CN1062898A - 2-(5-methoxyl group-1-heptyl) dicyclo (3,3, the O) synthetic method of octane-7-ketone - Google Patents
2-(5-methoxyl group-1-heptyl) dicyclo (3,3, the O) synthetic method of octane-7-ketone Download PDFInfo
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Abstract
The invention provides a kind of chemical formula is:
Description
The present invention relates to 2-(5-methoxyl group-1-heptyl) synthetic method of dicyclo [3.3.0] octane-7-ketone (hereinafter to be referred as X-Andron), particularly the present invention relates to method with the synthetic X-Andron of new synthetic route.
The chemical name of X-Andron is 2-(5-methoxyl group-1-heptyl) dicyclo [3.3.0] octane-7-ketone, its molecular formula is C
16H
28O
2, chemical structural formula is
As a kind of effective antiandrogen (ANTI-ANDROGEN), X-Andron is able to promotion and application in fields such as medicine, health care, cosmetics.Its concrete application example has anticancer, controls male sex's bald head, controls arteriosclerosis, and is crease-resistant, eliminates acne, ultraviolet radiation resisting, many aspects such as skin moisten.Consumption is minimum can to obtain unusual effect, not only can external application but also can take orally.Therefore have good use value and huge potentiality to be exploited.
About the method for making of X-Andron, at present the feasible method that can retrieve have only a kind of, i.e. U.S. Water J.Kasha ﹠amp; Four step synthesis methods of Chantal S.Burnison invention in 1987 are referring to United States Patent (USP) 4689345.This method is a starting raw material with 3-chlorine cyclopentenes and 1-chloro-5-methoxyl group heptane, by Ge Shi linked reaction, cycloaddition reaction, diazomethane insertion reaction and reduction reaction etc., separates then that finally to obtain X-Andron pure
The most important significance of foregoing invention is that it provides a kind of feasible method for X-Andron synthetic the earliest.But there is a fatal weakness in this method, and promptly its most basic starting raw material 1-chloro-5-methoxyl group heptane promptly can't have been bought on market, does not have simple and convenient preparation method again, causes this method to run into exceptional hardship on commercially producing.
Once the synthetic method (PCT/US 83700721) of 1-chloro-5-methoxyl group heptane that patent report arranged:
Three steps were removed synthetic 1-chloro-5-methoxyl group heptane though this method is retrodicted on original basis, but still did not solve final raw material problem, because its used starting raw material 5-hydroxyl enanthic acid neither business-like product, and did not have easy method for making.
The inventor for solving above-mentioned problems of the prior art through extensive and deep research, has found a kind of practicable synthetic method just, has finished the present invention thus.
Therefore, an object of the present invention is to provide a kind of method of synthetic X-Andron.
Another object of the present invention provides a kind of method with the raw material that is easy to get and the brand-new synthetic X-Andron of synthetic method.
A further object of the present invention provides a kind of method that is easy to the synthetic X-Andron of suitability for industrialized production easy and simple to handle.
Other purpose of the present invention can be by finding out in the following specification sheets.
Above-mentioned purpose of the present invention realizes by using following raw material and synthetic method.
In the present invention, select commerce-change on the market for use 1-bromo-4-chlorobutane be initial starting raw material, can obtain the final product X-Andron through simple and easy to do chemical reaction process, promptly chemical name is 2-(5-methoxyl group-1-heptyl) dicyclo [3,3,0] compound of octane-7-ketone.
