CN1709859A - Method for preparing dextroa-[2-(naphthoxy, ethyl] phenyl methylamine derivatives - Google Patents
Method for preparing dextroa-[2-(naphthoxy, ethyl] phenyl methylamine derivatives Download PDFInfo
- Publication number
- CN1709859A CN1709859A CN 200510012624 CN200510012624A CN1709859A CN 1709859 A CN1709859 A CN 1709859A CN 200510012624 CN200510012624 CN 200510012624 CN 200510012624 A CN200510012624 A CN 200510012624A CN 1709859 A CN1709859 A CN 1709859A
- Authority
- CN
- China
- Prior art keywords
- dextrorotation
- ethyl
- naphthyloxy
- general formula
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
This invention involves a synthesis method for dextrorotatory alpha- [2-(naphthoxy) ethyl] toluidine derivatives, including: make benzaldehyde react with malonic acid and ammonium acetate, then split it with dextrorotatory anhydrous tartaric to get dextrorotatory beta-aminophenylpropionic acid, after alkyl substitution and deoxidizing to alcohol, react with alpha-bromonaphthalene. This invention has saved the raw materials consumption that every step reacts afterwards, the castoff is reduced greatly, thus reduced the cost.
Description
Affiliated technical field
The present invention relates to a kind of preparation dextrorotation α-[2-(naphthyloxy) ethyl] benzenemethanamine derivatives, with and in the method for pharmacy acceptable salt.
Background technology
It should be noted that the intake of monoamine and multiple disease and symptom have confidential relation, for example, Fluoxetine hydrochloride is a kind of selective seronine uptake inhibitor, is used for the treatment of dysthymia disorders, eating disorder, alcoholism and other obstacle disease.
Dapoxetine (Dapoxetine), chemical name N, N-dimethyl-α-[2-(naphthyloxy) ethyl] benzene methanamine hydrochloride (N, N-dimethyl-α-[2-(naphthalenyloxy) ethyl] benyenemethanaminehydrochloride), it is a kind of optionally seronine uptake inhibitor, can be used for treating diseases such as melancholia and excessive drinking, fat-reducing, memory loss, to forgetful, irritability, depressed, unsociable and eccentric effective, also be that first is used for the treatment of the oral pharmaceutical of prospermia of males in the world simultaneously.This medicine is a kind of optionally seronine uptake inhibitor, and to not directly effect of neuronal acceptor.Because such medicine can not suppress other monoamine effectively, so the expection side effect is smaller after dispenser.
According to the academic conference introduction, have dissatisfied to the sexual life of oneself above 50% people.Wherein 78.5% people be because age growth, unable to do what one wishes due to, and 48.8% people is because premature ejaculation and worries.Dapoxetine is a kind of buccal tablet, and there was the male ejaculation time triple effect of prolongation onset time after 30 minutes.
According to research, the consumption of dapoxetine treatment premature ejaculation is 60mg, and then result of treatment is poor to be less than 60mg, and consumption is when reaching 100mg, and side effects such as vomiting can appear in the people more than 90%.Owing to have only the dextrorotatory form of dapoxetine just effective to the treatment premature ejaculation, and levo form is invalid thing, if use DL body treatment premature ejaculation, consumption should reach 120mg, this is unsafe to the user, so can not use the DL body treatment premature ejaculation of dapoxetine on the clinical practice.
In addition because the singularity of treatment premature ejaculation drug use, require medication after, can take effect in the short period of time, even get instant result.Because the base compound absorbs very slowly in human body, onset time reached more than 3 hours, so the salt that needs clinically to use above-claimed cpd is as the finished product, so that 5～9 times of the onset time of medicine shortenings.
1988, U.S. Eli Lilly Company applied for the pharmaceutical patent of α-[2-(naphthyloxy) ethyl] benzene methanamine and derivative thereof, the DL body that is actually α-[2-(naphthyloxy) ethyl] benzenemethanamine derivatives that this patent relates to.Among the target compound preparation method who in this patent, provides, a kind of effective means is by with benzaldehyde derivative and propanedioic acid and ammonium acetate reaction, generate corresponding beta-amino phenylpropionic acid, and further be converted into the corresponding carboxylic acid ester, restore and be alcohol, at last the hydroxy intermediate of gained is handled with alkalimetal hydride and generated corresponding alkali metal salt, with the suitable compound reaction that contains good leavings group, make target compound again.
Summary of the invention
The objective of the invention is the preparation method of above-mentioned α-[2-(naphthyloxy) ethyl] benzenemethanamine derivatives is improved, a kind of method for preparing dextrorotation α-[2-(naphthyloxy) ethyl] benzenemethanamine derivatives is provided.
