinyl Chemical group 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 101710138860 Hypoxia-inducible factor prolyl hydroxylase Proteins 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- XJOTXKZIRSHZQV-RXHOOSIZSA-N (3S)-3-amino-4-[[(2S,3R)-1-[[(2S)-1-[[(2S)-1-[(2S)-2-[[(2S,3S)-1-[[(1R,6R,12R,17R,20S,23S,26R,31R,34R,39R,42S,45S,48S,51S,59S)-51-(4-aminobutyl)-31-[[(2S)-6-amino-1-[[(1S,2R)-1-carboxy-2-hydroxypropyl]amino]-1-oxohexan-2-yl]carbamoyl]-20-benzyl-23-[(2S)-butan-2-yl]-45-(3-carbamimidamidopropyl)-48-(hydroxymethyl)-42-(1H-imidazol-4-ylmethyl)-59-(2-methylsulfanylethyl)-7,10,19,22,25,33,40,43,46,49,52,54,57,60,63,64-hexadecaoxo-3,4,14,15,28,29,36,37-octathia-8,11,18,21,24,32,41,44,47,50,53,55,58,61,62,65-hexadecazatetracyclo[32.19.8.26,17.212,39]pentahexacontan-26-yl]amino]-3-methyl-1-oxopentan-2-yl]carbamoyl]pyrrolidin-1-yl]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-imidazol-4-yl)-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-4-oxobutanoic acid Chemical compound CC[C@H](C)[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1cnc[nH]1)NC(=O)[C@@H](NC(=O)[C@@H](N)CC(O)=O)[C@@H](C)O)C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@@H]2CSSC[C@@H]3NC(=O)[C@@H]4CSSC[C@H](NC(=O)[C@H](Cc5ccccc5)NC(=O)[C@@H](NC1=O)[C@@H](C)CC)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](Cc1cnc[nH]1)NC3=O)C(=O)NCC(=O)N[C@@H](CCSC)C(=O)N2)C(=O)NCC(=O)N4)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O XJOTXKZIRSHZQV-RXHOOSIZSA-N 0.000 description 1
- 241001547070 Eriodes Species 0.000 description 1
- 102000008946 Fibrinogen Human genes 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 206010058116 Nephrogenic anaemia Diseases 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 210000003298 dental enamel Anatomy 0.000 description 1
- 230000010437 erythropoiesis Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229940012952 fibrinogen Drugs 0.000 description 1
- 102000018511 hepcidin Human genes 0.000 description 1
- 229940066919 hepcidin Drugs 0.000 description 1
- 108060003558 hepcidin Proteins 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229940042040 innovative drug Drugs 0.000 description 1
- 230000010438 iron metabolism Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Abstract
The invention belongs to the field of preparation of pharmaceutical intermediates, and particularly relates to a preparation method of an important intermediate 3e of roflumilast; the method takes 3c as a starting material, and reacts with hydrogen supply compound and palladium carbon or Raney nickel in a solvent to prepare 3e, wherein the hydrogen supply compound is selected from one or more of formate, formic acid, triethylsilane and the like; the molar ratio of the hydrogen-supplying compound to the 3c raw material is 1-100, preferably 5-50, more preferably 10-30; the method has mild reaction conditions, can perform the reaction under normal pressure without high temperature and high pressure, is suitable for industrial scale-up, and has the yield equivalent to that of a comparison document CN 103435546B.
Description
Technical Field
The invention belongs to the field of preparation of pharmaceutical intermediates, and particularly relates to a preparation method of an important intermediate of roflumilast.
Background
Luo Shasi he, trade name: eriod, a first small molecule hypoxia inducible factor prolyl hydroxylase (HIF-PH) inhibitor developed by fibrinogen corporation (chinese famous enamel), regulates iron metabolism by stimulating erythropoiesis, reduces hepcidin to treat renal anemia, month 12, 17 in 2018, which was first marketed worldwide by a priority review batch procedure in China, is a class 1 innovative drug which is currently temporarily not marketed in the united states, japan, and has the chemical name N- [ (4-hydroxy-1-methyl-7-phenoxy-3-isoquinolinyl) carbonyl ] glycine, and has the chemical structure:
paragraph [ 0633 ] of CN103435546B specification example 3 discloses a process for preparing compound 3e by reacting compound 3c under anhydrous sodium carbonate, palladium on carbon system and hydrogen under heat and pressure, the reaction formula is as follows:
the specific procedure for the preparation of compound 3e is:
the reactor was charged with 3C (16.0 g), pd/C (2.08 g), anhydrous sodium carbonate (2.56 g) and ethyl acetate (120 ml). The flask was purged with nitrogen (3X) vacuum and purified with hydrogen (3X) vacuum. The flask may then be pressurized with hydrogen and stirred at about 60 ℃ until the reaction is complete. The flask was cooled to 20-25 ℃, the pressure released to ambient, the headspace purged three times with nitrogen and the mixture filtered. The filtrate was concentrated. Methanol was added. The mixture was stirred and then cooled. The product precipitated, was filtered and dried in an oven (yield: 90%, HPLC: 99.7%)
Compound 3e is an important intermediate for preparing Luo Shasi, but the reaction introduced in the prior art adopts palladium-carbon and hydrogen high-pressure reaction, and sometimes needs heating, has harsh conditions of high temperature and high pressure, has high requirements on sites and safety, and is difficult to popularize and use for producing a large quantity of Luo Shasi raw materials.
