CN106543108A - A kind of industrialized process for preparing of 3 propyIoxirane, 2 carbonyl ring propionic acid amide. - Google Patents
A kind of industrialized process for preparing of 3 propyIoxirane, 2 carbonyl ring propionic acid amide. Download PDFInfo
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- CN106543108A CN106543108A CN201610858330.3A CN201610858330A CN106543108A CN 106543108 A CN106543108 A CN 106543108A CN 201610858330 A CN201610858330 A CN 201610858330A CN 106543108 A CN106543108 A CN 106543108A
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- acid
- amide
- hexene
- propionic acid
- oxirane
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D301/00—Preparation of oxiranes
- C07D301/02—Synthesis of the oxirane ring
- C07D301/03—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds
- C07D301/12—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds with hydrogen peroxide or inorganic peroxides or peracids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/48—Compounds containing oxirane rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. ester or nitrile radicals
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Abstract
The invention discloses a kind of industrialized process for preparing of 2 carbonyl ring propionic acid amide. of 3 propyIoxirane, belongs to medicinal chemistry art, its step is：With malonic acid as initiation material, malonic acid (A) is added hexenoic acid (C), hexenoic acid is obtained with hutanal (B) condensation after alkali（C）Interior addition acylating reagent; after generation acylation reaction, it is concentrated to give hexene acyl chlorides (D), hexene acyl chlorides (D) and cyclopropylamine reaction obtains hexene amide (E), hexene amide (E) generation epoxidation reaction and obtains 3 propyIoxirane, 2 carbonyl ring propionic acid amide.；The synthetic method of the present invention adopts malonic acid for raw material, compared with traditional handicraft, material is easy to get, and cost is only the 20% or so of " route 1 ", it is greatly reduced, yield is higher, reaches more than 90%, and yield improves more than 15% compared with " route 1 ", more than 30% is improved compared with " route 2 ", reaction condition milder, more convenient operation can adapt to the requirement of industrialized great production.
Description
Technical field
The present invention relates to medicinal chemistry art, the work of more particularly to a kind of 3- propyl group-oxirane -2- carbonyl ring propionic acid amide .s
Industry preparation method.
Background technology
3- propyl group-oxirane -2- carbonyl ring propionic acid amide .s, its structural formula as shown in I,
,
It is to prepare antiviral drugs VX-960（Telaprevir）Important intermediate, Telaprevir is for treating the third type
Hepatitis active drug.
Hepatitis C viruss（HCV）Infection has become the disease of serious harm publilc health, can cause after human infection HCV
Liver chronic necrosis and fibrosiss, can partly develop into liver cirrhosis even hepatocarcinoma.In the world, HCV serum prevalence rates are about
3%, only may there are nearly 4,000,000 people's infection, Chinese HCV infection number about 40,000,000 in the U.S..Telaprevir is the U.S.
A kind of new serpin of Vertex pharmaceutical developments, being at present only being capable of effectively treatment serious symptom hepatitis C patient
One of several drugses.It is reported that, it is combined with interferon and ribavirin, to hepatitis C cure rate up to 79%.3- propyl group-
Oxirane -2- carbonyl ring propionic acid amide .s are the key intermediates for synthesizing Telaprevir, with the good market demand, its synthesis
Method is aroused extensive attention at home and abroad.
At present, the synthetic method of more document report 3- propyl group-oxirane -2- carbonyl ring propionic acid amide .s is had both at home and abroad,
It is different according to the initiation material for using, can be divided into following two：
1st, method one：
Route 1
Patent WO2007109023, US2008108632, CN200610129431 are reported with trans- 2- hexenoic acids as Material synthesis
The method of 3- propyl group-oxirane -2- carbonyl ring propionic acid amide .s（Described above " route 1 "）.Trans- 2- hexenoic acids can elder generation's Jing epoxies
Change reaction and obtain epoxidated intermediates, then 3- propyl group-oxirane -2- carbonyl ring propionic acid amide .s are condensed to yield with cyclopropylamine；Or
First 3- propyl group-oxirane -2- carbonyl ring propionic acid amide .s are obtained with cyclopropylamine condensation, then Jing epoxidation reactions.What the circuit was used
The trans- 2- hexenoic acids of raw material are expensive, are difficult a large amount of buyings, though therefore it is domestic adopt this route compared with multiple enterprises, be difficult to
3- propyl group-oxirane -2- carbonyl ring propionic acid amide. prepare with scale.
