CN86108706A - Synthesizing of alchol of antimelancholic ' Nomifensin ' intermediate nitro-acetophenone hydrochloride - Google Patents
Synthesizing of alchol of antimelancholic ' Nomifensin ' intermediate nitro-acetophenone hydrochloride Download PDFInfo
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- CN86108706A CN86108706A CN 86108706 CN86108706A CN86108706A CN 86108706 A CN86108706 A CN 86108706A CN 86108706 CN86108706 CN 86108706 CN 86108706 A CN86108706 A CN 86108706A CN 86108706 A CN86108706 A CN 86108706A
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- reaction
- methylamine
- solution
- bromoacetophenone
- hydrochloride
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Abstract
The present invention be one new, be convenient to industrial alchol of antimelancholic ' Nomifensin ' intermediate W-[N-(2-nitrobenzyl)-methylamino-]-synthetic method of methyl phenyl ketone hydrochloride, it be adopt Ortho Nitro Benzaldehyde be raw material earlier with methylamine react corresponding Shiff alkali, use potassium boron hydrogen selective reduction-CH=N-key to get N-(2-nitrobenzyl)-methylamine hydrochloride again, the bromoacetophenone reaction solution that makes with bromine and methyl phenyl ketone condensation and making in water then.This law yield height, cost is low, and is easy and simple to handle.
Description
The technical field of the invention is left-handed 1, and 2-dihydroxyl-3-TERTIARY BUTYL AMINE base propane (I) synthetic method is improved.
(1) is the intermediate of synthetic beta blocker, can be used for synthetic treatment cardiovascular drug and glaucoma medicine timolol bunitrolol etc.Former synthetic method is divided two steps, the (1) 1,2,5,6 diisopropyls justice N.F,USP MANNITOL (II) fragment into the D-different third adopted Glycerose (III) under oxygenant lead tetra-acetate or sodium periodate effect, (2) (III) and TERTIARY BUTYL AMINE addition reaction, reaction solution is hydrogenated into amine under palladium/carbon catalysis, get (I) through hydrochloric acid hydrolysis again.Reaction equation is seen below.
The reaction of (1) step has 1. lead tetra-acetate oxidation style of problem in the former synthetic method: (III) of generation needs vacuum distilling to isolate; Two step yields 70%; Lead salt toxicity is big, and it is difficult to reclaim, and easily pollutes, and uses tetrahydrofuran (THF), dry-out benzene inflammable dangerous as solvent.Though 2. sodium periodate method is difficult shortcoming, former report is the method for He oxazoline and thiazoline derivative, can not get (I) by carrying out the reaction of (2) step after its method (seeing below) operation again.
Characteristics of the present invention are to adopt sodium periodate to be oxygenant and to be improved under reaction conditions in the reaction of (1) step.1. reduce the proportioning original (II) of solvent water: water is 1: 20, now changes 1: 4 into.Can make like this: the sodium iodate 100% that reaction generates is separated out, and the non-oxidation agent exists when (2) goes on foot hydrogenation, and yield can improve; Solvent methanol and water ratio are suitable during hydrogenation; Dewatering time is short, guarantees the quality of (I).2. adopt sodium bicarbonate to replace more than the phosphoric acid salt control PH7, (III) of generation do not separate, and directly carries out the reaction of (2) step, and two step yields are more than 80%.
Synthetic of the present invention (I) is used for timolol production and had 3 years.
Embodiment:
In the there-necked flask of 3 liters, add 800 milliliters of entry, sodium bicarbonate 3 grams and 1,2,5,6-diisopropyl justice N.F,USP MANNITOL 210 grams, gradation adds sodium periodate 170 grams in the time of 40 ℃, adds 300 milliliters of methyl alcohol, cross elimination precipitation, the filtrate that obtains (the D-different third adopted Glycerose aqueous solution) can carry out (2) step react (I)
Former report sodium periodate oxidation operation:
With raw material 1,2,5,6-diisopropyl justice N.F,USP MANNITOL 20.4 restrains in the phosphate buffered saline buffer that is dissolved in 400 milliliters, when PH6, adds the sodium periodates of 20.4 grams, and the mixture stirring was promptly got the D-different third adopted Glycerose aqueous solution after 20 minutes.(carrying out the next step De oxazoline derivative then).
