CN106478506B - The preparation method of half light green Ka Selin hydrochloride - Google Patents
The preparation method of half light green Ka Selin hydrochloride Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/16—Benzazepines; Hydrogenated benzazepines
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- C—CHEMISTRY; METALLURGY
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract
The invention discloses the preparation methods of half light green Ka Selin hydrochloride.The preparation method includes the following steps: that compound shown in (1) formula III reacts to obtain compound shown in formula II with ammonia；(2) under nitrogen protection, compound shown in formula II is dissolved in organic solvent, the hydrogen chloride solution that solvent is organic solvent is added and carries out salt-forming reaction, water is then added and hexamethylene forms semihydrate, compound shown in formula I can be obtained；The organic solvent is isopropanol or 1,4- dioxane.The present invention replaces potassium carbonate in the prior art using ammonium hydroxide, and generation potassium chloride causes the ignition residue of finished product unqualified after can avoid solution salt；Traditional hydrogen chloride gas is replaced using hydrochloric acid aqueous isopropanol, can avoid causing to introduce other impurity during the preparation process because the control of the dosage and rate of gas is improper.
Description
Technical field
The present invention relates to pharmaceutical synthesis field more particularly to the preparation methods of half light green Ka Selin hydrochloride.
Background technique
Green card color woods is the drug for acting on central nervous system impression appetite, in 2005 by U.S.'s Ai Nina pharmacy public affairs
Department develops, and on June 27th, 2012 is in the granted listing in the U.S., trade name Belviq.Green card is reported in CN102321023
There are three types of crystal forms for color woods hydrochloride tool.Crystal form I and crystal form II are anhydrous, moisture absorption forms, both forms are all easy in exposure
More stable crystal form III is converted into after moisture.The medicinal listing crystal form of the product is green card color woods hydrochloride Form III, i.e.,
Half light green Ka Selin hydrochloride.
Half light green Ka Selin hydrochloride, also known as green card color woods hydrochloride semi-hydrate, half water dextrorotation green card color woods hydrochloride,
Dextrorotation green card color woods hydrochloride semi-hydrate etc., chemical name are the chloro- 1- methyl -2,3 of (R) -8-, 4,5- tetrahydro -1H-3- benzos
Azatropylidene hydrochloride semi-hydrate, English name be (R) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-
Benzazepine hydrochloride hemihydrate, molecular formula C11H14ClN·HCl·0.5H2O, structural formula such as formula
Shown in I, CAS number is 856681-05-5.
CN100486967 is to carry out acylation reaction with trifluoroacetic anhydride under pyridine to chlorophenethylamine, then in two pyridines
Iodine tetrafluoro benzene sulfonic acid and the lower progress iodination reaction of trifluoromethanesulfonic acid effect, carry out cyclization reaction and hydrogenation after carrying out bromination reaction
Deprotection, solution salt obtain the lorcaserin of racemization.The synthetic route is longer, while used reagent is not conventional reagent, is made
Increase at the Material Cost of bulk pharmaceutical chemicals, is unfavorable for commercially producing.Specific synthetic route is as follows:
CN101547892 is carried out under the effect of 2,5,6- trifluoro-benzoic acid in toluene with 4-Chlorophenylacetic acid and isopropanolamine
Amidation process, through sodium borohydride reduction carbonyl reduction, in the catalysis after thionyl chloride carries out chlorination reaction in aluminium chloride
Lower progress Fu Ke cyclization reaction obtains the lorcaserin of racemization, then obtains R- structure first at salt then in solution salt with L-TARTARIC ACID
The lorcaserin of type.Specific synthetic line is as follows:
The problems such as ignition residue that this method still has finished product is unqualified, low in relation to content of material.
Summary of the invention
The object of the present invention is to provide the preparation method of half light green Ka Selin hydrochloride, this method is prepared half light green
The purity is high (HPLC purity up to 99.95% or more) of Ka Selin hydrochloride, related content of material is low, and optical purity is up to 100%, item
Part temperature, synthetic thread are short out.
The preparation method of half light green Ka Selin hydrochloride (compound shown in formula I) provided by the invention, includes the following steps:
(1) compound shown in formula III reacts to obtain compound shown in formula II with ammonia；
(2) under nitrogen protection, compound shown in formula II is dissolved in organic solvent, it is organic solvent that solvent, which is added,
Hydrogen chloride solution carries out salt-forming reaction, and water is then added and hexamethylene forms semihydrate, compound shown in formula I can be obtained；
The organic solvent is isopropanol or 1,4- dioxane.
In above-mentioned preparation method, compound shown in formula III can be prepared as follows:
1) under the catalytic action of nitrogen protection and aluminium chloride, compound shown in formula V carries out Fu Ke cyclization reaction, obtains
Compound shown in formula IV；
2) compound shown in formula IV is reacted into salt with L-TARTARIC ACID, compound shown in formula III can be obtained.
Above-mentioned preparation method, in step 1), the molar ratio of compound shown in formula V and aluminium chloride can for 15.08:(22~
23), such as 15.08:22.61.The temperature of the reaction can be 120~130 DEG C (such as 120~125 DEG C).The time of the reaction can
It is determined using TLC detection (methylene chloride/methanol=10/1), such as 1~3h, 3 hours.
In step 2), the molar ratio of compound shown in formula IV and L-TARTARIC ACID can be 14.6:(3~4), such as 14.6:3.6.
The temperature of the reaction can be 45~50 DEG C, and the time can be 2~4h.The solvent of the reaction can be acetone, dimethylformamide
(DMF), dimethyl sulfoxide (DMSO), acetonitrile isopolarity aprotic solvent.The L-TARTARIC ACID can be with the aqueous solution of tartaric acid
Form is added.The mass concentration of the aqueous solution of the tartaric acid concretely 0.55~0.60g/mL, such as 0.57g/mL.
The crude product of compound shown in the formula III that the method obtains after later further including to reaction in step 2) carries out essence
The step of the step of processed, the purification, is as follows: by the aqueous solution of the crude product dissolution acetone of compound shown in formula III, being added and lives
Property charcoal stirring, heat filtering, take filtrate；Acetone is added in the filtrate, through the crystallization that cools down, chemical combination shown in formula III can be obtained
Object.The mass concentration of the aqueous solution of the acetone can be 25%~75%, concretely 25%~50%, 50%~75%,
25%, 50% or 75%.The number of the purification can be 3~4 times, concretely 3 times or 4 times.
In above-mentioned preparation method, in step (1), the molar ratio of compound shown in formula III and the ammonia can be 1:(2.10
~2.15), concretely 1:2.13.The ammonia is added in the form of the aqueous solution of ammonia, the quality of the aqueous solution of the ammonia
Concentration can be 5%~10%.
In above-mentioned preparation method, in step (1), the temperature of the reaction can be 120~130 DEG C, the time can for 1~
3h。
In above-mentioned preparation method, the concrete operations in step (1) are as follows: compound shown in formula III being added to the water and is stirred
It mixes, ammonia spirit then is added and ethyl acetate, agitated and liquid separation take ethyl acetate phase；The ethyl acetate phase is through drying
With compound shown in formula II can be obtained after reduced pressure.
