CN109134352A - A method of preparing slightly solubility compound or its solvate - Google Patents
A method of preparing slightly solubility compound or its solvate Download PDFInfo
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- CN109134352A CN109134352A CN201811113737.9A CN201811113737A CN109134352A CN 109134352 A CN109134352 A CN 109134352A CN 201811113737 A CN201811113737 A CN 201811113737A CN 109134352 A CN109134352 A CN 109134352A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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Abstract
The present invention provides the compound of formula (I) and its isomers or the preparation method of its solvate, the compound or its solvate of formula (I) is prepared in aqueous solvent with formula (II) compound and formula (III) compound, wherein X is expressed as the monovalence, divalent or trivalent acid group of inorganic acid or organic acid, and M is the cation that monovalence, the metal ion of divalent or trivalent or organic amine and proton are formed.Method of the invention is used only pure water and is applicable in a small amount of organic solvent as solvent or only, is suitble to sterilization preparation, is a kind of environmentally protective preparation method.
Description
Technical field
The present invention relates to field of medicinal chemistry, and in particular to the preparation side of a kind of slightly solubility compound or its solvate
Method.
Background technique
PCT/CN2018/080424 provides compound or its solvate of formula (a) structure and preparation method thereof.Wherein
The compound of one special case formula (I) structure, i.e., bis- [1- butyl-N- (2,6- xylyl) -2- piperidine formamide] pas are not sour
(Bis (1-Butyl-N- (2,6-dimethylphenyl) piperidine-2-carboxamide) pamoate) (abbreviation: double
(Bupivacaine) pa is not sour).More specific special case, X-ray single crystal diffraction show, the structure cell of the compound of formula (I) structure be by
Acid, four molecule Bupivacaines and four molecular solvents do not close the eutectic that object forms to two molecule pas.The compound of formula (I) structure and its molten
Agent close object using Bupivacaine free alkali and Pa Mo acid in organic solvent at salt and crystallization obtain solvate (methanol solvate,
Ethanolates etc.), it is then translated into hydrate in water, is eventually used for preparing injection.
Acid is not a kind of slightly solubility compound for being used to prepare long-acting solid particle suspension injection to bis- (Bupivacaine) pas,
It is with low-down solubility, and active constituent Bupivacaine is molten in simulated body fluid (pH7.4,0.01M phosphate buffer)
Xie Du is less than 0.1mg/ml.Use the preparation of this slightly solubility compound or its solvate sustainable release drug in vivo
Object maintains drug effect concentration to be up to 72 hours or more, reaches the analgesic effect to postoperative pain 72 hours or more.So as to improve
The shortcomings that common local anesthetic effective acting time relatively short (typically lasting for less than 7 hours), be conducive to Rehabilitation.
In the production preparation process of chemicals, seeking more environmentally protective and economic preparation method is skill in field
Striving direction well known to art personnel.Therefore, it for bis- (Bupivacaine) pas not acid and its solvate, needs a kind of more to meet
Industrial requirement and environmentally protective preparation method.
Summary of the invention
The invention discloses the preparation methods of a kind of slightly solubility compound or its solvate, more specifically, the present invention
Disclose the compound of formula (I) and its isomers or a kind of preparation method of its solvate.
Referred to as bis- (Bupivacaine) pas are not sour again for formula (I) compound, and formula (I) isomers has bis- (chirocaine) pas not
Sour (formula (I a)), bis- (right Bupivacaine) pas not sour (formula (I b)) and the mixture of both.
Preparation method characteristic provided by the invention is that water-soluble Bupivacaine salt (formula (II)) and water-soluble pa be not sour
The compound or its solvate of formula (I) is prepared in salt (formula (III)) in aqueous solvent,
Wherein X is expressed as the monovalence, divalent or trivalent acid group of inorganic acid or organic acid, and M is the gold of monovalence, divalent or trivalent
Belong to the cation that ion or organic amine and proton are formed.Skilled in the art realises that if you need to the isomers formula (I of preparation formula (I)
A), formula (I b), the isomers formula for needing formula (II) corresponding (II a), formula (II b).
" water solubility " refers to formula (II) or formula (III) compound solubility >=0.01g/ml in pure water at room temperature；
The Bupivacaine salt refers to that the salt that Bupivacaine and inorganic acid or organic acid are formed, inorganic acid include but is not limited to
Hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitric acid and phosphoric acid；Organic acid include but is not limited to formic acid, acetic acid, trifluoroacetic acid, propionic acid,
Lactic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, methanesulfonic acid, ethylenehydrinsulfonic acid, benzene sulfonic acid, to methylbenzene sulphur
Acid, benzoic acid, ascorbic acid or salicylic acid.The acid group X of the Bupivacaine salt-It indicates, can be monovalence anion,
It is also possible to dianions or trivalent anion.
Hydrochlorate does not refer to the pa dibasic carboxylic acid salt that acid group and metal ion or organic amine cation are not formed, metal to the pa
Ion includes but is not limited to sodium, potassium, lithium, calcium, magnesium, zinc and aluminium；Organic amine cation include but is not limited to ammonia, methylamine, dimethylamine,
Trimethylamine, ethamine, diethylamine, triethylamine, dicyclohexylamine, tri-butylamine, nafoxidine, pyrroles, imidazoles, pyrazoles, pyridine, piperazine
The cation that pyridine, piperazine, morpholine, meglumine and amino acid such as arginine, lysine and proton are formed.The pa not hydrochlorate
Cation part M+It indicates, can be monovalence cation, be also possible to bivalent positive ion or trivalent cation.
The aqueous solvent refers to the mixed solvent of pure water or water and organic solvent, wherein the volume ratio of in the mixed solvent water
Example is greater than 10%.The organic solvent refers to and water energy is with any solvent than dissolving each other, such as methanol, ethyl alcohol, isopropanol, third
Ketone, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, N-Methyl pyrrolidone.
What preparation method provided by the invention obtained can be solvent-free conjunction object, be also possible to solvate, preferred solvent
Conjunction object is hydrate, methanol solvate, ethanolates, more preferably hydrate.
The present invention is preferably in pure water solvent or prepared by the mixed solvent of the aqueous volume ratio greater than 90%, more preferably pure
It is prepared in water.
The preferred Bupivacaine salt of the present invention is bupivacaine HCl, sulfuric acid Bupivacaine, hydrobromic acid Bupivacaine, nitric acid cloth
Than cacaine, tartaric acid Bupivacaine, citric acid Bupivacaine, more preferably bupivacaine HCl.
Hydrochlorate is not pa not not sour two lithiums of the not sour dipotassium of acid disodium, pa, pa, pa not acid diamine to the preferred pa of the present invention.It is more excellent
It is selected as pa not acid disodium.
Preparation method provided by the invention obtains the salt of 2:1, the molar ratio of Bupivacaine salt and Pa Mo hydrochlorate in order to stablize
It should be greater than 2.0, preferably 2:1 to 3:1.
Hydrochlorate not can be pure chemicals to Bupivacaine salt or pa used in preparation method provided by the invention, can also
To be existing system, such as Bupivacaine free alkali suspends in water, and proper inorganic acid or organic acid, which is added, to be made into salt and be dissolved in
It can be prepared by corresponding water-soluble Bupivacaine salt in water, acid does not suspend in water likewise, being insoluble in the pa of water, is added suitable
Alkaline matter such as sodium hydroxide, sodium bicarbonate, potassium carbonate, ammonium hydroxide keep pa not sour at salt and are dissolved in water and water is now made
Dissolubility pa not hydrochlorate.