Synthetic method of the present invention comprises the steps:
1) in the presence of solvent and magnesium 1-bromo-4-chlorobutane is made single Grignard reagent, this reagent makes intermediate 3-(4-chloro-1-butyl with the coupling of 3-chlorine cyclopentenes in the presence of solvent) cyclopentenes;
2) in the presence of solvent and magnesium with the intermediate 3-(4-chloro-1-butyl of step 1)) cyclopentenes makes Grignard reagent, this reagent is made intermediate 3-(5-hydroxyl-1-heptyl with the propionic aldehyde reaction in solvent) cyclopentenes;
3) use diverse ways with step 2) in intermediate 3-(5-hydroxyl-1-heptyl of making) cyclopentenes methylates and makes intermediate 3-(5-methoxyl group-1-heptyl) cyclopentenes, the present invention relates to following four kinds of methods: a) in the presence of solvent and boron trifluoride, make methylating reagent to intermediate 3-(5-hydroxyl-1-heptyl with diazomethane) cyclopentenes methylates; B) in the presence of solvent and sulfuric acid, with trimethyl orthoformate as methylating reagent to intermediate 3-(5-hydroxyl-1-heptyl) cyclopentenes methylates; C), under the existence of potassium hydroxide and phase-transfer catalyst, make methylating reagent to step 2 with methyl-sulfate at solvent) intermediate 3-(5-hydroxyl-1-heptyl) cyclopentenes methylates; D) under alkali-metal effect, make methylating reagent to step 2 with fontanel methane) intermediate 3-(5-hydroxyl-1-heptyl) cyclopentenes methylates;
4) under different condition, allowing the intermediate 3-(5-methoxyl group-1-heptyl of Ethylene Dichloride ketone and step 3)) cyclopentenes carries out cycloaddition reaction and generates intermediate 6,6-two chloro-2-(5-methoxyl group-1-heptyl) dicyclo [3,2,0] heptane-7-ketone, source difference according to Ethylene Dichloride ketone the present invention relates to following three kinds of methods: a) in the presence of solvent and triethylamine, the intermediate 3-(5-methoxyl group-1-heptyl of dichloroacetyl chloride and step 3)) the cyclopentenes reaction makes intermediate 6,6-two chloro-2-(5-methoxyl group-1-heptyl) dicyclo [3.2.0] heptane-7-ketone; B) at solvent, phosphorus oxychloride and nitrogen exist down, allow activated zinc, the intermediate 3-(5-methoxyl group-1-heptyl of trichoroacetic chloride and step 3)) cyclopentenes carries out cycloaddition reaction and makes intermediate 6,6-two chloro-2-(5-methoxyl group-1-heptyl) dicyclo [3.2.0] heptane-7-ketone; C) in the presence of solvent and zinc-copper idol, in nitrogen atmosphere, allow the intermediate 3-(5-methoxyl group-1-heptyl of trichoroacetic chloride and step 3)) cyclopentenes reacts and makes intermediate 6,6-two chloro-2-(5-methoxyl group-1-heptyl) dicyclo [3.2.0] heptane-7-ketone;
5) in the presence of catalyzer, diazomethane in solution with the intermediate 6 of step 4), 6-two chloro-2-(5-methoxyl group-1-heptyl) dicyclo [3,2,0] heptane-7-ketone carries out insertion reaction, generates intermediate 6,6-two chloro-2-(5-methoxyl group-1-heptyl) dicyclo [3.3.0] octane-7-ketone;
6) a) in the presence of carboxylic acid, with the intermediate 6 of zinc powder reduction step 5), 6-two chloro-2-(5-methoxyl group-1-heptyl) dicyclo [3.3.0] octane-7-ketone obtains the finished product X-Andron, i.e. 2-(5-methoxyl group-1-heptyl) dicyclo [3.3.0] octane-7-ketone; B) in the presence of solvent and ammonium chloride, with the intermediate 6 of zinc powder reduction step 5), 6-two chloro-2-(5-methoxyl group-1-heptyl) dicyclo [3,3,0] octane-7-ketone gets the product X-Andron.
Aforesaid method of the present invention also is following reaction process:
Solvent in the aforesaid method of the present invention in the step 1) is selected from ethers, as is selected from ether, tetrahydrofuran (THF), and tetrahydropyrans etc., preferred solvent is a tetrahydrofuran (THF); Magnesium is selected from commercial metals magnesium chips, chemical reagent-grade; 1-bromo-4-chlorobutane is selected from the import commercial goods, purity＞98%; 3-chlorine cyclopentenes carries out addition reaction by hydrogenchloride and cyclopentadiene and makes.Temperature of reaction is 0 ℃～-35 ℃ of single Grignard reagents of system, and preferable range is-10 ℃～-25 ℃, with 10 ℃～-30 ℃ preferable range of 3-chlorine cyclopentenes coupling be 5 ℃～-15 ℃.The amount ratio of used three kinds of raw materials is a mol ratio such as basic, and permissible error is＜10%.Solvent load is every mole metal magnesium 500～1000ML.
