CN102249937A - Preparation method of 1-(S)-4, 5-dimethyamino-1-methylaminomethyl-benzocyclobutane - Google Patents
Preparation method of 1-(S)-4, 5-dimethyamino-1-methylaminomethyl-benzocyclobutane Download PDFInfo
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- ZNTNZZSGPNCART-VIFPVBQESA-N CNC([C@@H](Cc1c2)c1cc(OC)c2OC)=O Chemical compound CNC([C@@H](Cc1c2)c1cc(OC)c2OC)=O ZNTNZZSGPNCART-VIFPVBQESA-N 0.000 description 1
- SAVVFXUMMFHSJC-SECBINFHSA-N CNC[C@@H](Cc1c2)c1cc(OC)c2OC Chemical compound CNC[C@@H](Cc1c2)c1cc(OC)c2OC SAVVFXUMMFHSJC-SECBINFHSA-N 0.000 description 1
- HJTHVTHXHHFXMJ-UHFFFAOYSA-N COc(cc(CC1C#N)c1c1)c1OC Chemical compound COc(cc(CC1C#N)c1c1)c1OC HJTHVTHXHHFXMJ-UHFFFAOYSA-N 0.000 description 1
- KWOMYIGRWBBSTL-UHFFFAOYSA-N COc(cc(CC1C(O)=N)c1c1)c1OC Chemical compound COc(cc(CC1C(O)=N)c1c1)c1OC KWOMYIGRWBBSTL-UHFFFAOYSA-N 0.000 description 1
- IHPWCJZOCLQJPX-QMMMGPOBSA-N COc(cc(C[C@@H]1C(O)=O)c1c1)c1OC Chemical compound COc(cc(C[C@@H]1C(O)=O)c1c1)c1OC IHPWCJZOCLQJPX-QMMMGPOBSA-N 0.000 description 1
Abstract
The invention provides a preparation method of 1-(S)-4, 5-dimethyamino-1-methylaminomethyl-benzocyclobutane (compound I). The preparation method comprises the following steps that (S)-4, 5-dimethoxy benzocyclobutyl-1-carboxylic acid (compound III) is prepared through the split of 4, 5-dimethoxy-1-carboxyl benzocyclobutane (compound IV); then compound III obtained from the previous step undergoes a condensation reaction to form 4, 5-dimethoxy-1-methylaminoformyl benzocyclobutane (compound II); and compound II obtained from the previous step undergoes a reduction reaction to form 1-(S)-4, 5-dimethyamino-1-methylaminomethyl-benzocyclobutane (compound I). The preparation method has the advantages of less reduction steps, no need of reagents such as ethyl chloroformate and the like, simple and convenient processes, low production cost and great application values.
Description
Technical field
The present invention relates to medication preparation, be specifically related to the key intermediate 1-(S) 4 of medicine S 16257-2 in synthetic, the preparation method of 5-dimethoxy-1-methylamino methyl benzocyclobutane.
Background technology
S 16257-2 (Ivabradine) is the medicine of forbidding or not tolerating beta-blocker, the normal chronic stable angina pectoris of sinus rhythm that is used for the treatment of by Switzerland Se Weier company (claiming Shi Weiya company again) research and development.Its chemistry is by name: (+)-3-[3-[N-[4,5-dimethoxy benzo tetramethylene base-1 (S)-methyl]-the N-methylamino] propyl group]-7,8-dimethoxy-2,3,4,5-tetrahydrochysene-1H-3-benzene tiny-2-keto hydrochloride.As shown in the formula VI:
S 16257-2 is hyperpolarization activated cyclic nucleotide gate ionic channel (I
f) selectivity retardance agent, belong to HCN (hyperpolarization activated cyclic nucleotidegated) ionic channel family.I
fElectric current is a kind of cardiac pacing electric current, mainly participates in myocardial cell's depolarization process of diastole, is playing an important role aspect the formation of the rhythm of the heart and the auto-control.But thereby this passage decreasing heart rate of specific inhibition, thereby reduce the danger that cardiovascular disorder takes place.S 16257-2 is as specificity I
fThe electric current retarding agent, (it only and I for its selectivity
fPassage and do not interact with other passage) and specificity (its electric current-dependence rather than voltage-dependence) all make it be applied to all pathologic conditions of decreasing heart rate independently safely and effectively, so prospect is quite arranged in the treatment of coronary heart disease, for the pharmacological agent of coronary heart disease provides a new angle.
