CN100584839C - Method for producing (S)-(+)-N,N-dimethyl-3-(1-naphthoxy)-3-(2-thienyl)propanamine - Google Patents
Method for producing (S)-(+)-N,N-dimethyl-3-(1-naphthoxy)-3-(2-thienyl)propanamine Download PDFInfo
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- CN100584839C CN100584839C CN200810052237A CN200810052237A CN100584839C CN 100584839 C CN100584839 C CN 100584839C CN 200810052237 A CN200810052237 A CN 200810052237A CN 200810052237 A CN200810052237 A CN 200810052237A CN 100584839 C CN100584839 C CN 100584839C
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Abstract
The invention discloses a preparation method for (S)-(plus)-N, N-dimethyl-3-(1- naphthoxy)-3-(2-thienyl) propylamine: mixing (S)-(-)-N, N-dimethyl-3- oxhydryl-3-(2-thienyl) propylamine with sodium hydride in an organic solvent, adding sylvine with a granularity less than 200 mesh to evenly mix, then adding 1-fluoronaphthalene for a plurality of times to react for 2 to 4 hours at a temperature of 55-70 DEG C, lowering the temperature after the reaction is over, adjusting the pH value by acid, adding ethyl acetate to extract, abandoning a fat phrase and keeping an aqueous phase, adjusting the pH of the aqueous phase to alkalinity, extracting a plurality of times with one of the normal paraffin hydrocarbon among C5 to C10 at a temperature of 10 to 25 DEG C, combining an organic horizon extracted by the normal paraffin hydrocarbon, and steaming out the normal paraffin hydrocarbon after washing, drying, filtrating and depressurizing to acquire a brown viscous product. The purity of the high pressure liquid chromatography of the product is about 99 percent; the product can be directly applied to duloxetine synthesis, which cuts off a salt formation purification method, simplifies the technology and reduces the cost.
Description
Technical field
The present invention relates to a kind of (S)-(+)-N, the preparation method of N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine, especially with (S)-(-)-N, N-dimethyl-3-hydroxyl-3-(2-thienyl) propylamine (S-first thiophene alcohol) is a raw material, preparation duloxetine hydrochloride raw material midbody (S)-(+)-N, the preparation method of N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine.
Background technology
At the sickness rate of the lifelong dysthymia disorders of western developed country between 6 ~ 8%, it is predicted 2008, these national dysthymia disorders sickness rate are up to 20 ~ 30%, the analyst thinks, domestic antidepressant drug market is just approaching with the characteristics in the antidepressant drug market of the main developed country of America and Europe, domestic spiritual class disease is in rising trend to be about to enter aging society with China, and the potentiality in antidepressant drug market can be quite big.Duloxetine is mainly used in the treatment of dysthymia disorders.Meanwhile, duloxetine also is developed to the medicine for treatment of stress urinary incontinence and diabetes type neuralgia.Duloxetine is developed by Lilly Co., Eli., and its commodity are called Cymbalta (enteric piller glue Nang).Send in one's application at FDA in calendar year 2001, on August 4th, 2004, FDA has ratified this launch, and Cymbalta is mainly used in the treatment of dysthymia disorders.Meanwhile, duloxetine also is developed to the medicine for treatment of stress urinary incontinence and diabetes type neuralgia.In November, 2002, gift comes and Boehringer Ingelheim is formed business alliance, promotes duloxetine jointly.In Europe, the trade(brand)name of duloxetine is Yentreve/Ariclaim, and it is approved for the treatment of the peripheral neuralgia of stress urinary incontinence and maturity-onset diabetes secondary in August, 2004.
First naphthalene thiophene amine ((S)-(+)-N, N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine, formula as follows) is the key intermediate of antidepressant new drug " duloxetine hydrochloride " (synthetic route is the side as follows), is an organic alkaloids.It is synthetic by (S)-(-)-N, and N-dimethyl-3-hydroxyl-3-(2-thienyl) propylamine (S-first thiophene alcohol) and 1-fluoronaphthalene make in the alkaline condition reaction.From alkaline reactant, obtain purity first naphthalene thiophene amine preferably, bibliographical information (US patent 5,362,886 1994, EP0457 559 A2 1991) method is, under alkaline condition, with organic solvents such as ethyl acetate or methylene dichloride it is proposed, extract purity: high pressure liquid chromatography purity is about 85%, and yield is about 80%, and it is synthetic that extract can not be directly used in duloxetine.Then change into phosphoric acid salt or oxalate etc. to its purifying, transferring first naphthalene thiophene amine through alkalizing again to, can be used for synthetic duloxetine.