Step 2) the selecting for use and the same step 1) of amount ratio of solvent and magnesium in, propionic aldehyde is selected from the commercial goods.Magnesium, 3-(4-chloro-1-butyl) amount ratio of cyclopentenes and propionic aldehyde is (1～1.1): (1～1.1): (1～1.3) [mol ratio].The temperature of reaction of system Grignard reagent is the reflux temperature of solvent.The temperature of Grignard reagent and propionic aldehyde reaction is 0 ℃～36 ℃, and preferred temperature is 0 ℃～10 ℃.
Method solvent a) is selected from ethers and alcohols in the step 3), as is selected from ether, tetrahydrofuran (THF), methyl alcohol, ethanol, propyl alcohol, butanols etc., and preferred solvent is an ether.Boron trifluoride is selected from commercially available chemical reagent, and diazomethane reacts in solution with a-methyl-a-nitrosourea and potassium hydroxide and makes, and the insertion reaction temperature is 0 ℃～36 ℃, and preferred temperature is a room temperature.Diazomethane, boron trifluoride and 3-(5-hydroxyl-1-heptyl) amount ratio of cyclopentenes is (1.5～1.9): (0.04～0.05): 1[mol ratio], the consumption of solvent is every mole of 3-(5-hydroxyl-1-heptyl) cyclopentenes 800ML～1500ML; Method b) solvent in is selected from alcohols, as is selected from methyl alcohol, ethanol, Virahol n-propyl alcohol etc., and preferred solvent is a methyl alcohol, and trimethyl orthoformate is selected from the commercial goods, and sulfuric acid is selected from commercially available 98% the vitriol oil, and reacting preferred temperature is room temperature.Trimethyl orthoformate, sulfuric acid and 3-(5-hydroxyl-1-heptyl) amount ratio of cyclopentenes is (0.5～1.2): (0.05～0.1): (0.15～0.2) [mol ratio], the consumption of solvent are every mole of trimethyl orthoformate 100ML～150ML; Method c) solvent in is a water, and potassium hydroxide is selected from the commercial goods, and phase-transfer catalyst is selected from tetrabutyl fontanel ammonium salt.As be selected from tetrabutylammonium chloride, Tetrabutyl amonium bromide, tetrabutylammonium iodide etc.Methyl-sulfate is selected from the commercial goods.Reacting preferred temperature is room temperature, 3-(5-hydroxyl-1-heptyl) amount ratio of cyclopentenes, potassium hydroxide, water, methyl-sulfate and tetrabutyl fontanel ammonium is (150～200): (150～200): (250～400): (150～200): the 1(weight ratio); Method d) basic metal is selected from potassium, sodium etc. in, is preferably sodium, fontanel methane is selected from methyl chloride, monobromethane, methyl iodide etc., is preferably methyl chloride and methyl iodide.Temperature of reaction is 0 ℃～50 ℃, and preferred temperature is 30 ℃～50 ℃, basic metal, fontanel methane and 3-(5-hydroxyl-1-heptyl) amount ratio of cyclopentenes is (1～3): (2～5): the 1(mol ratio).
In the step 4) method a) solvent be selected from small molecules alkane, as be selected from sherwood oil, pentane, hexane, hexanaphthene, heptane etc., preferred solvent is a hexane.Triethylamine and dichloroacetyl chloride all are selected from the commercial goods.Triethylamine, dichloroacetyl chloride and 3-(5-methoxyl group-1-heptyl) amount ratio of cyclopentenes is (0.3～4): (0.3～4): the 1(mol ratio), temperature of reaction is-5 ℃～80 ℃, and preferred temperature is 50 ℃～70 ℃; Method b) solvent is selected from ethers, as is selected from ether, tetrahydrofuran (THF), butyl ethyl ether etc., and preferred solvent is an ether, and phosphorus oxychloride is selected from the commercial goods, and nitrogen is used to form inert environments in reaction.Trichoroacetic chloride is selected from the import commercial goods, activated zinc makes with the commercially available zinc powder of copper sulphate for activation, react the reflux temperature that preferred temperature is a solvent, 3-(5-methoxyl group-1-heptyl) cyclopentenes, activated zinc, the amount ratio of trichoroacetic chloride and phosphorus oxychloride is 1: (2-2.5): (1-1.2): (1-1.2) [mol ratio], the consumption of solvent are every mole of trichoroacetic chloride 2000～5000ML; Method c) solvent is selected from ethers, as be selected from ether, tetrahydrofuran (THF), butyl ethyl ether etc., preferred solvent is an ether, zinc-copper is to make with metal zinc reduction copper-bath by chance, trichoroacetic chloride is with method b), the nitrogen effect is with method b), temperature of reaction is a room temperature, 3-(5-methoxyl group-1-heptyl) cyclopentenes, zinc-copper idol, the amount ratio of trichoroacetic chloride is 1: (5～10): (2.5～3) [mol ratio], solvent load are every mole of 3-(5-methoxyl group-1-heptyl) cyclopentenes 10000～120000ML.
