CN103450081A - Preparation method of meptazinol hydrochloride intermediate 1-methyl-3-(3-oxo-1-cyclohexyl-1-alkenyl)-6H-azepin-2-one - Google Patents
Preparation method of meptazinol hydrochloride intermediate 1-methyl-3-(3-oxo-1-cyclohexyl-1-alkenyl)-6H-azepin-2-one Download PDFInfo
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Abstract
The invention discloses a preparation method of a meptazinol hydrochloride intermediate 1-methyl-3-(3-oxo-1-cyclohexyl-1-alkenyl)-6H-azepin-2-one. The method comprises a step that a coupling reaction of a raw material 3-ethoxy-2-cyclohexenyl-1-one represented by a structural formula (I) with N-methylcaprolactam represented by a structural formula (II) is carried out in an inert solvent in the presence of an alkali at a certain temperature to form 1-methyl-3-(3-oxo-1-cyclohexyl-1-alkenyl)-6H-azepin-2-one represented by a structural formula (III). The yield and the content of a product prepared through the method disclosed in the invention are obviously higher than the yield and the content of the product prepared through present methods.
Description
Technical field
The present invention relates to the preparation method of compound, relate more specifically to the preparation method of the important intermediate 1-methyl-3-(3-oxygen-cyclohexyl-1-alkene) of Wy-22811-6H-azatropylidene-2-ketone.
Background technology
Wy-22811 is anodyne of new generation, and the nineteen eighty-three listing, collected by British Pharmacopoeia in 1998.
Wy-22811, without habituation, is non-control class anodyne [soup light, modern pharmacology [M] Beijing: Chinese Medicine science and technology press, 1997:246-248].The anodyne of current clinical use is mostly with habituation, and by contrast, the side effect of Wy-22811 is little, is desirable substitute products.
Wy-22811 is applicable to acute and chronic pain, as wound, postoperative, and obstetrics and cancer pain etc., be used in particular for inhibiting pain in parturition safe and effective, do not affect again Neonatal Health.
Prepare at present the main method of Wy-22811 as shown in Scheme 1 (route one).
American documentation literature US4197241 etc. mentions take cyclohexanedione as raw material, and under the condition that is catalyzer at tosic acid, toluene band water obtains structural formula 2 compounds, and this route raw material is easy to get, low price; Step is short, easy handling.
We are in use Scheme 1 (route one) prepares the process of Wy-22811, the preparation of finding intermediate 1-methyl-3-(3-oxygen-cyclohexyl-1-alkene)-6H-azatropylidene-2-ketone (structural formula 3 compounds in Scheme 1) is one of key problem in technology, but the method for preparing at present this intermediate can't be satisfactory, concrete document analysis is as follows:
Document " European Journal of Medicinal Chemistry, 15 (4), 375-85,1980; Fine-chemical intermediate, 40 (4), 27-30,2010 " react rear and 3-methoxyl group-2-tetrahydrobenzene-1-ketone coupling in N-methyl cyclohexane lactan with LDA, obtain formula 3 compounds, finally with toluene-sherwood oil system crystallization, yield 88%, the content of finding product while but repeating this condition is low, and purity is also unsatisfactory; Document " preparation and technology, 17 (6), 120-121,2010 " has been used 3-isopropoxy-2-tetrahydrobenzene-1-ketone coupling instead, and yield is lower, only has 50.6%; Therefore, this area is in the urgent need to developing the method for the intermediate 1-methyl-3-for preparing Wy-22811 new, high-efficient simple (3-oxygen-cyclohexyl-1-alkene)-6H-azatropylidene-2-ketone.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of more economical, method of more safely preparing Wy-22811 intermediate 1-methyl-3-(3-oxygen-cyclohexyl-1-alkene)-6H-azatropylidene-2-ketone.
