CN105777638B - The preparation method of lorcaserin impurity - Google Patents
The preparation method of lorcaserin impurity Download PDFInfo
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- CN105777638B CN105777638B CN201610002253.1A CN201610002253A CN105777638B CN 105777638 B CN105777638 B CN 105777638B CN 201610002253 A CN201610002253 A CN 201610002253A CN 105777638 B CN105777638 B CN 105777638B
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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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Abstract
The present invention relates to the methods of preparation lorcaserin impurity compound (I), using Raney's nickel, platinum dioxide, 10% palladium/carbon catalyst catalytic hydrogenation obtains impurity compound (I), investigates the influence of catalyst type, reaction time, reaction temperature and reaction pressure to hydrogenation reaction.
Description
Technical field
The present invention relates to drug fields, and in particular to a kind of preparation method of lorcaserin impurity.
Background technique
The present invention relates to a kind of preparation methods of lorcaserin impurity, belong to process for preparing medicine technical field.
If above-mentioned structural compounds (I) is a kind of lorcaserin critical impurities, chemical name are as follows: (1R) -1- methyl -2,3,
4,5- tetrahydro -1H-3- benzene azatropylidenes.
The entitled chloro- 1- methyl -2,3 of (1R) -8- of chemistry of lorcaserin, 4,5- tetrahydro -1H-3- benzazepines.It is
The New Drug Application that in December, 2009, Arena company submitted to FDA for the first time.On June 27th, 2012, U.S. FDA are ratified by Switzerland
The listing license of the Belviq (lorcaserin) of Arena drugmaker exploitation.Lorcaserin is FDA from approval Xenical in 1999
After (orlistat), the slimming drugs of first approval over 13 years.For the fat or overweight of adult status's index (BMI) >=27
Person, and patient's at least disease (such as hypertension, diabetes B or hyperlipidemia) relevant to weight.Lorcaserin
It is considered selectively activating 5-HT2C receptor attenuating food consumption by being located at appetite parent's opium melanin cortical neuron on hypothalamus
Amount and promotion full sense, definite effect mechanism are unclear.
The main preparation process of lorcaserin is as follows:
Summary of the invention
In the R&D process of lorcaserin bulk pharmaceutical chemicals, it has been found that the route is easy to produce impurity (I), producing cause
It is as follows:
The method that the present invention explores and has developed a set of preparation lorcaserin impurity compound (I), this method use thunder
Buddhist nun's nickel, platinum dioxide, 10% palladium/carbon catalyst catalytic hydrogenation obtain impurity compound (I), when investigating catalyst type, reaction
Between, the influence of reaction temperature and reaction pressure to hydrogenation reaction.
Preparation route is as follows:
The selection of hydrogenation catalyst is respectively Raney's nickel, platinum dioxide, and 10% palladium/carbon catalyst adds hydrogen to prepare impurity 1
Performance is compared, and the results are shown in Table 1.
The comparison of 1 different catalysts of table
| Catalyst | Catalyst amount | Reaction condition | Conversion ratio |
| Raney's nickel | 5% | 1atm, 30 DEG C~35 DEG C, 5 hours | 86% |
| Platinum dioxide | 5% | 1atm, 30 DEG C~35 DEG C, 5 hours | 98% |
| 10% palladium carbon | 5% | 1atm, 30 DEG C~35 DEG C, 5 hours | 100% |
As can be seen from Table 1, when Raney's nickel is as catalyst, reaction conversion ratio is minimum；When platinum dioxide is as catalyst,
Hydrogenation conversion makes moderate progress.10% palladium-carbon catalyst hydrogenation conversion is best, shows palladium-carbon catalyst tool when preparing impurity I
There are higher catalytic hydrogenation activity and selectivity.
The present invention studies palladium carbon reduction hydrogenation reaction, and when using methanol as solvent, substrate (D) is dispersed
In methanol, so that substrate sufficiently dissolves, influence of the differential responses concentration for reaction rate has been investigated.