Solvent is selected from ethers in the step 5), as is selected from methyl ethyl ether, ether, and tetrahydrofuran (THF), the temperature of reaction is a room temperature, catalyzer is selected from alcohols, as is selected from methyl alcohol, ethanol, Virahol etc.Preferred catalyst is a methyl alcohol, diazomethane, catalyzer, 6,6-two chloro-2-(5-methoxyl group-1-heptyl) amount ratio of dicyclo [3.2.0] heptane-7-ketone is: (1.3～1.9): (1～4): the 1(mol ratio), solvent consumption be every mole of diazomethane 1000ML～2000ML.
A) acetic acid and zinc powder all are selected from the commercial goods to method in the step 6), acetic acid, zinc powder and 6,6-two chloro-2-(5-methoxyl group-1-heptyl) amount ratio of dicyclo [3.3.0] octane-7-ketone is (5～12): (5～12): 1[mol ratio], the temperature of reaction is 10 ℃～100 ℃, and preferred temperature is 60 ℃～80 ℃.Method b) solvent is selected from alcohols in, as be selected from methyl alcohol, ethanol, preferred solvent is a methyl alcohol, ammonium chloride and zinc powder all are selected from the commercial goods, ammonium chloride, zinc powder and 6,6-two chloro-2-(5-methoxyl group-1-heptyl) amount ratio of dicyclo [3.3.0] octane-7-ketone is (4～10): (5～10): 1[mol ratio], the consumption of solvent is that to react preferred temperature be room temperature to every mole of zinc 1500ML～2500ML, obtain as stated above needing to purify behind the thick product of X-Andron through column chromatography for separation, purifying is with commercially available column chromatography silica gel (100～300 order), developping agent is selected from organic solvent, as being selected from sherwood oil and ether, the proportion of composing of developping agent is a sherwood oil: ether=4: the 1(volume ratio).
More than in each step, except that step 6), gained crude product intermediate all need carry out rectification under vacuum purification rear and can be used for next step reaction.
With embodiment the present invention is further elaborated below, these embodiment just describe method of the present invention, and scope of the present invention is not had any restriction.
[example one]
The preparation of [3-(4-chloro-1-butyl) cyclopentenes]
Method one.At one electric mixer is housed; in the 1000ML there-necked flask of reflux condensing tube and low-reading thermometer; place activatory metal magnesium chips 24g(1.0MOLE) and the 30ML absolute thf; logical nitrogen protection; and cool the temperature to-25 ℃; preparation 1-bromo-4-chlorobutane 171.5g(1.0MOLE) tetrahydrofuran solution 500ML at first adds sub-fraction (about 20ML) by constant pressure funnel.After question response causes, rest part is slowly added (needing 6 hours approximately), remain temperature＜-15 ℃ in the reaction process.Adding the back continues to stir 2 hours, under-25 ℃, slowly add 3-chlorine cyclopentenes 100g(1.0MOLE) tetrahydrofuran solution 200ML, continue to stir 2 hours, and make temperature rise to room temperature, slowly reaction solution is poured into the 2000ML saturated aqueous ammonium chloride, quench with ether and to get three times, merge the back normal pressure and boil off ether and tetrahydrofuran (THF), underpressure distillation then gets product 94g(0.6MOLE)～60%.