Key intermediate 1-(S) 4 as the preparation S 16257-2, the preparation method of 5-dimethoxy-1-methylamino methyl benzocyclobutane such as patent EPO534859 report, 4,5-dimethoxy-benzocyclobutane nitrile is reduced to primary amine, split the primary amine that obtains the R-configuration then, with the Vinyl chloroformate synthesis of carbamates, become target product with tetrahydrochysene lithium aluminium reducing at last again.
There is obvious defects in this method: use the bigger Vinyl chloroformate reagent of toxicity in the preparation process, and need the reduction of two steps, cyano reduction wherein is difficulty relatively, will be with big, the unworkable reagent of toxicity such as borine, reaction is difficult to control, and the aftertreatment complexity is difficult to realize industrialization.
Summary of the invention
Technical problem to be solved by this invention is to overcome above-mentioned weak point, a kind of synthetic route of research and design is short, need not the reagent that uses toxicity big and easy handling, the preparation 1-(S)-4 that production cost is low, the method for 5-dimethoxy-1-methylamino methyl-benzocyclobutane.
The invention provides a kind of preparation 1-(S)-4, the preparation method of 5-dimethoxy-1-methylamino methyl-benzocyclobutane (Compound I).
The inventive method is by 4, and 5-dimethoxy-1-carboxyl benzocyclobutane (compound IV) by splitting, is condensed into 4,5-dimethoxy-1-methylamine formyl radical benzocyclobutane (Compound I I), and reduction prepares then.
The inventive method comprises the following steps:
(1) 4,5-dimethoxy benzo cyclobutyronitrile (compound V) preparation 4,5-dimethoxy benzo cyclobutyl-1-carboxylic acid (compound IV);
(2) 4,5-dimethoxy benzo cyclobutyl-1-carboxylic acids (compound IV) are by splitting preparation (S)-4,5-dimethoxy benzo cyclobutyl-1-carboxylic acid (compound III)
(3) (S)-4,5-dimethoxy benzo cyclobutyl-1-carboxylic acid (compound III) obtains by condensing agent and methylamine condensation prepared or by becoming behind the acyl chlorides and methylamine condensation prepared acquisition 1-(S) 4,5-dimethoxy-1-methylamine formyl radical benzocyclobutane (Compound I I) with becoming the acyl chlorides reagent preparation;
(4) (S)-4,5-dimethoxy-1-methylamine formyl radical benzocyclobutane (Compound I I) uses reductive agent, is methylene radical with carbonyl reduction, makes (S)-4,5-dimethoxy-1-methylamino-N-methyl benzocyclobutane (Compound I);
Step (1) 4,5-dimethoxy benzo cyclobutyl-1-carboxylic acid (compound IV) is by document Tetrahedron.Vol 29, and the described method of pp73-76 makes.4,5-dimethoxy benzo cyclobutyronitrile (compound V) reacts with the ethanolic soln of sodium hydroxide or potassium hydroxide, obtains 4,5-dimethoxy benzo cyclobutyl-1-carboxylic acid (compound IV);
The described resolving agent of step (2) is alkaline resolving agent brucine, vauqueline, Quinidine, quinine, cinchovatin, quinotoxol, cinchotoxine, ephedrine, (S)-(-)-α-Ben Yian, (R)-(+)-α-Ben Yian or (S)-(-)-α-naphthalene ethylamine, is preferably cinchovatin or (S)-(-)-α-Ben Yian; The mol ratio of resolving agent and compound IV is 0.5-1.0, is preferably 1.0;
The fractionation solvent for use is one or more the mixed solvent in methyl alcohol, ethanol, the trimethyl carbinol or the ethyl acetate; Compound IV and resolving agent salify split 25 ℃-150 ℃ of salifiable temperature, are preferably the reflux temperature of solvent, and the salt-forming reaction time is 0.5-2.0 hour, is preferably 0.5-1.0 hour; Then, leave standstill or stir and be cooled to 0 ℃ of-25 ℃ of slow crystallization; The time of placing crystallization is 2 hours-24 hours, is preferably 2 hours-10 hours;
