CN108976200B - Method for preparing pimobendan from side product of pimobendan synthesis - Google Patents
Method for preparing pimobendan from side product of pimobendan synthesis Download PDFInfo
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- CN108976200B CN108976200B CN201811091291.4A CN201811091291A CN108976200B CN 108976200 B CN108976200 B CN 108976200B CN 201811091291 A CN201811091291 A CN 201811091291A CN 108976200 B CN108976200 B CN 108976200B
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- pimobendan
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- GLBJJMFZWDBELO-UHFFFAOYSA-N pimobendane Chemical compound C1=CC(OC)=CC=C1C1=NC2=CC=C(C=3C(CC(=O)NN=3)C)C=C2N1 GLBJJMFZWDBELO-UHFFFAOYSA-N 0.000 title claims abstract description 45
- 229960002164 pimobendan Drugs 0.000 title claims abstract description 44
- 239000006227 byproduct Substances 0.000 title claims abstract description 27
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 14
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 14
- 238000000034 method Methods 0.000 title claims abstract description 10
- 239000000126 substance Substances 0.000 claims abstract description 10
- 239000012043 crude product Substances 0.000 claims abstract description 7
- 239000012046 mixed solvent Substances 0.000 claims abstract description 7
- 239000003960 organic solvent Substances 0.000 claims abstract description 6
- 238000001914 filtration Methods 0.000 claims abstract description 5
- 238000001816 cooling Methods 0.000 claims abstract description 4
- 238000010438 heat treatment Methods 0.000 claims abstract description 4
- 238000004519 manufacturing process Methods 0.000 claims abstract description 4
- 238000010992 reflux Methods 0.000 claims abstract description 4
- 238000001035 drying Methods 0.000 claims abstract description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 238000007670 refining Methods 0.000 claims description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims 2
- 229910002651 NO3 Inorganic materials 0.000 claims 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims 2
- RYERVRSILQKFBE-UHFFFAOYSA-N 3-[2-(4-methoxyphenyl)-3-[(4-methoxyphenyl)methyl]benzimidazol-5-yl]-4-methyl-4,5-dihydro-1H-pyridazin-6-one Chemical group COC1=CC=C(CN2C(=NC3=C2C=C(C=C3)C=2C(CC(NN=2)=O)C)C2=CC=C(C=C2)OC)C=C1 RYERVRSILQKFBE-UHFFFAOYSA-N 0.000 claims 1
- XMPZTFVPEKAKFH-UHFFFAOYSA-P ceric ammonium nitrate Chemical compound [NH4+].[NH4+].[Ce+4].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O XMPZTFVPEKAKFH-UHFFFAOYSA-P 0.000 abstract description 18
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 abstract description 7
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 abstract description 6
- 239000000047 product Substances 0.000 abstract description 3
- 239000002699 waste material Substances 0.000 abstract description 3
- 239000007787 solid Substances 0.000 description 9
- FZERHIULMFGESH-UHFFFAOYSA-N N-phenylacetamide Chemical compound CC(=O)NC1=CC=CC=C1 FZERHIULMFGESH-UHFFFAOYSA-N 0.000 description 8
- 239000007858 starting material Substances 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- AAILEWXSEQLMNI-UHFFFAOYSA-N 1h-pyridazin-6-one Chemical compound OC1=CC=CN=N1 AAILEWXSEQLMNI-UHFFFAOYSA-N 0.000 description 4
- AVPYQKSLYISFPO-UHFFFAOYSA-N 4-chlorobenzaldehyde Chemical compound ClC1=CC=C(C=O)C=C1 AVPYQKSLYISFPO-UHFFFAOYSA-N 0.000 description 4
- 229960001413 acetanilide Drugs 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 102000010861 Type 3 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 description 2
- 108010037543 Type 3 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 206010007556 Cardiac failure acute Diseases 0.000 description 1
- 206010007558 Cardiac failure chronic Diseases 0.000 description 1
- 102000002585 Contractile Proteins Human genes 0.000 description 1
- 108010068426 Contractile Proteins Proteins 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 238000004176 ammonification Methods 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 230000003177 cardiotonic effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229940124975 inotropic drug Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a novel method for preparing pimobendan from a by-product of pimobendan synthesis, which comprises the following steps: the by-product (chemical name is (5RS) -6- [1- (4-methoxybenzyl) -2- (4-methoxyphenyl) -1) obtained from the synthesis of pimobendanH-benzimidazol-6-yl]-5-methyl-4, 5-dihydro-3 (2)H) -pyridazinone) is dissolved in a mixed solvent and reacts with Ceric Ammonium Nitrate (CAN) for 2-3 hours at the temperature of 20-25 ℃ to obtain a pimobendan crude product; heating and refluxing the obtained pimobendan crude product in an organic solvent, cooling, filtering and drying to obtain the pimobendan. The invention converts the unnecessary by-products into the required pimobendan product, changes waste into valuable and greatly reduces the production cost.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemicals, in particular to a novel method for preparing pimobendan from a by-product of pimobendan synthesis.
