CN106316954A - Method for preparing optically-pure (+)- or (-)-N-desmethyl Meptazinol - Google Patents
Method for preparing optically-pure (+)- or (-)-N-desmethyl Meptazinol Download PDFInfo
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- CN106316954A CN106316954A CN201510354529.8A CN201510354529A CN106316954A CN 106316954 A CN106316954 A CN 106316954A CN 201510354529 A CN201510354529 A CN 201510354529A CN 106316954 A CN106316954 A CN 106316954A
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- meptazinol
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D223/04—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with only hydrogen atoms, halogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
Abstract
The invention relates to a method for preparing optically-pure (+)- or (-)-N-desmethyl Meptazinol. The method comprises the steps of (a) subjecting optically-pure monomer Meptazinol to a reaction with trichloroethyl-2,2,2-chloroformate in the presence of alkali in an inert solvent, then, adding a mixed solvent of glacial acetic acid and water and zinc powder, and performing a reaction, thereby preparing the optically-pure (+)- or (-)-N-desmethyl Meptazinol. Compared with methods in the prior art, the preparation method disclosed by the invention has the advantages that an intermediate compound obtained in the step (a) is not required to be purified, and the target product can be obtained directly through a one-step hydrolysis reaction. Reaction steps are shortened, and aftertreatment operation is simplified; and the total yield of reaction is greatly increased (to 80% or more from original 40% to 51%), and the production cost is reduced substantially.
Description
Technical field
The present invention relates to the preparation method of N-demethyl meptazinol, particularly to prepare optical voidness (+)-N-
Demethyl meptazinol or (-) method of-N-demethyl meptazinol.
Background technology
Meptazinol (Meptazinol), molecular formula C15H23NO, chemical entitled 3-(3-ethyl-1-methyl isophthalic acid H-
Hexahydro azatropylidene-3-base) phenol, it is the analgesic of listing in 1986, its analgesic activities and pentazocine,
Pethidine and Dextropoxypheene are suitable, but more weak than morphine, and compared with other opium kind analgesicses, its breathing presses down
System waits side effect extremely low with additive, therefore does not belongs to " anaesthetic " management area.Known meptazinol is applicable to
Acute or chronic pain, such as wound, postoperative, obstetrics and cancer pain etc., it is especially useful in inhibiting pain in parturition is safe and effective, no
Affect neonatal health.After listing, clinical efficacy is reliable, records for British Pharmacopoeia in 1998.
Use the racemic modification of meptazinol hydrochloride clinically, have research, with optically pure tartaric acid or
Its derivant is resolving agent, raceme meptazinol is carried out chemical resolution obtain optical voidness meptazinol or its
Salt, confirms e.e. value ＞ 99% through capillary electrophoresis method, determines levo form by single crystal X diffraction
Absolute configuration be (3S), the absolute configuration of d-isomer is (3R).Through mouse brain inhibiting activity of acetylcholinesterase
Measure, it is thus achieved that (-)-meptazinol has the pharmacologically active of acetylcholinesteraseinhibition inhibition.
Chinese patent ZL201110033828.3 and ZL201110153195.X of the applicant discloses series
Left-handed meptazinol derivant has the purposes for the treatment of presenile dementia.(-)-N-demethyl meptazinol is to close
Become the most important intermediate of these compounds." new nanomole level cholinesterase inhibitor dinor-is beautiful
His phenol general has efficient inhibitory action to β-starch peptide aggregation " (Xie Qiong etc., J.Med.Chem.2008,51,
2027 2036) and Chinese patent application CN101037430A discloses the preparation method of this compound: left
Rotation meptazinol and haloformate in atent solvent, in the presence of alkali reaction prepare (-) N, O-dialkoxy formyl
The nor-meptazinol of base-N-, then under weak basic condition hydrolysis prepare intermediate (-)-N-alkoxyl formyl
The nor-meptazinol of-N-, finally again by hydrolysis prepare (-)-N-demethyl meptazinol.Described lazy
Property solvent selected from oxolane (THF), chloroform, dichloromethane, benzene, toluene, N, N-dimethyl formyl
In the mixture of amine (DMF) or above-mentioned solvent；Described haloformate is selected from ethyl chloroformate, chloro-carbonic acid second
Alkene ester, phenyl chloroformate or trichloroethyl chloroformate；Described alkali is selected from potassium bicarbonate or sodium；Described finally
One one-step hydrolysis reaction can be carried out under the conditions of aqueous sulfuric acid or hydrazine hydrate solution or tetrahydrofuran aqueous solution.
