CN102408346A - Preparation method of 4,5-dimethoxy-1-(methyl amino-methyl)-benzo-cyclobutane - Google Patents
Preparation method of 4,5-dimethoxy-1-(methyl amino-methyl)-benzo-cyclobutane Download PDFInfo
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- CN102408346A CN102408346A CN2011103381961A CN201110338196A CN102408346A CN 102408346 A CN102408346 A CN 102408346A CN 2011103381961 A CN2011103381961 A CN 2011103381961A CN 201110338196 A CN201110338196 A CN 201110338196A CN 102408346 A CN102408346 A CN 102408346A
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- MJYPXCAWZVTAGZ-NTUHNPAUSA-N C/N=C/C(Cc1c2)c1cc(OC)c2OC Chemical compound C/N=C/C(Cc1c2)c1cc(OC)c2OC MJYPXCAWZVTAGZ-NTUHNPAUSA-N 0.000 description 1
- JZUHTDGMBPTQNJ-UHFFFAOYSA-N COC1C=C(CC2CO)C2=CC1OC Chemical compound COC1C=C(CC2CO)C2=CC1OC JZUHTDGMBPTQNJ-UHFFFAOYSA-N 0.000 description 1
- LOLYILQTXGVBCK-UHFFFAOYSA-N COc(cc(CC1C=O)c1c1)c1OC Chemical compound COc(cc(CC1C=O)c1c1)c1OC LOLYILQTXGVBCK-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses a preparation method of 4,5-dimethoxy-1-(methyl amino-methyl)-benzo-cyclobutane. The preparation method comprises the following steps of: taking 4,5-dimethoxy benzo-cyclobutane-1-methanol as a raw material to synthesize 4,5-dimethoxy benzo-cyclobutane-1-formaldehyde through an oxidation reaction; allowing the 4,5-dimethoxy benzo-cyclobutane-1-formaldehyde to react with amine so as to generate Schiff base; and finally obtaining the 4,5-dimethoxy-1-(methyl amino-methyl)-benzo-cyclobutane through a reduction reaction. The preparation method has the advantages of mild reaction conditions, lower cost and higher yield, thus being applicable to large-scale industrial production.
Description
Technical field
The present invention relates to a kind of important intermediate 4 of ivabradine, the preparation method of 5-dimethoxy-1-(methylamino methyl)-benzocyclobutane belongs to field of medicine and chemical technology.
Background technology
Hydrochloric acid Ivabradine; First sinus node If electric current that is the exploitation of French Shi Weiya company is selected specific inhibitor; The effect that it slows down heart rate merely is the most important progress of stable angina pectoris medicine in recent years, is used to treat with normal sinus rhythm, taboo maybe can not tolerate to beta-blockers chronic stable angina pectoris.This medicine is in the listing of a plurality of countries.Structural formula is formula (I) as follows
Its base S 16257-2 can be obtained by following formula:
Route 1
Wherein, 4,5-dimethoxy-1-(methylamino methyl)-benzocyclobutane is the important intermediate of synthesis of ivabradine, its structural formula is as shown in the formula (II)
In recent years, this midbody receives increasing concern, and the report of synthetic this compound of multiple route is also arranged both at home and abroad: disclose with 1-cyanic acid-4 like EP0534859,5-dimethoxy benzo tetramethylene is a raw material, prepares the method for II, and its main route is following:
Route 2
CN101671265 discloses with 1-cyanic acid-4, and 5-dimethoxy benzo tetramethylene is a raw material, through oxidation, and amidation, reduction obtains, and main route is following:
Route 3
CN101857549 discloses with 1-cyanic acid-4, and 5-dimethoxy benzo tetramethylene is a raw material, and through hydrolysis, reduction, sulfonylation, hydrocarbonylation, deprotection prepare the method for II, and its main route is following:
Route 4
In above-mentioned several the routes, reaction conditions is comparatively harsh, and the aftertreatment difficulty, causes total recovery not high, and the yield of route 2 is lower than 10%, and the yield of route 3 reports is at 20-25%, and route 4 disclosed yields are 42%, all the needs of suitable for mass production not.
Summary of the invention
The objective of the invention is on the basis of existing technology, a kind of new preparation 4 is provided, the method for 5-dimethoxy-1-(methylamino methyl)-benzocyclobutane.
The object of the invention can reach through following measure:
A kind of 4; The preparation method of 5-dimethoxy-1-(methylamino methyl)-benzocyclobutane, it is with 4, and 5-dimethoxy benzo tetramethylene-1-methyl alcohol is that raw material is through oxidizing reaction synthetic 4; 5-dimethoxy benzo tetramethylene-1-formaldehyde; Generate schiff bases with the amine reaction again, make through reduction reaction at last, its reaction scheme is:
Among the present invention, compound 5-1 is carried out oxidation obtain target compound 5-2, its method can adopt oxidations such as SRM 935a, potassium permanganate, chromium trioxide, Manganse Dioxide, preferably adopts the chromium trioxide oxidation.The solvent of oxidizing reaction is selected from third and changes in ketone, THF, the water one or more, and preferred acetone and water is as mixed solvent, most preferably the volume ratio 1: 1 of acetone and water.