The invention provides the method for dextrorotation α-[2-(naphthyloxy) ethyl] benzenemethanamine derivatives of a kind of preparation general formula (I) expression,
In the formula, R
1And R
2Be methyl or ethyl independently of one another,
Comprise,
1, makes the reaction of phenyl aldehyde and propanedioic acid and ammonium acetate, obtain the beta-amino phenylpropionic acid;
2, use the anhydrous tartrate of dextrorotation that the beta-amino phenylpropionic acid is split, obtain dextrorotation beta-amino phenylpropionic acid;
3, make the compound reaction of dextrorotation beta-amino phenylpropionic acid and general formula (III) expression,
In the formula, R
1And R
2Definition the same,
Obtain the compound of general formula (IV) expression,
In the formula, R
1And R
2Definition the same;
4, the compound with general formula (IV) expression restores the compound that is converted into general formula (II) expression,
In the formula, R
1And R
2Definition the same;
5, make the compound and the α-Xiu Dainai reaction of general formula (II) expression, obtain dextrorotation α-[2-(naphthyloxy) ethyl] benzenemethanamine derivatives of general formula (I) expression.
The compound of above-mentioned preparation is an amine, belongs to the base compound, according to needs clinically, preferably above-claimed cpd is converted into corresponding acid salt class.The acid that generally is used to form this salt comprises inorganic acids example hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, nitric acid and phosphoric acid, organic acid such as paratolunitrile, methylsulfonic acid, oxalic acid, succsinic acid, citric acid, phenylformic acid, acetate, tartrate and other relevant organic acid.
A part is obtained by preparation method of the present invention, and the examples of compounds that is suitable for pharmacological agent purpose of the present invention can be:
S-(+) N, N-dimethyl-α-[2-(naphthyloxy) ethyl] benzene methanamine hydrochloride;
S-(+) N, N-diethyl-α-[2-(naphthyloxy) ethyl] benzene methanamine hydrochloride;
S-(+) N, N-dimethyl-α-[2-(naphthyloxy) ethyl] benzene methanamine vitriol;
S-(+) N, N-diethyl-α-[2-(naphthyloxy) ethyl] benzene methanamine vitriol;
S-(+) N, N-dimethyl-α-[2-(naphthyloxy) ethyl] benzene methanamine tartrate;
S-(+) N, N-diethyl-α-[2-(naphthyloxy) ethyl] benzene methanamine tartrate;
S-(+) N, N-dimethyl-α-[2-(naphthyloxy) ethyl] benzene methanamine oxalate;
S-(+) N, N-diethyl-α-[2-(naphthyloxy) ethyl] benzene methanamine oxalate;
S-(+) N, N-dimethyl-α-[2-(naphthyloxy) ethyl] benzene methanamine lactic acid salt;
S-(+) N, N-dimethyl-α-[2-(naphthyloxy) ethyl] benzene methanamine lactic acid salt;
Or the like.
In preparation method of the present invention, the first step is to make phenyl aldehyde and propanedioic acid and ammonium acetate prepared in reaction beta-amino phenylpropionic acid, this is reflected to have such as dimethyl formamide, tetrahydrofuran (THF), benzene etc. and carries out in the better deliquescent medium, the phenyl aldehyde that is fit to and the reaction mol ratio of propanedioic acid and amine acetate can be 1: 0.8～1.3: 0.7～1.3,30～150 ℃ of temperature of reaction.If temperature of reaction is lower, may prolong the reaction times, productive rate is reduced.The present invention utilizes distinctive alkalescence of amino acid and acidic-group character, uses soda acid dissolving and sedimentary method that the beta-amino phenylpropionic acid is carried out purification processes, has obtained purer beta-amino phenylpropionic acid.In purification process, the control of pH value is very big to the yield influence of beta-amino phenylpropionic acid, and the present invention controls pH=3～4 of solution.
Different with other preparation feedback, the present invention is from a generation optically-active compound, and promptly the beta-amino phenylpropionic acid begins, promptly the optically-active compound that produces is split, rather than traditional splitting again to the finished product.
The present invention uses the anhydrous tartrate of dextrorotation that beta-amino phenylpropionic acid DL body is split, and obtains dextrorotation beta-amino phenylpropionic acid.Beta-amino phenylpropionic acid DL body and the anhydrous tartrate of dextrorotation react in anhydrous solvent with 1: 0.75～1.4 reaction mol ratio.Because the levo form of beta-amino phenylpropionic acid is very similar to dextrorotatory form solubleness, so different solvents, different quantity of solvent and different temperature, yield and quality differential for products obtained therefrom are very big, preferred solvent is a Virahol, also can use methyl alcohol or ethanol, the mol ratio of preferred beta-amino phenylpropionic acid DL body and solvent is 1: 5～20, and filtration temperature is 10～40 ℃, and the dextrorotation beta-amino phenylpropionic acid content that obtain this moment should be more than 90%.
And then, the present invention uses the alkylamine of general formula (III) expression that dextrorotation beta-amino phenylpropionic acid is carried out the compound that the alkyl substitution on the amino is represented with synthetic general formula (IV).The dextrorotation beta-amino phenylpropionic acid that is fit to and the reaction mol ratio of alkylamine are 1: 0.75～1.35, are reflected in the straight chain alcohol system and carry out, and temperature of reaction is the reflux temperature of solvent.In order to improve the quality of general formula (IV) reaction product, the present invention also makes with extra care with water-insoluble solvent the crude product of reaction product, and preferred solvent is chloroform, acetic acid fourth vinegar, ether etc.The volume ratio of reaction product crude product and solvent can be 1: 5～20, and certainly, solvent volume is big, the quality better of refined products then, but yield is low.