Concrete grammar more economical, that more safely prepare 1-methyl-3-(3-oxygen-cyclohexyl-1-alkene)-6H-azatropylidene-2-ketone provided by the invention is as follows:
In inert solvent, 3-oxyethyl group-2-tetrahydrobenzene-1-the ketone (structure formula I compound) of take is raw material, under the condition of alkali and certain temperature, carry out linked reaction with N-methyl caprolactam (structure formula II compound), form 1-methyl-3-(3-oxygen-cyclohexyl-1-alkene)-6H-azatropylidene-2-ketone, i.e. structure formula III compound;
Through research repeatedly, it is the Perfected process of preparation 1-methyl-3-(3-oxygen-cyclohexyl-1-alkene)-6H-azatropylidene-2-ketone (structure formula III compound) that the applicant finds to use 3-oxyethyl group-2-tetrahydrobenzene-1-ketone (structure formula I compound), and has completed on this basis the present invention.
Preparation method of the present invention is below more specifically described.However, it should be understood that the present invention is not limited to following given concrete reaction conditions (as the amount of solvent, compound used therefor, temperature of reaction, reaction required time etc.).
Preparation method of the present invention can mean by following flow process:
In inert solvent, 3-oxyethyl group-2-tetrahydrobenzene-1-the ketone (structure formula I compound) of take is raw material, under the condition of alkali and certain temperature, carry out linked reaction with N-methyl caprolactam (structure formula II compound), form 1-methyl-3-(3-oxygen-cyclohexyl-1-alkene)-6H-azatropylidene-2-ketone, i.e. structure formula III compound.
In the present invention, " linked reaction " (English: Coupled reaction), also making coupling reaction, coupled reaction, oxidative coupling, is carried out certain chemical reaction and obtained the process of an organic molecule by two organic chemistry units (molecules).
In the present invention, can use inert solvent to be selected from any one or a few in toluene, tetrahydrofuran (THF), 2-methyltetrahydrofuran, methyl tertiary butyl ether, ether, Isosorbide-5-Nitrae-dioxane and isopropyl ether.The inert solvent preferably used is tetrahydrofuran (THF) (THF).
The alkali used comprises that organic metallic lithium compound is (as butyllithium, di-isopropyl ammonia lithium, benzyl lithium, Grignard reagent, alkyl copper lithium etc.), sodium alkoxide or potassium alcoholate be (as sodium methylate, sodium ethylate, potassium ethylate, sodium tert-butoxide, potassium etc.), aminocompound is (as potassium amide, sodium amide etc.) and alkalimetal hydride (as NaH, KH etc.).The alkali preferably used is di-isopropyl ammonia lithium (LDA).
The temperature of reaction of described linked reaction is-80 ~ 30 ℃, is preferably-40 ~-10 ℃.
The reaction times of described linked reaction is not particularly limited, and 0.5-30 hour, be preferably 1-10 hour usually.
Compared with prior art, the beneficial effect of the inventive method is:
Visible with reference example (adopting 3-methoxyl group-2-tetrahydrobenzene-1-ketone or 3-isopropoxy-2-tetrahydrobenzene-1-ketone as raw material) contrast through the embodiment of the present invention (adopting 3-oxyethyl group-2-tetrahydrobenzene-1-ketone as raw material), the present invention is with 3-oxyethyl group-2-tetrahydrobenzene-1-ketone and the coupling under the condition of alkali and certain temperature of N-methyl caprolactam, obtain structure formula III compound, preparing product yield and product content obviously are better than existing method (as reference example).
Embodiment
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only are not used in and limit the scope of the invention for the present invention is described.The experimental technique of unreceipted concrete reaction conditions in the following example, usually according to normal condition, or the condition of advising according to manufacturer, 3-oxyethyl group-2-tetrahydrobenzene-1-ketone prepares or directly buys from the market according to american documentation literature US4197241 method, and other starting material are commercial product.
In all embodiment, thermometer is not proofreaied and correct;
1varian Mercury 400 nuclear magnetic resonance analyser records for H-NMR, chemical shift means with δ (ppm); GC is the Shimadzu system; Mass spectrum is measured with Agilent 6120LC-MS LC-MS instrument, content HPLC external standard method.
