CN104496830A - Dapoxetine hydrochloride synthetic method - Google Patents
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Abstract
The invention provides a dapoxetine hydrochloride synthetic method. The method includes the steps of (1) subjecting a compound (9) and (-)-beta-chlorodiisopinocampheylborane to reduction reaction in an organic solvent at the temperature of 10 DEG C-80 DEG C to obtain a compound (12); (2) subjecting a compound (8) and alkali to reaction in an organic solvent for 2 hours-14 hours at the temperature of 0 DEG C-10 DEG C, adding the compound (12) obtained in step (1), and performing alkylation reaction for 15 hours-40 hours at the temperature of 0 DEG C-10 DEG C to obtain a compound (13); (3) subjecting the compound (13) obtained in step (2) and thionyl chloride to reaction in an organic solvent at the temperature of -10 DEG C-0 DEG C to obtain a compound (14); (4) subjecting the compound (14) obtained in step (3) and dimethylamine to reaction in an organic solvent at the temperature of 20 DEG C-30 DEG C to obtain dapoxetine free amine and to reaction with an ethanol solution of hydrogen chloride to obtain hydrochloric acid dapoxetine. The dapoxetine hydrochloride synthetic method is high in yield and product optical purity. The reaction scheme is shown in the description.
Description
Technical field
The present invention relates to small-molecule chemical pharmaceutical formulating art, relate more specifically to a kind of synthetic method of dapoxetine hydrochloride.
Background technology
Dapoxetine (Dapoxetine, LY-210448), chemistry (S)-N by name, N-dimethyl-3-(1-naphthyloxy)-1-phenyl-1-propylamine, originally be a kind of selectivity serotonin reuptake inhibithors being used for Cure of depression, but it is evident in efficacy that relevant medical clinical testing data shows its treatment prospermia of males, has very wide market outlook, use its hydrochloride clinically.First in February, 2009 in European Finland and Sweden's listing, for the treatment as required of man's premature ejaculation, become the new drug improving prospermia of males.Clinical study results shows, dapoxetine can suppress the re-uptake of compound amine in blood rapidly, direct effect is not had to neuronal acceptor and the transformation period short, act on rapider, untoward reaction rate is lower, can effectively control to send out in the premature ejaculation symptom of young men.
The route of current bibliographical information synthesis dapoxetine is as follows:
(1) people such as Yin Lingli utilizes 3-phenyl propanol (2) to be starting raw material, under NaH exists and 1-fluoronaphthalene through Williamson etherification reaction, the ether (4) that synthesis is corresponding.Compound 4 and NBS are obtained by reacting corresponding bromo-derivative 5.Bromo-derivative 5 and dimethylamine carry out the raceme that amination obtains dapoxetine.(+)-tartrate is resolving agent to use L-, and obtaining needs configuration (S)-dapoxetine (fractionation rate 36.5%).Last and HCl gas salify obtains its hydrochloride (Yin Lingli etc., Chinese pharmaceutical chemistry magazine, 2011,21,37-39).
(2) people such as Robertson utilizes 3-phenyl third chlorine (bromine) (7) to be starting raw material, and under KOH exists, and-naphthols is through Williamson etherification reaction, the ether (4) that synthesis is corresponding.Compound 4 and NBS are obtained by reacting corresponding bromo-derivative 5.Bromo-derivative 5 and dimethylamine carry out the raceme (6) that amination obtains dapoxetine.(+)-tartrate is resolving agent to use L-, and obtaining needs configuration (S)-dapoxetine (fractionation rate 36.5%).Last and HCl gas salify obtains its hydrochloride (Robertson, D.W., et al, EP0288188,1988).
(3) people such as Chen Pingang reports that 3-chlorophenyl acetone (9) is starting raw material, uses NaBH4 reduction to obtain 3-chlorobenzene propyl alcohol (10).Then under KOH exists, and alphanaphthol reaction obtains corresponding ether (11).Compound (G) and MsCl reaction, carry out amination with dimethylamine further and obtain racemization dapoxetine.(+)-tartrate is resolving agent to use L-, obtains (S)-dapoxetine (6, fractionation rate 32%).Last and HCl gas obtains its hydrochloride (Chen Pingang etc., CN1821212,2006).