Above-mentioned preparation method, in step (2), the amount ratio of compound shown in formula II and the hydrogen chloride solution can be
1g:(1.5~1.6) mL, concretely 1g:1.5897mL；The molar concentration of the hydrogen chloride solution can be 3.3~3.4mol/
L, such as 3.4mol/L.
Above-mentioned preparation method, in step (2), compound shown in formula II and the organic solvent (compound shown in formula II
The organic solvent of dissolution) amount ratio can be 1g:(1.6~1.7) mL, concretely 1g:1.62mL.Organic solvent (the formula
The organic solvent of the dissolution of compound shown in II), the volume ratio of the water and the hexamethylene can be 1:(0.06~0.067):
(4.0~5.0), concretely 1:0.0617:4.76.
Above-mentioned preparation method, in step (2), the temperature of the reaction can be 60~65 DEG C, the time can for 10min~
30min。
Above-mentioned preparation method, in step (2), the method further include after the water and the hexamethylene is added
The step of 2~3h (such as 3h) is stirred at 0~5 DEG C.
The invention has the following beneficial effects:
The present invention replaces potassium carbonate in the prior art using ammonium hydroxide, and generation potassium chloride leads to finished product after can avoid solution salt
Ignition residue it is unqualified；Using hydrochloric acid aqueous isopropanol replace traditional hydrogen chloride gas, can avoid because gas dosage and
The control of rate is improper to be caused to introduce other impurity during the preparation process.In addition to this, the present invention has the further advantage that (1)
It can obtain the finished product of high chiral purity；(2) mild controllable, industrialized production preferably is reacted；(3) it is steady to be capable of providing crystal form
Fixed finished product；(4) synthetic route is shorter, and yield is preferable.
Detailed description of the invention
Fig. 1 is the process flow chart that half light green Ka Selin hydrochloride is prepared in embodiment.
Fig. 2 is the uv absorption spectra for half light green Ka Selin hydrochloride being prepared in embodiment 1, wherein Fig. 2 (A)
For uv absorption spectra (neutrality), Fig. 2 (B) is uv absorption spectra (acidity), and Fig. 2 (C) is uv absorption spectra (alkali
Property).
Fig. 3 is the infrared spectrogram for half light green Ka Selin hydrochloride being prepared in embodiment 1.
Fig. 4 is the hydrogen spectrogram for half light green Ka Selin hydrochloride being prepared in embodiment 1.
Fig. 5 is the hydrogen-hydrogen chemical shifts correlation spectrogram for half light green Ka Selin hydrochloride being prepared in embodiment 1.
Fig. 6 is the carbon-13 nmr spectra figure for half light green Ka Selin hydrochloride being prepared in embodiment 1.
Fig. 7 is the DEPT spectrogram for half light green Ka Selin hydrochloride being prepared in embodiment 1, and wherein Fig. 1 (A) is
DEPT90 ° of spectrogram, Fig. 1 (B) are DEPT135 ° of spectrogram.
Fig. 8 is the HMBC spectrogram for half light green Ka Selin hydrochloride being prepared in embodiment 1.
Fig. 9 is the hsqc spectrum figure for half light green Ka Selin hydrochloride being prepared in embodiment 1.
Figure 10 is the mass spectrogram for half light green Ka Selin hydrochloride being prepared in embodiment 1.
Figure 11 is the powder X-ray diffractogram for half light green Ka Selin hydrochloride being prepared in embodiment 1.
Figure 12 is TG, DSC spectrogram for half light green Ka Selin hydrochloride being prepared in embodiment 1.
Figure 13 is the elemental analysis report for half light green Ka Selin hydrochloride being prepared in embodiment 1.
Figure 14 is that half light green Ka Selin hydrochloride being prepared and the HPLC of marketed tablet compare spectrogram in embodiment 1.
Specific embodiment
Experimental method used in following embodiments is conventional method unless otherwise specified.
The materials, reagents and the like used in the following examples is commercially available unless otherwise specified.
Experimental method in following embodiments carries out at normal temperatures and pressures unless otherwise specified.
The chloro- N- of starting material 2- (4- chlorobenzene ethyl) propyl- 1- amine hydrochlorate (code name SM-A) as used in the following examples
Purchased from Beijing Mai Suo chemical technology Co., Ltd, other reagents are purchased from Beijing Chemical Plant unless otherwise specified.
Embodiment 1, half light green Ka Selin hydrochloride of preparation
The experiment parameter range of the present embodiment is scale up test batch, and the heating in workshop and refrigeration system error range are ± 5
DEG C, it is the parameter area value that quantity accumulation is determining through a large number of experiments.
One, preparation method
Half light green Ka Selin hydrochloride is prepared according to process flow chart shown in Fig. 1, specific step is as follows
(1) the chloro- 1- methyl -2,3 of intermediate (RS) -8-, 4,5- tetrahydro -1H-3- benzazepines (code name LCS-1, knot
Structure formula is as shown in formula IV) preparation
In 20L reaction flask, under nitrogen protection, 4050.0g (15.08mol) SM-A (1- [(2- (4- is sequentially added under stirring
Chlorphenyl) ethyl) amino] -2 cbloropropane isopropyl chloride hydrochloride, structural formula is as shown in formula V), 3015.0g (22.61mol) aluminium chloride, add
Heat to 120~125 DEG C of meltings, insulated and stirred is reacted 3 hours.TLC detection (methylene chloride/methanol=10/1) raw material has reacted
Finish.Stop heating, is cooled to 50~55 DEG C.It is slowly added to 8.1L water, after being added dropwise.In 50L reaction kettle, by reaction system
It is added to the sodium hydroxide solution of 2025ml 20%, adds 405g diatomite and 16.2L ethyl acetate, stirs 30min, liquid separation.Have
Machine is added 8.1L saturated common salt water washing × 2, liquid separation, organic addition 1.0kg anhydrous sodium sulfate drying.Filtering, filtrate 40~45
DEG C be concentrated under reduced pressure, obtain LCS-1:2861.2g.Yield: 97.0%.White powder, HPLC purity are 99.754%.
Structure verification data are as follows:1HNMR(500MHz,DMSO),δ(ppm):7.282-7.079(m,3H),3.079-
2.991(m,1H),2.888-2.780(m,3H),2.752-2.574(m,3H),1.236-1.222(s,3H).LCS-1 mass spectrum is
196 (M+1), actual measurement molecular weight are 195.69.Verified structure is correct.
(2) the chloro- 1- methyl -2,3,4,5- tetrahydro -1H-3- benzazepine of intermediate (R) -8--L-TARTARIC ACID salt (code name
For LCS-2, structural formula is as shown in formula III) preparation
In 20L reaction flask, 2860.0g (14.6mol) LCS-1 being prepared in step (1) is added under stirring
In 10.3L acetone, 50 DEG C are warming up to, starts to be slowly added dropwise and dissolves the water-soluble of 548.4g (3.6mol) L-TARTARIC ACID with 960ml water
Liquid, temperature control is at 45~50 DEG C during dropwise addition.