Background
Pimopendan, also known as Pimobendan (Pimobendan), is commercially available under the trade name Acardi, having the chemical name 4, 5-dihydro-6- [2- (4-methoxyphenyl) -1H-benzimidazol-5-yl ] -5-methyl-3 (2H) -pyridazinone, which was developed by Boechringer Ingelhem, Germany, and was first marketed in Japan in 1994. The pimobendan has the pharmacological action characteristic of enhancing the sensitivity of cardiac contractile protein to calcium ions, inhibiting the activity of phosphodiesterase III (PDE-3) and simultaneously expanding blood vessels, so that the pimobendan is an ideal inotropic drug and is clinically used for treating acute and chronic heart failure as a cardiotonic drug.
Currently, the methods for synthesizing pimobendan are classified into three categories according to the initial raw materials used: (1) acetanilide is used as a starting material; (2) p-chlorobenzaldehyde is used as a starting material; (3) benzene chloride is used as a starting material. Since the synthesis process using chlorobenzene as a starting material involves many reaction steps (13-step reaction) and uses unit reaction operations such as liquid bromine and high-pressure ammonification, it is not suitable for industrial production. Therefore, pimobendan is synthesized by using p-chlorobenzaldehyde and acetanilide as starting materials.
The synthetic route using acetanilide as a starting material is as follows:
the synthetic route using p-chlorobenzaldehyde as a starting material is as follows:
respectively taking acetanilide and p-chlorobenzaldehyde as initial raw materials to synthesize pimobendan, and finally, synthesizing pimobendan through the same condensation reaction in the last step, wherein the reaction formula is as follows:
in fact, not only the pimobendan product is produced in this last condensation reaction, but a by-product is inevitably formed, the reaction formula is as follows:
the amount of by-products produced is about 10% of the amount of pimobendan, and since the by-products are unavoidable, it is extremely important whether the by-products produced can be converted into pimobendan. The invention aims to solve the problem of how to convert the generated by-product into pimobendan. The technical route of the invention is as follows:
disclosure of Invention
The invention discloses a novel method for converting a by-product of pimobendan synthesis into pimobendan, which changes waste into valuable and greatly reduces the production cost of the pimobendan.
The method comprises the following steps:
step 1): the by-product (chemical name is (5RS) -6- [1- (4-methoxybenzyl) -2- (4-methoxyphenyl) -1) obtained from the synthesis of pimobendanH-benzimidazol-6-yl]-5-methyl-4, 5-dihydro-3 (2)H) Pyridazinone) is dissolved in a mixed solvent, and reacts with Ceric Ammonium Nitrate (CAN) for 2-3 hours at the temperature of 20-25 ℃, and a by-product is oxidized to obtain a pimobendan crude product. Wherein the solvent is mixture of acetone and water, and the amount of the mixture is 5 ml of acetone and 2.5 ml of water/mmol of byproduct (chemical name is (5RS) -6- [1- (4-methyl)Oxybenzyl) -2- (4-methoxyphenyl) -1H-benzimidazol-6-yl]-5-methyl-4, 5-dihydro-3 (2)H) -pyridazinone), the volume ratio of acetone to water being 2: 1; the by-product (chemical name is (5RS) -6- [1- (4-methoxybenzyl) -2- (4-methoxyphenyl) -1)H-benzimidazol-6-yl]-5-methyl-4, 5-dihydro-3 (2)H) -pyridazinone) and Ceric Ammonium Nitrate (CAN) in a molar ratio of 1:2 to 3.