(4) Xue great Quan etc. with 3-chlorophenyl acetone (9) for starting raw material, through NaBH4/ (S)-(-)-, the asymmetric reduction of-phenylbenzene proline(Pro)/SnCl2 obtains hand-type alcohol 12, then through Williamson etherification reaction, the ether (13) that synthesis is corresponding.Then, ether and MsCl reaction, carry out amination with dimethylamine further and obtain (S)-dapoxetine, and last and HCl gas salify obtains 1.(Xue great Quan etc., synthetic chemistry, 2010,18, p647-649).
(5) people such as Mahale with hand-type oxazaborolidine for catalyzer, at N, under N-diethylaniline-borane complex compound (DEANB) exists, asymmetric reduction is carried out to 3-chlorophenyl acetone (9), obtain hand-type alcohol 12, then through Williamson etherification reaction, the ether (13) that synthesis is corresponding.Ether 13 and MsCl reaction, carry out amination with dimethylamine further and obtain (S)-dapoxetine subsequently, and last and HCl gas salify obtains 1.(Mahale,R.D.，Org.Process Res.Dev.2012,16,710-713)。
So far, bibliographical information route existing problems are as follows: in synthetic route (1), (2) and (3), final step needs to use L-, and (+)-tartrate is that resolving agent carries out hand-type fractionation, wherein half (R)-anomeric product becomes refuse, cannot recycle, therefore the overall yield of route is lower.Synthetic route (4) needs to use SnCl
2, toxicity is comparatively large, and hand-type reductive agent part ((S)-(-)-α, α-diphenyl-2-pyrrolinemethanol) price is more expensive, and asymmetric reduction productive rate is lower.Synthetic route (5) needs to use expensive hand-type reductive agent (S)-α, α-diphenyl-2-pyrrolinol price more expensive, and cost is higher.In addition; in route (4) and (5) reaction process; need to use methylsulfonyl chloride to be used for carrying out sulfonylation to (R)-ol compound 13; reaction can produce the chloro thing of by product (S)-configuration; the chloro thing of this (S)-configuration and dimethylamine carry out amination and obtain (R)-dapoxetine, thus cause the optical purity of the finished product to reduce.Final step, uses HCl gas to carry out salify, operation and control ratio more difficult.
Summary of the invention
For overcoming the problems referred to above of the prior art, the invention provides a kind of synthetic method of dapoxetine hydrochloride, the method circuit is short, and the low and environmental friendliness of cost, is suitable for suitability for industrialized production.
The technical solution used in the present invention is:
A synthetic method for dapoxetine hydrochloride, comprises the following steps:
(1) compound (9) and (-) diisopinocampheylchloroborane base chloroborane in organic solvent, issue raw reduction reaction at 10 ~ 80 DEG C, obtain compound (12);
(2) compound (8) and alkali react 2-14 hour in organic solvent at 0 ~ 10 DEG C, then the compound (12) obtained in step (1) is added, at 0 ~ 10 DEG C, react 15-40 hour again, obtain compound (13);
(3) compound (13) obtained in step (2) and sulfur oxychloride in organic solvent, are obtained by reacting compound (14) at-10-0 DEG C; And
(4) compound (14) obtained in step (3) and dimethylamine in organic solvent, are obtained by reacting dapoxetine unhindered amina, then are obtained by reacting dapoxetine hydrochloride with the ethanolic soln of hydrogenchloride at 20 ~ 30 DEG C;
Further, in step (1), described organic solvent is selected from one or more in Isosorbide-5-Nitrae-dioxane, 2-methyltetrahydrofuran, tetrahydrofuran (THF), methyl tertiary butyl ether, toluene, normal hexane and normal heptane.
Further, in step (1), the time of described reduction reaction is 10 ~ 24 hours.
Further, in step (2), described alkylated reaction carries out under the katalysis of catalyzer, and catalyzer is potassiumiodide or tetra-n-butyl ammonium bromide.
Further, in step (2), described alkali is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium carbonate, salt of wormwood, sodium hydride, one or more in sodium ethylate, potassium tert.-butoxide, sodium tert-butoxide, triethylamine and diisopropyl ethyl amine.
Further, in step (2), described organic solvent is selected from DMF, N, N-N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, methylene dichloride, tetrahydrofuran (THF), methyl-sulphoxide, one or more in acetonitrile, methyl tertiary butyl ether and toluene.
