CN104974072B - A kind of method for preparing Silodosin intermediate - Google Patents
A kind of method for preparing Silodosin intermediate Download PDFInfo
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- CN104974072B CN104974072B CN201410143671.3A CN201410143671A CN104974072B CN 104974072 B CN104974072 B CN 104974072B CN 201410143671 A CN201410143671 A CN 201410143671A CN 104974072 B CN104974072 B CN 104974072B
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- 0 CC(C)C(CC(C)N(C(c1c2cccc1)=O)*2=O)=CC(C#N)=CNC(C)=O Chemical compound CC(C)C(CC(C)N(C(c1c2cccc1)=O)*2=O)=CC(C#N)=CNC(C)=O 0.000 description 7
- QRTLUWRDMYFNCH-UHFFFAOYSA-N CC(C)C(c(cc1CC2)ccc1N2C(C)=O)=O Chemical compound CC(C)C(c(cc1CC2)ccc1N2C(C)=O)=O QRTLUWRDMYFNCH-UHFFFAOYSA-N 0.000 description 1
- LMIVAZNCPMAQTI-UHFFFAOYSA-N CCC(C(c(cc1)cc(CC2)c1N2C(C)=O)=O)N(C(c1ccccc11)=O)C1=O Chemical compound CCC(C(c(cc1)cc(CC2)c1N2C(C)=O)=O)N(C(c1ccccc11)=O)C1=O LMIVAZNCPMAQTI-UHFFFAOYSA-N 0.000 description 1
- PHIRCBAQQSMDAS-UHFFFAOYSA-N CCC(Cc1cc(CC(C)N(C(c2ccccc22)=O)C2=O)c2)N(C(C)=O)c1c2Br Chemical compound CCC(Cc1cc(CC(C)N(C(c2ccccc22)=O)C2=O)c2)N(C(C)=O)c1c2Br PHIRCBAQQSMDAS-UHFFFAOYSA-N 0.000 description 1
- HOESCGGAWXOPCH-UHFFFAOYSA-N CCCc1cc(C#N)c2N(CCCOC(c3ccccc3)=O)CCc2c1 Chemical compound CCCc1cc(C#N)c2N(CCCOC(c3ccccc3)=O)CCc2c1 HOESCGGAWXOPCH-UHFFFAOYSA-N 0.000 description 1
- TZQKUFUVNIEEAL-MRXNPFEDSA-N C[C@H](Cc1cc(C#N)c2N(CCCOC(c3ccccc3)=O)CCc2c1)C(O)=O Chemical compound C[C@H](Cc1cc(C#N)c2N(CCCOC(c3ccccc3)=O)CCc2c1)C(O)=O TZQKUFUVNIEEAL-MRXNPFEDSA-N 0.000 description 1
- GCKCREURICWFPY-UHFFFAOYSA-N O=C(c1ccccc1)OCCCCl Chemical compound O=C(c1ccccc1)OCCCCl GCKCREURICWFPY-UHFFFAOYSA-N 0.000 description 1
- DGCIPHNRGLERLO-UHFFFAOYSA-N O=CN(CC1)c2c1cccc2 Chemical compound O=CN(CC1)c2c1cccc2 DGCIPHNRGLERLO-UHFFFAOYSA-N 0.000 description 1
- BRQFIORUNWWNBM-ZIAGYGMSSA-N OC[C@@H](CCCC1)[C@@H]1NCc1ccccc1 Chemical compound OC[C@@H](CCCC1)[C@@H]1NCc1ccccc1 BRQFIORUNWWNBM-ZIAGYGMSSA-N 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/235—Saturated compounds containing more than one carboxyl group
- C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
- C07C59/255—Tartaric acid
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Abstract
The invention discloses a kind of method for preparing Silodosin intermediate, the structural formula of the intermediate is as shown in formula A.The present invention uses indoline for initial feed, and target product is finally made by the reaction such as friedel-crafts acylation, carbonyl reduction, drop cloth riel, chiral resolution.The preparation method has the features such as low simple to operate, cost, high income, product are easy to purification, process stabilizing, is suitable for industrialized production.The invention also discloses the new midbody compound being related in the method.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to a kind of method for preparing Silodosin intermediate and in the party
Involved new midbody compound in method.
