CN106674085B - Synthesis method of N-1, 3-difluoro isopropyl-4-aminopiperidine compound - Google Patents
Synthesis method of N-1, 3-difluoro isopropyl-4-aminopiperidine compound Download PDFInfo
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- CN106674085B CN106674085B CN201611183379.XA CN201611183379A CN106674085B CN 106674085 B CN106674085 B CN 106674085B CN 201611183379 A CN201611183379 A CN 201611183379A CN 106674085 B CN106674085 B CN 106674085B
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- 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 synthesis method of an N-1, 3-difluoro isopropyl-4-aminopiperidine compound, and particularly relates to a target compound N-1, 3-difluoro isopropyl-4-aminopiperidine compound which is obtained by taking 1, 3-difluoro propane-2-alcohol as a raw material through two-step reaction. The method has the advantages of simple raw materials, low cost, easy obtainment, simple reaction conditions and high chemical purity of the obtained product.
Description
Technical Field
The invention relates to a synthetic method of an organic drug intermediate, in particular to a synthetic method of an N-1, 3-difluoro isopropyl-4-aminopiperidine compound.
Background
4-aminopiperidine is an important pharmaceutical intermediate. Is mainly used for synthesizing and producing drugs for preventing or treating various pains such as postoperative pain, migraine, visceral pain, neuropathic pain and the like and symptoms such as addiction, tolerance and the like caused by analgesic drugs such as opioid.
Fluorine-containing compounds have occupied a considerable specific gravity among the drugs on the market in recent years. Pharmaceutical chemists increasingly recognize that selective introduction of fluorine atoms or fluorine-containing groups into organic compounds can bring subtle changes to their biological effects, and thus, how to introduce fluorine atoms into compounds has become a hot research topic. The synthesis of tert-butyl- (1- (1, 3-difluoropropan-2-yl) piperidin-4-yl) carbamate has not been reported so far. A known method is the synthetic method reported in patent PCT int.appl., 2012049277. The method takes 1, 3-difluoropropane-2-ketone as a raw material to react with tert-butyl piperidine-4-carbamate to generate tert-butyl- (1- (1, 3-difluoropropane-2-yl) piperidine-4-yl) carbamate. The method has high cost, needs a reagent with low atom economy such as sodium borohydride acetate, is not environment-friendly, is not easy to operate and has low yield.
Disclosure of Invention
The invention aims to solve the technical problem of providing a synthetic method of an N-1, 3-difluoro isopropyl-4-aminopiperidine compound, which has short synthetic route, can effectively control the cost and improve the economic benefit.
In order to solve the technical problems, the invention adopts the technical scheme that:
a compound having the following general formula I: a method for synthesizing N-1, 3-difluoro isopropyl-4-amino piperidine compounds,
the method comprises the following steps: (1) dissolving 1, 3-difluoropropane-2-ol and alkali A in a solvent A, then dropwise adding methanesulfonyl chloride, and separating to obtain 1, 3-difluoropropane-2-yl-methanesulfonic acid;
(2) dissolving the compound of the general formula II in a solvent B, adding an alkali B, heating for reaction,
after the reaction is finished, separating and purifying to obtain the N-1, 3-difluoro isopropyl-4-aminopiperidine compound, wherein R is1，R2Each independently selected from: hydrogen, tert-butoxycarbonyl, C1-C8 alkyl, 3-methylbutyl, benzyl, 3-methyl-2-en-1-yl, 2-methoxyethyl, 2-ethylbutyl, hexyl, octyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, cyclopropylmethyl, 2-cyclopropylethyl, 2-pyrroethyl, 2- (N-ethylpyrrol-2-yl) -ethyl, cyclopentyl, cyclohexyl, 3, 4-dimethoxyphenethyl.
Preferably, R1，R2Each independently selected from: hydrogen, tert-butoxycarbonyl.
Preferably, the base A is an organic base, and the base B is an inorganic base.