Further, in step (3), described organic solvent is selected from tetrahydrofuran (THF), methylene dichloride, toluene, Isosorbide-5-Nitrae-dioxane, 1, one or more in 2-ethylene dichloride, methyl-sulphoxide, N-Methyl pyrrolidone, acetonitrile, methyl tertiary butyl ether and DMF.
Further, in step (3), the time of described reaction is 4 ~ 8 hours.
Further, in step (4), described organic solvent is selected from one or more in tetrahydrofuran (THF), 2-methyltetrahydrofuran, methyl tertiary butyl ether and ether.
Compared with prior art, the present invention has the following advantages: the synthetic method that the invention provides a kind of dapoxetine hydrochloride, and the method is simple and practical, high yield, and high purity obtains dapoxetine hydrochloride.This operational path is brief, and cost is lower, useful environment and be easy to suitability for industrialized production.Advantage is specific as follows: 1, present method uses low-cost (-) diisopinocampheylchloroborane base chloroborane [(-)-DIPCl] (200 yuan/kg) to be reductive agent, asymmetric reduction is carried out to 3-chlorophenyl acetone, high yield, high selection obtains hand-type alcohol (chemical purity and optical purity >=99%).Avoid using poisonous and harmful raw material tin protochloride and more expensive chiral auxiliary(reagent) (S)-(-)-α of price, α-diphenyl-2-pyrrolinemethanol and (S)-α, α-diphenyl-2-pyrrolinol.2, when alkylated reaction generates compound (13), use catalyzer KI, n-Bu4NBr etc., accelerated reaction also improves yield.3, SOCl is used
2replace methyl yellow acyl chlorides, selectivity obtains retention of configuration (R)-configuration chloro thing, avoids the chloro thing producing by product (S)-configuration, avoids product dapoxetine racemization phenomenon, improve product optical purity.
Embodiment
Below in conjunction with specific embodiment, the present invention is further elaborated.
Embodiment 1
Synthetic compound (12)
By compound (9) (16.8g, 0.1mol) be dissolved in 1, in 4-dioxane (40mL), (-) diisopinocampheylchloroborane base chloroborane [(-)-DIPCl] (64g is added at 25 DEG C, 0.12mol, 1.2eq, 60% tetrahydrofuran solution), at this temperature, 12h is reacted.Slowly add frozen water (200mL), keep temperature to be no more than 25 DEG C, stir 30 minutes, stratification, aqueous phase ethyl acetate (3 × 100mL) extracts.Merge organic phase, saturated sodium bicarbonate aqueous solution washing is to weakly acidic pH, and anhydrous MgSO4 is dry, filter, concentrated boil off organic solvent and obtain compound (12) (white solid, mp=56-58 DEG C, productive rate 92%, HPLC purity 99.2%, ee value=99.2%).
1H-NMR(CDCl
3，400MHz，δppm)：2.00(s,1H，OH),2.05-2.10(m,1H),2.12-2.26(m,1H),3.52-3.60(m,1H),3.72-3.80(m,1H),5.00(dd,J＝4.8Hz,J＝8.2Hz,1H),7.33-7.40(m,5H)。
Embodiment 2
Compound (9) (16.8g, 0.1mol) is dissolved in 2-methyltetrahydrofuran (60mL), at 10 DEG C, adds (-)-DIPCl (80g, 0.15mol, 1.5eq, 60% hexane solution), at this temperature, 14h is reacted.Slowly add frozen water (250mL), keep temperature to be no more than 10 DEG C, stir 50 minutes, stratification, aqueous phase ethyl acetate (3 × 100mL) extracts.Merge organic phase, saturated sodium bicarbonate aqueous solution washs to weakly acidic pH, anhydrous MgSO
4drying, filters, and concentrated boil off organic solvent and obtains compound (12) (white solid, productive rate 95%, HPLC purity 99.5%, ee value=99.1%).
Embodiment 3
Compound (9) (16.8g, 0.1mol) is dissolved in THF (100mL), at 40 DEG C, adds (-)-DIPCl (106g, 0.20mol, 2.0eq, 60% n-heptane solution), at this temperature, 16h is reacted.Slowly add frozen water (300mL), keep temperature to be no more than 0 DEG C, stir 50 minutes, stratification, aqueous phase ethyl acetate (3 × 100mL) extracts.Merge organic phase, saturated sodium bicarbonate aqueous solution washs to weakly acidic pH, anhydrous MgSO
4drying, filters, and concentrated boil off organic solvent and obtains compound 12 (white solid, productive rate 96%, HPLC purity 99.3%, ee value=99.2%).