First naphthalene thiophene amine
Synthetic route:
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of (S)-(+)-N, the preparation method of N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine, the product yield height can directly apply to duloxetine and synthesize, and has sliced off the salify method of purification, simplify technology, reduced cost.
In order to solve the problems of the technologies described above, the technical solution used in the present invention is: a kind of (S)-(+)-N, the preparation method of N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine, may further comprise the steps: with (S)-(-)-N, N-dimethyl-3-hydroxyl-3-(2-thienyl) propylamine mixes with sodium hydride in organic solvent, add granularity less than 200 purpose sylvite, mix, add the 1-fluoronaphthalene then several times, 55-70 ℃ of reaction 2～4 hours, reaction finished the back cooling, use acid for adjusting pH value, add ethyl acetate extraction, give up oil phase and keep water, water pH regulator alkalize, carry out multiple extraction at 10～25 ℃ with a kind of normal alkane among C5～C10, merge the organic layer that normal alkane is extracted, through washing, dry, filter, decompression steams normal alkane etc., gets brown thickness product.
Described (S)-(-)-N, the mol ratio of N-dimethyl-3-hydroxyl-3-(2-thienyl) propylamine and 1-fluoronaphthalene is 1: 1.0-1.2, the 1-fluoronaphthalene adds at twice, add for the first time 75-82%, in 55-70 ℃ of reaction 2 hours, add the 1-fluoronaphthalene of remaining 18-25% again, continue reaction 1-2 hour.
Described sylvite is potassium benzoate.
Transfer reactant PH=4.4-5.0 with concentrated hydrochloric acid, it is constant to stir 5-15 minute pH value.
Water is transferred pH=9.5-10.5 with sodium hydroxide, carries out multiple extractionly with a kind of in C5～C10 normal alkane at 10-20 ℃, and each extraction all need effectively be stirred 5-15 minute.
Described water is transferred pH=10.25 with 40% sodium hydroxide, 10-20 ℃ with a kind of extractions in C5～C10 normal alkane three times, extraction all need effectively be stirred 5-15 minute at every turn.
Use no salt solution, saturated sodium-chloride water washing successively, anhydrous magnesium sulfate drying, the filtering siccative, decompression steams normal alkane.
The invention has the beneficial effects as follows:
1, preparation method of the present invention, according to first naphthalene thiophene amine and raw materials used " S-first thiophene alcohol " and the different solvabilities of relative substance in the saturated hydrocarbons organic solvent, adopt at a lower temperature, from alkaline reactant, extract first naphthalene thiophene amine with a kind of normal alkane among C5～C10, products therefrom " first naphthalene thiophene amine " high pressure liquid chromatography purity is about 99%, obviously is better than organic solvent extract purity (high pressure liquid chromatography purity about 85%) such as ethyl acetate.Do not need salify purifying again, it is synthetic to be directly applied for duloxetine.
2, preparation method of the present invention, in first naphthalene thiophene amine synthetic reaction process that raw material " 1-fluoronaphthalene " gradation is reinforced, impel another raw material " S-first thiophene alcohol " to react to greatest extent.
3, preparation method of the present invention, used benzene feedstock potassium formiate granularity little (crossing 200 mesh sieves) in order to keep chirality is so that react completely.
Preparation method's products therefrom of the present invention " first naphthalene thiophene amine " stable yield reaches (HPLC purity 98.5-99.50%, yield 94.5-97.0%) more than 90%.Be higher than bibliographical information yield (about 80%).Its high pressure liquid chromatography purity is about 99%, and it is synthetic to directly apply to duloxetine, has sliced off the salify method of purification, has simplified technology, has reduced cost.
Embodiment
To the present invention (S)-(+)-N, the preparation method of N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine is described in further detail below in conjunction with specific embodiment:
The present invention (S)-(+)-N, the preparation method of N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine, may further comprise the steps: with (S)-(-)-N, N-dimethyl-3-hydroxyl-3-(2-thienyl) propylamine mixes with sodium hydride in organic solvent, add granularity less than 200 purpose sylvite, mix, add the 1-fluoronaphthalene then several times, 55-70 ℃ of reaction 2～4 hours, reaction finishes the back cooling, uses acid for adjusting pH value, adds ethyl acetate extraction, give up oil phase and keep water, with water pH regulator alkalize, carry out multiple extractionly with a kind of normal alkane among C5～C10 at 10～25 ℃, merge the organic layer that normal alkane is extracted, through washing, dry, filter, decompression steams normal alkane etc., gets brown thickness product.