2nd, method two：
Route 2
Patent WO2013189978, documentJournal of Medicinal Chemistry, 2009,52 (24), 7993 reports
With 2- hexin -1- alcohol as raw material, Jing reduction is aoxidized twice, and synthesis obtains trans- 2- hexenoic acids, and by condensation, epoxidation is anti-in road
3- propyl group-oxirane -2- carbonyl ring propionic acid amide .s should be obtained（Described above " route 2 "）.The route reaction step is longer, total to receive
Rate is low, and raw material 2- hexin -1- alcohol is expensive, it is difficult to a large amount of to purchase, at all no industrial value.Therefore, the method is only
3- propyl group-oxirane -2- carbonyl ring propionic acid amide .s are prepared in a small amount for laboratory.
At present, preparation of industrialization 3- propyl group-oxirane -2- carbonyl rings propionic acid amide. mainly adopts " route 1 ".But " road
Raw material in line 1 " is trans- 2- hexenoic acids, expensive, and is difficult a large amount of buyings, causes 3- propyl group-oxirane -2- carbonyls
Ring propionic acid amide. production cost is higher, it is difficult to meet the market demand.
The content of the invention
The present invention goal of the invention be：A kind of industrialization system of 3- propyl group-oxirane -2- carbonyl ring propionic acid amide .s is provided
Preparation Method, to solve the above problems.
The technical solution used in the present invention is such：A kind of industry of 3- propyl group-oxirane -2- carbonyl ring propionic acid amide .s
Change preparation method, with malonic acid as initiation material, realized by following steps：
（1）Malonic acid (A) is added hexenoic acid (C) is obtained with hutanal (B) condensation, acid adjustment, concentration after alkali；
（2）To hexenoic acid obtained by step (1)（C）Interior addition acylating reagent, after there is acylation reaction, is concentrated to give hexene acyl chlorides
(D)；
（3）Another reaction vessel adds aqueous slkali, then suction toluene and cyclopropylamine, or suction DMF and cyclopropylamine, then Deca
Hexene acyl chlorides (D) obtained by step (2), after stirring reaction, extraction, concentration, recrystallization obtain hexene amide (E)；In this step,
The effect of toluene or DMF is dilution dispersion, it is preferred to use toluene, because toluene is cheap, facilitates recovery, easily removes；
（4）By hexene amide (E) obtained by step (3) and solvent input reaction vessel, oxidant, reaction after dissolving, is added to finish,
Aqueous alkali is quenched, extraction, concentration, and crystallization obtains product 3- propyl group-oxirane -2- carbonyls ring propionic acid amide. (F).
As preferred technical scheme, step（1）In, malonic acid (A) is 1.0 with the mol ratio of alkali：0.5~3.0；The third two
Sour (A) is 1.0 with the mol ratio of hutanal (B):1.0~5.0；Acid used during acid adjustment is sulphuric acid, hydrochloric acid, nitric acid, acetic acid；Adjust
Acid pH is 1 ~ 3；Reaction temperature is 10 DEG C ~ 80 DEG C；Response time is 5 ~ 30h；
Its synthetic route is as follows：
。
As preferred technical scheme, step（1）In, the alkali be pyridine-piperidines, pyridine-piperazine, pyridine-triethylamine,
Pyridine-diethylamine, pyridine-acetic acid ammonium.
As preferred technical scheme, step（2）In, hexenoic acid (C) is 1.0 with the mol ratio of acylating reagent：0.9~
3.0；The acylating reagent is thionyl chloride, chloroacetic chloride, acetic anhydride, the one kind in glacial acetic acid；Solvent is DMF, petroleum ether, dichloro
One kind in ethane, chloroform, acetone, ethyl acetate, Carbon bisulfide；Acylation reaction temperature is 10 DEG C ~ 80 DEG C；The acylation reaction time
For 0.5 ~ 10h.
As preferred technical scheme, step（3）In, the alkali be potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate,
At least one in sodium hydroxide, potassium hydroxide, aqueous slkali mass concentration are 10% ~ 50%；Hexene acyl chlorides (D) is rubbed with cyclopropylamine
You are than being 1.0:0.8~3.0；The acylation reaction time is 2 ~ 10h；Recrystallization solvent is petroleum ether, normal hexane, hexamethylene, positive heptan
Alkane；Hexene acyl chlorides (D) is 1.0 with the weight ratio of recrystallization solvent:1.0~10.0.