Preferably, the base A is triethylamine, and the base B is potassium carbonate or sodium carbonate.
Preferably, the solvent A is dichloromethane, and the solvent B is dimethyl sulfoxide.
Preferably, the volume weight ratio (ml/g) of the dichloromethane to the 1, 3-difluoropropan-2-ol is 3-10: 1; the volume-to-weight ratio (ml/g) of the dimethyl sulfoxide to the compound of the general formula II is 3-10: 1.
preferably, the molar ratio of the added amount of the methane sulfonyl chloride to the 1, 3-difluoropropane-2-ol is 0.5-2.5: 1; the molar ratio of the added 1, 3-difluoropropane-2-ol to the compound of the general formula II is 0.5-2.5: 1.
the term "alkyl" in the present invention includes straight-chain and branched alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, 2-ethyl-butyl, hexyl, heptyl, octyl and the like;
the term "t-butyloxycarbonyl" as used herein refers to a Boc substituent.
The starting materials used in the present invention are either commercially available or synthesized using methods well known in the art.
The invention achieves the following beneficial effects:
the synthetic method of the invention does not need special production equipment and does not have (extremely) low-temperature operation; and can provide high-purity products (not less than 97 percent), thereby obtaining higher economic benefits; for some products, the method uses low-cost raw materials, has low cost and high yield, and the raw materials are easy to obtain.
Drawings
FIG. 1 is a synthesis scheme for the product of example 1.
Detailed Description
The invention is further described below with reference to the accompanying drawings. The following examples are only for illustrating the technical solutions of the present invention more clearly, and the protection scope of the present invention is not limited thereby.
Example 1
As shown in fig. 1: a method for synthesizing tert-butyl- (1- (1, 3-difluoropropan-2-yl) piperidin-4-yl) carbamate, comprising the following steps:
dissolving raw materials 1, 3-difluoropropane-2-ol and triethylamine in dichloromethane, and dropwise adding methane sulfonyl chloride into the solution at zero degree. After dropping, the mixture was stirred at zero degrees centigrade for one hour, and then warmed to room temperature and stirred for one hour until the reaction was complete. Pouring the reaction mixture into an ice water solution, separating, extracting by dichloromethane, washing an organic layer by using one mole of hydrochloric acid at zero degree until the pH value is 2-3, washing the organic layer by using water, washing the organic layer by using a saturated sodium bicarbonate aqueous solution at zero degree until the pH value is 8-9, washing the organic layer by using water, drying the organic layer by using anhydrous sodium sulfate, and concentrating under reduced pressure to obtain the 1, 3-difluoropropan-2-yl-methane sulfonic acid.
Dissolving a raw material piperidine-4-carbamic acid tert-butyl ester in dimethyl sulfoxide, adding 1, 3-difluoropropane-2-yl-methane sulfonic acid and potassium carbonate, and heating to one hundred twenty ℃ until the reaction is complete. After cooling to room temperature, the reaction mixture was poured into water, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to obtain tert-butyl- (1- (1, 3-difluoropropan-2-yl) piperidin-4-yl) carbamate.
Wherein, the used raw materials of piperidine-4-carbamic acid tert-butyl ester and 1, 3-difluoropropane-2-alcohol are commercially available chemicals, have low price and can be conveniently obtained.
Example 2
28.8 g of 1, 3-difluoropropan-2-ol, 60.6 g of triethylamine and 300 ml of dichloromethane are added into a three-neck reaction bottle with a stirrer, 41.2 g of methanesulfonyl chloride is added dropwise at zero centigrade, the mixture is stirred at zero centigrade for one hour, then the stirring is continued for one hour at room temperature, the reaction mixture is poured into 200 ml of ice water solution, dichloromethane is used for extraction (100 ml of × 2) at zero centigrade, one mol of hydrochloric acid is used for washing an organic layer until the pH value is 2-3, an organic layer is washed with water (100 ml), saturated sodium bicarbonate aqueous solution is used for washing the organic layer at zero centigrade until the pH value is 8-9, the organic layer is washed with water (100 ml), the organic layer is dried by anhydrous sodium sulfate and concentrated under reduced pressure to obtain 43 g of 1, 3-difluoropropan-2-yl-methanesulfonic acid, the yield is 86%, and the purity is 98%.
54 g of raw material piperidine-4-carbamic acid tert-butyl ester is dissolved in 500 ml of dimethyl sulfoxide, 43 g of 1, 3-difluoropropan-2-yl-methane sulfonic acid and 37 g of potassium carbonate are added, and the temperature is raised to one hundred twenty ℃ until the reaction is completed. After cooling to room temperature, the reaction mixture was poured into 100 ml of water, extracted with ethyl acetate (100 ml of X3), and the organic layer was dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to give 59 g of tert-butyl- (1- (1, 3-difluoropropan-2-yl) piperidin-4-yl) carbamate as a white solid in 79% yield and 97% purity.
Example 3
28.8 g of 1, 3-difluoropropan-2-ol, 60.6 g of triethylamine and 300 ml of dichloromethane were added to a three-necked reaction flask with a stirrer, 41.2 g of methanesulfonyl chloride was added dropwise thereto, the mixture was reacted at zero degrees centigrade for one hour, and then the reaction mixture was poured into 200 ml of ice water, extracted with dichloromethane (100 ml of × 2), washed with one mole of hydrochloric acid at zero degrees centigrade to pH 2-3, washed with an organic layer (100 ml), washed with a saturated aqueous solution of sodium bicarbonate at zero degrees centigrade to pH 8-9, washed with an organic layer (100 ml), dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a colorless liquid 43.8 g of 1, 3-difluoropropan-2-yl-methanesulfonic acid with a yield of 87% and a purity of 98%.
55 g of raw material piperidine-4-carbamic acid tert-butyl ester is dissolved in 500 ml of dimethyl sulfoxide, 43.5 g of 1, 3-difluoropropan-2-yl-methane sulfonic acid and 38 g of potassium carbonate are added, and the temperature is raised to one hundred twenty ℃ until the reaction is completed. After cooling to room temperature, the reaction mixture was poured into 100 ml of water, extracted with ethyl acetate (100 ml of X3), and the organic layer was dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to give 60 g of t-butyl- (1- (1, 3-difluoropropan-2-yl) piperidin-4-yl) carbamate as a white solid in a yield of 80% and a purity of 97%.
Example 4
28.8 g of 1, 3-difluoropropan-2-ol, 60.6 g of triethylamine and 300 ml of dichloromethane are added into a three-neck reaction bottle with a stirrer, 41.2 g of methanesulfonyl chloride is added dropwise under zero centigrade, the mixture is reacted for one hour under zero centigrade, then the reaction mixture is poured into 200 ml of ice water, dichloromethane is used for extraction (100 ml of × 2), one mol of hydrochloric acid is used for washing an organic layer under zero centigrade till the pH value is 2-3, the organic layer is washed with water (100 ml), saturated aqueous sodium bicarbonate solution is used for washing the organic layer under zero centigrade till the pH value is 8-9, the organic layer is washed with water (100 ml), the organic layer is dried by anhydrous sodium sulfate and concentrated under reduced pressure to obtain colorless liquid 44 g of 1, 3-difluoropropan-2-yl-methanesulfonic acid, the yield is 88%, and the purity is 98%.
56 g of piperidine-4-carbamic acid tert-butyl ester serving as a raw material is dissolved in 500 ml of dimethyl sulfoxide, 44 g of 1, 3-difluoropropan-2-yl-methane sulfonic acid and 40 g of potassium carbonate are added, and the temperature is raised to one hundred twenty ℃ until the reaction is completed. After cooling to room temperature, the reaction mixture was poured into 100 ml of water, extracted with ethyl acetate (100 ml of X3), and the organic layer was dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to give 61 g of t-butyl- (1- (1, 3-difluoropropan-2-yl) piperidin-4-yl) carbamate as a white solid in a yield of 80% and a purity of 97%.
