CN104086431A - Method for synthesizing intermediate of reboxetine mesylate - Google Patents
Method for synthesizing intermediate of reboxetine mesylate Download PDFInfo
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- CN104086431A CN104086431A CN201410346781.XA CN201410346781A CN104086431A CN 104086431 A CN104086431 A CN 104086431A CN 201410346781 A CN201410346781 A CN 201410346781A CN 104086431 A CN104086431 A CN 104086431A
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Abstract
The invention discloses a method for manufacturing an intermediate, namely, (2RS, 3RS)-3-(2-ethoxyphenoxy)-2-hydroxy-1-(4-nitrobenzoyloxy)-3-phenylpropane, of reboxetine mesylate. According to the method, a compound I and nitrobenzoyl chloride are taken as raw materials and reacted to obtain (2RS, 3RS)-3-(2-ethoxyphenoxy)-2-hydroxy-1-(4-nitrobenzoyloxy)-3-phenylpropane (the compound II) in the presence of a catalyst and an acid-binding agent in a solvent, wherein the solvent is C1 or C2 halogenated hydrocarbon or ethyl acetate or tetrahydrofuran, the acid-binding agent is potassium carbonate or sodium carbonate and the catalyst is dimethyl tin dichloride. The method disclosed by the invention is simple and has the advantages of mild reaction conditions, low energy consumption and environment friendliness and is more suitable for large-scale industrial production.
Description
Technical field
The present invention relates to pharmaceutical chemistry field, be specifically related to centre (2RS, 3RS)-3-(2-ethoxy phenoxy of reboxetine mesylate)-2-hydroxyl-1-(4-nitrobenzoyl acyloxy) synthetic method of-3-phenylpropyl alcohol alkane.
Background technology
Reboxetine mesylate is that first listing is for real selectivity norepinephrine (NA) reuptake inhibitor for the treatment of depression, curative effect is identical with selective serotonin reuptake inhibitor (SSRIs) with tricyclic antidepressants (TCAS), even surpasses SSRIs.There are some researches show and be better than fluoxetine improving aspect some social function, as the contacts with other people with feel, and the improvement of power and energy aspect.In general, the drug effect of Reboxetine and fluoxetine is close, and is better than fluoxetine in following several respects: 1, major depression patient's treatment; 2, patient's social behavior improves, especially power shortage and the improvement feeling; 3, good tolerance; 4, the validity of life-time service and security.
At document Tetrahedron Vol-41, No.7.PP 1393-1399, intermediate (2RS to reboxetine mesylate in 1985,3RS)-3-(2-ethoxy phenoxy)-2-hydroxyl-1-(4-nitrobenzoyl acyloxy) synthetic being described of-3-phenylpropyl alcohol alkane, wherein solvent and acid binding agent are pyridine, aftertreatment, with in a large amount of acid and pyridine, produces a large amount of three wastes, is unfavorable for environmental protection.
Application number is 200610088359.4 patent, with the halohydrocarbon below C4 or tetrahydrofuran (THF), makees solvent, take pyridine as acid binding agent, synthetic (2RS, 3RS)-3-(2-ethoxy phenoxy)-2-hydroxyl-1-(4-nitrobenzoyl acyloxy)-3-phenylpropyl alcohol alkane.Owing to having two adjacent primary hydroxyls and secondary hydroxyl in raw material, with the rising of temperature of reaction, the esterified probability of secondary hydroxyl is larger, and it is more that by product generates, and the purity of product is lower, and yield is lower.The temperature of reaction of this Patent right requirement is-30 ℃ ~ 15 ℃, is preferably-20 ℃ ~-15 ℃, therefore needs low-temp reaction equipment, and energy consumption is higher.
Summary of the invention
Technical problem to be solved by this invention is for synthetic (2RS in above-mentioned prior art, 3RS)-3-(2-ethoxy phenoxy)-2-hydroxyl-1-(4-nitrobenzoyl acyloxy) the defect of-3-phenylpropyl alcohol alkane, provide a kind of simple to operate, environmental protection, reaction conditions is gentle, products obtained therefrom purity is high, is suitable for industrial technical scheme.
