CN104292147B - The preparation method of a kind of 2-martonite base-3-methoxyl group-1-piperidine carboxylate - Google Patents
The preparation method of a kind of 2-martonite base-3-methoxyl group-1-piperidine carboxylate Download PDFInfo
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- CN104292147B CN104292147B CN201410364580.2A CN201410364580A CN104292147B CN 104292147 B CN104292147 B CN 104292147B CN 201410364580 A CN201410364580 A CN 201410364580A CN 104292147 B CN104292147 B CN 104292147B
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- RFCXXKWROOFQSI-UHFFFAOYSA-N O=C(c1c2)NC=Nc1cc(Br)c2Cl Chemical compound O=C(c1c2)NC=Nc1cc(Br)c2Cl RFCXXKWROOFQSI-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/42—Oxygen atoms attached in position 3 or 5
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- Hydrogenated Pyridines (AREA)
Abstract
The invention discloses the preparation method of a kind of 2-martonite base-3-methoxyl group-1-piperidine carboxylate, comprise the following steps: carry out substitution reaction with brominated reagent and 2-acetonyl-3-methoxy piperide and generate 2-martonite base-3-methoxyl group-1-piperidines, then 2-martonite base-3-methoxyl group-1-piperidines again with Vinyl chloroformate Reactive Synthesis 2-martonite base-3-methoxyl group-1-piperidine carboxylate.Brominated reagent is used in the present invention, better active, and selectivity is better, just can carry out substitution reaction, greatly reduce the difficulty of reaction, improve reaction yield at medium polar solvent; And brominated reagent is environmentally friendly, can not environmental pollution be caused, cheap and easy to get, can greatly reduce costs.
Description
Technical field
The invention belongs to organic synthesis field, particularly relate to the preparation method of a kind of 2-martonite base-3-methoxyl group-1-piperidine carboxylate.
Background technology
Halofuginone hydrobromide (Halofuginone) is a kind of alkaloid extracted from medicinal plant Changshan, have another name called halofuginone, Hai Lefu essence, it is a kind of high-efficiency broad-spectrum insect medicine, obvious inhibitory or killing effect is all had to coccidia sporozoite, 1st generation schizont and 2nd generation schizont, it is larger to the sphere of action of coccidia life cycle, early lesion is made not continue development, keep enteron aisle normal absorption function, thus animal has been increased weight good guarantee effect, thus there is on anticoccidial effect absolute advantage.
Halofuginone hydrobromide and other anticoccidial drugs existing are without cross-resistance; And due to the stronger insecticidal action of halofuginone hydrobromide, make it not easily develop immunity to drugs, efficacy stability not easily weakens, and drug action is irreversible.Metabolism is very fast in the tissue for halofuginone hydrobromide simultaneously, and excretes with ight soil, and almost do not have drug residue in meat, security is better, and toxicity is little.Compared with other anticoccidiosis medicine, halofuginone hydrobromide has original advantage.
Halofuginone hydrobromide has following structure:
Synthesis halofuginone hydrobromide has two key intermediates, one of them, bromo-4 (the 3H)-quinazolinones of the chloro-7-of 6-, structure is as follows:
Another intermediate 2-martonite base-3-methoxyl group-1-piperidine carboxylate, structure is as follows:
US Patent No. 2775597 discloses the synthetic method of 2-martonite base-3-methoxyl group-1-piperidine carboxylate: 2-acetonyl-3-methoxy piperide (formula four) is added in the acetic acid solution containing hydrogen bromide by (1), then brominated acetic acid solution is dripped, as a child reduced pressure afterwards at room temperature reaction 2 and rotated solvent evaporated, obtain 2-martonite base-3-methoxyl group-1-piperidines (formula five), (2) 2-martonite base-3-methoxyl group-1-piperidines is dissolved with chloroform, divide and add saturated sodium bicarbonate and Vinyl chloroformate 2 times, 0 DEG C of reaction, (3) chloroform layer hydrochloric acid cleaning, be drying to obtain 2-martonite base-3-methoxyl group-1-piperidine carboxylate (formula three).Concrete reaction is as follows:
There is following shortcoming in prior art: because the activity of bromine is lower, and selectivity is poor, replaces hydrogen and need higher temperature, and will just have desirable yield in the solvent that polarity is very strong; Bromine is poisonous, and volatility is extremely strong, and to skin, mucous membrane etc. have extraordinary strong stimulus and corrosion, very unfriendly to environment, are unfavorable for large-scale production.