The 4th step of reaction is that the compound of mutual-through type (IV) expression carries out, with the alcohol compound of synthetic general formula (II) expression.This reaction is that the compound and the lithium aluminum hydride of general formula (IV) expression are carried out in non-polar solvent according to 1: 0.9～1.1 mol ratio, described non-polar solvent such as dichlorobenzene, chloroform, chlorobenzene, benzene etc., it also can be dimethyl formamide, temperature of reaction should not be lower than 10 ℃, otherwise reaction is difficult to carry out.
Owing to (II) be liquid, need evaporation remove reaction solvent, (II) separated, in order to obtain (II) of better quality, should guarantee sufficient stirring and enough vacuum tightness during the recovery solvent, usually, vacuum tightness should be on 680mmHg.
At last, make the compound and the α-Xiu Dainai reaction of general formula (II) expression, obtain dextrorotation α-[2-(naphthyloxy) ethyl] benzenemethanamine derivatives of general formula (I) expression.(II) can be 1: 0.85～1.2 with the reaction mol ratio of α-bromination naphthalene, reaction needed be carried out in the less solvent of polarity, as chlorobenzene, dichlorobenzene, benzene etc., helps reacting the eliminating of the hydrogen bromide of generation like this.Reaction times should be greater than 8 hours, otherwise the yield of product is lower.(I) that reaction finally obtains preferably uses anhydrous straight chain alcohol washing, to remove residual solvent in the dereaction.
The present invention is a kind of improvement to α-[2-(naphthyloxy) ethyl] benzenemethanamine derivatives preparation method, its topmost improvement is from producing optically-active compound, be that DL beta-amino phenylpropionic acid begins, promptly split, rather than traditional obtaining split behind the finished product again.This technology of the present invention can be saved the raw material consumption of each step reaction subsequently greatly, thereby reduces product cost greatly, simultaneously, adopts preparation method of the present invention, and the discarded levorotatory amount of generation also reduces greatly, only is 1/4 of traditional method.
Embodiment
Embodiment 1:
S-(+) N, the preparation of N-dimethyl-α-[2-(naphthyloxy) ethyl] benzene methanamine hydrochloride:
1, the preparation of beta-amino phenylpropionic acid
13g phenyl aldehyde, 14g propanedioic acid and the disposable adding of 7g amine acetate are filled in the 250ml three-necked bottle of 150mlDMF, stirred down under 122 ℃ of temperature back flow reaction 8 hours.After reaction finishes, add 1.5g gac filtered while hot, filtrate is evaporate to dryness under 720mmHg pressure.Add chloroform and each 100ml of 10% sodium bicarbonate aqueous solution in the evaporate to dryness thing, the powerful stirring half an hour, static minute water-yielding stratum, organic layer adds the washing of 100ml sodium bicarbonate aqueous solution again, merge the water layer that secondary is told, drip 15% hydrochloric acid soln, the pH=3 of regulator solution～4, to obtain the beta-amino phenylpropionic acid of 12.2g after throw out filtration, the oven dry, fusing point mp is 128～132 ℃.
2, the preparation of dextrorotation beta-amino phenylpropionic acid
18g beta-amino phenylpropionic acid is dissolved in the 180ml dehydrated alcohol, adds the anhydrous tartrate of 17.2g dextrorotation, back flow reaction 4 hours.After reaction finishes, add 0.2g gac filtered while hot, filtrate is cooled to 18 ± 0.5 ℃, filters rapidly, obtains the 18.8g solid.
Above-mentioned solid is added in the 50ml deionized water, drip pH=3～3.5 of 10% hydrochloric acid soln regulator solution, be cooled to 10 ℃ of filtrations, filtrate is regulated pH=7～7.2 with 10% sodium hydroxide solution, be cooled to 10 ℃ of filtrations, obtain dextrorotation beta-amino phenylpropionic acid solid, fusing point mp is 128～133 ℃.
3, dextrorotation β-N, the preparation of N-dimethylamino phenylpropionic acid
Be with in the three-necked bottle that stirs at 250ml, adding 150ml dehydrated alcohol and 16g dextrorotation beta-amino phenylpropionic acid, in 20 ℃ of feeding 5g anhydrous dimethyl amine gas, 20～22 ℃ were reacted 2 hours down under stirring.Reaction steams ethanol after finishing under normal pressure, obtain dextrorotation β-N, N-dimethylamino phenylpropionic acid crude product.With crude product chloroform dissolving with 10 times of volumes under room temperature, filter, steam chloroform under the normal pressure, obtain 14.2g dextrorotation β-N, N-dimethylamino phenylpropionic acid, fusing point mp are 22～23 ℃.
4, dextrorotation β-N, the preparation of N-dimethylamino phenylpropyl alcohol
In the three-necked bottle of the stirring of 250ml band, interior Sheng 150mlDMF, add 19g dextrorotation β-N, N-dimethylamino phenylpropionic acid and 25g lithium aluminum hydride, reaction is 20 hours under 34 ± 2 ℃ of conditions.After reaction finishes, solids removed by filtration, filtrate obtains buttery dextrorotation β-N, N-dimethylamino phenylpropyl alcohol 12.4g after DMF is reclaimed in evaporation under the 680mmHg pressure.