A kind of preferred concrete reaction conditions is: with acetone and water as mixed solvent, under sulfuric acid catalysis, with chromium trioxide oxidation 4,5-dimethoxy benzo tetramethylene-1-methyl alcohol.Chromium trioxide and 4, the mol ratio of 5-dimethoxy benzo tetramethylene-1-methyl alcohol is 1: 1-3: between 1, preferred 1.5: 1.The temperature of oxidizing reaction is controlled at 0-10 ℃, preferred 5 ℃.
The present invention can obtain schiff bases with compound 5-2 and amine reaction.Amine wherein adopts methylamine hydrochloride, or the salt of other form of methylamine, the hydrochloride of preferred methylamine.The solvent of this step reaction can be selected from one or more in THF, methylene dichloride, the acetone.4, the mol ratio of 5-dimethoxy benzo tetramethylene-1-formaldehyde and amine is 1.1: 1-2: between 1, and preferred 1.2: 1.Temperature of reaction is at 20 ℃-65 ℃, preferred 40 ℃.
Among the present invention compound 5-3 schiff bases reduction can be made the target compound of formula II.Reduction reaction can be reduced for compound 5-3 is fed hydrogen under the metal catalyst existence reaches less than the pressure of 3MPa; Also can be for directly using chemical reducing agent to reduce to compound 5-3.
Wherein metal catalyst is nickel catalyzator or palladium catalyst etc.; Chemical reducing agent is NaBH
4, NaBH
3CN or (CH
3COO)
3BHNa, preferred (CH
3COO)
3BHNa.The mol ratio of chemical reducing agent and substrate is 1.2: 1-2: 1, and preferred 1.5: 1.
The solvent of reduction reaction is selected from THF, methylene dichloride, 1, one or more in 2-ethylene dichloride, ethanol, methyl alcohol, Virahol, toluene, the YLENE, preferred THF.Temperature of reaction is controlled at (5 ℃～5 ℃) below 5 ℃, preferred 0 ℃.
Compared with prior art, this technology invention have reaction temperature with, yield is high, environmental friendliness, characteristics such as cost is low, suitability for mass industrialized production.
Embodiment
Below with concrete embodiment technical scheme of the present invention is described, but protection scope of the present invention is not limited to this:
Embodiment 1:4, the preparation of 5-dimethoxy benzo tetramethylene-1-formaldehyde
500 milliliters of round-bottomed flasks, magnetic stirs, and drops into 4,5-dimethoxy benzo tetramethylene-1-methyl alcohol (10 grams; 51.5mmol), 100 milliliters in acetone, 100 milliliters in water is cooled to below 5 ℃; Stir down, slowly be added dropwise to 25 milliliters of the Jones reagents (sulphuric acid soln of chromium trioxide) of 3mol/l, drip and finish, remained on this thermotonus 30 minutes; Rise to room temperature, add 100 milliliters of ether, 5 milliliters of Virahols mix.Filter, the filtering solid, filtrating is with extracted with diethyl ether (3*100 milliliter), and saturated sodium bicarbonate washs, and anhydrous sodium sulfate drying filters, and decompression steams solvent, obtains faint yellow oily thing 9.2 grams, yield: 93%, IR:2731,2654,1737,1560,1455.
Embodiment 2:4, the preparation of 5-dimethoxy benzo tetramethylene-1-formaldehyde
500 milliliters of round-bottomed flasks, mechanical stirring drops into 4,5-dimethoxy benzo tetramethylene-1-methyl alcohol (10 grams, 51.5mmol), 200 milliliters in water; Stir, add in batches SRM 935a (22 the gram, 75mmol), 5 milliliters of the vitriol oils, controlled temperature is no more than 10 ℃, finishes; Rise to 25 ℃, restir 1 hour filters, with extracted with diethyl ether (3*200 milliliter), and the saturated sodium bicarbonate washing; Anhydrous sodium sulfate drying filters, and decompression steams solvent, obtains faint yellow oily thing 6.8 grams, yield 70%.
Embodiment 3:4, the preparation of 5-dimethoxy-1-(methylamino methyl)-benzocyclobutane
4, and 5-dimethoxy benzo tetramethylene-1-formaldehyde (7.5 grams, 39mmol), with 100 milliliters of THFs; The adding methylamine hydrochloride (2.5 grams, 32mmol), after the stirring and dissolving, back flow reaction 6 hours; Be cooled to zero degree stir add down sodium triacetoxy borohydride (10.25 grams, 48mmol), insulation reaction 15 minutes, evaporated under reduced pressure solvent; Add 50 milliliters in the sodium hydroxide of 1mol/l to residue, mixing use dichloromethane extraction, and organic layer is with washing; Anhydrous magnesium sulfate drying filters evaporate to dryness, obtains faint yellow oily thing 5.9 grams, yield: 89%.IR：3357，1560，1455。
Claims (10)
1. one kind 4; The preparation method of 5-dimethoxy-1-(methylamino methyl)-benzocyclobutane is characterized in that with 4, and 5-dimethoxy benzo tetramethylene-1-methyl alcohol is that raw material is through oxidizing reaction synthetic 4; 5-dimethoxy benzo tetramethylene-1-formaldehyde; Generate schiff bases with the amine reaction again, make through reduction reaction at last, its reaction scheme is:
2. method according to claim 1, the oxygenant that it is characterized in that said oxidizing reaction is SRM 935a, potassium permanganate, chromic anhydride or Manganse Dioxide; The solvent of oxidizing reaction is selected from one or more in acetone, THF, the water.
