CN108314639A - Compound（E）-3-（1- methylpyrrolidin- 2- bases）Acrylic acid hydrochloride and synthetic method - Google Patents
Compound（E）-3-（1- methylpyrrolidin- 2- bases）Acrylic acid hydrochloride and synthetic method Download PDFInfo
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- CN108314639A CN108314639A CN201810440934.5A CN201810440934A CN108314639A CN 108314639 A CN108314639 A CN 108314639A CN 201810440934 A CN201810440934 A CN 201810440934A CN 108314639 A CN108314639 A CN 108314639A
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- methylpyrrolidin
- yls
- acrylic acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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 hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
Abstract
The invention discloses (1 crassitude, the 2 base) acrylic acid hydrochloride of compound (E) 3 and synthetic methods.Shown in the compound structure such as formula (I).Its synthetic method is：With BOC L prolinols (or BOC D prolinols) for starting material; it is oxidized at aldehyde; take off BOC protective agents; it is reacted again with alkyl halide; again synthesis (S is reacted through Wittig; E) 3 (1 crassitude, 2 base) ethyl acrylate; after hydrolysis (S is obtained at salt; E) 3 (1 crassitude, 2 base) acrylic acid hydrochlorides [or (R, E) 3 (1 crassitude, 2 base) acrylic acid hydrochloride].The compound can prepare quinazoline or quinolines derivative as medicine intermediate.
Description
Technical field
The present invention relates to organic synthesis fields, relate generally to compound (E) -3- (1- methylpyrrolidin- 2- yls)-acrylic acid
Hydrochloride and synthetic method.
Background technology
The application of quinazoline or quinolines anticancer drug derivative clinically is more and more extensive, wherein the synthesis of mesosome with
Innovation is more and more important, and patent CN102020639 describes 6- amido quinazolines or 3- cyano quinolines analog derivative, its preparation side
Method and its application in medicine.The particular compound that is arrived involved in above-mentioned patent compound 1-6 as shown in table 1 below, wherein
Compound 1,4,5 all refers to (E) -3- (1- methylpyrrolidin- 2- yls)-propylene structure.
1 6- amido quinazolines of table or 3- cyano quinolines analog derivatives
(S, E)-N- { 4- [the chloro- 4- of 3- (pyridine -2- ylmethoxies)-the anilino-] -3- cyanogen provided in above patent document
Base -7- ethoxy yl-quinoline -6- bases } -3- (1- methyi-pyrrofidinium -2- bases)-acrylamide (compound 1) specific synthesis side
Method：Using compound 1c as raw material, is first reacted with diethyl phosphate guanidine-acetic acid and generate compound 1d, then life is reacted with compound 1b
At compound 1, synthetic route is as follows.
Substance (S) -1- methyi-pyrrofidinium -2- formaldehyde (compound 1b) is difficult to buy on the market in said synthesis route,
Its synthesis condition harshness (being reacted at -30 DEG C), yield is low (31.36%), is unfavorable for industrialized production, and this substance is easily by oxygen
Change is not easy to the next step, also process overall yields can be made low.
(S) -1- methyi-pyrrofidiniums -2- is also related in the building-up process of compound 4 disclosed in patent CN102020639
Formaldehyde (compound 1b)；R types involved in the building-up process of compound 5 disclosed in patent CN102020639 to compound 1b are different
Structure body, i.e. (R) -1- methyi-pyrrofidinium -2- formaldehyde (compound 5c).Therefore, there is also above-mentioned " synthesis condition harshness, yields
It is low, the next step is easily not easy to by oxidation " the problems such as.
Invention content
The present invention overcomes above-mentioned the deficiencies in the prior art, provide a kind of compound (E) -3- (1- methylpyrrolidin- 2-
Base)-acrylic acid hydrochloride and its synthetic method.The present invention is with compound (S, E) -3- (1- methylpyrrolidin- 2- yls)-propylene
Acid hydrochloride carries out amidation process as intermediate, with compound 1c, can directly generate compound 1, chemical reaction equation
Formula is as follows, can also synthesize other quinazolines or quinoline using (E) -3- (1- methylpyrrolidin- 2- yls)-acrylic acid hydrochloride
Quinoline class medicaments derivative.The compound of the present invention (E) -3- (1- methylpyrrolidin- 2- yls)-acrylic acid hydrochloride stable structure,
Reaction condition is suitble to big production, provides new method for synthesis quinazoline or quinolines derivative, and substantially increase production
Object total recovery.