Method two.At one electric mixer is housed; in the 1000ML there-necked flask of reflux condensing tube and low-reading thermometer; place activatory metal magnesium chips 24g(1.0MOLE) and the 30ML absolute ether; logical nitrogen protection; and cool the temperature to-5 ℃; preparation 1-bromo-4-chlorobutane 171.5g(1.0MOLE) diethyl ether solution 500ML at first adds sub-fraction (about 20ML) by constant pressure funnel.After question response causes, rest part is slowly added (needing 5 hours approximately), remain temperature＜-10 ℃ in the reaction process.Adding the back continues to stir 2 hours, under-20 ℃, slowly add 3-chlorine cyclopentenes 100g(1.0MOLE) diethyl ether solution 200ML, continue to stir 2 hours, and make temperature rise to room temperature, then reaction solution is poured into the 2000ML saturated aqueous ammonium chloride, quench with ether and to get three times, merge the back normal pressure and boil off ether, underpressure distillation then gets product 44g(0.28MOLE)～28%.
[example two]
The preparation of [3-(5-hydroxyl-1-heptyl) cyclopentenes]
On the there-necked flask of 1000ML, load onto electric mixer, reflux condensing tube, add magnesium chips 24g(1.0MOLE) and the 30ML ether, preparation 3-(4-chloro-1-butyl) diethyl ether solution 500ML cyclopentenes 156.5g(1.0MOLE), and at first add sub-fraction (about 20ML) by dropping funnel, reflux causes reaction, dripping rest part then continuously makes system keep spontaneous backflow, finish and continued reflux 2 hours, cool off reaction solution with frozen water, dropping propionic aldehyde 58g(1.0MOLE) diethyl ether solution 200ML after adding, refluxed 1 hour.Add 15% aqueous sulfuric acid of q.s then, tell organic layer, again with the ether water intaking layer of quenching, merge organic layer and use anhydrous sodium sulfate drying after washing with water, underpressure distillation 3MMHg, 118 ℃ gets product 128g(0.7MOLE)～70%.
[example three]
The preparation of [3-(5-methoxyl group-1-heptyl) cyclopentenes]
Method one.To fill 3-(5-hydroxyl-1-heptyl) cyclopentenes 55G(0.3MOLE), the 500ML Erlenmeyer flask of the diethyl ether solution 100ML of boron trifluoride 1.0G is placed on the magnetic stirrer, with a-methyl-a-nitrosourea is that raw material adds the diethyl ether solution 250ML that potassium hydroxide aqueous solution prepares diazomethane 23g, add in the above-mentioned solution, normal temperature stirred 4 hours down in batches.Add and boil off ether after the 2ML Glacial acetic acid is removed remaining diazomethane, underpressure distillation 3MMHg, 105-108 ℃ then, product 44g(～0.22MOLE)～75%.
Method two.To a solution methyl alcohol 1580ML who is stirring, trimethyl orthoformate 1533g(14.4MOLES), and sulfuric acid 63ML, add 3-(5-hydroxyl-1-heptyl) cyclopentenes 455g(2.5MOLES), at room temperature stirred three days, and washed with sodium bicarbonate aqueous solution then and cause neutrality, quench with ether and get 3 times, combined ether layer anhydrous sodium sulfate drying, remove ether after underpressure distillation get product 382g(1.95MOLES)～78%.
Method three.In flask at the bottom of the garden of 1000ML, put into 3-(5-hydroxyl-1-heptyl) cyclopentenes 600g(3.3MOLES), stir down, add sodium Metal 99.5 accumulation 60.7g(2.64MOLES) in batches, after treating that sodium all is exhausted, adding methyl iodide 470g(～3.4MOLES), refluxed 2 hours.Add washing and remove the sodium iodide that generates, and with ether quench the water intaking merge with organic phase, use anhydrous sodium sulfate drying after removing ether, add sodium Metal 99.5 60.7g(2.64MOLES after the filtration again) repeat aforesaid operations, at last the underpressure distillation of gained crude product is got product 490g(2.5MOLES)～75.7%.
Method four.At 600g(3.3MOLES) 3-(5-hydroxyl-1-heptyl) add sodium Metal 99.5 60.7g(2.64MOLES in the cyclopentenes), stirred 2 hours, cooling feeds monochloro methane gas with airway after causing room temperature, system weightening finish 125g stops ventilation, remove by filter the sodium-chlor of generation, add the 60g sodium Metal 99.5 again, repeat aforesaid operations, weightening finish this time is 40 one-tenth a sodium-chlor, add the 60g sodium Metal 99.5 again, repeat aforesaid operations, weightening finish this time is that underpressure distillation gets product 510g(2.6MOLES about 40g)～79%.