Preparation method provided by the invention mixes water-soluble Bupivacaine and Pa Mo acid in the solution, pair of formation
Acid is not precipitated from solution (Bupivacaine) pa in solid form, and the salt MX of superfluous component and generation remains in solution
In.
Predictable to be, it is as solvent or only applicable a small amount of organic that pure water can be used only in preparation method provided by the invention
Solvent is suitble to sterilization preparation, is a kind of environmentally protective preparation method.
Detailed description of the invention
Hereinafter, providing attached drawing so that embodiment according to the present invention is described in detail, in which:
Fig. 1 shows the x-ray diffraction pattern (crystal form A) with reference to the not sour powder of bis- (Bupivacaine) pas of preparation example 1.
Fig. 2 shows the x-ray diffraction pattern (crystal form B) with reference to the not sour powder of bis- (Bupivacaine) pas of preparation example 3.
Fig. 3 shows the x-ray diffraction pattern (crystal form C) with reference to the not sour powder of bis- (Bupivacaine) pas of preparation example 4.
The comparison of the x-ray diffraction pattern of the not sour powder of bis- (Bupivacaine) pas of Fig. 4 display preparation embodiment 1-3 preparation
Figure.
Fig. 5 display preparation embodiment 2 prepare bis- (Bupivacaine) pas not acid hydrate TGA-DTA scheme.
Fig. 6 display preparation embodiment 3 prepare bis- (Bupivacaine) pas not acid hydrate TGA-DTA scheme.
The comparison diagram of the not sour x-ray diffraction pattern of bis- (chirocaine) pas of Fig. 7 display preparation embodiment 37-40 preparation.
Specific embodiment
Below with reference to specific embodiment, present invention is further described in detail.It will be appreciated that, it is contemplated that other realities
Mode is applied, and does not depart from the scope or spirit of the invention, it is possible to implement these other embodiments.Therefore, below to retouch in detail
It states and is non-limiting.
Unless otherwise specified, expression characteristic size, quantity and materialization used in specification and claims are special
All numbers of property be construed as to be modified by term " about " in all cases.Therefore, unless there are opposite
Illustrate, the numerical parameter otherwise listed in description above and the appended claims is approximation, those skilled in the art
Member can seek the required characteristic obtained using teachings disclosed herein, suitably change these approximations.With endpoint table
The use for the numberical range shown includes all numbers within the scope of this and any range within the scope of this, for example, 1 to 5 includes
1,1.1,1.3,1.5,2,2.75,3,3.80,4 and 5 etc..
Embodiment
Examples provided below helps to understand the content of present invention, but does not limit the content of present invention.
Used drug or reagent in the present invention are unless otherwise instructed conventional commercial product.
The present invention couple high-efficient liquid phase chromatogram condition relevant to Bupivacaine detects by the following method unless otherwise specified.
High-efficient liquid phase chromatogram condition:
HPLC-a: being filler with octadecylsilane chemically bonded silica, 250 × 4.6mm, 5 μm, using methanol as mobile phase A,
0.1% trifluoroacetic acid is Mobile phase B, and by following gradient, flow velocity 1.0ml/min, column temperature is 35 DEG C, and Detection wavelength is
216nm。
| Time/min | Mobile phase A (%) | Mobile phase B (%) |
| 0.01 | 55 | 45 |
| 10 | 55 | 45 |
| 14 | 90 | 10 |
| 23 | 90 | 10 |
| 30 | 55 | 45 |
| 35 | 55 | 45 |
| 36 | Stop |
It is outer unless stated otherwise, 10% sulfuric acid, 10% nitric acid, 10% hydrobromic acid, 20% tartaric acid, 20% in embodiment
Methanesulfonic acid, 10% sodium hydroxide solution, 10% sodium carbonate liquor, 5% ammonium hydroxide are the mass-volume concentration (W/V) of solute, are matched
Method processed is to dilute to be made according to a certain concentration purified water using commercial goods (solution or solid).
Bupivacaine used in embodiment (CAS#2180-92-9) is purchased from Jinan Rui Xing Pharmaceutical Technology Co., Ltd；Salt
Sour chirocaine is purchased from Shandong Boyuan Chemical Co., Ltd.；Pa is not sour to start Chemical Co., Ltd. purchased from Taizhou；Pa not acid two
Sodium monohydrate is purchased from Jinan Shang Bo Biotechnology Co., Ltd.
X-ray powder diffraction figure is measured with DX-27mini diffractometer (the great member in Dandong).Location parameter: wavelength=1.5406
Angstrom (Cu/ κ α 1)；Stepping measurement；0.02 ° of stride；4 ° of start angle；40 ° of termination point；1.0 seconds/step of scanning speed；Tube voltage
35KV；Tube current 15mA.
Some summary descriptions are done with reference to PCT/CN2018/080424 with reference to preparation example preparation method as follows.
Not sour, the crystal form A for preparing bis- (Bupivacaine) pas with reference to preparation example 1
Bupivacaine 7.21g (25mmol) is dissolved in 200ml dehydrated alcohol, is heated to flowing back, it is not sour that pa is slowly added dropwise
Dimethyl sulphoxide solution (3.88g (10mmol) is dissolved in 10ml dimethyl sulfoxide), is added dropwise, and maintains reflux 2h, then slowly
Be cooled to 30 DEG C, filtering, a small amount of ethanol washing, be dried in vacuo in 50 DEG C 7.1g yellow solid be bis- (Bupivacaine) pas not
Acid, yield 74%.High performance liquid chromatography (HPLC-a) and nuclear magnetic resonance (H-NMR) result confirmation Bupivacaine and Pa Mo acid rub
Your ratio is 2:1.GC analyzes ethanol content 8.85%.
Endothermic peak: 149.3 DEG C (differential thermal analysis, SHIMADZU DTG-60A, 10 DEG C/min of heating rate)；
It melts weightless (105 to 188 DEG C): 7.712% (thermogravimetric analysis, SHIMADZU DTG-60A, 10 DEG C of heating rate/
min)；As a result comprehensive to be shown to be the not sour ethanolates of bis- (Bupivacaine) pas.
X powder diffraction figure has diffraction maximum at about 4.9 ± 0.2,9.8 ± 0.2 and 12.0 ± 0.2.Confirmation is crystal form A.
See attached drawing 1.
Not sour, the crystal form A for preparing bis- (Bupivacaine) pas with reference to preparation example 2
Bupivacaine 50.5g (175mmol) is dissolved in 1400ml dehydrated alcohol, is heated to flowing back, pa is slowly added dropwise not
Sour dimethyl sulphoxide solution (27.2g (70mmol) is dissolved in 76ml dimethyl sulfoxide), is added dropwise, and maintains reflux 2h, then delays
Slowly 30 DEG C are cooled to, filtering, a small amount of ethanol washing, be dried in vacuo in 50 DEG C 51.3g yellow solid is bis- (Bupivacaines)
Pa is not sour, yield 75.9%.High performance liquid chromatography (HPLC-a) and nuclear magnetic resonance (H-NMR) result confirmation Bupivacaine and Pa Mo
The molar ratio of acid is 2:1.GC analyzes ethanol content 7.48%.