The technical scheme is that：Compound (E) -3- (1- methylpyrrolidin- 2- yls)-acrylic acid hydrochloride, knot
Structure formula is as follows：
Its molecular formula is C8H13O2N·HCl。
The compound is (S, E) -3- (1- methylpyrrolidin- 2- yls)-acrylic acid hydrochlorides or (R, E) -3- (1- methyl pyrroles
Cough up alkane -2- bases) mixture of both configurations of-acrylic acid hydrochloride or above two configuration, wherein (S, E)-configuration and
The structural formula difference of (R, E)-configuration is as follows：
The invention also discloses the synthetic methods of above compound, characterized in that with BOC-L- prolinols (or BOC-D-
Prolinol) it is starting material, it is oxidized to take off BOC protective agents (BOC protective agents are preferably taken off using trifluoroacetic acid) at aldehyde, then
It is reacted with alkyl halide (preferably iodomethane) and generates S-1- methyi-pyrrofidinium -2- formaldehyde (or R-1- methyi-pyrrofidinium -2- first
Aldehyde), then (carry out Wittig with ethoxycarbonyl methylene triphenyl phosphine to react) synthesis (S, E) -3- (1- first through Wittig reactions
Base pyrrolidin-2-yl)-ethyl acrylate, after hydrolysis (S, E) -3- (1- methylpyrrolidin- 2- yls)-acrylates is obtained at salt
Hydrochlorate [or (R, E) -3- (1- methylpyrrolidin- 2- yls)-acrylic acid hydrochloride], synthetic route is as follows：
The synthetic method of above-mentioned (S, E) -3- (1- methylpyrrolidin- 2- yls)-acrylic acid hydrochloride, specifically includes following step
Suddenly：
1) BOC-L- prolinols are dissolved using organic solvent, and sodium bromide and TEMPO (tetramethyl piperidine nitrogen oxidations is then added
Object)；Cooling, dropwise addition mix up the liquor natrii hypochloritis of pH=8~9 until the reaction is complete in advance；It is static after after raw material, the reaction was complete
Layering, stays organic layer, post-treated, obtains BOC-L- dried meat ammonium aldehydes；
2) solvent and trifluoroacetic acid is added in BOC-L- dried meat ammonium aldehydes, insulation reaction is stirred, after the reaction was complete after raw material after
Handle to obtain S- pyrrolidines -2- formaldehyde；
3) solvent and potassium carbonate is added in above-mentioned S- pyrrolidines -2- formaldehyde, after stirring evenly, iodomethane is added dropwise, after adding
Room temperature reaction, it is post-treated after the completion of reaction to obtain S-1- methyi-pyrrofidinium -2- formaldehyde；
4) solvent is added in S-1- methyi-pyrrofidinium -2- formaldehyde, adds ethoxycarbonyl methylene triphenyl phosphine, stirs
It mixes overnight, through post-processing (S, E) -3- (1- methylpyrrolidin- 2- yls)-ethyl acrylate after after raw material, the reaction was complete；
5) ethyl alcohol and sodium hydroxide solution is added in above-mentioned (S, E) -3- (1- methylpyrrolidin- 2- yls)-ethyl acrylate,
Stirring, with dilute hydrochloric acid tune pH=7, solvent evaporated；Be evaporated object be added ethyl acetate stirring and dissolving, filter out inorganic salts, cool down to
It is passed through hydrogen chloride gas in mother liquor, solid is precipitated, filters, drying obtains (S, E) -3- (1- methylpyrrolidin- 2- yls)-propylene
Acid hydrochloride.
Wherein, step (1) the N-BOC-L- prolinols, sodium bromide and TEMPO molar ratios 1：0.2~0.4：0.02~
0.04, preferably 1：0.3：0.03.
Wherein, step (1) solvent is chloroform, dichloromethane, tetrahydrofuran, n-hexane etc., preferably dichloromethane.
Wherein, step (1) reaction temperature：- 10~5 DEG C, preferably -5~0 DEG C.
Wherein, the post-processing of the step (1) is：It is washing, dry and be evaporated, it washs and is：Respectively with 1% sulfuric acid solution,
5% hypo solution and saturated salt solution is respectively washed once.
Wherein, the molar ratio of step (2) the BOC-L- dried meat ammonium aldehyde and trifluoroacetic acid is 1:2.5~3.5, preferably 1：3.
Wherein, step (2) solvent is：Chloroform, dichloromethane, n-hexane etc., preferably dichloromethane.
Wherein, step (2) holding temperature：25~35 DEG C, preferably 29~31 DEG C；Reaction time：10~15h, preferably
12~13h.