Background technology
Benign prostatic hyperplasis（BPH）It is middle-aging male common disease and frequently-occurring disease, is clinically used to treat BPH's at present
Medicine is broadly divided into two classes：The adrenocepters of α 1（α-AR）Antagonist and 5 alpha reductase inhibitors.Wherein α-AR antagonists have
The characteristics of having quick, safe efficient.Silodosin is the α-AR antagonists of BPH a kind of, for treating benign prostatic hyperplasia
Caused dysuria.
Silodosin shrinks for urethral smooth muscle has selective inhibitory, and reduces urethra internal pressure, and to blood
Pressure does not have a significant impact, Small side effects, thus available for treatment benign prostatic hyperplasis.
1- acetyl group -7- cyano group -5-（2- aminopropyls）Indoline（That is compound A）It is to be used to synthesize west in the prior art
A Luo Duoxin key intermediate.Reported according to documents and materials, in the prior art, prepare 1- acetyl group -7- cyano group -5-（2-
Aminopropyl）Indoline a synthetic route is main by following three：
First synthetic route has described in Publication No. EP0600675A1 patent application：
The major defect of the route has：Tribromo pyrrolidones costly is used when a, bromination；B, two steps hydrogenation are also
Original reaction will use the catalyst platinum oxide of costliness；This step yield of c, cyanogenation is relatively low, to use column chromatography for separation and carry
It is pure.Therefore, the implementation cost of the route is higher, and is difficult industrialized production.
Article 2 synthetic route has described in Publication No. CN101759627A patent application：
The major defect of the route is that the reaction selectivity of bromination step is poor, and yield is low, and purification is more difficult；Bromination mistake
Violent in toxicity Cymag will be used by being applied in journey during expensive tribromo pyrrolidones, cyanogenation.And its explanation
Specific process conditions are not disclosed in book, a general introduction, therefore the work of the route have only been done to whole technological process
Industry value is not also high.
Article 3 synthetic route has described in publication number CN102690223A patent application：
The major defect of the route is that the reaction selectivity of denitrification step is poor, and yield is low, and purification is more difficult.The route
Industrial value it is also not high.
The compound A that above-mentioned route synthesis is obtained stills need 7 reactions steps when to prepare silodosin, subsequently,
And most end-product needs to carry out fractionation purification, so causes the yield of final product also relatively low, causes road
The implementation cost of line is higher, and is easily caused certain risk to the control of byproduct of reaction in subsequent step.
JP2001199956 reports the R- compounds shown in formula A（R1=benzoyl）
Preparation method, this method passes through compound ii
Asymmetric reduction amination with L- benzene glycinols obtains target product.This method uses L- benzene glycinols, reduces amine
Change intermediate shown in the following formula III of obtained diastereoisomer mixing（Diastereoisomer ratio 3.8:1）,
Then in the presence of Pd/C, catalytic hydrogenation sloughs benzyl carbinol part, and finally carrying out optics with L-TARTARIC ACID purifies,
Obtain the R- compounds shown in single formula A（R1=benzoyl）.The process employs more expensive reagent L- benzene glycinol and L-
Tartaric acid.
JP2002265444 reports 5- [(2R) -2- aminopropyls] -1- [3- (benzoyloxy) propyl group] -- 7- cyano group
The preparation method of indoline, this method obtains target compound by the fractionation to compound (11).The synthesis road of this method
Line length, resolution yield is low, and resolution reagent used is difficult to obtain, and is not suitable for large-scale production.
It is above-mentioned in the prior art, formula A optical activity intermediate is the key intermediate for preparing silodosin.
As the key intermediate for preparing silodosin, formula A compound, which is used to prepare silodosin, to exist
Had been reported in CN101759627A, JP2001199956, JP2006188470, WO2011124704.
Based on prior art when synthesizing silodosin, the key intermediate prepare generally make synthesis technique complicate and
Cost is higher, so propose the present invention.
The content of the invention
It is an object of the invention to for above-mentioned not enough offer one kind is easy to purification, yield is higher, reduce actual production behaviour
Make the new preparation method of the Silodosin intermediate compound of difficulty and cost.
