CN106674085A - Synthetic method for N-1,3-difluoro isopropyl-4-aminopiperidine compounds - Google Patents
Synthetic method for N-1,3-difluoro isopropyl-4-aminopiperidine compounds Download PDFInfo
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- CN106674085A CN106674085A CN201611183379.XA CN201611183379A CN106674085A CN 106674085 A CN106674085 A CN 106674085A CN 201611183379 A CN201611183379 A CN 201611183379A CN 106674085 A CN106674085 A CN 106674085A
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- Prior art keywords
- synthetic method
- difluoropropane
- piperidine compounds
- amino piperidine
- alkali
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- PKZCRWFNSBIBEW-UHFFFAOYSA-N CC(C)(CN)N(C)C Chemical compound CC(C)(CN)N(C)C PKZCRWFNSBIBEW-UHFFFAOYSA-N 0.000 description 1
Classifications
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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
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
Abstract
The invention discloses a synthetic method for N-1,3-difluoro isopropyl-4-aminopiperidine compounds. The synthetic method concretely comprises the steps of by taking 1,3-acetone fluoride-2-alcohol as a raw material, and conducting reaction in two steps to obtain target compounds, i.e., the N-1,3-difluoro isopropyl-4-aminopiperidine compounds. According to the synthetic method for the N-1,3-difluoro isopropyl-4-aminopiperidine compounds, the raw materials are simple, low in costs, and easily available, the reaction condition is simple, and the chemical purity of the obtained products is high.
Description
Technical field
The present invention relates to a kind of synthetic method of organic drug intermediate, and in particular to N-1,3- difluoro isopropyl -4- ammonia
The synthetic method of phenylpiperidines class compound.
Background technology
4- amino piperidines are a kind of important medicine intermediates.It is mainly used in synthesizing and producing prevention or treat Post operation aching
Bitterly, various pain such as migraine, Encelialgia, neuropathic pain and by cause additive of the analgesics such as opiatess and tolerance
The medicine of the diseases such as property.
Fluorochemical occupies suitable proportion in marketed drug in recent years.Pharmaceutical Chemist is becoming increasingly recognized that having
Fluorine atom or fluoro-containing group are selectively introduced in machine compound, delicate change can be brought to its biological effect, thus, how
Fluorine atom is introduced in compound also just into study hotspot.The tert-butyl group-(1- (1,3- difluoropropane -2- bases) piperidin-4-yl)
At present report is few for the synthesis of carbamate.Known method is patent PCT Int.Appl., the conjunctions of 2012049277 reports
Into method.The method with 1,3- difluoropropane -2- ketone be raw material, with piperidines -4- t-butyl carbamates reaction generate the tert-butyl group -
(1- (1,3- difluoropropane -2- bases) piperidin-4-yl) carbamate.The method high cost, needs to use acetic acid sodium borohydride
This kind of Atom economy is not than relatively low reagent and unfriendly to environment, easy to operate and yield is low.
The content of the invention
The technical problem to be solved in the present invention is to provide a kind of N-1,3- difluoros isopropyl -4- amino piperidine compounds
Synthetic method, the method synthetic route is short, can effective control cost, increase economic efficiency.
To solve above-mentioned technical problem, the technical solution used in the present invention is：
One kind has below general formula I：The synthetic method of N-1,3- difluoro isopropyl -4- amino piperidine compounds,
Including step：(1) 1,3- difluoropropane -2- alcohol and alkali A are dissolved in solvent orange 2 A, then Deca methane sulfonyl chloride, point
From 1,3- difluoropropanes -2- bases-Loprazolam；
(2) compound of formula II is dissolved in solvent B, adds alkali B, reacting by heating,
Isolate and purify to obtain N-1 after having reacted, 3- difluoro isopropyl -4- amino piperidine compounds, wherein, R1, R2It is only respectively
Vertical is selected from：Hydrogen, tertbutyloxycarbonyl, the alkyl of C1-C8,3- methyl butyls, benzyl, 3- methyl -2- alkene -1- butyl, 2- methoxies
Base ethyl, 2- ethyl-butyls, hexyl, octyl group, 2- dimethylaminoethyls, 3- dimethylamino-propyls, the methyl of ring third, 2- cyclopropyl second
Base, 2- pyrrolylethyls, 2- (N- N-ethyl pyrrole N--2- bases)-ethyl, cyclopenta, cyclohexyl, 3,4- Dimethoxyphenethyls.
Preferably, R1, R2It is independently selected from：Hydrogen, tertbutyloxycarbonyl.
Preferably, the alkali A is organic base, and the alkali B is inorganic base.
Preferably, the alkali A is triethylamine, and the alkali B is potassium carbonate or sodium carbonate.