Endothermic peak: 149.7 DEG C (differential thermal analysis, SHIMADZU DTG-60A, 10 DEG C/min of heating rate).
It melts weightless (105 to 180 DEG C): 7.137% (thermogravimetric analysis, SHIMADZU DTG-60A, 10 DEG C of heating rate/
min)；As a result comprehensive to be shown to be the not sour ethanolates of bis- (Bupivacaine) pas.
X powder diffraction figure is shown as crystal form A.
Not sour, the crystal form B for preparing bis- (Bupivacaine) pas with reference to preparation example 3
1000ml methanol and 1000ml third is added in Bupivacaine (216g, 0.75mol) and pa not sour (116g, 0.3mol)
The in the mixed solvent of ketone is heated to clarifying, and room temperature, stirring and crystallizing 4h, filtering, filter cake use are gradually cooled to after filtering while hot
The mixed solvent of 500ml methanol/acetone (1:1, V/V) is beaten washing, is dried in vacuo to obtain faint yellow solid in 60 DEG C after filtering
231g is that bis- (Bupivacaine) pas are not sour, yield 79.9%.High performance liquid chromatography (HPLC-a) and nuclear magnetic resonance (H-NMR) knot
Fruit confirms that the molar ratio of Bupivacaine and Pa Mo acid is 2:1, remains containing methanol.Gas chromatography (GC) analyze methanol be containing
Amount 5.26%.
Endothermic peak: 119.0 DEG C, 138.5 DEG C (differential thermal analysis, SHIMADZU DTG-60A, 10 DEG C/min of heating rate).Knot
Fruit is comprehensive to be shown to be the not sour ethanolates of bis- (Bupivacaine) pas.
X powder diffraction figure has diffraction maximum at about 10.9 ± 0.2,12.6 ± 0.2 and 13.7 ± 0.2.Confirmation is crystal form
B.See attached drawing 2.
Not sour, the crystal form C for preparing bis- (Bupivacaine) pas with reference to preparation example 4
With reference to not sour (crystal form A) powder 1.5g of resulting bis- (Bupivacaine) pas of preparation example 2,25ml purified water, room is added
Temperature stirring 20 hours, filtering, a small amount of purified water elution, gained wet product are dried in vacuo in 60 DEG C, obtain faint yellow solid powder 1.4g,
Yield 93.3%.High performance liquid chromatography (HPLC-a) and nuclear magnetic resonance (H-NMR) result confirmation Bupivacaine and Pa Mo acid rub
Your ratio is 2:1, no ethyl alcohol residual.Gas chromatography analysis ethanol content 0.19%.
Endothermic peak: 136.2 DEG C (differential thermal analysis, SHIMADZU DTG-60A, 10 DEG C/min of heating rate)
It melts weightless (105 to 185 DEG C): 3.465% (thermogravimetric analysis, SHIMADZU DTG-60A, 10 DEG C of heating rate/
Min), as a result comprehensive to be shown to be as the not sour dihydrate of bis- (Bupivacaine) pas.
X powder diffraction figure has diffraction maximum at about 10.8 ± 0.2,12.6 ± 0.2 and 13.7 ± 0.2.Confirmation is crystal form
C.See attached drawing 3.
Not sour, the crystal form C for preparing bis- (Bupivacaine) pas with reference to preparation example 5
With reference to not sour (crystal form A) powder 10.3g of resulting bis- (Bupivacaine) pas of preparation example 2,110ml purified water is added,
It is stirred at room temperature 12 hours, filters, a small amount of purified water elution, gained wet product is dried in vacuo in 60 DEG C, obtains faint yellow solid powder
9.3g, yield 90.3%.High performance liquid chromatography (HPLC-a) and nuclear magnetic resonance (H-NMR) result confirmation Bupivacaine and Pa Mo acid
Molar ratio be 2:1, no ethyl alcohol residual.Gas chromatography analysis ethanol content 0.10%.
Endothermic peak: 136.7 DEG C (differential thermal analysis, SHIMADZU DTG-60A, 10 DEG C/min of heating rate)；
It melts weightless (105 to 185 DEG C): 3.674% (thermogravimetric analysis, SHIMADZU DTG-60A, 10 DEG C of heating rate/
Min), the results showed that for the not sour dihydrate of bis- (Bupivacaine) pas.
X powder diffraction figure is shown as crystal form C.
Not sour, the crystal form C for preparing bis- (Bupivacaine) pas with reference to preparation example 6
With reference to not sour (crystal form B) powder 10.0g of resulting bis- (Bupivacaine) pas of preparation example 3,100ml purified water is added,
It is stirred at room temperature 12 hours, filters, a small amount of purified water elution, gained wet product is dried in vacuo in 60 DEG C, obtains faint yellow solid powder
9.0g, yield 90.0%.High performance liquid chromatography (HPLC-a) and nuclear magnetic resonance (H-NMR) result confirmation Bupivacaine and Pa Mo acid
Molar ratio be 2:1, no methanol residual.Gas chromatography analysis methanol content 0.15%.
Endothermic peak: 137.8 DEG C (differential thermal analysis, SHIMADZU DTG-60A, 10 DEG C/min of heating rate)
It melts weightless (105 to 185 DEG C): 3.575% (thermogravimetric analysis, SHIMADZU DTG-60A, 10 DEG C of heating rate/
Min), the results showed that for the not sour dihydrate of bis- (Bupivacaine) pas.
X powder diffraction figure is shown as crystal form C.
Bupivacaine HCl is prepared with reference to preparation example 7
Reaction flask puts into Bupivacaine (28.8g), is added ethyl acetate (288ml), is stirred to dissolve clarification, dense salt is added dropwise
Stirring 20 minutes, filtering is added dropwise in sour (10ml), and filter cake elutes (50ml*2 times) with ethyl acetate, and filter cake is in 60 DEG C dry 8
Hour, white solid is obtained, is bupivacaine HCl, weight 31g, yield 95.4%.Unless otherwise instructed, hydrochloric acid cloth of the present invention
The preparation of this method is pressed than cacaine.
It is not sour that preparation embodiment 1 prepares bis- (Bupivacaine) pas
2.4g bupivacaine HCl (7.38mmol, 2.2 equivalents) is dissolved in 200ml purified water.By 1.5g pa not acid disodium
Salt monohydrate (3.33mmol) is dissolved in 20ml purified water, is stirred at room temperature down, by pa not acid disodium salt aqueous solution fast drop
2 minutes time-consuming into bupivacaine HCl aqueous solution, stirring is filtered after five minutes, and a small amount of to purify water washing filter cake, filter cake is in 60
It DEG C is dried overnight, obtains faint yellow solid 2.8g, yield 87.2%.High performance liquid chromatography (HPLC-a) and nuclear magnetic resonance (H-NMR)
As a result the molar ratio for confirming Bupivacaine and Pa Mo acid is 2:1.
Differential thermal and thermogravimetric analysis show no endothermic peak (differential thermal analysis, SHIMADZU DTG-60A, 10 DEG C of heating rate/
min)；It is as the result is shown bis- (Bupivacaine) pas not sour solvent-free conjunction object.