The total recovery of its reaction is generally about 40-51%.
The art be highly desirable to obtain the preparation method of a kind of novelty prepare (+)-N-demethyl is beautiful
His phenol general or (-)-N-demethyl meptazinol, its total recovery is relative to total receipts of prior art preparation method
Rate is greatly improved, and operating procedure is simplified, thus can be greatly lowered optical voidness (+)-N-goes
Methyl meptazinol or (-) preparation cost of-N-demethyl meptazinol.
Summary of the invention
It is an object of the present invention to provide low cost, the optical voidness that yield is high (+)-N-demethyl meptazinol
Or (-) preparation method of-N-demethyl meptazinol.
It is an object of the invention to be realized by following design:
A kind of optically pure lower formula (I) or the preparation method of (II) compound,
Including (a) in atent solvent, in the presence of alkali, make optical voidness monomer meptazinol (III) and chlorine
Formic acid-2,2,2-trichloro ethyl esters (IV) react,
Obtain the carbamates intermediate of formula (V)
B () adds glacial acetic acid and water mixed solvent and zinc in formula (V) intermediate of step (a) gained
Powder, reaction prepares optically pure formula (I) or formula (II) compound.
In one embodiment, optical voidness monomer meptazinol (III) and chloro-carbonic acid-2,2,2-tri-chloroethenes
The mol ratio of ester (IV) is 1:7.5.
In another embodiment, described zinc powder is the zinc powder of activation, and activation method uses known in the art
Dilute hydrochloric acid processing method (Synthesis 2005,17,2,838 2844), its consumption and chloro-carbonic acid-2,2,
2-trichloro ethyl ester (IV) equivalent.
In a further embodiment, described atent solvent is selected from oxolane (THF), chloroform, dichloromethane
Alkane, benzene, toluene, DMF (DMF) or its mixture；Described alkali is selected from bicarbonate
Potassium or sodium.
In preferred embodiments, in glacial acetic acid described in step (b) and water mixed solvent, glacial acetic acid
Being 2:1～6:1 with the weight ratio of water, preferred weight ratio is 4:1.
Preferably, step (a) is carried out under being heated to backflow；Step (b) is carried out under ice cooling, 4.
Described reaction process is as follows:
What in one embodiment, the inventive method prepared is (-)-N-demethyl meptazinol.
In another embodiment, preparation be (+)-N-demethyl meptazinol.
Detailed description of the invention
Further illustrate the present invention with preparing embodiment below, but be not intended to the present invention.
Embodiment 1
Will (-) meptazinol (5.0g, 21.4 mMs), anhydrous K HCO3(37.5g, 364.9 millis
Mole) and the mixing of 130mL chloroform, heated and stirred makes meptazinol be completely dissolved, and continues to be heated to backflow,
Drip rapidly chloro-carbonic acid-2,2,2-trichloro ethyl esters (34.1g, 160.5 mMs), continue back flow reaction 1
Hour, TLC monitoring reaction (DCM:MeOH=25:1), treat that substrate reactions is complete, cooling, filter,
Concentrate, obtain light yellow oil 27.5g (theoretical value 12.2g), be dissolved in 20mL water and 80mL
In glacial acetic acid, lower point of 3-4 of ice bath criticizes the zinc powder (10.5g, 160.5 mMs) adding activation, and stirring is anti-
Answer 2 hours, after TLC monitoring reaction completely, filter, concentrate, add 200mL DCM and 150mL
Water, adjusts pH to 9～10 with ammonia under ice bath.Separate organic layer, water layer with DCM extract (200mL ×
3), merge DCM layer solution, and wash three times with saturated NaCl aqueous solution, be dried through anhydrous sodium sulfate.
