CN107118191A - Flavoxate hydrochloride is coupled the preparation method of impurity - Google Patents
Flavoxate hydrochloride is coupled the preparation method of impurity Download PDFInfo
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- CN107118191A CN107118191A CN201710516984.2A CN201710516984A CN107118191A CN 107118191 A CN107118191 A CN 107118191A CN 201710516984 A CN201710516984 A CN 201710516984A CN 107118191 A CN107118191 A CN 107118191A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
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Abstract
The preparation method of flavoxate hydrochloride coupling impurity is the invention provides the preparation method that a kind of flavoxate hydrochloride is coupled impurity, with compound 2（R is methyl, ethyl or hydrogen atom）For starting material, the coupling reaction of two molecules can be first carried out, then build phenyl ring branched structure, the structure that can also first carry out branched structure is coupled again.By the acquisition of the coupling impurity, the impurity of flavoxate hydrochloride can be made to compose definitely, and by investigating the separating degree between impurity, make analysis method more accurate, so as to further improve the quality of flavoxate hydrochloride bulk drug, ensure efficacy and safety.
Description
Technical field
The present invention relates to a kind of flavoxate hydrochloride coupling impurity and preparation method thereof, belong to pharmaceutical technology field.
Background technology
Flavoxate hydrochloride is the smooth muscle solution banning drugs by Italy profit Kang Huagong and pharmaceutical Co. Ltd's research and development, 1979
First in Japan's listing.Flavoxate hydrochloride piece is applied to frequent micturition, urgent urination, odynuria, dysuria and urine caused by following disease
The symptoms such as incontinence：1. lower urinary tract infection disease (prostatitis, cystitis, urethritis etc.)；2. lower urinary tract obstruction disease
(early, mid-term hyperplasia of prostate, spastic, feature ankylurethria)；3. after lower urinary tract instrumental examination or Post operation (prostate
Enucleation, urethral dilatation, bladder intracavity operation)；4. urethra symptom group；5. urge incontinence.
Further to improve drug quality, pharmaceutical effectiveness and security are ensured, we are to flavoxate hydrochloride and its each step
The impurity situation of intermediate is conducted in-depth research.The road of three synthetic hydrochloric acid flavoxates is summarized by literature survey
Line：
Route one：
Route two：
Route three：
Bibliography：US4634768A、US4533732A、US2921070、《The synthesis of 3- methyl flavones -8- carboxylic acids is ground
Study carefully》--- Zhejiang University's master thesis, 2006.5
This three routes are directed to catalytic hydrogenation dehalogenate step, and corresponding coupling impurity can be produced in the step course of reaction,
The final flavoxate hydrochloride for being changed into two molecule coupling labeleds enters finished product, shown in structure following formula：
The content of the invention
It is an object of the invention to provide a kind of flavoxate hydrochloride coupling impurity and preparation method thereof.
The technical scheme is that compound or its salt hydrochlorate shown in a kind of formula 1,
The compound is prepared using the compound of formula 2 as substrate, R is selected from methyl, ethyl or hydrogen atom, comprises the following steps：
The first step, compound 2 obtains compound 3 under sodium benzoate effect with chlorobenzoyl chloride by cyclization；
Second step, compound 3 obtains compound 4 by esterification；
3rd step, compound 4 passes through coupling reaction prepare compound 1；
As needed, above-mentioned three-step reaction products therefrom is acidified through persalt, you can obtain the hydrochloride of compound 1.
According to the present invention, compound 3 with N- hydroxyethyl piperidines when carrying out esterification, in order to which the reaction for strengthening carboxyl is lived
Property, corresponding acyl chlorides first can be changed into by 3, then compound 4 is obtained with the esterification of N- hydroxyethyl piperidines.
According to the present invention, the coupling reaction described in the 3rd step is completed under palladium catalyst effect, preferably four (triphenyl phosphorus)
Palladium, [1,1'- double (diphenylphosphine) ferrocene] palladium chloride, palladium, more preferably four (triphenyl phosphorus) palladiums.
According to the present invention, when coupling reaction described in the 3rd step makees catalyst using four (triphenyl phosphorus) palladiums, reaction needs add
Plus connection boric acid pinacol ester, alkali, alkali used is selected from triethylamine, sodium formate, potassium acetate, sodium acetate or potassium carbonate, preferably potassium carbonate.