Summary of the invention
In view of this, be necessary for above-mentioned problem, the preparation method of a kind of 2-martonite base-3-methoxyl group-1-piperidine carboxylate of improvement is provided.
To achieve these goals, the present invention adopts following technical scheme:
A 2-martonite base-3-methoxyl group-1-piperidine carboxylate's preparation method, comprises the following steps:
1. the preparation of 2-martonite base-3-methoxyl group-1-piperidines: 2-acetonyl-3-methoxy piperide medium polar solvent dissolves, cool to-15 DEG C ~ 0 DEG C, then brominated reagent is dripped, mol ratio 1:1 ~ 1.05 of described 2-acetonyl-3-methoxy piperide and bromo element; Bromination terminates rear filtration, and decompression evaporates solvent, and column chromatography obtains 2-martonite base-3-methoxyl group-1-piperidines;
2. the preparation of 2-martonite base-3-methoxyl group-1-piperidine carboxylate: 2-martonite base-3-methoxyl group-1-piperidines chloroform is dissolved, then add sodium bicarbonate and water stirs; Then drip the chloroformic solution use containing Vinyl chloroformate, detect with thin-layer chromatography and namely stop (reaction) to reaction raw materials disappearance, temperature of reaction is 0 DEG C ~ 25 DEG C; Layering, divide and take off a layer organic phase, wash an organic phase again with saturated sodium bicarbonate aqueous solution, discard upper strata aqueous phase, lower floor's organic phase evaporated under reduced pressure solvent, column chromatography obtains 2-martonite base-3-methoxyl group-1-piperidine carboxylate; The mol ratio of described 2-martonite base-3-methoxyl group-1-piperidines and Vinyl chloroformate is 1:1 ~ 1.2, and the mol ratio of described 2-martonite base-3-methoxyl group-1-piperidines and sodium bicarbonate is 1:1 ~ 1.5.
Preferably, step 1. described in brominated reagent be tribromo tricarbimide, dibromo isocyanurate or C5H6Br2N2O2.
Preferably, step bromination temperature is 1.-10 DEG C ~ 0 DEG C.
More preferably, step bromination temperature is 1.-5 DEG C ~ 0 DEG C.
Preferably, step 1. described in 2-acetonyl-3-methoxy piperide and the mol ratio 1:1 of bromo element.
Preferably, step 1. described in medium polar solvent be ethanol, ethyl acetate, tetrahydrofuran (THF) or acetone.
More preferably, step 1. described in medium polar solvent be acetone.
Preferably, step 2. in temperature of reaction be 0 DEG C ~ 5 DEG C.
Compared with prior art, the preparation method of 2-martonite base-3-methoxyl group-1-piperidine carboxylate of the present invention, has obvious beneficial effect:
1) prior art uses bromine to carry out substitution reaction, and because the activity of bromine is lower, and selectivity is poor, replaces hydrogen and needs higher temperature, and will just have desirable yield in the solvent that polarity is very strong; Brominated reagent is used in the present invention, better active, and selectivity is good, just can carry out substitution reaction, greatly reduce the difficulty of reaction, improve reaction yield at medium polar solvent.
2) brominated reagent is comparatively stronger than bromine oxidisability, at relatively high temperatures can oxyl ring, and be unfavorable for the carrying out of bromination substitution reaction, the temperature therefore in the present invention during bromination should not be too high; If but temperature is too low, brominated reagent can be separated out in a solvent, is difficult to dissolve, and reaction also slows down and even substantially bromination substitution reaction do not occur slowly, and temperature when therefore bromination replaces in the present invention is-15 DEG C ~ 0 DEG C.
3) used in the present invention brominated reagent is environmentally friendly, can not cause environmental pollution; And brominated reagent is cheap and easy to get, can greatly reduce costs.
Embodiment
For a better understanding of the present invention, be described further below in conjunction with specific embodiment.If no special instructions, the various raw materials adopted in following examples all derive from commercially available.The method adopted is routine techniques means.
The present invention's brominated reagent and 2-acetonyl-3-methoxy piperide carry out substitution reaction and generate 2-martonite base-3-methoxyl group-1-piperidines, then 2-martonite base-3-methoxyl group-1-piperidines again with Vinyl chloroformate Reactive Synthesis 2-martonite base-3-methoxyl group-1-piperidine carboxylate.
