CN101289441A - Method for synthesizing 5-methyl-5-propyl-1,3-dioxane-2-ketone and carisoprodol - Google Patents
Method for synthesizing 5-methyl-5-propyl-1,3-dioxane-2-ketone and carisoprodol Download PDFInfo
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Abstract
The invention discloses a synthetic method for 5-methyl-5-propyl-1, 3-dioxane-2-ketone and carisoprodol, which uses 2-methyl-2-propyl-1, 3-propanediol as an original material, and the 5-methyl-5-propyl-1,3-dioxane-2-ketone can be generated through a condensation reaction with urea under the catalysis of activated metal oxide; the obtained 5-methyl-5-propyl-1, 3-dioxane-2-ketone is ammonolyzed with isopropylamine, and 2-methyl-2-ethyl-3-hydroxypropyl-N-isopropylcarbamate can be prepared; the 2-methyl-2-ethyl-3-hydroxypropyl-N-isopropylcarbamate reacts with sodium cyanate, and the carisoprodol is prepared. The synthetic method for the 5-methyl-5-propyl-1, 3-dioxane-2-ketone and the carisoprodol is cheap and easily available in raw material, simple in preparation technology and more economical.
Description
Technical field
The present invention relates to a kind of preparation method of compound, is carisoprodol and intermediate 5-methyl-5-propyl group-1 thereof specifically, the synthetic method of 3-dioxane-2-ketone.
Background technology
Carisoprodol is the skeletal muscle relaxation medicine that is most widely used, and its compound preparation has all obtained very high evaluation at the clinical treatment that the America and Europe is widely used in pain in doctors and patients; This medicine is recorded by multinational pharmacopeia, has very large user demand.
Two kinds of technologies of synthetic existence of present carisoprodol:
(1) phosgene route
Be by 2-methyl-2-propyl group-1, the ammediol phosgenation, with the Isopropylamine reaction, and then phosgenation, and ammonification; Domestic route also has the 2-of use methyl-2-propyl group-1, and ammediol and triphosgene reaction generate cyclic carbonate, and aminolysis, Zassol obtain the crude product of carisoprodol.
This route has used the substitute solid phosgene of phosgene photoreactive gas, sees that totally yield is unsatisfactory, and environmental stress is big, and labour protection requires high, so just progressively abandon the use of this route in the middle of the actual production.
(2) carbonic ether route
With 2-methyl-2-propyl group-1, ammediol is a raw material, with diethyl carbonate condensation in the presence of metal alcoholate, obtain 5-methyl-5-propyl group-1, the 3-dioxane-2-ketone, make 2-methyl-2-propyl group-3-hydroxypropyl-N-sec.-propyl carbamate with the Isopropylamine aminolysis, with the Zassol reaction, crystallization obtains the carisoprodol crude product then.This carbonic ether route is reported in U.S. Pat 2937119, Chinese patent application number be in 200510046686.9 detailed analysis the problem that exists of United States Patent (USP), for example condition harshness, yield low, be difficult to industrialization, quality stability deficiency, and the method in the United States Patent (USP) is improved.In condensation course, add toluene as solvent, reduced the temperature of whole reaction system, reduced side reaction; And utilize the binary composition azeotropic effect of ethanol and toluene, the ethanol that produces in the process is separated from system, be beneficial to reaction and carry out; Metal alcoholate adopts the acetic acid neutralization, avoids in the water washing process 5-methyl-5-propyl group-1, the destruction of 3-dioxane-2-ketone.
Although China Patent No. is 200510046686.9 document related work is improved, still have following deficiency: (1) is feedstock production intermediate 5-methyl-5-propyl group-1 with the diethyl carbonate, 3-dioxane-2-ketone, raw materials cost height.(2) owing to be with diethyl carbonate and 2-methyl-2-propyl group-1, ammediol condensation, condensation reaction have ethanol to produce, and need in the production process by distillation it to be separated with the methylbenzene azeotropic thing earlier, not only cause the complex process complex operation, and increased energy consumption.(3) when separating alcohol, also have a spot of material carbon diethyl phthalate and steamed, cause the raw material consumption height.
Summary of the invention
First purpose of the present invention is to provide a kind of 5-methyl-5-propyl group-1, the novel synthesis of 3-dioxane-2-ketone, this method adopted more cheap and the easier urea that obtains as one of raw material, not only can reduce raw materials cost, and the ammonia that produces is more prone to separate, and simplified production technique.
Second purpose of the present invention is to provide a kind of novel synthesis of carisoprodol.
