CN105439974B - A kind of preparation method of lipase inhibitor - Google Patents
A kind of preparation method of lipase inhibitor Download PDFInfo
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- CN105439974B CN105439974B CN201410429315.8A CN201410429315A CN105439974B CN 105439974 B CN105439974 B CN 105439974B CN 201410429315 A CN201410429315 A CN 201410429315A CN 105439974 B CN105439974 B CN 105439974B
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Abstract
The invention belongs to pharmaceutical technology field; more particularly to the methyl 4H 3 of 2 hexadecane epoxide of lipase inhibitor 6; the preparation method of the ketone of 1 benzoxazine 4; the present invention passes through the methyl benzoyl carbamate formula (II) of 2 halo of intermediate cetyl 5; under catalyst action; 1 (2 halogenophenyl) 1 is prepared by the halo benzamide cyclization rearrangement reaction of N acyl groups 2; 3 diketone; lactams four-membered ring is initially formed by NH in acid imide and halogen dehydrohalogenation, then forms the ketone structure of benzoxazine 4 through C N rearrangement reactions.The present invention has the characteristics of product purity is high, simple for process and safe, suitable industrialization production requirements.
Description
Technical field
The invention belongs to pharmaceutical technology field, in particular it relates to a kind of lipase inhibitor 2- hexadecane epoxides-
The preparation method of 6- methyl -4H-3,1- benzoxazine -4- ketone (hereafter with its adopted name west for take charge of his Cetilistat).
Background technology
Due to the rapid development of science, the improvement of material life condition and unreasonable, the obesity morbidity of dietary structure
Rate rises year by year, and rejuvenation situation occurs.Whole world obesity patient at present at least 1,200,000,000, and will be doubled with every 5 years
Speed increase.Ratio that China adult human body weight is overweight about 20%~30%, big city is up to 35%~40%, past 10 years
In, schoolgirl rises to 7% from 3% in Students ' Obesity patient, and boy student rises to 8% from 2%, and overweight number is then fat number
3~4 times.
West is a kind of new gastrointestinal lipases inhibitor for his (Cetilistat) is taken charge of, and it is (and same that the medicine is used for obesity
When with dyslipidemia and diabetes, body mass index >=25) treatment its great advantage be not act on nervous system, not shadow
Other enzymatic activitys of intestines and stomach are rung, is not absorbed and does not enter blood, not appetite-suppressing, without dietary restriction.24h is after medication
The phenomenon (floating on water volume oil droplet) of defecation band oil is may occur in which, that is, excludes undigested fat.
WO00/40247 describes west for his preparation method is taken charge of, using the methyl benzoic acid of 2- amino -5 and chloro-carbonic acid hexadecane
Ester is prepared by one-step method or two step method.By the two, direct polycondensation and cyclization in excess pyridine obtain product to one-step method.This side
In method, 2- amino -5- methyl benzoic acids cost of material is costly；Chloro-carbonic acid hexadecane ester is used as cyclization again as reactant
Catalyst, but active poor due to hexadecyl ester, catalytic capability is weak, therefore yield relatively low only 15% or so, and need
Column chromatography purifies；Catalyst of the methylchloroformate used in two step method as cyclization, total recovery only have 31%.Used in patent
Pyridine as solvent and acid binding agent, dosage is big, it is expensive can not reclaim, and foul smelling has larger infringement to operator.
CN1785967, by bromination, Carboxylation, obtains 2- 16 using cetyl -4- methyl phenyl carbamates
Alkoxycarbonyl amino -5- methyl benzoic acids, then prepare product in pyridine with ethyl chloroformate reaction.This method step
Grow, complex operation, have in technique using operations such as bromine, high-pressure catalytic reactions, be unfavorable for industrial production.
The content of the invention
It is an object of the present invention to provide a kind of west for his improved preparation method is taken charge of.The method of the present invention has production
Product purity is high, simple for process and safe, be adapted to industrialization production requirements the characteristics of.
Technical scheme provided by the invention is as follows：
The present invention is being urged by intermediate cetyl -2- halo -5- methyl-benzOylamino formic acid esters formulas (II)
Under agent effect, 1- (2- halogenophenyls) -1,3- diketone is prepared by N- acyl group -2- halos benzamides cyclization-rearrangement reaction, led to
Cross-NH and halogen dehydrohalogenation in acid imide and be initially formed lactams four-membered ring, then through C-N rearrangement reactions formed benzoxazine-
4- ketone structures.
