A kind of method for synthesizing high-purity losartan side chain TTBB
Technical field
The invention belongs to the synthesis technical field of husky smooth class medicine intermediate, and in particular to one kind synthesis high-purity Sha Tan sides
The method of chain TTBB, specially synthesizes antihypertensive sartans intermediate N (trityl group) -5- (4'- bromomethyls
Biphenyl -2- bases) tetrazotized zole compound method.
Background technology
Sartans are to be used for clinical drug for hypertension after pril medicine, are in global cardiovascular market
Mainstream kind.In all antihypertensive drugs, since the tolerance of husky smooth class is best, its security is similar to placebo, bad
React slight, of short duration, less generation low blood pressure, cough effect, receive the favor of numerous hyperpietics.
Since first sartans LOSARTAN POTASSIUM in 1994 is since Sweden lists, up to the present there is the figured silk fabrics husky in succession
A variety of sartans listings such as smooth, Candesartan, irbesartan.Since sartans have good antihypertensive effect, dry
The side reactions such as cough are low and the compliance of patient is good, have become the first-line drug for the treatment of hypertension.
N- (trityl group) -5- (4'- bromomethylbiphenyl -2- bases) tetrazotized zole compound is that synthesis antihypertensive sand is smooth
The key intermediate of class medicine, is applied to production N- (trityl group) -5- (4 '-bromomethylbiphenyl -2- bases) tetrazole at present
Compound uses following process route:
Detailed process is:Using 4- methyl -2- cyanobiphenyls as raw material, in the catalytic action of lewis acid triethylamine hydrochloride
It is lower ring-closure reaction occurs with Sodium azide to generate 5- [2- (4'- methyl biphenyls)] tetrazole compound, then in alkaline conditions with
Triphenylchloromethane reaction generation N- (trityl group) -5- (4'- methyl biphenyl -2- bases) tetrazotized zole compound, finally two
Target product is generated under conditions of bromine glycolylurea.But there is following deficiency in the synthetic method:In the preparation process of compound 4 always
With raw material (TTMB) and dibrominated accessory substance so that target product reaction yield declines, and the separation of target product is non-
It is often difficult, considerably increase production cost and influence the quality of target product.
The content of the invention
The technical problem to be solved by the present invention is to provide a kind of simple, the of low cost and higher product purity synthesis of technique
The method of high-purity losartan side chain TTBB.
The present invention adopts the following technical scheme that to solve above-mentioned technical problem, a kind of to synthesize high-purity losartan side chain TTBB's
Method, it is characterised in that concretely comprise the following steps:
(1) using 4- methyl -2- cyanobiphenyls as starting material, under the catalytic action of lewis acid triethylamine hydrochloride with
Ring-closure reaction generation 5- [2- (4'- methyl biphenyls)] tetrazole compound, wherein lewis acid triethylamine hydrochloric acid occurs for Sodium azide
Salt is carried on macropore sulfuric acid resin and recycles lewis acid triethylamine hydrochloride repeated recycling utilize;
(2) 5- [2- (4'- methyl biphenyls)] tetrazole compound reacts with triphenylchloromethane generate in alkaline conditions
N- (trityl group) -5- (4'- methyl biphenyl -2- bases) tetrazotized zole compound;
(3) N- (trityl group) -5- (4'- methyl biphenyl -2- bases) tetrazotized zole compound is under the action of bromo-containing substance
The mixture of reaction generation compound TTBB and compound Br-TTBB;
(4) mixture of compound TTBB and compound Br-TTBB promote compound under the action of diethyl phosphite
Br-TTBB is converted into compound TTBB, finally obtained high-purity losartan side chain TTBB.
Further preferably, lewis acid triethylamine hydrochloride described in step (1) and 4- methyl -2- cyanobiphenyls feed intake
Molar ratio is 1:1-5:1, reaction temperature is preferably 30-130 DEG C, and solvent for use is DMF in reaction process.
Further preferably, [2- (4'- the methyl biphenyls)] tetrazole compounds of 5- described in step (2) and triphenylchloromethane
Molar ratio be 1:1-1:3, reaction temperature is preferably 0-40 DEG C.
Further preferably, bromo-containing substance described in step (3) is bromine, NBS or C5H6Br2N2O2, bromo-containing substance and N- (three
Phenyl methyl) molar ratio of -5- (4'- methyl biphenyl -2- bases) tetrazotized zole compound is 0.5-2:1.