The brominated reagent used in the present invention is tribromo tricarbimide (formula six), dibromo isocyanurate (formula seven) or C5H6Br2N2O2 (formula eight), and concrete structure formula is as follows:
The route that tribromo tricarbimide and 2-acetonyl-3-methoxy piperide synthesize 2-martonite base-3-methoxyl group-1-piperidines is as follows:
The route that dibromo isocyanurate and 2-martonite base-3-methoxy piperide synthesize 2-martonite base-3-methoxyl group-1-piperidines is as follows:
The route that C5H6Br2N2O2 and 2-martonite base-3-methoxy piperide synthesize 2-martonite base-3-methoxyl group-1-piperidines is as follows:
The route that 2-martonite base-3-methoxyl group-1-piperidines and Vinyl chloroformate synthesize 2-martonite base-3-methoxyl group-1-piperidine carboxylate is as follows:
Example 1
2-acetonyl-3-the methoxy piperide of 1. 3.42 grams (0.02 moles) is dissolved in the acetone of 80 milliliters, then 0 DEG C ~-5 DEG C are cooled to, again the time of the 80 milliliters of acetone solns being dissolved with 2.56 grams of (0.007 mole) tribromo tricarbimides with 30 minutes is dripped, dropping terminates rear continuation stirring 10 minutes, thin-layer chromatography detection reaction raw material disappears, stopped reaction, filter, removing uric acid, then decompression evaporates acetone, column chromatography (silicagel column, the volume ratio of elutriant PetroChina Company Limited. ether and ethyl acetate is 3:1) obtain product 2-martonite base-3-methoxyl group-1-piperidines 4.3 grams, GC content 98.8%, yield 86%.
2. the 2-martonite base-3-methoxyl group-1-piperidines getting 5 grams (0.02 moles) adds 50 milliliters of chloroforms, the sodium bicarbonate of 1.7 grams, 50 ml waters stir, then 0 DEG C is cooled to, 50 milliliters of chloroformic solutions containing 2.39 grams of (0.022 mole) Vinyl chloroformates were dripped with 1 hour, dropping terminates rear continuation stirring 2 hours, thin-layer chromatography detection reaction raw material disappears, stopped reaction, layering, divide and take off a layer organic phase, organic phase is washed one time with saturated sodium bicarbonate aqueous solution 50 milliliters again, discard upper strata aqueous phase, lower floor's organic phase evaporated under reduced pressure solvent, column chromatography (silicagel column, in elutriant, the volume ratio of normal hexane and ethyl acetate is 2.5:1) obtain 2-martonite base-3-methoxyl group-1-piperidine carboxylate 6.12 grams, content 97.3% is analyzed through GC, yield 95%.
Embodiment 2
1. the 2-acetonyl-3-methoxy piperide getting 3.42 grams (0.02 moles) is dissolved in the acetone of 80 milliliters, then-5 DEG C ~-10 DEG C are cooled to, again the time of the 80 milliliters of acetone solns being dissolved with 2.56 grams of (0.007 mole) tribromo tricarbimides with 30 minutes is dripped, dropping terminates rear continuation stirring 3 hours, thin-layer chromatography detection reaction raw material disappears, stopped reaction, filter, removing uric acid, then decompression evaporates acetone, column chromatography obtains product 3.7 grams, GC content 98.0%, yield 74%.
2. the 2-martonite base-3-methoxyl group-1-piperidines getting 5 grams (0.02 moles) adds 50 milliliters of chloroforms, the sodium bicarbonate of 1.7 grams, 50 ml waters stir, then 0 DEG C is cooled to, 50 milliliters of chloroformic solutions containing 2.39 grams of (0.022 mole) Vinyl chloroformates were dripped with 1 hour, dropping terminates rear continuation stirring 2 hours, thin-layer chromatography detection reaction raw material disappears, stopped reaction, layering, divide and take off a layer organic phase, organic phase is washed one time with saturated sodium bicarbonate aqueous solution 50 milliliters again, discard upper strata aqueous phase, lower floor's organic phase evaporated under reduced pressure solvent, column chromatography obtains target compound 6.12 grams, content 97.3% is analyzed through GC, yield 95%.