Method five.In the 1000ML there-necked flask of electric mixer is housed, add 3-(5-hydroxyl-1-heptyl) cyclopentenes 182g(1.0MOLE), potassium hydroxide 200g(3.57MOLES), water 300ML, methyl-sulfate 189g(1.5MOLES) tetrabutylammonium iodide 1.0g at room temperature stirred 8 hours, and reflux is 1.5 hours then, tell organic layer, quench with ether and to get three times, merge the back and uses anhydrous sodium sulfate drying, underpressure distillation to get product 140g(0.71MOLE)～71%.
[example four]
The preparation of [6,6-two chloro-2-(5-methoxyl group-1-heptyl) dicyclo [3.2.0] heptane-7-ketone]
Method one.On there-necked flask at the bottom of the 1000ML garden, load onto reflux condensing tube and mechanical stirrer.Add 3-(5-methoxyl group-1-heptyl) cyclopentenes 150g(0.76MOLE), 100ML hexane and 351g dichloroacetyl chloride (2.4MOLES) reflux.Drip triethylamine 252g(2.49MOLES) hexane solution 300ML, 4 hours after-filtration of heated and stirred, solution boil off underpressure distillation behind the solvent, column chromatography for separation gets product 170g(0.55MOLE then)～72%.
Method two.The 1000ML there-necked flask.Load onto reflux condensing tube, mechanical stirrer and nitrogen are introduced conduit, add 40g(0.2MOLE) 3-(5-methoxyl group-1-heptyl) cyclopentenes.Activated zinc 28.7g(0.44MOLE), the 400ML anhydrous diethyl ether stirs under nitrogen atmosphere, drips trichoroacetic chloride 36.6g(0.2MOLE) and the 200ML anhydrous ether solution of 30.6g phosphorus oxychloride need 2 hours approximately, continue backflow 3 hours afterwards.Filtering reacting liquid with the washing precipitation of 100ML ether, concentrated ethyl ether solution to 25%, adds the pentane of equivalent, and have zinc salt to separate out this moment.Inclining the ether layer and washes with water, with the saturated sodium carbonate neutralization, uses anhydrous sodium sulfate drying again, and underpressure distillation gets product 53.4g(0.174MOLE)～87%.
Method three.Vigorous stirring 3-(5-methoxyl group-1-heptyl) 400ML anhydrous ether solution zinc-copper idol 4g(0.06MOLE cyclopentenes 1.62g(8.25MMOLES)), feeding nitrogen adding trichoroacetic chloride 4g(22MMOLES) 400ML anhydrous ether solution, need 4 hours, at room temperature continue then to stir 24 hours.The zinc chloride that elimination zinc-copper even summation generates.With sodium bicarbonate aqueous solution neutralization reaction liquid, underpressure distillation gets product 2.0g(～6.6MMOLES)～80%.
[example five]
The preparation of [6,6-two chloro-2-(5-methoxyl group-1-heptyl) dicyclo [3.3.0] octane-7-ketone]
With a-methyl-a-nitroso-group 20.6g(0.2MOLE) add the potassium hydroxide of 60ML50% and the solution of 200ML ether, the diethyl ether solution 150ML(that makes diazomethane contains diazomethane 5.3～5.9g), make itself and 25g(0.08MOLE) 6,6-two chloro-2-(5-methoxyl group-1-heptyl) the 50ML diethyl ether solution effect of dicyclo [3.2.0] heptane-7-ketone.And adding methyl alcohol 10ML.The following reaction of normal temperature adds in a small amount after 5 hours glacial acetic acid destroys unnecessary diazomethane.Get orange-yellow oily thing for next step use after removing ether.
[example six]
The preparation of [2-(5-methoxyl group-1-heptyl) dicyclo [3.3.0] octane-7-ketone].
Method one.96.3g(0.3MOLE) 6,6-two chloro-2-(5-methoxyl group-1-heptyl) dicyclo [3.3.0] octane-7-ketone, 126g Glacial acetic acid (2.1MOLES) and 136.5g(2.1MOLES) zinc powder add together.Kept 4 hours down at 70 ℃, cooled and filtered is removed the zinc acetate of unreacted zinc and generation, merge with twice of ether washing precipitation and filtrate, boil off solvent after, column chromatography for separation (sherwood oil=4: the 1(volume ratio)) product 60g(0.24MOLE)～82%.