X powder diffraction figure is shown as essentially amorphous, sees the CM160 of attached drawing 4.
It is not sour that preparation embodiment 2 prepares bis- (Bupivacaine) pas
7.15g bupivacaine HCl (22mmol, 2.2 equivalents) is dissolved in 250ml purified water, is heated to 60 DEG C.By 4.5g
Acid disodium salt monohydrate (10mmol) is not dissolved in 50ml water pa, and under stirring, by pa, acid disodium salt aqueous solution is not slowly added dropwise
It is 2 hours time-consuming into the bupivacaine HCl aqueous solution of heat (60 DEG C), it is added dropwise and continues to keep 60 DEG C of stirrings 1.5 hours, take advantage of
Heat filtering, purified water 50ml × 2 time elute filter cake, and filter cake uses the mashing of 200ml purified water room temperature stirring 1 hour again, filters and take out
Dry, filter cake is dried overnight in 60 DEG C, obtains faint yellow solid 9.3g, yield 92.9%.High performance liquid chromatography (HPLC-a) and nuclear-magnetism
The molar ratio of (H-NMR) result that resonates confirmation Bupivacaine and Pa Mo acid is 2:1.
Endothermic peak: 137.6 DEG C (differential thermal analysis, SHIMADZU DTG-60A, 10 DEG C/min of heating rate)
105 to 180 DEG C of weightlessness: 3.788% (thermogravimetric analysis, SHIMADZU DTG-60A, 10 DEG C/min of heating rate), knot
Fruit synthesis display is the not sour dihydrate of bis- (Bupivacaine) pas.TGA-DTA spectrogram is shown in the CM157 of attached drawing 5.
X powder diffraction figure is shown as crystal form C, sees the CM157 of attached drawing 4.
Preparation embodiment 3 prepares bis- (Bupivacaine) pas not acid hydrate
24g bupivacaine HCl (73.8mmol, 2.2 equivalents) is dissolved in 2000ml purified water, is heated to 60 DEG C.By 15g
Acid disodium salt monohydrate is not dissolved in 200ml purified water (33.3mmol) pa, and under 60 DEG C of stirrings, by pa, acid disodium salt is not water-soluble
Liquid is slowly dropped in bupivacaine HCl aqueous solution, 4 hours time-consuming, is added dropwise and is continued to keep 60 DEG C of stirrings 13 hours, takes advantage of
Heat filtering, purified water 300ml elute filter cake, and filter cake uses the mashing of 300ml purified water room temperature stirring 0.5 hour again, filters and drain,
Filter cake is 3 hours dry in 60 DEG C, obtains faint yellow solid 30.0g, yield 90.0%.High performance liquid chromatography (HPLC-a) and nuclear-magnetism are total
The molar ratio of (H-NMR) result of shaking confirmation Bupivacaine and Pa Mo acid is 2:1.
Endothermic peak: 137.2 DEG C (differential thermal analysis, SHIMADZU DTG-60A, 10 DEG C/min of heating rate)
105 to 185 DEG C of weightlessness: 3.600% (thermogravimetric analysis, SHIMADZU DTG-60A, 10 DEG C/min of heating rate), knot
Fruit synthesis display is the not sour dihydrate of bis- (Bupivacaine) pas.TGA-DTA spectrogram is shown in the CM161 of attached drawing 6.
X powder diffraction figure is shown as crystal form C, sees the CM161 of attached drawing 4.
Preparation embodiment 4 prepares bis- (Bupivacaine) pas not acid hydrate
1.95g pa not sour (5mmol) is suspended in 30ml purified water, is added sodium hydroxide solution (10% concentration, 4.1ml)
Make the not sour solid dissolved clarification (pH8~10) of pa, pa is made, and acid disodium aqueous solution is not spare.4.1g bupivacaine HCl (12.6mmol,
2.5 equivalents) it is dissolved in 300ml purified water, it is heated to 60 DEG C.Under stirring, by the pa of existing system, acid disodium aqueous solution is not added drop-wise to salt
In sour Bupivacaine aqueous solution, be added dropwise continue keep 60 DEG C be stirred overnight (8~12h), filter while hot, 50ml purified water leaching
Filter wash cake, filter cake use 50ml purified water mashing stirring 1h again, filter and drain, filter cake is 3~5 hours dry in 60 DEG C, obtains yellowish
Color solid 4.61g, yield 92.0%.High performance liquid chromatography (HPLC-a) and nuclear magnetic resonance (H-NMR) result confirm Bupivacaine
Sour molar ratio is not 2:1 with pa.
Differential thermal analysis and thermal gravimetric analysis results are shown as the not sour dihydrate of bis- (Bupivacaine) pas, and X powder diffraction figure is aobvious
It is shown as crystal form C, experimental result is the same as preparation 3 compound of embodiment.
Preparation embodiment 5 prepares bis- (Bupivacaine) pas not acid hydrate
Sodium hydroxide solution is replaced with 10% sodium carbonate liquor (11.3ml), obtains 4.45g by operation with preparation embodiment 4,
Yield 89%, analysis result is the same as preparation 4 compound of embodiment.
Preparation embodiment 6 prepares bis- (Bupivacaine) pas not acid hydrate
Acid is not suspended in 200ml water 19.4g pa, is added with stirring 11.2g potassium hydroxide, filtering, and filtrate is true in 50 DEG C
Sky concentration is evaporated off water, and residue is added 200ml ethyl alcohol, mashing stirring 1 hour, filtering, filter cake with ethanol rinse twice (50ml ×
2 times), it drains, filter cake is 6 hours dry in 60 DEG C, and obtaining 27.4g solid is the not sour dipotassium of pa.
4.1g bupivacaine HCl (12.6mmol, 2.5 equivalents) is dissolved in 300ml purified water, is heated to 60 DEG C.Stirring
Under, not sour two aqueous solutions of potassium (now the not sour dipotassium of pa processed is dissolved in 30ml water 2.33g, 5mmol) of pa are added drop-wise to hydrochloric acid Bu Bika
Because in aqueous solution, be added dropwise continue keep 60 DEG C be stirred overnight (8~12h), filter while hot, 50ml purified water elute filter cake,
Filter cake uses 50ml purified water mashing stirring 1h again, filters and drains, filter cake is 3~5 hours dry in 60 DEG C, obtains faint yellow solid
4.4g, yield 88.0%.High performance liquid chromatography (HPLC-a) and nuclear magnetic resonance (H-NMR) result confirmation Bupivacaine and Pa Mo acid
Molar ratio be 2:1.
Differential thermal analysis and thermal gravimetric analysis results are shown as the not sour dihydrate of bis- (Bupivacaine) pas, and X powder diffraction figure is aobvious
It is shown as crystal form C, experiment analysis results are the same as preparation 3 compound of embodiment.
Preparation embodiment 7 prepares bis- (Bupivacaine) pas not acid hydrate
Sodium hydroxide solution is replaced with 10% potassium hydroxide solution (6.5ml), obtained by operation with preparation embodiment 4
4.43g, yield 88.6%, analysis result is the same as preparation 4 compound of embodiment.
Preparation embodiment 8 prepares bis- (Bupivacaine) pas not acid hydrate
Sodium hydroxide solution is replaced with 10% solution of potassium carbonate (18ml), obtains 4.52g by operation with preparation embodiment 4, is received
Rate 90.4%, analysis result is the same as preparation 4 compound of embodiment.
Preparation embodiment 9 prepares bis- (Bupivacaine) pas not acid hydrate
Sodium hydroxide solution is replaced with 5% ammonium hydroxide (4.3ml), obtains 4.60g, yield by operation with preparation embodiment 4
92%, analysis result is the same as preparation 4 compound of embodiment.
Preparation embodiment 10 prepares bis- (Bupivacaine) pas not acid hydrate
Sodium hydroxide solution is replaced with lithium hydroxide monohydrate (0.42g), obtained by operation with preparation embodiment 4
4.62g, yield 92.4%, analysis result is the same as preparation 4 compound of embodiment.
Preparation embodiment 11 prepares bis- (Bupivacaine) pas not acid hydrate
Sodium hydroxide solution is replaced with triethylamine (1.15g), obtains 4.35g by operation with preparation embodiment 4, yield 87%,
Result is analyzed with preparation 4 compound of embodiment.
Preparation embodiment 12 prepares bis- (Bupivacaine) pas not acid hydrate
8g Bupivacaine free alkali (27.7mmol, 2.7 equivalents) is suspended in 800ml purified water, and hydrochloric acid is slowly added dropwise
(2M, 15ml) makes dissolved clarification (pH3~5), is then heated to 60 DEG C.By 4.5g pa, acid disodium salt monohydrate (10mmol) is not molten again
In 60ml purified water, under 60 DEG C of stirrings, by pa, acid disodium salt aqueous solution is not slowly dropped to the bupivacaine HCl water of existing system
In solution, be added dropwise continue keep 60 DEG C be stirred overnight (8~12h), filter while hot, 100ml purified water elute filter cake, filter cake
Again with 100ml purified water mashing stirring 1h, filtering and drain, filter cake is 3~5 hours dry in 60 DEG C, faint yellow solid 8.9g is obtained,
Yield 89.0%.High performance liquid chromatography (HPLC-a) and nuclear magnetic resonance (H-NMR) result confirmation Bupivacaine and Pa Mo acid rub
Your ratio is 2:1.
Differential thermal analysis and thermal gravimetric analysis results are shown as the not sour dihydrate of bis- (Bupivacaine) pas, and X powder diffraction figure is aobvious
It is shown as crystal form C, experimental result is the same as preparation 3 compound of embodiment.
Preparation embodiment 13 prepares bis- (Bupivacaine) pas not acid hydrate
Hydrochloric acid is replaced with 10% sulfuric acid (15ml) with preparation embodiment 12 by operation, obtains 8.5g, yield 85.0%, analysis
As a result with preparation 12 compound of embodiment.
Preparation embodiment 14 prepares bis- (Bupivacaine) pas not acid hydrate
Hydrochloric acid is replaced with 10% nitric acid (19ml) with preparation embodiment 12 by operation, obtains 8.6g, yield 86.0%, analysis
As a result with preparation 12 compound of embodiment.
Preparation embodiment 15 prepares bis- (Bupivacaine) pas not acid hydrate
Hydrochloric acid is replaced with 10% hydrobromic acid (25ml) with preparation embodiment 12 by operation, obtains 8.9g, and yield 89.0% divides
Result is analysed with preparation 12 compound of embodiment.
Preparation embodiment 16 prepares bis- (Bupivacaine) pas not acid hydrate
Hydrochloric acid is replaced with 20% aqueous citric acid solution (28ml), obtains 8.4g, yield by operation with preparation embodiment 12
84.0%, analysis result is the same as preparation 12 compound of embodiment.
Preparation embodiment 17 prepares bis- (Bupivacaine) pas not acid hydrate
Hydrochloric acid is replaced with glacial acetic acid (2.4g) with preparation embodiment 12 by operation, obtains 9.1g, yield 91.0%, analysis knot
Fruit is the same as preparation 12 compound of embodiment.
Preparation embodiment 18 prepares bis- (Bupivacaine) pas not acid hydrate
Hydrochloric acid is replaced with succinic acid solid (3.3g) with preparation embodiment 12 by operation, obtains 9.05g, and yield 90.5% divides
Result is analysed with preparation 12 compound of embodiment.
Preparation embodiment 19 prepares bis- (Bupivacaine) pas not acid hydrate
Hydrochloric acid is replaced with maleic acid solid (3.5g) with preparation embodiment 12 by operation, obtains 8.95g, and yield 89.5% divides
Result is analysed with preparation 12 compound of embodiment.
Preparation embodiment 20 prepares bis- (Bupivacaine) pas not acid hydrate
Hydrochloric acid is replaced with 20% aqueous tartaric acid solution (22ml), obtains 9.15g, yield by operation with preparation embodiment 12
91.5%, analysis result is the same as preparation 12 compound of embodiment.
Preparation embodiment 21 prepares bis- (Bupivacaine) pas not acid hydrate
Hydrochloric acid is replaced with 20% aqueous methane sulfonic acid (14.4ml), obtains 9.1g, yield by operation with preparation embodiment 12
91.0%, analysis result is the same as preparation 12 compound of embodiment.
Preparation embodiment 22 prepares bis- (Bupivacaine) pas not acid hydrate
1.95g pa not sour (5mmol) is suspended in 30ml purified water, and sodium hydroxide solution (10% concentration, 4ml), which is added, to be made
The not sour solid dissolved clarification (pH8~10) of pa, pa is made, and acid disodium aqueous solution is not spare.
3.6g Bupivacaine free alkali (12.5mmol, 2.5 equivalents) is suspended in 360ml purified water, and hydrochloric acid is slowly added dropwise
(2M, 6.7ml) makes dissolved clarification (pH3~5), is then heated to 60 DEG C.
By pa, acid disodium salt aqueous solution is not slowly dropped in the bupivacaine HCl aqueous solution of existing system, and continuation is added dropwise
It is kept for 60 DEG C and is stirred overnight (8~12h), filtered while hot, 50ml purified water elutes filter cake, and filter cake is stirred with the mashing of 50ml purified water again
1h is mixed, filter and is drained, filter cake is 3~5 hours dry in 60 DEG C, obtains faint yellow solid 4.58g, yield 91.6%.Efficient liquid phase
The molar ratio of chromatography (HPLC-a) and nuclear magnetic resonance (H-NMR) result confirmation Bupivacaine and Pa Mo acid is 2:1.
Differential thermal analysis and thermal gravimetric analysis results are shown as the not sour dihydrate of bis- (Bupivacaine) pas, and X powder diffraction figure is aobvious
It is shown as crystal form C, experimental result is the same as preparation 3 compound of embodiment.
Preparation embodiment 23 prepares bis- (Bupivacaine) pas not acid hydrate
Sodium hydroxide solution is replaced with 10% potassium hydroxide solution (6.5ml), by hydrochloric acid with preparation embodiment 22 by operation
10% sulfuric acid (6.7ml) is replaced with, 4.38g, yield 87.6% are obtained.Result is analyzed with preparation 22 compound of embodiment.
Preparation embodiment 24 prepares bis- (Bupivacaine) pas not acid hydrate
Sodium hydroxide solution is replaced with 10% sodium carbonate liquor (11ml), hydrochloric acid is replaced by operation with preparation embodiment 22
It is changed to 20% aqueous citric acid solution (12.6ml), obtains 4.25g, yield 85.0%.Result is analyzed with preparation 22 compound of embodiment.
Preparation embodiment 25 prepares bis- (Bupivacaine) pas not acid hydrate
Sodium hydroxide solution is replaced with 5% ammonium hydroxide (4.4ml), and hydrochloric acid is replaced with preparation embodiment 22 by operation
For 20% aqueous tartaric acid solution (10ml), 4.30g, yield 86.0% are obtained.Result is analyzed with preparation 22 compound of embodiment.
Preparation embodiment 26 prepares bis- (Bupivacaine) pas not acid hydrate
Operation replaces with sodium hydroxide solution 10% sodium carbonate liquor (11ml), and with preparation embodiment 22 by salt
Acid replaces with 20% aqueous methane sulfonic acid (6.4ml), obtains 4.20g, yield 84.0%.Result is analyzed with preparation 22 chemical combination of embodiment
Object.
Preparation embodiment 27 prepares bis- (Bupivacaine) pas not acid hydrate
2.4g bupivacaine HCl (7.38mmol, 2.2 equivalents) is dissolved in 200ml purified water, is added ethyl alcohol (20ml), is added
Heat is to 60 DEG C.By 1.5g (3.33mmol) pa, acid disodium salt monohydrate is not dissolved in 20ml purified water again, will under 60 DEG C of stirrings
Acid disodium salt aqueous solution is not slowly dropped in bupivacaine HCl aqueous solution pa, be added dropwise continue keep 60 DEG C stirring 8~
It 12 hours, filters while hot, purified water 30ml elutes filter cake, and filter cake uses the mashing of 30ml purified water room temperature stirring 1 hour again, and filtering is simultaneously
It drains, filter cake is 3~5 hours dry in 60 DEG C, obtains faint yellow solid 2.75g, yield 82.6%.High performance liquid chromatography (HPLC-a)
The molar ratio that Bupivacaine and Pa Mo acid are confirmed with nuclear magnetic resonance (H-NMR) result is 2:1, organic solvent-free residual.
Differential thermal analysis and thermal gravimetric analysis results are shown as the not sour dihydrate of bis- (Bupivacaine) pas, and X powder diffraction figure is aobvious
It is shown as crystal form C, experimental result is the same as preparation 3 compound of embodiment.
Preparation embodiment 28 prepares bis- (Bupivacaine) pas not acid hydrate
Ethyl alcohol is replaced with methanol (20ml) and 60 DEG C of heating temperature replaces with 50 DEG C by operation with preparation embodiment 27.
Obtain 2.45g, yield 73.6%.Result is analyzed with preparation 27 compound of embodiment.
Preparation embodiment 29 prepares bis- (Bupivacaine) pas not acid hydrate
Ethyl alcohol is replaced with acetone (10ml), obtains 2.95g, yield 88.6% by operation with preparation embodiment 27.Analyze result
With preparation 27 compound of embodiment.
Preparation embodiment 30 prepares bis- (Bupivacaine) pas not acid hydrate
Ethyl alcohol is replaced with dimethyl sulfoxide (10ml), obtains 2.35g, yield 70.6% by operation with preparation embodiment 27.Point
Result is analysed with preparation 27 compound of embodiment.
Preparation embodiment 31 prepares bis- (Bupivacaine) pas not acid hydrate
Ethyl alcohol is replaced with n,N-Dimethylformamide (10ml), obtains 2.30g, yield by operation with preparation embodiment 27
69.1%.Result is analyzed with preparation 27 compound of embodiment.
Preparation embodiment 32 prepares bis- (Bupivacaine) pas not acid hydrate
1.95g pa not sour (5mmol) is suspended in 30ml purified water, and 10% potassium hydroxide solution (6.5ml), which is added, makes pa
It is spare that not sour two aqueous solutions of potassium of pa are made in not sour solid dissolved clarification.
3.6g Bupivacaine free alkali (12.5mmol, 2.5 equivalents) is suspended in 360ml purified water, adds ethyl alcohol
(30ml), 10% sulfuric acid (6.7ml), which is slowly added dropwise, makes dissolved clarification (pH3.0), is then heated to 60 DEG C.
By pa, acid disodium salt aqueous solution is not slowly dropped in the sulfuric acid Bupivacaine aqueous solution of existing system, and continuation is added dropwise
It is kept for 60 DEG C and is stirred overnight (8~12h), filtered while hot, 50ml purified water elutes filter cake, and filter cake is stirred with the mashing of 50ml purified water again
1h is mixed, filter and is drained, filter cake is 3~5 hours dry in 60 DEG C, obtains faint yellow solid 3.6g, yield 72.0%.High-efficient liquid phase color
The molar ratio for composing (HPLC-a) and nuclear magnetic resonance (H-NMR) result confirmation Bupivacaine and Pa Mo acid is 2:1, organic solvent-free
Residual.
Differential thermal analysis and thermal gravimetric analysis results are shown as the not sour dihydrate of bis- (Bupivacaine) pas, and X powder diffraction figure is aobvious
It is shown as crystal form C, experimental result is the same as preparation 3 compound of embodiment.
Preparation embodiment 33 prepares bis- (Bupivacaine) pas not acid hydrate
1.95g pa not sour (5mmol) is suspended in 30ml purified water, and 5% ammonium hydroxide (4.5ml), which is added, keeps the not sour solid of pa molten
It is spare that not sour two aqueous ammoniums of pa are made in (pH8.5) clearly.
3.6g Bupivacaine free alkali (12.5mmol, 2.5 equivalents) is suspended in 360ml purified water, adds acetone
(18ml), 20% aqueous tartaric acid solution (10ml), which is slowly added dropwise, makes dissolved clarification (pH4.5), is then heated to 50 DEG C.
Not sour two aqueous ammoniums of pa are slowly dropped in the tartaric acid Bupivacaine aqueous solution of existing system, continuation is added dropwise
It is kept for 50 DEG C and is stirred overnight (8~12h), filtered while hot, 50ml purified water elutes filter cake, and filter cake is stirred with the mashing of 50ml purified water again
1h is mixed, filter and is drained, filter cake is 3~5 hours dry in 60 DEG C, obtains faint yellow solid 4.1g, yield 82.0%.High-efficient liquid phase color
The molar ratio for composing (HPLC-a) and nuclear magnetic resonance (H-NMR) result confirmation Bupivacaine and Pa Mo acid is 2:1, organic solvent-free
Residual.
Differential thermal analysis and thermal gravimetric analysis results are shown as the not sour dihydrate of bis- (Bupivacaine) pas, and X powder diffraction figure is aobvious
It is shown as crystal form C, experimental result is the same as preparation 3 compound of embodiment.
Preparation embodiment 34 prepares the not sour ethanolates of bis- (Bupivacaine) pas
Preparation 1 compound of embodiment (amorphous powder) 1.5g is suspended in dehydrated alcohol (30ml), and it is small to stir 5 at room temperature
When, filtering, a small amount of ethanol rinse filter cake is dried in vacuo to obtain faint yellow solid 1.45g, yield 88.4% in 50 DEG C.Efficient liquid phase
The molar ratio of chromatography (HPLC-a) and nuclear magnetic resonance (H-NMR) result confirmation Bupivacaine and Pa Mo acid is 2:1.GC analyzes second
Alcohol content 7.26%.