In order to realize first purpose of the present invention, adopt following technical scheme: a kind of 5-methyl-5-propyl group-1, the synthetic method of 3-dioxane-2-ketone, be with 2-methyl-2-propyl group-1, ammediol is a starting raw material, under the activatory metal oxide oxidation catalyst, generate 5-methyl-5-propyl group-1,3-dioxane-2-ketone with urea generation condensation reaction;
This process reaction formula is as follows:
The present invention also provides a kind of synthetic method of carisoprodol, and this method comprises following process:
(1) with 2-methyl-2-propyl group-1, ammediol is a starting raw material, under the activatory metal oxide oxidation catalyst, generates 5-methyl-5-propyl group-1,3-dioxane-2-ketone with urea generation condensation reaction;
This process reaction formula is as follows:
(2) gained 5-methyl-5-propyl group-1,3-dioxane-2-ketone again with Isopropylamine generation aminolysis, make 2-methyl-2-propyl group-3-hydroxypropyl-N-sec.-propyl carbamate;
This process reaction formula is as follows:
(3) 2-methyl-2-propyl group-3-hydroxypropyl-N-sec.-propyl carbamate and Zassol reaction obtains carisoprodol;
This process reaction formula is as follows:
In the present invention, described 2-methyl-2-propyl group-1, the condensation reaction of ammediol and urea can be chosen under the non-solvent condition to be carried out, temperature of reaction must reach more than 90 ℃ when carrying out under the non-solvent, promptly near and surpass under the decomposition temperature of urea and carry out, but temperature is unsuitable too high, otherwise urea decomposes fast and influence yield, and Preliminary experiment results is for should not be higher than 160 ℃; Also can in hexanaphthene, normal hexane, ethylene dichloride or aromatic series benzene series thing equal solvent, carry out, the basic reflux temperature of the temperature of reaction of low boiling point solvent near solvent, the temperature of reaction of high boiling solvent is between more than 90 ℃, to reflux temperature.
Though from reaction formula 2-methyl-2-propyl group-1, the molar ratio that two kinds of raw materials of ammediol and urea participate in reaction is 1: 1, described 2-methyl-2-propyl group-1, no matter who is excessive for two kinds of raw materials of ammediol and urea, can obtain desired product.But when ratio was above at 2: 1, reaction can be efficiently single-minded obtained target intermediate 5-methyl-5-propyl group-1, and the 3-dioxane-2-ketone considers that actual economy and efficient selects 2: 1 for relatively more appropriate.Excessive 2-methyl-2-propyl group-1, ammediol then can be used for building-up process next time, so that it can be fully utilized.
Described metal oxide can be ZnO, MgO, CaO, Al
2O
3, La
2O
3, ZrO
2, SnO
2, BaO, MnO
2, CoO, PbO, CuO, CrO
3Deng, before using, metal oxide activates through high temperature sintering, and general activation temperature can be 450 ℃, and the time is 2 hours.As the equal reusable edible of the metal oxide of catalyzer, investigate circulation and use for 10 times discovery not significantly influence of yield.
Need water-less environment during the Isopropylamine aminolysis, can select aromatic series benzene series thing is solvent, progressively adds the normal Isopropylamine of 2-3, and control reaction temperature, the TLC endpoint detection washes out excessive Isopropylamine after reaction is finished, solvent evaporated obtains the oily matter compound, need not to distill oily matter.Solvent-free in the Chinese patent 200510046686.9, direct and Isopropylamine reaction must be distilled the oily matter of purifying and obtaining at last.
2-methyl-2-propyl group-3-hydroxypropyl-N-sec.-propyl carbamate can directly add toluene and solid Zassol, slowly feed the exsiccant hydrogen chloride gas under the room temperature, after progressively accelerate ventilation speed, reaction system heats up naturally, TCL monitoring reaction terminal point when the system color becomes green.After reaction was finished, cool to room temperature added the water termination reaction, and organic phase is washed with saturated sodium bicarbonate solution, washes neutrality with water, the most of toluene of reclaim under reduced pressure, and crystallisation by cooling obtains the carisoprodol of crude product.
This method of the present invention is with 2-methyl-2-propyl group-1, ammediol and urea are that starting raw material carries out condensation reaction, with compare with diethyl carbonate, urea more cheaply is easy to get, its price is far below diethyl carbonate, and consumption is relatively low, and the ammonia that generates in the reaction process is as the gas separation of overflowing from the reactant system, adopts receiving trap to reclaim, and need not distillation, simplify production technique and need not extra heating thermal source, reduced energy consumption.And when selecting 2-methyl-2-propyl group-1, the molar ratio of ammediol and urea is at 2: 1 when above, reaction can be efficiently single-minded obtain target intermediate 5-methyl-5-propyl group-1, the 3-dioxane-2-ketone, make excessive raw material 2-methyl-2-propyl group-1, the raw material that ammediol can be recycled and react as next time is to improve utilization ratio of raw materials.Therefore, this synthetic method more economically.