Method two.6.44g(20MMOLES) 6,6-two chloro-2-(5-methoxyl group-1-heptyl) dicyclo [3.3.0] octane-7-ketone, 300ML methyl alcohol, 5.0g adding with the 10g zinc powder, ammonium chloride is in the same place, stirred 1 hour under the room temperature, remove by filter the zinc chloride of unreacted zinc and generation, boil off methyl alcohol, column chromatography for separation (sherwood oil: ether=4: 1) get product 4.13g(16.4MOLES)～82%.
The invention effect
The present invention is with the CYOCTOL that synthesized of the brand-new scheme success of a cover. Its main feature has:
(1) successful avoidance the difficulty of out-of-date methods Raws, on the market commercialization reagent as initiation material, synthesized CYOCTOL. Have raw material and be easy to get, cheap, the productive rate advantages of higher.
(2) it is available that committed step all has two or more methods, increased the present invention's flexibility in actual applications.
(3) some step to out-of-date methods is optimized improvement, or makes it simplified control and be easy to suitability for industrialized production. Or cost is to obtain higher economic benefit.
To one skilled in the art, said method of the present invention can suitably change under different conditions, and these change all within the scope of the invention.
Claims (7)
1, a kind of chemical name is 2-(5-methoxyl group-1-heptyl) dicyclo [3.3.0] octane-7-ketone, structural formula as shown in the formula synthetic method,
This method comprises:
1) in the presence of solvent and magnesium 1-bromo-4-chlorobutane is made single Grignard reagent, this reagent makes 3-(4-chloro-1-butyl) cyclopentenes with the coupling of 3-chlorine cyclopentenes in the presence of solvent;
2) in the presence of solvent and magnesium 3-(the 4-chloro-1-butyl) cyclopentenes of step 1) is made Grignard reagent, this reagent is made 3-(5-hydroxyl-1-heptyl) cyclopentenes with the propionic aldehyde reaction in solvent;
3) 3-that makes step 2) (5-hydroxyl-1-heptyl) cyclopentenes is made 3-(5-methoxyl group-1-heptyl) cyclopentenes through methylation reaction;
4) 3-(5-methoxyl group-1-heptyl) cyclopentenes that allows Ethylene Dichloride ketone and step 3) make carries out addition reaction generation 6,6-two chloro-2-(5-methoxyl group-1-heptyl) dicyclo [3.2.0] heptane-7-ketone;
5) diazomethane solution in the presence of alcohol with step 4) generate 6,6-two chloro-2-(5-methoxyl group-1-heptyl) dicyclo [3.2.0] heptane-7-ketone carries out insertion reaction and generates 6,6-two chloro-2-(5-methoxyl group-1-heptyl) dicyclo [3.3.0] octane-7-ketone;
6) with being selected from the method reduction step 5 of one of the following) generate 6,6-two chloro-2-(5-methoxyl group-1-heptyl) dicyclo [3.3.0] octane-7-ketone obtains product 2-(5-methoxyl group-1-heptyl) dicyclo [3.3.0] octane-7-ketone.
A) be reductive agent with carboxylic acid and zinc powder; B) be reductive agent with methyl alcohol, ammonium chloride and zinc powder.
2, according to the method for claim 1, wherein solvent is selected from ethers in the step 1), and temperature of reaction is for 0 ℃～-35 ℃ of the single Grignard reagents of system, with 10 ℃～-30 ℃ of 3-chlorine cyclopentenes couplings, the consumption of three kinds of raw materials is a mol ratio such as basic, and the consumption of solvent is every mole metal magnesium 500～1000ML.
3, according to the method for claim 1, step 2 wherein) magnesium, 3-(4-chloro-1-butyl in) amount ratio of cyclopentenes and propionic aldehyde is (1～1.1): (1～1.1): (1～1.3) [mol ratio], the temperature of reaction of system Grignard reagent is the reflux temperature of solvent, and Grignard reagent and propionic aldehyde temperature of reaction are 0 ℃～36 ℃.