One aspect of the invention provides the preparation method of compound shown in formula A, successively including following 12 steps：
Specifically, the method that the present invention provides compound shown in a kind of formula A, the described method comprises the following steps：
1）By the compound of formula 1
Under the alkalescence condition that there is alkaline reagent, and excess acetyl chloride, obtain the compound of formula 2
2）Under Louis acid catalysis, the compound of the formula 2 and 2- chlorpromazine chlorides are reacted, the compound of formula 3 is obtained
3）By the compound and phthalic amide nak response of the formula 3, the compound of formula 4 is obtained
4）In trifluoroacetic acid solvent, the compound of the formula 4 and triethyl silicane are reacted, the compound of formula 5 is obtained
5）By the compound of the formula 5 and hydration hydrazine reaction, the compound of formula 6 is obtained
6）By the compound and D- tartaric acids of the formula 6, the compound for obtaining formula 7 is split in acetone and water
7）Under the alkalescence condition that there is alkaline reagent, by the compound and Boc anhydride reactions of the formula 7, formula 8 is obtained
Compound
8）By the compound of the formula 8 in the hydrolyzed under basic conditions reaction that there is alkaline reagent, the compound of formula 9 is obtained
9）Under the alkalescence condition that there is alkaline reagent, by the compound of the formula 9 and the compound of the formula 9-1
Reaction, obtains the compound of formula 10
10）The compound of the formula 10 and brominated reagent are subjected to bromo-reaction, the compound of formula 11 is obtained
11）Nitrogen is protected, at a temperature of 80~120 DEG C, four（Triphenylphosphine）Under palladium chtalyst effect, by the change of the formula 11
Compound and zinc cyanide reaction, obtain the compound of formula 12
12）In acid condition, the compound of the formula 12 is subjected to deprotection reaction, obtains the chemical combination of the formula A
Thing.
In some embodiments, the step 1）、2）、3）、5）、8）、9）、10）、11）With 12）It is in organic solvent
In the presence of carry out, the step 1）、2）、3）、5）、8）、9）、10）、11）With 12）In the organic solvent independently of one another
Selected from by C1-C4Lower alcohol, dichloromethane, dimethyl sulfoxide, trifluoroacetic acid, ethyl acetate, N,N-dimethylformamide and its group
The group being combined into.
In some embodiments, the alkaline reagent is selected from by sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, iodine
Change the group of potassium, sodium acid carbonate, diisopropyl ethylenediamine and triethylamine composition.
In some embodiments, the step 10）In the brominated reagent be selected from by C5H6Br2N2O2, N- bromos fourth two
The group of acid imide and bromine composition.
In some embodiments, the step 12）In the acid condition by add acid or hydrogen chloride gas obtain
, wherein the acid is selected from the group being made up of 36% hydrochloric acid, trifluoroacetic acid, acetic acid and formic acid.
Preferably, the step 10）In the brominated reagent be N- bromo-succinimides.
Preferably, the step 12）Described in acid be 36% hydrochloric acid.
In some embodiments, the step 1）Reaction temperature be -10~30 DEG C, the reaction time be 0.5~3h, it is excellent
It is -5~15 DEG C to select reaction temperature, and the reaction time is 0.5~1h.
In some embodiments, the step 2）Reaction temperature be -10~30 DEG C, the reaction time be 0.5~10h,
Preferable reaction temperature is -5~15 DEG C, and the reaction time is 0.5~5h.
In some embodiments, the step 3）Reaction temperature be 10~100 DEG C, the reaction time be 0.5~5h, it is excellent
It is 50~90 DEG C to select reaction temperature, and the reaction time is 1~3h.
In some embodiments, the step 4）Reaction temperature be -10~50 DEG C, 5~30h of reaction time, preferably
Reaction temperature is -10~30 DEG C, and the reaction time is 10~30h.
In some embodiments, the step 5）Reaction temperature be 10~100 DEG C, 0.5~5h of reaction time, preferably
Reaction temperature is 50~90 DEG C, and the reaction time is 0.5~3h.
In some embodiments, the step 6）Reaction temperature be -10~20 DEG C, 0.5~5h of reaction time, preferably
Reaction temperature is -5~10 DEG C, and the reaction time is 0.5~3h.
In some embodiments, the step 7）Reaction temperature be -10~20 DEG C, 5~30h of reaction time, preferably
Reaction temperature is -5~10 DEG C, and the reaction time is 10~30h.
In some embodiments, the step 8）Reaction temperature be -10~50 DEG C, 5~30h of reaction time, preferably
Reaction temperature is 0~30 DEG C, and the reaction time is 10~20h.
In some embodiments, the step 9）Reaction temperature be 50~200 DEG C, 5~30h of reaction time, preferably
Reaction temperature is 50~150 DEG C, and the reaction time is 5~15h.