Wherein, the step (2), which post-processes, is：Saturated sodium carbonate solution, stirring, ethyl acetate extraction is added in solvent evaporated
It takes, anhydrous sodium sulfate drying, filtering is evaporated.
Wherein, the molar ratio of step (3) S- pyrrolidines -2- formaldehyde and iodomethane, potassium carbonate is 1:1~1.5：1~
1.5, preferably 1：1.2：1.05.
Wherein, step (3) solvent is：Methanol, ethyl alcohol, isopropanol, preferably methanol.
Wherein, step (3) reaction time：6~10h, preferably 8~8.5h.
Wherein, step (3) dropping temperature：10~20 DEG C, preferably 15~18 DEG C
Step (3) post-processes：Water, dichloromethane is added in evaporated under reduced pressure, stirs dissolved clarification, separates organic layer, washing one
Secondary, anhydrous sodium sulfate drying, filtering is evaporated.
Wherein, step (4) S-1- methyi-pyrrofidinium -2- formaldehyde and ethoxycarbonyl methylene triphenyl phosphine mole
Than： 1:1.3~1.5, preferably 1：1.2.
Wherein, step (4) solvent chloroform, dichloromethane, n-hexane etc., preferably dichloromethane.
Wherein, step (4) the cooling temperature：5~15 DEG C, preferably 10~12 DEG C.
Above-mentioned steps (4) post-process：Petroleum ether, ethyl acetate is added in solvent evaporated, and return stirring cools down, filtering,
It is evaporated, crosses silica gel column purification.
Above-mentioned steps (5) the cooling temperature：5~15 DEG C, preferably 10~12 DEG C.(S, E) -3- (1- methylpyrrolidin- 2-
Base) molar ratio of-ethyl acrylate and sodium hydroxide is 1：0.5~1.2.
It should be noted that：The synthetic method of (R, E) -3- (1- methylpyrrolidin- 2- yls)-acrylic acid hydrochloride only needs
BOC-L- prolinols are changed to BOC-D- prolinols.
The present invention with compound (S, E) -3- (1- methylpyrrolidin- 2- yls)-acrylic acid hydrochlorides as medicine intermediate,
Amidation process can be carried out with compound 1c, the compound 1 of (S, E) configuration can be directly generated.Certainly with (R, E) -3- (1-
Methylpyrrolidin- 2- yls)-acrylic acid hydrochloride as intermediate, can carry out amidation process, Ke Yizhi with compound 1c
Deliver a child into the isomers (compound 5 i.e. in table 1) of the R configurations of compound 1.With (S, E) -3- (1- methylpyrrolidin- 2-
Base)-acrylic acid hydrochloride as intermediate, can carry out amidation process with compound 4e, can directly generate the change in table 1
Close object 4.
The beneficial effects of the invention are as follows：
1, from the point of view of compound structure, (E) -3- (1- methylpyrrolidin- 2- yls)-acrylic acid hydrochloride compares (S) -1- first
Base-pyrrolidines -2- formaldehyde or (R) -1- methyi-pyrrofidinium -2- formaldehyde stable structure, it is not easy to be aoxidized；
2, (E) -3- (1- methylpyrrolidin- 2- yls)-acrylic acid hydrochlorides is used to synthesize compound 1,4 and 5 for intermediate,
One-step synthesis route is not only omitted in it, and it is common amidation process to react, and enormously simplifies reaction process, and it is reacted
Condition is suitble to big production；
3, the synthesis of (E) -3- (1- methylpyrrolidin- 2- yls)-acrylic acid hydrochloride of the invention can be to synthesize other
Quinazoline or quinolines derivative containing (E) -3- (1- methylpyrrolidin- 2- yls)-propylene structure (or similar structures)
New method is provided, and substantially increases product total recovery.
Description of the drawings
Fig. 1 is (S, E) -3- (1- methylpyrrolidin- 2- yls)-acrylic acid hydrochloride IR collection of illustrative plates；
Fig. 2 is (R, E) -3- (1- methylpyrrolidin- 2- yls)-acrylic acid hydrochloride IR collection of illustrative plates；
Fig. 3 is (R, E) -3- (1- methylpyrrolidin- 2- yls)-acrylic acid hydrochloride1H NMR spectras；
Fig. 4 is (R, E) -3- (1- methylpyrrolidin- 2- yls)-acrylic acid hydrochloride1H NMR spectra partial enlarged views；
Fig. 5 is (R, E) -3- (1- methylpyrrolidin- 2- yls)-acrylic acid hydrochloride13C NMR spectras.
Fig. 6 is the mass spectrogram of (R, E) -3- (1- methylpyrrolidin- 2- yls)-acrylic acid hydrochloride.