Further preferably, the detailed process of step (4) is:The mixture of compound TTBB and compound Br-TTBB is molten
In solvent THF, add inorganic base potassium carbonate and diethyl phosphite is added dropwise, heating stirring reaction, stops after complete reaction
Only react, be cooled to room temperature, be then filtered to remove inorganic base potassium carbonate, most solvent THF are evaporated off, recycle ethyl acetate
Heating recrystallization, filtering, high-purity target product losartan side chain TTBB is obtained using ethanol rinse.
The present invention has the following advantages compared with prior art:
The present invention will directly be difficult to separated double bromine compounds Br-TTBB by chemical method and directly convert in target product
For target product TTBB, so as to avoid improving the purity of target product by repeated recrystallize using conventional method, so
It is possible to prevente effectively from the cumbersome link of repeated recrystallize operation and a large amount of of solvent use the increase for causing cost, meanwhile, with
Macropore sulfuric acid resin is the multiple utilization of the Louis triethylenetetraminehexaacetic acid amine hydrochlorate catalyst of carrier, reduction cost that can be larger.Cause
This, new synthesis technique is more economical, environmentally friendly, efficient and easy.
Embodiment
Detailed description of the present invention particular content in conjunction with the embodiments.
Embodiment 1
The synthesis of 5- [2- (4'- methyl biphenyls)] tetrazole compound (compound 2)
Weigh 4- methyl -2- cyanobiphenyls 1 (200g) to be added in four-hole bottle, the middle addition DMF solvent into four-hole boiling flask
(500mL), after 4- methyl -2- cyanobiphenyls stir dissolved clarification, the DMF clarifications at room temperature to 4- methyl -2- cyanobiphenyls are molten
Et of the addition using macropore sulfuric acid resin as carrier in liquid3NHCl (285.3g), begins to warm up, and between 40-50 DEG C, starts in batches
Add Sodium azide (134.7g), start gradually heating after adding, until (raw material reaction is endless for 115 DEG C of reaction 30h, HPLC detections
Entirely), it is cooled to room temperature, first filters out the lewis acid triethylamine hydrochloride using macropore sulfuric acid resin as carrier, then adds toluene
The NaOH solution (120mL) of (200mL), water (800mL) and 48wt%.Stirring separates toluene layer, repeatedly adds toluene to ensure
Water layer does not have raw material (amounting to three times, 600mL).TLC detection raw material abstractions are complete.Extract water layer is added dropwise between 0-10 DEG C
Into concentrated hydrochloric acid (215mL), stirring 2.5h is dripped, then filters, is washed twice with water (500mL), then in 50 DEG C of air blast
It is dried to obtain compound as white solid 2 (220g), yield:90%, HPLC:99.97%.
Embodiment 2
The synthesis of 5- [2- (4'- methyl biphenyls)] tetrazole compound (compound 2)
Weigh 4- methyl -2- cyanobiphenyls 1 (20g) to be added in four-hole bottle, the middle addition DMF solvent into four-hole boiling flask
(50mL), after 4- methyl -2- cyanobiphenyls stir dissolved clarification, at room temperature to the DMF settled solutions of 4- methyl -2- cyanobiphenyls
Et of the middle addition using macropore sulfuric acid resin as carrier3NHCl (28.5g), adds Sodium azide (13.4g), after adding under microwave radiation
Start gradually heating, until 65 DEG C of reaction 2h, HPLC detections are cooled to room temperature, it is carrier Louis first to filter out big ring sulfonate resin
This triethylenetetraminehexaacetic acid amine hydrochlorate, then adds the NaOH solution (12mL) of toluene (20mL), water (80mL) and 48wt%.Stirring separates first
Benzene layer, repeatedly adds toluene to ensure that water layer does not have raw material (amounting to three times, 60mL).TLC detection raw material abstractions are complete.Extraction
Liquid water layer is added drop-wise between 0-10 DEG C in concentrated hydrochloric acid (21.5mL), drips stirring 2.5h.Then filter, washed with water (50mL)
Wash twice, compound as white solid 2 (20g), yield are obtained then at 50 DEG C of forced air dryings:95%, HPLC:99.98%.
Embodiment 3
The synthesis of 5- [2- (4'- methyl biphenyls)] tetrazole compound (compound 2)
- 2 cyanobiphenyl 1 (10g) of 4- methyl is weighed to be added in four-hole bottle;The middle addition DMF solvent into four-hole boiling flask
(25mL), after -2 cyanobiphenyl of 4- methyl stirs dissolved clarification, at room temperature into the DMF settled solutions of -2 cyanobiphenyl of 4- methyl
Add the Et using macropore sulfuric acid resin as carrier3NHCl (15g), adds Sodium azide (7g), is opened after adding under ultrasonic wave wave radiation
Begin gradually to heat up, until 35 DEG C of reaction 3h.HPLC detections are cooled to room temperature, and first filter out lewis acid triethylamine hydrochloride, so
Afterwards plus toluene (20mL), water (60mL) and 48wt% NaOH solution (12mL).Stirring separate toluene layer, repeatedly add toluene with
Ensure that water layer does not have raw material (amounting to three times, 50mL).TLC detection raw material abstractions are complete.Extract water layer between 0-10 DEG C
It is added drop-wise in concentrated hydrochloric acid (12mL), drips stirring 2.5h, then filter, washed twice with water (50mL), then at 50 DEG C of air blast
It is dried to obtain compound as white solid 2 (20g), yield:96%, HPLC:99.98%.