As preferred technical scheme, step（4）In, hexene amide (E) is 1.0 with the weight ratio of solvent:1.0~5.0；
Hexene amide (E) is 1.0 with the weight ratio of oxidant:5.0~20.0；Extractant be dichloromethane, chloroform, ethyl acetate or
Toluene.
It should be noted that concentration involved in the present invention, including acid, alkali concn, unless stated otherwise, each mean matter
Amount percentage concentration.
In sum, as a result of above-mentioned technical proposal, the invention has the beneficial effects as follows：The synthetic method of the present invention is adopted
It is raw material with malonic acid, compared with traditional handicraft, material is easy to get, cost is only the 20% or so of " route 1 ", is greatly reduced, yield
It is higher, more than 90% is reached, yield improves more than 15% compared with " route 1 ", improves more than 30% compared with " route 2 ", and reaction condition is warmer
With more convenient operation can adapt to the requirement of industrialized great production.
Specific embodiment
The present invention is described in detail below.
In order that the objects, technical solutions and advantages of the present invention become more apparent, with reference to embodiments, to the present invention
It is further elaborated.It should be appreciated that specific embodiment described herein is not used to only to explain the present invention
Limit the present invention.
" content " in following embodiments, unless stated otherwise, each means weight/mass percentage composition.
Embodiment 1：
A kind of industrialized process for preparing of 3- propyl group-oxirane -2- carbonyl ring propionic acid amide .s, with malonic acid as initiation material, leads to
Cross following steps realization：
（1）The preparation of hexenoic acid
By 38kg pyridines, 2.39kg diethylamine input reactor, open cycle water, add 50kg malonic acid, temperature control below 40 DEG C,
Deca 35.34kg hutanal, period control temperature within 50 DEG C, are stirred at room temperature 15 hours after completion of dropping, reduce pressure in 90 DEG C
Diethylamine is boiled off, is lowered the temperature, when being down to 50 DEG C or so, added 42kg toluene, continue to be cooled to less than 20 DEG C；Deca 53.2kg
50% hydrochloric acid, within 25 DEG C, to reacting liquid pH value to 1, evaporated under reduced pressure obtains hexene acid crude to period temperature control, cooling, standby,
This step obtains hexene acid crude weight 50.1kg, normalization method content 91.2%, yield 83.3%；
（2）The preparation of hexene amide
Take 50.1kg steps（1）Obtained hexene acid crude, adds 2.6kgDMF, stirs, Deca 57.5kg bis- under room temperature
Chlorine sulfoxide, is stirred at room temperature 1 ~ 2h after dripping off, decompression boils off excessive thionyl chloride, adds 50.1kg ethanol dilutions afterwards, standby；It is another
Add 75.2kg water and 67.6kg potassium hydroxide in reactor, stirring and dissolving completely, rear suction 100.2kg toluene and 27.6kg rings
Propylamine, at 50 DEG C, Deca acyl chlorides, after dripping, then less than 15 DEG C insulation reaction 2 hours are concentrated to dryness, add while hot
81.2kg petroleum ether, is heated to 60-65 DEG C of dissolving completely, opens ice maker and be cooled within 10 DEG C, and little in 0-10 DEG C of stirred crystallization 2
When, rejection filter with the cold petroleum ethers of 25.2kg once, dries to obtain hexene crude amide, send dry drying；
Hexene crude amide weight 54.3kg obtained by this step, normalization method content 98.8%, ignition residue 4.44%, yield 87.5%；
（3）The preparation of 3- propyl group-oxirane -2- carbonyl ring propionic acid amide .s
Take 54.3kg steps（2）Oneself dilute crude amide of gained and 162.9kg methanol input reactor, stirring are completely dissolved, afterwards plus
Enter 126.6kg hydrogen peroxide, stir 1 hour, 10% potassium bicarbonate solutions of suction 380.1kg, suction second batch after reacting 6 hours
126.6kg hydrogen peroxide, then react 6 hours suction last batch of 126.6kg hydrogen peroxide.After having reacted, with the two of 163.2kg × 3
Chloromethanes are extracted three times, merge organic faciess, and the washing of 10% sodium thiosulfate of 54.3kg, normal pressure concentration organic faciess are solvent-free to steam
Dry product 3- propyl group-oxirane -2- carbonyl ring propionic acid amide .s are evaporated to again；
Products obtained therefrom 3- propyl group-oxirane -2- carbonyl ring propionic acid amide. weight 61.3kg, normalization method content 94.49%, raw material oneself
Dilute amide residue 1.376%, yield 96.5%.