The described condensing agent of step (3) is: dicyclohexylcarbodiimide (DCC), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (EDCI), I-hydroxybenzotriazole (HOBt) or 1-pyridone and triazole (HOAt), temperature of reaction is 0 ℃-150 ℃, and temperature of reaction is preferably the reflux temperature of solvent; Reaction times is 0.5-10 hour, is preferably 1-5 hour;
The mol ratio of condensing agent and compound III is 1.0-3.0, is preferably 1.0-2.0;
Step (3) also can be passed through compound (III) XianCheng acyl chlorides, and the mode with the condensation of first ammonia prepares then; Described one-tenth acyl chlorides reagent is sulfur oxychloride, oxalyl chloride, three chlorotriazines, phosphorus trichloride, phosphorus pentachloride or phosphorus oxychloride; Temperature of reaction is 0 ℃-50 ℃, is preferably 0 ℃-25 ℃.Reaction times is 0.5-20 hour, is preferably 2-5 hour;
Acyl chlorides reagent and compound (III) mol ratio 1.0-10 is preferably 1.0-5.0;
Described solvent is methylene dichloride, trichloromethane, 1,2-ethylene dichloride, toluene, dimethylbenzene, tetrahydrofuran (THF), dioxane, glycol dimethyl ether, isopropyl ether, tertbutyl ether, methyl tertiary butyl ether, N, the mixture of one or more solvents in dinethylformamide or the dioxane is preferably ether solvent or methylene dichloride.
The described reductive agent of step (4) is tetrahydrochysene lithium aluminium, borine, sodium cyanoborohydride, acetic acid sodium borohydride or trifluoracetic acid sodium borohydride, is preferably tetrahydrochysene lithium aluminium and trifluoracetic acid sodium borohydride; The mol ratio of reductive agent and Compound I I is 1.0-5.0, and mol ratio is preferably 1.0-2.0;
Described solvent is toluene, dimethylbenzene, ether, tetrahydrofuran (THF), dioxane, glycol dimethyl ether, isopropyl ether, tertbutyl ether, methyl tertiary butyl ether, N, and the mixture of one or more solvents in the dinethylformamide is preferably ether solvent.
Temperature of reaction is-25 ℃-150 ℃, and when tetrahydrochysene lithium aluminium was reductive agent, temperature of reaction was preferably the reflux temperature of solvent, and the reaction times is 1-10 hour, is preferably 2-4 hour; Borine, sodium cyanoborohydride, acetic acid sodium borohydride, when the trifluoracetic acid sodium borohydride is reductive agent, temperature of reaction is preferably-10 ℃--25 ℃, the reaction times is 1-20 hour, is preferably 5-10 hour;
The present invention has improved reduction reaction, helps the reduction of cost, and has got rid of unworkable reagent and step such as borine, avoids using the big reagent of toxicity such as Vinyl chloroformate simultaneously, and easy and simple to handle, production cost is low, and very big industrial production using value is arranged.
Embodiment
Embodiment 1:4,5-dimethoxy-1-carboxyl benzocyclobutane (compound IV) synthetic
With 6 grams 4,5-dimethoxy-1-cyano group benzocyclobutane (compound V) joins in the ethanolic soln (2 mol) of 24 milliliters potassium hydroxide, and controlled temperature is at 10-25 ℃, and stirring is spent the night, and adds 8 ml waters, refluxes 3 hours.After being cooled to 0-5 ℃ with ice-water bath, pour in 200 ml waters.Add 10 milliliters of concentrated hydrochloric acids, adjust pH stirred 2 hours to 4-5, filtered, and filter residue is with 100 milliliters of toluene wash, and 50 ℃ vacuumized drying 24 hours.Obtain white solid (compound IV) 6.0 grams, yield is 90%.