Embodiment 4-7 is four utilizations using macropore sulfuric acid resin as the lewis acid triethylamine hydrochloride of carrier
Embodiment 4
Weigh 4- methyl -2- cyanobiphenyls 1 (20g) to be added in four-hole bottle, the middle addition DMF solvent into four-hole boiling flask
(50mL), after 4- methyl -2- cyanobiphenyls stir dissolved clarification, at room temperature to the DMF settled solutions of 4- methyl -2- cyanobiphenyls
The Et using macropore sulfuric acid resin as carrier of middle addition recycling3NHCl (28.53g), begins to warm up, and between 40-50 DEG C, starts
In batches plus Sodium azide (13.47g), gradually heating is started after adding, until (raw material reacts not for 115 DEG C of reaction 30h, HPLC detections
Completely), it is cooled to room temperature, first filters out the lewis acid triethylamine hydrochloride using macropore sulfuric acid resin as carrier, then adds first
The NaOH solution (12mL) of benzene (20mL), water (80mL) and 48wt%.Stirring separates toluene layer, repeatedly adds toluene to ensure water
Layer (amounts to three times, 60mL) without raw material.TLC detection raw material abstractions are complete.Extract water layer is added drop-wise between 0-10 DEG C
In concentrated hydrochloric acid (22mL), stirring 2.5h is dripped, then filters, is washed twice with water (50mL), then in 50 DEG C of forced air dryings
Obtain compound as white solid 2 (20.2g), yield:83%, HPLC:99.92%.
Embodiment 5
Weigh 4- methyl -2- cyanobiphenyls 1 (20g) to be added in four-hole bottle, the middle addition DMF solvent into four-hole boiling flask
(50mL), after 4- methyl -2- cyanobiphenyls stir dissolved clarification, at room temperature to the DMF settled solutions of 4- methyl -2- cyanobiphenyls
The Et using macropore sulfuric acid resin as carrier of middle addition recycling3NHCl (28.53g), begins to warm up, and between 40-50 DEG C, starts
In batches plus Sodium azide (13.47g), gradually heating is started after adding, until (raw material reacts not for 115 DEG C of reaction 30h, HPLC detections
Completely), it is cooled to room temperature, first filters out the lewis acid triethylamine hydrochloride using macropore sulfuric acid resin as carrier, then adds first
The NaOH solution (12mL) of benzene (20mL), water (80mL) and 48wt%.Stirring separates toluene layer, repeatedly adds toluene to ensure water
Layer (amounts to three times, 60mL) without raw material.TLC detection raw material abstractions are complete.Extract water layer is added drop-wise between 0-10 DEG C
In concentrated hydrochloric acid (22mL), stirring 2.5h is dripped, then filters, is washed twice with water (50mL), then in 50 DEG C of forced air dryings
Obtain compound as white solid 2 (18.2g), yield:75%, HPLC:99.90%.
Embodiment 6
Weigh 4- methyl -2- cyanobiphenyls 1 (20g) to be added in four-hole bottle, the middle addition DMF solvent into four-hole boiling flask
(50mL), after 4- methyl -2- cyanobiphenyls stir dissolved clarification, at room temperature to the DMF settled solutions of 4- methyl -2- cyanobiphenyls
The Et using macropore sulfuric acid resin as carrier of middle addition recycling3NHCl (28.53g), begins to warm up, and between 40-50 DEG C, starts
In batches plus Sodium azide (13.47g), gradually heating is started after adding, until (raw material reacts not for 115 DEG C of reaction 30h, HPLC detections
Completely), it is cooled to room temperature, first filters out the lewis acid triethylamine hydrochloride using macropore sulfuric acid resin as carrier, then adds first
The NaOH solution (12mL) of benzene (20mL), water (80mL) and 48wt%.Stirring separates toluene layer, repeatedly adds toluene to ensure water
Layer (amounts to three times, 60mL) without raw material.TLC detection raw material abstractions are complete.Extract water layer is added drop-wise between 0-10 DEG C
In concentrated hydrochloric acid (22mL), stirring 2.5h is dripped, then filters, is washed twice with water (50mL), then in 50 DEG C of forced air dryings
Obtain compound as white solid 2 (17.1g), yield:70%, HPLC:99.85%.