Embodiment
The invention will be further described below in conjunction with specific embodiment, to help understanding content of the present invention.
1,5-methyl-5-propyl group-1, the preparation of 3-dioxane-2-ketone (Compound I I) can adopt non-solvent and two kinds of prepared of solvent are arranged.
(1) non-solvent preparation
Add 264 gram 2-methyl-2-propyl group-1 in the reaction flask, ammediol, 8.1 grams are zinc oxide and the 60 gram urea that calcination in 2 hours activates through 450 ℃ of times, heat to 110 ℃, stir successive reaction under this temperature, do not discharge to there being ammonia substantially.The ammonia that discharges is accepted by receiving trap.Underpressure distillation went out product 5-methyl-5-propyl group-1 after reaction was finished, and 3-dioxane-2-ketone (Compound I I) obtains 139 grams, and distillation temperature is 150-160 ℃, and pressure is 15-20mmHg.To urea calculated yield 88%.The distillation residue cooling obtains the off-white color solid, and note is heavy, adds 2-methyl-2-propyl group-1, can continue on for preparation process next time behind the ammediol.
(2), the solvent preparation is arranged
In reaction flask, add 264 gram 2-methyl-2-propyl group-1, ammediol, zinc oxide that 8.1 gram activation are good and 60 gram urea, 500ml toluene, reflux does not discharge to there being ammonia substantially.The ammonia that discharges is accepted by receiving trap.After reaction was finished, directly reaction solution was cooled off in cooling in proper order, filtered the solid that cooling separates out, Weighing is that 153.3 grams (are added 2-methyl-2-propyl group-1, be directly used in next time preparation behind the ammediol), about 90% to the urea calculated yield, toluene solution is directly used in next step reaction.
2, the preparation of 2-methyl-2-propyl group-3-hydroxypropyl-N-sec.-propyl carbamate (compound III)
5-methyl-5-propyl group-1, promptly 0.9 mole of 3-dioxane-2-ketone toluene solution (containing Compound I I) 142.2 gram drip 133 gram Isopropylamines and 100 milliliters of mixed solutions that toluene forms at 12～15 ℃.Then at 20 ℃ of reactions 12-15 hour, TLC detection reaction terminal point.Reaction solution adds water washing to neutral, and drying concentrates to such an extent that oily matter is 2-methyl-2-propyl group-3-hydroxypropyl-N-sec.-propyl carbamate 176 grams, and yield is 90%.
3, the preparation of carisoprodol (Compound I)
2-methyl-2-propyl group-3-hydroxypropyl-N-sec.-propyl carbamate (compound III) 108.5 grams are 0.5 mole, 500 milliliters of toluene, 97.5 gram Zassol, slowly feed the exsiccant hydrogen chloride gas under the room temperature, the ice-water bath control reaction temperature is in 35 ℃, accelerate to feed the speed of hydrogenchloride after one hour, heat up naturally.When turing green, the reaction system color controls reaction end with TLC.Add 50 milliliters of termination reactions of water, organic phase washes neutrality with water again with 100 milliliters of saturated sodium bicarbonate solution washed twice, the most of toluene of reclaim under reduced pressure, and crystallisation by cooling, the carisoprodol (Compound I) 110 that obtains crude product restrains.
The Compound I of crude product adds ethyl acetate-oil mystery-weight of material than=1: 3: 1, recrystallization obtained 102 gram carisoprodols, and yield 78.5%, fusing point are 92-93 ℃, and gained carisoprodol structural identification is consistent with document.
Claims (11)
1, a kind of 5-methyl-5-propyl group-1, the synthetic method of 3-dioxane-2-ketone is with 2-methyl-2-propyl group-1, ammediol is a starting raw material, under the activatory metal oxide oxidation catalyst, generate 5-methyl-5-propyl group-1,3-dioxane-2-ketone with urea generation condensation reaction.
2, synthetic method as claimed in claim 1 is characterized in that: described 2-methyl-2-propyl group-1, and the condensation reaction of ammediol and urea is carried out under the non-solvent condition, and temperature of reaction is 90 ℃～160 ℃.
3, synthetic method as claimed in claim 2 is characterized in that: after condensation reaction is finished, isolate 5-methyl-5-propyl group-1 by underpressure distillation, continue on for preparation process next time after the distillation residue cooling of 3-dioxane-2-ketone.
4, synthetic method as claimed in claim 1, it is characterized in that: described 2-methyl-2-propyl group-1, the condensation reaction of ammediol and urea is carried out in hexanaphthene, normal hexane, ethylene dichloride or aromatic series benzene series thing solvent, directly lower the temperature after reaction is finished and cool off reaction solution, filter the solid that separates out after the cooling.