Preferably, described solvent orange 2 A is dichloromethane, and the solvent B is dimethyl sulfoxide.
Preferably, the envelope-bulk to weight ratio (ml/g) of described dichloromethane and described 1,3- difluoropropane -2- alcohol be 3~
10：1；Described dimethyl sulfoxide is 3~10 with the envelope-bulk to weight ratio (ml/g) of the compound of the formula II：1.
Preferably, the addition and the mol ratio of described 1,3- difluoropropane -2- alcohol of described methane Huang acyl chlorides is 0.5
~2.5：1；The addition of described 1,3- difluoropropane -2- alcohol is 0.5~2.5 with the mol ratio of the compound of formula II：1.
Term " alkyl " includes the alkyl of straight chain and side chain, such as methyl, ethyl, propyl group, isopropyl, fourth in the present invention
Base, isobutyl group, sec-butyl, amyl group, 2- Ethyl-butyls, hexyl, heptyl, octyl group etc.；
Tertbutyloxycarbonyl in the present invention refers to Boc substituent groups.
The present invention is raw materials used commercially available, or is obtained using method known in the art synthesis.
The beneficial effect that the present invention is reached：
The synthetic method of the present invention is not required to special producing equipment, without (pole) low-temperature operation；And high purity product can be provided (no
Less than 97%), so as to obtain higher economic benefit；For some products, cost of material that this method is used is relatively low, into
This cheap, yield is higher, and raw material is readily obtained.
Description of the drawings
Fig. 1 is the synthetic route chart of the product of embodiment 1.
Specific embodiment
Below in conjunction with the accompanying drawings the invention will be further described.Following examples are only used for clearly illustrating the present invention
Technical scheme, and can not be limited the scope of the invention with this.
Embodiment 1
As shown in Figure 1：The synthesis side of the tert-butyl group-(1- (1,3- difluoropropane -2- bases) piperidin-4-yl) carbamate
Method, comprises the following steps：
By raw material 1,3- difluoropropane -2- alcohol and triethylamine are dissolved in dichloromethane, to Deca first in solution under zero degree
Alkanesulphonyl chlorides.Drop finishes, and stirs one hour under zero degrees celsius, is then warmed to room temperature stirring one hour and extremely reacts complete.Will reaction
Mixture is poured in ice water solution, then under a point liquid, dichloromethane extraction, zero degree with a molar salt pickling organic layer extremely
PH=2-3, organic layer is washed to pH=8-9 under washing organic layer, zero degree with saturated sodium bicarbonate aqueous solution, is washed organic layer, is incited somebody to action
Organic layer anhydrous sodium sulfate drying, it is concentrated under reduced pressure to give 1,3- difluoropropanes -2- bases-Loprazolam.
Raw material piperidines -4- t-butyl carbamates are dissolved in dimethyl sulfoxide, 1,3- difluoropropanes -2- bases-methane is added
Sulfonic acid and potassium carbonate, are warming up to 120 degrees Celsius and extremely react complete.After being cooled to room temperature, reactant liquor is poured into water, acetic acid
Ethyl ester extracts, organic layer anhydrous sodium sulfate drying, concentration, column chromatography is obtained the tert-butyl group-(1- (1,3- difluoropropane -2-
Base) piperidin-4-yl) carbamate.
Wherein, raw materials used piperidines -4- t-butyl carbamates and 1,3- difluoropropane -2- alcohol are commercial chemicals,
It is cheap, can readily obtain.
Embodiment 2
Add 28.8 grams of 1,3- difluoropropane -2- alcohol in three mouthfuls of reaction bulbs with agitator, 60.6 grams of triethylamine and
300 milliliters of dichloromethane, 41.2 grams of Deca methane sulfonyl chloride under zero degrees celsius.Drop finishes, and stirs one hour in zero degree, then in room
Temperature continues to stir one hour.Reactant mixture is poured in 200 milliliters of ice water solutions, with dichloromethane extraction (100 milliliters ×
2).Under zero degrees celsius, with a molar salt pickling organic layer to pH=2-3, washing organic layer (100 milliliters)；Under zero degrees celsius, use
Saturated sodium bicarbonate aqueous solution washes organic layer to pH=8-9, washing organic layer (100 milliliters).By organic layer anhydrous sodium sulfate
It is dried, concentrating under reduced pressure obtains 43 grams of 1,3- difluoropropanes -2- bases-Loprazolams of colourless liquid, yield 86%, purity 98%.
