CN108314639B - Compound (E) -3-(1- methylpyrrolidin- 2- yl)-acrylic acid hydrochloride and synthetic method - Google Patents
Compound (E) -3-(1- methylpyrrolidin- 2- yl)-acrylic acid hydrochloride and synthetic method Download PDFInfo
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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 compound (E) -3- (1- methylpyrrolidin- 2- yl)-acrylic acid hydrochloride and synthetic methods.Shown in the compound structure such as formula (I).Its synthetic method are as follows: with BOC-L- prolinol (or BOC-D- prolinol) for starting material; through being oxidized to aldehyde; take off BOC protective agent; it is reacted again with alkyl halide; synthesis (S is reacted through Wittig again; E) -3- (1- methylpyrrolidin- 2- yl)-ethyl acrylate; (S is obtained at salt after hydrolysis; E) -3- (1- methylpyrrolidin- 2- yl)-acrylic acid hydrochloride [or (R, E) -3- (1- methylpyrrolidin- 2- yl)-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- yl)-acrylic acid
Hydrochloride and synthetic method.
Background technique
Quinazoline or quinolines anticancer drug derivative clinically using more and more extensive, wherein the synthesis of mesosome with
Innovation is more and more important, and patent CN102020639 describes 6- amido quinazoline or 3- cyano quinolines analog derivative, its preparation side
Method and its application in medicine.The particular compound being related 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- yl)-propylene structure.
1 6- amido quinazoline of table or 3- cyano quinolines analog derivative
(S, E)-N- { 4- [the chloro- 4- of 3- (pyridine -2- ylmethoxy)-the anilino-] -3- cyanogen provided in above patent document
Base -7- ethoxy yl-quinoline -6- base } -3- (1- methyi-pyrrofidinium -2- base)-acrylamide (compound 1) specific synthesis side
Method: it using compound 1c as raw material, is first reacted with diethyl phosphate guanidine-acetic acid and generates compound 1d, then react life 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 (reacting 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-pyrrofidinium -2- is also related in the synthesis process of compound 4 disclosed in patent CN102020639
Formaldehyde (compound 1b)；The R type for being related to compound 1b in the synthesis process of compound 5 disclosed in patent CN102020639 is different
Structure body, i.e. (R) -1- methyi-pyrrofidinium -2- formaldehyde (compound 5c).Therefore, there is also above-mentioned " synthesis condition harshnesses, yield
Low, easy be oxidized is not easy to the next step " the problems such as.
Summary of the invention
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- yl)-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- yl)-acrylic acid hydrochloride
Quinoline class medicaments derivative.The compound of the present invention (E) -3- (1- methylpyrrolidin- 2- yl)-acrylic acid hydrochloride stable structure,
Reaction condition is suitble to mass 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- yl)-acrylic acid hydrochloride, knot
Structure formula is as follows:
Its molecular formula is C8H13O2N·HCl。
The compound is (S, E) -3- (1- methylpyrrolidin- 2- yl)-acrylic acid hydrochloride or (R, E) -3- (1- methyl pyrrole
Cough up alkane -2- base) 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- prolinol (or BOC-D-
Prolinol) it is starting material, it is oxidized to aldehyde, is taken off BOC protective agent (BOC protective agent is preferably taken off using trifluoroacetic acid), 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 through Wittig reaction (Wittig is carried out with ethoxycarbonyl methylene triphenyl phosphine to react) synthesis (S, E) -3- (1- first
Base pyrrolidin-2-yl)-ethyl acrylate, (S, E) -3- (1- methylpyrrolidin- 2- yl)-acrylates is obtained at salt after hydrolysis
Hydrochlorate [or (R, E) -3- (1- methylpyrrolidin- 2- yl)-acrylic acid hydrochloride], synthetic route is as follows:
The synthetic method of above-mentioned (S, E) -3- (1- methylpyrrolidin- 2- yl)-acrylic acid hydrochloride, specifically includes following step
It is rapid:
1) BOC-L- prolinol is dissolved using organic solvent, and sodium bromide and TEMPO (tetramethyl piperidine nitrogen oxidation 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 raw material fully reacting
Layering, stays organic layer, post-treated, obtains BOC-L- dried meat ammonium aldehyde；
2) solvent and trifluoroacetic acid is added in BOC-L- dried meat ammonium aldehyde, insulation reaction is stirred, after raw material fully reacting after
Handle to obtain S- pyrrolidines -2- formaldehyde；
3) solvent and potassium carbonate is added in above-mentioned S- pyrrolidines -2- formaldehyde, after mixing evenly, iodomethane is added dropwise, after adding
Room temperature reaction, it is post-treated after the reaction was completed 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, (S, E) -3- (1- methylpyrrolidin- 2- yl)-ethyl acrylate is post-processed after raw material fully reacting；
5) ethyl alcohol and sodium hydroxide solution is added in above-mentioned (S, E) -3- (1- methylpyrrolidin- 2- yl)-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- yl)-propylene
Acid hydrochloride.