Example 5
The following compounds were prepared:
wherein R is1＝H,R2The starting material used in this example is benzyl:
wherein R1 ═ H and R2 ═ benzyl, instead of tert-butyl piperidine-4-carbamate in example 1, the amount of 1, 3-difluoropropan-2-ol used as the starting material was 5 times the amount used in example 1, and the amounts of the other reagents were 5 times the amounts used in example 1, and the remainder were the same as in example 1, and the final product yield was 83% and the purity was 98%.
Example 6
The following compounds were prepared:
wherein R is1Methyl, R2The starting material used in this example is benzyl:
wherein R is1Methyl, R2Instead of tert-butyl piperidine-4-carbamate in example 1, the amount of 1, 3-difluoropropan-2-ol used as the starting material was 3 times the amount used in example 1, the remaining reagents were 3 times the amount used in example 1, and the remainder was the same as in example 1, giving a final product with a yield of 81% and a purity of 97%.
The above description is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, several modifications and variations can be made without departing from the technical principle of the present invention, and these modifications and variations should also be regarded as the protection scope of the present invention.
Claims (7)
1. A compound having the following general formula I: a synthesis method of N-1, 3-difluoro isopropyl-4-amino piperidine compounds is characterized in that,
the method comprises the following steps: (1) dissolving 1, 3-difluoropropane-2-ol and alkali A in a solvent A, then dropwise adding methylsulfonyl chloride, and separating to obtain 1, 3-difluoropropane-2-yl-methanesulfonic acid;
(2) dissolving a compound shown in a general formula II in a solvent B, adding a base B and 1, 3-difluoropropane-2-yl-methanesulfonic acid, heating for reaction,
after the reaction is finished, separating and purifying to obtain the N-1, 3-difluoro isopropyl-4-aminopiperidine compound, wherein R is1，R2Each independently selected from: hydrogen, tert-butoxycarbonyl, C1-C8 alkyl, benzyl, 3-methyl-2-en-1-butyl, 2-methoxyethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, cyclopropylmethyl, 2-cyclopropylethyl, 2-pyrrolylethyl, 2- (N-ethylpyrrol-2-yl) -ethyl, cyclopentyl, cyclohexyl, 3, 4-dimethoxyphenethyl.
2. The method for synthesizing N-1, 3-difluoroisopropyl-4-aminopiperidine compounds as claimed in claim 1, wherein R1 and R2 are independently selected from: hydrogen, tert-butoxycarbonyl.
3. The method for synthesizing an N-1, 3-difluoroisopropyl-4-aminopiperidine compound according to claim 1 or 2, wherein the base a is an organic base and the base B is an inorganic base.
4. The method for synthesizing an N-1, 3-difluoroisopropyl-4-aminopiperidine compound as claimed in claim 3, wherein the base A is triethylamine and the base B is potassium carbonate or sodium carbonate.
5. The method for synthesizing N-1, 3-difluoroisopropyl-4-aminopiperidine compounds according to claim 1 or 2, wherein the solvent A is dichloromethane and the solvent B is dimethylsulfoxide.
6. The method for synthesizing N-1, 3-difluoroisopropyl-4-aminopiperidine compounds according to claim 5, wherein the volume/weight ratio ml/g of the dichloromethane to the 1, 3-difluoropropan-2-ol is 3 to 10: 1; the volume-weight ratio ml/g of the dimethyl sulfoxide to the compound of the general formula II is 3-10: 1.
7. the method for synthesizing N-1, 3-difluoroisopropyl-4-aminopiperidine compounds according to claim 1 or 6, wherein the molar ratio of the added methanesulfonyl chloride to the 1, 3-difluoropropan-2-ol is 0.5 to 2.5: 1; the molar ratio of the added 1, 3-difluoropropane-2-ol to the compound of the general formula II is 0.5-2.5: 1.
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| 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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| 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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