It is added dropwise, is stirred to react 3h.2860ml acetone is added, cools to 25~30 DEG C, temperature control is stirred at 25~30 DEG C
Crystallization 1h.0~5 DEG C is cooled to again, is stirred for crystallization 2h.It is filtered under low temperature, filter cake is eluted with 2860mL acetone.Filter cake 40~45
DEG C forced air drying.Obtain LCS-2:1666.7g.
Above-mentioned obtained LCS-2 crude product is refined three times, is operated as follows:
Successively 6.7L water, 6.7L acetone and 1666.7g LCS-2 crude product are added in 20L reaction flask under stirring, heated up
To 70~75 DEG C, system is clarified.Add 106.0g active carbon, stirs 30min, heat filtering.Filtrate is transferred in 50L reaction kettle, will
10L acetone is added in filtrate.25~30 DEG C are cooled to, stirring and crystallizing 1h.0~5 DEG C is cooled to, stirring and crystallizing 2h.Filtering, filter
Cake is eluted with 1.6L acetone.40~45 DEG C of forced air dryings, obtain a refined product: 975.0g.
Successively 3.9L water, 3.9L acetone and LCS-2 a refined product 975.0g are added in 20L reaction flask, stirring rises
Temperature to 70~75 DEG C, clarify by system.Add 62.4g active carbon, stirs 30min, heat filtering.Filtrate is transferred in 20L reaction flask.It will
5850ml acetone is added in filtrate.25~30 DEG C are cooled to, stirring and crystallizing 1h.0~5 DEG C is cooled to, stirring and crystallizing 2h.It crosses
Filter, filter cake are eluted with 970ml acetone.40~45 DEG C of forced air dryings, obtain secondary fine product: 810.2g.
Successively 3240ml water, 3240ml acetone and LCS-2 secondary fine product 810.2g are added in 20L reaction flask, stirred
It mixes and is warming up to 70~75 DEG C, system clarification.Add 51.8g active carbon, stirs 30min, heat filtering.Filtrate is transferred to 20L reaction flask
In.4860ml acetone is added in filtrate, cools to 25~30 DEG C, stirring and crystallizing 1h.0~5 DEG C is cooled to, stirring and crystallizing
2h, filtering, filter cake are eluted with 800ml acetone.40~45 DEG C of forced air dryings, obtain LCS-2:706.5g.Total recovery: 17.9%.
White powder, HPLC purity are 99.971%, optical purity 100%.
Structure verification data are as follows:1HNMR(500MHz,DMSO),δ(ppm):7.198-7.155(m,6H),3.861-
3.859(d,2H),3.253-3.195(m,2H),3.054-2.918(m,6H),2.961-2.724(m,6H),1.299-1.284
(m,6H).LCS-2 mass spectrum is 196 (M+1), and actual measurement molecular weight is 195.69.Verified structure is correct.
(3) the chloro- 1- methyl -2,3 of intermediate (R) -8-, 4,5- tetrahydro -1H-3- benzazepines (code name LCS-3, knot
Structure formula is as shown in formula II) preparation
In 20L reaction flask, the LCS-2 that 706.0g step (2) is prepared is added in 3530ml water, stirring.It is added
1060ml5% ammonia spirit and 5200ml ethyl acetate stir 30min.Liquid separation, water phase add 2000ml ethyl acetate to wash, point
Liquid.Merge organic addition water washing 3500ml × 3, liquid separation.The dry 3h of organic addition 1.0kg anhydrous sodium sulfate.Filtering, filtrate 40
~45 DEG C of reduced pressures, obtain the grease LCS-3 of theoretical amount.
Structure verification data are as follows:1HNMR(500MHz,DMSO),δ(ppm):7.142-7.071(m,3H),3.030-
2.975(d,1H),2.888-2.798(m,3H),2.581-2.503(m,3H),1.263-1.217(s,3H).LCS-3 mass spectrum is
196 (M+1), actual measurement molecular weight are 195.69.Verified structure is correct.
(4) the chloro- 1- methyl -2,3,4,5- tetrahydro -1H-3- benzazepine hydrochloride semihydrate of target product (R) -8-
The preparation of (code name LCS, shown in structural formula I)
Under nitrogen protection, 745ml isopropanol is added to the LCS-3 being prepared in step (3) in 10L reaction flask
In, stirring and dissolving.724ml 3.4mol/L hydrochloric acid aqueous isopropanol (compound shown in formula II and hydrochloric acid aqueous isopropanol is added dropwise
Amount ratio is 1g:1.59mL), after being added dropwise, stirring is warming up to 60~65 DEG C, and system clarification is stirred 10 minutes.Add 46ml water
With 3060ml hexamethylene (volume ratio of isopropanol, water and hexamethylene is 1:0.0617:4.76).After charging, 20 are cooled to
~25 DEG C.It is cooled back to 0~5 DEG C, stirs 3h.Filtering, filter cake are eluted with hexamethylene.35~40 DEG C of vacuum drying, obtain LCS:
510.1g, total recovery: 81.1%.HPLC purity is 99.952%, optical purity 100%.
The structural verification test of LCS
1, ultra-violet absorption spectrum
Take the above-mentioned hydrochloric acid lorcaserin being prepared accurate water, the 0.1M hydrochloric acid solution for being configured to 12.5 μ g/mL respectively
With the sodium hydroxide solution of 0.1M.By spectrophotometry (2010 editions two annex IVA of Chinese Pharmacopoeia) in the wave of 190~400nm
Scanning in long range.Ultra-violet absorption spectrum is as shown in Fig. 2, test result is consistent with the structure of hydrochloric acid lorcaserin.
2, infrared absorption spectrum
It is infrared with polystyrene film using U.S.'s PerkinElmer Frontier Fourier transformation infrared spectrometer
Spectral absorption peak is corrected (with reference to two IV C of annex of Chinese Pharmacopoeia version in 2010), using KBr pressed disc method instrument wave number.
Infrared spectroscopy is as shown in figure 3, test result is consistent with the structure of hydrochloric acid lorcaserin.
3, nuclear magnetic resonance map
Using Bruker 500M type high score rate superconduction nuclear magnetic resonance spectrometer, test solvent DMSO-d6.Nuclear-magnetism spectrum is shown in figure
4- Fig. 9, wherein Fig. 4 is hydrogen spectrum, and Fig. 5 is hydrogen-hydrogen chemical shifts Correlated Spectroscopy, and Fig. 6 is carbon-13 nmr spectra, and Fig. 7 is DEPT spectrum, figure
8 compose for HMBC, and Fig. 9 is hsqc spectrum, and test result is consistent with the structure of hydrochloric acid lorcaserin.
4, mass spectrum
Using Shimadzu LC-MS 2010EV System liquid chromatography mass combined instrument；Test condition: electron spray electricity
From source (ESI), positive ion detection, acetonitrile-water (80: 20).Mass spectrogram is as shown in Figure 10, as a result with the molecule of hydrochloric acid lorcaserin
Structure is consistent.