Through a large amount of tests, grope, we use salt of wormwood instead or sodium carbonate is acid binding agent, and take dimethyltin chloride as catalyzer, 15 ℃ ~ 45 ℃ reactions, obtained qualified (2RS, 3RS)-3-(2-ethoxy phenoxy)-2-hydroxyl-1-(4-nitrobenzoyl acyloxy)-3-phenylpropyl alcohol alkane.Because salt of wormwood, sodium carbonate are insoluble in reaction system, salt of wormwood, sodium carbonate must pulverize and sieve, and to increase itself and the contacting of material, reach the object of accelerating reaction process.In addition, salt of wormwood, the sodium carbonate easy moisture absorption in depositing process, and because one of reactant of this reaction is acyl chlorides, meeting water easily decomposes, impact reaction is carried out, thus salt of wormwood, sodium carbonate pulverize after must through 100 ℃ ~ 150 ℃ dry 2 hours, anhydrous to guarantee it.Reaction conditions of the present invention is gentle, has reached the effect of environmental protection and save energy.
For achieving the above object, the invention discloses following technical scheme:
A kind of reboxetine mesylate intermediate (2RS, 3RS)-3-(2-ethoxy phenoxy)-2-hydroxyl-1-(4-nitrobenzoyl acyloxy) the synthetic method of-3-phenylpropyl alcohol alkane, it is characterized in that take that chemical compounds I and paranitrobenzoyl chloride are as raw material, halohydrocarbon or the ethyl acetate of take below C3 are solvent, take through pulverizing dry salt of wormwood or sodium carbonate is acid binding agent, take dimethyltin chloride as catalyzer, 15 ℃ ~ 45 ℃ reactions, obtain (2RS, 3RS)-3-(2-ethoxy phenoxy)-2-hydroxyl-1-(4-nitrobenzoyl acyloxy)-3-phenylpropyl alcohol alkane (compound ii):
Chemical compounds I wherein: paranitrobenzoyl chloride molar ratio is 1:1.
Halohydrocarbon below C3 of the present invention is selected from methylene dichloride, trichloromethane, tetracol phenixin, methylene bromide or monochloroethane.Salt of wormwood or sodium carbonate need grinding and sieving, and sieve number is 100 ~ 150 orders; After sieving, 150 ℃ again ~ 200 ℃ are dried 2 hours.
The molar ratio of salt of wormwood or sodium carbonate and chemical compounds I is 1:1 ~ 4:1.The molar ratio of dimethyltin chloride and chemical compounds I is 0.05:1 ~ 1:1; Preferred 0.1:1 ~ 0.4:1.
The synthetic method of reboxetine mesylate intermediate disclosed by the invention is compared with prior art:
(1) to take mineral alkali salt of wormwood or sodium carbonate be acid binding agent in the present invention, during aftertreatment, and direct filtration, washing filtrate, does not need to neutralize with hydrochloric acid environmental protection more.
(2) temperature of reaction of the present invention is 15 ℃ ~ 45 ℃, without low-temp reaction equipment, more energy-conservation, has reduced and has become to produce cost.
(3) the product content obtaining by method of the present invention meets quality standard.
Embodiment
For simple and object clearly, below appropriate omission the description of known technology, in order to avoid those unnecessary details impact descriptions to the technical program.Below in conjunction with preferred embodiment, synthetic method of the present invention is further illustrated, that be illustrated especially is chemical compounds I reference Tetrahedron Vol-41, and No.7.PP 1393-1399 1985 prepares dimethyltin chloride, paranitrobenzoyl chloride can have been bought from the market.