Disclosure of Invention
The invention aims to provide a novel preparation method of an important intermediate 3e of roflumilast, which has mild reaction conditions, can react under normal pressure without high temperature and high pressure, is suitable for industrial scale-up, and has the yield and purity equivalent to those of a comparison document CN 103435546B.
Specifically, the invention discloses a preparation method of an important intermediate 3e of roflumilast, which comprises the following steps: 3c is taken as a starting material, and reacts with hydrogen-supplying compound and palladium carbon or Raney nickel in a solvent to prepare 3e, and the preparation process is as follows:
wherein the hydrogen-supplying compound is selected from one or more of formate, formic acid, triethylsilane, etc.
Preferably, the formate is an amine formate.
Preferably, the molar ratio of the hydrogen-supplying compound to the 3c raw material is 1-100.
More preferably, the molar ratio of the hydrogen donor compound to the 3c raw material is 5 to 50.
More preferably, the molar ratio of the hydrogen donor compound to the 3c raw material is 10 to 30.
More preferably, the molar ratio of the hydrogen donor compound to the 3c raw material is 15 to 25.
Preferably, the mass ratio of the palladium carbon or the Raney nickel to the 3c raw material is 0.02-5.
More preferably, the mass ratio of the palladium carbon or the Raney nickel to the 3c raw material is 0.1-1.
Further preferably, the mass ratio of the palladium carbon or Raney nickel to the 3c raw material is 0.5 to 0.8.
Preferably, the solvent is selected from one or more of methanol, ethanol, isopropanol, formic acid, acetic acid, ethyl acetate, acetone, tetrahydrofuran, N-dimethylformamide, and the like.
More preferably, the volume molar ratio of the solvent to the 3c raw material is 1 to 20ml/mmol.
More preferably, the volume molar ratio of the solvent to the 3c raw material is 2 to 8ml/mmol.
Further preferably, the volume molar ratio of the solvent to the 3c raw material is 4 to 6ml/mmol.
Preferably, the reaction temperature is 60 ℃ to 100 ℃, and for solvents with lower melting points, the reaction temperature is below 20 ℃ to the solvent reflux temperature.
Preferably, the reaction time is 4 hours to 5 days.
More preferably, the reaction time is from 6 hours to 2 days.
Further preferably, the reaction time is from 6 hours to 1 day.
Detailed Description
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental procedures, which are not specified in the following examples, are generally carried out under conventional conditions or under conditions recommended by the manufacturer.
Example 1
Taking raw material 3c (1 g,2.7 mmol), adding 5ml of ethyl acetate and 5ml of methanol, adding palladium carbon (0.6 g), adding ammonium formate (4 g,63.4 mmol), formic acid (5 g,0.109 mol), heating to 60 ℃ for reaction for 6 hours, detecting that the raw material is completely reacted by TLC, cooling to room temperature, filtering by pad diatomite, washing by ethyl acetate, collecting filtrate, concentrating under reduced pressure until the filtrate is dry, pulping by methanol, filtering by suction, drying to obtain a final product 3e of 0.78g, and obtaining the yield: 93%.
Example 2
Taking raw material 3C (1 g,2.7 mmol), adding tetrahydrofuran (20 mL), adding palladium carbon (0.02 g), adding ammonium formate (4 g,63.4 mmol), heating to 60 ℃ for reaction for 52 hours, detecting that the TL C is completely reacted, cooling to room temperature, filtering with kieselguhr, washing with ethyl acetate, collecting filtrate, concentrating the filtrate under reduced pressure until the filtrate is dry, pulping with methanol, filtering, drying to obtain a final product 3e 0.74g, yield: 88%.