Analyze and press C
11H
17ON calculates,
Theoretical value: C, 73.74; H, 9.50; N, 7.8;
Experimental value: C, 73.50; H, 9.55; N, 7.82.
5, dextrorotation N, the preparation of N-dimethyl-α-[2-(naphthyloxy) ethyl] benzene methanamine
With 18g dextrorotation N, N-dimethylamino phenylpropyl alcohol and 21g α-Xiu Dainai are dissolved in the 200ml dichlorobenzene, under 70 ± 2 ℃ of temperature, reaction is 15 hours in the 250ml three-necked bottle, constantly have bromize hydrogen gas to produce in the reaction process, control vacuum tightness is in bromize hydrogen gas suction withdrawing can, hydrogen bromide content in dichlorobenzene solution is lower than 0.5%, and reaction finishes.Reaction solution is cooled to 0 ℃, is incubated 2 hours after-filtration, a small amount of absolute ethanol washing of filter cake obtains dextrorotation N after the drying, N-dimethyl-α-[2-(naphthyloxy) ethyl] benzene methanamine.
6, S-(+)-N, the preparation of N-dimethyl-α-[2-(naphthyloxy) ethyl] benzene methanamine hydrochloride
With 15g dextrorotation N, N-dimethyl-α-[2-(naphthyloxy) ethyl] benzene methanamine adding fills in the 200ml95% alcoholic acid 250ml three-necked bottle, add 30% hydrochloric acid soln of 12ml, back flow reaction was cooled to 30 ± 1 ℃ after 30 minutes, drip 40%NaOH solution, the pH=3 of regulator solution～4 are cooled to 5 ℃, are incubated 30 minutes after-filtration, filter cake is with 95% washing with alcohol two times, till washing lotion neutrality.Behind the filtration cakes torrefaction, obtain S-(+)-N, N-dimethyl-α-[2-(naphthyloxy) ethyl] benzene methanamine hydrochloride finished product 13.2g.
Analyze and press C
21H
24ONCl calculates,
Theoretical value: C, 73.86; H, 7.03; N, 4.10;
Measured value: C, 73.88; H, 7.00; N, 4.11.
Embodiment 2:
S-(+) N, the preparation of N-diethyl-α-[2-(naphthyloxy) ethyl] benzene methanamine hydrochloride:
1, the preparation of beta-amino phenylpropionic acid
13g phenyl aldehyde, 14.2g propanedioic acid and the disposable adding of 7.5g amine acetate are filled in the 250ml three-necked bottle of 150mlDMF, stir down 115 ℃ of temperature back flow reaction 5 hours.After reaction finishes, add 1.5g gac filtered while hot, filtrate is evaporate to dryness under 720mmHg pressure.Add chloroform and each 150ml of 10% sodium bicarbonate aqueous solution in the evaporate to dryness thing, the powerful stirring half an hour, static minute water-yielding stratum, organic layer adds the washing of 100ml sodium bicarbonate aqueous solution again, merge the water layer that secondary is told, drip 15% hydrochloric acid soln, the pH=3 of regulator solution～4, to obtain the beta-amino phenylpropionic acid of 11.5g after throw out filtration, the oven dry, fusing point mp is 128～131 ℃.
2, the preparation of dextrorotation beta-amino phenylpropionic acid
16g beta-amino phenylpropionic acid is dissolved in the 200ml anhydrous methanol, adds the anhydrous tartrate of 18.8g dextrorotation, back flow reaction 5 hours.After reaction finishes, add 0.2g gac filtered while hot, filtrate is cooled to 20 ± 0.5 ℃, filters rapidly, obtains the 20.0g solid.
Above-mentioned solid is added in the 50ml deionized water, drip pH=3～3.5 of 15% hydrochloric acid soln regulator solution, be cooled to 15 ℃ of filtrations, filtrate is regulated pH=7～7.2 with 10% sodium hydroxide solution, be cooled to 15 ℃ of filtrations, obtain dextrorotation beta-amino phenylpropionic acid solid, fusing point mp is 128～132 ℃.
3, dextrorotation β-N, the preparation of N-diethylamino phenylpropionic acid
In the three-necked bottle that the 250ml band stirs, adding 200ml anhydrous methanol and 18g dextrorotation beta-amino phenylpropionic acid, in 10 ℃ of 50% diethylamine methanol solutions that add 12g, 22～24 ℃ were reacted 10 hours down under stirring.Reaction steams methyl alcohol after finishing under normal pressure, obtain dextrorotation β-N, N-diethylamino phenylpropionic acid crude product.With crude product N-BUTYL ACETATE dissolving with 5 times of volumes under room temperature, filter, steam N-BUTYL ACETATE under the normal pressure, obtain 14.0g dextrorotation β-N, N-diethylamino phenylpropionic acid, fusing point mp are 22～24 ℃.
