| Identification | More | [Name]
Brinzolamide | [CAS]
138890-62-7 | [Synonyms]
BIRNZOLAMIDE
BRINZOLAMIDE
2H-Thieno[3,2-e]-1,2-thiazine-6-sulfonamide, 4-(ethylamino)-3,4-dihydro-2-(3-methoxypropyl)-, 1,1-dioxide, (4R)-
2H-Thieno[3,2-e]-1,2-thiazine-6-sulfonamide, 4-(ethylamino)-3,4-dihydro-2-(3-methoxypropyl)-, 1,1-dioxide, (R)-
AL 4862
Brinlolamide
(R)-4-(Ethylamino)-3,4-dihydro-2-(3-methoxypropyl)-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide
(4R)-4-(Ethylamino)-3,4-dihydro-2-(3-methoxypropyl)-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-Dioxide
AL-4682
Azopt
-4-(Ethylamino)-3，4-dihydro-2-(3-methoxypropyl)-2H-thieno[3，2-e]-1，2-thiazine-6-sulfonamide1，1-dioxide | [EINECS(EC#)]
620-511-8 | [Molecular Formula]
C12H21N3O5S3 | [MDL Number]
MFCD08067749 | [Molecular Weight]
383.51 | [MOL File]
138890-62-7.mol |
| Chemical Properties | Back Directory | [Appearance]
Crystalline Solid | [Melting point ]
130.0 to 134.0 °C | [Boiling point ]
586.0±60.0 °C(Predicted) | [density ]
1.50±0.1 g/cm3(Predicted) | [storage temp. ]
-20°C | [solubility ]
DMSO: ≥10mg/mL | [form ]
powder | [pka]
9.62±0.40(Predicted) | [color ]
white to beige | [Usage]
Carbonic anhydrase inhibitor. Antiglaucoma agent | [Merck ]
14,1376 | [InChIKey]
HCRKCZRJWPKOAR-JTQLQIEISA-N | [CAS DataBase Reference]
138890-62-7(CAS DataBase Reference) |
| Hazard Information | Back Directory | [Description]
Brinzolamide was introduced as Azopt in the US for the treatment of
elevated intraocular pressure (IOP) in patients with ocular hypertension or openangle
glaucoma. Brinzolamide is a potent inhibitor of human carbonic anhydrase
Ⅱ lowering IOP after topical administration . It is the second of this class after
dorzolamide (1995). Brinzolamide can be prepared in an eight-step sequence
from 3-acetyl-2,5-dichlorothiophene. In patients with primary open-angle
glaucoma or ocular hypertension, brinzolamide produced significant reductions
in IOP and showed less ocular discomfort than dorzolamide. | [Chemical Properties]
Crystalline Solid | [Originator]
Alcon (US) | [Definition]
ChEBI: Brinzolamide is a sulfonamide and a thienothiazine. It has a role as an antiglaucoma drug and an EC 4.2.1.1 (carbonic anhydrase) inhibitor. | [Indications]
Brinzolamide, a heterocyclic sulfonamide, is a topical CAI suspension that has a high affinity for the carbonic anhydrase II isoenzyme.Because the ocular hypotensive effect of the drug is equivalent whether dosed twice or three times daily, brinzolamide 1% may be administered twice daily. | [Preparation]
Brinzolamide synthesis method: using thiophene as raw material, 3-acetyl-2,5-dichlorothiophene (4) is obtained by chlorination and acetylation, and 4 is reacted with sodium benzyl sulfide to obtain 6,6, which is chlorinated and ammoniated. Chemical and oxidation reactions "one-pot" synthesis of 7, Carbon-based α-hydrobromination of 7 with Pyridinium tribromide gives 9,9 is asymmetrically reduced under the action of (+)-Ipc2BCl to obtain 11, which is then subjected to N-alkylation and sulfonamidation to generate (S)-3,4-dihydro-4-hydroxy-2-(3-methoxyl propyl)-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide-1,1-dioxide, the sulfonamide group was protected with trimethyl orthoacetate to give 15 , first introduce p-toluenesulfonyl group and then replace it with ethylamino group, and remove the sulfonamide group protecting group to obtain brinzolamide. The synthesis of intermediate 4 in this route is convenient, and each step of the reaction does not require column chromatography, and the total yield is 13.4%.