Embodiment 2:
With 20 grams 4,5-dimethoxy-1-carboxyl benzocyclobutane and 12 gram (S)-(-)-α-Ben Yians join in 200 milliliters of ethanol, stir, heating refluxed 2 hours, stopped to stir, stop heating, be cooled to 10-25 ℃, left standstill 5-10 hour, filter, get solid, add 150 milliliters of ethanol, heating, refluxed 0.5 hour, stop to stir, stop heating, be cooled to 10-25 ℃, left standstill 5-10 hour, filter, solid transfers to pH=1.0 with dilute hydrochloric acid, filters, obtain white solid (compound III) 8.2 grams, yield 41%;
E.e value:＞99%
MS(ESI)：209(M+1)
1HNMR(CDCl
3)：δ3.38(2H，m)，3.83(6H，s)，4.22(2H，t，J＝4Hz)，6.69(s，1H)，6.75(s，1H)。
Embodiment 3:
With 20 grams 4,5-dimethoxy-1-carboxyl benzocyclobutane and 30 gram cinchovatins join in 300 milliliters of ethanol, stir heating, refluxed 2 hours, and stopped to stir, stop heating, be cooled to 10-25 ℃, left standstill 5-10 hour, and filtered, get solid, add 200 milliliters of ethanol, heating refluxed 0.5 hour, stopped to stir, and stopped heating, be cooled to 10-25 ℃, left standstill 5-10 hour, filter, solid transfers to pH=1.0 with dilute hydrochloric acid, filter, obtain white solid (compound III) 6.7 grams, yield 34%;
E.e value:＞95%
Embodiment 4:1-(S)-4,5-dimethoxy-1-methylamine formyl radical benzocyclobutane (Compound I I) synthetic
With 2.16 grams 4,5-dimethoxy-1-carboxyl benzocyclobutane (compound IV) is dissolved in 26 ml methanol, drips 2.6 milliliters of thionyl chlorides, backflow 2-5 hour in 5 minutes.Cool off back 30 ℃ of water-baths and revolve steaming except that desolvating, add 11 milliliters of methylamine methanol solutions, controlled temperature spends the night 10-25 ℃ of stirring, filters 40 ℃ and vacuumizes dry 24 hours, obtains white solid (Compound I I) 1.68 grams, yield: 73%.
MS(ESI)：222(M+1)
1HNMR(CDCl
3)：δ2.80(3H，d，J＝4.9Hz)，3.13(1H，m)，3.48(1H，m)，3.84(m，6H)，4.08(m，1H)，6.72(m，2H)。
Embodiment 5:
With 2.0 grams 4,5-dimethoxy-1-carboxyl benzocyclobutane (compound IV) is dissolved in 20 milliliters of methylene dichloride, under the argon shield; drip 2.0 milliliters of oxalyl chlorides in 5 minutes, and drip a N, dinethylformamide; stirred under the 10-25 ℃ of temperature 0.5-1.0 hour, and clarified to system.30 ℃ of water-baths are revolved to steam to remove and are desolvated and excessive oxalyl chloride, add 20 milliliters of methylene dichloride, 0.5 be added dropwise to 11 milliliters of methylamine methanol solutions in hour, controlled temperature spends the night 10-25 ℃ of stirring, filtering 40 ℃ vacuumized dry 24 hours, obtain white solid (Compound I I) 2.05 grams, yield: 93%.
Embodiment 6:
With 2.0 grams 4,5-dimethoxy-1-carboxyl benzocyclobutane (compound IV) is dissolved in 20 milliliters of methylene dichloride, under the argon shield; disposable adding 6.0 gram phosphorus pentachloride chlorine; and dripping a N, dinethylformamide stirred 0.5-1.0 hour under the 10-25 ℃ of temperature.Remove by filter unreacted phosphorus pentachloride, 30 ℃ of water-baths are revolved to steam and are removed the phosphorus oxychloride of desolvating and producing, add 20 milliliters of methylene dichloride, 0.5 be added dropwise to 11 milliliters of methylamine methanol solutions in hour, controlled temperature spends the night 10-25 ℃ of stirring, filter 40 ℃ and vacuumized dry 24 hours, obtain white solid (Compound I I) 1.81 grams, yield: 82%.