Embodiment 7
Weigh 4- methyl -2- cyanobiphenyls 1 (20g) to be added in four-hole bottle, the middle addition DMF solvent into four-hole boiling flask
(50mL), after 4- methyl -2- cyanobiphenyls stir dissolved clarification, at room temperature to the DMF settled solutions of 4- methyl -2- cyanobiphenyls
It is middle addition recycling using macropore sulfuric acid resin as carrier Et3NHCl (28.53g), begins to warm up, and between 40-50 DEG C, starts point
Criticize and add Sodium azide (13.47g), start gradually heating after adding, 30h is reacted up to 115 DEG C, (raw material reaction is endless for HPLC detections
Entirely), it is cooled to room temperature, first filters out the lewis acid triethylamine hydrochloride using macropore sulfuric acid resin as carrier, then adds toluene
The NaOH solution (12mL) of (20mL), water (80mL) and 48wt%.Stirring separates toluene layer, repeatedly adds toluene to ensure water layer
There is no raw material (amounting to three times, 60mL).TLC detection raw material abstractions are complete.Extract water layer is added drop-wise between 0-10 DEG C dense
In hydrochloric acid (22mL), stirring 2.5h is dripped, is then filtered, is washed twice with water (50mL), then obtained in 50 DEG C of forced air dryings
To compound as white solid 2 (15.40g), yield:63%, HPLC:90.34%.
Embodiment 8
The synthesis of N- (trityl group) -5- (4'- methyl biphenyl -2- bases) tetrazotized zole compound (compound 3)
Compound 2 (200g) is dissolved in the acetone of 700mL in 40 DEG C of stirrings, adds sodium hydrate aqueous solution (40.67g
Sodium hydroxide is dissolved in 160mL water), continue to stir 1h, start that (270.8 grams of the acetone soln dissolved with triphenylchloromethane is added dropwise
Triphenylchloromethane is dissolved in 800mL acetone), it is added dropwise and progressively separates out solid, is changed into white casse liquid.TLC monitorings are reacted to complete
Entirely, filter, wash that to obtain solid be intermediate 3, solid obtains white intermediate 3 (385g), yield in 50 DEG C of forced air dryings:
95.2%, HPLC:99.44%.
Embodiment 9
The synthesis of N- (trityl group) -5- (4'- bromomethylbiphenyl -2- bases) tetrazole TTBB and compound 4A
Compound 3 (TTMB, 300g) and DMDBH (123.9g) and initiator A IBN (10.28g) are added to four mouthfuls of 3L
In flask, solvent chlorobenzene (1.2L) is added, begins to warm up, is heated to that DBDMH is added portionwise at 80 DEG C, reaction HPLC tracking prisons
Survey, (i.e. TTBB-20140113-1 after reaction to a certain extent:TTMB:1.60%) heating, stirring, when room temperature is dropped to, are stopped
Add Na2S2O3Reaction is quenched in solution, and separation, adds NaHCO3Solution, removes accessory substance, and saturation NaCl washing separation is dry,
It is spin-dried for removing most of solvent chlorobenzene and obtains thick liquid, is beaten to obtain the mixture of compound 4 and compound 4A using ethanol,
HPLC:TTBB:73.73%, TTMB:0.49%, Br-TTBB:23.74%, yield:78.6%.
Embodiment 10
The synthesis of N- (trityl group) -5- (4'- bromomethylbiphenyl -2- bases) tetrazotized zole compound TTBB of high-purity
The mixture 150g of compound 4 and compound 4A is dissolved in a certain amount of THF solvents (375mL), adds inorganic base
Potassium carbonate, is added dropwise into diethyl phosphite, heating stirring reaction, HPLC detecting and trackings, waits (TTBB after the reaction was complete:
93.93%, TTMB:0.52%, Br-TTBB 1.82%) stop reaction, temperature is reduced to room temperature, is then filtered to remove inorganic
Alkali, then evaporates the THF solvents of the overwhelming majority, is then heated and recrystallized using solvent ethyl acetate, filtering, utilizes a small amount of ethanol
Elute to obtain target product TTBB (125g), yield:87%, HPLC:TTBB:98.638%, TTMB:0.373%, Br-TTBB:
0.574%.
Have been shown and described above the basic principle of the present invention, main feature and advantage, do not depart from spirit of the invention and
On the premise of scope, the present invention also has various changes and modifications, these changes and improvements both fall within claimed invention
Scope.