Wherein, step (1) the N-BOC-L- prolinol, sodium bromide and TEMPO molar ratio 1:0.2~0.4:0.02~
0.04, preferably 1:0.3:0.03.
Wherein, step (1) solvent is chloroform, methylene chloride, tetrahydrofuran, n-hexane etc., preferably methylene chloride.
Wherein, step (1) reaction temperature: -10~5 DEG C, preferably -5~0 DEG C.
Wherein, the post-processing of the step (1) are as follows: it is washing, dry and be evaporated, wash are as follows: 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 are as follows: chloroform, methylene chloride, n-hexane etc., preferably methylene chloride.
Wherein, step (2) holding temperature: 25~35 DEG C, preferably 29~31 DEG C；Reaction time: 10~15h, preferably
12~13h.
Wherein, step (2) post-processing are as follows: saturated sodium carbonate solution, stirring, ethyl acetate extraction is added in solvent evaporated
It takes, anhydrous sodium sulfate dries, filters, and is evaporated.
Wherein, step (3) S- pyrrolidines -2- formaldehyde and iodomethane, potassium carbonate molar ratio be 1:1~1.5:1~
1.5, preferably 1:1.2:1.05.
Wherein, step (3) solvent are as follows: 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-processing are as follows: water, methylene chloride is added in evaporated under reduced pressure, stirs dissolved clarification, separates organic layer, washing one
Secondary, anhydrous sodium sulfate dries, filters, and 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, methylene chloride, n-hexane etc., preferably methylene chloride.
Wherein, step (4) the cooling temperature: 5~15 DEG C, preferably 10~12 DEG C.
Above-mentioned steps (4) post-processing are as follows: 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 understood that the synthetic method of (R, E) -3- (1- methylpyrrolidin- 2- yl)-acrylic acid hydrochloride only needs
BOC-L- prolinol is changed to BOC-D- prolinol.
The present invention with compound (S, E) -3- (1- methylpyrrolidin- 2- yl)-acrylic acid hydrochloride 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- yl)-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 configuration 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 present invention are:
1, from the point of view of compound structure, (E) -3- (1- methylpyrrolidin- 2- yl)-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 oxidized；
2, (E) -3- (1- methylpyrrolidin- 2- yl)-acrylic acid hydrochloride is used to synthesize compound 1,4 and 5 for intermediate,
One-step synthesis route is not only omitted in it, and reacting is common amidation process, enormously simplifies reaction process, and it is reacted
Condition is suitble to mass production；
3, the synthesis of (E) -3- of the invention (1- methylpyrrolidin- 2- yl)-acrylic acid hydrochloride can be to synthesize other
Quinazoline or quinolines derivative containing (E) -3- (1- methylpyrrolidin- 2- yl)-propylene structure (or similar structures)
New method is provided, and substantially increases product total recovery.
Detailed description of the invention
Fig. 1 is (S, E) -3- (1- methylpyrrolidin- 2- yl)-acrylic acid hydrochloride IR map；
Fig. 2 is (R, E) -3- (1- methylpyrrolidin- 2- yl)-acrylic acid hydrochloride IR map；
Fig. 3 is (R, E) -3- (1- methylpyrrolidin- 2- yl)-acrylic acid hydrochloride1H NMR spectra；
Fig. 4 is (R, E) -3- (1- methylpyrrolidin- 2- yl)-acrylic acid hydrochloride1H NMR spectra partial enlarged view；
Fig. 5 is (R, E) -3- (1- methylpyrrolidin- 2- yl)-acrylic acid hydrochloride13C NMR spectra.