Embodiment 3
1. the 2-acetonyl-3-methoxy piperide getting 3.42 grams (0.02 moles) is dissolved in the ethanol of 80 milliliters, then-5 DEG C ~ 0 DEG C is cooled to, again the time of the 60 milliliters of ethanolic solns being dissolved with 2.87 grams of (0.01 mole) dibromo isocyanurates with 30 minutes is dripped, dropping terminates rear continuation stirring 3 hours, thin-layer chromatography detection reaction raw material disappears, stopped reaction, filter, removing uric acid, then decompression evaporates ethanol, column chromatography obtains product 3.8 grams, GC content 98.7%, yield 76%.
2. the 2-martonite base-3-methoxyl group-1-piperidines getting 5 grams (0.02 moles) adds 50 milliliters of chloroforms, the sodium bicarbonate of 1.7 grams, 50 ml waters stir, then 0 DEG C is cooled to, 50 milliliters of chloroformic solutions containing 2.39 grams of (0.022 mole) Vinyl chloroformates were dripped with 1 hour, dropping terminates rear continuation stirring 2 hours, thin-layer chromatography detection reaction raw material disappears, stopped reaction, layering, divide and take off a layer organic phase, organic phase is washed one time with saturated sodium bicarbonate aqueous solution 50 milliliters again, discard upper strata aqueous phase, lower floor's organic phase evaporated under reduced pressure solvent, column chromatography obtains target compound 6.12 grams, content 97.3% is analyzed through GC, yield 95%.
Embodiment 4
1. the 2-acetonyl-3-methoxy piperide getting 3.42 grams (0.02 moles) is dissolved in the tetrahydrofuran (THF) of 80 milliliters, then-15 DEG C ~-10 DEG C are cooled to, to be dissolved with in 80 milliliters of tetrahydrofuran (THF)s of 2.87 grams of (0.01 mole) dibromo isocyanurates again, drip with the times of 40 minutes, dropping terminates rear continuation stirring 2 hours, thin-layer chromatography detection reaction raw material disappears, stopped reaction, filter, removing uric acid, then decompression evaporates tetrahydrofuran (THF), and column chromatography obtains product 3.0 grams, GC content 98.7%, yield 60%.
2. the 2-martonite base-3-methoxyl group-1-piperidines getting 5 grams (0.02 moles) adds 50 milliliters of chloroforms, the sodium bicarbonate of 1.7 grams, 50 ml waters stir, then 0 DEG C is cooled to, 50 milliliters of chloroformic solutions containing 2.39 grams of (0.022 mole) Vinyl chloroformates were dripped with 1 hour, dropping terminates rear continuation stirring 2 hours, thin-layer chromatography detection reaction raw material disappears, stopped reaction, layering, divide and take off a layer organic phase, organic phase is washed one time with saturated sodium bicarbonate aqueous solution 50 milliliters again, discard upper strata aqueous phase, lower floor's organic phase evaporated under reduced pressure solvent, column chromatography obtains target compound 6.12 grams, content 97.3% is analyzed through GC, yield 95%.
Embodiment 5
1. the 2-acetonyl-3-methoxy piperide getting 3.42 grams (0.02 moles) is dissolved in the ethyl acetate of 50 milliliters, then 0 DEG C ~-5 DEG C are cooled to, to be dissolved with in 90 milliliters of ethyl acetate of 2.86 grams of (0.01 mole) C5H6Br2N2O2s again, drip with the times of 50 minutes, dropping terminates rear continuation stirring 1 hour, thin-layer chromatography detection reaction raw material disappears, stopped reaction, filter, removing glycolylurea, then decompression evaporates ethyl acetate, and column chromatography obtains product 3.1 grams, GC content 98.5%, yield 62%.
2. the 2-martonite base-3-methoxyl group-1-piperidines getting 5 grams (0.02 moles) adds 50 milliliters of chloroforms, the sodium bicarbonate of 1.7 grams, 50 ml waters stir, then 0 DEG C is cooled to, 50 milliliters of chloroformic solutions containing 2.39 grams of (0.022 mole) Vinyl chloroformates were dripped with 1 hour, dropping terminates rear continuation stirring 2 hours, thin-layer chromatography detection reaction raw material disappears, stopped reaction, layering, divide and take off a layer organic phase, organic phase is washed one time with saturated sodium bicarbonate aqueous solution 50 milliliters again, discard upper strata aqueous phase, lower floor's organic phase evaporated under reduced pressure solvent, column chromatography obtains target compound 6.12 grams, content 97.3% is analyzed through GC, yield 95%.