4, dextrorotation β-N, the preparation of N-diethylamino phenylpropyl alcohol
In the three-necked bottle of the stirring of 250ml band, interior Sheng 150ml chloroform, add 21g dextrorotation β-N, N-diethylamino phenylpropionic acid and 30g lithium aluminum hydride, reaction is 10 hours under 64 ± 2 ℃ of conditions.After reaction finishes, solids removed by filtration, filtrate obtains buttery dextrorotation β-N, N-diethylamino phenylpropyl alcohol 13.0g after chloroform is reclaimed in evaporation under the 680mmHg pressure.
Analyze and press C
13H
21ON calculates,
Theoretical value: C, 75.36; H, 10.14; N, 6.76;
Experimental value: C, 75.35; H, 10.13; N, 6.75.
5, dextrorotation N, the preparation of N-diethyl-α-[2-(naphthyloxy) ethyl] benzene methanamine
With 20g dextrorotation N, N-diethylamino phenylpropyl alcohol and 24g α-Xiu Dainai are dissolved in the 150ml benzene, under 102 ± 2 ℃ of temperature, reaction is 10 hours in the 250ml three-necked bottle, constantly have bromize hydrogen gas to produce in the reaction process, control vacuum tightness is in bromize hydrogen gas suction withdrawing can, hydrogen bromide content in benzole soln is lower than 0.5%, and reaction finishes.Reaction solution is cooled to 10 ℃, is incubated 1 hour after-filtration, filter cake washs with a small amount of anhydrous methanol, obtains dextrorotation N after the drying, N-diethyl-α-[2-(naphthyloxy) ethyl] benzene methanamine.
6, S-(+)-N, the preparation of N-diethyl-α-[2-(naphthyloxy) ethyl] benzene methanamine hydrochloride
With 15g dextrorotation N, N-diethyl-α-[2-(naphthyloxy) ethyl] benzene methanamine adding fills in the 150ml95% alcoholic acid 250ml three-necked bottle, add 30% hydrochloric acid of 10ml, back flow reaction was cooled to 40 ± 1 ℃ after 10 minutes, drip 20%NaOH solution, the pH=3 of regulator solution～4 are cooled to 10 ℃, are incubated 30 minutes after-filtration, filter cake is with 95% washing with alcohol two times, till washing lotion neutrality.Behind the filtration cakes torrefaction, obtain S-(+)-N, N-diethyl-α-[2-(naphthyloxy) ethyl] benzene methanamine hydrochloride finished product 13.0g.
Analyze and press C
23H
28ONCl calculates,
Theoretical value: C, 74.70; H, 7.58; N, 3.79;
Measured value: C, 74.68; H, 7.58; N, 3.75.
Embodiment 3:
S-(+) N, the preparation of N-dimethyl-α-[2-(naphthyloxy) ethyl] benzene methanamine vitriol:
1, the preparation of beta-amino phenylpropionic acid
13g phenyl aldehyde, 14g propanedioic acid and the disposable adding of 14g amine acetate are filled in the 250ml three-necked bottle of 150ml benzene, stir down 62 ℃ of reactions 5 hours.After reaction finishes, add 1.5g gac filtered while hot, filtrate is evaporate to dryness under 720mmHg pressure.Add chloroform and each 100ml of 10% sodium bicarbonate aqueous solution in the evaporate to dryness thing, the powerful stirring half an hour, static minute water-yielding stratum, organic layer adds the washing of 100ml sodium bicarbonate aqueous solution again, merge the water layer that secondary is told, drip 15% hydrochloric acid soln, the pH=3 of regulator solution～4, to obtain the beta-amino phenylpropionic acid of 12.3g after throw out filtration, the oven dry, fusing point mp is 127～132 ℃.
2, the preparation of dextrorotation beta-amino phenylpropionic acid
17.5g beta-amino phenylpropionic acid is dissolved in the 180ml Virahol, adds the anhydrous tartrate of 16.8g dextrorotation, back flow reaction 3 hours.After reaction finishes, add 0.2g gac filtered while hot, filtrate is cooled to 10 ℃ ± 0.5 ℃, filters rapidly, obtains the 16.9g solid.
Above-mentioned solid is added in the 50ml deionized water, drip pH=3～3.5 of 10% hydrochloric acid soln regulator solution, be cooled to 12 ℃ of filtrations, filtrate is regulated pH=7～7.2 with 10% sodium hydroxide solution, be cooled to 12 ℃ of filtrations, obtain dextrorotation beta-amino phenylpropionic acid solid, fusing point mp is 129～132 ℃.
3, dextrorotation β-N, the preparation of N-dimethylamino phenylpropionic acid
In the three-necked bottle that the 250ml band stirs, adding 150ml Virahol and 20g dextrorotation beta-amino phenylpropionic acid, in 25 ℃ of 30% decil alcoholic solutions that add 10g, 24～28 ℃ were reacted 4 hours down under stirring.Reaction steams Virahol after finishing under normal pressure, obtain dextrorotation β-N, N-dimethylamino phenylpropionic acid crude product.With crude product ether dissolution with 15 times of volumes under room temperature, filter, steam ether under the normal pressure, obtain 13.3g dextrorotation β-N, N-dimethylamino phenylpropionic acid, fusing point mp are 22～23 ℃.