Mantoquita catalyzed coupling reaction can easily generate the keys such as C-C, C-N, C-O, C-S, especially in recent years in Ullmann
Obtained a very large progress in reaction.Such as Acc.Chem.Res, 2008,4 (11)：1450 report and are closed under mantoquita catalyst system and catalyzing
Into the method for benzimidazole.The present invention includes stannous chloride, cuprous bromide, cuprous iodide etc. using cuprous halide catalyst.
Reaction of the present invention needs certain acid binding agent to be used to remove the hydrogen halides taken off, because highly basic is to ester group meeting
Destruction is produced, therefore acid binding agent uses inorganic weak bases, such as potassium carbonate, sodium carbonate, potassium phosphate, sodium phosphate, potassium acetate, acetic acid
Sodium etc., cesium carbonate.
In addition, unexpected effect can be produced to reaction by adding some neutral salt, reaction yield significantly improves.It is described to be
Neutral salt such as magnesia, calcium oxide, calcium chloride, magnesium sulfate, calcium sulfate etc., it may be possible to play part effect in the reaction, favorably
Carried out in reaction.
This method is related to noval chemical compound intermediate, cetyl -2- halo -5- methyl-benzOylamino formic acid esters formulas
(II), the compound can be prepared by the following method：
Method 1：
Halobenzamides (III) ,-NH2Compound reaction of the group with phosgene or generation phosgene in situ or comprising phosgene turns
It is changed into isocyanates (IV), then reacts formula (II) with hexadecanol.
X is substituted by halogen, including bromine and iodine.
Compound of the isocyanate reagents for phosgene or generation phosgene in situ or comprising phosgene is prepared with acid amides reaction, including
Phosgene, surpalite, triphosgene and oxalyl chloride etc..
Method 2：
Halo phenyl ethylamine (V) amido and chloro-carbonic acid hexadecane ester reaction formula (VI), then aoxidize formula (II).
X is substituted by halogen, including bromine and iodine.
Method 3：
Acid amides directly reacts formula (II) with the palm ester of carbonic acid two or chloro-carbonic acid hexadecane ester.
X is substituted by halogen, including bromine and iodine.
Embodiment
Illustrate the present invention referring to specific embodiment.It will be appreciated by those skilled in the art that these embodiments are only
For the purpose of illustrating the invention, its scope not limiting the invention in any way.
Embodiment 1The bromo- 5- methyl-benzoyls based isocyanates of 2-
The bromo- 5- methyl-benzamides 21.3g (0.1mol) of 2-, dichloromethane 200mL are added in three-necked bottle, and 0 DEG C slowly
Oxalyl chloride 33.3mL (0.4mol) is added dropwise, is warmed to room temperature reaction 1 hour, is then refluxed for reacting 2 hours, is produced to without gas.
Reaction solution is cooled to room temperature, is concentrated under reduced pressure and steams solvent, obtains isocyanates crude product, is directly used in and reacts in next step.
Embodiment 2The bromo- 5- methyl-benzOylaminos formic acid esters of cetyl -2-
The bromo- 5- methyl-benzoyls based isocyanates of 2- prepared by upper step are added in dichloromethane 250mL, add 16
Triethylamine 18mL is added dropwise in alcohol 24.2g (0.1mol), room temperature, reacts at room temperature 3 hours, adds water 100mL, is layered, and organic layer is anhydrous
Sodium sulphate is dried.Decompression steams solvent, obtains crude product and adds Ethyl acetate-cyclohexane crystallization, obtains white solid 39.6g, receive
Rate 82%.1HNMR:δ=0.96ppm (t, 3H ,-CH3), 1.26~1.44 (m, 26H ,-CH2), 1.73 (m, 2H ,-CH2), 2.35
(s,3H,CH3), 4.22 (t, 2H ,-CH2), 7.20 (d, 1H, phenyl ring), 7.49 (dd, 1H, phenyl ring), 7.64 (d, 1H, phenyl ring),
9.98 (br, 1H, N-H) ESI m/z C25H40BrNO3[M+1]483
Embodiment 3The iodo- 5- methyl-benzoyls based isocyanates of 2-
The iodo- 5- methyl-benzamides 52.0g (0.2mol) of 2- are added to toluene solution 250ml, are warming up to 90 DEG C of slowly drops
Add double (trichloromethyl) carbonic ester 29.7g (0.1mol) 200mL toluene solutions, then add 30mL triethylamines, be then refluxed for anti-
Answer 2h.Reaction solution is cooled to room temperature, and decompression steams solvent, obtains isocyanates crude product, is directly used in and reacts in next step.