3. method according to claim 2 is characterized in that the condition of said oxidizing reaction is: with acetone and water as mixed solvent, under sulfuric acid catalysis, with chromium trioxide oxidation 4,5-dimethoxy benzo tetramethylene-1-methyl alcohol.
4. method according to claim 1 is characterized in that chromium trioxide and 4, and the mol ratio of 5-dimethoxy benzo tetramethylene-1-methyl alcohol is 1: 1～3: 1, and oxidizing reaction temperature is 20 ℃～40 ℃.
5. method according to claim 1 is characterized in that said amine is methylamine or methylamine salt, is preferably methylamine hydrochloride; The reaction solvent of compound 5-2 and amine is selected from one or more in THF, methylene dichloride, the acetone.
6. method according to claim 5 is characterized in that 4, and the mol ratio of 5-dimethoxy benzo tetramethylene-1-formaldehyde and amine is 1.1: 1～2: 1; 4, the temperature of reaction of 5-dimethoxy benzo tetramethylene-1-formaldehyde and amine is 20 ℃～65 ℃.
7. method according to claim 1 is characterized in that said reduction reaction is for reducing compound 5-3 feeding hydrogen under the metal catalyst existence reaches less than the pressure of 3MPa; Perhaps use chemical reducing agent to reduce to compound 5-3.
8. method according to claim 7 is characterized in that said metal catalyst is nickel catalyzator or palladium catalyst; Said chemical reducing agent is NaBH
4, NaBH
3CN or (CH
3COO)
3BHNa, preferred (CH
3COO)
3BHNa.
9. method according to claim 7, the mol ratio that it is characterized in that said chemical reducing agent and compound 5-3 is 1.2: 1～2: 1; The temperature of reduction reaction is-5 ℃～5 ℃.
10. method according to claim 1 is characterized in that the solvent of said reduction reaction is selected from THF, methylene dichloride, 1, one or more in 2-ethylene dichloride, ethanol, methyl alcohol, Virahol, toluene, the YLENE, preferred THF.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10221141B2 (en) | 2015-06-03 | 2019-03-05 | Urquima, S.A. | Method for the preparation of highly pure ivabradine base and salts thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4647559A (en) * | 1983-04-29 | 1987-03-03 | William H. Rorer, Inc. | Bicyclic benzenoid aminoalkylene ethers and thioethers, pharmaceutical compositions and use |
| CN1699331A (en) * | 2004-05-19 | 2005-11-23 | 瑟维尔实验室 | Process for the synthesis of (is)-4,5-dimethoxy-1-(methylaminomethyl)-benzocyclobutane and uses thereof |
| EP1608377B1 (en) * | 2003-03-17 | 2008-10-01 | Affinium Pharmaceuticals, Inc. | Pharmaceutical compositions comprising inhibitors of fab i and further antibiotics |
| CN101857549A (en) * | 2010-06-22 | 2010-10-13 | 浙江美诺华药物化学有限公司 | Synthetic method of (1S)-4,5-Dimethoxy-1-(aminomethyl)benzocyclobutane |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4647559A (en) * | 1983-04-29 | 1987-03-03 | William H. Rorer, Inc. | Bicyclic benzenoid aminoalkylene ethers and thioethers, pharmaceutical compositions and use |
| EP1608377B1 (en) * | 2003-03-17 | 2008-10-01 | Affinium Pharmaceuticals, Inc. | Pharmaceutical compositions comprising inhibitors of fab i and further antibiotics |
| CN1699331A (en) * | 2004-05-19 | 2005-11-23 | 瑟维尔实验室 | Process for the synthesis of (is)-4,5-dimethoxy-1-(methylaminomethyl)-benzocyclobutane and uses thereof |
| CN101857549A (en) * | 2010-06-22 | 2010-10-13 | 浙江美诺华药物化学有限公司 | Synthetic method of (1S)-4,5-Dimethoxy-1-(aminomethyl)benzocyclobutane |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10221141B2 (en) | 2015-06-03 | 2019-03-05 | Urquima, S.A. | Method for the preparation of highly pure ivabradine base and salts thereof |
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Address after: 223800 No.5 Yanshan Road, eco Chemical Technology Industrial Park, Suqian City, Jiangsu Province Patentee after: Jiangsu alpha Pharmaceutical Co.,Ltd. Address before: 223809 No.9, Yanshan Road, Suqian eco Chemical Technology Industrial Park, Suqian City, Jiangsu Province Patentee before: ALPHA PHARMACEUTICAL Co.,Ltd. JIANGSU PROVINCE |