Embodiment 7:
With 2.1 gram 5-dimethoxy-1-carboxyl benzocyclobutanes (compound IV), 2.5 gram dicyclohexyl carbon imide, N-hydroxybenzotriazole 1.6 grams join in the tetrahydrofuran (THF) of 30 milliliters of no water treatments, 20 ℃-25 ℃ were stirred 0.5 hour down, add methylamine hydrochloride 0.7 gram, continue to stir 4 hours, thin-layer chromatography is monitored to compound IV and is disappeared, filter, tetrahydrofuran (THF) is revolved in 25 ℃ of water-baths, adds 50 milliliters of methylene dichloride, dilute hydrochloric acid with 0.1N is washed once for 50 milliliters, 50 milliliters saturated saturated sodium bicarbonate aqueous solution is washed once, and 50 milliliters of saturated common salts are washed once anhydrous sodium sulfate drying, filter, methylene dichloride is revolved in 25 ℃ of water-baths, obtains 1.98 gram white solids (Compound I I), and yield is 90%.
Embodiment 8:1-(S)-4,5-dimethoxy-1-methylamino methyl benzocyclobutane (Compound I) synthetic
In 1000 milliliters of three-necked bottles of exsiccant; under the nitrogen protection; the tetrahydrofuran (THF) that adds 500 milliliters of no water treatments; sodium borohydride 50 grams; cryosel is bathed and is cooled to-25 ℃--and-0 ℃; slowly drip 158 gram trifluoroacetic acids and be dissolved in 100 milliliters of anhydrous tetrahydrofuran solutions; dripped off in 100 minutes, and be warming up to 10 ℃-25 ℃ naturally, stir after 0.5 hour slowly Dropwise 50 gram 4; 5-dimethoxy-1-methylamine formyl radical benzocyclobutane is dissolved in the tetrahydrofuran solution of 150 milliliters of no water treatments; dripped off in 100 minutes, stirred 4 hours, 25 ℃ of water-bath rotations boil off desolventizing; be neutralized to pH value＞8,50 milliliter dichloromethane extraction three times with 200 milliliters of saturated sodium bicarbonate aqueous solutions, 100 milliliters of saturated common salts are washed 2 times; anhydrous sodium sulfate drying obtains faint yellow oily thing (compound III) 44.5 grams.Yield: 95%
MS(ESI)：222(M+1)
1HNMR(CDCl
3)：δ1.82(1H，s)，2.47(3H，s)，2.70(1H，d，J＝13.58)，2.76-2.88(2H，m)，3.16-3.19(1H，dd，J＝13.58)3.53-3.56(1H，m)，3.81(3H，s)，3.82(3H，s)，6.67(1H，s)，6.69(1H，s)
Embodiment 9:
With 3.8g4,5-dimethoxy-1-methylamine formyl radical benzocyclobutane is dissolved in the tetrahydrofuran (THF) of 300mL, adds 1.33g tetrahydrochysene lithium aluminium, and reflux is after 2 hours, and TLC follows the tracks of and reacts completely.Add the 10mL shrend reaction of going out after ice-water bath is cooled to 0-5 ℃, filter back 30 ℃ of water-baths and revolve to steam and remove tetrahydrofuran (THF), ethyl acetate extraction (3x50mL), the water washing of 50mL saturated common salt is once.Behind the anhydrous sodium sulfate drying, 25 ℃ of water-baths are revolved to steam to remove and are desolvated, and obtain faint yellow oily thing (Compound I) 2.3 grams.Yield is 65%.