4, dextrorotation β-N, the preparation of N-dimethylamino phenylpropyl alcohol
In the three-necked bottle of the stirring of 250ml band, interior Sheng 150ml dichlorobenzene, add 17g dextrorotation β-N, N-dimethylamino phenylpropionic acid and 30g lithium aluminum hydride, reaction is 30 hours under 60 ± 2 ℃ of conditions.After reaction finishes, solids removed by filtration, filtrate obtains buttery dextrorotation β-N, N-dimethylamino phenylpropyl alcohol 13.2g after dichlorobenzene is reclaimed in evaporation under the 680mmHg pressure.
5, dextrorotation N, the preparation of N-dimethyl-α-[2-(naphthyloxy) ethyl] benzene methanamine
With 18g dextrorotation N, N-dimethylamino phenylpropyl alcohol and 25g α-Xiu Dainai are dissolved in the 200ml dichlorobenzene, under 86 ± 2 ℃ of temperature, reaction is 21 hours in the 250ml three-necked bottle, constantly have bromize hydrogen gas to produce in the reaction process, control vacuum tightness is in bromize hydrogen gas suction withdrawing can, hydrogen bromide content in dichlorobenzene solution is lower than 0.5%, and reaction finishes.Reaction solution is cooled to 5 ℃, is incubated 2 hours after-filtration, filter cake washs with a small amount of anhydrous methanol, obtains dextrorotation N after the drying, N-dimethyl-α-[2-(naphthyloxy) ethyl] benzene methanamine.
6, S-(+)-N, the preparation of N-dimethyl-α-[2-(naphthyloxy) ethyl] benzene methanamine vitriol
With 15g dextrorotation N, N-dimethyl-α-[2-(naphthyloxy) ethyl] benzene methanamine adding fills in the 200ml95% alcoholic acid 250ml three-necked bottle, add 30% sulphuric acid soln of 45ml, back flow reaction 30 minutes is cooled to 40 ± 1 ℃, drip 40%NaOH solution, the pH=3 of regulator solution～4 are cooled to 10 ℃, are incubated 30 minutes after-filtration, filter cake is with 95% washing with alcohol two times, till washing lotion neutrality.Behind the filtration cakes torrefaction, obtain S-(+)-N, N-dimethyl-α-[2-(naphthyloxy) ethyl] benzene methanamine sulphate finished product 14.7g.
Embodiment 4:
S-(+)-N, the preparation of N-dimethyl-α-[2-(naphthyloxy) ethyl] benzene methanamine tartrate
1, the preparation of dextrorotation beta-amino phenylpropionic acid
13g phenyl aldehyde, 14.2g propanedioic acid and the adding of 8g amine acetate are filled in the 250ml three-necked bottle of 120ml tetrahydrofuran (THF), stir, back flow reaction is 15 hours under 96 ℃ of temperature, after reaction finishes, add the anhydrous tartrate of 21g dextrorotation, back flow reaction 14 hours, after reaction finishes, drip pH=3～3.5 of 15% hydrochloric acid conditioning solution, add the 0.2g gac in 50 ℃ and stirred 30 minutes, filtered while hot, filtrate is regulated pH=7.2 with 10% sodium hydroxide solution under room temperature, be chilled to room temperature and filter, obtain dextrorotation beta-amino phenylformic acid.
2, dextrorotation β-N, the preparation of N-dimethylamino phenylpropyl alcohol
In the three-necked bottle that the 250ml band stirs, add 150mlDMF and 15g dextrorotation beta-amino phenylpropionic acid, in 15 ℃ of 30% decil alcoholic solutions that add 15g, in 22 ± 1 ℃ of reactions 6 hours.After reaction finishes, add the 30g lithium aluminum hydride, in 60 ℃ ± 2 ℃ reactions 18 hours.After reaction finishes, filtered while hot, filtrate boils off DMF, obtains 12.0g β-N, N-dimethylamino phenylpropyl alcohol.
3, S-(+)-N, the preparation of N-dimethyl-α-[2-(naphthyloxy) ethyl] benzene methanamine tartrate
With 18g dextrorotation N, N-dimethylamino phenylpropyl alcohol and 22g α-Xiu Dainai are dissolved in the chlorobenzene of 180ml, in 95 ℃ ± 1 ℃ reaction 12 hours, after reaction finishes, extract hydrogen bromide with vacuum pump, and hydrogen bromide concentration boils off chlorobenzene below 0.5% to the solution.The industrial alcohol that adds 200ml, stir and add 16g tartrate down, back flow reaction 15 minutes, be chilled to room temperature, drip 40% sodium hydroxide solution again, regulate pH=5～6, be chilled to 0 ℃ of filtration, filter cake is washed till neutrality with 95% ethanol, obtains S-(+)-N, N-dimethyl-α-[2-(naphthyloxy) ethyl] benzene methanamine tartrate finished product 17.2g.
Dextrorotation α-[2-(naphthyloxy) ethyl] benzenemethanamine derivatives is with oral preparations during use as the medicine that prolongs the male ejaculation time, comprises that tablet, capsule, oral liquid are employed, and using dosage is 20～200mg/ time.When the above-mentioned preparation of preparation, vehicle, disintegrating agent, binding agent, correctives, weighting agent be should be aided with, starch, dextrin, Microcrystalline Cellulose, HPMC, Walocel MT 20.000PV, the fine brilliant element of ethyl, methylcellulose gum, Potenlini, protein sugar, fructose etc. comprised.