Graphical Synthetic Routes of Olanzapine | [Manufacturing Process]
To a solution of 3-(2,5,5-trimethyl-1,3-dioxane-2-yl)thiophene (2.5 g, 11.7
mmol) in hexane (30 mL) cooled to 0°C was added via syringe n-butyl lithium
in hexane (2.5 M, 10.3 mL, 25.7 mmol) over 5 min. The mixture was stirred
at 0°C for 20 min, the ice bath was removed and the stirring was continued
for 30 min. At this time a white precipitate formed. The mixture was cooled to -60°C and THF (20 mL) was added. Sulfur dioxide was then passed through
the surface of the mixture for 30 min. The mixture was warmed to ambient
temperature and stirred for an additional 15 min. The volatiles were
evaporated and to the residue was added water (50 mL) and sodium acetate
trihydrate (9.55 g, 70.2 mmol). The solution was cooled on an ice bath and
hydroxylamine-O-sulfonic acid (4.62 g, 40.9 mmol) was added. The mixture
was stirred at ambient temperature for 1 h, extracted with ethyl acetate
(3x100 mL) and the combined extracts were washed with a sodium
bicarbonate solution, brine and dried over molecular sieves. Evaporation to
dryness gave a viscous liquid (4.93 g), which was chromatographed (silica,
eluting with 33% ethyl acetate-hexane) to give a solid 3-(2,5,5-trimethyl-1,3-
dioxane-2-yl)-2-thiophenesulfonamide (2.47 g, 72%): m.p. 200°-202°C.
The last compound (9.45 g, 32.5 mmol) and 1 N HCl (100 mL) in THF (100
mL) was heated at reflux for 1 h. The THF was evaporated and the aqueous
solution was made basic by the addition of sodium bicarbonate. The mixture
was cooled using an ice bath and the precipitate was filtered, washed with
cold water and dried in vacuo to give 5.83 g (88%) of a solid 3-acetyl-2-
thiophenesulfonamide: m.p. 193°-196°C.
The last product (5.73 g, 28.0 mmol) was dissolved in hot THF (200 mL). The
solution was cooled to 10°C and pyridinium bromide perbromide (10.73 g,
33.5 mmol) was added. The mixture was allowed to stir at ambient
temperature for 1 h. The volatiles were evaporated and the residue was mixed
with water. The precipitate was filtered, washed with cold water and dried in
vacuo overnight to give 7.77 g of a solid. A portion of this solid (3.49 g, 12.3
mmol) was suspended in ethanol (100 mL) and treated with sodium
borohydride (266 mg, 7.04 mmol). The suspension turned clear after 10 min
and was heated at reflux for 1 h. The ethanol was evaporated and the residue
was extracted with ethyl acetate, washed with brine and evaporated to give
3,4-dihydro-4-hydroxy-2H-thieno[3,2-e]-1,2-thiazine 1,1-dioxide (1.80 g,
71%): m.p. 138°-140°C.
A solution of the above product (19.2 g, 0.093 mol) in DMF (125 mL) was
added to a suspension of sodium hydride (3.08 g, 80% oil dispersion, 0.103
mol) in DMF at 006. When the addition was completed the ice bath was
removed and the reaction 20 mixture stirred at ambient temperature for 1 h.
The reaction mixture was cooled to 0°C and 2-bromoethyl methylether (13.6
mL, 0.14 mol) was added. The reaction mixture was stirred at ambient
temperature for 18 h after which time it was evaporated to dryness. The
residue was suspended in brine (100 mL) and extracted with methylene
chloride (4x80 mL). The combined extracts were dried (MgSO4), filtered and
evaporated to a solid which was recrystallized from ethyl acetate to give the
desired subject (17.4 g). Chromatography of the mother liquor (silica, 3%
ethanol/methylene chloride) furnished more subject which was combined with
the first batch to give a total of 19.3 g (78%) of 3,4-dihydro-4-hydroxy-2-(2-
methoxy)ethyl-2H-thieno[3,2-e]-1,2-thiazine 1,1-dioxide.
3,4-Dihydro-4-hydroxy-2-(2-methoxy)ethyl-2H-thieno[3,2-e]-1,2-thiazine 1,1-
dioxide (4.9 g, 50 18.6 mmol) was converted to the 4-(1-ethoxy)ethoxy-3,4-
dihydro-2-(2-methoxy)ethyl-2H-thieno[3,2-e]-1,2-thiazine 1,1-dioxide (6.2 g,
99%) using the reaction with p-toluensulfonic acid and ethylvinyl ether at 0°C
in tetrahydrofuran for 2 hrs.
The last one (6.2 g, 18.4 mmol) was converted into 3,4-dihydro-4-hydroxy-2-
(2-methoxy)ethyl-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide
(4.87 g, 77%) m.p. 187°C by using the reaction with n-butyl lithium in
anhydrous THF at -40°C for 40 min, and then bubbling sulfur dioxide gas for
20 min after which time the mixture was warmed to room temperature. After
30 min at room temperature the mixture was concentrated the residue was
dissolved in water, cooled (0°C), sodium acetate trihydrate was added
followed by hydroxylamine-O-sulfonic acid. The reaction mixture was stirred at
room temperature for 18 h after which time was basified with solid sodium
bicarbonate and extracted with ethyl acetate.