Embodiment 10:
Under the argon shield; triethoxy sodium borohydride 3.0 grams; join in the tetrahydrofuran (THF) of 30 milliliters of no water treatments; temperature of reaction is controlled at 10 ℃-25 ℃; stir down; add 1.0 grams 4,5-dimethoxy-1-methylamine formyl radical benzocyclobutane stirred after 1 hour, was warming up to backflow; refluxed 4 hours; thin-layer chromatography monitoring raw material (Compound I I) point disappears, and 25 ℃ of water-bath rotations boil off desolventizing, are neutralized to pH value＞8 with 200 milliliters of saturated sodium bicarbonate aqueous solutions; 50 milliliters of dichloromethane extractions three times; 100 milliliters of saturated common salts are washed 2 times, and anhydrous sodium sulfate drying obtains faint yellow oily thing (Compound I) 0.71 gram.Yield: 75%
Claims (10)
1. one kind prepares 1-(S)-4, and the preparation method of 5-dimethoxy-1-methylamino methyl-benzocyclobutane (chemical compounds I) is characterized in that this method comprises the following steps:
(1) 4,5-dimethoxy benzo cyclobutyronitrile compound V preparation 4,5-dimethoxy benzo cyclobutyl-1-carboxylic acid cpd IV;
(2) 4,5-dimethoxy benzo cyclobutyl-1-carboxylic acid cpd IV are by splitting preparation (S)-4,5-dimethoxy benzo cyclobutyl-1-carboxylic acid cpd III;
(3) (S)-4,5-dimethoxy benzo cyclobutyl-1-carboxylic acid cpd III is by condensing agent and methylamine condensation prepared or by becoming behind the acyl chlorides and methylamine condensation prepared 1-(S) 4,5-dimethoxy-1-methylamine formyl radical benzocyclobutane compounds II with becoming the acyl chlorides reagent preparation again;
(4) 1-(S) 4,5-dimethoxy-1-methylamine formyl radical benzocyclobutane compounds II is used reductive agent, is methylene radical with carbonyl reduction, makes 1-(S) 4,5-dimethoxy-1-methylamino-N-methyl benzocyclobutane chemical compounds I.
2. according to the described preparation method of claim 1, it is characterized in that step (1) 4,5-dimethoxy benzo cyclobutyl-1-carboxylic acid cpd IV is by 4, the ethanolic soln reaction of 5-dimethoxy benzo cyclobutyronitrile compound V and sodium hydroxide or potassium hydroxide, obtain 4,5-dimethoxy benzo cyclobutyl-1-carboxylic acid cpd IV.
3. according to the described preparation method of claim 1, it is characterized in that the described resolving agent of step (2) is brucine, vauqueline, Quinidine, quinine, cinchovatin, quinotoxol, cinchotoxine, ephedrine, (S)-(-)-α-Ben Yian, (R)-(+)-α-Ben Yian or (S)-(-)-α-naphthalene ethylamine; The mol ratio of resolving agent and compound IV is 0.5-1.0; The fractionation solvent for use is one or more the mixed solvent in methyl alcohol, ethanol, the trimethyl carbinol or the ethyl acetate; The salifiable temperature of compound IV and resolving agent is 25 ℃-150 ℃; The salt-forming reaction time is 0.5-2.0 hour; Then, leave standstill or stir and be cooled to 0 ℃ of-25 ℃ of slow crystallization; The time of placing crystallization is 2 hours-24 hours.
4. according to the described preparation method of claim 3, it is characterized in that described resolving agent is cinchovatin or (S)-(-)-α-Ben Yian; The mol ratio of resolving agent and compound IV is 1.0; The salifiable temperature of compound IV and resolving agent is the reflux temperature of solvent, and the salt-forming reaction time is 0.5-1.0 hour; Then, leave standstill or stir and be cooled to 0 ℃ of-25 ℃ of slow crystallization; The time of placing crystallization is 2 hours-10 hours.
5. according to the described preparation method of claim 1, it is characterized in that the described condensing agent of step (3) is dicyclohexylcarbodiimide, 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate, I-hydroxybenzotriazole or 1-pyridone and triazole; Temperature of reaction is 0 ℃-150 ℃, is preferably the reflux temperature of reaction solvent; Reaction times is 0.5-10 hour, is preferably 1-5 hour; The mol ratio of condensing agent and compound III is 1.0-3.0, is preferably 1.0-2.0.
6. according to the described preparation method of claim 1, it is characterized in that step (3) by compound III XianCheng acyl chlorides, is sulfur oxychloride, oxalyl chloride, three chlorotriazines, phosphorus trichloride, phosphorus pentachloride or phosphorus oxychloride with the acyl chlorides reagent that becomes described in the first ammonia condensation prepared compound ii then; Temperature of reaction is 0 ℃-50 ℃, is preferably 0 ℃-25 ℃; Reaction times is 0.5-20 hour, is preferably 2-5 hour; Acyl chlorides reagent and compound (III) mol ratio 1.0-10 is preferably 1.0-5.0.