Embodiment 2：
A kind of industrialized process for preparing of 3- propyl group-oxirane -2- carbonyl ring propionic acid amide .s, with malonic acid as initiation material, leads to
Cross following steps realization：
（1）The preparation of hexenoic acid
By 152kg pyridines, 9.56kg triethylamines input reactor, open cycle water, add 200kg malonic acid, temperature control 40 DEG C with
Under, Deca 167.4kg hutanal, period control temperature within 50 DEG C, be stirred at room temperature 15 hours, subtract in 90 DEG C after completion of dropping
Pressure boils off triethylamine, lowers the temperature, and when being down to 50 DEG C or so, adds 168kg ethanol, continues to be cooled to less than 20 DEG C, Deca
50% phosphoric acid of 212.8kg, within 25 DEG C, to reacting liquid pH value to 3 or so, evaporated under reduced pressure obtains hexene acid crude to period temperature control,
Cooling, it is standby；
Hexene acid crude weight 202kg obtained by this step, normalization method content 92.4%, yield 85.1%；
（2）The preparation of hexene amide
To 202kg steps（1）10.6kgDMF is added in the hexene acid crude of gained, is stirred, Deca 231.6kg under room temperature
Thionyl chloride, is stirred at room temperature after dripping off 1 ~ 2 hour, boils off excessive thionyl chloride less than 35 DEG C of decompressions, adds 202kg acetic acid second afterwards
Ester dilutes, standby；606kg water and 272.7kg sodium hydroxide are added in another reactor, stirring and dissolving is complete, rear suction
111.2kg cyclopropylamines, at 50 DEG C, Deca acyl chlorides, after dripping, insulation reaction 2 hours, stratification is concentrated to dryness, while hot
352.5kg petroleum ether is added, 60-65 DEG C of dissolving is heated to completely, is opened ice maker and be cooled within 10 DEG C, and in 0-10 DEG C of stirring knot
Brilliant 2 hours, rejection filter with cold petroleum ether once, dries to obtain hexene crude amide, send dry drying；
Hexene crude amide weight 216.1kg obtained by this step, normalization method content 98.54%, yield 85.0%；
（3）The preparation of 3- propyl group-oxirane -2- carbonyl ring propionic acid amide .s
By 216.1kg steps（2）The hexene crude amide and 648kg ethanol input reactor of gained, stirring is completely dissolved, afterwards plus
Enter 504kg hydrogen peroxide, stir 1 hour.The slow suction 1513kg10% sodium bicarbonate solutions in control vacuum≤0.02, reaction 6 are little
When after suction second batch 504kg hydrogen peroxide, then react 6 hours suction last batch of 504kg hydrogen peroxide, after having reacted, use 650kg
× 3 dichloromethane is extracted three times, merges organic faciess, and 10% sodium thiosulfate of 216kg is washed to system non-oxidative, and normal pressure is dense
Contracting organic faciess, solvent-free steaming be evaporated to again dry product；
Products obtained therefrom weight 246.3kg, normalization method content 95.3%, raw material oneself dilute amide residue 1.017%, yield 96.2%.
Claims (6)
1. the industrialized process for preparing of a kind of 3- propyl group-oxirane -2- carbonyl ring propionic acid amide .s, it is characterised in that with malonic acid
For initiation material, realized by following steps：
（1）Malonic acid (A) is added hexenoic acid (C) is obtained with hutanal (B) condensation, acid adjustment, concentration after alkali；
（2）To hexenoic acid obtained by step (1)（C）Interior addition acylating reagent, after there is acylation reaction, is concentrated to give hexene acyl chlorides
(D)；
（3）Another reaction vessel adds aqueous slkali, then suction toluene and cyclopropylamine, or suction DMF and cyclopropylamine, then Deca
Hexene acyl chlorides (D) obtained by step (2), after stirring reaction, extraction, concentration, recrystallization obtain hexene amide (E)；
（4）By hexene amide (E) obtained by step (3) and solvent input reaction vessel, oxidant, reaction after dissolving, is added to finish,
Aqueous alkali is quenched, extraction, concentration, and crystallization obtains product 3- propyl group-oxirane -2- carbonyls ring propionic acid amide. (F).