Embodiment 1
The preparation of 1-methyl-3-(3-oxygen-cyclohexyl-1-alkene)-6H-azatropylidene-2-ketone
N-Butyl Lithium (2.5L, 2.5mol/L, 1.5eq) is dissolved into to THF(3.0L) in, be cooled to-20 ℃, start to drip Diisopropylamine (885mL, 6.25mol, 1.5eq).Drip and finish, stir 30min, start to drip N-methyl caprolactam (765g, 6.25mol, 1.5eq).Dropwise, stir 30min, start to drip 3-oxyethyl group-2-tetrahydrobenzene-1-ketone (585g, 4.15mol, 1.0eq).The TLC monitoring reaction is complete, in reaction solution, drips water (1L), then with concentrated hydrochloric acid, adjusts PH to 1.Stir separatory, methylene dichloride (1.5L*3) aqueous phase extracted.Merge organic phase, revolve and desolventize, ethyl acetate (700mL) recrystallization obtains white solid 900g, yield: 97.5%, and content: 99.0%.
1H?NMR(400MHz,CDCl
3)δ5.83(d,J=0.8Hz,1H),3.59(dd,J=15.4,10.9Hz,1H),3.37(d,J=10.2Hz,1H),3.21(ddd,J=5.9,5.2,1.2Hz,1H),2.98(s,3H),2.68–2.46(m,1H),2.45–2.35(m,2H),2.35–2.20(m,1H),2.13–1.92(m,3H),1.92–1.34(m,6H).
MS：[M+H]:222.1
Embodiment 2
The preparation of 1-methyl-3-(3-oxygen-cyclohexyl-1-alkene)-6H-azatropylidene-2-ketone
Potassium tert.-butoxide (119.5g, 1.07mol, 1.5eq) is dissolved into to THF(700mL) in, after being cooled to 0 ℃, drip N-methyl caprolactam (130.4g, 1.07mol, 1.5eq).Dropwise, stir 30min, start to drip 3-oxyethyl group-2-tetrahydrobenzene-1-ketone (100g, 0.71mol, 1.0eq).The TLC monitoring reaction is complete, and decompression is revolved and removed approximately half solvent, adds water (200L), then with concentrated hydrochloric acid, adjusts PH to 1.Stir separatory, methylene dichloride (1.5L*3) aqueous phase extracted.Merge organic phase, revolve and desolventize, ethyl acetate (120mL) recrystallization obtains white solid 142.0g, yield: 90%, and content: 98.0%.
Embodiment 3
The preparation of 1-methyl-3-(3-oxygen-cyclohexyl-1-alkene)-6H-azatropylidene-2-ketone
N-Butyl Lithium (1.0L, 2.5mol/L, 1.5eq) is dissolved in toluene (1.2L), is cooled to-20 ℃, start to drip Diisopropylamine (354mL, 2.5mol, 1.5eq).Drip and finish, stir 30min, start to drip N-methyl caprolactam (306g, 2.5mol, 1.5eq).Dropwise, stir 30min, start to drip 3-oxyethyl group-2-tetrahydrobenzene-1-ketone (234g, 1.66mol, 1.0eq).The TLC monitoring reaction is complete, in reaction solution, drips water (400L), then with concentrated hydrochloric acid, adjusts PH to 1.Stir separatory, toluene (600mL*2) aqueous phase extracted.Merge organic phase, revolve and desolventize, ethyl acetate (280mL) recrystallization obtains white solid 339.5g, yield: 91.0%, and content: 97.0%.