Embodiment 4The iodo- 5- methyl-benzOylaminos formic acid esters of cetyl -2-
The iodo- 5- methyl-benzoyls based isocyanates of 2- prepared by upper step are added in dichloromethane 500mL, add 16
Triethylamine 36mL is added dropwise in alcohol 48.4g (0.2mol), room temperature, reacts at room temperature 3 hours, adds water 100mL, is layered, and organic layer is anhydrous
Sodium sulphate is dried.Decompression steams solvent, obtains crude product and adds Ethyl acetate-cyclohexane crystallization, obtains white solid 80.6g, receive
Rate 76%.1HNMR:δ=0.95ppm (t, 3H ,-CH3), 1.26~1.44 (m, 26H ,-CH2), 1.72 (m, 2H ,-CH2), 2.33
(s,3H,CH3), 4.22 (t, 2H ,-CH2), 7.08 (d, 1H, phenyl ring), 7.52 (dd, 1H, phenyl ring), 7.70 (d, 1H, phenyl ring),
(9.97 br, 1H, N-H) ESI m/z C25H40INO3[M+1]530
EmbodimentThe bromo- 5- methylbenzylcarbamates of 5 cetyl -2-
The bromo- 5- methyl-benzyls amine 40g (0.2mol) of 2-, dichloromethane 500ml, add triethylamine 86ml (0.6mol), cooling 0
DEG C, chloro-carbonic acid hexadecane ester 45.8g (0.15mol) is added dropwise, is warming up to room temperature, reacts at room temperature 3 hours, adds water 200mL, point
Layer, organic layer anhydrous sodium sulfate drying.Decompression steams solvent, obtains crude product and adds tetrahydrofuran-hexamethylene crystallization, obtains white
Solid 82.5g, yield 88%.1HNMR:δ=0.96ppm (t, 3H ,-CH3), 1.29~1.45 (m, 26H ,-CH2), 1.76 (m,
2H,-CH2), 2.36 (s, 3H, CH3), 4.10 (t, 2H ,-CH2), 4.25 (s, 2H ,-CH2), 6.75 (d, 1H, phenyl ring), 6.76
(dd, 1H, phenyl ring), 7.19 (d, 1H, phenyl ring), 8.02 (, 1H, N-H) and ESI m/z C25H42BrNO2[M+1]469
EmbodimentThe bromo- 5- methyl-benzOylaminos formic acid esters of 6 cetyl -2-
Periodic acid 69g (0.3mol) and CrO330min is stirred at room temperature in 0.25g (5mol%) acetonitriles 500ml, then adds
Acetic anhydride 31g (0.3mol), 0 DEG C is cooled down, add the bromo- 5-methylbenzylcarbamate 23.4g of cetyl-2-
(0.05mol), mixture reaction 2h, add water 500ml, ethyl acetate 2L extractions, layering, saturated sodium carbonate solution and saturation sulphur
Sodium thiosulfate solution washs, and dries, and decompression steams solvent, adds tetrahydrofuran-normal heptane recrystallization, obtains white solid
21.8g, yield 90%.ESI m/z C25H40BrNO3[M+1]483
Embodiment7 cetyls-2-iodo- 5- methylbenzylcarbamates
The iodo- 5- methyl-benzyls amine 49.4g (0.2mol) of 2-, dichloromethane 500ml, add triethylamine 86ml (0.6mol), cold
But 0 DEG C, chloro-carbonic acid hexadecane ester 45.8g (0.15mol) is added dropwise, is warming up to room temperature, reacts at room temperature 3 hours, adds water 200mL,
Layering, organic layer anhydrous sodium sulfate drying.Decompression steams solvent, obtains crude product and adds tetrahydrofuran-hexamethylene crystallization, obtains white
Color solid 91.8g, yield 89%.1HNMR:δ=0.96ppm (t, 3H ,-CH3), 1.29~1.45 (m, 26H ,-CH2), 1.76
(m,2H,-CH2), 2.36 (s, 3H, CH3), 4.10 (t, 2H ,-CH2), 4.25 (s, 2H ,-CH2), 6.75 (d, 1H, phenyl ring),
6.76 (dd, 1H, phenyl ring), 7.19 (d, 1H, phenyl ring), 8.02 (, 1H, N-H) and ESI m/z C25H42INO2[M+1]516
Embodiment 8The iodo- 5- methyl-benzOylaminos formic acid esters of cetyl -2-
Periodic acid 69g (0.3mol) and CrO330min is stirred at room temperature in 0.25g (5mol%) acetonitriles 500ml, then adds
Acetic anhydride 31g (0.3mol), 0 DEG C is cooled down, add cetyl-2-iodo- 5-methylbenzylcarbamate 25.8g
