CN109867679A - The preparation method of hydrochloric acid Pilsicainide intermediate - Google Patents
The preparation method of hydrochloric acid Pilsicainide intermediate Download PDFInfo
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Abstract
The present invention provides a kind of preparation method of hydrochloric acid Pilsicainide intermediate, it is characterised by comprising: Step 1: polymerization reaction generation N- (3- carboxypropyl) butyrolactam (III) occurs for butyrolactam (I) and gamma-butyrolacton (II) under highly basic, predetermined condition；Step 2: N- (3- carboxypropyl) butyrolactam (III), which is cyclized under malonic acid list isopropyl ester solvent high temperature and is condensed with malonic acid monoester salt, generates 7 α-double pyrrolizidine pyridine-acetic acid esters；It is preferably selected as and generates 7 α-double pyrrolizidine pyridine-isopropyl acetate (V).Step 3: 7 α-double pyrrolizidine pyridine-acetic acid esters hydrolyzes in acid generates corresponding pharmaceutically acceptable salt.Preparation method of the invention avoids expensive or unobtainable raw material, avoids using liquefied ammonia in synthesis process, and reduce reaction step, easy to operate, the three wastes are few, high income.
Description
Technical field
The present invention relates to a kind of preparation methods of hydrochloric acid Pilsicainide intermediate, belong to field of medicaments.
Background technique
Entitled N- (2,6- 3,5-dimethylphenyl) -2- (the 1,2,3,5,6,7- hexahydropyrrolo alkane piperazine -8- of hydrochloric acid Pilsicainide chemistry
Base) acetamide hydrochloride (VII), it is a kind of Ic class antiarrhythmics, is used for treating paroxysmal supraventricular arrhythmia cordis.Clinical test table
Bright, hydrochloric acid Pilsicainide, which flutters supraventricular premature beat, ventricular premature beat, Paroxysmal Atrial Fibrillation, room, to have clear improvement.
According to the report of document (EP0089061, EP0153855, J.MED.CHEM 1985 (28) 714 etc.), compound
It (VII) is Material synthesis by 7 α-double pyrrolizidine pyridine-acetic acid hydrochloride (VI), 2,6- dimethylaniline (VIII) etc..
Wherein, intermediate VII is big chemical products, cheap and easily-available, and intermediate VI is the pass of hydrochloric acid Pilsicainide synthesis
Key intermediate.
Currently, synthesis 7 α-double pyrrolizidine pyridine-acetic acid hydrochloride (VI) document and few.CN101914101 describes 7
α-double pyrrolizidine pyridine-acetic acid hydrochloride (VI) preparation method, first in concentrated ammonia liquor and ammonia atmosphere, by 1,7- bis- to nitro
Benzene sulfonate -4- heptanone and ammonia, ammonium chloride generate double pyrrolizidine thiamine hydrochloride, then react with cyanoacetic acid sodium and generate 8- second
Itrile group double pyrrolizidine pyridine, hydrolyzes under strongly acidic conditions, obtains 7 α-double pyrrolizidine pyridine-acetic acid hydrochloride after purification by soda acid
(VI):
This method raw material 1, bis- p-nitrophenyl sulphonic acid ester -4- heptanone of 7- is expensive, and synthesis is cumbersome, and reacts and need to use
High pressure ammonia is not suitable for large-scale production.
EP0703233 describe with the chloro- 4- heptanone of 1,7- bis- be raw material, in ammonia atmosphere with diethyl malonate list potassium
Reactant salt synthesizes 7 α-double pyrrolizidine pyridine-ethyl acetate, then hydrolysis obtains 7 α-double pyrrolizidine pyridine-acetic acid hydrochloride in acid condition
The method of salt (VI):
The shortcomings that this method equally faces raw material 1, and the chloro- 4- heptanone of 7- bis- is expensive, and reaction needs to use high pressure ammonia,
And overall yield of reaction only has 20%, is not suitable for large-scale production.
Document " Studies on pyrrolizidines and related compounds.Part IV.A new
route to 8-substituted pyrrolizidines"(Heterocycles,16(5),755-8；1981) describe with
Lower synthesis 7 α-double pyrrolizidine pyridine-acetic acid hydrochloride (VI) method:
This method raw material bicyclic pyrrole pyridine is unstable, is easily polymerized to diploid, and at present without producer's production and supply, with cyanogen
Guanidine-acetic acid preparation 8- acetonitrile-base bicyclic pyrrole pyridine yield is lower, is not suitable for quantization production.