Application examples 1:
Use following composition and prepare tablet (in per ten thousand):
S-(+) N, N-dimethyl-α-[2-(naphthyloxy) ethyl] benzene methanamine hydrochloride 1kg
Vltra tears 1.2kg
Zulkovsky starch 2.2kg
Microcrystalline Cellulose 1kg
Dextrin 0.3kg
Protein sugar 0.01kg
Lactose 0.5kg
Amount to 6.11kg.
Application examples 2:
Use following composition and prepare capsule (in per ten thousand hard capsule, No. 1 capsule dress):
S-(+) N, N-diethyl-α-[2-(naphthyloxy) ethyl] benzene methanamine oxalic salt 0.5kg
Starch 1.5kg
Dextrin 0.55kg
Amount to 2.55kg.
Application examples 3:
Use following composition and prepare oral liquid (every bottle of 20ml):
S-(+) N, N-dimethyl-α-[2-(naphthyloxy) ethyl] benzene methanamine tartrate 30mg
Lactic acid 0.1mg
Fructose 0.01kg
Water 15ml
Amount to 20ml.
Claims (9)
1, the method for dextrorotation α-[2-(naphthyloxy) ethyl] benzenemethanamine derivatives of a kind of preparation general formula (I) expression,
In the formula, R
1And R
2Be methyl or ethyl independently of one another,
Comprise the compound that makes general formula (II) expression,
In the formula, R
1And R
2Definition the same, with α-Xiu Dainai reaction, it is characterized in that,
Make the reaction of phenyl aldehyde and propanedioic acid and ammonium acetate, obtain the beta-amino phenylpropionic acid, after the anhydrous tartrate of dextrorotation splits, obtain dextrorotation beta-amino phenylpropionic acid, the compound with general formula (III) expression reacts again,
In the formula, R
1And R
2Definition the same, obtain the compound of general formula (IV) expression,
In the formula, R
1And R
2Definition the same;
The compound of general formula (IV) expression restores the compound that is converted into general formula (II) expression.
2, the method for preparing dextrorotation α-[2-(naphthyloxy) ethyl] benzenemethanamine derivatives according to claim 1 is characterized in that dextrorotation α-[2-(naphthyloxy) ethyl] benzenemethanamine derivatives of preparation further is converted into sour additive salt.
3, the method for preparing dextrorotation α-[2-(naphthyloxy) ethyl] benzenemethanamine derivatives according to claim 1, it is characterized in that phenyl aldehyde and propanedioic acid and amine acetate according to 1: 0.8～1.3: 0.7～1.3 mol ratio, under 30～150 ℃ temperature, react preparation beta-amino phenylpropionic acid.
4, the method for preparing dextrorotation α-[2-(naphthyloxy) ethyl] benzenemethanamine derivatives according to claim 1, it is characterized in that beta-amino phenylpropionic acid DL body and the anhydrous tartrate of dextrorotation are reacted in anhydrous solvent with 1: 0.75～1.4 mol ratio, split and obtain dextrorotation beta-amino phenylpropionic acid.
5, the method for preparing dextrorotation α-[2-(naphthyloxy) ethyl] benzenemethanamine derivatives according to claim 4 is characterized in that described anhydrous solvent is Virahol, methyl alcohol or ethanol, preferred Virahol.
6, the method for preparing dextrorotation α-[2-(naphthyloxy) ethyl] benzenemethanamine derivatives according to claim 1 is characterized in that the compound of dextrorotation beta-amino phenylpropionic acid and general formula (III) expression prepares the compound of general formula (IV) expression according to 1: 0.75～1.35 molar ratio reaction.
7, the method for preparing dextrorotation α-[2-(naphthyloxy) ethyl] benzenemethanamine derivatives according to claim 1, it is characterized in that making the compound and the lithium aluminum hydride of general formula (IV) expression in non-polar solvent, to react the compound of synthetic general formula (II) expression according to 1: 0.9～1.1 mol ratio.
8, the method for preparing dextrorotation α-[2-(naphthyloxy) ethyl] benzenemethanamine derivatives according to claim 7 is characterized in that described non-polar solvent is a kind of in dichlorobenzene, chloroform, chlorobenzene, benzene, the dimethyl formamide.