Embodiment 1
To dropping into 100.0g chemical compounds I (0.347mol), 48.7g salt of wormwood (0.347mol) (through pulverizing 120 mesh sieves 150 ℃ dry 2 hours), 7.7g dimethyltin chloride (0.035mol) and 1000mL methylene dichloride in reaction flask, stir, at 15 ℃ ~ 18 ℃, the solution that dropping is comprised of 64.4g paranitrobenzoyl chloride (0.347mol) and 600mL methylene dichloride, drip altogether 1 hour, after dropwising, stirring reaction is 4 hours at 15 ℃.Filter, filtrate is washed layering with 500mL, organic layer anhydrous sodium sulfate drying, and concentrating under reduced pressure goes after methylene dichloride must yellow solid, with isopropyl ether: the solution weight crystallization of ethyl acetate (12:1) obtains compound ii 97g, yield 63.9%, content 97.2%.
The compound ii of embodiment 1 preparation is measured:
The spectroscopic data recording is as follows:
IR(KBr)cm
-1?:?3540(OH),1730(CO),1590,1500(C=C),1525,1350(NO
2)
1H-NMR（CDCl
3）δ：1.50（3H,t,CH
3),3.4(1H,d,OH),?4.18(2H,q,CH
2CH
3),?4.30(1h,M,CH-OH),4.60(2H,d,CH
2OCO),5.20(1h,D,Ph-CH,J=4.5Hz),?6.7-7.1(4H,m,Ph-O),7.2-7.7(5H,m,Ph-C),8.0-8.4(4H,m,Ph-N)
The obtained compound ii of above spectroscopic data proof embodiment 1 is (2RS, 3RS)-3-(2-ethoxy phenoxy)-2-hydroxyl-1-(4-nitrobenzoyl acyloxy)-3-phenylpropyl alcohol alkane.
Embodiment 2
To dropping into 100.0g chemical compounds I (0.347mol), 191.8g salt of wormwood (1.388mol) (through pulverizing 120 mesh sieves 150 ℃ dry 2 hours), 30.3g dimethyltin chloride (0.138mol) and 1000mL methylene dichloride in reaction flask, stir, at 22 ℃ ~ 25 ℃, the solution that dropping is comprised of 64.4g paranitrobenzoyl chloride (0.347mol) and 600mL methylene dichloride, drip altogether 1 hour, after dropwising, stirring reaction is 4 hours at 25 ℃.Filter, filtrate is washed layering with 500mL, organic layer anhydrous sodium sulfate drying, and concentrating under reduced pressure goes after methylene dichloride must yellow solid, with isopropyl ether: the solution weight crystallization of ethyl acetate (12:1) obtains compound ii 101g, yield 66.6%, content 97.9%.
Embodiment 3
To dropping into 100.0g chemical compounds I (0.347mol), 95.9g salt of wormwood (0.694mol) (through pulverizing 120 mesh sieves 150 ℃ dry 2 hours), 15.2g dimethyltin chloride (0.069mol) and 1000mL methylene dichloride in reaction flask, stir, at 32 ℃ ~ 35 ℃, the solution that dropping is comprised of 64.4g paranitrobenzoyl chloride (0.347mol) and 600mL methylene dichloride, drip altogether 1 hour, after dropwising, stirring reaction is 4 hours at 35 ℃.Filter, filtrate is washed layering with 500mL, organic layer anhydrous sodium sulfate drying, and concentrating under reduced pressure goes after methylene dichloride must yellow solid, with isopropyl ether: the solution weight crystallization of ethyl acetate (12:1) obtains compound ii 107g, yield 70.5%, content 98.5%.
Embodiment 4
To dropping into 100.0g chemical compounds I (0.347mol), 36.8g salt of wormwood (0.347mol) (through pulverizing 120 mesh sieves 150 ℃ dry 2 hours), 30.3g dimethyltin chloride (0.138mol) and 1000mL ethyl acetate in reaction flask, stir, at 43 ℃ ~ 45 ℃, the solution that dropping is comprised of 64.4g paranitrobenzoyl chloride (0.347mol) and 600mL ethyl acetate, drip altogether 1 hour, after dropwising, stirring reaction is 4 hours at 45 ℃.Filter, filtrate is washed layering with 500mL, organic layer anhydrous sodium sulfate drying, and concentrating under reduced pressure goes after ethyl acetate must yellow solid, with isopropyl ether: the solution weight crystallization of ethyl acetate (12:1) obtains compound ii 95g, yield 62.6%, content 96.9%.