According to the present invention, coupling reaction solvent described in the 3rd step is selected from DMF, toluene, formamide, isopropanol, tetrahydrofuran
Or Isosorbide-5-Nitrae-dioxane, preferably toluene or DMF, reaction temperature is at 90-115 DEG C, and preferably 100 DEG C to flowing back.
According to above-mentioned reaction scheme, by adjusting cyclisation, esterification, the order for being coupled three-step reaction, difference can also be passed through
Route compound 1 and its hydrochloride is made, selectable route has：
R is as defined above, and compound 2 is first carried out being coupled obtaining compound 5, then the side chain of the phenyl ring of compound 5 is cyclized
Compound 6, finally be esterified obtaining compound 1, wherein, each step reaction condition is the same as those described above.
According to the present invention, the selectable route of compound 1 can also be：
R is as defined above, and the cyclisation that compound 2 first carries out phenyl ring side chain obtains compound 3, and compound 3 carries out coupling again
Compound 6, finally be esterified obtaining compound 1, wherein, each step reaction condition is the same as those described above.
The beneficial effects of the invention are as follows by studying the coupling impurity, the impurity spectrum of flavoxate hydrochloride can be made brighter
Really, and by investigating the separating degree between impurity, make analysis method more accurate, so that it is former further to improve flavoxate hydrochloride
Expect the quality of medicine, ensure efficacy and safety.
Embodiment：
Content, is described further with reference to specific embodiment for a better understanding of the present invention, but the present invention is not only limited to
This.
One of route：
1st, the synthesis of compound 3
14.6g chlorobenzoyl chlorides, the bromo- 3- propionyl salicylic acids methyl esters of 10.0g 5- are sequentially added into 100ml there-necked flask（Chemical combination
Thing 2, R is methyl）160-170 DEG C is warming up to 17.1g sodium benzoates, 6h is incubated.110 DEG C or so are cooled to, is added to system
10mlDMF stirs 10min, and system is poured into the 150ml frozen water dissolved with 7.0g sodium hydroxides, stirs 0.5h, filtering.By filter cake
It is added to 2.1g sodium hydroxides in 70ml methanol, flow back 2h, is down to room temperature, adds 30ml water, stirs 0.5h, filtering, filtrate
Enriching salt acid for adjusting pH=1, filtering, filter cake drying, dry weight 8.8g, yield 70.4%.
2nd, the synthesis of compound 4
8.5g compounds 3 and 5.6g thionyl chlorides are added in 200ml toluene, 90 DEG C or so are heated to, 3h is incubated.Decompression is dense
Contracting toluene, removes the unnecessary thionyl chloride of system, in 40-50 DEG C, and the toluene solution dissolved with 3.7g N- hydroxyethyl piperidines is added dropwise,
90 DEG C or so are warming up to, 3h is incubated.25 DEG C or so are down to, the 50ml aqueous solution dissolved with 1.4g sodium hydroxides is added to system, stirs
0.5h is mixed, system dissolved clarification, point liquid, toluene mutually uses anhydrous sodium sulfate drying 0.5h, filters, and it is left that toluene is mutually concentrated under reduced pressure into 50ml
The right side, plus salt ice bath cooling crystallization, filtering.Dry weight 9.9g, yield 89%.
3rd, the synthesis of compound 1
Example 1
100ml N,N-dimethylformamides are added into 250ml there-necked flask（DMF）, 10.0g compounds 4,0.5g palladiums
With 3ml triethylamines, extraction nitrogen 3 times is warming up to 110 DEG C or so, insulation reaction 7h under nitrogen protection.Room temperature is down to, to system
200ml water is added, pH=6-7 is adjusted with concentrated hydrochloric acid, 200ml toluene extraction point liquid is added, aqueous phase is extracted with 2 × 100ml toluene,
Divide liquid.Merge organic phase to be washed with 200ml, organic phase is concentrated under reduced pressure, column chromatography.Obtain product 2.0g, yield 24%.