5, powder x-ray diffraction is composed
Using X-ray polycrystal powder diffractometer (Rigaku)；Determination condition: 25 DEG C of temperature, relative humidity 50%, copper
Target.Powder X-ray diffractogram is shown in Figure 11, the 2 θ angles of diffraction 13.615,14.765,15.397,15.738,16.780,
At 19.078, there is apparent characteristic peak.Chromatogram characteristic with application No. is 200580043392.9, entitled " (R) -8-
Institute in the crystal form of chloro- 1- methyl -2,3,4,5- tetrahydro -1H-3- benzazepine hydrochloride " application for a patent for invention Publication Specification
The 2 θ diffraction angular data of feature of the powder x-ray diffraction of disclosed III crystal form is almost consistent, shows that the present invention is prepared and obtains
To green card color woods hydrochloride be really III crystal form (semihydrate).
6, heat analysis
Using the Q600 type DSC+TGA combined instrument of TA company, the U.S.；Test condition: N2, 10 DEG C of heating rate is per minute.
TG, DSC spectrogram spectrum are shown in Figure 12.Chromatogram characteristic with application No. is 200580043392.9, entitled " the chloro- 1- first of (R) -8-
Disclosed in the crystal form of base -2,3,4,5- tetrahydro -1H-3- benzazepine hydrochloride " application for a patent for invention Publication Specification
Unanimously, show that the preparation-obtained green card color woods hydrochloride of the present invention is III crystal form (semihydrate) really.
7, elemental analysis
Using III type elemental analyser (Germany) of Elementar VARIO EL；Method: organic compound C, H, N content are surveyed
It is fixed；Elemental analysis report is shown in Figure 13.The result shows that hydrochloric acid lorcaserin test sample C, H and N content actual measurement average value with
Calculated value is respectively less than 0.3%.The molecular formula that compound can be primarily determined by elemental analysis and mass spectrum is C11H14ClN·
HCl·0.5H2O。
8, the determination of absolute configuration
Hydrochloric acid lorcaserin is developed jointly by Arena Pharmaceuticals and Eisai, U.S. FDA approval in 2012
U.S.'s listing.Reference substance I (R configuration) is the marketed tablet of the said firm, and reference substance II (S configurational isomer) is made as follows
It is standby to obtain: by racemization lorcaserin L-TARTARIC ACID in acetone/water system at salt after by way of recrystallization, separate R type
With S type isomers, S configurational isomer is then enriched in the mother liquor of recrystallization.
Under the conditions of controlling the HPLC of optical purity, by reference substance I, the hydrochloric acid lorcaserin of the invention synthesized, reference substance
II is compared, as a result, it has been found that the present invention half light green Ka Selin hydrochloride being prepared and the active constituent of marketed tablet exist
Go out peak position in HPLC to be completely coincident, S configurational isomer good can also separate, as shown in figure 14.This illustrates preparation of the present invention
The absolute configuration of the light green Ka Selin hydrochloride of half obtained is identical as commercially available product, is R configuration.
Three, impurity
1, impurity situation analysis
Issuable organic impurities during using the method for the present invention half light green Ka Selin hydrochloride of preparation, is shown in Table 1.
Table 1, organic impurities situation analysis table
2, the preparation of impurity
(1) preparation of impurity A
After SM-A carries out cyclization, the carbon atom being connected with methyl forms chiral centre, and there are two optical isomers.It is logical
It crosses after being split with L-TARTARIC ACID, obtains the product of purer R configuration, there is a small amount of S configuration in product, by recrystallization
Effectively remove.The LCS-1 for containing more S configuration in remaining mother liquor arrives enantiomter impurity A at salt by acid
(such as following formula).
Concrete operations are as follows: LCS-2 mother liquor being concentrated to dryness, 16g solid is obtained, 10g this solid, 50ml water are added
Enter into reaction flask, 5% ammonium hydroxide of 15ml, 80ml ethyl acetate is added in stirring, stirs 30min, pH value > 10, liquid separation, water phase add
The extraction of 30ml ethyl acetate, merges organic phase, and anhydrous sodium sulfate dries, filters after organic water washing of addition 50ml × 3, and filtrate subtracts
Pressure concentration, obtaining dope, 7.2g dope is added in reaction flask by: 7.2g, is added in 30ml acetone, is heated to T
It is interior=50 DEG C, the 1.2gD- tartaric acid solution dissolved with 2ml water is added dropwise, process is added dropwise at 45~50 DEG C in temperature control during dropwise addition
In have solid precipitation, be added dropwise, system is gradually clarified, insulated and stirred 3h, be added acetone 7ml, start cooling dropped in 1.5h
Temperature is to 25~30 DEG C, insulated and stirred 1h, then cools to 0~5 DEG C, insulated and stirred 1h, and filtering, filter cake is eluted with a small amount of acetone, filters
40~45 DEG C of forced air dryings of cake, obtain 3.2g white solid, and 3.2g white solid, 20ml water are added in reaction flask, stirring
Lower 5% ammonium hydroxide of addition 4.8ml, 30ml ethyl acetate stir 30min, and pH value is greater than 10, and liquid separation, water phase adds 10ml ethyl acetate
Extraction merges organic phase, adds 5g anhydrous sodium sulfate to dry, filter after organic water agitator treating of addition 20ml × 3, filtrate decompression is dense
Contracting, obtains dope: 2.3g；Add 3.4ml isopropanol to dissolve 2.3g dope, it is molten to stir lower dropwise addition 3.3ml hydrochloric acid isopropanol
Liquid after being added dropwise, is warming up to 60~65 DEG C, and dissolution adds water 0.2ml and 14ml hexamethylene, cools to 0~5 DEG C, insulated and stirred
2h, filtering, 35~40 DEG C of filter cake vacuum drying obtain white solid impurity A: 2.4g, total recovery: 16.8%
Structure verification data are as follows: 1HNMR (500MHz, DMSO), and δ (ppm): 9.440~9.224 (br, 2H), 7.273
~7.226 (d, 3H), 3.445 (d, 1H), 3.312~3.286 (s, 3H), 3.046~3.000 (s, 1H), 2.904 (s, 2H),
1.356~1.341 (s, 3H).Impurity A mass spectrum is 196 (M+1), and actual measurement molecular weight is 195.69.Verified structure is correct.