Specific implementation mode
Embodiment 1：The synthesis of (S, E) -3- (1- methylpyrrolidin- 2- yls)-acrylic acid hydrochloride
1) BOC-L- dried meat ammonium aldehyde synthesizes
It weighs 100g BOC-L- prolinols to be placed in four mouthfuls of reaction bulbs of 2L, the dichloromethane of 1.5L is added, is stirred at room temperature
15.4g sodium bromides, 2.3gTEMPO are added after dissolving, -10 DEG C of cooling is hereinafter, start to be added dropwise the secondary chlorine for mixing up pH=8~9 in advance
Acid sodium solution keeps temperature -5~-10 DEG C.TLC tracks (solvent ethyl acetate：Petroleum ether=1：1), wait for that the reaction was complete for raw material
Stop that liquor natrii hypochloritis's (500ml is about added dropwise) is added dropwise afterwards, static layering stays organic layer, respectively with 1% sulfuric acid solution 800ml,
5% hypo solution 800ml and saturated salt solution 800ml is respectively washed once, and anhydrous magnesium sulfate dries organic layer, is filtered,
It is evaporated, obtains BOC-L- dried meat ammonium aldehydes 94g.
2) S- pyrrolidines -2- formaldehyde synthesizes
Product BOC-L- dried meat ammonium aldehyde 94g are walked on being added in reaction bulb, 600ml dichloromethane, 162g trifluoro second is then added
Acid.29~31 DEG C of 12~13h of stirring of heat preservation, TLC (solvent ethyl acetate：Petroleum ether=1：1) it is steamed after, after raw material, the reaction was complete
500ml saturated sodium carbonate solutions are added in dry solvent, and 30min is stirred at room temperature, and ethyl acetate extracts (200ml × 3), anhydrous slufuric acid
Sodium is dried, and filtering is evaporated, obtains S- pyrrolidines -2- formaldehyde 40g.
3) S-1- methyi-pyrrofidiniums -2- formaldehyde synthesizes
200ml methanol is added into above-mentioned 40g S- pyrrolidines -2- formaldehyde, is gone to after dissolving in 1L reaction bulbs, then add
200ml methanol, 60g potassium carbonate, after stirring evenly, 15~18 DEG C of dropwise addition 69g iodomethane of control temperature react at room temperature 8 after adding
Water 300ml, dichloromethane 300ml is added in~8.5h, evaporated under reduced pressure, stirs dissolved clarification, separates organic layer, and 200ml washings are primary,
Anhydrous sodium sulfate is dried, and filtering is evaporated to obtain S-1- methyi-pyrrofidinium -2- formaldehyde 42g.
4) S, E) synthesis of -3- (1- methylpyrrolidin- 2- yls)-ethyl acrylate
500ml dichloromethane is added to above-mentioned 42gS-1- methyi-pyrrofidiniums -2- formaldehyde, 1L reaction bulbs are gone to after dissolving
In, 155g ethoxycarbonyl methylene triphenyl phosphines are added at room temperature, are stirred overnight, TLC (solvent ethyl acetate：Petroleum ether
=1：1), wait for that the reaction was complete for raw material, petroleum ether 300ml, ethyl acetate 100ml, return stirring 1h, cooling is added in solvent evaporated
10~12 DEG C, filtering is evaporated, and crosses silica gel column purification (ethyl acetate：Petroleum ether=7:2) (S, E) -3- (1- methylpyrroles, are obtained
Alkane -2- bases)-ethyl acrylate 51g.
5) (S, E) -3- (1- methylpyrrolidin- 2- yls)-acrylic acid hydrochloride synthesizes
600ml ethyl alcohol, 200ml 1M is added to above-mentioned 51g (S, E) -3- (1- methylpyrrolidin- 2- yls)-ethyl acrylate
4h is stirred at room temperature in sodium hydroxide solution, and with dilute hydrochloric acid tune pH=7,200 ethyl acetate, stirring and dissolving, mistake is added in solvent evaporated
Inorganic salts are filtered, 10~12 DEG C is cooled to and is passed through hydrogen chloride gas into mother liquor, solid is precipitated, filter, drying obtains (S, E)-
3- (1- methylpyrrolidin- 2- yls)-acrylic acid hydrochloride 45g.
Total yield of products is 47.3%, and the IR collection of illustrative plates of (S, E) -3- (1- methylpyrrolidin- 2- yls)-acrylic acid hydrochloride is such as
Shown in Fig. 1.