2 palladium carbon of table is the comparison of catalyst differential responses concentration
| Reaction dissolvent | Reaction density | Reaction condition | Conversion ratio | Reaction time |
| Methanol | 1g/10ml | 1atm, 30 DEG C~35 DEG C | 100% | 12 hours |
| Methanol | 1g/5ml | 1atm, 30 DEG C~35 DEG C | 100% | 8 hours |
| Methanol | 1g/2ml | 1atm, 30 DEG C~35 DEG C | 100% | 4 hours |
| Non- solubilizer | 1g | 1atm, 30 DEG C~35 DEG C | 100% | 3 hours |
As can be seen from Table 2, discovery reaction density is higher, and the reaction time is shorter, but when reaction density is very high, reaction
Rate can slightly decline.
The present invention is investigated further to co-catalyst, and co-catalyst specifically includes that hydrochloric acid, acetic acid, sulfonic acid etc.
Proton acid and water.
3 co-catalyst of table influences reaction.
| Reaction dissolvent | Reaction condition | Co-catalyst | Reaction time |
| Non- solubilizer | 1atm, 30 DEG C~35 DEG C | Acetic acid | 1 hour |
| Non- solubilizer | 1atm, 30 DEG C~35 DEG C | Hydrochloric acid | 0.5 hour |
| Non- solubilizer | 1atm, 30 DEG C~35 DEG C | Water | 2 hours |
| Methanol | 1atm, 30 DEG C~35 DEG C | Hydrochloric acid | 4 hours |
As can be seen from Table 3, it be not added any reaction dissolvent, in the reaction system of 10% palladium carbon of same catalyst, is adding
Enter co-catalyst, greatly improves reaction rate.This method avoid the uses of solvent, largely avoid post-reaction treatment
Waste liquid.Simple and easy to get, operating method is simple, and catalyst is reusable, is conducive to environmental protection.
It keeps between system pH value 6-7, uses in conclusion a small amount of co-catalyst (acetic acid, hydrochloric acid or water) is added
10% palladium carbon adds hydrogen to have preferable catalytic activity and selectivity, without adding solvent, in 30 DEG C~35 DEG C of reaction temperature, reaction
Pressure 1atm and under the conditions of reaction time 30-180 minute, hydrogenation conversion is up to 100%.This method avoid the use of solvent,
Largely avoid liquid waste processing.Operating method is simple, and catalyst is reusable repeatedly.
Detailed description of the invention
Fig. 1: lorcaserin impurity I nuclear-magnetism1HNMR spectrogram
Fig. 2: compound D nuclear-magnetism1HNMR spectrogram
Specific embodiment
In order to make those skilled in the art that the present invention may be better understood, illustrate this hair referring to embodiment
It is bright.These embodiments are merely to illustrate the present invention, the range being not intended to restrict the invention.
The preparation of 1 lorcaserin impurity I of embodiment
About 5g compound D educt is dissolved in 5ml methanol, a small amount of wet palladium carbon about 0.2g is added, displaced air is passed through
30 DEG C~35 DEG C of hydrogen are stirred 8 hours.TLC monitors fully reacting and carries out.Filtering, arriving for 45 DEG C of -50 DEG C of reduced pressures of filtrate are light
Yellow oily transparency liquid about 3.7g, yield 90%.
TLC condition: (ethyl acetate: n-hexane=1: 1) about 0.2 impurity I Rf
The preparation of 2 lorcaserin impurity I of embodiment
A small amount of wet palladium carbon about 0.3g will be added in about 10g compound D, displaced air is passed through 30 DEG C~35 DEG C of hydrogen stirrings 3
Hour.TLC monitors fully reacting and carries out.Filtering, 45 DEG C of -50 DEG C of reduced pressures of filtrate arrive faint yellow oily transparency liquid about
3.8g。
TLC condition: (ethyl acetate: n-hexane=1: 1) about 0.2 impurity I Rf
The preparation of 3 lorcaserin impurity I of embodiment
To be added a small amount of wet palladium carbon about 0.3g and 0.3g water in about 10g compound D, displaced air, be passed through 30 DEG C of hydrogen~
35 DEG C are stirred 3 hours.TLC monitors fully reacting and carries out.Filtering, -50 DEG C of reduced pressures of 45 DEG C of filtrate it is saturating to faint yellow oily
Prescribed liquid about 9.5g.