Attached: the operation of (2) step:
The D-that the obtains different third adopted Glycerose aqueous solution and 720 milliliters of TERTIARY BUTYL AMINE are mixed stirring 1 hour, be cooled to 0 ℃, the sodium iodate precipitation that elimination generates.
Above filtrate is joined in the 5 liter there-necked flasks, add 10% palladium/carbon 60 gram filtrates and under cooling, drip concentrated hydrochloric acid 1 liter, add air distillation to 100 ℃ of temperature, add activated carbon decolorizing, the sodium hydroxide neutralization, cooling, chloroform extraction, dry, boil off solvent, residue is pulverized and is added ether, filters to such an extent that (I) 188 restrains, secondary yield 80%, m.P.83.5-85 ℃
Reaction equation:
（1）Weinstock：J????Org.Chem.Vol????41∶3121（1976）
（2）George：Can????J????Chem.54，1260（1976）
Claims (7)
1, the method for a kind of synthetic nomifensine intermediate nitro-acetophenone (I), be to generate the methylamine thing by adjacent nitro bromine (chlorine) benzyl and methylamine alcohol solution reaction, form with bromoacetophenone condensation under anhydrous condition then, the present invention is characterised in that this method is made of following reaction: (1) Ortho Nitro Benzaldehyde and aqueous methylamine solution react corresponding Shiff alkali.(2) Shiff alkali and potassium (sodium) boron hydrogen carries out selective reduction and gets methylamine thing hydrochloride.(3) the bromoacetophenone reaction solution condensation in water that makes of methylamine thing hydrochloride and bromine and methyl phenyl ketone gets (I).
2, by the described reaction of claim 1, when it is characterized in that adjacent benzaldehyde and aqueous methylamine solution react its mole ratio should be 1: 1.1～1.5.
3, described by claim 2, it is characterized in that in the time of 0-15 ℃, adding aqueous methylamine solution, insulation reaction 3-10 hour then, 30-40 ℃ of reaction 1-3 hour again heated up.
4, by the described reaction of claim 1, its mole ratio should be 1～3 when it is characterized in that with potassium (sodium) boron hydrogen reduction Shiff alkali: 1.
5, described by claim 4, it is characterized in that adding reductive agent afterreaction liquid and should be warmed to 25-55 ℃ of reaction more than 3 hours, and then widely different stream is more than 10 minutes.
6, by the described reaction of claim 1, it is characterized in that methylamine thing hydrochloride and bromoacetophenone its mole ratio of condensation in alkaline aqueous solution is 1: 1～1.5.
7, described by claim 6, it is characterized in that setting-up point is 20-40 ℃, the reaction times is 4-8 hour.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN86108706A CN1003013B (en) | 1986-12-29 | 1986-12-29 | Synthetic method of nitro-acetophenone hydrocloride for intermediate of antidepresant nomifensine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN86108706A CN1003013B (en) | 1986-12-29 | 1986-12-29 | Synthetic method of nitro-acetophenone hydrocloride for intermediate of antidepresant nomifensine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN86108706A true CN86108706A (en) | 1987-12-23 |
| CN1003013B CN1003013B (en) | 1989-01-04 |
Family
ID=4804020
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN86108706A Expired CN1003013B (en) | 1986-12-29 | 1986-12-29 | Synthetic method of nitro-acetophenone hydrocloride for intermediate of antidepresant nomifensine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1003013B (en) |
-
1986
- 1986-12-29 CN CN86108706A patent/CN1003013B/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| CN1003013B (en) | 1989-01-04 |
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| 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 |