7. according to claim 5 or 6 described preparation methods, it is characterized in that described solvent is methylene dichloride, trichloromethane, 1,2-ethylene dichloride, toluene, dimethylbenzene, tetrahydrofuran (THF), dioxane, glycol dimethyl ether, isopropyl ether, tertbutyl ether, methyl tertiary butyl ether, N, the mixture of one or more solvents in dinethylformamide or the dioxane is preferably ether solvent or methylene dichloride.
8. according to the described preparation method of claim 1, it is characterized in that the described reductive agent of step (4) is tetrahydrochysene lithium aluminium, borine, sodium cyanoborohydride, acetic acid sodium borohydride or trifluoracetic acid sodium borohydride; The mol ratio of reductive agent and compound ii is 1.0-5.0; Described solvent is toluene, dimethylbenzene, ether, tetrahydrofuran (THF), dioxane, glycol dimethyl ether, isopropyl ether, tertbutyl ether, methyl tertiary butyl ether, N, the mixture of one or more solvents in the dinethylformamide; Temperature of reaction is-25 ℃-150 ℃; Reaction times is 1-20 hour.
9. described according to Claim 8 preparation method is characterized in that described reductive agent is tetrahydrochysene lithium aluminium or trifluoracetic acid sodium borohydride; The mol ratio of reductive agent and compound ii is 1.0-2.0; Described solvent is the mixture of one or more solvents in glycol dimethyl ether, isopropyl ether, tertbutyl ether or the methyl tertiary butyl ether.
10. described according to Claim 8 preparation method, when it is characterized in that described tetrahydrochysene lithium aluminium is reductive agent, temperature of reaction is the reflux temperature of solvent, the reaction times is 1-10 hour, is preferably 2-4 hour; When borine, sodium cyanoborohydride, acetic acid sodium borohydride or trifluoracetic acid sodium borohydride were reductive agent, temperature of reaction was-10 ℃--25 ℃, the reaction times is 1-20 hour, is preferably 5-10 hour.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102827019A (en) * | 2012-09-12 | 2012-12-19 | 江苏宇田生物医药科技有限公司 | One group of novel benzene cyclobutane compounds and application of novel benzene cyclobutane compounds in chemical synthesis |
| EA023883B1 (en) * | 2013-02-28 | 2016-07-29 | Ле Лаборатуар Сервье | Process for enzymatic synthesis of (7s)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid and application in the synthesis of ivabradine and salts thereof |
| CN106349144A (en) * | 2016-08-30 | 2017-01-25 | 山东默得森生物制药有限公司 | Preparation method of (S)-oxiracetam intermediate |
| CN108947800A (en) * | 2018-06-20 | 2018-12-07 | 安徽美诺华药物化学有限公司 | A kind of synthetic method of (1S) -4,5- dimethoxy -1- (carbonylamino-methyl) benzocyclobutane |
| 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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| CN102827019A (en) * | 2012-09-12 | 2012-12-19 | 江苏宇田生物医药科技有限公司 | One group of novel benzene cyclobutane compounds and application of novel benzene cyclobutane compounds in chemical synthesis |
| EA023883B1 (en) * | 2013-02-28 | 2016-07-29 | Ле Лаборатуар Сервье | Process for enzymatic synthesis of (7s)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid and application in the synthesis of ivabradine and salts thereof |
| US10221141B2 (en) | 2015-06-03 | 2019-03-05 | Urquima, S.A. | Method for the preparation of highly pure ivabradine base and salts thereof |
| CN106349144A (en) * | 2016-08-30 | 2017-01-25 | 山东默得森生物制药有限公司 | Preparation method of (S)-oxiracetam intermediate |
| CN108947800A (en) * | 2018-06-20 | 2018-12-07 | 安徽美诺华药物化学有限公司 | A kind of synthetic method of (1S) -4,5- dimethoxy -1- (carbonylamino-methyl) benzocyclobutane |
| CN108947800B (en) * | 2018-06-20 | 2021-07-27 | 安徽美诺华药物化学有限公司 | Synthesis method of (1S) -4, 5-dimethoxy-1- (carbonylaminomethyl) benzocyclobutane |
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