Embodiment 5
To dropping into 100g chemical compounds I (0.347mol), 95.9g salt of wormwood (0.694mol) (through pulverizing 120 mesh sieves 150 ℃ dry 2 hours), 7.7g dimethyltin chloride (0.035mol) and 1000mL ethyl acetate in reaction flask, stir, at 33 ℃ ~ 35 ℃, the solution that dropping is comprised of 64.4g paranitrobenzoyl chloride (0.347mol) and 600mL ethyl acetate, drip altogether 1 hour, after dropwising, stirring reaction is 4 hours at 35 ℃.Filter, filtrate is washed layering with 500mL, organic layer anhydrous sodium sulfate drying, and concentrating under reduced pressure goes after ethyl acetate must yellow solid, with isopropyl ether: the solution weight crystallization of ethyl acetate (12:1) obtains compound ii 102g, yield 67.2%, content 98.4%.
Embodiment 6
To dropping into 100.0g chemical compounds I (0.347mol), 147.1g sodium carbonate (1.388mol) (through pulverizing 120 mesh sieves 150 ℃ dry 2 hours), 30.3g dimethyltin chloride (0.138mol) and 1000mL ethyl acetate in reaction flask, stir, at 23 ℃ ~ 25 ℃, the solution that dropping is comprised of 64.4g paranitrobenzoyl chloride (0.347mol) and 600mL ethyl acetate, drip altogether 1 hour, after dropwising, stirring reaction is 4 hours at 25 ℃.Filter, filtrate is washed layering with 500mL, organic layer anhydrous sodium sulfate drying, and concentrating under reduced pressure goes after ethyl acetate must yellow solid, with isopropyl ether: the solution weight crystallization of ethyl acetate (12:1) obtains compound ii 99g, yield 65.3%, content 97.5%.
Embodiment 7
The midbody compound II that adopts embodiment 1 to make is prepared reboxetine mesylate.
Method: reference Tetrahedron Vol-41, No.7.PP 1393-1399,1985
Step: compound ii makes reboxetine mesylate through methylsulfonyl reaction, epoxidation reaction, aminating reaction, amidate action, cyclization reaction, reduction reaction.The measured spectroscopic data of reboxetine mesylate of preparation is as follows:
IR（KBr）cm-1:?3000-2400(NH2),1590-1500(arom.C=C),?1250(Ar-O-Alk),?1210(Alk-O-Alk),?1190-1035(SO3)
1H-NMR（CDCl3）δ：1.43(3H,t,CH2-CH3),?2.68(3H,s,CH3S),?2.90-4.30(7H,m,CH2-N-CH2,CH2-O-CH),4.04(2H,q,CH2-CH3),?5.10(1H,d,Ph-CH),?6.60-6.90(4H,m,Ar-O),?7.30(5H,m,Ph-C)
The obtained compound of above spectroscopic data proof embodiment 7 is reboxetine mesylate.
Claims (7)
1. a reboxetine mesylate intermediate (2RS, 3RS)-3-(2-ethoxy phenoxy)-2-hydroxyl-1-(4-nitrobenzoyl acyloxy) the synthetic method of-3-phenylpropyl alcohol alkane, it is characterized in that take that chemical compounds I and paranitrobenzoyl chloride are as raw material, halohydrocarbon or the ethyl acetate of take below C3 are solvent, take through pulverizing dry salt of wormwood or sodium carbonate is acid binding agent, take dimethyltin chloride as catalyzer, 15 ℃ ~ 45 ℃ reactions, obtain (2RS, 3RS)-3-(2-ethoxy phenoxy)-2-hydroxyl-1-(4-nitrobenzoyl acyloxy)-3-phenylpropyl alcohol alkane (compound ii):
Chemical compounds I wherein: the molar ratio of paranitrobenzoyl chloride is 1:1.