(2) preparation of impurity B, C, D
It is might have during preparing starting material in the presence of neighbour S1 and S1, is carrying out docking reaction with isopropanolamine
Afterwards, it then carries out cyclization reaction impurity B, C, D can be obtained.It reacts as follows:
The preparation of impurity B:
Concrete operations are as follows: 20g o-chlorobenzene acetic acid (adjacent S1) being added in 200ml tetrahydrofuran, stirring cools to 0
DEG C, 8.9g Lithium Aluminium Hydride is added portionwise, finishes, is warming up to 25~30 DEG C of reactions, water 300ml, dichloromethane are added after completion of the reaction
Alkane 400ml, liquid separation, organic 30~35 DEG C of reduced pressures after being added to the drying of 20g anhydrous sodium sulfate obtain light yellow oil
(adjacent S1-1): 18.3g；Under ice bath, toward equipped with phosphorus tribromide is added dropwise in S1-1 bottles of neighbour, temperature control is at 0~10 DEG C during dropwise addition, drop
Insulated and stirred 10min, has white cigarette generation, is warming up to 75~80 DEG C, insulated and stirred 2h after finishing, and 30ml saturation is added after completion of the reaction
Sodium bicarbonate solution, 200ml ethyl acetate, stir 20min, and liquid separation is organic to be added to 40~45 after 20g anhydrous sodium sulfate is dried
DEG C be concentrated under reduced pressure, obtain yellow liquid (adjacent S2): 22.4g yield: 87.0%
22.6g isopropanolamine is added in reaction flask, is warming up to 80~85 DEG C, temperature control is slowly added at 80~85 DEG C
22g neighbour S2, drop finishes, and after insulation reaction 4h, cools to 45~50 DEG C, 80ml water and 160ml toluene is added, stir 30min, point
Liquid, water phase are extracted with toluene 40ml × 2, are concentrated under reduced pressure after merging organic phase, are obtained faint yellow solid, faint yellow solid is added
Into 16ml toluene and 160ml hexamethylene, it is warming up to reflux, 0~5 DEG C is cooled to after stirring 30min, is stirred for 1h, is filtered, filter
Cake is eluted with 20ml hexamethylene, and 40~45 DEG C of solid vacuum drying obtain white solid (adjacent S3): 15.4g.Yield: 71.9%
15g neighbour S3, toluene and DMF are added in 500ml reaction flask, 55~60 DEG C of dissolution clarifications are warming up to, temperature control exists
8.8ml thionyl chloride is added dropwise at 55~60 DEG C, after insulation reaction 3h, cools to 25~30 DEG C, filtering, filter cake adds 30ml toluene to drench
It is added to after washing in 100ml isopropanol and 5ml water, is warming up to reflux, 25~30 DEG C of stirrings are cooled to after insulated and stirred 30min
30min, then 0~5 DEG C of stirring 30min is cooled to, it filters, filter cake is eluted with 10ml isopropanol, and 40~45 DEG C of vacuum drying obtain
Off-white powder (adjacent S4): 7.6g.Yield: 50.0%
Adjacent S4 and alchlor are added in reaction flask, are warming up to 120~125 DEG C, is cooled in T after being stirred to react 3h
=55 DEG C, reaction system is added in 3.5ml20% sodium hydroxide solution after slowly adding water 14ml, drop to finish, then plus 50ml second
Acetoacetic ester stirs the organic addition 20ml saturated common salt water washing of liquid separation, and organic phase reduced vacuum is dry, obtains dope: 5.0g,
Dope 7.3ml isopropanol is dissolved, lower dropwise addition 7.1ml hydrochloric acid aqueous isopropanol is stirred and is warming up to 60~65 after drop finishes
DEG C, dissolution adds water 0.5ml and 30ml hexamethylene, cools to 0~5 DEG C, filter after insulated and stirred 2h, 35~40 DEG C of vacuum of filter cake
It is dry, obtain white solid (impurity B) 5.1g, yield: 84.3%
Structure verification data are as follows:1HNMR (500MHz, DMSO), δ (ppm): 9.529~9.136 (br, 2H), 7.422
~7.390 (t, 1H), 7.287~7.167 (m, 2H), 3.521 (s, 1H), 3.475~3.232 (m, 4H), 2.920~2.860
(dd, 2H), 1.367~1.323 (dd, 3H).Impurity B mass spectrum is 196 (M+1), and actual measurement molecular weight is 195.69.Verified structure
Correctly.
The preparation of impurity C, D:
Concrete operations are as follows: successively chlorobenzene acetic acid between 20g are added in 200ml tetrahydrofuran, stirring cools to 0 DEG C,
Start that 8.9g Lithium Aluminium Hydride is added portionwise, 25~30 DEG C are warming up to after charging, water 300ml, dichloromethane is added after reacting 4h
Alkane 400ml liquid separation, it is organic be added to 20g anhydrous sodium sulfate it is dry after 30~35 DEG C of reduced pressures, obtain light yellow oil (
S1-1): 18.3g；Under ice bath, phosphorus tribromide is added dropwise in S1-1 between being equipped with, at 0~10 DEG C, drop finishes temperature control during dropwise addition, protects
It is warming up to 75~80 DEG C after temperature stirring 10min, 30ml saturated sodium bicarbonate solution, 200ml acetic acid second is added after insulated and stirred 2h
Ester, stirs 20min liquid separation, and 40~45 DEG C of filtrate decompression concentrations of organic phase obtain yellow liquid (S2): 22.4g.Yield:
87.0%.
22.6g isopropanolamine is added in reaction flask, is warming up to 80~85 DEG C, is slowly added to S2 between 22g, process is added dropwise
Middle temperature control is at 80~85 DEG C, and drop finishes, insulation reaction 4h, cools to 45~50 DEG C, and 80ml water and 160ml toluene, stirring is added
30min, liquid separation, water phase are extracted with toluene 40ml × 2, are concentrated under reduced pressure after merging organic phase, are obtained faint yellow solid, yellow is consolidated
Body is added in 16ml toluene and 160ml hexamethylene, is warming up to reflux, and insulated and stirred 30min cools to 0~5 DEG C, is stirred for
1h, filtering, filter cake are eluted with 20ml hexamethylene, and 40~45 DEG C of solid vacuum drying obtain white solid (S3): 15.4g.It receives
Rate: 71.9%.
S3, toluene and DMF are added in 500ml reaction flask by between, are warming up to 55~60 DEG C, and 8.8ml is added dropwise in dissolution clarification
Thionyl chloride, temperature control drips insulated and stirred after finishing and reacts 3h, cool to 25~30 DEG C, filter at 55~60 DEG C during dropwise addition, filter
Cake is added in 100ml isopropanol and 5ml water after being eluted with 30ml toluene, is warming up to reflux, insulated and stirred 30min is cooled to
25~30 DEG C of stirring 30min, then 0~5 DEG C of stirring 30min is cooled to, it filtering, filter cake is eluted with 10ml isopropanol, and 40~45 DEG C
Vacuum drying, obtains off-white powder (S4): 7.6g.Yield: 50.0%.
S4 and alchlor are added in reaction flask by between, are warming up to 120~125 DEG C, are cooled in T after being stirred to react 3h
=55 DEG C, slowly adds water 14ml, reaction system is added in 3.5ml20% sodium hydroxide solution, 50ml ethyl acetate is added, point
Liquid, organic addition 20ml saturated common salt water washing, organic phase reduced vacuum is dry, obtains dope: 5.0g, by dope column layer
Analysis respectively obtains impurity C free alkali: 2.0g after purification, impurity D free alkali: 2.1g, then uses 3.4mol/L hydrochloric acid isopropanol respectively
Solution, at salt, respectively obtains impurity C:2.1g, impurity D:2.2g at 60~65 DEG C.