TLC condition: (ethyl acetate: n-hexane=1: 1) about 0.2 impurity I Rf
The preparation of 4 lorcaserin impurity I of embodiment
A small amount of wet palladium carbon about 0.3g and 0.2ml hydrochloric acid will be added in about 10g compound D, displaced air is passed through 20 DEG C of hydrogen
~25 DEG C are stirred 0.5 hour.TLC monitors fully reacting and carries out.Filtering, 45 DEG C -50 DEG C of filtrate are concentrated under reduced pressure to give faint yellow oil
Shape transparency liquid about 9.3g.
1 impurity I hydrochloride nuclear-magnetism of attached drawing1HNMR spectrogram
1HNMR (400MHz, CDCl3) δ 9.50-10.30 (s, 2H), δ 7.40-7.00 (m, 4H), δ 3.75-2.85 (m,
7H), δ 1.56-1.31 (d, 3H).
C11H15The MS calculated value of N+H: 162, measured value: 162
TLC condition: (ethyl acetate: n-hexane=1: 1) about 0.2 impurity I Rf
The preparation of 5 lorcaserin impurity I of embodiment
A small amount of wet palladium carbon about 0.3g and 0.2ml acetic acid will be added in about 10g compound D, displaced air is passed through 30 DEG C of hydrogen
~35 DEG C are stirred 1 hour.TLC monitors fully reacting and carries out.Faint yellow oily is arrived in filtering, 45 DEG C of -50 DEG C of reduced pressures of filtrate
Transparency liquid about 9.3g.
TLC condition: (ethyl acetate: n-hexane=1: 1) about 0.2 impurity I Rf
Embodiment 6: the preparation of compound A
In 2L reaction flask, 1- [[2- (4- chlorphenyl) ethyl] amino] -2- propyl alcohol (200g, 9mol), first will be sequentially added
Benzene 1.6L and n,N-Dimethylformamide (20g, 3mol) are heated with stirring to 55 DEG C -60 DEG C.By thionyl chloride (140g, 1.2mol)
It is slowly added dropwise into reaction kettle, control rate of addition is that reaction temperature is no more than 65 DEG C.After being added dropwise to complete, 60 are adjusted the temperature to
DEG C -65 DEG C, continue stirring 2 hours.HPLC detects fully reacting, is cooled to 15 DEG C -20 DEG C.Filtering reacting liquid.Filter cake is added
75 DEG C -82 DEG C are heated in 800ml isopropanol and 60ml water, until reaction solution is clarified, is cooled to 0 DEG C -5 DEG C, filtering, filter cake is placed in
White powder 210g is dried to obtain in forced air drying.
HPLC condition: being filler (4 × 150mm, 5 μm) with octadecylsilane chemically bonded silica；It (is taken with triethylamine solution
Triethylamine 5ml adds water to 1000ml, is mobile phase with glacial acetic acid tune pH value to 4.5)-methanol (40: 60)；Detection wavelength is
220nm；Flow velocity is 1.0ml per minute；Column temperature is 30 DEG C.
Embodiment 7: the preparation of compound B
By compound A (210g, 7.8mol) and AlCl3(156g, 1.2mol) is added in reaction flask.The lower heating of argon gas protection
It is stirred 2 hours to 125 DEG C -130 DEG C.HPLC detects fully reacting.60 DEG C -70 DEG C are adjusted the temperature to, 400ml hexamethylene is slowly added to
Alkane.It finishes, cooling reaction solution to room temperature.Reaction solution is slowly added to sodium hydrate aqueous solution, pH is adjusted to 11 extractions, it is dry, have