4, according to the process of claim 1 wherein that the method that is selected from one of the following in the step 4) is carried out cycloaddition reaction:
A) in the presence of solvent and triethylamine, make 3-(5-methoxyl group-1-heptyl in dichloroacetyl chloride and the step 3)) cyclopentenes reaction generation 6,6-two chloro-2-(5-methoxyl group-1-heptyl) dicyclo [3.2.0] heptane-7-ketone; B) in the presence of solvent, phosphorus oxychloride and activated zinc, the 3-(5-methoxyl group-1-heptyl that makes in trichoroacetic chloride and the step 3)) cyclopentenes reaction generation 6,6-two chloro-2-(5-methoxyl group-1-heptyl) dicyclo [3.2.0] heptane-7-ketone; C) in the presence of solvent and zinc-copper idol, the 3-(5-methoxyl group-1-heptyl that makes in trichoroacetic chloride and the step 3)) cyclopentenes reaction generation 6,6-two chloro-2-(5-methoxyl group-1-heptyl) dicyclo [3.2.0] heptane-7-ketone.
5, according to the method for claim 4, wherein the reaction conditions of each method is respectively: a) triethylamine, dichloroacetyl chloride and 3-(5-methoxyl group-1-heptyl) amount ratio of cyclopentenes is (0.4～4): (0.3～4): 1[mol ratio], temperature of reaction is-5 ℃～80 ℃;
B) 3-(5-methoxyl group-1-heptyl) amount ratio of cyclopentenes, activated zinc, trichoroacetic chloride and phosphorus oxychloride is 1: (2～2.5): (1～1.2): (1～1.2) [mol ratio] temperature of reaction is the reflux temperature of solvent;
C) 3-(5-methoxyl group-1-heptyl) amount ratio of cyclopentenes, zinc-ketone idol, trichoroacetic chloride is 1: (5～10): (2.5～3) [mol ratio].
6, according to the method for claim 1, wherein solvent is selected from ethers in the step 5), alcohol is selected from methyl alcohol, diazomethane, catalyzer, 6,6-two chloro-2-(5-methoxyl group-1-heptyl) amount ratio of dicyclo [3.2.0] heptane-7-ketone is (1.3～1.9): (1～4): 1[mol ratio].
7, according to the method for claim 1, wherein the reaction conditions of step 6) is: a) 6,6-two chloro-2-(5-methoxyl group-1-heptyl) amount ratio of dicyclo [3.3.0] octane-7-ketone, zinc powder, acetic acid is 1: (5～12): (5～12) [mol ratio], temperature of reaction are 10 ℃～100 ℃; B) 6,6-two chloro-2-(5-methoxyl group-1-heptyl) amount ratio of dicyclo [3.3.0] octane-7-ketone, zinc powder, ammonium chloride is 1: (5～10): (4～10) [mol ratio], temperature of reaction is a room temperature, and the consumption of solvent is every mole of zinc powder 1500～2500ML.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 91111949 CN1062898A (en) | 1991-12-30 | 1991-12-30 | 2-(5-methoxyl group-1-heptyl) dicyclo (3,3, the O) synthetic method of octane-7-ketone |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 91111949 CN1062898A (en) | 1991-12-30 | 1991-12-30 | 2-(5-methoxyl group-1-heptyl) dicyclo (3,3, the O) synthetic method of octane-7-ketone |
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| Publication Number | Publication Date |
|---|---|
| CN1062898A true CN1062898A (en) | 1992-07-22 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 91111949 Pending CN1062898A (en) | 1991-12-30 | 1991-12-30 | 2-(5-methoxyl group-1-heptyl) dicyclo (3,3, the O) synthetic method of octane-7-ketone |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111807943A (en) * | 2020-07-30 | 2020-10-23 | 常州沃腾化工科技有限公司 | Preparation method of cyclobutanone |
| EP3838881A1 (en) * | 2013-03-11 | 2021-06-23 | Grey Pacific Labs, LLC | Method of synthesizing 6-(5-ethoxyhept-1-yl)bicyclo[3.3.0]octan-3-one |
-
1991
- 1991-12-30 CN CN 91111949 patent/CN1062898A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3838881A1 (en) * | 2013-03-11 | 2021-06-23 | Grey Pacific Labs, LLC | Method of synthesizing 6-(5-ethoxyhept-1-yl)bicyclo[3.3.0]octan-3-one |
| CN111807943A (en) * | 2020-07-30 | 2020-10-23 | 常州沃腾化工科技有限公司 | Preparation method of cyclobutanone |
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