5, as described synthetic method one of in the claim 1 to 4, it is characterized in that: described metal oxide is ZnO, MgO, CaO, Al
2O
3, La
2O
3, ZrO
2, SnO
2, BaO, MnO
2, CoO, PbO, CuO or CrO
3
6, synthetic method as claimed in claim 6 is characterized in that: described metal oxide activates through high temperature sintering.
7, a kind of synthetic method of carisoprodol is with 2-methyl-2-propyl group-1, and ammediol is a starting raw material, under the activatory metal oxide oxidation catalyst, generates 5-methyl-5-propyl group-1,3-dioxane-2-ketone with urea generation condensation reaction; Gained 5-methyl-5-propyl group-1,3-dioxane-2-ketone again with Isopropylamine generation aminolysis, make 2-methyl-2-propyl group-3-hydroxypropyl-N-sec.-propyl carbamate; 2-methyl-2-propyl group-3-hydroxypropyl-N-sec.-propyl carbamate and Zassol reaction obtain carisoprodol.
8, synthetic method as claimed in claim 8, it is characterized in that: described carbonic ether 5-methyl-5-propyl group-1,3-dioxane-2-ketone and Isopropylamine generation aminolysis are to be that solvent carries out liquid phase reaction with aromatic series benzene series thing, wash out excessive Isopropylamine after reaction is finished, solvent evaporated obtains 2-methyl-2-propyl group-3-hydroxypropyl-N-sec.-propyl carbamate.
9, synthetic method as claimed in claim 8 or 9 is characterized in that: described 2-methyl-2-propyl group-1, and the condensation reaction of ammediol and urea is carried out under the non-solvent condition, and temperature of reaction is 90 ℃～160 ℃; Perhaps carry out in hexanaphthene, normal hexane, ethylene dichloride or aromatic series benzene series thing solvent, the cooling reaction solution of directly lowering the temperature after reaction is finished filters the solid that separates out after the cooling.
10, synthetic method as claimed in claim 8 or 9, it is characterized in that: described metal oxide is ZnO, MgO, CaO, Al
2O
3, La
2O
3, ZrO
2, SnO
2, BaO, MnO
2, CoO, PbO, CuO or CrO
3
11, synthetic method as claimed in claim 8 or 9 is characterized in that: described metal oxide activates through high temperature sintering.
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| CNB2008101108747A CN100519548C (en) | 2008-06-17 | 2008-06-17 | Method for synthesizing 5-methyl-5-propyl-1,3-dioxane-2-ketone and carisoprodol |
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| CNB2008101108747A CN100519548C (en) | 2008-06-17 | 2008-06-17 | Method for synthesizing 5-methyl-5-propyl-1,3-dioxane-2-ketone and carisoprodol |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102369183A (en) * | 2009-03-10 | 2012-03-07 | 康斯乔最高科学研究公司 | One-pot production of carbamates using solid catalysts |
| CN102531965A (en) * | 2011-12-27 | 2012-07-04 | 山东鑫泉医药有限公司 | Synthesis method for carisoprodol |
| CN103641744A (en) * | 2013-11-28 | 2014-03-19 | 山东鑫泉医药有限公司 | Synthesis method of carisoprodol intermediate compound |
| CN113087695A (en) * | 2021-03-31 | 2021-07-09 | 武汉大学 | Rapid energy-saving integrated method for preparing aliphatic polycarbonate monomer |
| CN114421012A (en) * | 2022-01-25 | 2022-04-29 | 河北松辰医药科技有限公司 | Lithium battery electrolyte additive and preparation method thereof |
-
2008
- 2008-06-17 CN CNB2008101108747A patent/CN100519548C/en not_active Expired - Fee Related
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102369183A (en) * | 2009-03-10 | 2012-03-07 | 康斯乔最高科学研究公司 | One-pot production of carbamates using solid catalysts |
| CN102369183B (en) * | 2009-03-10 | 2014-07-30 | 康斯乔最高科学研究公司 | One-pot production of carbamates using solid catalysts |
| CN102531965A (en) * | 2011-12-27 | 2012-07-04 | 山东鑫泉医药有限公司 | Synthesis method for carisoprodol |
| CN103641744A (en) * | 2013-11-28 | 2014-03-19 | 山东鑫泉医药有限公司 | Synthesis method of carisoprodol intermediate compound |
| CN103641744B (en) * | 2013-11-28 | 2016-02-24 | 山东鑫泉医药有限公司 | The synthetic method of carisoprodol intermediate compound |
| CN113087695A (en) * | 2021-03-31 | 2021-07-09 | 武汉大学 | Rapid energy-saving integrated method for preparing aliphatic polycarbonate monomer |
| CN114421012A (en) * | 2022-01-25 | 2022-04-29 | 河北松辰医药科技有限公司 | Lithium battery electrolyte additive and preparation method thereof |
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