Example 2
100ml DMF, 10.0g compound 4,6.3g potassium acetates and 0.3g [1,1'- double (two are added into 250ml there-necked flask
Phenylphosphine) ferrocene] palladium chloride, nitrogen displacement 3 times, be heated under nitrogen protection backflow, insulation reaction 5h.It is down to room
Temperature, filtering.Organic phase is less than 3 with acidic alcohol regulation pH, is cooled to 0 DEG C or so, stirs 0.5h, filtering.Filter cake is returned with ethanol
Stream mashing, filtering obtains product 1.9g, yield 22%.
Example 3
100ml DMF, 10.0g compound 4,5.8g potassium carbonate and 0.2g tetra- are added into 250ml there-necked flask（Triphenyl phosphorus）
Palladium, nitrogen displacement 3 times is warming up to 100 DEG C or so, insulation reaction 2h under nitrogen protection.Sample after TLC detection reactions completely,
Room temperature is down to, 5.0g compounds 5 is added to system, under nitrogen protection, is warming up to 100 DEG C or so, insulation reaction 3h.Heat filter,
Filtrate is less than 3 with acidic alcohol regulation pH, is cooled to 0 DEG C or so, stirs 0.5h, filtering.Filter cake is beaten with alcohol reflux, is down to
Room temperature, filtering, obtains product 2.4g, yield 35%.
Example 4
100ml toluene and 10ml DMF backflow band water 1h are added into 250ml there-necked flask, 10.0g compounds are added to system
4,2.7g connection boric acid pinacol esters, 5.8g potassium carbonate and 0.2g tetra-（Triphenyl phosphorus）After palladium, nitrogen displacement 3 times, in nitrogen protection
Lower back flow reaction 6h.Heat filter, point liquid after mother liquor is washed with 2 × 50ml, toluene is added anhydrous sodium sulfate stirring 0.5h, filtering.Will
Organic phase is concentrated, column chromatography, dry weight 5.7g, yield 69%.
1H NMR (600 MHz, CDCl3): 8.76 (s, 2H), 8.60 (s, 2H), 7.82 (d, 4H),
7.56-7.58 (m, 6H), 4.54 (t, 4H), 2.74 (t, 4H), 2.45 (t, 8H), 2.28 (s, 6H),
1.54-1.58 (m, 8H), 1.41-1.42 (m, 4H).
LCMS-ESI (m/z): 781.35 ([M+H]+)
The two of route：
1st, compound 5（R is methyl）Synthesis
100ml toluene and 10ml DMFs backflow band water 1h are added into 250ml there-necked flask, then to body
System adds the bromo- 3- propionyl salicylic acids methyl esters of 10.0g 5-, 4.43g connection boric acid pinacol esters, 9.62g potassium carbonate and 0.2g tetra-
After (triphenyl phosphorus) palladium, nitrogen displacement 3 times, back flow reaction 3h under nitrogen protection.System is down to room temperature and adds hydrochloric acid/ethanol
Adjust PH=2, filtering.Filter cake is placed in 150ml water, with concentrated hydrochloric acid pH=2, filtering.Filter cake is beaten 1h with methanol eddy, is down to
Room temperature, filtering.Obtain 3.0g products, yield 45%.
2nd, the synthesis of compound 6
8.7g chlorobenzoyl chlorides, 3.0g compounds 5 and 10.1g sodium benzoates are added into 100ml there-necked flask, 160- is heated to
170 DEG C of insulation reaction 7h.110 DEG C or so are cooled to, adds after 5ml DMF stirrings 10min, pours into dissolved with 5.2g sodium hydroxides
In 100ml frozen water, 0.5h, filtering are stirred.Filter cake and 0.9g sodium hydroxides are added into backflow in 50ml methanol to stay overnight, then,
System is down to room temperature filtering, and filter cake is adjusted after pH=2 or so, stirring 0.5h with concentrated hydrochloric acid, filtering.Filter cake ethyl acetate backflow
Mashing, filtering.Filter cake is dried, dry weight 2.8g, yield 69%.