In some embodiments, the step 10）Reaction temperature be 0~50 DEG C, 1~10h of reaction time, preferably instead
It is 0~30 DEG C to answer temperature, and the reaction time is 5~10h.
In some embodiments, the step 11）Reaction temperature be 50~150 DEG C, 5~20h of reaction time, preferably
Reaction temperature is 50~100 DEG C, and the reaction time is 5~15h.
In some embodiments, the step 12）Reaction temperature be 0~50 DEG C, 0.1~5h of reaction time, preferably
Reaction temperature is 0~30 DEG C, and the reaction time is 0.1~2h.
Another aspect of the present invention is to provide a kind of compound being shown below：
Another aspect of the present invention is to provide a kind of compound being shown below：
The method that the present invention also provides compound shown in a kind of formula 9-1.
Methods described specifically includes the following steps：
In organic solvent, under alkalescence condition, at a temperature of 0~50 DEG C, chlorobenzoyl chloride and 3- chloropropyl alcohols are reacted into 1~5h,
Obtain formula 9-1 compound.
It will be understood by those skilled in the art that above-mentioned reaction condition, include the reaction of compound shown in foregoing synthesis type M
Condition, is not the sole mode for realizing technical solution of the present invention.Those skilled in the art can not depart from present inventive concept
On the basis of, the reaction condition is modified and realizes technical scheme according to being actually needed.
The advantage of the invention is that：Compound shown in the formula A synthesized by the inventive method, can be used as midbody compound
To synthesize silodosin.This method has the advantage that：
1. needed for supplementary material be commercially available industrial chemicals, buying cost is low, so as to reduce production cost；
2. overcoming, yield present in prior art is relatively low, purification difficult defect, and not only reaction yield is high, operation letter
Singly, danger is reduced, and is easy to purification.
Therefore, implementation cost can be substantially reduced using the preparation method of the present invention, is advantageously implemented industrialized production, has
High industrial application value.
Brief description of the drawings
Fig. 1 is compound 9-1 MS figures；
Fig. 2 is the MS figures of compound 2；
Fig. 3 is the MS figures of compound 3；
Fig. 4 is the MS figures of compound 4；
Fig. 5 is the MS figures of compound 5；
Fig. 6 is compound 71H NMR scheme；
Fig. 7 is compound 81H NMR scheme；
Fig. 8 is the MS figures of compound 9；
Fig. 9 is compound 101H NMR scheme；
Figure 10 is compound 111H NMR scheme；
Figure 11 is compound 121H NMR scheme；And
Figure 12 is compound A1H NMR scheme.
Embodiment
Illustrate the present invention below with reference to specific embodiment.It should be noted that the following examples are the present invention
Example, only for illustrating the present invention, and be not limited to the present invention.
Embodiment 1
1）Compound 9-1 preparation
Weigh 140g chlorobenzoyl chlorides（It is commercially available）It is added in 1L single port bottles, adds 600mL dichloromethane, 70g triethylamines is cold
But to 0 DEG C, slowly it is added dropwise below 94g3- chloropropyl alcohols, 10 DEG C of keeping temperature.Continue to react 1h after dripping.
After TLC monitoring reactions completely, 300mL*3 washing organic layers, anhydrous sodium sulfate drying, concentrated solvent obtains 188g
Colourless liquid（Compound 9-1）, purity 99%.MS m/z：198(M+), yield：95%.
Compound 9-1 MS figures are referring to Fig. 1.
2）The preparation of compound 2
Weigh 132g compounds 1（It is commercially available）Add in 2L there-necked flasks, then add 1L dichloromethane and the second of 167g tri- thereto
Amine, is cooled to 0 DEG C, chloroacetic chloride is slowly added dropwise（130g, 1.5eq）, below 10 DEG C of keeping temperature.Continue to react 1h after dripping.
After TLC monitoring reactions completely, 700mL*3 washing organic layers, anhydrous sodium sulfate drying, concentrated solvent, ethanol is tied again
Crystalline substance, obtains 145g yellow solids（Compound 2）.MS m/z：161(M+), yield：81%.
The MS figures of compound 2 are referring to Fig. 2.
3）The preparation of compound 3
333g alchlors and 1L dichloromethane are added into 2L there-necked flasks.5 DEG C are cooled to, 193g dichloro propionyl is added dropwise
Chlorine, is dripped off, insulated and stirred 1h.The dichloromethane solution of 5 DEG C of dropwise addition compounds 2 of temperature control（500mL bis- is dissolved in 175g compounds 2
Chloromethanes）, drip off, insulated and stirred 2h, reaction 2h, TLC be warmed to room temperature naturally and shows that reaction terminates.