By raw material piperidines -4- t-butyl carbamates, 54 grams are dissolved in 500 milliliters of dimethyl sulfoxide, add 1,3- difluoros third
37 grams of alkane -2- bases -43 grams of Loprazolam and potassium carbonate, are warming up to 120 degrees Celsius and extremely react complete.After being cooled to room temperature, will
Reactant liquor is poured in 100 milliliters of water, ethyl acetate extraction (100 milliliters of X3), by organic layer anhydrous sodium sulfate drying, concentration,
Column chromatography obtains the white solid tert-butyl group-(1- (1,3- difluoropropane -2- bases) piperidin-4-yl) 59 grams of carbamate, yield
79%, purity 97%.
Embodiment 3
Add 28.8 grams of 1,3- difluoropropane -2- alcohol in three mouthfuls of reaction bulbs with agitator, 60.6 grams of triethylamine and
300 milliliters of dichloromethane.Under zero degrees celsius, 41.2 grams of Deca methane sulfonyl chloride.Drop finishes, zero degree reaction one hour, then room temperature
Reaction one hour.Reactant mixture is poured in 200 milliliters of frozen water, with dichloromethane extraction (100 milliliters × 2), zero degrees celsius
Under use a molar salt pickling organic layer to pH=2-3, use saturated sodium bicarbonate under washing organic layer (100 milliliters), zero degrees celsius
Aqueous solution washes organic layer to pH=8-9, washing organic layer (100 milliliters), by organic layer anhydrous sodium sulfate drying, concentrating under reduced pressure
Obtain 43.8 grams of 1,3- difluoropropanes -2- bases-Loprazolams of colourless liquid, yield 87%, purity 98%.
By raw material piperidines -4- t-butyl carbamates, 55 grams are dissolved in 500 milliliters of dimethyl sulfoxide, add 1,3- difluoros third
38 grams of alkane -2- bases -43.5 grams of Loprazolam and potassium carbonate, are warming up to 120 degrees Celsius and extremely react complete.After being cooled to room temperature,
Reactant liquor is poured in 100 milliliters of water, ethyl acetate extraction (100 milliliters of X3), by organic layer anhydrous sodium sulfate drying, dense
Contracting, column chromatography obtain the white solid tert-butyl group-(1- (1,3- difluoropropane -2- bases) piperidin-4-yl) 60 grams of carbamate, receive
Rate 80%, purity 97%.
Embodiment 4
Add 28.8 grams of 1,3- difluoropropane -2- alcohol in three mouthfuls of reaction bulbs with agitator, 60.6 grams of triethylamine and
300 milliliters of dichloromethane.Under zero degrees celsius, 41.2 grams of Deca methane sulfonyl chloride.Drop finishes, zero degree reaction one hour, then room temperature
Reaction one hour.Reactant mixture is poured in 200 milliliters of frozen water, with dichloromethane extraction (100 milliliters × 2), zero degrees celsius
Under use a molar salt pickling organic layer to pH=2-3, it is molten with saturated sodium bicarbonate water under washing organic layer (100 milliliters), zero degree
Liquid washes organic layer to pH=8-9, washes organic layer (100 milliliters), organic layer anhydrous sodium sulfate drying, concentrating under reduced pressure are obtained into nothing
44 grams of 1,3- difluoropropanes -2- bases-Loprazolams of color liquid, yield 88%, purity 98%.
By raw material piperidines -4- t-butyl carbamates, 56 grams are dissolved in 500 milliliters of dimethyl sulfoxide, add 1,3- difluoros third
40 grams of alkane -2- bases -44 grams of Loprazolam and potassium carbonate, are warming up to 120 degrees Celsius and extremely react complete.After being cooled to room temperature, will
Reactant liquor is poured in 100 milliliters of water, ethyl acetate extraction (100 milliliters of X3), by organic layer anhydrous sodium sulfate drying, concentration,
Column chromatography obtains the white solid tert-butyl group-(1- (1,3- difluoropropane -2- bases) piperidin-4-yl) 61 grams of carbamate, yield
80%, purity 97%.
Embodiment 5
Prepare following compound：Wherein R1=H, R2=benzyl, raw material used in the present embodiment：Wherein R1=H, R2=benzyl, replaces the piperidines -4- t-butyl carbamates in embodiment 1, raw material 1,3-
The usage amount of difluoropropane -2- alcohol is 5 times measured used in embodiment 1, and remaining reagent dosage is also consumption in embodiment 1
5 times, remaining is same as Example 1, final that product yield is 83%, purity 98%.
Embodiment 6
Prepare following compound：Wherein R1=methyl, R2=benzyl, raw material used in the present embodiment：Wherein R1=methyl, R2=benzyl, the piperidines -4- t-butyl carbamates in replacement embodiment 1, raw material 1,
The usage amount of 3- difluoropropane -2- alcohol is 3 times measured used in embodiment 1, and remaining reagent dosage is also consumption in embodiment 1
3 times, remaining is same as Example 1, and final product yield is 81%, purity 97%.