Embodiment 4
Compound (9) (16.8g, 0.1mol) is dissolved in methyl tertiary butyl ether (150mL), at 80 DEG C, adds (-)-DIPCl (106g, 0.20mol, 2.0eq, 60% toluene solution), react 18h at this temperature.Slowly add frozen water (300mL), keep temperature to be no more than 5 DEG C, stir 40 minutes, stratification, aqueous phase ethyl acetate (3 × 100mL) extracts.Merge organic phase, saturated sodium bicarbonate aqueous solution washs to weakly acidic pH, anhydrous MgSO
4drying, filters, and concentrated boil off organic solvent and obtains compound (12) (white solid, productive rate 92%, HPLC purity 99.0%, ee value=99.3%).
Embodiment 5
Compound 9 (16.8g, 0.1mol) is dissolved in toluene (200mL), at 60 DEG C, adds (-)-DIPCl (106g, 0.20mol, 2.0eq, 60% toluene solution), and react 22h at this temperature.Slowly add frozen water (300mL), keep temperature to be no more than 0 DEG C, stir 30 minutes, stratification, aqueous phase ethyl acetate (3 × 100mL) extracts.Merge organic phase, saturated sodium bicarbonate aqueous solution washs to weakly acidic pH, anhydrous MgSO
4drying, filters, and concentrated boil off organic solvent and obtains compound (12) (white solid, productive rate 95%, HPLC purity 99.2%, ee value=99.0%).
Embodiment 6
Synthetic compound (13)
NaOH (4.8g, 0.12mol) is added DMF (DMF, 100ml) and KI (0.5g), be cooled to 0-5 DEG C.Under stirring state, add the DMF (50mL) of ɑ-naphthols (15.8g, 0.11mol), then stir 2h.Add compound (12) (17.6g, 0.10mol), react 30h at this temperature.Slowly add frozen water (400mL), crystallization filters, and filter cake is washed to neutrality, then dry, obtains compound (13) (white solid, yield 70%, HPLC purity 99.3%, ee value=99.2%).
1H-NMR(CDCl
3,400MHz,δppm)：1.22(s,1H，OH),2.35-2.40(m,2H),4.18-4.36(m,2H),5.15-5.22(m,1H),6.83(d,J＝7.5Hz,1H),7.33-7.53(m,9H),1H),7.88(d,J＝3.3Hz,6.2Hz,1H),8.25(dd,J＝3.4and 6.2Hz)。
Embodiment 7
KOH (6.7g, 0.12mol) is added N,N-dimethylacetamide (DMAc, 120ml) and potassiumiodide (KI) (0.5g), be cooled to 0 DEG C.Under stirring state, add the DMAc (60mL) of compound (8) ɑ-naphthols (15.8g, 0.11mol), then stir 3h.Add compound (12) (17.6g, 0.10mol), at this temperature, reaction 35h.Then slowly add frozen water (400mL), crystallization filters, and filter cake is washed to neutrality, then dry, obtains compound (13) (white solid, yield 73%, HPLC purity 99.5%, ee value=99.3%).
Embodiment 8
LiOH (5.0g, 0.12mol) is added N-Methyl pyrrolidone (NMP, 140ml) and KI (0.5g), be cooled to 0 DEG C.Under stirring state, add the NMP (60mL) of ɑ-naphthols (15.8g, 0.11mol), then stir 4h.Add compound (12) (17.6g, 0.10mol), at this temperature, reaction 35h.Then slowly add frozen water (400mL), crystallization filters, and filter cake is washed to neutrality, then dry, obtains compound (13) (white solid, yield 71%, HPLC purity 99.1%, ee value=99.0%).
Embodiment 9
By Cs
2cO
3(18g, 0.12mol) adds methylene dichloride (150ml), water (50ml), and tetra-n-butyl ammonium bromide [n-Bu4NCl] (0.2g), is cooled to 0-10 DEG C.Under stirring state, add the methylene dichloride (50mL) of ɑ-naphthols (15.8g, 0.11mol), then stir 7h.Add compound (12) (17.6g, 0.10mol), at this temperature, reaction 40h.Slowly add frozen water (400mL), crystallization filters, and filter cake is washed to neutrality, then dry, obtains compound (13) (white solid, yield 78%, HPLC purity 99.4%, ee value=99.1%).