Post processing：Under stirring, reaction solution is poured slowly into 1.5L frozen water, a small amount of watery hydrochloric acid is added（2mol/L）.Divide liquid,
Water layer is extracted with 300mL*2 dichloromethane, is merged organic layer, is washed to neutrality, separates organic layer, with anhydrous sodium sulfate drying,
Dry solvent is concentrated, the crude product of compound 3 is obtained.Crude product 200mL ethyl acetate+200mL ethanol+250mL dichloromethane weights
Crystallization obtains 227g（Compound 3）, MS m/z：251(M+), yield 83.5%.
The MS figures of compound 3 are referring to Fig. 3.
4）The preparation of compound 4
224g compounds 3 and 14.24g phthalic amide potassium are weighed, and measures 1L DMF（N,N-dimethylformamide）,
It is added in 2L there-necked flasks, is warming up to 80 DEG C, react 2h, TLC shows that reaction terminates.
Post processing：Under quick stirring, reaction solution is poured slowly into 4L frozen water, a large amount of solids are separated out, 30min is stirred, takes out
Filter, washing filter cake three times, dries and obtains 305g pale yellow powders naturally（Compound 4）.MS m/z：362(M+), yield：
94.4%。
The MS figures of compound 4 are referring to Fig. 4.
5）The preparation of compound 5
203g compounds 4 and 800mL trifluoroethanols are added in 2L there-necked flasks, -10 DEG C, temperature control are cooled under nitrogen protection
At -10 DEG C to -5 DEG C, 130g triethyl silicanes, about 40min completion of dropping is added dropwise.Drip off, temperature control is in 0 DEG C of 2h stirred below, certainly
So it is warmed to room temperature, reaction is stayed overnight.
Post processing：Concentration of reaction solution, reclaims trifluoroacetic acid, and 1L water is added into the reaction solution after above-mentioned concentration, is quickly stirred
Mix down, then reaction solution pH to 8 or so is adjusted with 25% sodium hydrate aqueous solution, separate out a large amount of solids, continue to stir 20min, take out
Filter, filter cake ethanol rinse dries and obtains 210g off-white powders naturally（Compound 5）.MS m/z：348(M+)。
The MS figures of compound 5 are referring to Fig. 5.
6）The preparation of compound 7
Weigh 201g compounds 5,113g hydrazine hydrates（80%）, 1.5L ethanol add in 2L there-necked flasks, be warming up to 85 DEG C it is anti-
Should, there are a large amount of white solids suddenly in reaction 30min, continues to react 3h, TLC shows that reaction terminates.
Post processing：It is cooled to room temperature, suction filtration, the ethanol rinse of filter cake heat is twice.Above-mentioned filtrate is concentrated to 1/3 volume, it is cold
To room temperature, there is a small amount of white insoluble matter to occur, filter out white insoluble matter, the hot white insoluble matter of ethanol washing once, then is concentrated
Alcohol solvent is removed, 150g thick white shape solids are obtained（Compound 6）.
Above-claimed cpd 6 is added in 3L there-necked flasks（150g, thick white shape solid）With 1300mL acetone, 0 DEG C is cooled to,
The lower methanol solution that D- tartaric acid is added dropwise of stirring（103g D- tartaric acid is dissolved in 600mL methanol）.Completion of dropping continues 0 DEG C instead
Answer 2h, TLC to show that reaction terminates, filter, filter cake weight in wet base obtains 450g（The crude product of compound 7）.The crude product of compound 7 is through 4
Secondary acetone/water recrystallization, 19.77g white solids are obtained after drying（Compound 7）, yield：20%（Calculated with compound 3）.
Compound 71H NMR figures are referring to Fig. 6.
7）The preparation of compound 8
29.6g compounds 7,16.2g triethylamines and 200mL dichloromethane are added in 250mL there-necked flasks, 0 DEG C is cooled to,
Boc acid anhydrides is added dropwise（Di-tert-butyl dicarbonate）Dichloromethane solution（18.2gBoc acid anhydrides is dissolved in 50mL dichloromethane）, it is added dropwise
Finish, be warmed to room temperature naturally, reaction is stayed overnight, TLC shows that reaction terminates.