Differential thermal analysis and thermal gravimetric analysis results are shown as the not sour ethanolates of bis- (Bupivacaine) pas
X powder diffraction figure is shown as crystal form A.
Preparation embodiment 35 prepares the not sour ethanolates of bis- (Bupivacaine) pas
Preparation embodiment 3 compound (crystal form C) 5.0g is suspended in dehydrated alcohol (150ml), is stirred 20 hours at room temperature,
Filtering, a small amount of ethanol rinse filter cake are dried in vacuo to obtain faint yellow solid 4.96g, yield 93.8% in 50 DEG C.High performance liquid chromatography
(HPLC-a) and nuclear magnetic resonance (H-NMR) result confirms that the molar ratio of Bupivacaine and Pa Mo acid is 2:1.GC analysis ethyl alcohol contains
Amount 8.25%.
Differential thermal analysis and thermal gravimetric analysis results are shown as the not sour ethanolates of bis- (Bupivacaine) pas
X powder diffraction figure is shown as crystal form A.
Preparation embodiment 36 prepares the not sour ethanolates of bis- (Bupivacaine) pas
Preparation embodiment 3 compound (crystal form C) 5.0g is suspended in anhydrous methanol (100ml), is stirred 15 hours at room temperature,
Filtering, a small amount of methanol elute filter cake, faint yellow solid 4.65g, yield 90.4% are dried in vacuo to obtain in 50 DEG C.High performance liquid chromatography
(HPLC-a) and nuclear magnetic resonance (H-NMR) result confirms that the molar ratio of Bupivacaine and Pa Mo acid is 2:1.GC analysis methanol contains
Amount 5.38%.
Differential thermal analysis and thermal gravimetric analysis results are shown as the not sour methanol solvate of bis- (Bupivacaine) pas
X powder diffraction figure is shown as crystal form B.
It is not sour that preparation embodiment 37 prepares bis- (chirocaine) pas
7.2g Levobupivacaine HCL (22mmol) is dissolved in 200ml water, and is heated to 60 DEG C.By 4.5g pa not acid disodium
Monohydrate (10mmol) is dissolved in 40ml water, and is added drop-wise in Levobupivacaine HCL aqueous solution under stiring, is added dropwise,
To continue to keep 60 DEG C of stirring 1.5h, filter while hot, 50ml × 2 time elute filter cake, and filter cake is used the mashing stirring of 200ml water again, filtered,
It drains, filter cake is dried overnight in 60 DEG C, obtains faint yellow solid 9.1g, yield 94.3%.High performance liquid chromatography (HPLC-a) and core
Magnetic resonance (H-NMR) result confirms that the molar ratio of chirocaine and Pa Mo acid is 2:1.
Differential thermal and thermogravimetric analysis show no endothermic peak (differential thermal analysis, SHIMADZU DTG-60A, 10 DEG C of heating rate/
min)；It is as the result is shown bis- (chirocaine) pas not sour solvent-free conjunction object.
X powder diffraction figure is shown as amorphous state, sees the CM156 of attached drawing 7.
It is not sour that preparation embodiment 38 prepares bis- (chirocaine) pas
71.5g Levobupivacaine HCL (0.22mol) is dissolved in 1450ml water, and is heated to 60 DEG C.By 45g pa not acid two
Sodium monohydrate (0.1mol) is dissolved in 450ml water, and is added drop-wise in Levobupivacaine HCL aqueous solution under stiring, is dripped
To finish, continues to keep 60 DEG C of stirring 0.5h, filter while hot, 250ml × 2 time elute filter cake, and filter cake uses the mashing stirring of 1000ml water again,
Filtering, is drained, filter cake is dried overnight in 60 DEG C, obtains faint yellow solid 90g, yield 93.3%.High performance liquid chromatography (HPLC-a)
The molar ratio that chirocaine and Pa Mo acid are confirmed with nuclear magnetic resonance (H-NMR) result is 2:1.
Differential thermal and thermogravimetric analysis show no endothermic peak (differential thermal analysis, SHIMADZU DTG-60A, 10 DEG C of heating rate/
min)；As the result is shown it is bis- (chirocaine) pas not sour solvent-free conjunction object, sees attached drawing 3.
X powder diffraction figure is shown as amorphous state, sees the CM163 of attached drawing 7.
It is not sour that preparation embodiment 39 prepares bis- (chirocaine) pas
3.6g Levobupivacaine HCL (11mmol) is dissolved in 190ml water, adds 10ml ethyl alcohol, is heated to 60 DEG C.It will
Acid disodium monohydrate (5mmol) is not dissolved in 30ml water 2.25g pa, and it is water-soluble to be added drop-wise to Levobupivacaine HCL under stiring
It in liquid, is added dropwise, continues to keep 60 DEG C of stirring 0.5h, filter while hot, 30ml × 2 time elute filter cake, and filter cake uses 100ml water again
Mashing stirring, filtering are drained, and filter cake is stayed overnight in 60 DEG C of forced air dryings, obtain faint yellow solid 4.2g, yield 87.0%.Efficient liquid
It is 2:1 that phase chromatography (HPLC-a) and nuclear magnetic resonance (NMR), which are analyzed to identify chirocaine and the molar ratio of Pa Mo acid, and without second
Alcohol residual.
Differential thermal and thermogravimetric analysis show no endothermic peak (differential thermal analysis, SHIMADZU DTG-60A, 10 DEG C of heating rate/
min)；It is as the result is shown bis- (chirocaine) pas not sour solvent-free conjunction object.
X powder diffraction figure shows essentially amorphous state, sees the CM164 of attached drawing 7.
It is not sour that preparation embodiment 40 prepares bis- (chirocaine) pas
4.0g Levobupivacaine HCL (12.3mmol) is dissolved in 200ml water, adds 10ml methanol, is heated to 50 DEG C.
By 2.25g pa, acid disodium monohydrate (5mmol) is not dissolved in 30ml water, and is added drop-wise to Levobupivacaine HCL water under stiring
It in solution, is added dropwise, continues to keep 50 DEG C of stirring 0.5h, filter while hot, 30ml × 2 time elute filter cake, and filter cake uses 100ml again
Water mashing stirring, filtering are drained, filter cake is dried overnight in 60 DEG C, obtains faint yellow solid 4.0g, yield 82.9%.Efficient liquid phase
It is 2:1 that chromatography (HPLC-a) and nuclear magnetic resonance (NMR), which are analyzed to identify chirocaine and the molar ratio of Pa Mo acid, and without methanol
Residual.
Differential thermal and thermogravimetric analysis show no endothermic peak (differential thermal analysis, SHIMADZU DTG-60A, 10 DEG C of heating rate/
min)；It is as the result is shown bis- (chirocaine) pas not sour solvent-free conjunction object.
X powder diffraction figure shows essentially amorphous state, sees the CM165 of attached drawing 7.