Impurity C-structure verify data is as follows:1HNMR (500MHz, DMSO), δ (ppm): 9.424~9.031 (br, 2H),
7.386~7.354 (m, 1H), 7.317~7.272 (dd, 2H), 3.535 (s, 1H), 3.463~3.211 (m, 3H), 3.071~
3.005 (m, 1H), 2.964~2.865 (d, 2H), 1.356~1.333 (m, 3H).Impurity C mass spectrum is 196 (M+1), actual measurement point
Son amount is 195.69.Verified structure is correct.
Impurity D structure verification data are as follows:1HNMR (500MHz, DMSO), δ (ppm): 9.341~8.855 (br, 2H),
7.386~7.354 (m, 1H), 7.214~7.166 (m, 2H), 3.930~3.914 (m, 1H), 3.481~3.210 (m, 4H),
3.027~2.949 (m, 2H), 3.071~3.005 (m, 1H), 1.333~1.317 (m, 1H).Impurity D mass spectrum is 196 (M+1),
Surveying molecular weight is 195.69.Verified structure is correct.
(3) preparation of impurity F, G
The present invention prepares impurity F using SM-A and LCS-1 condensation.
Concrete operations are as follows: 40g 4-Chlorophenylacetic acid being added to 400ml tetrahydrofuran, dissolution is stirred at room temperature；It is added portionwise
Lithium Aluminium Hydride, temperature control is at 25~30 DEG C, after insulated and stirred reacts 20h, slowly adds water 200ml, is added dropwise, adds ethyl acetate
400ml stirs 30min, and liquid separation, after organic addition 200ml saturated common salt water washing plus 20g anhydrous sodium sulfate dries, filters, and 40
~45 DEG C of filtrate decompression concentrations, obtain grease (S2) 36.7g；S2 is added in reaction flask, 0~5 DEG C is cooled under ice water,
Phosphorus tribromide is slowly added dropwise, temperature control is added dropwise at 0~5 DEG C during dropwise addition, it is warming up to 25~30 DEG C, after insulated and stirred 3h,
Add water 80ml, stir 30min, liquid separation, water phase adds methylene chloride the extraction of 100ml × 2, is concentrated under reduced pressure, obtains after merging organic phase
Grease (S3): 48.8g.Yield: 94.9%.
Isopropanolamine is added in reaction flask, is warming up to 80~85 DEG C, is slowly added to S3, temperature control is 80 during dropwise addition
~85 DEG C, after insulation reaction 4h, 45~50 DEG C are cooled to, 80ml water and 160ml toluene is added, stirs 30min liquid separation, water phase adds
The extraction of the toluene of 40ml × 2, is concentrated under reduced pressure after merging organic phase, obtains faint yellow solid, faint yellow solid is added to 16ml first
In benzene and 160ml hexamethylene, 0~5 DEG C is cooled to after being warming up to return stirring 30min, is stirred for 1h, filtered, filter cake 20ml
Hexamethylene elution, 40~45 DEG C of solid vacuum drying, obtains white solid (S4): 27.2g.Yield: 69.8%.
At room temperature, 15g S4,150mlDMF, 27.2g DIPEA are added in reaction flask, are added after stirring and dissolving
13.7gSM-A is warming up to 70~75 DEG C, 25~30 DEG C is cooled to after insulation reaction 5h, reaction system is concentrated, obtains oily
Object, column chromatographic purifying obtain the free alkali of impurity F: 6.1g, and 10ml 3.4mol/L hydrochloric acid aqueous isopropanol is added to impurity F
Free alkali in, stirring and dissolving cools to 0~5 DEG C, stirs 1h, filtering, and it is solid to obtain white for 35~40 DEG C of filter cake vacuum drying
Body impurity F: 5.5g.Yield: 18.3%.
Structure verification data are as follows:1HNMR (500MHz, DMSO), δ (ppm): 11.359,9.646 (br, 2H), 7.423
~7.237 (m, 7H), 4.031 (m, 1H), 3.814~3.775 (m, 2H), 3.658~3.553 (m, 4H), 3.483~3.259
(m, 3H), 3.184~2.868 (m, 4H), 1.403 (s, 6H).Impurity F mass spectrum is 391 (M+1), and actual measurement molecular weight is 390.16.
Verified structure is correct.
Impurity G is prepared for using SM-A and S4 condensation.
Concrete operations are as follows: at room temperature, by 12g S4,120ml n,N-Dimethylformamide, 30ml diisopropylethylamine
It is added in reaction flask, 15gSM-A is added after stirring and dissolving, be warming up to 70~75 DEG C, cool to 25~30 after insulation reaction 5h
DEG C, reaction system is concentrated, obtains grease, after grease column chromatographic purifying, obtains impurity G:5.1g, yield: 22.3%.
Structure verification data are as follows:1HNMR (500MHz, DMSO), δ (ppm): 7.318~7.198 (d, 8H), about 4.3
(br, 1H), 4.234~4.208 (s, 1H), 3.619~3.549 (m, 1H), 2.797~2.752 (m, 1H), 2.693~2.610
(m, 4H), 2.596~2.525 (m, 4H), 2.383~2.256 (m, 4H), 0.961~0.838 (m, 6H).Impurity G mass spectrum is
409 (M+1), actual measurement molecular weight are 408.17.Verified structure is correct.
(4) preparation of impurity E
The present invention is made using bromo S1, i.e. 4- bromo-acid as raw material through amidation, reduction, chloro and cyclization reaction
Impurity E.
Concrete operations are as follows: will be added in 200ml tetrahydrofuran to bromo-acid, stirring cools to after 0 DEG C to be added in batches
Enter Lithium Aluminium Hydride, charging terminates, and water 300ml is added after being warming up to 25~30 DEG C of reaction 2h, methylene chloride 400ml liquid separation is organic
It is added to 20g anhydrous sodium sulfate to dry, filter, 30~35 DEG C of filtrate reduced pressures obtain light yellow oil (bromo S1-1):
18.7g, under ice bath, toward equipped with phosphorus tribromide is added dropwise in bromo S1-1, temperature control is added dropwise at 0~10 DEG C during dropwise addition, protects
Temperature stirring 10min, has white cigarette generation, stirs, and is warming up to 75~80 DEG C, and it is molten that 30ml saturated sodium bicarbonate is added after insulated and stirred 2h
Liquid, 200ml ethyl acetate, stir 20min liquid separation, and 40~45 DEG C of filtrate decompression concentrations of organic phase obtain yellow liquid (bromo
S2): 22.1g.Yield: 90.0%.
18.8g isopropanolamine is added in reaction flask, is warming up to 80~85 DEG C, 22g bromo S2 is slowly added to, was added dropwise
Temperature control is added dropwise at 80~85 DEG C in journey, and 45~50 DEG C are cooled to after insulation reaction 4h, and 80ml water and 160ml toluene is added,
30min liquid separation is stirred, the toluene of 40ml × 2 is added in water phase, and liquid separation is concentrated under reduced pressure after merging organic phase, obtains faint yellow solid, will
Faint yellow solid is added in 16ml toluene and 160ml hexamethylene, is warming up to reflux, and insulated and stirred 30min cools to 0~5
DEG C, it is stirred for 1h, is filtered, filter cake is eluted with 20ml hexamethylene, and 40~45 DEG C of solid vacuum drying obtain white solid (bromo
S3): 15.6g.Yield: 72.5%.