9, the method for preparing dextrorotation α-[2-(naphthyloxy) ethyl] benzenemethanamine derivatives according to claim 1, the compound that it is characterized in that general formula (II) expression and α-Xiu Dainai obtain the compound that general formula (I) is represented according to 1: 0.85～1.2 molar ratio reaction.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510012624 CN1279018C (en) | 2005-06-22 | 2005-06-22 | Method for preparing dextroa-[2-(naphthoxy, ethyl] phenyl methylamine derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510012624 CN1279018C (en) | 2005-06-22 | 2005-06-22 | Method for preparing dextroa-[2-(naphthoxy, ethyl] phenyl methylamine derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1709859A true CN1709859A (en) | 2005-12-21 |
| CN1279018C CN1279018C (en) | 2006-10-11 |
Family
ID=35706155
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200510012624 Expired - Fee Related CN1279018C (en) | 2005-06-22 | 2005-06-22 | Method for preparing dextroa-[2-(naphthoxy, ethyl] phenyl methylamine derivatives |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1279018C (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008035358A3 (en) * | 2006-06-05 | 2008-05-15 | Cadila Healthcare Ltd | Process for preparing dapoxetine |
| CN101875666A (en) * | 2010-07-28 | 2010-11-03 | 爱斯特（成都）医药技术有限公司 | Optical pure 1,3-alkamine compound as well as preparation method and application thereof in preparing Dapoxetine and analogues thereof |
| US8546615B2 (en) | 2009-11-13 | 2013-10-01 | Symed Labs Limited | Solid dapoxetine |
| CN109456211A (en) * | 2018-11-06 | 2019-03-12 | 康化（上海）新药研发有限公司 | A method of synthesis (R) -3- amino -3- (2- nitrobenzophenone) propionic acid |
| CN113877543A (en) * | 2021-11-03 | 2022-01-04 | 上海工程技术大学 | Chiral metal organic framework functionalized composite material and preparation method and application thereof |
-
2005
- 2005-06-22 CN CN 200510012624 patent/CN1279018C/en not_active Expired - Fee Related
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008035358A3 (en) * | 2006-06-05 | 2008-05-15 | Cadila Healthcare Ltd | Process for preparing dapoxetine |
| US8546615B2 (en) | 2009-11-13 | 2013-10-01 | Symed Labs Limited | Solid dapoxetine |
| CN101875666A (en) * | 2010-07-28 | 2010-11-03 | 爱斯特（成都）医药技术有限公司 | Optical pure 1,3-alkamine compound as well as preparation method and application thereof in preparing Dapoxetine and analogues thereof |
| CN101875666B (en) * | 2010-07-28 | 2011-12-28 | 爱斯特（成都）医药技术有限公司 | Optical pure 1,3-alkamine compound as well as preparation method and application thereof in preparing Dapoxetine and analogues thereof |
| CN109456211A (en) * | 2018-11-06 | 2019-03-12 | 康化（上海）新药研发有限公司 | A method of synthesis (R) -3- amino -3- (2- nitrobenzophenone) propionic acid |
| CN113877543A (en) * | 2021-11-03 | 2022-01-04 | 上海工程技术大学 | Chiral metal organic framework functionalized composite material and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1279018C (en) | 2006-10-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1119319C (en) | Asymmetric synthesis of (-) 6 -chloro-4-cyclopropyl-ethynyl-4-trifluoromethyl-1, 4dihydro-2H-3, 1-benzoxazin-2-one | |
| CN1308603A (en) | Phenoxyacetic acid derivatives and medicinal compositions containing the same | |
| CN1680284A (en) | New process for the synthesis and new crystalline form of agomelatine and pharmaceutical compositions containing it | |
| CN101062897A (en) | Improved process for preparing 2,3-dihydro-1H-indenes-1-amine and derivative thereof | |
| CN101039917A (en) | Process for preparing telmisartan | |
| CN1279018C (en) | Method for preparing dextroa-[2-(naphthoxy, ethyl] phenyl methylamine derivatives | |
| CN1658861A (en) | Novel formate salt of o-desmethyl-venlafaxine | |
| CN104672124B (en) | The synthetic method of the formic acid of indoline 2 of enantiomer enrichment | |
| JP2009501229A (en) | Highly selective serotonin and norepinephrine double reuptake inhibitors and uses thereof | |
| CN1090633C (en) | Chlorophyll alpha degraded product metal complex, its preparation method and medicament for anti-gastric ulcer | |
| CN1578762A (en) | Process for resolution of tamsulosin and compounds, compositons, and processes associated therewith | |
| CN112441938B (en) | Method for synthesizing lidocaine hydrochloride | |
| TW201002668A (en) | Preparing method of repaglinide | |
| CN1279019C (en) | Processes for the production of alpha-difluoromethyl ornithine (DFMO) | |
| CN1145613C (en) | Cathecol hydrazone derivatives, process for preparing the same and pharmaceutical composition containing the same | |
| CN110759914A (en) | Preparation method of medicine for treating diabetes | |
| CN100345848C (en) | Leavo halogenated salt and its preparation process and use | |
| CN1173968C (en) | Production method of halogenated hexahydroxydiphenic derivative and its medicinal application | |
| CN107698595A (en) | Preparation method of tofacitinib citrate substance | |
| CN111170847B (en) | Novel method for preparing drotaverine hydrochloride intermediate | |
| CN107382813B (en) | synthesis method of key intermediate of glimepiride | |
| CN1217953C (en) | Buxanines compounds with cardiovascular activity and cardiovascular and cerebrovascular medicine using them as active component | |
| CN104370769B (en) | A kind of method for preparing hydroxyadamantane glycine derivative | |
| CN109232434A (en) | A kind of new method synthesizing flibanserin | |
| CN113277980B (en) | Tolvaptan impurity and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C19 | Lapse of patent right due to non-payment of the annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |