CN106631992B - A kind of synthetic method of 4- oxygen -3,4- dihydro -2H- pyridine -1- t-butyl formate - Google Patents
A kind of synthetic method of 4- oxygen -3,4- dihydro -2H- pyridine -1- t-butyl formate Download PDFInfo
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Abstract
The present invention relates to the synthetic methods of 4- oxygen -3,4- dihydro -2H- pyridine -1- t-butyl formate, mainly solve the existing technical problem for causing enterprise, environmental pollution and reaction condition at high cost to be acutely difficult to control using noble metal reagent of existing synthetic method.Synthetic method of the present invention obtains 3- hydroxyl -4,4- dimethoxy-piperidines -1- t-butyl formate the following steps are included: react in the presence of sodium methoxide using N- tertbutyloxycarbonyl -4- piperidones as raw material with iodine；Then it is reacted with activated group, obtains 3- activated group -4,4- dimethoxy-piperidines -1- t-butyl formate；Later in the presence of alkali, elimination reaction obtains 4,4- dimethoxy -3,4- dihydro -2H- pyridine -1- t-butyl formate；Last Deprotection obtains 4- oxygen -3,4- dihydro -2H- pyridine -1- t-butyl formate.Such compound is important medical compounds structural modification small molecule in new drug research field.
Description
Technical field
The present invention relates to the synthetic methods of 4- oxygen -3,4- dihydro -2H- pyridine -1- t-butyl formate, such compound is new
Medicine research field is important medical compounds structural modification small molecule.
Background technique
4- oxygen -3,4- dihydro -2H- pyridine -1- t-butyl formate compound and its derivative are one in organic synthesis field
Class is by the compound of extensive concern, it has the characteristics that, and chemical property is special, reactivity is high, unique structure.This kind of compound
Usually as the intermediate of Michael addition reaction, to construct C-C key, other reactions are compared, this kind of reaction has better official
Tolerance can be rolled into a ball, more efficiently synthetic route, it is simpler that skeleton framework is carried out to molecule.Recently as similar structures
Drug candidate is developed in succession, and the application that this kind of compound is in terms of C-C key formation, molecular skeleton is built rapidly is also more next
It is more extensive.In biological medicine research field, the compound with piperidines and pyridine ring synthesis anticancer drug, anti-tumor drug,
Anti- deterioration drug etc. has more application.4- oxygen -3,4- dihydro -2H- pyridine -1- t-butyl formate is to construct such
The key intermediate of compound structure can be widely used in medicament research and development and synthesis aspect.
The actually rare report of synthetic method of 4- oxygen -3,4- dihydro -2H- pyridine -1- t-butyl formate, and similar compound
Synthetic method it is also few.Here is one such synthetic method:
1. " American Chemical Society's magazine " discloses N- t-butoxycarbonylpiperidin ketone and oxygen in catalyst: trifluoracetic acid palladium
4- oxygen -3,4- dihydro -2H- pyridine -1- t-butyl formate (formula 1, Journal of the American are prepared under catalysis
Chemical Society, 2011, vol. 133, # 37 p. 14566-14569)；
Although this method route is short, palladium metal catalyst and oxygen are used, the use of noble metal can bring environment
Pollution, environment are unfriendly.The intervention of oxygen can be such that reaction is acutely difficult to control, and be not suitable for quickly preparation, to accomplish low cost,
Need many additional controls.
Formula 1:
2. Li Lai company discloses by methoxypyridine, after reacting by plurality of reagents, 4- is finally obtained
Oxygen -3,4- dihydro -2H- pyridine -1- t-butyl formate (formula 2, EP1204659 B1)；
Although this method route is brief, equally there is reaction reagent to methoxypyridine valuableness, and be not readily available.Instead
The problems such as answering yield not high.In addition the route needs low-temp reaction, and maintaining reaction temperature is at -40 DEG C, this is to synthesis device also band
Difficulty centainly is carried out.
Formula 2:
Summary of the invention
The purpose of the invention is to provide one kind can efficiently obtain 4- oxygen -3,4- dihydro -2H- pyridine -1- formic acid
The synthetic method of tert-butyl ester compound, mainly solve existing synthetic method it is existing caused using noble metal reagent it is at high cost
The technical problem that enterprise, environmental pollution and reaction condition are acutely difficult to control.
Technical solution of the present invention: a kind of synthetic method (formula 3) of 4- oxygen -3,4- dihydro -2H- pyridine -1- t-butyl formate,
The following steps are included: the first step, is reacted using N- tertbutyloxycarbonyl -4- piperidones as raw material with elemental halogen under alkaline condition,
Obtain 3- hydroxyl -4,4- dimethoxy-piperidines -1- t-butyl formate；Second step, 3- hydroxyl -4,4- dimethoxy-piperidines -1-
T-butyl formate is reacted with activated group G, obtains 3-G-4,4- dimethoxy-piperidines -1- t-butyl formate；Third step, 3-G-
For 4,4- dimethoxys-piperidines -1- t-butyl formate under the action of highly basic, elimination reaction obtains 4,4- dimethoxy -3,4- bis-
Hydrogen -2H- pyridine -1- t-butyl formate；4th step, 4,4- dimethoxy -3,4- dihydro -2H- pyridine -1- t-butyl formates are in acid
Deprotection obtains 4- oxygen -3,4- dihydro -2H- pyridine -1- t-butyl formate under the conditions of property.
Formula 3:
。
The activated group G is Trifluoromethanesulfonic anhydride or Loprazolam acid anhydride, halogen etc..
It is potassium hydroxide or sodium methoxide that the alkaline condition (first step), which is related to compound,.The highly basic (third step) can be with
It, can also be with for organic base (for 1,8- diazabicylo, 11 carbon -7- alkene, potassium tert-butoxide, sodium methoxide, sodium ethoxide or Sodamide etc.)
For inorganic base (sodium hydroxide, potassium hydroxide, cesium carbonate etc.).It is to toluene that the acid condition (the 4th step), which is related to compound,
One of sulfonic acid, hydrochloric acid or acidic silica gel.
Beneficial effects of the present invention: the raw material N- tertbutyloxycarbonyl -4- piperidones (6000 yuan/1.0 used in the present invention
Kg) cheap, be easy to get, other reagents used also are conventional reagent, and preparation cost is very cheap, avoids using high risk
Triisopropyl potassium borohydride or and its expensive rare heavy metal catalyst.Pass through four step popular responses, operation side
Just, post-processing is simple, product be easy to get to, avoid high-temperature high-voltage reaction condition or heavy metal catalyst, the controllability of reaction and
Repeatability is all fine.
Specific embodiment
Embodiment 1
1) 3- hydroxyl -4,4- dimethoxy-piperidines -1- t-butyl formate
In a 10 dry L there-necked flasks, 3800 mL methanol and 311g potassium hydroxide is added.Reaction solution is cooling
To 0 DEG C, 38 g N- tertbutyloxycarbonyl -4- piperidones are into reaction solution.532 g iodines are dissolved in 3000 mL methanol, are delayed
Slowly it is added drop-wise in reaction solution.Reaction solution, which is stirred at room temperature to raw material, to disappear.Concentration of reaction solution removes most of methanol.It is added 1500
ML toluene stirs 30 minutes into reaction flask.It is filtered to remove inorganic salts.Vacuum distillation removes solvent.400 mL petroleum are added
Ether stirs 30 minutes into reaction flask.Yellow solid is obtained after filtering.It is dried under reduced pressure to obtain 30g product, yield 60%.1H-NMR
(300 MHz, CDCl3): δ4.10-3.72 (m, 3H), 3.24 (s, 3H), 3.23 (s, 3H), 3.12-3.09
(broad d, 1H), 2.87-2.81 (broad t, 1H), 2.29 (broad s, 1H), 1.81-1.78 (m,
1H), 1.73-1.69 (m, 1H), 1.44 (s, 9H)。
) 3- trifluoromethayl sulfonic acid ester group -4,4- dimethoxy-piperidines -1- t-butyl formate
In a 100 dry mL there-necked flasks, 2.0 g 3- hydroxyl -4,4- dimethoxys-piperidines -1- formic acid is added
The tert-butyl ester and 20 mL anhydrous methylene chlorides.2.0 mL pyridines are added into the reaction solution.Reaction solution is cooled to -15 ~ 0 DEG C.
2.28 g Trifluoromethanesulfonic anhydrides are slowly added drop-wise in reaction solution.Reaction solution stirs 1 hour at -15 ~ 0 DEG C.It is added 20
ML water urges reaction of going out into reaction flask.Liquid separation retains organic layer.Water layer continues to be extracted with 15 mL methylene chloride secondary.It is associated with
Machine layer is simultaneously dry with anhydrous sodium sulfate.Removal solvent is concentrated under reduced pressure and obtains 2.8 g of light brown product liquid.1H-NMR (300
MHz, CDCl3): δ4.87-4.80 (m, 1H), 4.48-4.34 (m, 1H), 4.20-3.89 (m, 1H), 3.27
(s, 6H), 3.26-3.16 (m, 1H), 2.90-2.78 (m, 1H), 1.90-1.78 (m, 2H), 1.46 (s,
9H)。
) 4,4- dimethoxy -3,4- dihydro -2H- pyridine -1- t-butyl formate
In a 50 dry mL there-necked flasks, 0.5 g 3- trifluoromethayl sulfonic acid ester group -4,4- dimethoxy-is added
Piperidines -1- carboxylic acid tert-butyl ester and 4.0 mL toluene.0.77 g sodium methoxide is added in the mixture.The mixture is heated to arrive
50 DEG C, and react 3 hours at such a temperature.As 10 mL water and 6mL methyl tertiary butyl ether(MTBE) are added in reaction solution.Retain organic
Layer, and remaining water layer is extracted twice with 6 mL methyl tertiary butyl ether(MTBE)s.Merge organic layer.It is concentrated to dryness, obtains 4,4- dimethoxy
0.28 g of base -3,4- dihydro -2H- pyridine -1- t-butyl formate.Yield 90%.1H-NMR (300 MHz, CDCl3): δ7.01-
6.84 (dd, 1H), 4.96-4.85 (dd, 1H), 3.65-3.60(m, 2H), 3.25 (s, 6H), 1.92 (m,
2H), 1.49 (s, 9H)。
) 4- oxygen -3,4- dihydro -2H- pyridine -1- t-butyl formate
In a 50 dry mL there-necked flasks, 0.28 g 4,4- dimethoxy -3,4- dihydro -2H- pyridine -1- is added
T-butyl formate and 4.0 mL acetone.0.01 g p-methyl benzenesulfonic acid is added in the mixture.The mixture is heated to 30 degree, and
It reacts 1 hour at such a temperature.It is concentrated to dryness, obtains 0.52 g of 44- oxygen -3,4- dihydro -2H- pyridine -1- t-butyl formate.
Yield 40%.1H-NMR (300 MHz, CDCl3): δ7.81 (d, 1H), 5.30-5.28 (d, 1H), 3.98-3.94
(t, 2H), 2.56-2.52 (t, 2H), 1.48 (s, 9H)。
Embodiment 2:
2) 3- Loprazolam ester group -4,4- dimethoxy-piperidines -1- t-butyl formate
In a 100 dry mL there-necked flasks, 1.0 g 3- hydroxyl -4,4- dimethoxys-piperidines -1- formic acid is added
The tert-butyl ester and 10 mL anhydrous methylene chlorides.1.0 mL pyridines are added into the reaction solution.Reaction solution is cooled to 0 DEG C.It will
0.46 g Loprazolam acid anhydride is slowly added drop-wise in reaction solution.Reaction solution stirs 1 hour at 0 DEG C.20 mL water are added to reaction
Reaction of going out is urged in bottle.Liquid separation retains organic layer.Water layer continues to be extracted with 15 mL methylene chloride secondary.Merge organic layer and uses nothing
Aqueous sodium persulfate is dry.Removal solvent is concentrated under reduced pressure and obtains 1.1 g of light brown product liquid.By silica gel group chromatographic purifying, this is thick
Product obtain 3- Loprazolam ester group -4,4- dimethoxy -0.5 g of piperidines -1- t-butyl formate.1H-NMR (300 MHz,
CDCl3): δ4.77-4.72 ( m, 1H), 4.45-4.30 (m, 1H), 4.20-3.87 (m, 1H), 3.12 (s,
6H), 3.10-3.02 (m, 1H), 2.89-2.80 (m, 1H), 1.85-1.78 (m, 2H), 1.47 (s, 9H)。
) 4,4- dimethoxy -3,4- dihydro -2H- pyridine -1- t-butyl formate
In a 50 dry mL there-necked flasks, 0.2 g 3- Loprazolam ester group -4,4- dimethoxy-piperidines-is added
11 carbon -7- alkene (DBU) of 1- carboxylic acid tert-butyl ester and 4.0 mL 1,8- diazabicylo.The mixture is heated to 90 DEG C, and
It reacts 3 hours at such a temperature.As 20 mL water and 20mL methyl tertiary butyl ether(MTBE) are added in reaction solution.Retain organic layer, is used in combination
10 mL methyl tertiary butyl ether(MTBE)s extract remaining water layer twice.Merge organic layer.It is concentrated to dryness, obtains 4,4- dimethoxy -3,4-
0.072 g of dihydro -2H- pyridine -1- t-butyl formate.Yield 51%.1H-NMR (300 MHz, CDCl3): δ7.01-6.84
(dd, 1H), 4.96-4.85 (dd, 1H), 3.65-3.60(m, 2H), 3.25 (s, 6H), 1.92 (m, 2H),
1.49 (s, 9H)。
Embodiment 3, it is sodium methoxide that first step alkaline condition, which is related to compound, and it is salt that the 4th step acid condition, which is related to compound,
Acid, remaining is the same as embodiment 1.
Embodiment 4, the activated group G are bromine, and highly basic described in third step is potassium hydroxide, and the 4th step acid condition is related to
Compound is acidic silica gel, remaining is the same as embodiment 1.
Embodiment 5, the activated group G are Trifluoromethanesulfonic anhydride, and highly basic described in third step is pyridine, remaining is the same as implementation
Example 1.
Claims (4)
1. a kind of synthetic method of 4- oxygen -3,4- dihydro -2H- pyridine -1- t-butyl formate, it is characterized in that the following steps are included:
The first step is reacted under alkaline condition as raw material with elemental halogen using N- tertbutyloxycarbonyl -4- piperidones, obtains hydroxyl -4 3-,
4- dimethoxy-piperidines -1- t-butyl formate；Second step, 3- hydroxyl -4,4- dimethoxy-piperidines -1- t-butyl formate and work
Change group G Trifluoromethanesulfonic anhydride or Loprazolam anhydride reactant, obtains 3-G-4,4- dimethoxy-piperidines -1- t-butyl formate；
Third step, for 3-G-4,4- dimethoxy-piperidines -1- t-butyl formate under the action of organic base, elimination reaction obtains 4,4- bis-
Methoxyl group -3,4- dihydro -2H- pyridine -1- t-butyl formate；4th step, 4,4- dimethoxy -3,4- dihydro -2H- pyridine -1-
Deprotection obtains 4- oxygen -3,4- dihydro -2H- pyridine -1- t-butyl formate to t-butyl formate in acid condition, and reaction equation is such as
Under:
。
2. a kind of synthetic method of 4- oxygen -3,4- dihydro -2H- pyridine -1- t-butyl formate according to claim 1,
Being characterized in that alkaline condition described in the first step is related to compound is potassium hydroxide or sodium methoxide.
3. a kind of synthetic method of 4- oxygen -3,4- dihydro -2H- pyridine -1- t-butyl formate according to claim 1,
It is characterized in that organic base described in third step is one of 11 carbon -7- alkene of sodium methoxide, sodium ethoxide or 1,8- diazabicylo.
4. a kind of synthetic method of 4- oxygen -3,4- dihydro -2H- pyridine -1- t-butyl formate according to claim 1,
Being characterized in that the 4th step acid condition is related to compound is one of p-methyl benzenesulfonic acid, hydrochloric acid or acidic silica gel.
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