3rd, the synthesis of compound 1
2.5g compounds 6,2.13g thionyl chlorides are added in 100ml toluene, 90 DEG C or so are warming up to, 3h is incubated, decompression is steamed
Fall 20ml toluene.At 40-50 DEG C, the toluene solution dissolved with 1.45g N- hydroxyethyl piperidines is added to system, 90 DEG C of left sides are warming up to
The right side, is incubated 4h.System is cooled to 25 DEG C or so, adds after the 40ml aqueous solution dissolved with 0.4g sodium hydroxides, system dissolved clarification and divides
Liquid, point liquid after toluene is mutually washed with 3 × 40ml.Toluene mutually uses anhydrous sodium sulfate drying 0.5h, and filtering, toluene is mutually concentrated under reduced pressure into
After 20ml or so, plus salt ice bath is cooled to-10-- 5 DEG C of stirring 1h, and crystallization, filtering, filter cake dries, the g of dry weight 1.4, yield
40%。
The three of route：
1st, the synthesis of compound 3
14.7g chlorobenzoyl chlorides, the bromo- 3- propionyl salicylic acids methyl esters of 10.0g 5- and 17.1g benzene are added into 100ml there-necked flask
Sodium formate, is heated to 160-170 DEG C of insulation reaction 6h.110 DEG C or so are cooled to, adds after 10ml DMF stirrings 10min, pours into
Dissolved with the 100ml frozen water of 7.0g sodium hydroxides, 0.5h is stirred, is filtered.Filter cake and 2.1g sodium hydroxides are added to 70ml first
In alcohol, it is heated to reflux, is incubated 2h, system is down to room temperature, add water, is less than 3 with concentrated hydrochloric acid regulation pH, stirs 0.5h, filtering.
Filter cake is beaten with ethyl acetate backflow, is down to room temperature, filtering.Filter cake is dried, dry weight 8.9g, yield 71%.
2nd, the synthesis of compound 6
100ml toluene and 10ml DMFs backflow band water 1h are added into 250ml there-necked flask, then to body
System adds 8.9g compounds 3,3.1g connection boric acid pinacol esters, 10.3g potassium carbonate and 0.2g tetra- (triphenyl phosphorus) palladium, nitrogen displacement
After 3 times, back flow reaction 3h under nitrogen protection.System is down to room temperature and adds hydrochloric acid/ethanol regulation pH value less than 3, filtering.Will
Filter cake is placed in 200ml water, is less than 3, filtering with concentrated hydrochloric acid pH value.Filter cake is beaten 1h with methanol eddy, is down to room temperature, filters.
Obtain 3.1g products, yield 45%.
3rd, the synthesis of compound 1
3.0g compounds 6,2.6g thionyl chlorides are added in 100ml toluene, 90 DEG C or so are warming up to, 3h is incubated, decompression is steamed
Fall 20ml toluene.At 40-50 DEG C, the toluene solution dissolved with 1.7g N- hydroxyethyl piperidines is added to system, 90 DEG C of left sides are warming up to
The right side, is incubated 4h.System is cooled to 25 DEG C or so, adds after the 50ml aqueous solution dissolved with 0.5g sodium hydroxides, system dissolved clarification and divides
Liquid, toluene mutually uses anhydrous sodium sulfate drying 0.5h, filtering, and toluene is mutually concentrated under reduced pressure into after 20ml or so, plus salt ice bath be cooled to-
10-- 5 DEG C of stirring 1h, crystallization, filtering, filter cake dries, dry weight 1.8g, yield 43%.
Claims (5)
1. compound or its salt hydrochlorate shown in a kind of formula 1：
。
2. the preparation method of compound described in claim 1, it is characterised in that using the compound of formula 2 as substrate, R is selected from methyl, second
Base or hydrogen atom, comprise the following steps：
The first step, compound 2 obtains compound 3 under sodium benzoate effect with chlorobenzoyl chloride by cyclization；
Second step, compound 3 obtains compound 4 by esterification；
3rd step, compound 4 by coupling reaction prepare compound 1,；
As needed, above-mentioned three-step reaction products therefrom is acidified through persalt, you can obtain the hydrochloride of compound 1.
3. preparation method according to claim 2, it is characterised in that the coupling reaction described in the 3rd step is made in palladium catalyst
Completed with lower, preferably four (triphenyl phosphorus) palladiums, [1,1'- double (diphenylphosphine) ferrocene] palladium chloride, palladium, more preferably four
(triphenyl phosphorus) palladium.