Embodiment 10
By K
2cO
3(16.6g, 0.12mol) adds ethylene dichloride (100ml), water (50ml), and KI (1.0g, 0.12mol), n-Bu4NCl (0.2g), be cooled to 0-10 DEG C.Under stirring state, add the ethylene dichloride (50mL) of ɑ-naphthols (15.8g, 0.11mol), then stir 6h.Add compound (12) (17.6g, 0.10mol), at this temperature, reaction 40h.Slowly add frozen water (400mL), crystallization filters, and filter cake is washed to neutrality, then dry, obtains compound (13) (white solid, yield 77%, HPLC purity 99.1%, ee value=99.2%).
Embodiment 11
NaH (2.9g, 0.12mol) is added tetrahydrofuran (THF) (120ml) and KI (0.5g), be cooled to 0-10 DEG C.Under stirring state, add the tetrahydrofuran (THF) (50mL) of ɑ-naphthols (15.8g, 0.11mol), then stir 5h.Add compound (12) (17.6g, 0.10mol), at this temperature, reaction 40h.Slowly add frozen water (400mL), crystallization filters, and filter cake is washed to neutrality, then dry, obtains compound (13) (white solid, yield 83%, HPLC purity 99.3%, ee value=99.0%).
Embodiment 12
EtONa (8.2g, 0.12mol) is added methyl-sulphoxide (DMSO, 150ml) and KI (0.5g), be cooled to 0-10 DEG C.Under stirring state, add the methyl-sulphoxide (50mL) of ɑ-naphthols (15.8g, 0.11mol), then stir 6h.Add compound (12) (17.6g, 0.10mol), at this temperature, reaction 16h.Slowly add frozen water (400mL), crystallization filters, and filter cake is washed to neutrality, then dry, obtains compound (13) (white solid, yield 75%, HPLC purity 99.0%, ee value=99.3%).
Embodiment 13
NaOH (4.8g, 0.12mol) is added toluene (150ml), water (50ml), n-Bu4NBr (0.5g), is cooled to 0 DEG C.Under stirring state, add toluene (50mL) solution of ɑ-naphthols (15.8g, 0.11mol), then vigorous stirring 13h.Add compound (12) (17.6g, 0.10mol), at this temperature, reaction 20h.Slowly add frozen water (400mL), crystallization filters, and filter cake is washed to neutrality, then dry, obtains compound (13) (white solid, yield 66%, HPLC purity 99.1%, ee value=99.6%).
In this step reaction, use bases can be selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium carbonate, salt of wormwood, sodium hydride, any one or a few in sodium ethylate, potassium tert.-butoxide, sodium tert-butoxide, triethylamine, diisopropyl ethyl amine and in sodium ethylate.Use solvent can select in DMF, N,N-dimethylacetamide, N-Methyl pyrrolidone, methylene dichloride, tetrahydrofuran (THF), methyl-sulphoxide, acetonitrile, methyl tertiary butyl ether and toluene any one or a few.
Embodiment 14
Synthetic compound (14)
Compound (13) (27.8g, 0.1mol) is joined THF (100ml), is cooled to-10 DEG C, agitation and dropping SOCl
2(20.8g, 0.18mol), stirs 6h at-10 DEG C, then slowly adds frozen water (100mL), crystallization filters, and filter cake is washed to neutrality, then dry, obtain compound (14) (white solid, yield 88%, HPLC purity 99.1%).
1H-NMR(CDCl
3,400MHz,δppm)：2.34-2.40(m,2H),4.20-4.34(m,2H),5.22-5.28(m,1H),6.86(d,J＝7.5Hz,1H),7.35-7.56(m,9H),1H),7.86(d,J＝3.4Hz,6.5Hz,1H),8.25(dd,J＝3.4and 6.5Hz)。MS:m/z＝296.10(M+),298.10(M+)。
Embodiment 15
Compound (13) (27.8g, 0.1mol) is joined CH
2cl
2(100ml), 0 DEG C is cooled to, agitation and dropping SOCl
2(20.8g, 0.18mol), stirs 4h at 0 DEG C, then slowly adds frozen water (100mL), crystallization filters, and filter cake is washed to neutrality, then dry, obtain compound (14) (white solid, yield 90%, HPLC purity 99.3%).