Embodiment 2：(S, E)-N- ﹛ 4- [the chloro- 4- of 3- (pyridine -2- ylmethoxies)-anilino-] -3- cyano -7- ethyoxyls -
The synthesis of quinoline -6- Ji ﹜ -3- (1- methyi-pyrrofidinium -2- bases)-acrylamide (compound 1)
(S, E) -3- (1- methylpyrrolidin- 2- yls)-acrylic acid hydrochloride 7.7g that embodiment 1 obtains is added to and is equipped with
In the reaction bulb of tetrahydrofuran 60ml, DMF 1ml are added, stir lower dropwise addition oxalyl chloride 7.6g, control temperature is protected at 20~25 DEG C
After 2~3h of temperature stirring；Reaction solution is cooled to -5~0 DEG C by cold pump, and 4- [4- [(2- pyridyl groups) methoxyl group] -3- chloroanilines are added dropwise
Base] -6- Amino 3 cyano -7- ethoxyquinolines tetrahydrofuran solution (4- [4- [(2- pyridyl groups) methoxyl group] -3- chloroanilines
Base] -6- Amino 3 cyano -7- ethoxyquinolines 16.3g, tetrahydrofuran 70ml), keep 0 DEG C of temperature hereinafter, being protected after dripping
Triethylamine 24g is added dropwise in 1~2h of temperature, and 0~5 DEG C of 4~5h of stirring, addition methanol 2ml, dense by reaction solution after adding at this temperature
It is reduced to dry, the addition ethyl alcohol 90ml and purified water 90ml into concentrate, return stirring 2h, temperature is down to 10 DEG C hereinafter, filtering, dries
It is dry, obtain solid (S, E)-N- ﹛ 4- [the chloro- 4- of 3- (pyridine -2- ylmethoxies)-anilino-] -3- cyano -7- ethoxies yl-quinoline -
6- Ji ﹜ -3- (1- methyi-pyrrofidinium -2- bases)-acrylamide 16.5g.
Embodiment 3：The synthesis of (R, E) -3- (1- methylpyrrolidin- 2- yls)-acrylic acid hydrochloride
1) BOC-D- dried meat ammonium aldehyde synthesizes
It weighs 100g BOC-D- prolinols to be placed in four mouthfuls of reaction bulbs of 2L, the dichloromethane of 1.5L is added, is stirred at room temperature
15.5g sodium bromides, 2.5gTEMPO are added after dissolving, -10 DEG C of cooling is hereinafter, start to be added dropwise the secondary chlorine for mixing up pH=8~9 in advance
Acid sodium solution keeps temperature -5~-10 DEG C.TLC tracks (solvent ethyl acetate：Petroleum ether=1：1), wait for that the reaction was complete for raw material
Afterwards, stop that liquor natrii hypochloritis's (500ml is about added dropwise) is added dropwise, static layering stays organic layer, respectively with 1% sulfuric acid solution
800ml, 5% hypo solution 800ml and saturated salt solution 800ml respectively wash once, anhydrous magnesium sulfate dry organic layer,
Filtering, is evaporated, obtains BOC-D- dried meat ammonium aldehydes 95g.
2) R- pyrrolidines -2- formaldehyde synthesizes
Product BOC-D- dried meat ammonium aldehyde 95g are walked on being added in reaction bulb, 600ml dichloromethane, 165g trifluoro second is then added
Acid.30 DEG C of stirring 13h of heat preservation, TLC (solvent ethyl acetate：Petroleum ether=1：1) solvent evaporated after, the reaction was complete after raw material,
500ml saturated sodium carbonate solutions are added, 30min is stirred at room temperature, ethyl acetate extracts (200ml × 3), anhydrous sodium sulfate drying,
Filtering, is evaporated, obtains R- pyrrolidines -2- formaldehyde 42g.
3) R-1- methyi-pyrrofidiniums -2- formaldehyde synthesizes
200ml methanol is added into above-mentioned 42g R- pyrrolidines -2- formaldehyde, is gone to after dissolving in 1L reaction bulbs, then add
200ml methanol, 63g potassium carbonate, after stirring evenly, 15~18 DEG C of dropwise addition 72g iodomethane of control temperature react at room temperature 8 after adding
Water 300ml, dichloromethane 300ml is added in~8.5h, evaporated under reduced pressure, stirs dissolved clarification, separates organic layer, and 200ml washings are primary,
Anhydrous sodium sulfate is dried, and filtering is evaporated to obtain R-1- methyi-pyrrofidinium -2- formaldehyde 43g.