Fig. 6 is the mass spectrogram of (R, E) -3- (1- methylpyrrolidin- 2- yl)-acrylic acid hydrochloride.
Specific embodiment
Embodiment 1:(S, E) -3- (1- methylpyrrolidin- 2- yl)-acrylic acid hydrochloride synthesis
1) BOC-L- dried meat ammonium aldehyde synthesizes
It weighs 100g BOC-L- prolinol to be placed in four mouthfuls of reaction flasks of 2L, the methylene chloride of 1.5L is added, is stirred at room temperature
15.4g sodium bromide, 2.3gTEMPO are added after dissolution, -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), to raw material fully reacting
Stop that liquor natrii hypochloritis (about dropwise addition 500ml) 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, the dry organic layer of anhydrous magnesium sulfate, filtering,
It is evaporated, obtains BOC-L- dried meat ammonium aldehyde 94g.
2) S- pyrrolidines -2- formaldehyde synthesizes
Product BOC-L- dried meat ammonium aldehyde 94g is walked on being added in reaction flask, 600ml methylene chloride, 162g trifluoro second is then added
Acid.29~31 DEG C of stirring 12~13h, TLC (solvent ethyl acetate: petroleum ether=1:1) are kept the temperature, are steamed after raw material fully reacting
500ml saturated sodium carbonate solution is added in dry solvent, and 30min is stirred at room temperature, and ethyl acetate extracts (200ml × 3), anhydrous slufuric acid
Sodium dries, filters, and is evaporated, and obtains S- pyrrolidines -2- formaldehyde 40g.
3) S-1- methyi-pyrrofidinium -2- formaldehyde synthesizes
200ml methanol is added into above-mentioned 40g S- pyrrolidines -2- formaldehyde, is gone to after dissolution in 1L reaction flask, then add
200ml methanol, 60g potassium carbonate control 15~18 DEG C of dropwise addition 69g iodomethane of temperature, react at room temperature 8 after adding after mixing evenly
Water 300ml, methylene chloride 300ml is added in~8.5h, evaporated under reduced pressure, stirs dissolved clarification, separates organic layer, and 200ml washing is primary,
Anhydrous sodium sulfate dries, filters, and is evaporated to obtain S-1- methyi-pyrrofidinium -2- formaldehyde 42g.
4) S, E) synthesis of -3- (1- methylpyrrolidin- 2- yl)-ethyl acrylate
500ml methylene chloride is added to above-mentioned 42gS-1- methyi-pyrrofidinium -2- formaldehyde, 1L reaction flask is gone to after dissolution
In, 155g ethoxycarbonyl methylene triphenyl phosphine is added at room temperature, is stirred overnight, TLC (solvent ethyl acetate: petroleum ether
=1:1), to raw material fully reacting, petroleum ether 300ml, ethyl acetate 100ml, return stirring 1h, cooling is added in solvent evaporated
10~12 DEG C, filtering is evaporated, and is crossed silica gel column purification (ethyl acetate: petroleum ether=7:2), is obtained (S, E) -3- (1- methylpyrrole
Alkane -2- base)-ethyl acrylate 51g.
5) (S, E) -3- (1- methylpyrrolidin- 2- yl)-acrylic acid hydrochloride synthesizes
600ml ethyl alcohol, 200ml 1M is added to above-mentioned 51g (S, E) -3- (1- methylpyrrolidin- 2- yl)-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- yl)-acrylic acid hydrochloride 45g.
Total yield of products is 47.3%, and the IR map of (S, E) -3- (1- methylpyrrolidin- 2- yl)-acrylic acid hydrochloride is such as
Shown in Fig. 1.