Example 3
Taking raw material 3c (1 g,2.7 mmol), adding 10ml of acetic acid, adding palladium carbon (1.0 g), adding ammonium formate (0.85 g,13.5 mmol), heating to 100 ℃ for reaction for 6 hours, detecting the complete reaction of the raw material by TLC, cooling to room temperature, filtering by pad diatomite, washing by ethyl acetate, collecting filtrate, concentrating under reduced pressure until the filtrate is dry, pulping by methanol, filtering by suction, and drying to obtain a final product 3e0.78g, and obtaining the yield: 93%.
Example 4
Taking a raw material 3c (1 g,2.7 mmol), adding 10ml of N, N-dimethylformamide, adding palladium-carbon (0.5 g), dropwise adding triethylsilane (15.7 g,135 mmol) at room temperature, heating to 100 ℃ for 48 hours after dropwise adding, detecting that the raw material is completely reacted by TLC, cooling to room temperature, filtering by pad diatomite, washing by ethyl acetate, collecting filtrate, concentrating under reduced pressure until the filtrate is dry, pulping by methanol, filtering by suction, drying to obtain a final product 3e of 0.76g, and obtaining the yield: 91%.
Claims (8)
1. A method for preparing an important intermediate 3e of roflumilast, which comprises the following steps: 3c is taken as a starting material, and reacts with hydrogen-supplying compound and palladium-carbon in a solvent to prepare 3e, and the preparation process is as follows:
wherein the solvent is selected from one or more of methanol, ethanol, isopropanol, formic acid, acetic acid, ethyl acetate, tetrahydrofuran and N, N-dimethylformamide; the hydrogen supply compound is selected from one or more of formate, formic acid and triethylsilane; the mol ratio of the hydrogen supply compound to the 3c raw material is 1-100:1; the mass ratio of the palladium carbon to the 3c raw material is 0.02-5:1; the volume mol ratio of the solvent to the 3c raw material is 1-20:1 ml/mmol; the reaction temperature is 60-100 ℃; the reaction time is 4 hours to 5 days.
2. The method of manufacturing according to claim 1, characterized in that: the formate is amine formate.
3. The method of manufacturing according to claim 1, characterized in that: the molar ratio of the hydrogen supply compound to the 3c raw material is 5-50:1.
4. The method of manufacturing according to claim 1, characterized in that: the molar ratio of the hydrogen supply compound to the 3c raw material is 10-30:1.
5. The method of manufacturing according to claim 1, characterized in that: the mass ratio of the palladium carbon to the 3c raw material is 0.1-1:1.
6. The method of manufacturing according to claim 1, characterized in that: the volume mole ratio of the solvent to the 3c raw material is 2-8:1 ml/mmol.
7. The method of manufacturing according to claim 1, characterized in that: the reaction time is 6 h-2 days.
8. The method of manufacturing according to claim 7, wherein: the reaction time is 6 h-1 day.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201910825689.4A CN112441975B (en) | 2019-09-03 | 2019-09-03 | Preparation method of important intermediate of roflumilast |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910825689.4A CN112441975B (en) | 2019-09-03 | 2019-09-03 | Preparation method of important intermediate of roflumilast |
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| CN112441975A CN112441975A (en) | 2021-03-05 |
| CN112441975B true CN112441975B (en) | 2023-10-31 |
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| CN115124467A (en) * | 2022-07-11 | 2022-09-30 | 天津力生制药股份有限公司 | Preparation method of key intermediate of roxasistat |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103435546A (en) * | 2012-07-16 | 2013-12-11 | 菲布罗根有限公司 | Method for preparing isoquinoline compounds |
| CN108017583A (en) * | 2016-11-01 | 2018-05-11 | 徐州万邦金桥制药有限公司 | A kind of preparation method for winning U.S. |
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- 2019-09-03 CN CN201910825689.4A patent/CN112441975B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103435546A (en) * | 2012-07-16 | 2013-12-11 | 菲布罗根有限公司 | Method for preparing isoquinoline compounds |
| CN108017583A (en) * | 2016-11-01 | 2018-05-11 | 徐州万邦金桥制药有限公司 | A kind of preparation method for winning U.S. |
Non-Patent Citations (4)
| Title |
|---|
| APPLICATION OF THE VILSMEIER FORMYLATION IN THE SYNTHESIS OF 11-13C LABELLED IRIDOIDS;SOREN ROSENDAL JENSEN, et al;《Tetrahedron》;19871231;第43卷(第8期);第1949-1954页 * |
| 刘鹰翔.药物合成反应.中国中医药出版社,2017,(第1版),第258-260页. * |
| 化学工业部人事教育司 等.氢离子传递还原.《有机定量分析》.化学工业出版社,1997,第49页. * |
| 甲酸铵及其他甲酸衍生物在药物合成中的应用;周家成;《中国药科大学学报》;19891231;第20卷(第5期);第313-320页 * |
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