Reference example 1
The preparation of 1-methyl-3-(3-oxygen-cyclohexyl-1-alkene)-6H-azatropylidene-2-ketone
N-Butyl Lithium (500mL,, 2.5mol/L, 1.5eq) is dissolved into to THF(600mL) in, be cooled to-20 ℃, start to drip Diisopropylamine (177mL, 1.25mol, 1.5eq).Drip and finish, stir 30min, start to drip N-methyl caprolactam (153g, 1.25mol, 1.5eq).Dropwise, stir 30min, start to drip 3-methoxyl group-2-tetrahydrobenzene-1-ketone (105g, 0.83mol, 1.0eq).The TLC monitoring reaction is complete, in reaction solution, drips water (200mL), then with concentrated hydrochloric acid, adjusts PH to 1.Stir separatory, methylene dichloride (300mL*3) aqueous phase extracted.Merge organic phase, revolve and desolventize, toluene (300mL)/sherwood oil (150mL) recrystallization.Obtain faint yellow look solid 157.2g, yield: 85.0%, content: 90%.
Reference example 2
The preparation of 1-methyl-3-(3-oxygen-cyclohexyl-1-alkene)-6H-azatropylidene-2-ketone
N-Butyl Lithium (500mL, 2.5mol/L, 1.5eq) is dissolved into to THF(600mL) in, be cooled to-20 ℃, start to drip Diisopropylamine (177mL, 1.25mol, 1.5eq).Drip and finish, stir 30min, start to drip N-methyl caprolactam (153g, 1.25mol, 1.5eq).Dropwise, stir 30min, start to drip 3-isopropoxy-2-tetrahydrobenzene-1-ketone (128.4g, 0.83mol, 1.0eq).The TLC monitoring reaction is complete, in reaction solution, drips water (200mL), then with concentrated hydrochloric acid, adjusts PH to 1.Stir separatory, methylene dichloride (300mL*3) aqueous phase extracted.Merge organic phase, revolve and desolventize, toluene (300mL)/sherwood oil (150mL) recrystallization.Obtain faint yellow solid 129.4g, yield: 70.0%, content: 88.0%.
Claims (10)
1. the preparation method of a Wy-22811 intermediate 1-methyl-3-(3-oxygen-cyclohexyl-1-alkene)-6H-azatropylidene-2-ketone, is characterized in that, comprises the steps:
In inert solvent, the oxyethyl group of 3-shown in the structure formula I-2-tetrahydrobenzene-1-ketone of take is raw material, under the condition of alkali and certain temperature, carry out linked reaction with N-methyl caprolactam shown in the structure formula II, form 1-methyl-3-(3-oxygen-cyclohexyl-1-alkene)-6H-azatropylidene-2-ketone shown in the structure formula III, its reaction formula is as follows:
2. the method for claim 1, is characterized in that, described inert solvent is selected from toluene, tetrahydrofuran (THF), 2-methyltetrahydrofuran, methyl tertiary butyl ether, ether, any one or a few in Isosorbide-5-Nitrae-dioxane and isopropyl ether.
3. method as claimed in claim 2, is characterized in that, described inert solvent is tetrahydrofuran (THF).
4. the method for claim 1, is characterized in that, described alkali is selected from any one or a few in organo-metallic lithium compound, sodium alkoxide or potassium alcoholate, aminocompound and alkalimetal hydride.
5. method as claimed in claim 4, is characterized in that, described organo-metallic lithium compound comprises butyllithium, di-isopropyl ammonia lithium, benzyl lithium, Grignard reagent, alkyl copper lithium; Described sodium alkoxide or potassium alcoholate comprise sodium methylate, sodium ethylate, potassium ethylate, sodium tert-butoxide, potassium tert.-butoxide; Described aminocompound comprises potassium amide, sodium amide; Described alkalimetal hydride comprises NaH, KH.
6. method as described as claim 4 or 5, is characterized in that, described alkali is di-isopropyl ammonia lithium.
7. the method for claim 1, is characterized in that, the temperature of reaction of described linked reaction is-80 ~ 30 ℃.
8. method as claimed in claim 7, is characterized in that, the temperature of reaction of described linked reaction is-40 ~-10 ℃.
9. the method for claim 1, is characterized in that, the reaction times of described linked reaction is 0.5-30 hour.
10. method as claimed in claim 9, is characterized in that, the reaction times of described linked reaction is 1-10 hour.
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Application publication date: 20131218 |