(0.05mol), mixture reaction 2h, add water 500ml, ethyl acetate 2L extractions, layering, saturated sodium carbonate solution and saturation sulphur
Sodium thiosulfate solution washs, and dries, and decompression steams solvent, adds tetrahydrofuran-normal heptane recrystallization, obtains white solid
24.1g, yield 91%.ESI m/z C25H40INO3[M+1]530
Embodiment 9The palm ester of carbonic acid two
By palmityl alcohol 72.6g (0.3mol), catalyst potassium carbonate 0.8g, it is added in reaction bulb, is passed through nitrogen, be warming up to
160 DEG C, dimethyl carbonate 8.5ml (0.1mol) is added dropwise, finishes and keeps thermotonus 4h.Collect the azeotropic mixture of methanol and product
Rectifying is carried out, obtains the palm ester 31.6g of carbonic acid two, yield 62%.1HNMR:δ=0.85 (t, 6H, CH3),1.18-1.76(m,
56H,CH2),4.22(t,4H,CH2),C33H66O3Calculated value C 77.58%, H13.02%；Measured value C77.31%,
H13.31%.
Embodiment 10The bromo- 5- methyl-benzOylaminos formic acid esters of cetyl -2-
The bromo- 5- methyl-benzamides 21.3g (0.1mol) of 2-, DMAP 14.6g (0.12mol), dichloromethane
Alkane 800mL is added in three-necked bottle, and the palm ester 24.5g (0.048mol) of carbonic acid two is added portionwise, and is reacted at room temperature 18 hours.Reaction
Terminate, saturated sodium bicarbonate is washed, washing and drying, and decompression steams solvent, obtains grease.Tetrahydrofuran-normal heptane is added to tie again
Crystalline substance, obtain white solid 32.8g, yield 67.9%.1HNMR:δ=0.96ppm (t, 3H ,-CH3), 1.26~1.44 (m, 26H ,-
CH2), 1.73 (m, 2H ,-CH2), 2.35 (s, 3H, CH3), 4.22 (t, 2H ,-CH2), 7.20 (d, 1H, phenyl ring), 7.49 (dd,
1H, phenyl ring), 7.64 (d, 1H, phenyl ring), 9.98 (br, 1H, N-H) ESI m/z C25H40BrNO3[M+1]483
Embodiment 11Cetyl-2-iodo- 5- methyl-benzOylamino formic acid esters
The iodo- 5- methyl-benzamides 26.0g (0.1mol) of 2-, triethylamine 43ml (0.3mol), tetrahydrofuran 200mL add
Enter into three-necked bottle, chloro-carbonic acid hexadecane ester 36.7g (0.12mol) is added dropwise, react at room temperature 2 hours, it is small to be then refluxed for reaction 2
When.Reaction terminates, and reaction solution is poured into 100ml water after cooling, separates out solid.Tetrahydrofuran-normal heptane recrystallization is added, is obtained
To white solid 30.7g, yield 58%.ESI m/z C25H40INO3[M+1]530
Embodiment 12For department, his prepares in west
Cuprous bromide 0.7g (5mmol), potassium phosphate 2.12g (10mmol), magnesium sulfate 1.2g (10mmol) are added to anhydrous
In toluene 500ml, after being passed through nitrogen, the bromo- 5- methyl-benzOylaminos formic acid esters 24.2g of lower addition cetyl -2- are stirred
(0.05mol), it is warming up to backflow 3h.Reaction is filtered after terminating, and filtrate decompression is concentrated to give grease, adds normal heptane-ethanol
Recrystallization, obtains off-white powder 14.2g, yield 71%.ESI m/z C25H39NO3 [M+1]4021HNMR:δ=0.86ppm
(t,3H,-CH3), 1.24~1.44 (m, 26H ,-CH2), 1.79 (m, 2H ,-CH2), 2.40 (s, 3H, CH3), 4.40 (t, 2H ,-
CH2), 7.28 (d, 1H, phenyl ring), 7.50 (dd, 1H, phenyl ring) 7.88 (d, 1H, phenyl ring), HPLC 99.87%
Embodiment 13For department, his prepares in west
Cuprous iodide 1g (5mmol), potassium phosphate 2.12g (10mmol), calcium chloride 1.11g (10mmol) are added to dioxy six