4. preparation method according to claim 3, it is characterised in that the coupling reaction is done using four (triphenyl phosphorus) palladiums
During catalyst, reaction needs addition connection boric acid pinacol ester, alkali, and alkali used is selected from triethylamine, sodium formate, potassium acetate, sodium acetate
Or potassium carbonate, preferred potassium carbonate.
5. preparation method according to claim 2, it is characterised in that second step reaction first can change into compound 3
Corresponding acyl chlorides, then react prepare compound 4 with N- hydroxyethyl piperidines.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111153881A (en) * | 2020-01-13 | 2020-05-15 | 辽宁海德制药有限公司 | Preparation method for synthesizing intermediate 3-methylflavone-8-carboxylic acid of flavoxate hydrochloride |
| CN114736183A (en) * | 2022-04-14 | 2022-07-12 | 迪嘉药业集团有限公司 | Preparation method of 3-methylflavone-8-carboxylic acid |
| CN115960065A (en) * | 2023-01-06 | 2023-04-14 | 山东鲁西药业有限公司 | Preparation method of flavoxate hydrochloride |
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| US2921070A (en) * | 1957-11-05 | 1960-01-12 | Recordati Lab Farmacologico S | Basic esters of 3-methylflavone-8-carboxylic acid |
| US4533732A (en) * | 1982-09-30 | 1985-08-06 | Yamamoto Chemical Industrial Company, Limited | 3-Propionylsalicylic acid derivatives and process for the preparation of the same |
| US4634768A (en) * | 1982-09-30 | 1987-01-06 | Yamamoto Chemical Industrial Co., Ltd. | Halo-containing 3-methylflavone-8-carboxylic acid derivatives |
| CN104031015A (en) * | 2014-06-10 | 2014-09-10 | 金坛德培化工有限公司 | Preparation method for 3-methyl flavone-8-carboxylic acid |
-
2017
- 2017-06-29 CN CN201710516984.2A patent/CN107118191A/en not_active Withdrawn
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2921070A (en) * | 1957-11-05 | 1960-01-12 | Recordati Lab Farmacologico S | Basic esters of 3-methylflavone-8-carboxylic acid |
| US4533732A (en) * | 1982-09-30 | 1985-08-06 | Yamamoto Chemical Industrial Company, Limited | 3-Propionylsalicylic acid derivatives and process for the preparation of the same |
| US4634768A (en) * | 1982-09-30 | 1987-01-06 | Yamamoto Chemical Industrial Co., Ltd. | Halo-containing 3-methylflavone-8-carboxylic acid derivatives |
| CN104031015A (en) * | 2014-06-10 | 2014-09-10 | 金坛德培化工有限公司 | Preparation method for 3-methyl flavone-8-carboxylic acid |
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| TODD D. NELSON 等: "Cu, Ni, and Pd mediated homocoupling reactions in biaryl syntheses: The Ullmann reaction", 《ORGANIC REACTIONS》 * |
| YOSHIHITO KOHARI 等: "Efficient synthesis of biflavones having A ring-A ring of two flavone units using Suzuki cross-coupling reactions", 《HETEROCYCLES》 * |
| 辛成伟: "3-甲基黄酮-8-羧酸的合成研究", 《中国优秀硕士学位论文全文数据库 工程科技Ⅰ辑》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111153881A (en) * | 2020-01-13 | 2020-05-15 | 辽宁海德制药有限公司 | Preparation method for synthesizing intermediate 3-methylflavone-8-carboxylic acid of flavoxate hydrochloride |
| CN114736183A (en) * | 2022-04-14 | 2022-07-12 | 迪嘉药业集团有限公司 | Preparation method of 3-methylflavone-8-carboxylic acid |
| CN114736183B (en) * | 2022-04-14 | 2023-10-17 | 迪嘉药业集团股份有限公司 | Preparation method of 3-methyl flavone-8-carboxylic acid |
| CN115960065A (en) * | 2023-01-06 | 2023-04-14 | 山东鲁西药业有限公司 | Preparation method of flavoxate hydrochloride |
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Application publication date: 20170901 |