Bromo S3, toluene and DMF are added in 500ml reaction flask, are warming up to 55~60 DEG C, dissolution clarification is added dropwise
8.8ml thionyl chloride, temperature control is added dropwise at 55~60 DEG C during dropwise addition, cools to 25~30 after insulated and stirred reaction 3h
DEG C, filtering, filter cake adds 30ml toluene to elute, and filter cake is added in 100ml isopropanol and 5ml water, is warming up to reflux, heat preservation is stirred
30min is mixed, is cooled to 25~30 DEG C, stirs 30min, then 0~5 DEG C is cooled to, 30min is stirred, is filtered, filter cake is different with 10ml
Propyl alcohol elution, 40~45 DEG C of vacuum drying, obtains off-white powder (bromo S4): 7.6g, yield: 50.0%.
Bromo S4 and alchlor are added in reaction flask, are warming up to 120~125 DEG C, is cooled down after being stirred to react 3h, T
It is interior=55 DEG C, slowly add water 14ml, is added dropwise, reaction system is added in 3.5ml20% sodium hydroxide solution
Add 50ml ethyl acetate, stirring is layered, organic addition 20ml saturated common salt water washing, and organic phase reduced vacuum is dry
Dry, obtaining dope: 5.0g dissolves dope plus 7.3ml isopropanol, stirs lower dropwise addition 7.1ml hydrochloric acid aqueous isopropanol, drop
After adding, 60~65 DEG C are warming up to, dissolution adds water 0.5ml and 30ml hexamethylene, cools to 0~5 DEG C, insulated and stirred 2h, mistake
Filter, 35~40 DEG C of filter cake vacuum drying, obtains white solid impurity E: 5.1g, yield: 84.3%.
Structure verification data are as follows:1HNMR(500MHz,DMSO),δ(ppm):9.533(s,1H),9.130(s,1H),
7.444~7.164 (m, 3H), 3.472~3.395 (m, 1H), 3.247~3.163 (m, 3H), 3.047~2.989 (m, 1H),
2.989 (m, 2H), 1.352~1.327 (m, 3H).Impurity E mass spectrum is 240 (M+1), and actual measurement molecular weight is 239.03.It is verified
Structure is correct.
3, in relation to the detection of substance in preparation process
(1) in relation to the detection of substance in LCS-1
Detection method: referring to HPLC method (two V D of annex of Chinese Pharmacopoeia version in 2010), chromatographic condition is as follows: chromatographic column:
Octadecylsilane chemically bonded silica is filler (Agilent Zorbax Eclipse Plus C18250 × 4.6mm, 5 μm)；
Mobile phase: A phase: water-acetonitrile-triethylamine (90:10:0.2) (with phosphorus acid for adjusting pH value to 3.0)；B phase: water-acetonitrile-triethylamine
(20:80:0.2) (with phosphorus acid for adjusting pH value to 3.0)；Detector: UV detector；Detection wavelength: 220nm；Column temperature: 40 DEG C；Into
Sample volume: 20 μ l；Flow velocity: 1.0ml/min；Solvent: mobile phase A；Number of theoretical plate is based on the peak hydrochloric acid lorcaserin intermediate LCS-1
It calculates and is not less than 2000.
The gradient elution of table 2, LCS-1
Testing result: total impurities 0.246%.
(2) in relation to the detection of substance in LCS-2
Detection method: in LSC-1 in relation to the detection method of substance.
Testing result: single contaminant 0.012%, total impurities 0.050%.
(3) in relation to the detection of substance in LSC
Detection method: in LSC-1 in relation to the detection method of substance.
Testing result: the content of impurity E is 0.010%, single contaminant 0.013%, total impurities 0.048%；Impurity A and miscellaneous
Matter D is not detected.
Comparative example 1, half light green Ka Selin hydrochloride of preparation
Half light green Ka Selin hydrochloride is prepared in accordance with the following steps:
(1) the chloro- 1- methyl -2,3 of intermediate (RS) -8-, 4,5- tetrahydro -1H-3- benzazepines (code name LCS-1, knot
Structure formula is as shown in formula IV) preparation
The specific steps are the same as those in embodiment 1.
(2) the chloro- 1- methyl -2,3,4,5- tetrahydro -1H-3- benzazepine of intermediate (R) -8--L-TARTARIC ACID salt (code name
For LCS-2, structural formula is as shown in formula III) preparation
The specific steps are the same as those in embodiment 1.
(3) the chloro- 1- methyl -2,3 of intermediate (R) -8-, 4,5- tetrahydro -1H-3- benzazepines (code name LCS-3, knot
Structure formula is as shown in formula II) preparation
Concrete operations are as follows: being packed into partly equipped in the reactor of overhead type stirrer and helium entrance in a designated order
The chloro- 1- methyl -2,3 of tartaric acid 8-, 4,5- tetrahydro -1H-3- benzazepines (1.0Kg, containing 7.5wt% water, 1.71mol,
0.5 equivalent), potassium carbonate (0.508Kg, 3.68mol, 1.076 equivalent), ethyl acetate (2.68Kg) and pure water (2.68Kg).?
20~25 degree stirring gained mixture 30-40 minutes lower, then separates 0.5-1 hours each phase.Lower layer mutually drains at waste
Reason.Pure water (2.68Kg) is added into reactor, and is vigorously stirred gained mixture 10-20 minutes.Made each phase through 1-1.5 hours
Separation.Lower layer mutually drains into waste processing.Reactor content temperature be 40-45 degree under, in the pressure for being down to 46 supports from 153 supports
Pass through vacuum distillation removal solvent under power.Residue is cooled down to 20-25 degree.It is packed into ethyl acetate (3.81Kg) into reactor,
And if also dissolving bottoms in day.Being analyzed by Ka Feixue confirms that the water content of acquired solution is less than 0.8%wt.%.Through
Fine filter filtering solution.Being analyzed with previously passed Ka Feixue confirms that water content is less than the ethyl acetate of 0.05%wt.%
(2.33Kg) passes through filter clearance response device, and combined ethyl acetate is stand-by.