Described (S)-(-)-N, the mol ratio of N-dimethyl-3-hydroxyl-3-(2-thienyl) propylamine and 1-fluoronaphthalene is 1: 1.0-1.2, the 1-fluoronaphthalene adds at twice, add for the first time 75-82%, in 55-70 ℃ of reaction 2 hours, add the 1-fluoronaphthalene of remaining 18-25% again, continue reaction 1-2 hour.
Described sylvite is potassium benzoate.
Transfer reactant PH=4.4-5.0 with concentrated hydrochloric acid, it is constant to stir 5-15 minute pH value.
Water is transferred pH=9.5-10.5 with sodium hydroxide, carries out multiple extractionly with a kind of in C5～C10 normal alkane at 10-20 ℃, and each extraction all need effectively be stirred 5-15 minute.
Described water is transferred pH=10.25 with 40% sodium hydroxide, 10-20 ℃ with a kind of extractions in C5～C10 normal alkane three times, extraction all need effectively be stirred 5-15 minute at every turn.
Use no salt solution, saturated sodium-chloride water washing successively, anhydrous magnesium sulfate drying, the filtering siccative, decompression steams normal alkane.
Embodiment 1
Stirring is being housed, thermometer, the top is furnished with CaCl
2The reflux exchanger of drying tube in the 1000ml four-hole bottle of dried and clean, adds 32g S-first thiophene alcohol, the 256ml dimethyl sulfoxide (DMSO).Stir, at 25 ℃, the sodium hydride gradation with 8.32g content 60% in 0.5 hour adds, synthermal stirring down 20 minutes.Add 2.72g (crossing 200 mesh sieves) potassium benzoate, continue to stir 10 minutes.Then add 30.0g 1-fluoronaphthalene, in 55 ℃ of reactions two hours.Add 11.0g 1-fluoronaphthalene again, continue reaction 1.0 hours.Cooling is poured reactant in the 1024ml water into, transfers reactant PH=4.4 with concentrated hydrochloric acid, stirs 5 minutes, and pH value is constant, extracts once with ethyl acetate 400ml, need effectively stir 10 minutes.Layering, water layer is transferred PH=9.5 with 40% sodium hydroxide, at 10 ℃ with Skellysolve A 320ml * 2,240ml extracts, and each extraction all need effectively be stirred 5 minutes, merged the organic layer that Skellysolve A extracts, with no salt solution 240ml, saturated sodium-chloride water 240ml washs, anhydrous magnesium sulfate drying successively.Filtering siccative then, siccative are with Skellysolve A washing three times, and washings merges, and decompression steams Skellysolve A, brown dope 51.9g, HPLC purity 98.5.0%, yield 94.5%.
Embodiment 2
Stirring is being housed, thermometer, the top is furnished with CaCl
2The reflux exchanger of drying tube in the 1000ml four-hole bottle of dried and clean, adds 32g S-first thiophene alcohol, the 256ml dimethyl sulfoxide (DMSO).Stir, at 27 ℃, the sodium hydride gradation with 8.32g content 60% in 0.8 hour adds, synthermal stirring down 20 minutes.Add 2.72g (crossing 200 mesh sieves) potassium benzoate, continue to stir 10 minutes.Then add 31.0g 1-fluoronaphthalene, in 60 ℃ of reactions two hours.Add 10.5g 1-fluoronaphthalene, continuing reaction 1.2 hours.Cooling is poured reactant in the 1024ml water into, transfers reactant PH=4.7 with concentrated hydrochloric acid, stirs 10 minutes, and pH value is constant, extracts once with ethyl acetate 400ml, need effectively stir 10 minutes.Layering, water layer is transferred PH=10.25 with 40% sodium hydroxide, at 13 ℃ with normal hexane 320ml * 2,240ml extracts, and each extraction all need effectively be stirred 10 minutes, merged the organic layer of normal hexane extraction, with no salt solution 240ml, saturated sodium-chloride water 240ml washs, anhydrous magnesium sulfate drying successively.Filtering siccative then, siccative are with normal hexane washing three times, and washings merges, and decompression steams normal hexane, brown dope 51.9g, HPLC purity 99.4%, yield 96.2%.