2. the industrialized process for preparing of 3- propyl group according to claim 1-oxirane-2- carbonyl ring propionic acid amide .s, which is special
Levy and be, step（1）In, malonic acid (A) is 1.0 with the mol ratio of alkali：0.5~3.0；Malonic acid (A) is rubbed with hutanal (B's)
You are than being 1.0:1.0~5.0；Acid used during acid adjustment is sulphuric acid, hydrochloric acid, nitric acid, acetic acid；Acid adjustment pH value is 1 ~ 3；Reaction temperature
For 10 DEG C ~ 80 DEG C；Response time is 5 ~ 30h.
3. the industrialized process for preparing of 3- propyl group according to claim 1-oxirane-2- carbonyl ring propionic acid amide .s, which is special
Levy and be, step（1）In, the alkali is pyridine-piperidines, pyridine-piperazine, pyridine-triethylamine, pyridine-diethylamine, pyridine-second
Sour ammonium.
4. the industrialized process for preparing of 3- propyl group according to claim 1-oxirane-2- carbonyl ring propionic acid amide .s, which is special
Levy and be, step（2）In, hexenoic acid (C) is 1.0 with the mol ratio of acylating reagent：0.9~3.0；The acylating reagent is dichloro
One kind in sulfoxide, chloroacetic chloride, acetic anhydride, glacial acetic acid；Solvent is DMF, petroleum ether, dichloroethanes, chloroform, acetone, acetic acid second
One kind in ester, Carbon bisulfide；Acylation reaction temperature is 10 DEG C ~ 80 DEG C；The acylation reaction time is 0.5 ~ 10h.
5. the industrialized process for preparing of 3- propyl group according to claim 1-oxirane-2- carbonyl ring propionic acid amide .s, which is special
Levy and be, step（3）In, the alkali be potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, sodium hydroxide, in potassium hydroxide
At least one, alkaline concentration be 10% ~ 50%；Hexene acyl chlorides (D) is 1.0 with the mol ratio of cyclopropylamine:0.8~3.0；It is acylated
Response time is 2 ~ 10h；Recrystallization solvent is petroleum ether, normal hexane, hexamethylene, normal heptane；Hexene acyl chlorides (D) is molten with recrystallization
The weight ratio of agent is 1.0:1.0~10.0.
6. the industrialized process for preparing of 3- propyl group according to claim 1-oxirane-2- carbonyl ring propionic acid amide .s, which is special
Levy and be, step（4）In, hexene amide (E) is 1.0 with the weight ratio of solvent:1.0~5.0；Hexene amide (E) and oxidant
Weight ratio is 1.0:5.0~20.0；Extractant is dichloromethane, chloroform, ethyl acetate or toluene.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112159372A (en) * | 2020-10-22 | 2021-01-01 | 怀化宝华生物科技有限公司 | Preparation method of bicalutamide |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080108632A1 (en) * | 2006-11-02 | 2008-05-08 | Taigen Biotechnology Co., Ltd. | Hcv protease inhibitors |
| CN101200421A (en) * | 2006-12-12 | 2008-06-18 | 上海香料研究所 | Method for synthesizing 3-hexenoic acid |
| CN101454274A (en) * | 2006-03-16 | 2009-06-10 | 弗特克斯药品有限公司 | Processes and intermediates for preparing steric compounds |
| CN101503370A (en) * | 2009-03-02 | 2009-08-12 | 上海应用技术学院 | Method for synthesizing N-cyclopropyl-trans-2-cis-6-nonadienoic acid acidamide |
| CN105152959A (en) * | 2015-08-24 | 2015-12-16 | 上海合全药业股份有限公司 | Synthesis method of (2S, 3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide hydrochloride |
-
2016
- 2016-09-29 CN CN201610858330.3A patent/CN106543108A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101454274A (en) * | 2006-03-16 | 2009-06-10 | 弗特克斯药品有限公司 | Processes and intermediates for preparing steric compounds |
| US20080108632A1 (en) * | 2006-11-02 | 2008-05-08 | Taigen Biotechnology Co., Ltd. | Hcv protease inhibitors |
| CN101200421A (en) * | 2006-12-12 | 2008-06-18 | 上海香料研究所 | Method for synthesizing 3-hexenoic acid |
| CN101503370A (en) * | 2009-03-02 | 2009-08-12 | 上海应用技术学院 | Method for synthesizing N-cyclopropyl-trans-2-cis-6-nonadienoic acid acidamide |
| CN105152959A (en) * | 2015-08-24 | 2015-12-16 | 上海合全药业股份有限公司 | Synthesis method of (2S, 3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide hydrochloride |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112159372A (en) * | 2020-10-22 | 2021-01-01 | 怀化宝华生物科技有限公司 | Preparation method of bicalutamide |
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