Embodiment 2:(S, E)-N- ﹛ 4- [the chloro- 4- of 3- (pyridine -2- ylmethoxy)-anilino-] -3- cyano -7- ethyoxyl -
The synthesis of quinoline -6- Ji ﹜ -3- (1- methyi-pyrrofidinium -2- base)-acrylamide (compound 1)
(S, E) -3- (1- methylpyrrolidin- 2- yl)-acrylic acid hydrochloride 7.7g that embodiment 1 obtains is added to and is equipped with
In the reaction flask of tetrahydrofuran 60ml, DMF 1ml is added, stirs lower dropwise addition oxalyl chloride 7.6g, controls temperature at 20~25 DEG C, protect
After 2~3h of temperature stirring；Reaction solution is cooled to -5~0 DEG C by cold pump, and 4- [4- [(2- pyridyl group) methoxyl group] -3- chloroaniline is added dropwise
Base] -6- Amino 3 cyano -7- ethoxyquinoline tetrahydrofuran solution (4- [4- [(2- pyridyl group) methoxyl group] -3- chloroaniline
Base] -6- Amino 3 cyano -7- ethoxyquinoline 16.3g, tetrahydrofuran 70ml), 0 DEG C of temperature of holding after dripping hereinafter, protect
Triethylamine 24g, 0~5 DEG C of 4~5h of stirring is added dropwise in 1~2h of temperature, and methanol 2ml is added at this temperature, after adding that reaction solution is dense
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- ylmethoxy)-anilino-] -3- cyano -7- ethoxy yl-quinoline -
6- Ji ﹜ -3- (1- methyi-pyrrofidinium -2- base)-acrylamide 16.5g.
Embodiment 3:(R, E) -3- (1- methylpyrrolidin- 2- yl)-acrylic acid hydrochloride synthesis
1) BOC-D- dried meat ammonium aldehyde synthesizes
It weighs 100g BOC-D- prolinol to be placed in four mouthfuls of reaction flasks of 2L, the methylene chloride of 1.5L is added, is stirred at room temperature
15.5g sodium bromide, 2.5gTEMPO are added after dissolution, -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), to raw material fully reacting
Afterwards, stop that liquor natrii hypochloritis (about dropwise addition 500ml) 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, the dry organic layer of anhydrous magnesium sulfate,
Filtering, is evaporated, obtains BOC-D- dried meat ammonium aldehyde 95g.
2) R- pyrrolidines -2- formaldehyde synthesizes
Product BOC-D- dried meat ammonium aldehyde 95g is walked on being added in reaction flask, 600ml methylene chloride, 165g trifluoro second is then added
Acid.Keep the temperature 30 DEG C of stirring 13h, TLC (solvent ethyl acetate: petroleum ether=1:1), the solvent evaporated after raw material fully reacting,
500ml saturated sodium carbonate solution is added, 30min is stirred at room temperature, ethyl acetate extracts (200ml × 3), and anhydrous sodium sulfate is dry,
Filtering, is evaporated, obtains R- pyrrolidines -2- formaldehyde 42g.
3) R-1- methyi-pyrrofidinium -2- formaldehyde synthesizes
200ml methanol is added into above-mentioned 42g R- pyrrolidines -2- formaldehyde, is gone to after dissolution in 1L reaction flask, then add
200ml methanol, 63g potassium carbonate control 15~18 DEG C of dropwise addition 72g iodomethane of temperature, react at room temperature 8 after adding after mixing evenly
Water 300ml, methylene chloride 300ml is added in~8.5h, evaporated under reduced pressure, stirs dissolved clarification, separates organic layer, and 200ml washing is primary,
Anhydrous sodium sulfate dries, filters, and is evaporated to obtain R-1- methyi-pyrrofidinium -2- formaldehyde 43g.
4) (R, E) -3- (1- methylpyrrolidin- 2- yl)-ethyl acrylate synthesizes
500ml methylene chloride is added to above-mentioned 43g R-1- methyi-pyrrofidinium -2- formaldehyde, 1L reaction flask is gone to after dissolution
In, 158g ethoxycarbonyl methylene triphenyl phosphine is added at room temperature, is stirred overnight, TLC (solvent ethyl acetate: petroleum ether
=1:1), to raw material fully reacting, petroleum ether 300ml, ethyl acetate 100ml, return stirring 1h, cooling is added in solvent evaporated
10~12 DEG C, filtering is evaporated, and is crossed silica gel column purification (ethyl acetate: petroleum ether=7:2), is obtained (R, E) -3- (1- methylpyrrole
Alkane -2- base)-ethyl acrylate 52g.