2. the synthetic method of claim 1, is characterized in that the halohydrocarbon below described C3 is selected from methylene dichloride, trichloromethane, tetracol phenixin, methylene bromide or monochloroethane.
3. the synthetic method of claim 1, is characterized in that salt of wormwood or sodium carbonate need grinding and sieving, and sieve number is 100 ~ 150 orders; After sieving, 150 ℃ again ~ 200 ℃ are dried 2 hours.
4. the synthetic method of claim 1, the molar ratio that it is characterized in that salt of wormwood or sodium carbonate and chemical compounds I is 1:1 ~ 4:1.
5. the synthetic method of claim 1, the molar ratio that it is characterized in that dimethyltin chloride and chemical compounds I is 0.05:1 ~ 1:1.
6. the synthetic method of claim 1, the molar ratio that it is characterized in that dimethyltin chloride and chemical compounds I is 0.1:1 ~ 0.4:1.
7. the synthetic method of claim 1, is characterized in that described temperature of reaction is 15 ℃ ~ 45 ℃.
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5068433A (en) * | 1984-08-02 | 1991-11-26 | Farmitalia Carlo Erba, S.R.L. | Process for preparation of 3-substituted derivatives of 1-amino-2-hydroxy propane |
| JP2007523153A (en) * | 2004-02-20 | 2007-08-16 | ファルマシア・アンド・アップジョン・カンパニー・エルエルシー | Method for producing aryl ether |
| CN102101831A (en) * | 2009-12-17 | 2011-06-22 | 天津药物研究院 | Preparation method of (2RS, 3RS)-3-(2-ethoxy phenoxy)-2-hydroxy-1-(4-nitrobenzoyloxy)-3-phenyl propane |
| CN102351704A (en) * | 2011-08-25 | 2012-02-15 | 浙江巍华化工有限公司 | Method for synthesizing methyl 3-(trifluoromethyl)benzoate |
| JP2012111695A (en) * | 2010-11-19 | 2012-06-14 | Daicel Corp | Method for producing monohydroxy ester |
| CN102516072A (en) * | 2011-12-13 | 2012-06-27 | 江苏长青农化股份有限公司 | Preparation method of benzoic acid herbicide dicamba |
| CN103319345A (en) * | 2012-03-23 | 2013-09-25 | 英德广农康盛化工有限责任公司 | Method for preparing bifenthrin |
-
2014
- 2014-07-21 CN CN201410346781.XA patent/CN104086431A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5068433A (en) * | 1984-08-02 | 1991-11-26 | Farmitalia Carlo Erba, S.R.L. | Process for preparation of 3-substituted derivatives of 1-amino-2-hydroxy propane |
| JP2007523153A (en) * | 2004-02-20 | 2007-08-16 | ファルマシア・アンド・アップジョン・カンパニー・エルエルシー | Method for producing aryl ether |
| CN102101831A (en) * | 2009-12-17 | 2011-06-22 | 天津药物研究院 | Preparation method of (2RS, 3RS)-3-(2-ethoxy phenoxy)-2-hydroxy-1-(4-nitrobenzoyloxy)-3-phenyl propane |
| JP2012111695A (en) * | 2010-11-19 | 2012-06-14 | Daicel Corp | Method for producing monohydroxy ester |
| CN102351704A (en) * | 2011-08-25 | 2012-02-15 | 浙江巍华化工有限公司 | Method for synthesizing methyl 3-(trifluoromethyl)benzoate |
| CN102516072A (en) * | 2011-12-13 | 2012-06-27 | 江苏长青农化股份有限公司 | Preparation method of benzoic acid herbicide dicamba |
| CN103319345A (en) * | 2012-03-23 | 2013-09-25 | 英德广农康盛化工有限责任公司 | Method for preparing bifenthrin |
Non-Patent Citations (1)
| Title |
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