(4) the chloro- 1- methyl -2,3,4,5- tetrahydro -1H-3- benzazepine hydrochloride semihydrate of target product (R) -8-
The preparation of (code name LCS)
By the LSC-3 being prepared in step (3) first in methylene chloride, methyl tertiary butyl ether(MTBE) at salt, it is concentrated to get salt
Hydrochlorate.At semihydrate in isopropanol, water and hexamethylene system.Concrete operations are as follows: by chloro- methyl -2 1- (R) -8-,
3,4,5- tetrahydro -1H-3- benzazepine unhindered aminas (2.2g), 30ml methylene chloride and 17.4ml are in methyl tertiary butyl ether(MTBE)
1M HCl is added in a clean, dry 250ml round-bottomed flask.Mixture 5min is stirred at room temperature.Decompression is lower to be removed
Solvent obtains white solid, i.e. HCl salt.Salt is re-dissolved in methylene chloride (30ml) and adds the 1M of other 1.74ml
HCl and solution is stirred at room temperature again 5 minutes.Decompression is lower to remove solvent, obtains the required chloro- 1- methyl-of (R) -8-
2,3,4,5- tetrahydro -1H-3- benzazepine HCl salts.Salt obtained above first is handled with isopropanol, gained mixture is heated
To 60 degree, clear solution is obtained.After temperature required by reaching, purified water is added, then adds thiacyclohexane, this is added twice
It is to be carried out under 60 degree to 40 degree.After be slowly stirred through 2 hours solution made to be cooled to 20 degree to 25 degree.After sample crystallization,
Suspension is cooled to 0 degree to 5 degree, and in 0~5 degree of insulated and stirred 3h.It filters, 35~45 degree of lower vacuum drying are made (R)-
The chloro- 1- methyl -2,3 of 8-, 4,5- tetrahydro -1H-3- benzazepine HCl salt semihydrates.
When preparing half water lorcaserin hydrochloride using the above method, inorganic salts KCl ignition residue is far more than for 0.28%
0.1% limit, ignition residue are unqualified.The yield of the light green Ka Selin hydrochloride of half be prepared is 71.8%, and purity is
99.216%, largest single impurity 0.023%.Although after carrying out into salt with methylene chloride, methyl tertiary butyl ether(MTBE), then carrying out turning brilliant work
Skill does not change significantly substantially in relation to substance and optical purity.It is titrated by moisture, discovery contains half of crystallization water, obtains
Qualified LCS.But compared with Example 1, the step operation is more complex, while yield is relatively low, has apparent defect (to implement
The yield of example 1: 81.1%, HPLC purity are 99.952%, optical purity 100%.)
Embodiment 2, half light green Ka Selin hydrochloride of preparation
Half light green Ka Selin hydrochloride is prepared according to the step in embodiment 1, only by the concentration of ammonia spirit in step (3)
Replaced with for 10% (molar ratio of LSC-2 and ammonia is same as Example 1), the HPLC purity of gained final product is 99.066%.
Embodiment 3, half light green Ka Selin hydrochloride of preparation
Half light green Ka Selin hydrochloride is prepared according to the step in embodiment 1, isopropanol in step (4) is only replaced with 1,
4- dioxane, the HPLC purity of gained final product are 99.116%.
Embodiment 4, half light green Ka Selin hydrochloride of preparation
(1) number is refined
Half light green Ka Selin hydrochloride is prepared according to the step in embodiment 1, only distinguishes the purification number in step (2)
It replaces with 0 time, 1 time, 2 times and 4 times, the results are shown in Table 1.
(2) concentration of aqueous acetone solution used in
Half light green Ka Selin hydrochloride is prepared according to step in embodiment 1, only replaces with the concentration of aqueous acetone solution
25%, 75%, the yield of gained LSC-2 is respectively 42%, 44%.
Claims (7)
1. the preparation method of compound shown in formula I, includes the following steps:
(1) compound shown in formula III reacts to obtain compound shown in formula II with ammonia；
(2) under nitrogen protection, compound shown in formula II is dissolved in organic solvent, the chlorination that solvent is organic solvent is added
Hydrogen solution carries out salt-forming reaction, and water is then added and hexamethylene forms semihydrate, compound shown in formula I can be obtained；It is described
Organic solvent is isopropanol or 1,4- dioxane.
2. preparation method according to claim 1, it is characterised in that: in step (1), compound shown in formula III and the ammonia
Molar ratio be 1:(2.10~2.15).
3. preparation method according to claim 2, it is characterised in that: the ammonia is added in the form of the aqueous solution of ammonia
Add, the mass concentration of the aqueous solution of the ammonia is 5%~10%.
4. preparation method according to any one of claim 1-3, it is characterised in that: in step (1), the temperature of the reaction
Degree is 120~130 DEG C, and the time is 1~3h.
5. preparation method according to any one of claim 1-3, it is characterised in that: in step (2), chemical combination shown in formula II
The ratio of object and the hydrogen chloride solution is 1g:(1.5~1.6) mL；The molar concentration of the hydrogen chloride solution be 3.3~
3.4mol/L。
6. preparation method according to any one of claim 1-3, it is characterised in that: in step (2), chemical combination shown in formula II
The ratio of object and the organic solvent is 1g:(1.6~1.7) mL；The volume of the organic solvent, the water and the hexamethylene
Than for 1:(0.06~0.067): (4.0~5.0).
7. preparation method according to any one of claim 1-3, it is characterised in that: in step (2), the temperature of the reaction
Degree is 60~65 DEG C, and the time is 10min~30min.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101084193A (en) * | 2004-12-21 | 2007-12-05 | 艾尼纳制药公司 | Crystalline forms of (r)-8-chloro-1-methyl- 2,3,4,5-tetrahydro-1h-3-benzazepine hydrochloride |
| CN101547892A (en) * | 2006-12-05 | 2009-09-30 | 艾尼纳制药公司 | Processes for preparing (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and intermediates thereof |
| CN102627608A (en) * | 2012-03-31 | 2012-08-08 | 武汉武药制药有限公司 | Preparation method for analgesic and antipyretic drug-analgin |
| CN104031028A (en) * | 2014-06-23 | 2014-09-10 | 上海图维医药科技有限公司 | Environment-friendly method for preparing imatinib intermediate |
| CN105348196A (en) * | 2015-10-23 | 2016-02-24 | 湖北朗昕生化药业有限公司 | Lorcaserin hydrochloride hemihydrate preparation method |
| WO2016151451A1 (en) * | 2015-03-24 | 2016-09-29 | Aurobindo Pharma Ltd | A process for the preparation of lorcaserin hydrochloride |
-
2016
- 2016-09-30 CN CN201610871536.XA patent/CN106478506B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101084193A (en) * | 2004-12-21 | 2007-12-05 | 艾尼纳制药公司 | Crystalline forms of (r)-8-chloro-1-methyl- 2,3,4,5-tetrahydro-1h-3-benzazepine hydrochloride |
| CN101547892A (en) * | 2006-12-05 | 2009-09-30 | 艾尼纳制药公司 | Processes for preparing (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and intermediates thereof |
| CN102627608A (en) * | 2012-03-31 | 2012-08-08 | 武汉武药制药有限公司 | Preparation method for analgesic and antipyretic drug-analgin |
| CN104031028A (en) * | 2014-06-23 | 2014-09-10 | 上海图维医药科技有限公司 | Environment-friendly method for preparing imatinib intermediate |
| WO2016151451A1 (en) * | 2015-03-24 | 2016-09-29 | Aurobindo Pharma Ltd | A process for the preparation of lorcaserin hydrochloride |
| CN105348196A (en) * | 2015-10-23 | 2016-02-24 | 湖北朗昕生化药业有限公司 | Lorcaserin hydrochloride hemihydrate preparation method |
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