Embodiment 16
Compound (13) (27.8g, 0.1mol) is joined toluene (100ml), is cooled to 0 DEG C, agitation and dropping SOCl
2(20.8g, 0.18mol), stirs 4h at 0 DEG C, then slowly adds frozen water (100mL), crystallization filters, and filter cake is washed to neutrality, then dry, obtain compound (14) (white solid, yield 88%, HPLC purity 99.2%).
Embodiment 17
Compound 13 (27.8g, 0.1mol) is joined Isosorbide-5-Nitrae-dioxane (100ml), be cooled to 0 DEG C, agitation and dropping SOCl
2(20.8g, 0.18mol), stirs 4h at 0 DEG C, then slowly adds frozen water (100mL), crystallization filters, and filter cake is washed to neutrality, then dry, obtain compound (14) (white solid, yield 82%, HPLC purity 99.5%).
Embodiment 18
Compound (13) (27.8g, 0.1mol) is joined 1,2-ethylene dichloride (100ml), is cooled to 0 DEG C, agitation and dropping SOCl
2(20.8g, 0.18mol), stirs 6h at 0 DEG C, then slowly adds frozen water (100mL), crystallization filters, and filter cake is washed to neutrality, then dry, obtain compound (14) (white solid, yield 80%, HPLC purity 99.0%).
Embodiment 19
Compound (13) (27.8g, 0.1mol) is joined methyl-sulphoxide (100ml), is cooled to 0 DEG C, agitation and dropping SOCl
2(20.8g, 0.18mol), stirs 5h at 0 DEG C, then slowly adds frozen water (100mL), crystallization filters, and filter cake is washed to neutrality, then dry, obtain compound (14) (white solid, yield 78%, HPLC purity 99.2%).
Embodiment 20
Compound (13) (27.8g, 0.1mol) is joined N-Methyl pyrrolidone (NMP, 100ml), is cooled to 0 DEG C, agitation and dropping SOCl
2(20.8g, 0.18mol), stirs 7h at 0 DEG C, then slowly adds frozen water (100mL), crystallization filters, and filter cake is washed to neutrality, then dry, obtain compound (14) (white solid, yield 75%, HPLC purity 99.0%).
Embodiment 21
Compound 13 (27.8g, 0.1mol) is joined DMF (DMF, 100ml), is cooled to 0 DEG C, agitation and dropping SOCl
2(20.8g, 0.18mol), stirs 8h at 0 DEG C, then slowly adds frozen water (100mL), crystallization filters, and filter cake is washed to neutrality, then dry, obtain compound (14) (white solid, yield 73%, HPLC purity 99.2%).
Solvent that this step reaction uses can select tetrahydrofuran (THF), methylene dichloride, toluene, 1,4-dioxane, 1, any one or a few in 2-ethylene dichloride, methyl-sulphoxide, acetonitrile, methyl tertiary butyl ether, N-Methyl pyrrolidone and DMF.
Embodiment 22
Prepare compound (1) dapoxetine hydrochloride
Compound (14) (29.8g, 0.1mol) is dissolved in THF (200ml), then passes into dimethylamine gas (9g, 0.2mol).24h is reacted at 25 DEG C.Evaporated under reduced pressure THF, after add water (150ml), use the 10%NaOH aqueous solution to be adjusted to pH=13, then crystallization, filter, filter cake makes to wash neutrality with water, 50 DEG C of dryings.Dried dissolution of solid is in EtOAc (300ml), then the HCl ethanolic soln of 1M is added (by Acetyl Chloride 98Min. and ethanol, react at 0 DEG C and be prepared from), filtration obtains compound (1), i.e. dapoxetine hydrochloride (white solid, yield 65%, mp=178.5-179.4 DEG C, HPLC purity 99.5%, ee=99.1%).