Step 2): purifying and refining the pimobendan crude product obtained in the step 1), heating and refluxing in an organic solvent, cooling, filtering and drying to obtain the pimobendan. Wherein the organic solvent is ethyl acetate, and the dosage of the organic solvent is 15 ml of ethyl acetate/g of pimobendan crude product.
The invention has the advantages that: the unnecessary by-products are converted into the required pimobendan product, so that the waste is changed into valuable, and the production cost is greatly reduced.
Detailed Description
Example 1
The by-product (chemical name is (5RS) -6- [1- (4-methoxybenzyl) -2- (4-methoxyphenyl) -1) obtained from the synthesis of pimobendanH-benzimidazol-6-yl]-5-methyl-4, 5-dihydro-3 (2)H) Pyridazinone) (4.54 g, 10 mmol) was dissolved in a mixed solvent of 50 ml of acetone and 25 ml of water, ceric ammonium nitrate (10.96 g, 20 mmol) was added, and the mixture was stirred at 25 ℃ for 2 hours to precipitate, which was then filtered, collected, and the resulting solid was washed with 100 ml of water and 20 ml of acetone in this order and dried to obtain 3.03 g of a white solid. And adding 45 ml of ethyl acetate into the obtained white solid, stirring, heating and refluxing for 30 minutes, cooling, and filtering to obtain a white precipitate, wherein 2.94 g of pimobendan is obtained, and the yield is 88.1%. m.p. 241.1-242.5 ℃. 1 H-NMR(500MHz, DMSO-d6)δ: 12.86（br s, 0.5H），12.83（br s, 0.5H），10.91（br s, 0.5H），10.88（br s, 0.5H），8.12（d, J = 9.0, 2H），8.02（br s, 0.5H），7.85（br s, 0.5H），7.73（d, J= 8.5 Hz, 0.5H），7.66（br s, 0.5H），7.64（br s, 0.5H），7.51（d, J= 8.0 Hz, 0.5H），7.11（d, J= 9.0 Hz, 2H），3.83(s, 3H), 3.48～3.51（m, 1H），2.71（d, J= 16.0 Hz, 1H），2.25（d, J= 17.0 Hz, 1H），1.12（d, J= 7.5 Hz, 3H）。
Example 2
The by-product (chemical name is (5RS) -6- [1- (4-methoxybenzyl) -2- (4-methoxyphenyl) -1) obtained from the synthesis of pimobendanH-benzimidazol-6-yl]-5-methyl-4, 5-dihydro-3 (2)H) Pyridazinone) (9.08 g, 20 mmol) was dissolved in a mixed solvent of 100 ml of acetone and 50 ml of water, ceric ammonium nitrate (32.9 g, 60 mmol) was added, and the mixture was stirred at 22 ℃ for 2.5 hours to precipitate, which was then filtered, collected, and the resulting solid was washed with 200 ml of water and 40 ml of acetone in this order and dried to obtain 6.23 g of a white solid. The obtained white solid is added with 90 ml of ethyl acetate, stirred, heated and refluxed for 30 minutes, cooled and filtered to obtain white precipitate, 6.01 g of pimobendan is obtained, and the yield is 90%.