4) (R, E) -3- (1- methylpyrrolidin- 2- yls)-ethyl acrylate synthesizes
500ml dichloromethane is added to above-mentioned 43g R-1- methyi-pyrrofidiniums -2- formaldehyde, 1L reaction bulbs are gone to after dissolving
In, 158g ethoxycarbonyl methylene triphenyl phosphines are added at room temperature, are stirred overnight, TLC (solvent ethyl acetate：Petroleum ether
=1：1), wait for that the reaction was complete for raw material, petroleum ether 300ml, ethyl acetate 100ml, return stirring 1h, cooling is added in solvent evaporated
10~12 DEG C, filtering is evaporated, and crosses silica gel column purification (ethyl acetate：Petroleum ether=7:2) (R, E) -3- (1- methylpyrroles, are obtained
Alkane -2- bases)-ethyl acrylate 52g.
5) (R, E) -3- (1- methylpyrrolidin- 2- yls)-acrylic acid hydrochloride synthesizes
600ml ethyl alcohol, 200ml 1M is added to above-mentioned 52g (R, E) -3- (1- methylpyrrolidin- 2- yls)-ethyl acrylate
4h is stirred at room temperature in sodium hydroxide solution, and with dilute hydrochloric acid tune pH=7, solvent evaporated is added 200ml ethyl acetate, stirring and dissolving,
Inorganic salts are filtered out, 10~12 DEG C is cooled to and is passed through hydrogen chloride gas into mother liquor, solid is precipitated, filter, drying obtains (R, E)
- 3- (1- methylpyrrolidin- 2- yls)-acrylic acid hydrochloride 48g.
Total yield of products is 50.4%, and the IR collection of illustrative plates of (R, E) -3- (1- methylpyrrolidin- 2- yls)-acrylic acid hydrochloride is such as
Shown in Fig. 2.1H NMR spectras are as shown in Figure 3-4,13C NMR spectras are as shown in Figure 5；Mass spectrogram is as shown in fig. 6, wherein [M-HCl
+H]+=156.1.The structure of the compounds of this invention is further demonstrated by above-mentioned spectrogram.
Embodiment 4：(R, E)-N- ﹛ 4- [the chloro- 4- of 3- (pyridine -2- ylmethoxies)-anilino-] -3- cyano -7- ethyoxyls -
The synthesis (synthesis of compound 5) of quinoline -6- Ji ﹜ -3- (1- methyi-pyrrofidinium -2- bases)-acrylamide
(R, E) -3- (1- methylpyrrolidin- 2- yls)-acrylic acid hydrochloride 7.7g prepared by embodiment 3 is added to and is equipped with
In the reaction bulb of tetrahydrofuran 60ml, DMF 1ml are added, stir lower dropwise addition oxalyl chloride 7.6g, control temperature is protected at 20~25 DEG C
After 2~3h of temperature stirring, reaction solution is cooled to -5~0 DEG C by cold pump, and 4- [4- [(2- pyridyl groups) methoxyl group] -3- chloroanilines are added dropwise
Base] -6- Amino 3 cyano -7- ethoxyquinolines tetrahydrofuran solution (4- [4- [(2- pyridyl groups) methoxyl group] -3- chlorobenzenes
Amido] -6- Amino 3 cyano -7- ethoxyquinolines 16.3g, tetrahydrofuran 70ml), after 0 DEG C of temperature of holding is hereinafter, drip
1~2h is kept the temperature, triethylamine 24g, 0~5 DEG C of 4~5h of stirring is added dropwise and methanol 2ml is added at this temperature, by reaction solution after adding
Be concentrated to dryness, into concentrate be added ethyl alcohol 90ml and purified water 90ml, return stirring 2h, temperature be down to 10 DEG C hereinafter, filtering,
Drying, obtains solid (R, E)-N- ﹛ 4- [the chloro- 4- of 3- (pyridine -2- ylmethoxies)-anilino-] -3- cyano -7- ethyoxyls-quinoline
Quinoline -6- Ji ﹜ -3- (1- methyi-pyrrofidinium -2- bases)-acrylamide 16.8g.
Claims (10)
1. compound (E) -3- (1- methylpyrrolidin- 2- the yls)-acrylic acid hydrochloride indicated by formula (I),
2. compound (E) -3- (1- methylpyrrolidin- 2- yls)-acrylic acid hydrochloride as described in claim 1, characterized in that
It is (S, E) -3- (1- methylpyrrolidin- 2- yls)-acrylic acid hydrochlorides or (R, E) -3- (1- methylpyrrolidin- 2- yls) -
Acrylic acid hydrochloride or the two mixture.