Embodiment 3
Stirring is being housed, thermometer, the top is furnished with CaCl
2The reflux exchanger of drying tube in the 1000ml four-hole bottle of dried and clean, adds 32g S-first thiophene alcohol, the 256ml dimethyl sulfoxide (DMSO).Stir, at 28 ℃, the sodium hydride gradation with 8.32g content 60% in 0.8 hour adds, synthermal stirring down 28 minutes.Add 2.72g (crossing 200 mesh sieves) potassium benzoate, continue to stir 13 minutes.Then add the 32.0g1-fluoronaphthalene, in 62 ℃ of reactions two hours.Add 9.0g 1-fluoronaphthalene, continuing reaction 1.4 hours.Cooling is poured reactant in the 1024ml water into, transfers reactant PH=4.7 with concentrated hydrochloric acid, stirs 10 minutes, and pH value is constant, extracts once with ethyl acetate 400ml, need effectively stir 14 minutes.Layering, water layer is transferred PH=10.2 with 40% sodium hydroxide, 15 ℃ with normal heptane 320ml * 2,240ml extracts, each extraction all need effectively be stirred 10 minutes.The organic layer that merges normal heptane extraction, successively with no salt solution 240ml, saturated sodium-chloride water 240ml washing, anhydrous magnesium sulfate drying.Filtering siccative then, siccative are with normal heptane washing three times, and washings merges, and decompression steams normal heptane, brown dope 51.9g, HPLC purity 99.3%, yield 96.1%.
Embodiment 4
Stirring is being housed, thermometer, the top is furnished with CaCl
2The reflux exchanger of drying tube in the 1000ml four-hole bottle of dried and clean, adds 32g S-first thiophene alcohol, the 256ml dimethyl sulfoxide (DMSO).Stir, at 30 ℃, the sodium hydride gradation with 8.32g content 60% in 1 hour adds, synthermal stirring down 30 minutes.Add 2.72g (crossing 200 mesh sieves) potassium benzoate, continue to stir 15 minutes.Then add 32.5g 1-fluoronaphthalene, in 60-65 ℃ of reaction two hours.Add 8.5g 1-fluoronaphthalene, continuing reaction 1.5 hours.Cooling is poured reactant in the 1024ml water into, transfers reactant PH=4.75 with concentrated hydrochloric acid, stirs 10 minutes, and pH value is constant, extracts once with ethyl acetate 400ml, need effectively stir 10-15 minute.Layering, water layer is transferred PH=10.25 with 40% sodium hydroxide, 15 ℃ with octane 320ml * 2,240ml extracts, each extraction all need effectively be stirred 10 minutes.The organic layer that merges n-octane extraction, successively with no salt solution 240ml, saturated sodium-chloride water 240ml washing, anhydrous magnesium sulfate drying.Filtering siccative then, siccative are with octane washing three times, and washings merges, and decompression steams octane, brown dope 51.9g, HPLC purity 99.4%, yield 96.0%.
Embodiment 5
Stirring is being housed, thermometer, the top is furnished with CaCl
2The reflux exchanger of drying tube in the 1000ml four-hole bottle of dried and clean, adds 32g S-first thiophene alcohol, the 256ml dimethyl sulfoxide (DMSO).Stir, at 30 ℃, the sodium hydride gradation with 8.32g content 60% in 1.5 hours adds, synthermal stirring down 35 minutes.Add 2.72g (crossing 200 mesh sieves) potassium benzoate, continue to stir 20 minutes.Then add 32.8g 1-fluoronaphthalene, in 65 ℃ of reactions two hours.Add 8.0g 1-fluoronaphthalene, continuing reaction 1.5 hours.Cooling is poured reactant in the 1024ml water into, transfers reactant PH=4.75 with concentrated hydrochloric acid, stirs 15 minutes, and pH value is constant, extracts once with ethyl acetate 400ml, and each extraction all need effectively be stirred 15 minutes.Layering, water layer is transferred PH=10.25 with 40% sodium hydroxide, 15 ℃ with positive nonane 320ml * 2,240ml extracts, each extraction all need effectively be stirred 15 minutes.Merge the organic layer that positive nonane extracts, successively with no salt solution 240ml, saturated sodium-chloride water 240ml washing, anhydrous magnesium sulfate drying.Filtering siccative then, siccative are with positive nonane washing three times, and washings merges, and decompression steams positive nonane, brown dope 51.9g, HPLC purity 99.30%, yield 96.0%.