Example 3
The by-product (chemical name is (5RS) -6- [1- (4-methoxybenzyl) -2- (4-methoxyphenyl) -1) obtained from the synthesis of pimobendanH-benzimidazol-6-yl]-5-methyl-4, 5-dihydro-3 (2)H) Pyridazinone) (4.54 g, 10 mmol) was dissolved in a mixed solvent of 50 ml of acetone and 25 ml of water, ceric ammonium nitrate (13.7 g, 25 mmol) was added, and the mixture was stirred at 20 ℃ for reaction for 3 hours, to precipitate, and the precipitate was collected by filtration, and the obtained solid was washed with 100 ml of water and 20 ml of acetone in this order and dried to obtain 3.23 g of a white solid. The obtained white solid is added with 45 ml of ethyl acetate, stirred, heated and refluxed for 30 minutes, cooled and filtered to obtain white precipitate, and pimobendan 3.05 g is obtained, and the yield is 91%.
Claims (3)
1. A method for preparing pimobendan from a by-product of pimobendan synthesis, comprising the steps of:
step 1): dissolving a byproduct obtained by pimobendan synthesis, wherein the chemical name of the byproduct is (5RS) -6- [1- (4-methoxybenzyl) -2- (4-methoxyphenyl) -1H-benzimidazole-6-yl ] -5-methyl-4, 5-dihydro-3 (2H) -pyridazinone, dissolving the byproduct in a mixed solvent, adding ammonium ceric nitrate, reacting for 2-3 hours at 20-25 ℃ to obtain a pimobendan crude product, wherein the mixed solvent is acetone and water, the volume ratio of the acetone to the water is 2:1, and the molar ratio of the byproduct to the ammonium ceric nitrate is 1: 2-3;
step 2): purifying and refining the pimobendan crude product obtained in the step 1), heating and refluxing in an organic solvent, cooling, filtering and drying to obtain the pimobendan.
2. The method for producing pimobendan from the by-product of pimobendan synthesis as claimed in claim 1, wherein said step 1) is carried out in the presence of 5 ml of acetone and 2.5 ml of water per mmol of the by-product.
3. The method as claimed in claim 1, wherein the organic solvent used in the refining step 2) is ethyl acetate, and the amount of ethyl acetate used is 15 ml/g.
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| CN201811091291.4A CN108976200B (en) | 2018-09-19 | 2018-09-19 | Method for preparing pimobendan from side product of pimobendan synthesis |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004072047A1 (en) * | 2003-02-11 | 2004-08-26 | Fujisawa Pharmaceutical Co., Ltd. | Indoles, benzimidazoles or naphhimidazoles as histone deacetylase (hdac) inhibitors |
| CN102285904A (en) * | 2011-07-11 | 2011-12-21 | 中国科学院成都生物研究所 | Method for preparing rivastigmine |
| CN102477037A (en) * | 2010-11-25 | 2012-05-30 | 上海药明康德新药开发有限公司 | Synthesis method of polysubstituted tetrahydropyrazinyl [1,5-a ] imidazole-3 (5H) ketone compound |
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2018
- 2018-09-19 CN CN201811091291.4A patent/CN108976200B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004072047A1 (en) * | 2003-02-11 | 2004-08-26 | Fujisawa Pharmaceutical Co., Ltd. | Indoles, benzimidazoles or naphhimidazoles as histone deacetylase (hdac) inhibitors |
| CN102477037A (en) * | 2010-11-25 | 2012-05-30 | 上海药明康德新药开发有限公司 | Synthesis method of polysubstituted tetrahydropyrazinyl [1,5-a ] imidazole-3 (5H) ketone compound |
| CN102285904A (en) * | 2011-07-11 | 2011-12-21 | 中国科学院成都生物研究所 | Method for preparing rivastigmine |
Non-Patent Citations (1)
| Title |
|---|
| (6-0X0-3-PYRIDAZINYL)-BENZIMIDAZOLES AS POTENT ANGIOTENSIN II RECEPTOR ANTAGONISTS;Dieter Dorsch等;《Bioorganic & Jdedicinol Chemistry Letters》;19941231;第4卷(第11期);第1297-1302页 * |
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