5) (R, E) -3- (1- methylpyrrolidin- 2- yl)-acrylic acid hydrochloride synthesizes
600ml ethyl alcohol, 200ml 1M is added to above-mentioned 52g (R, E) -3- (1- methylpyrrolidin- 2- yl)-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- yl)-acrylic acid hydrochloride 48g.
Total yield of products is 50.4%, and the IR map of (R, E) -3- (1- methylpyrrolidin- 2- yl)-acrylic acid hydrochloride is such as
Shown in Fig. 2.1H NMR spectra is as shown in Figure 3-4,13C NMR spectra is 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- ylmethoxy)-anilino-] -3- cyano -7- ethyoxyl -
The synthesis (synthesis of compound 5) of quinoline -6- Ji ﹜ -3- (1- methyi-pyrrofidinium -2- base)-acrylamide
(R, E) -3- (1- methylpyrrolidin- 2- yl)-acrylic acid hydrochloride 7.7g prepared by embodiment 3 is added to and is equipped with
In the reaction flask of tetrahydrofuran 60ml, DMF 1ml is added, stirs lower dropwise addition oxalyl chloride 7.6g, controls temperature at 20~25 DEG C, protect
After 2~3h of temperature stirring, reaction solution is cooled to -5~0 DEG C by cold pump, and 4- [4- [(2- pyridyl group) methoxyl group] -3- chloroaniline is added dropwise
Base] -6- Amino 3 cyano -7- ethoxyquinoline tetrahydrofuran solution (4- [4- [(2- pyridyl group) methoxyl group] -3- chlorobenzene
Amido] -6- Amino 3 cyano -7- ethoxyquinoline 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, 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- ylmethoxy)-anilino-] -3- cyano -7- ethyoxyl-quinoline
Quinoline -6- Ji ﹜ -3- (1- methyi-pyrrofidinium -2- base)-acrylamide 16.8g.
Claims (5)
1. a kind of synthetic method of compound (E) -3- (1- methylpyrrolidin- 2- yl)-acrylic acid hydrochloride, characterized in that institute
It states shown in compound (E) -3- (1- methylpyrrolidin- 2- yl)-acrylic acid hydrochloride such as formula (I),
Compound (E) -3- (1- methylpyrrolidin- 2- the yl)-acrylic acid hydrochloride is (S, E) -3- (1- methylpyrrolidin-
2- yl)-acrylic acid hydrochloride or (R, E) -3- (1- methylpyrrolidin- 2- yl)-acrylic acid hydrochloride or the two
Mixture；
The synthetic method of (S, E) -3- (1- methylpyrrolidin- 2- the yl)-acrylic acid hydrochloride, specifically includes the following steps:
1) BOC-L- prolinol is 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 raw material fully reacting, static layering, there are machines
Layer, it is post-treated to obtain BOC-L- dried meat ammonium aldehyde；
2) solvent and trifluoroacetic acid is added in BOC-L- dried meat ammonium aldehyde, insulation reaction is stirred, through post-processing after raw material fully reacting
Obtain S- pyrrolidines -2- formaldehyde；
3) solvent and potassium carbonate is added in above-mentioned S- pyrrolidines -2- formaldehyde, after mixing evenly, iodomethane is added dropwise, adds rear room temperature
Reaction, it is post-treated after the reaction was completed 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 is post-processed (S, E) -3- (1- methylpyrrolidin- 2- yl)-ethyl acrylate after raw material fully reacting；
5) ethyl alcohol and sodium hydroxide solution is added in above-mentioned (S, E) -3- (1- methylpyrrolidin- 2- yl)-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- yl)-acrylic acid
Hydrochloride；
The synthetic method of (R, E) -3- (1- methylpyrrolidin- 2- the yl)-acrylic acid hydrochloride, specifically includes the following steps:
1) BOC-D- prolinol is 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 raw material fully reacting, static point
Layer, stays organic layer, post-treated, obtains BOC-D- dried meat ammonium aldehyde；
2) solvent and trifluoroacetic acid is added in BOC-D- dried meat ammonium aldehyde, insulation reaction is stirred, through post-processing after raw material fully reacting
Obtain R- pyrrolidines -2- formaldehyde；
3) solvent and potassium carbonate is added in above-mentioned R- pyrrolidines -2- formaldehyde, after mixing evenly, iodomethane is added dropwise, adds rear room temperature
Reaction, it is post-treated after the reaction was completed 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 is post-processed (R, E) -3- (1- methylpyrrolidin- 2- yl)-ethyl acrylate after raw material fully reacting；
5) ethyl alcohol and sodium hydroxide solution is added in above-mentioned (R, E) -3- (1- methylpyrrolidin- 2- yl)-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- yl)-acrylic acid
Hydrochloride.