The above embodiment only have expressed several embodiment of the present invention, and it describes comparatively concrete and detailed, but therefore can not be interpreted as the restriction to the scope of the claims of the present invention.It should be pointed out that for the person of ordinary skill of the art, without departing from the inventive concept of the premise, can also make some distortion and improvement, these all belong to protection scope of the present invention.Therefore, the protection domain of patent of the present invention should be as the criterion with claims.
Claims (6)
1. a preparation method for 2-martonite base-3-methoxy piperide carboxylic acid, ethyl ester, is characterized in that, comprise following steps:
1. the preparation of 2-martonite base-3-methoxyl group-1-piperidines: 2-acetonyl-3-methoxy piperide medium polar solvent dissolves, cool to-15 DEG C ~ 0 DEG C, then brominated reagent is dripped, mol ratio 1:1 ~ 1.05 of described 2-acetonyl-3-methoxy piperide and bromo element; Bromination terminates rear filtration, and decompression evaporates solvent, and column chromatography obtains 2-martonite base-3-methoxyl group-1-piperidines;
2. the preparation of 2-martonite base-3-methoxyl group-1-piperidine carboxylate: 2-martonite base-3-methoxyl group-1-piperidines chloroform is dissolved, then add sodium bicarbonate and water stirs; Then drip the chloroformic solution containing Vinyl chloroformate, detect to reaction raw materials disappearance and stopped reaction with thin-layer chromatography, temperature of reaction is 0 DEG C ~ 25 DEG C; Layering, divide and take off a layer organic phase, wash an organic phase again with saturated sodium bicarbonate aqueous solution, discard upper strata aqueous phase, lower floor's organic phase evaporated under reduced pressure solvent, column chromatography obtains 2-martonite base-3-methoxyl group-1-piperidine carboxylate; The mol ratio of described 2-martonite base-3-methoxyl group-1-piperidines and Vinyl chloroformate is 1:1 ~ 1.2, and the mol ratio of described 2-martonite base-3-methoxyl group-1-piperidines and sodium bicarbonate is 1:1 ~ 1.5;
Step 1. described in brominated reagent be tribromo tricarbimide, dibromo isocyanurate or C5H6Br2N2O2;
Step 1. described in medium polar solvent be ethanol, ethyl acetate, tetrahydrofuran (THF) or acetone.
2. the preparation method of 2-martonite base-3-methoxy piperide carboxylic acid, ethyl ester according to claim 1, it is characterized in that, step bromination temperature is 1.-10 DEG C ~ 0 DEG C.
3. the preparation method of 2-martonite base-3-methoxy piperide carboxylic acid, ethyl ester according to claim 2, it is characterized in that, step bromination temperature is 1.-5 DEG C ~ 0 DEG C.
4. the preparation method of 2-martonite base-3-methoxy piperide carboxylic acid, ethyl ester according to claim 1, is characterized in that, step 1. described in 2-acetonyl-3-methoxy piperide and the mol ratio 1:1 of bromo element.
5. the preparation method of 2-martonite base-3-methoxy piperide carboxylic acid, ethyl ester according to claim 1, is characterized in that, step 1. described in medium polar solvent be acetone.
6. the preparation method of 2-martonite base-3-methoxy piperide carboxylic acid, ethyl ester according to claim 1, is characterized in that, step 2. in temperature of reaction be 0 DEG C ~ 5 DEG C.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2775597A (en) * | 1954-02-12 | 1956-12-25 | American Cyanamid Co | Method for preparing quinazolone intermediates |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2775597A (en) * | 1954-02-12 | 1956-12-25 | American Cyanamid Co | Method for preparing quinazolone intermediates |
Non-Patent Citations (4)
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| 一种使用1,3-二溴-5,5-二甲基苯乙酮α-溴代新方法;高国锐等;《有机化学》;20071231;第27卷(第1期);第109-111页 * |
| 三氯异氰尿酸参与的水-甲醇可重复利用体系中的氯代反应;陈梓湛等;《化学世界》;20131231(第1期);第26-29、34页 * |
| 羰基化合物与二卤海因的α-卤代反应;陈梓湛等;《华东师范大学学报(自然科学版)》;20100731(第4期);第125-130，140页 * |
| 脂肪酮和β-酮酯类化合物与二卤海因的α-卤代反应;陈梓湛等;《世界农药》;20100228;第32卷(第1期);第36-38、47页 * |
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