The above is only the preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, on the premise of without departing from the technology of the present invention principle, some improvement and deformation can also be made, these improve and deform
Also should be regarded as protection scope of the present invention.
Claims (7)
1. it is a kind of that there is below general formula I：The synthetic method of N-1,3- difluoro isopropyl -4- amino piperidine compounds,
Including step：(1) 1,3- difluoropropane -2- alcohol and alkali A are dissolved in solvent orange 2 A, then Deca methane sulfonyl chloride, separates
1,3- difluoropropane -2- bases-Loprazolam；
(2) compound of formula II is dissolved in solvent B, adds alkali B, reacting by heating,
Isolate and purify to obtain N-1 after having reacted, 3- difluoro isopropyl -4- amino piperidine compounds, wherein, R1, R2Independently
It is selected from：Hydrogen, tertbutyloxycarbonyl, the alkyl of C1-C8,3- methyl butyls, benzyl, 3- methyl -2- alkene -1- butyl, 2- methoxyl group second
Base, 2- ethyl-butyls, hexyl, octyl group, 2- dimethylaminoethyls, 3- dimethylamino-propyls, the methyl of ring third, 2- cyclopropylethyls,
2- pyrrolylethyls, 2- (N- N-ethyl pyrrole N--2- bases)-ethyl, cyclopenta, cyclohexyl, 3,4- Dimethoxyphenethyls.
2. N-1 according to claim 1, the synthetic method of 3- difluoro isopropyl -4- amino piperidine compounds, its feature
It is that R1, R2 is independently selected from：Hydrogen, tertbutyloxycarbonyl.
3. N-1 according to claim 1 and 2, the synthetic method of 3- difluoro isopropyl -4- amino piperidine compounds, its
It is characterised by, the alkali A is organic base, the alkali B is inorganic base.
4. N-1 according to claim 3, the synthetic method of 3- difluoro isopropyl -4- amino piperidine compounds, its feature
It is that the alkali A is triethylamine, the alkali B is potassium carbonate or sodium carbonate.
5. N-1 according to claim 1 and 2, the synthetic method of 3- difluoro isopropyl -4- amino piperidine compounds, its
It is characterised by, described solvent orange 2 A is dichloromethane, the solvent B is dimethyl sulfoxide.
6. N-1 according to claim 5, the synthetic method of 3- difluoro isopropyl -4- amino piperidine compounds, its feature
It is that described dichloromethane and the envelope-bulk to weight ratio (ml/g) of described 1,3- difluoropropane -2- alcohol is 3~10：1；It is described
Dimethyl sulfoxide and the compound of the formula II envelope-bulk to weight ratio (ml/g) be 3~10：1.
7. the N-1 according to claim 1 or 6, the synthetic method of 3- difluoro isopropyl -4- amino piperidine compounds, its
It is characterised by, the described addition of methane Huang acyl chlorides and the mol ratio of described 1,3- difluoropropane -2- alcohol is 0.5~2.5：
1；The addition of described 1,3- difluoropropane -2- alcohol is 0.5~2.5 with the mol ratio of the compound of formula II：1.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111233751A (en) * | 2020-03-25 | 2020-06-05 | 丽水绿氟科技有限公司 | Preparation method of 3, 3-difluoro-4-aminopiperidine compound and derivative thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1487919A (en) * | 2000-12-01 | 2004-04-07 | New mandelic acid derivatives and their use as throbin inhibitors | |
| CN103167867A (en) * | 2010-10-29 | 2013-06-19 | Abbvie公司 | Solid dispersions containing an apoptosis-inducing agent |
| WO2016128465A1 (en) * | 2015-02-11 | 2016-08-18 | Basilea Pharmaceutica Ag | Substituted mono- and polyazanaphthalene derivatives and their use |
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2016
- 2016-12-20 CN CN201611183379.XA patent/CN106674085B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1487919A (en) * | 2000-12-01 | 2004-04-07 | New mandelic acid derivatives and their use as throbin inhibitors | |
| CN103167867A (en) * | 2010-10-29 | 2013-06-19 | Abbvie公司 | Solid dispersions containing an apoptosis-inducing agent |
| WO2016128465A1 (en) * | 2015-02-11 | 2016-08-18 | Basilea Pharmaceutica Ag | Substituted mono- and polyazanaphthalene derivatives and their use |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111233751A (en) * | 2020-03-25 | 2020-06-05 | 丽水绿氟科技有限公司 | Preparation method of 3, 3-difluoro-4-aminopiperidine compound and derivative thereof |
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