Embodiment 6
Stirring is being housed, thermometer, the top is furnished with CaCl
2The reflux exchanger of drying tube in the 1000ml four-hole bottle of dried and clean, adds 32g S-first thiophene alcohol, the 256ml dimethyl sulfoxide (DMSO).Stir, at 40 ℃, the sodium hydride gradation with 8.32g content 60% in 1 hour adds, synthermal stirring down 30 minutes.Add 2.72g (crossing 200 mesh sieves) potassium benzoate, continue to stir 15 minutes.Then add 33.0g 1-fluoronaphthalene, in 65 ℃ of reactions two hours.Add 8g 1-fluoronaphthalene, continuing reaction 2 hours.Cooling is poured reactant in the 1024ml water into, transfers reactant PH=4.75 with concentrated hydrochloric acid, stirs 20 minutes, and pH value is constant, extracts once with ethyl acetate 400ml, need effectively stir 15 minutes.Layering, water layer is transferred PH=10.25 with 40% sodium hydroxide, 20 ℃ with n-decane 320ml * 2,240ml extracts, each extraction all need effectively be stirred 15 minutes.Merge the organic layer that n-decane extracts, successively with no salt solution 240ml, saturated sodium-chloride water 240ml washing, anhydrous magnesium sulfate drying.Filtering siccative then, siccative are with n-decane washing three times, and washings merges, and decompression steams n-decane, brown dope 51.9g, HPLC purity 99.3%, yield 96.0%.
In sum, the present invention is to the mensuration of the profit partition ratio of duloxetine hydrochloride raw material midbody " first naphthalene thiophene amine " ((s) (+)-N.N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine), and optimizing with the normal alkane among C5～C10 is that solvent is 20 ℃ of technologies of extracting first naphthalene thiophene amine in alkaline reactant.Regulate pH with salt acid substitution acetic acid, hydrochloric acid is more cheap, and consumption is few, and the yield and the quality that obtain first naphthalene thiophene amine after the replacement do not change.With the 2-acetyl thiophene is starting raw material and Paraformaldehyde 96, and Dimethylammonium chloride carries out Mannich and reacts to such an extent that 3-dimethylamino-1-(2-thienyl) acetone hydrochloride (being called for short the first thienone) finally obtains duloxetine under acidic conditions.
Among the embodiment that content of the present invention is not confined to, the knowledgeable people in the same area can propose other embodiment easily within technical director's thought of the present invention, but this embodiment comprises within the scope of the present invention.
Claims (7)
1, a kind of (S)-(+)-N, the preparation method of N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine, may further comprise the steps: with (S)-(-)-N, N-dimethyl-3-hydroxyl-3-(2-thienyl) propylamine mixes with sodium hydride in organic solvent, add granularity less than 200 purpose sylvite, mix, add the 1-fluoronaphthalene then several times, 55-70 ℃ of reaction 2～4 hours, reaction finishes the back cooling, uses acid for adjusting pH value, adds ethyl acetate extraction, give up oil phase and keep water, with water pH regulator alkalize, carry out multiple extractionly with a kind of in C5～C10 normal alkane at 10～25 ℃, merge the organic layer that this normal alkane is extracted, through washing, dry, filter, decompression steams normal alkane, gets brown thickness product.
2, (S)-(+) according to claim 1-N, the preparation method of N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine, it is characterized in that, described (S)-(-)-N, the mol ratio of N-dimethyl-3-hydroxyl-3-(2-thienyl) propylamine and 1-fluoronaphthalene is 1: 1.0-1.2, the 1-fluoronaphthalene adds at twice, add for the first time 75-82%, in 55-70 ℃ of reaction 2 hours, add the 1-fluoronaphthalene of remaining 18-25% again, continue reaction 1-2 hour.
3, (S)-(+) according to claim 1-N, the preparation method of N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine is characterized in that described sylvite is potassium benzoate.
4, (S)-(+) according to claim 1-N, the preparation method of N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine is characterized in that, transfers reactant pH=4.4-5.0 with concentrated hydrochloric acid, stirs 5-15 minute, the pH value is constant.
5, (S)-(+) according to claim 1-N, the preparation method of N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine, it is characterized in that, water is transferred pH=9.5-10.5 with sodium hydroxide, carry out multiple extractionly with a kind of in C5～C10 normal alkane at 10-20 ℃, each extraction all need effectively be stirred 5-15 minute.
6, (S)-(+) according to claim 5-N, the preparation method of N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine, it is characterized in that, described water is transferred pH=10.25 with 40% sodium hydroxide, 10-20 ℃ with a kind of extraction in C5～C10 normal alkane three times, each extraction all need effectively be stirred 5-15 minute.
7, (S)-(+) according to claim 1-N, the preparation method of N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine is characterized in that, successively with no salt solution, saturated sodium-chloride water washing, anhydrous magnesium sulfate drying, the filtering siccative, decompression steams normal alkane.
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