Post processing：Reaction solution is poured into 250mL water, point liquid, organic layer is washed with water to neutrality, anhydrous sodium sulfate drying,
Concentrate dry solvent and obtain 29g yellow oily liquids（Crude product）.Column chromatography obtains 19.5g white powdery solids（Compound 8）, receive
Rate：76%.
Compound 81H NMR figures are referring to Fig. 7.
8）The preparation of compound 9
55g compounds 8,17g sodium hydroxides are weighed, 300mL ethanol, 100mL water is measured, is added in 1L single port bottles, is returned
Stream reaction 10h.
After TLC detection reactions terminates, room temperature is cooled to, 500mL water is added, is extracted with 300mL*3 ethyl acetate, is dried,
Concentration, column chromatography obtains 40g white solids（Compound 9）.MS m/z：276(M+), yield：83.8%.
The MS figures of compound 9 are referring to Fig. 8.
9）The preparation of compound 10
13.8g compounds 9,10g compounds 9-1,13.8g sodium carbonate, 0.83g KIs are weighed, 100mL DMF is measured and arrives
In single port bottle, 130 DEG C are warming up to, 8h is reacted.
After reaction terminates, 200mL water is added, the extraction of 150L*3 ethyl acetate merges organic layer, and washing organic layer 3 times is done
Dry, concentration, silica gel column chromatography obtains 14.6g grease（Compound 10）, yield：66%.
Compound 101H NMR figures are referring to Fig. 9.
10）The preparation of compound 11
Weigh 6.5g compounds 10 to be added in 100mL there-necked flasks, add 40mL DMF, weigh 3g N- bromo fourth acetyl
Diamines is dissolved in 10mL DMF, is added dropwise in substrate, and less than 30 DEG C are maintained the temperature at during dropwise addition, and it is small to be stirred at room temperature 5 after dripping off
When.
After reaction terminates, 100mL water is added, the extraction of 70mL*3 ethyl acetate merges organic layer, and washing organic layer 3 times is done
Dry, concentration, silica gel column chromatography obtains 6.3g colourless liquids（Compound 11）, yield：81%.
Compound 111H NMR figures are referring to Figure 10.
11）The preparation of compound 12
Weigh 1.1g compounds 11,0.58g zinc cyanides, 0.23g tetra-（Triphenylphosphine）Palladium, measures 8mL DMF to single port bottle
In, nitrogen protection is warming up to 90 DEG C, reacts 12h.
After TLC detection reactions terminate, a small amount of weak aqua ammonia is added（20%), 25mL*3 ethyl acetate is extracted, and merges organic layer,
Wash organic layer 2 times, saturation NaCl solution is washed 2 times, anhydrous sodium sulfate drying, concentration, silica gel column chromatography obtains 0.6g white solids
（Compound 12）, yield：64.6%.
Compound 121H NMR figures are referring to Figure 11.
12）Compound A preparation
Weigh 0.6g compounds 12 to be added in 10mL ethyl acetate, 2mL36% concentrated hydrochloric acids are added dropwise, 20min is stirred at room temperature.
After reaction terminates, careful regulation pH to 9.20mL water is added, the extraction of 15mL*3 ethyl acetate merges organic layer, water
Wash organic layer 3 times, dry, concentration obtains 0.5g light yellow liquids (compound A), yield：85.8%.
Compound A's1H NMR figures are referring to Figure 12.
Claims (8)
1. a kind of method of compound shown in formula A,
It the described method comprises the following steps：
1) by the compound of formula 1
Under the alkalescence condition that there is alkaline reagent, and excess acetyl chloride, obtain the compound of formula 2
2) under Louis acid catalysis, the compound of the formula 2 and 2- chlorpromazine chlorides is reacted, the compound of formula 3 is obtained
3) by the compound and phthalic amide nak response of the formula 3, the compound of formula 4 is obtained
4) in trifluoroacetic acid solvent, the compound of the formula 4 and triethyl silicane is reacted, the compound of formula 5 is obtained
5) by the compound of the formula 5 and hydration hydrazine reaction, the compound of formula 6 is obtained
6) by the compound and D- tartaric acids of the formula 6, the compound for obtaining formula 7 is split in acetone and water
7) under the alkalescence condition that there is alkaline reagent, by the compound and Boc anhydride reactions of the formula 7, the chemical combination of formula 8 is obtained
Thing
8) compound of the formula 8 is reacted in the hydrolyzed under basic conditions that there is alkaline reagent, obtains the compound of formula 9
9) under the alkalescence condition that there is alkaline reagent, by the compound of the formula 9 and the compound of the formula 9-1
Reaction, obtains the compound of formula 10
10) compound of the formula 10 and brominated reagent are subjected to bromo-reaction, obtain the compound of formula 11
11) nitrogen is protected, at a temperature of 80~120 DEG C, under tetrakis triphenylphosphine palladium catalytic action, by the compound of the formula 11
With zinc cyanide reaction, the compound of formula 12 is obtained
12) compound of the formula 12 in acid condition, is subjected to deprotection reaction, the compound of the formula A is obtained.