In ring 500ml, after being passed through nitrogen, the iodo- 5- methyl-benzOylaminos formic acid esters 26.6g of lower addition cetyl -2- are stirred
(0.05mol), it is warming up to backflow 3h.Reaction is filtered after terminating, and filtrate decompression is concentrated to give grease, adds normal heptane-ethanol
Recrystallization, obtains off-white powder 16.2g, yield 81%.ESI m/z C25H39NO3[M+1]4021HNMR:δ=0.86ppm
(t,3H,-CH3), 1.24~1.44 (m, 26H ,-CH2), 1.79 (m, 2H ,-CH2), 2.40 (s, 3H, CH3), 4.40 (t, 2H ,-
CH2), 7.28 (d, 1H, phenyl ring), 7.50 (dd, 1H, phenyl ring) 7.88 (d, 1H, phenyl ring), HPLC 99.85%.
Claims (7)
1. a kind of method of compound shown in formula (I), it is characterised in that by formula (II) compound be raw material, using halogenation
It is cuprous to be used as catalyst, using weak base as acid binding agent, it is made using neutral salt as cocatalyst,
Wherein X is bromine or iodine.
2. preparation method according to claim 1, it is characterised in that the cuprous halide is selected from stannous chloride, protobromide
Copper, cuprous iodide.
3. according to the method for claim 1, it is characterised in that the weak base is selected from potassium carbonate, sodium carbonate, potassium phosphate, phosphorus
Sour sodium, potassium acetate, sodium acetate, cesium carbonate.
4. according to the method for claim 1, it is characterised in that the neutral salt is selected from magnesia, calcium oxide, calcium chloride,
Magnesium sulfate, calcium sulfate.
5. according to the method for claim 1, formula (II) compound can be made as follows：
Wherein X is bromine or iodine；
Formula (III) compound substituted benzamide and phosgene or generation phosgene in situ or the substance reaction comprising phosgene；Obtained formula
(IV) compound is reacted with hexadecanol, obtains formula (II) compound.
6. according to the method for claim 1, formula (II) compound can be made as follows：
Formula (V) compound alpha substituted benzylamine reacts with chloro-carbonic acid hexadecane ester；Obtained formula (VI) compound obtains formula through peroxidating
(II) compound.
7. according to the method for claim 1, formula (II) compound can be made as follows：
Wherein X is bromine or iodine；
Formula (VII) compound substituted amide reacts with chloro-carbonic acid hexadecane ester or the palm ester of carbonic acid two, and formula (II) compound is made.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5948775A (en) * | 1997-03-19 | 1999-09-07 | American Home Products Corporation | 2- or 3-(substitutedaminoalkoxyphenyl)quinazolin-4-ones |
| CN1785967A (en) * | 2004-12-10 | 2006-06-14 | 兰爱克谢斯德国有限责任公司 | Process for the preparation of carbamic acid derivatives |
-
2014
- 2014-08-28 CN CN201410429315.8A patent/CN105439974B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5948775A (en) * | 1997-03-19 | 1999-09-07 | American Home Products Corporation | 2- or 3-(substitutedaminoalkoxyphenyl)quinazolin-4-ones |
| CN1785967A (en) * | 2004-12-10 | 2006-06-14 | 兰爱克谢斯德国有限责任公司 | Process for the preparation of carbamic acid derivatives |
Non-Patent Citations (3)
| Title |
|---|
| 一种新型减肥药物———奥利司他;杨义生;《国外医学内分泌学分册》;20001130;第20卷(第6期);全文 * |
| 脂肪酶抑制剂应用于抗肥胖的研究进展;杨志秋等;《现代生物医学进展》;20111130;第11卷(第21期);全文 * |
| 赛利司他(ATL -962)、利莫那班和赛尼可的研发与市场趋势;阎家麒等;《化工时刊》;20080202;第22卷(第2期);全文 * |
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