It is described the prefered embodiments of the present invention in detail above in conjunction with attached drawing, still, the present invention is not limited to above-mentioned realities
The detail in mode is applied, within the scope of the technical concept of the present invention, a variety of letters can be carried out to technical solution of the present invention
Monotropic type, these simple variants all belong to the scope of protection of the present invention.
It is further to note that specific technical features described in the above specific embodiments, in not lance
In the case where shield, can be combined in any appropriate way, in order to avoid unnecessary repetition, the present invention to it is various can
No further explanation will be given for the combination of energy.
In addition, various embodiments of the present invention can be combined randomly, as long as it is without prejudice to originally
The thought of invention, it should also be regarded as the disclosure of the present invention.
Claims (10)
1. the preparation method of the compound or its solvate of formula (I) and its isomers,
The compound of formula (I) is prepared in aqueous solvent with formula (II) compound and formula (III) compound or its solvent closes
Object,
,,
Wherein X is expressed as the monovalence, divalent or trivalent acid group of inorganic acid or organic acid, M be monovalence, divalent or trivalent metal from
The cation that son or organic amine and proton are formed.
2. preparation method according to claim 1, wherein X be selected from hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitric acid and
Phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, methanesulfonic acid,
Ethylenehydrinsulfonic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, benzoic acid, ascorbic acid or salicylic monovalence and divalent acid group；M is choosing
From in Na+、K+、Li+、Ca2+、、Mg2+、Al3+And the cation that organic amine and proton are formed, the organic amine are selected from ammonia, first
Amine, dimethylamine, trimethylamine, ethamine, diethylamine, triethylamine, dicyclohexylamine, tri-butylamine, nafoxidine, pyrroles, imidazoles, pyrrole
Azoles, pyridine, piperidines, piperazine, morpholine, meglumine, arginine, lysine.
3. preparation method according to claim 2, wherein X be selected from hydrochloric acid, sulfuric acid, hydrobromic acid, nitric acid, tartaric acid,
The monovalence and divalent acid group of citric acid；M is Na+、K+、Li+、NH4 +。
4. preparation method according to claim 1, wherein aqueous solvent is the mixing of pure water solvent or water and organic solvent
Solvent, the organic solvent are selected from methanol, ethyl alcohol, isopropanol, acetone, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, N, N- bis-
Methylformamide, N-Methyl pyrrolidone.
5. the preparation method according to claim 4, wherein aqueous solvent is the mixing of water or water and methanol, ethyl alcohol, acetone
Solvent, and the volume ratio of in the mixed solvent water is greater than or equal to 50%.
6. preparation method according to claim 5, wherein aqueous solvent is the mixing of water or water and methanol, ethyl alcohol, acetone
Solvent, and the volume ratio of in the mixed solvent water is greater than or equal to 90%.
7. preparation method according to claim 1, wherein solvate is hydrate, methanol solvate, ethanolates.
8. preparation method according to claim 2, wherein solvate is hydrate.
9. preparation method according to claim 7, wherein solvate is methanol solvate, ethanolates, increases and turn brilliant step
Suddenly, the compound or hydrate of modus ponens (I) are respectively placed in methanol or stirring turns crystalline substance in ethyl alcohol,
。
10. the molar ratio of preparation method according to claim 1, formula (II) compound and formula (III) is not less than 2:1, and adds
Entering sequence is,
,,
Formula (III) compound is added in formula (II) compound solution.
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|---|---|---|---|---|
| CN110530992A (en) * | 2019-08-30 | 2019-12-03 | 珠海润都制药股份有限公司 | A kind of method of inspection of Levobupivacaine HCL injection optical isomer |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2116313A1 (en) * | 1970-12-08 | 1972-07-13 | Synthelabo | Protokylol pamoate - with long-acting bronchodilator activity |
| US5232919A (en) * | 1987-11-13 | 1993-08-03 | Asta Pharma Aktiengesellschaft | Azelastine embonate and compositions which contain it |
| WO2004112713A2 (en) * | 2003-06-20 | 2004-12-29 | Royer Biomedical, Inc. | Drug polymer complexes |
| CN104039765A (en) * | 2011-11-29 | 2014-09-10 | 顾自强 | Donepezil pamoate, preparation method and its use |
| WO2017036408A1 (en) * | 2015-09-01 | 2017-03-09 | 四川海思科制药有限公司 | S-(-)-1-propyl-2',6'-aminoxyleneformylpiperidine crystal and sustained release preparation thereof |
| EP2956456B1 (en) * | 2013-02-13 | 2017-07-12 | Neuland Laboratories Ltd | A process for preparation of olanzapine pamoate |
| WO2017167180A1 (en) * | 2016-03-29 | 2017-10-05 | 上海华汇拓医药科技有限公司 | Vortioxetine pamoic acid salt and crystal form thereof |
| WO2018122626A1 (en) * | 2016-12-26 | 2018-07-05 | Cellix Bio Private Limited | Compositions and methods for the treatment of chronic pain |
-
2018
- 2018-09-21 CN CN201811113737.9A patent/CN109134352A/en active Pending
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2116313A1 (en) * | 1970-12-08 | 1972-07-13 | Synthelabo | Protokylol pamoate - with long-acting bronchodilator activity |
| US5232919A (en) * | 1987-11-13 | 1993-08-03 | Asta Pharma Aktiengesellschaft | Azelastine embonate and compositions which contain it |
| WO2004112713A2 (en) * | 2003-06-20 | 2004-12-29 | Royer Biomedical, Inc. | Drug polymer complexes |
| CN104039765A (en) * | 2011-11-29 | 2014-09-10 | 顾自强 | Donepezil pamoate, preparation method and its use |
| EP2956456B1 (en) * | 2013-02-13 | 2017-07-12 | Neuland Laboratories Ltd | A process for preparation of olanzapine pamoate |
| WO2017036408A1 (en) * | 2015-09-01 | 2017-03-09 | 四川海思科制药有限公司 | S-(-)-1-propyl-2',6'-aminoxyleneformylpiperidine crystal and sustained release preparation thereof |
| WO2017167180A1 (en) * | 2016-03-29 | 2017-10-05 | 上海华汇拓医药科技有限公司 | Vortioxetine pamoic acid salt and crystal form thereof |
| WO2018122626A1 (en) * | 2016-12-26 | 2018-07-05 | Cellix Bio Private Limited | Compositions and methods for the treatment of chronic pain |
Non-Patent Citations (3)
| Title |
|---|
| DAYSE N. MOREIRA ET AL.: "Brønsted acid-base pairs of drugs as dual ionic liquids: NMR ionicity studies", 《TETRAHEDRON》 * |
| NAOMI I. NAKANO ET AL.: "3-Hydroxy-2-naphthoates of lidocaine, mepivacaine, and bupivacaine and their dissolution characteristics", 《CHEM.PHARM.BULL.》 * |
| 中国医学百科全书编辑委员会: "《中国医学百科全书 药物学与药理学》", 31 October 1988, 上海科学技术出版社 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110530992A (en) * | 2019-08-30 | 2019-12-03 | 珠海润都制药股份有限公司 | A kind of method of inspection of Levobupivacaine HCL injection optical isomer |
| CN110530992B (en) * | 2019-08-30 | 2022-05-10 | 珠海润都制药股份有限公司 | Method for testing optical isomer of levobupivacaine hydrochloride injection |
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