3. the synthetic method of compound (E) -3- (1- methylpyrrolidin- 2- yls)-acrylic acid hydrochloride described in claim 1,
It is characterized in that
The synthetic method of (S, E) -3- (1- methylpyrrolidin- 2- the yls)-acrylic acid hydrochloride is：It is with BOC-L- prolinols
Starting material, it is oxidized at aldehyde, BOC protective agents are then taken off, then reacted with halide and generate S-1- methyi-pyrrofidiniums -2-
Formaldehyde, then synthesis (S, E) -3- (1- methylpyrrolidin- 2- yls)-ethyl acrylate is reacted through Wittig, it is obtained at salt after hydrolysis
(S, E) -3- (1- methylpyrrolidin- 2- yls)-acrylic acid hydrochloride；
The synthetic method of (R, E) -3- (1- methylpyrrolidin- 2- the yls)-acrylic acid hydrochloride is：It is with BOC-D- prolinols
Starting material, it is oxidized at aldehyde, BOC protective agents are then taken off, then reacted with halide and generate R-1- methyi-pyrrofidiniums -2-
Formaldehyde, then synthesis (R, E) -3- (1- methylpyrrolidin- 2- yls)-ethyl acrylate is reacted through Wittig, it is obtained at salt after hydrolysis
(R, E) -3- (1- methylpyrrolidin- 2- yls)-acrylic acid hydrochloride.
4. the synthesis side of compound (E) -3- (1- methylpyrrolidin- 2- yls)-acrylic acid hydrochloride as claimed in claim 3
Method, characterized in that BOC protective agents are taken off using trifluoroacetic acid；The halide is iodomethane；The Wittig reactions use
Wittig reagents be ethoxycarbonyl methylene triphenyl phosphine.
5. the synthesis side of compound (E) -3- (1- methylpyrrolidin- 2- yls)-acrylic acid hydrochloride as claimed in claim 4
Method, characterized in that
The synthetic method of (S, E) -3- (1- methylpyrrolidin- 2- the yls)-acrylic acid hydrochloride, specifically includes following steps：
1) BOC-L- prolinols are dissolved using organic solvent, and sodium bromide and tetramethyl piperidine nitrogen oxides is then added；Cooling, drop
Add and mixes up the liquor natrii hypochloritis of pH=8~9 until the reaction is complete in advance；After after raw material, the reaction was complete, static layering, there are machines
Layer, it is post-treated to obtain BOC-L- dried meat ammonium aldehydes；
2) solvent and trifluoroacetic acid is added in BOC-L- dried meat ammonium aldehydes, stirs insulation reaction, through post-processing after the reaction was complete after raw material
Obtain S- pyrrolidines -2- formaldehyde；
3) solvent and potassium carbonate is added in above-mentioned S- pyrrolidines -2- formaldehyde, after stirring evenly, iodomethane is added dropwise, adds rear room temperature
Reaction, it is post-treated after the completion of reaction to obtain S-1- methyi-pyrrofidinium -2- formaldehyde；
4) solvent is added in S-1- methyi-pyrrofidinium -2- formaldehyde, adds ethoxycarbonyl methylene triphenyl phosphine, it is stirred
Night, through post-processing (S, E) -3- (1- methylpyrrolidin- 2- yls)-ethyl acrylate after the reaction was complete after raw material；
5) ethyl alcohol and sodium hydroxide solution is added in above-mentioned (S, E) -3- (1- methylpyrrolidin- 2- yls)-ethyl acrylate, stirred
It mixes, with dilute hydrochloric acid tune pH=7, solvent evaporated；It is evaporated object and ethyl acetate stirring and dissolving is added, filter out inorganic salts, cool down to mother
It is passed through hydrogen chloride gas in liquid, solid is precipitated, filters, drying obtains (S, E) -3- (1- methylpyrrolidin- 2- yls)-acrylic acid
Hydrochloride；
The synthetic method of (R, E) -3- (1- methylpyrrolidin- 2- the yls)-acrylic acid hydrochloride, specifically includes following steps：
1) BOC-D- prolinols are dissolved using organic solvent, and sodium bromide and tetramethyl piperidine nitrogen oxides are added after stirring and dissolving；
Cooling, dropwise addition mix up the liquor natrii hypochloritis of pH=8~9 until the reaction is complete in advance；After after raw material, the reaction was complete, static point
Layer, stays organic layer, post-treated, obtains BOC-D- dried meat ammonium aldehydes；
2) solvent and trifluoroacetic acid is added in BOC-D- dried meat ammonium aldehydes, stirs insulation reaction, through post-processing after the reaction was complete after raw material
Obtain R- pyrrolidines -2- formaldehyde；
3) solvent and potassium carbonate is added in above-mentioned R- pyrrolidines -2- formaldehyde, after stirring evenly, iodomethane is added dropwise, adds rear room temperature
Reaction, it is post-treated after the completion of reaction to obtain R-1- methyi-pyrrofidinium -2- formaldehyde；
4) solvent is added in R-1- methyi-pyrrofidinium -2- formaldehyde, adds ethoxycarbonyl methylene triphenyl phosphine, it is stirred
Night, through post-processing (R, E) -3- (1- methylpyrrolidin- 2- yls)-ethyl acrylate after the reaction was complete after raw material；
5) ethyl alcohol and sodium hydroxide solution is added in above-mentioned (R, E) -3- (1- methylpyrrolidin- 2- yls)-ethyl acrylate, stirred
It mixes, with dilute hydrochloric acid tune pH=7, solvent evaporated；It is evaporated object and ethyl acetate stirring and dissolving is added, filter out inorganic salts, cool down to mother
It is passed through hydrogen chloride gas in liquid, solid is precipitated, filters, drying obtains (R, E) -3- (1- methylpyrrolidin- 2- yls)-acrylic acid
Hydrochloride.