Summary of the invention
The purpose of the present invention is to provide a kind of preparation methods of hydrochloric acid Pilsicainide intermediate, to solve the above problems.
It is an object of the present invention to provide a kind of 7 α of hydrochloric acid Pilsicainide intermediate-double pyrrolizidine pyridine-acetic acid is different
Propyl ester (V) has the yield optimized in the reaction of 7 α of hydrolysis-double pyrrolizidine pyridine-acetic acid hydrochloride (VI),
With following structure:
Another object of the present invention is to provide 7 α of hydrochloric acid Pilsicainide intermediate-double pyrrolizidine pyridine-acetic acid hydrochlorides
(VI) synthesis technology, using butyrolactam and gamma-butyrolacton as raw material, through dimerization, cyclisation-condensation, 7 α of hydrolysis-bis- thick pyrroles
Cough up pyridine-acetic acid hydrochloride.Above-mentioned technique includes the following steps:
Present invention employs following technical solutions:
A kind of preparation method of hydrochloric acid Pilsicainide intermediate characterized by comprising
Step 1: polymerization reaction life occurs for butyrolactam (I) and gamma-butyrolacton (II) under highly basic, predetermined temperature
At N- (3- carboxypropyl) butyrolactam (III)；
Step 2: N- (3- carboxypropyl) butyrolactam (III) is cyclized under predetermined temperature in malonic acid list isopropyl ester solvent
And it is condensed with malonic acid monoester salt and generates 7 α-double pyrrolizidine pyridine-acetic acid esters；It is preferably selected as and generates 7 α-double pyrrolizidine pyridine-second
Isopropyl propionate (V).
Step 3: 7 α-double pyrrolizidine pyridine-acetic acid esters hydrolyzes in acid generates corresponding pharmaceutically acceptable salt.
Further, the preparation method of hydrochloric acid Pilsicainide intermediate of the invention, also has a feature in that step 1
In, alkali be selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, metallic sodium, metallic potassium, sodium methoxide, potassium methoxide, sodium ethoxide and
One of which in potassium ethoxide or at least two composition.
Preferably metallic sodium
Further, the preparation method of hydrochloric acid Pilsicainide intermediate of the invention, also has a feature in that the dosage of alkali
For the 80%-120%, preferably 100-110% of the amount of compound (I) substance.
Further, the preparation method of hydrochloric acid Pilsicainide intermediate of the invention, also has a feature in that step 1
In, reaction temperature is 50-250 DEG C, preferably is selected from 100-150 DEG C.
Further, the preparation method of hydrochloric acid Pilsicainide intermediate of the invention, also has a feature in that step 1
In, alkali is added in gamma-butyrolacton (II), temperature reaction 0-1 hours, preferably 0.5 hour.Butyrolactam, temperature reaction is added dropwise
2-8 hours, preferably 4-5 hours.
Further, the preparation method of hydrochloric acid Pilsicainide intermediate of the invention, also has a feature in that step 2
In, the malonic acid monoester salt may be selected from but not limited to malonic acid monoester sylvite, malonic acid monoester sodium salt, malonic acid monoester ammonium salt
Deng preferred malonic acid monoester sylvite.
Further, the preparation method of hydrochloric acid Pilsicainide intermediate of the invention, also has a feature in that step 2
In, the malonic acid monoester sylvite may be selected from but not limited to malonic acid monomethyl ester sylvite, potassium ethyl malonate salt, malonic acid list
Isopropyl ester sylvite, mono-tert-butyl malonate sylvite malonic acid list benzene sylvite, malonic acid list benzyl ester sylvite etc., preferably malonic acid Dan Yi
Propyl ester sylvite.The malonic acid list isopropyl ester sylvite dosage is the 100%-150% of the amount of compound (III) substance, preferably
120-130%.
Further, the preparation method of hydrochloric acid Pilsicainide intermediate of the invention, also has a feature in that step 2
In, reaction is divided into temperature rise period and temperature-fall period, the reaction temperature of temperature rise period are as follows: and 100 DEG C -200 DEG C, the reaction of temperature-fall period
Temperature are as follows: 50-85 DEG C；PH=10-11 is adjusted after reaction, ethyl acetate extracts, and it is dry, it is concentrated to get 7 α-double pyrrolizidine pyridine-
Acetic acid esters.
Further, the preparation method of hydrochloric acid Pilsicainide intermediate of the invention, also has a feature in that step 3
In, compound (V) is dissolved in hydrochloric acid, concentration of hydrochloric acid is independent to be selected from 2-36%, preferably is selected from 10-20%, heating stirring, reaction
Temperature preferably is selected from 50-100 DEG C independently selected from 0-150 DEG C.
Further, the preparation method of hydrochloric acid Pilsicainide intermediate of the invention, also has a feature in that step 3
In, end of reaction concentration, recrystallization is dried to obtain compound (VI)；Recrystallization solvent is independently selected from methanol, ethyl alcohol, isopropyl
Alcohol, acetone, tetrahydrofuran, 2- methyltetrahydrofuran, ethyl acetate, butyl acetate, methylene chloride, chloroform, toluene, diformazan
Benzene, petroleum ether, n-hexane, the one of which in normal heptane or at least two mixture, preferred alcohol.Advantageous effect of the invention
Compared with the prior art, the advantages of the present invention are as follows with cheap and easily-available raw material butyrolactam and gamma-butyrolacton, lead to
7 α-double pyrrolizidine pyridine-acetic acid hydrochloride can easily be synthesized by crossing three-step reaction, avoid expensive or unobtainable raw material,
It avoids using liquefied ammonia in synthesis process, and reduces reaction step, easy to operate, the three wastes are few, high income.It is closed by one kettle way
At 7 α of intermediate-double pyrrolizidine pyridine-isopropyl acetate (V), then 7 α of hydrolysis-double pyrrolizidine pyridine-acetic acid hydrochloride (VI)
Method total recovery reach 55-60%, much higher than previous literature report the intermediate synthesis yield；
And method provided by the present invention, reaction condition is mild, and it is environmentally friendly, it is at low cost, hence it is evident that be superior to existing
Other synthetic technology routes of technical report.The stable product quality obtained using the method for the present invention is very suitable to hydrochloric acid pyrrole west
Block the industrialized production of Buddhist nun.
Detailed description of the invention
Fig. 1 is for 7 α of intermediate of the present invention-double pyrrolizidine pyridine-isopropyl acetate (V) hydrogen nuclear magnetic resonance spectrogram.
Fig. 2 is 7 α of intermediate of the present invention-double pyrrolizidine pyridine-methyl acetate (VIII) hydrogen nuclear magnetic resonance spectrogram.
Fig. 3 is 7 α of intermediate of the present invention-double pyrrolizidine pyridine-ethyl acetate (Ⅸ) hydrogen nuclear magnetic resonance spectrogram.
Fig. 4 is 7 α of intermediate of the present invention-double pyrrolizidine pyridine-acetic acid hydrochloride (VI) hydrogen nuclear magnetic resonance spectrogram.
Specific embodiment
Present invention is further described in detail with reference to embodiments.For a person skilled in the art, it is based on
The modification or deletion that the present invention carries out are still fallen within protection scope of the present invention.
Embodiment 1:
The preparation of N- (3- carboxypropyl) butyrolactam (III)
Equipped with mechanical stirring, condenser pipe, thermometer 250mL four-hole bottle in sequentially add, metallic sodium 18.4g
(0.8mol) and gamma-butyrolacton (II) 86.0g (1.0mol), is warming up to 100 DEG C, stirs and keeps the temperature dropwise addition butyrolactam (I)
85.0g (1.0mol) insulation reaction 2 hours, is poured slowly into ice water when being cooled to 70 DEG C, with concentrated hydrochloric acid be adjusted to PH=2~
3, it filters, washing, drying obtains 103.1g white solid, and 78-80 DEG C of fusing point, be in target compound N- (3- carboxypropyl) fourth
Amide (III), yield: 60.3%.
Embodiment 2:
The preparation of N- (3- carboxypropyl) butyrolactam (III)
Equipped with mechanical stirring, condenser pipe, thermometer 250mL four-hole bottle in sequentially add, metallic sodium 23.0g
(1.0mol) and gamma-butyrolacton (II) 86.0g (1.0mol) is warming up to 130 DEG C, stirs 0.5 hour, and butyrolactam is added dropwise in heat preservation
(I) 85.0g (1.0mol) insulation reaction 4 hours, is poured slowly into ice water when being cooled to 70 DEG C, is adjusted to PH=2 with concentrated hydrochloric acid
~3, it filters, washing, drying obtains 145.7g white solid, and 78-80 DEG C of fusing point, be target compound N- (3- carboxypropyl) fourth
Lactams (III), yield: 85.2%.
Embodiment 3:
The preparation of N- (3- carboxypropyl) butyrolactam (III)
Equipped with mechanical stirring, condenser pipe, thermometer 250mL four-hole bottle in sequentially add, metallic sodium 27.6g
(1.2mol) and gamma-butyrolacton (II) 86.0g (1.0mol) is warming up to 250 DEG C, stirs 1 hour, and butyrolactam is added dropwise in heat preservation
(I) 85.0g (1.0mol) insulation reaction 8 hours, is poured slowly into ice water when being cooled to 70 DEG C, is adjusted to PH=2 with concentrated hydrochloric acid
~3, it filters, washing, drying obtains 150.0g white solid, and 78-80 DEG C of fusing point, be target compound N- (3- carboxypropyl) fourth
Lactams (III), yield: 87.7%.
Embodiment 4:
The preparation of 7 α-double pyrrolizidine pyridine-isopropyl acetate (V)
Malonic acid list isopropyl ester 100g, N- (3- carboxyl are added in the 500mL four-hole bottle equipped with mechanical stirring, thermometer
Propyl) butyrolactam (III) 94.05g (0.55mol), it is warming up to 100 DEG C, stirs 2 hours, be cooled to 50 DEG C, people the third two is added dropwise
Monooctyl acid propyl ester sylvite 93.5g (0.55mol) is dissolved in the solution of 300ml malonic acid list isopropyl ester, is stirred 12 hours, is cooled to
Room temperature, is added in 500ml water, is adjusted to PH=10~11 with sodium hydroxide, extracts (100ml × 3) with methylene chloride, organic phase
Merge, obtains 7 α of colourless liquid-double pyrrolizidine pyridine-isopropyl acetate (V) 65.3g, yield 56.3% after dry concentration.Water phase
Middle malonic acid list isopropyl ester is recyclable, is adjusted to PH=2~3 with hydrochloric acid, is layered, the malonic acid list being concentrated to get after organic phase is dry
Isopropyl ester crude product is repeated after rectifying and is applied.
Embodiment 5:
The preparation of 7 α-double pyrrolizidine pyridine-isopropyl acetate (V)
Malonic acid list isopropyl ester 100g, N- (3- carboxyl are added in the 500mL four-hole bottle equipped with mechanical stirring, thermometer
Propyl) butyrolactam (III) 94.05g (0.55mol), it is warming up to 140-145 DEG C, is stirred 2 hours, is cooled to 80-85 DEG C, is added dropwise
People malonic acid list isopropyl ester sylvite 112.2g (0.66mol) is dissolved in the solution of 300ml malonic acid list isopropyl ester, and stirring 12 is small
When, be cooled to room temperature, be added in 500ml water, be adjusted to PH=10~11 with sodium hydroxide, with methylene chloride extract (100ml ×
3), organic phase merges, and obtains 7 α of colourless liquid-double pyrrolizidine pyridine-isopropyl acetate (V) 89.3g, yield after dry concentration
77.0%.Malonic acid list isopropyl ester is recyclable in water phase, is adjusted to PH=2~3 with hydrochloric acid, is layered, and is concentrated to give after organic phase is dry
To malonic acid list isopropyl ester crude product after rectifying repeat apply.
As shown in Figure 1, compound V 1H NMR (400MHz, CDCl3): δ 4.01 (q, 1H), 3.01 (m, 2H), 2.63 (m,
2H),2.23(s,2H),1.63-1.82(m,8H),1.11(d,6H)。
Embodiment 6:
The preparation of 7 α-double pyrrolizidine pyridine-isopropyl acetate (V)
Malonic acid list isopropyl ester 50g, N- (3- carboxyl third are added in the 500mL four-hole bottle equipped with mechanical stirring, thermometer
Base) butyrolactam (III) 37.02g (0.28mol), it is warming up to 110 DEG C, stirs 2 hours, be cooled to 80-85 DEG C, people the third two is added dropwise
Monooctyl acid propyl ester sylvite 56.1g (0.33mol) is dissolved in the solution of 300ml malonic acid list isopropyl ester, is stirred 12 hours, is cooled to
Room temperature, is added in 500ml water, is adjusted to PH=10~11 with sodium hydroxide, extracts (100ml × 3) with methylene chloride, organic phase
Merge, obtains 7 α of colourless liquid-double pyrrolizidine pyridine-isopropyl acetate (V) 40.3g, yield 69.3% after dry concentration.Water phase
Middle malonic acid list isopropyl ester is recyclable, is adjusted to PH=2~3 with hydrochloric acid, is layered, the malonic acid list being concentrated to get after organic phase is dry
Isopropyl ester crude product is repeated after rectifying and is applied.
Embodiment 7:
The preparation of 7 α-double pyrrolizidine pyridine-isopropyl acetate (V)
Malonic acid list isopropyl ester 50g, N- (3- carboxyl third are added in the 500mL four-hole bottle equipped with mechanical stirring, thermometer
Base) butyrolactam (III) 37.02g (0.28mol), it is warming up to 140-145 DEG C, is stirred 2 hours, is cooled to 60 DEG C, people third is added dropwise
Diacid list isopropyl ester sodium salt 51.2g (0.33mol) is dissolved in the solution of 300ml malonic acid list isopropyl ester, is stirred 12 hours, cooling
It to room temperature, is added in 500ml water, is adjusted to PH=10~11 with sodium hydroxide, extract (100ml × 3) with methylene chloride, it is organic
Mutually merge, obtains 7 α of colourless liquid-double pyrrolizidine pyridine-isopropyl acetate (V) 35.7g, yield 61.4% after dry concentration.Water
Malonic acid list isopropyl ester is recyclable in phase, is adjusted to PH=2~3 with hydrochloric acid, is layered, the malonic acid being concentrated to get after organic phase is dry
Single isopropyl ester crude product is repeated after rectifying and is applied.
Embodiment 8:
The preparation of 7 α-double pyrrolizidine pyridine-isopropyl acetate (V)
Malonic acid list isopropyl ester 100g, N- (3- carboxyl are added in the 500mL four-hole bottle equipped with mechanical stirring, thermometer
Propyl) butyrolactam (III) 94.05g (0.55mol), 200 DEG C are warming up to, is stirred 2 hours, is cooled to 80-85 DEG C, people third is added dropwise
Diacid list isopropyl ester sylvite 139.0g (0.825mol) is dissolved in the solution of 300ml malonic acid list isopropyl ester, is stirred 12 hours, drop
It warms to room temperature, is added in 500ml water, be adjusted to PH=10~11 with sodium hydroxide, extract (100ml × 3) with methylene chloride, have
Machine mutually merges, and obtains 7 α of colourless liquid-double pyrrolizidine pyridine-isopropyl acetate (V) 89.3g, yield 77.0% after dry concentration.
Malonic acid list isopropyl ester is recyclable in water phase, is adjusted to PH=2~3 with hydrochloric acid, is layered, the third two be concentrated to get after organic phase is dry
Monooctyl acid propyl ester crude product is repeated after rectifying and is applied.
Embodiment 9:
The preparation of 7 α-double pyrrolizidine pyridine-methyl acetate (VIII)
Malonic acid monomethyl ester 50g, N- (3- carboxyl third are added in the 500mL four-hole bottle equipped with mechanical stirring, thermometer
Base) butyrolactam (III) 37.02g (0.28mol), it is warming up to 140-145 DEG C, is stirred 2 hours, is cooled to 80-85 DEG C, people is added dropwise
Malonic acid monomethyl ester sylvite 43.7g (0.28mol) is dissolved in the solution of 300ml malonic acid monomethyl ester, is stirred 12 hours, is cooled to
Room temperature, is added in 500ml water, is adjusted to PH=10~11 with sodium hydroxide, extracts (100ml × 3) with methylene chloride, organic phase
Merge, obtains 7 α of colourless liquid-double pyrrolizidine pyridine-methyl acetate (VIII) 14.9g, yield 37.6% after dry concentration.
Embodiment 10:
The preparation of 7 α-double pyrrolizidine pyridine-methyl acetate (VIII)
Malonic acid monomethyl ester 50g, N- (3- carboxyl third are added in the 500mL four-hole bottle equipped with mechanical stirring, thermometer
Base) butyrolactam (III) 37.02g (0.28mol), it is warming up to 140-145 DEG C, is stirred 2 hours, is cooled to 80-85 DEG C, people is added dropwise
Malonic acid monomethyl ester sylvite 51.5g (0.33mol) is dissolved in the solution of 300ml malonic acid monomethyl ester, is stirred 12 hours, is cooled to
Room temperature, is added in 500ml water, is adjusted to PH=10~11 with sodium hydroxide, extracts (100ml × 3) with methylene chloride, organic phase
Merge, obtains 7 α of colourless liquid-double pyrrolizidine pyridine-methyl acetate (VIII) 16.2g, yield 40.8% after dry concentration.
As shown in Fig. 2, compound VIII 1H NMR (400MHz, CDCl3): δ 3.63 (s, 3H), 3.01 (m, 2H), 2.54 (m,
2H),2.42(s,2H),1.59-1.96(m,8H)。
Embodiment 11:
The preparation of 7 α-double pyrrolizidine pyridine-methyl acetate (VIII)
Malonic acid monomethyl ester 50g, N- (3- carboxyl third are added in the 500mL four-hole bottle equipped with mechanical stirring, thermometer
Base) butyrolactam (III) 37.02g (0.28mol), it is warming up to 200 DEG C, stirs 2 hours, be cooled to 80-85 DEG C, be added dropwise to the third two
Sour mono-methyl sylvite 65.5g (0.42mol) is dissolved in the solution of 300ml malonic acid monomethyl ester, stirs 12 hours, is cooled to room
Temperature, is added in 500ml water, is adjusted to PH=10~11 with sodium hydroxide, extracts (100ml × 3) with methylene chloride, organic to be harmonious
And 7 α of colourless liquid-double pyrrolizidine pyridine-methyl acetate (VIII) 13.1g, yield 33.0% are obtained after dry concentration.
Embodiment 12:
The preparation of 7 α-double pyrrolizidine pyridine-ethyl acetate (Ⅸ)
Monoethyl malonate 50g, N- (3- carboxyl third are added in the 500mL four-hole bottle equipped with mechanical stirring, thermometer
Base) butyrolactam (III) 0.28mol, 200 DEG C are warming up to, is stirred 2 hours, is cooled to 50 DEG C, people's potassium ethyl malonate is added dropwise
Salt 0.28mol is dissolved in the solution of 300ml malonic acid monomethyl ester, is stirred 12 hours, is cooled to room temperature, is added in 500ml water,
PH=10~11 are adjusted to sodium hydroxide, extract (100ml × 3) with methylene chloride, organic phase merges, and obtains nothing after dry concentration
7 α of color liquid-double pyrrolizidine pyridine-ethyl acetate (Ⅸ) 12.7g, yield 38.7%.
Compound Ⅸ 1H NMR (400MHz, CDCl3): δ 4.09 (q, 2H), 3.00 (m, 2H), 2.53 (m, 2H), 2.39
(s,2H),1.57-1.97(m,8H),1.22(t,3H)。
Embodiment 13:
The preparation of 7 α-double pyrrolizidine pyridine-ethyl acetate (Ⅸ)
Monoethyl malonate 50g, N- (3- carboxyl third are added in the 500mL four-hole bottle equipped with mechanical stirring, thermometer
Base) butyrolactam (III) 37.02g (0.28mol), it is warming up to 140-145 DEG C, is stirred 2 hours, is cooled to 80-85 DEG C, people is added dropwise
Potassium ethyl malonate salt 51.5g (0.33mol) is dissolved in the solution of 300ml malonic acid monomethyl ester, is stirred 12 hours, is cooled to
Room temperature, is added in 500ml water, is adjusted to PH=10~11 with sodium hydroxide, extracts (100ml × 3) with methylene chloride, organic phase
Merge, obtains 7 α of colourless liquid-double pyrrolizidine pyridine-ethyl acetate (Ⅸ) 16.2g, yield 49.6% after dry concentration.
Embodiment 14:
The preparation of 7 α-double pyrrolizidine pyridine-ethyl acetate (Ⅸ)
Monoethyl malonate 50g, N- (3- carboxyl third are added in the 500mL four-hole bottle equipped with mechanical stirring, thermometer
Base) butyrolactam (III) 0.28mol, it is warming up to 140-145 DEG C, is stirred 2 hours, is cooled to 80-85 DEG C, people's malonic acid list is added dropwise
Ethyl ester sylvite 0.42mol is dissolved in the solution of 300ml malonic acid monomethyl ester, is stirred 12 hours, is cooled to room temperature, is added to
In 500ml water, PH=10~11 are adjusted to sodium hydroxide, extract (100ml × 3) with methylene chloride, organic phase merges, and drying is dense
7 α of colourless liquid-double pyrrolizidine pyridine-ethyl acetate (Ⅸ) 10.35g, yield 31.7% are obtained after contracting.
Embodiment 15
The preparation of 7 α-double pyrrolizidine pyridine-acetic acid hydrochloride (VI)
7 α-double pyrrolizidine pyridine-isopropyl acetate (V) is added in the 500mL four-hole bottle equipped with mechanical stirring, thermometer
59.1g (0.28moL), 2% hydrochloric acid 100mL, opens mechanical stirring, is warming up to 150 DEG C and reacts 12 hours, cooling, and reaction solution is dense
Be reduced to it is dry, be added 100ml dehydrated alcohol be warming up to reflux, be cooled to after solution dissolved clarification 0~5 DEG C stir 0.5 hour, filter, 50
~55 DEG C of drying, obtain 7 α of white solid-double pyrrolizidine pyridine-acetic acid hydrochloride (VI) 40.56g, such as Fig. 4 institute of yield 70.5%
Show, compound VI 1H NMR (400MHz, DMSO-d6): δ 13.72 (s, 1H), 10.70 (s, 1H), 3.48 (m, 2H), 3.06 (m,
2H),2.90(s,2H),1.88-2.07(m,8H)。
Embodiment 16
The preparation of 7 α-double pyrrolizidine pyridine-acetic acid hydrochloride (VI)
7 α-double pyrrolizidine pyridine-isopropyl acetate (V) is added in the 500mL four-hole bottle equipped with mechanical stirring, thermometer
59.1g (0.28moL), 20% hydrochloric acid 100mL, opens mechanical stirring, is warming up to 80 DEG C and reacts 12 hours, cooling, reaction solution concentration
To doing, 100ml dehydrated alcohol is added and is warming up to reflux, 0~5 DEG C is cooled to after solution dissolved clarification and is stirred 0.5 hour, filtering, 50~
55 DEG C of drying, obtain 7 α of white solid-double pyrrolizidine pyridine-acetic acid hydrochloride (VI) 52.36g, yield 91.0%
Embodiment 17
The preparation of 7 α-double pyrrolizidine pyridine-acetic acid hydrochloride (VI)
7 α-double pyrrolizidine pyridine-isopropyl acetate (V) is added in the 500mL four-hole bottle equipped with mechanical stirring, thermometer
59.1g (0.28moL), 36% hydrochloric acid 100mL, opens mechanical stirring, is warming up to 50 DEG C and reacts 12 hours, cooling, reaction solution concentration
To doing, 100ml dehydrated alcohol is added and is warming up to reflux, 0~5 DEG C is cooled to after solution dissolved clarification and is stirred 0.5 hour, filtering, 50~
55 DEG C of drying, obtain 7 α of white solid-double pyrrolizidine pyridine-acetic acid hydrochloride (VI) 47.76g, yield 83.0%
Embodiment 18:
The preparation of 7 α-double pyrrolizidine pyridine-acetic acid hydrochloride (VI)
7 α-double pyrrolizidine pyridine-methyl acetate (VIII) is added in the 500mL four-hole bottle equipped with mechanical stirring, thermometer
27.6g (0.14moL), concentrated hydrochloric acid 100mL open mechanical stirring, are warming up to 80 DEG C and react 12 hours, cooling, reaction solution is concentrated into
It is dry, 100ml methanol is added and is warming up to reflux, 0~5 DEG C is cooled to after solution dissolved clarification and is stirred 0.5 hour, filtering, 50~55 DEG C of bakings
It is dry, obtain 7 α of white solid-double pyrrolizidine pyridine-acetic acid hydrochloride (VI) 19.4g, yield 75.8%.
Embodiment 19:
The preparation of 7 α-double pyrrolizidine pyridine-acetic acid hydrochloride (VI)
7 α-double pyrrolizidine pyridine-ethyl acetate (Ⅸ) is added in the 500mL four-hole bottle equipped with mechanical stirring, thermometer
25.6g (0.14moL), concentrated hydrochloric acid 100mL open mechanical stirring, are warming up to 80 DEG C and react 12 hours, cooling, reaction solution is concentrated into
It is dry, 100ml methanol is added and is warming up to reflux, 0~5 DEG C is cooled to after solution dissolved clarification and is stirred 0.5 hour, filtering, 50~55 DEG C of bakings
It is dry, obtain 7 α of white solid-double pyrrolizidine pyridine-acetic acid hydrochloride (VI) 21.5g, yield 78.1%
Using hydrochloride is prepared into above embodiment, in other embodiments, patent medicine can also be prepared
Acceptable sulfate, phosphate, tosilate, oxalates etc. on.Being prepared into pharmaceutically acceptable salt is ability
The method that field technique personnel generally grasp, details are not described herein again.