1H-NMR(CDCl
3,400MHz，δppm)：2.60(d,J＝4.4Hz,3H),2.92(d,J＝4.2Hz,3H),2.80-2.88(m,1H),3.12-3.18(m,1H),3.72-3.80(m,1H),4.20-4.26(m,1H),4.36-4.40(m,1H),6.60(d,J＝7.6Hz,1H),7.30(t,J＝7.8Hz,1H),7.40-7.50(m,6H),7.56-7.70(m,2H),7.78(d,J＝7.8Hz,1H),7.90(d,J＝8.2Hz,1H),13.0(s,1H)。
Embodiment 23
Compound (14) (29.8g, 0.1mol) is dissolved in 2-methyltetrahydrofuran (250ml), then passes into dimethylamine gas (9g, 0.2mol).18h is reacted at 25 DEG C.Evaporated under reduced pressure 2-methyltetrahydrofuran, add water (150ml).The 10%NaOH aqueous solution is used to be adjusted to pH=13.Crystallization, filter, filter cake makes to wash neutrality with water, 50 DEG C of dryings.Dried dissolution of solid is in EtOAc (300ml), then the HCl ethanolic soln of 1M is added (by Acetyl Chloride 98Min. and ethanol, reaction preparation at 0 DEG C), filtration obtains compound (1), i.e. dapoxetine hydrochloride, (white solid, yield 68%, HPLC purity 99.6%, ee=99.0%).
Claims (9)
1. a synthetic method for dapoxetine hydrochloride, is characterized in that, comprises the following steps:
(1) compound (9) and (-) diisopinocampheylchloroborane base chloroborane in organic solvent, issue raw reduction reaction at 10 ~ 80 DEG C, obtain compound (12);
(2) compound (8) and alkali react 2 ~ 14 hours in organic solvent at 0 ~ 10 DEG C, then the compound (12) obtained in step (1) is added, at 0 ~ 10 DEG C, there are alkylated reaction 15 ~ 40 hours again, obtain compound (13);
(3) compound (13) obtained in step (2) and sulfur oxychloride in organic solvent, are obtained by reacting compound (14) at-10 ~ 0 DEG C; And
(4) compound (14) obtained in step (3) and dimethylamine in organic solvent, are obtained by reacting dapoxetine unhindered amina, then are obtained by reacting dapoxetine hydrochloride with the ethanolic soln of hydrogenchloride at 20 ~ 30 DEG C;
2. the synthetic method of dapoxetine hydrochloride according to claim 1, it is characterized in that: in step (1), described organic solvent is selected from one or more in Isosorbide-5-Nitrae-dioxane, 2-methyltetrahydrofuran, tetrahydrofuran (THF), methyl tertiary butyl ether, toluene, normal hexane and normal heptane.
3. the synthetic method of dapoxetine hydrochloride according to claim 1, is characterized in that: in step (1), and the time of described reduction reaction is 10 ~ 24 hours.
4. the synthetic method of dapoxetine hydrochloride according to claim 1, is characterized in that: in step (2), described alkylated reaction carries out under the katalysis of catalyzer, and described catalyzer is potassiumiodide or tetra-n-butyl ammonium bromide.
5. the synthetic method of dapoxetine hydrochloride according to claim 1, it is characterized in that: in step (2), described alkali is selected from one or more in sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium carbonate, salt of wormwood, sodium hydride, sodium ethylate, potassium tert.-butoxide, sodium tert-butoxide, triethylamine and diisopropylethylamine.
6. the synthetic method of dapoxetine hydrochloride according to claim 1, it is characterized in that: in step (2), described organic solvent is selected from N, one or more in dinethylformamide, N,N-dimethylacetamide, N-Methyl pyrrolidone, methylene dichloride, tetrahydrofuran (THF), methyl-sulphoxide, acetonitrile, methyl tertiary butyl ether and toluene.
7. the synthetic method of dapoxetine hydrochloride according to claim 1, it is characterized in that: in step (3), described organic solvent is selected from tetrahydrofuran (THF), methylene dichloride, toluene, 1,4-dioxane, 1, one or more in 2-ethylene dichloride, methyl-sulphoxide, N-Methyl pyrrolidone, acetonitrile, methyl tertiary butyl ether and DMF.
8. the synthetic method of dapoxetine hydrochloride according to claim 1, is characterized in that: in step (3), and the time of described reaction is 4 ~ 8 hours.
9. the synthetic method of dapoxetine hydrochloride according to claim 1, is characterized in that: in step (4), and described organic solvent is selected from one or more in tetrahydrofuran (THF), 2-methyltetrahydrofuran, methyl tertiary butyl ether and ether.
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| CN110015944A (en) * | 2019-05-06 | 2019-07-16 | 福建康鸿生物科技有限公司 | A kind of synthetic method of highly selective luliconazole intermediate |
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