40 DEG C -45 DEG C of machine layer are concentrated under reduced pressure to obtain brown oil liquid 160g.
HPLC condition: being filler (4 × 150mm, 5 μm) with octadecylsilane chemically bonded silica；It (is taken with triethylamine solution
Triethylamine 5ml adds water to 1000ml, is mobile phase with glacial acetic acid tune pH value to 4.5)-methanol (40: 60)；Detection wavelength is
220nm；Flow velocity is 1.0ml per minute；Column temperature is 30 DEG C
Embodiment 8: the preparation of compound D
Gained oily liquids (160g, 0.7mol) is dissolved in acetone (410g).Be warming up to 47 DEG C -52 DEG C, dropwise plus
Enter L-TARTARIC ACID aqueous solution (24g/48g).It is added dropwise to complete, temperature is kept to continue stirring 2 hours.Cooling reaction solution is to room temperature to 0
℃-5℃.Filtering, 45 DEG C of -50 DEG C of forced air dryings of filter cake obtain compound D tartrate crude product (59g).The crude product is dissolved in
It is heated to solid in 100g acetone and 100g purified water all to dissolve, adds 110g acetone, slow cooling is stirred to 0 DEG C -5 DEG C
It mixes 2 hours, filters, filtration cakes torrefaction obtains white crystal 50g.White crystal is added in 200ml ethyl acetate, carbon is added dropwise
The aqueous solution (25g/100ml) of sour potassium 1 hour, stratification, extraction take organic layer to be concentrated to give pale yellow oily liquid compound
D(34g).Compound D's1HNMR
1HNMR (400MHz, CDCl3) δ 7.20-7.00 (m), δ 3.15-2.85 (m, 6H), δ 2.80-2.70 (q, 1H), δ
1.85-1.95 (s, 1H), δ 1.42-1.31 (d, 3H).
Claims (1)
1. the preparation method of lorcaserin impurity, it is characterised in that:
Lorcaserin impurity I is obtained using 10% palladium/carbon catalytic hydrogenation,
Preparation route is as follows:
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| CN110845475A (en) * | 2019-12-25 | 2020-02-28 | 深圳市祥根生物科技有限公司 | Preparation method of loratadine impurity |
| CN113121495A (en) * | 2020-01-10 | 2021-07-16 | 深圳市九明药业有限公司 | Preparation method of desloratadine |
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| CN1626519A (en) * | 2003-12-09 | 2005-06-15 | 无锡药明康德新药开发有限公司 | Industrialized method for preparing 2-chlorine-5-fluorin-nicotinic aicd |
| CN101208289A (en) * | 2005-06-27 | 2008-06-25 | 巴斯福股份公司 | Method for production of substituted phenylmalonate esters intermediate compounds and the use thereof for the production of 5, 7-dihydroxy-6-(2,4,6-trifluorophenyl)-(1,2,4)triazolo(1,5-a) pyrimidines |
| CN101274911A (en) * | 2003-06-17 | 2008-10-01 | 艾尼纳制药公司 | Benzazepine derivatives useful for the treatment of 5HT2C receptor associated diseases |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101274911A (en) * | 2003-06-17 | 2008-10-01 | 艾尼纳制药公司 | Benzazepine derivatives useful for the treatment of 5HT2C receptor associated diseases |
| CN1626519A (en) * | 2003-12-09 | 2005-06-15 | 无锡药明康德新药开发有限公司 | Industrialized method for preparing 2-chlorine-5-fluorin-nicotinic aicd |
| CN101208289A (en) * | 2005-06-27 | 2008-06-25 | 巴斯福股份公司 | Method for production of substituted phenylmalonate esters intermediate compounds and the use thereof for the production of 5, 7-dihydroxy-6-(2,4,6-trifluorophenyl)-(1,2,4)triazolo(1,5-a) pyrimidines |
Non-Patent Citations (3)
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| Asymmetric Synthesis of 1-Substituted Tetrahydro-3-benzazepines as NMDA Receptor Antagonists;Ursula Wirt et al.;《Eur.J.Org.Chem.》;20061121;462-475 |
| Dechlorination of lindane in the multiphase catalytic reduction system with Pd/C, Pt/C and Raney-Ni;Sergei S. Zinovyev et al.;《Applied Catalysis B: Environmental》;20041231;第47卷;27-36 |
| Selectivity issues in the catalytic multiphase reduction of functionalized halogenated aromatics over Pd/C, Pt/C, and Raney-Ni;Galina Evdokimova ET AL.;《Applied Catalysis A: General》;20041231;第271卷;129-136 |
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