6. the synthesis side of compound (E) -3- (1- methylpyrrolidin- 2- yls)-acrylic acid hydrochloride as claimed in claim 5
Method, characterized in that step (1) the N-BOC-L- prolinols or N-BOC-D- prolinols, sodium bromide and tetramethyl piperidine nitrogen
Oxide mol ratio 1：0.2~0.4：0.02~0.04；Solvent is chloroform, dichloromethane, tetrahydrofuran or n-hexane；Reaction
Temperature：- 10~5 DEG C；Post-processing is：Washing is dried and is evaporated.
7. the synthesis side of compound (E) -3- (1- methylpyrrolidin- 2- yls)-acrylic acid hydrochloride as claimed in claim 5
Method, characterized in that step (2) the BOC-L- dried meat ammonium aldehyde or the molar ratio of BOC-D- dried meat ammonium aldehyde and trifluoroacetic acid are 1:2.5
~3.5；Solvent is：Chloroform, dichloromethane or n-hexane；Holding temperature：25~35 DEG C；Reaction time：10~15h；After
Reason is：Saturated sodium carbonate solution, stirring is added in solvent evaporated, and ethyl acetate extracts, and anhydrous sodium sulfate drying, filtering is evaporated.
8. the synthesis side of compound (E) -3- (1- methylpyrrolidin- 2- yls)-acrylic acid hydrochloride as claimed in claim 5
Method, characterized in that step (3) S- pyrrolidines -2- formaldehyde or the molar ratio of R- pyrrolidines -2- formaldehyde and iodomethane are 1:
1~1.5；Solvent is：Methanol, ethyl alcohol or isopropanol；Reaction time：6~10h；Dropping temperature：10~20 DEG C；Post-processing is：
Water, dichloromethane is added in evaporated under reduced pressure, stirs dissolved clarification, separates organic layer, and washing is primary, dry, and filtering is evaporated.
9. the synthesis side of compound (E) -3- (1- methylpyrrolidin- 2- yls)-acrylic acid hydrochloride as claimed in claim 5
Method, characterized in that step (4) S-1- methyi-pyrrofidinium -2- formaldehyde or R-1- methyi-pyrrofidinium -2- formaldehyde and ethoxy
Formoxyl methylene triphenyl phosphine molar ratio is 1:1.3~1.5；Solvent is：Chloroform, dichloromethane or n-hexane；Cooling temperature
Degree：5~15 DEG C；Post-processing is：Petroleum ether, ethyl acetate is added in solvent evaporated, and return stirring cools down, and filtering is evaporated, and crosses silicon
Rubber column gel column purifies；Step (5) the cooling temperature：5~15 DEG C.
10. compound (E) -3- (1- methylpyrrolidin- 2- yls)-acrylic acid hydrochloride as claimed in claim 1 or 2 is preparing quinoline
Application in oxazoline or quinolines derivative.
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Denomination of invention: Compound (E) - 3 - (1-methylpyrrolidine-2-yl) - acrylic acid hydrochloride and its synthetic method Effective date of registration: 20211207 Granted publication date: 20190430 Pledgee: Qilu bank Limited by Share Ltd. Ji'nan science and technology innovation center sub branch Pledgor: SHANDONG BOYUAN PHARMACEUTICAL Co.,Ltd. Registration number: Y2021980014223 |
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