Filter, concentrate, obtain brown oil 10.2g, through silica gel column chromatography purification (eluant:
DCM:MeOH:NH3H2O=50:1:0.1), finally give (-)-N-demethyl meptazinol 4.0g (is
Yellow oil).Total recovery is 85.3% (by raw material (-)-meptazinol in terms of).MS(ESI):220.1
[M+H]+。
Above-mentioned yellow oil is dissolved in absolute ether, filters insoluble matter, drips anhydrous HCl-diethyl ether solution
Regulation pH to 4, separates out white powder.Filter, vacuum drying, obtain (-)-N-demethyl meptazinol
Hydrochlorate.Fusing point: 73-75 DEG C；[α]D=-7.12 ° (c=0.30, MeOH)；1HNMR(DMSO-d6):9.42
(s,H,Ar-OH),8.82(br s,1/2H,NH+, heavy water exchange disappears), 8.24 (br s, 1/2H, NH+, weight
Water coke slurry disappears) 7.16 (t, H, J=7.8Hz, ArH), 6.74-6.65 (m, 3H, ArH), 3.49 (d, H, J=
14.1Hz,N-CH2), 3.21 (d, H, J=14.5Hz, N-CH2),3.08-3.00(m,2H,N-CH2),2.14
(m,H,CH2),1.77-1.55(m,7H,CH2), 0.49 (t, 3H, J=7.4Hz, CH3)。
Embodiment 2
Will (+) meptazinol (5.0g, 21.4 mMs), anhydrous K HCO3(37.5g, 364.9 millis
Mole) and the mixing of 130mL chloroform, heated and stirred makes meptazinol be completely dissolved, and continues to be heated to backflow,
Drip rapidly chloro-carbonic acid-2,2,2-trichloro ethyl esters (34.1g, 160.5 mMs), continue back flow reaction 1
Hour, TLC monitoring reaction (DCM:MeOH=25:1), treat that substrate reactions is complete, cooling, filter,
Concentrate, obtain light yellow oil 26.2g (theoretical value 12.2g), be dissolved in 20mL water and 80mL
In glacial acetic acid, lower point of 3-4 of ice bath criticizes the zinc powder (10.5g, 160.5 mMs) adding activation, and stirring is anti-
Answer 2 hours, after TLC monitoring reaction completely, filter, concentrate, add 200mL DCM and 150mL
Water, adjusts pH to 9～10 with ammonia under ice bath.Separate organic layer, water layer with DCM extract (200mL ×
3), merge DCM layer solution, and wash three times with saturated NaCl aqueous solution, be dried through anhydrous sodium sulfate.
Filter, concentrate, obtain brown oil 10.2g, through silica gel column chromatography purification (eluant:
DCM:MeOH:NH3H2O=50:1:0.1), finally give (+)-N-demethyl meptazinol 3.8g (is
Light brown grease).Total recovery is 81.0% (by raw material (+)-meptazinol in terms of).MS(ESI):220.1
[M+H]+。
Comparative example 1:
Left-handed meptazinol (20.9g, 90 mMs) and phenyl chloroformate (97 milliliters, 770 mMs)
In chloroform, in the presence of potassium bicarbonate reaction prepare intermediate (-)-N, O-hexichol oxygen formoxyl-N-demethyl is beautiful
His phenol (yellow oil) general.Again above-mentioned grease is dissolved in methanol/water solution, in the presence of potassium carbonate
Hydrolysis, prepares crude product brown oil 34g, through silica gel column chromatography purification (E-C solution gradient
Eluting), obtain (-)-N-benzene oxygen formoxyl-N-demethyl meptazinol 29g, light yellow oil, yield:
95%.Then (-)-N-benzene oxygen formoxyl-N-demethyl meptazinol and 85% hydrazine hydrate mixing, water again
Solve reaction prepare (-)-N-demethyl meptazinol 8.0g (for yellow oil), yield 43%.MS(ESI):
220.1[M+H]+。
Above-mentioned overall yield of reaction 41%.
Comparative example 2:
Left-handed meptazinol (9.83g, 42.2 mMs) and ethyl chloroformate (34.8g, 320 mMs)
In chloroform, in the presence of potassium bicarbonate reaction prepare intermediate (-)-N, O-diethoxy formoxyl-N-demethyl is beautiful
His phenol (yellow oil) general.Again above-mentioned grease is dissolved in methanol/water solution, in the presence of potassium carbonate
Hydrolysis, prepare (-)-N-ethoxycarbonyl-N-demethyl meptazinol 11.17g, yield: 95%.So
Rear addition 50% aqueous sulfuric acid again be hydrolyzed reaction prepare (-)-N-demethyl meptazinol 4.58g
(for yellow oil), yield 54%.MS(ESI):220.1[M+H]+。
Above-mentioned overall yield of reaction 51%.
Above-mentioned yellow oil becomes salt in anhydrous HCl-diethyl ether solution, prepare (-)-N-demethyl U.S.