Claims (10)
1. a kind of preparation method of hydrochloric acid Pilsicainide intermediate characterized by comprising
Step 1: polymerization reaction generation N- occurs for butyrolactam (I) and gamma-butyrolacton (II) under highly basic, predetermined temperature
(3- carboxypropyl) butyrolactam (III)；
Step 2: N- (3- carboxypropyl) butyrolactam (III) in malonic acid list isopropyl ester solvent under predetermined temperature cyclisation and with
The condensation of malonic acid monoester salt generates 7 α-double pyrrolizidine pyridine-acetic acid esters；
Step 3: 7 α-double pyrrolizidine pyridine-acetic acid esters hydrolyzes in acid generates corresponding pharmaceutically acceptable salt.
2. the preparation method of hydrochloric acid Pilsicainide intermediate as described in claim 1, it is characterised in that:
In step 1, alkali is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, metallic sodium, metallic potassium, sodium methoxide, methanol
One of which in potassium, sodium ethoxide and potassium ethoxide or at least two composition, preferably metallic sodium, the dosage of alkali are compound
(I) 80%-120% of the amount of substance, preferably 100-110%.
3. the preparation method of hydrochloric acid Pilsicainide intermediate as described in claim 1, it is characterised in that:
In step 1, reaction temperature is 50-250 DEG C, preferably is selected from 100-150 DEG C.
4. the preparation method of hydrochloric acid Pilsicainide intermediate as described in claim 1, it is characterised in that:
In step 1, alkali is added in gamma-butyrolacton (II), temperature reaction 0-1 hours, preferably 0.5 hour.Acyl in fourth is added dropwise
Amine, temperature reaction 2-8 hours, preferably 4-5 hours.
5. the preparation method of hydrochloric acid Pilsicainide intermediate as described in claim 1, it is characterised in that:
In step 2, the malonic acid monoester salt may be selected from but not limited to malonic acid monoester sylvite, malonic acid monoester sodium salt, the third two
Acid monoester ammonium salt etc., preferably malonic acid monoester sylvite.
6. the preparation method of hydrochloric acid Pilsicainide intermediate as claimed in claim 5, it is characterised in that:
In step 2, the malonic acid monoester sylvite may be selected from but not limited to malonic acid monomethyl ester sylvite, potassium ethyl malonate
Salt, malonic acid list isopropyl ester sylvite, mono-tert-butyl malonate sylvite malonic acid list benzene sylvite, malonic acid list benzyl ester sylvite etc., it is excellent
Select malonic acid list isopropyl ester sylvite.The malonic acid list isopropyl ester sylvite dosage is the 100%- of the amount of compound (III) substance
150%, preferably 120-130%.
7. the preparation method of hydrochloric acid Pilsicainide intermediate as described in claim 1, it is characterised in that:
In step 2, reaction is divided into temperature rise period and temperature-fall period, the reaction temperature of temperature rise period are as follows: and 100 DEG C -200 DEG C, cooling
The reaction temperature in stage are as follows: 50-85 DEG C；PH=10-11 is adjusted after reaction, ethyl acetate extracts, and it is dry, it is concentrated to get 7 α-
Double pyrrolizidine pyridine-acetic acid esters.
8. the preparation method of hydrochloric acid Pilsicainide intermediate as described in claim 1, it is characterised in that:
In step 3, compound (V) is dissolved in hydrochloric acid, concentration of hydrochloric acid is independent to be selected from 2-36%, preferably is selected from 10-20%, heats up
Stirring, reaction temperature preferably are selected from 50-100 DEG C independently selected from 0-150 DEG C.
9. the preparation method of hydrochloric acid Pilsicainide intermediate as described in claim 1, it is characterised in that:
In step 3, end of reaction concentration, recrystallization is dried to obtain compound (VI)；Recrystallization solvent independently selected from methanol,
Ethyl alcohol, isopropanol, acetone, tetrahydrofuran, 2- methyltetrahydrofuran, ethyl acetate, butyl acetate, methylene chloride, chloroform,
Toluene, dimethylbenzene, petroleum ether, n-hexane, the one of which in normal heptane or at least two mixture, preferred alcohol.
10. a kind of hydrochloric acid Pilsicainide intermediate, which is characterized in that it is with following chemical formula:
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