2. preparation method as claimed in claim 1, wherein the step 1), 2), 3), 5), 8), 9), 10), 11) He 12)
Carry out in the presence of an organic, the step 1), 2), 3), 5), 8), 9), 10), 11) He 12) in it is described organic molten
Agent is each independently selected from by C1-C4Lower alcohol, dichloromethane, dimethyl sulfoxide, trifluoroacetic acid, ethyl acetate, N, N- dimethyl
The group of formamide and combinations thereof composition.
3. preparation method as claimed in claim 1, wherein the step 8) alkaline reagent be selected from by sodium hydroxide and hydrogen-oxygen
Change the group of potassium composition, the step 9) alkaline reagent be selected from and be made up of potassium carbonate, sodium carbonate, KI and sodium acid carbonate
Group, the step 1) and step 7) alkaline reagent be selected from the group that is made up of diisopropyl ethylenediamine and triethylamine.
4. preparation method as claimed in claim 1, wherein the step 10) in the brominated reagent be selected from by dibromo sea
The group of cause, N- bromo-succinimides and bromine composition.
5. preparation method as claimed in claim 1, wherein the step 12) in the acid condition pass through and add acid or chlorine
Change hydrogen to obtain, wherein the acid is selected from the group being made up of 36% hydrochloric acid, trifluoroacetic acid, acetic acid and formic acid.
6. preparation method as claimed in claim 4, wherein the step 10) in the brominated reagent be N- bromo succinyl
Imines.
7. preparation method as claimed in claim 5, wherein the step 12) described in acid be 36% hydrochloric acid.
8. a kind of compound being shown below：
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| ES2607639B1 (en) | 2015-09-30 | 2018-02-28 | Urquima, S.A | Maleic acid salt of a silodosin intermediate |
| CN105254553B (en) * | 2015-11-09 | 2018-04-10 | 黄欢 | The preparation method of Silodosin intermediate |
| CN106496092B (en) * | 2016-08-30 | 2019-03-29 | 江苏宇田医药有限公司 | It is a kind of for synthesizing the preparation method of the intermediate of silodosin |
| CN106380438B (en) * | 2016-08-30 | 2019-07-30 | 江苏宇田医药有限公司 | It is a kind of for synthesizing the preparation method of the indoline derivative object of silodosin |
| CN107056675B (en) * | 2017-05-10 | 2019-09-03 | 浙江天宇药业股份有限公司 | A kind of synthetic method of silodosin and its intermediate |
| CN109574903A (en) * | 2017-09-28 | 2019-04-05 | 安徽省庆云医药股份有限公司 | A method of preparing Silodosin intermediate |
| CN108033906B (en) * | 2017-12-28 | 2021-07-06 | 常州瑞明药业有限公司 | Preparation method of silodosin intermediate |
| CN108047116B (en) * | 2017-12-28 | 2021-08-13 | 常州瑞明药业有限公司 | Preparation method of R-5- (2-aminopropyl) -1- (3-hydroxypropyl) -7-nitrilindoline |
| KR102163068B1 (en) * | 2018-07-04 | 2020-10-07 | 주식회사 가피바이오 | The manufacturing method of intermediate for synthesis of silodosin and the manufacturing method of silodosin |
| CN111825702A (en) * | 2019-04-22 | 2020-10-27 | 成都科岭源医药技术有限公司 | Aza indazole derivative and preparation method and application thereof |
| CN114014793A (en) * | 2021-11-29 | 2022-02-08 | 安徽美致诚药业有限公司 | 5-substituted indoline derivative or salt thereof, preparation method and application thereof, and preparation method of silodosin |
| CN114751852B (en) * | 2022-05-23 | 2023-09-15 | 山西库邦生物医药科技有限公司 | Preparation method of silodosin key intermediate |
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