His phenates hydrochlorate general.Fusing point: 73-75 DEG C；[α]D=-7.10 ° (c=0.286, MeOH)；1HNMR
(DMSO-d6):9.42(s,H,Ar-OH),8.82(br s,1/2H,NH+, heavy water exchange disappears), 8.24 (br s,
1/2H,NH+, heavy water exchange disappears) and 7.16 (t, H, J=7.8Hz, ArH), 6.74-6.65 (m, 3H, ArH),
3.49 (d, H, J=14.1Hz, N-CH2), 3.21 (d, H, J=14.5Hz, N-CH2),3.08-3.00(m,2H,
N-CH2),2.14(m,H,CH2),1.77-1.55(m,7H,CH2), 0.49 (t, 3H, J=7.4Hz, CH3)。
(i.e. meptazinol first reacts again through two with haloformate for the preparation method of the present invention and art methods
One-step hydrolysis reacts) to compare, the formate ester intermediate of step (a) gained is not required to purification, can be directly through a step
Hydrolysis obtains target product.Which shorten reactions steps, simplify post-processing operation；It is greatly enhanced
Overall yield of reaction (bringing up to more than 80% from original 40～51%), considerably reduces production cost.
Claims (8)
1. optically pure lower formula (I) or the preparation method of (II) compound,
Described method includes:
A (), in atent solvent, in the presence of alkali, makes optical voidness monomer meptazinol (III) and chloro-carbonic acid-2,
2,2-trichloro ethyl esters (IV) react,
Obtain the carbamates intermediate of formula (V)
B () adds glacial acetic acid and water mixed solvent and zinc in formula (V) intermediate of step (a) gained
Powder, reaction prepares optically pure formula (I) or formula (II) compound.
2. the method for claim 1, it is characterised in that described atent solvent selected from oxolane,
Chloroform, dichloromethane, benzene, toluene, DMF (DMF) or its mixture.
3. method as claimed in claim 1 or 2, it is characterised in that described alkali is selected from potassium bicarbonate or sodium.
4. the method for claim 1, it is characterised in that glacial acetic acid described in step (b) and water
In mixed solvent, glacial acetic acid is 2:1～6:1 with the weight ratio of water.
5. method as claimed in claim 4, it is characterised in that glacial acetic acid is 4:1 with the weight ratio of water.
6. the method for claim 1, it is characterised in that described zinc powder is the zinc powder of activation.
7. method as claimed in claim 6, it is characterised in that the consumption of described zinc powder is 3～8 equivalents.
8. the method for claim 1, it is characterised in that described step (a) is being heated to backflow
Under carry out；Described step (b) is carried out under ice cooling, 4.
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| CN201510354529.8A CN106316954B (en) | 2015-06-24 | 2015-06-24 | The method for preparing optical voidness (+)-or (-)-N- demethyl meptazinol |
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| CN201510354529.8A CN106316954B (en) | 2015-06-24 | 2015-06-24 | The method for preparing optical voidness (+)-or (-)-N- demethyl meptazinol |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1974558A (en) * | 2006-12-20 | 2007-06-06 | 复旦大学 | (+)-Meptazinol diligand derivative and/or its salt and the prepn process |
| CN101037430A (en) * | 2006-07-27 | 2007-09-19 | 复旦大学 | (-)-meptazinol double-ligand derivative and/or its salt and preparation method and usage |
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2015
- 2015-06-24 CN CN201510354529.8A patent/CN106316954B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101037430A (en) * | 2006-07-27 | 2007-09-19 | 复旦大学 | (-)-meptazinol double-ligand derivative and/or its salt and preparation method and usage |
| CN1974558A (en) * | 2006-12-20 | 2007-06-06 | 复旦大学 | (+)-Meptazinol diligand derivative and/or its salt and the prepn process |
Non-Patent Citations (1)
| Title |
|---|
| QIONG XIE ET AL: "Bis-(?)-nor-meptazinols as Novel Nanomolar Cholinesterase Inhibitors with High Inhibitory Potency on Amyloid-β Aggregation", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
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Address after: 200032 Shanghai Xuhui District Xietu Road No. 2140 Patentee after: Shanghai Institute of biomedical technology Address before: 200032 Shanghai Xuhui District Xietu Road No. 2140 Patentee before: SHANGHAI INSTITUTE OF PLANNED PARENTHOOD RESEARCH |