2. the synthesis side of compound (E) -3- (1- methylpyrrolidin- 2- yl)-acrylic acid hydrochloride as described in claim 1
Method, characterized in that step (1) the N-BOC-L- prolinol or N-BOC-D- prolinol, sodium bromide and tetramethyl piperidine nitrogen
Oxide mol ratio 1:0.2~0.4:0.02~0.04；Solvent is chloroform, methylene chloride, tetrahydrofuran or n-hexane；Reaction
Temperature: -10~5 DEG C；Post-processing are as follows: washing is dried and is evaporated.
3. the synthesis side of compound (E) -3- (1- methylpyrrolidin- 2- yl)-acrylic acid hydrochloride as described in claim 1
Method, characterized in that the molar ratio of step (2) the BOC-L- dried meat ammonium aldehyde or BOC-D- dried meat ammonium aldehyde and trifluoroacetic acid is 1:2.5
~3.5；Solvent are as follows: chloroform, methylene chloride or n-hexane；Holding temperature: 25~35 DEG C；Reaction time: 10~15h；After
Reason are as follows: saturated sodium carbonate solution, stirring is added in solvent evaporated, and ethyl acetate extracts, and anhydrous sodium sulfate is dried, filtered, is evaporated.
4. the synthesis side of compound (E) -3- (1- methylpyrrolidin- 2- yl)-acrylic acid hydrochloride as described in claim 1
Method, characterized in that the molar ratio of step (3) S- pyrrolidines -2- formaldehyde or R- pyrrolidines -2- formaldehyde and iodomethane is 1:
1~1.5；Solvent are as follows: methanol, ethyl alcohol or isopropanol；Reaction time: 6~10h；Dropping temperature: 10~20 DEG C；Post-processing are as follows:
Water, methylene chloride is added in evaporated under reduced pressure, stirs dissolved clarification, separates organic layer, and washing is primary, dries, filters, is evaporated.
5. the synthesis side of compound (E) -3- (1- methylpyrrolidin- 2- yl)-acrylic acid hydrochloride as described in claim 1
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 are as follows: chloroform, methylene chloride or n-hexane；Cooling temperature
Degree: 5~15 DEG C；Post-processing are as follows: 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 purifying；Step (5) the cooling temperature: 5~15 DEG C.
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| CN111018767B (en) * | 2019-12-23 | 2021-09-28 | 江苏美迪克化学品有限公司 | Preparation method of D-proline derivative and intermediate thereof |
| CN112279838B (en) * | 2020-10-29 | 2021-07-13 | 苏州富士莱医药股份有限公司 | Preparation method of pyrroltinib |
| CN114409584A (en) * | 2022-03-08 | 2022-04-29 | 重庆医药高等专科学校 | Preparation method of 1-methylpyrrolidine-2-formaldehyde |
| CN114507173A (en) * | 2022-03-08 | 2022-05-17 | 重庆医药高等专科学校 | Preparation method of 1-methylpyrrolidine-2-acrylic acid hydrochloride |
| CN114736146A (en) * | 2022-03-17 | 2022-07-12 | 重庆医药高等专科学校 | Preparation method of novel 1-methylpyrrolidine-2-acrylic acid |
| CN114920682A (en) * | 2022-03-17 | 2022-08-19 | 重庆医药高等专科学校 | Method for reducing proline into prolinol and preparation method of 1-methylpyrrolidine-2-acrylic acid |
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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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