3,4-Dihydro-2-(2-methoxy)ethyl-4-propylamino-2H-thieno[3,2-e]-1,2-thiazine-
6-sulfonamide-1,1-dioxide hydrochloride was obtained by the reaction of 3,4-
dihydro-4-hydroxy-2-(2-methoxy)ethyl-2H-thieno[3,2-e]-1,2-thiazine-6-
sulfonamide-1,1-dioxide in THF containing triethylamine with tosyl chloride at
-16°C and the next stirring for 18 hrs at room temperature. After which time
the mixture was cooled to 0°C and propylamine was added, the desired
product (0.57 g, 46%) was obtained: m.p. 178°-181°C.
The desired 4-ethylamino-3,4-dihydro-2-(3-methoxy)propyl-2H-thieno[3,2-e]-
1,2-thriazine-6-sulfonamide-1,1-dioxide was prepared according to described
above procedure for 3,4-dihydro-4-hydroxy-2-(2-methoxy)ethyl-2Hthieno[
3,2-e]-1,2-thiazine-6-sulfonamide-1,1-dioxide substituting 2-
bromoethylmethylether for 2-(bromomethyl)ethyl-methylether. | [Brand name]
Azopt (Alcon). | [Therapeutic Function]
Antiglaucoma | [General Description]
Brinzolamide is a small molecular weight compound that has an ability to bind melanin. This drug is used in ocular therapy. | [Biochem/physiol Actions]
Brinzolamide is a carbonic anhydrase II inhibitor used to lower intraocular pressure. | [Clinical Use]
Brinzolamide is indicated for the treatment of elevated IOP in patients with ocular hypertension or open-angle glaucoma.The drug is commercially available as a sterile 1.0% aqueous suspension with a pH of approximately 7.5. BAC 0.01% is added as a preservative.
The efficacy and safety of brinzolamide 1%, either two or three times daily, were evaluated in 572 patients with open-angle glaucoma or ocular hypertension against timolol 0.5% twice daily and dorzolamide 2.0% three times daily. Mean IOP changes were -3.8 to -5.7 mm Hg, -4.2 to -5.6 mm Hg, and-4.3 to-5.9 mm Hg for two- and three-times-daily brinzolamide and dorzolamide dosing, respectively. The mean IOP changes for timolol 0.5% ranged from -5.6 to -6.3 mm Hg (Figure 10-15). Brinzolamide was well tolerated, with 1.8% (twice daily) and 3% (three times daily) of patients reporting ocular discomfort versus 16.4% with dorzolamide. Complaints of blurred vision were higher with brinzolamide (5–6%) than dorzolamide (1%) or timolol (0%).
A meta-analysis of randomized clinical trials reported peak ocular hypotensive effect on IOP of 17% (19% to 15%) and trough effect of 17% (19% to 15%). | [Veterinary Drugs and Treatments]
Brinzolamide is chemically similar to dorzolamide and reduces
aqueous humor production by altering H+/Na+ active transport
mechanisms associated with aqueous humor production in the ciliary
epithelial cells. It can be used as a substitute for dorzolamide
and some patients that exhibit excessive topical irritation following
application of dorzolamide drops, tolerate brinzolamide better or
vice versa. Cats seem to be particularly sensitive to irritation from
topical dorzolamide and often brinzolamide can be used in these
patients. Comparative data is available suggesting that brinzolamide
and dorzolamide are equally effective in animal patients. | [storage]
Store at -20°C | [Precautions]
Brinzolamide has the same contraindications and precautions as dorzolamide. | [References]
[1] desantis l. preclinical overview of brinzolamide. surv ophthalmol. 2000 jan;44 suppl 2:s119-29. |
| Questions And Answer(Q&A) | Back Directory | [Ophthalmic drugs]
Brinzolamide is a kind of novel heterocyclic sulfa topical carbonic anhydrase inhibitor. It has a strong affinity and inhibition on the carbonic anhydrase isoenzyme II (CAII) in human ciliary body. It can selectively and significantly inhibit the activity of isozyme II carbonic anhydrase with high-affinity. It can effectively reduce the intraocular pressure with high efficiency, low toxicity, and small side effects. Its physiological pH and suspension design makes the drug able to ensure eye comfort and thus admired by patients of all ages. It can be as a single drug treatment way for patients to whom β-blockers is ineffective or is contraindicated or used as a co-cure treatment drug together with β-blocker. After being dropped into the eye it can quickly enter into tissue, and has a long half-life in the iris, ciliary body, choroid, retina, and lens as well as in the blood. Treating rabbit eyes with brinzolamide can further increase blood flow to the optic nerve which helps patients of glaucoma optic neuropathy. It has become the primary way for treatment of open angle glaucoma line drugs.
Carbonic anhydrase (CA) is one of the major protein components of red blood cells. Its position is only second to hemoglobin in the blood cell, which is presented in many body tissues including the eye organizations. Carbonic anhydrase catalyzed hydration reaction of carbon dioxide into carbonic acid, and the reversible dehydration reaction of carbonic acid. Inhibition of carbonic anhydrase in the ocular ciliary body can reduce the water secretion of camera aquosa. It reduces the transport of sodium and water possibly by reducing the generation of bicarbonate ions, and ultimately reduces the intraocular pressure. IOP is an important risk factor for glaucoma optic nerve damage and glaucomatous visual field defects. Brinzolamide mainly inhibits the dominant carbonic anhydrase type 2 isoenzyme in the eye tissue. In vitro tests had shown that the IC50 was 3.2nM and the Ki value ??to the carbonic anhydrase type-II isoenzyme was 0.13 nM.
| [Brinzolamide eye drops]
Brinzolamide eye drops (BrinzolamideEye Drops) is currently a good drug in the treatment of ocular hypertension and open-angle glaucoma remission within elevated intraocular pressure. In April 1998, it had entered into market for the first time in the United States, and has currently entered into market in nearly 30 countries. It was approved for import in China in 2002. It can be as a single drug treatment way for patients to whom β-blockers is ineffective or is contraindicated or used as a co-cure treatment drug together with β-blocker. Its brand name is Azopt.
Brinzolamide eye drops is a sulfa drug, although used as eye drops, but can still be absorbed systemically. Therefore, adverse reactions of sulfa drugs may still occur in the eye drops with time. If severe adverse reactions or allergies occur, you should immediately stop using eye-drops.
For patients subject to oral administration of carbonic anhydrase inhibitors or eye-drop of Azpot, there may be known systemic adverse reactions which are related with carbonic anhydrase inhibition. There have been no studies concerning the co-orally administration of carbonic anhydrase inhibitor and Azopt, thus it is not recommended to use both drugs in combination. Currently there is only limited experience on brinzolamide’s treatment of pseudo-capsular exfoliative and pigmentary glaucoma. In the combination therapy of glaucoma, people mainly evaluate the effects of brinzolamide and timolol. Therefore, information on joint use and other anti-glaucoma drugs is limited.
There have been no studies on the effects of brinzolamide eye drops in patients with acute angle-closure glaucoma and severe renal impairment. Owing to that the product and most of its major metabolites are mainly excreted by the kidney, so those two kinds of patients are not recommended.
Benzalkonium chloride is a commonly used ophthalmic preservative, and it has been reported to cause the punctate keratopathy or (and) ulcerative keratopathy. Azopt contains benzalkonium chloride as a preservative. It can be absorbed by soft contact lenses so it is necessary to wear contact lens only at 15 minutes after being subject to Brinzolamide eye drops. It is not allowed to apply its eye-drop at the same time of wearing contact lenses.
Patients of diabetics, patients with dry eye, corneal lesion need to be closely observed. Pregnant and lactating women or children less than 18 years-old should use with caution.
The above information is edited by the Chemicalbook of Dai Xiongfeng.
| [Dosage]
Shake uniformly before using. As a monotherapy or co-therapy, drop one drop into the conjunctival sac 2 times per day; 3 times a day may be better for some patients.
When use it as a substitute of another anti-glaucoma drug. Stop using that drug first and start using brinzolamide eye drops in the next day.
Treatment with more than one drug should be separated by at least five minutes. It is generally recommended that oppress nasolacrimal duct or gently close your eyes after the medication in order to reduce systemic absorption.
| [Side effects]
According to reports, the incidence of adverse reactions which is or may be related with brinzolamide eye drops were less than 10% commonly, and less than 1% rarely in clinical studies.
In clinical tests of more than 1500 patients, when brinzolamide eye drops was either used alone or in combination with the use of timolol (0.5%), the most common treatment-related adverse reactions and local symptoms include: changes in taste (mouth pain and odor) (5.3%), transient blurred vision after treatment which lasts a few seconds to a few minutes (4.8%).
It is reported in 1% to 5% of cases about pharyngitis, dermatitis, eye, foreign body sensation, headache, congestion, eye discharge, eye irritation, keratitis, eye pain, ocular pruritus and rhinitis.
Very rare serious side effects include stomach pain, dark urine, easy bruising or bleeding, vision changes, persistent sore throat, and fever.
Brinzolamide ophthalmic solution is contraindicated for people may be allergic to it.
| [Uses]
It is carbonic anhydrase inhibitors suitable for treating high intraocular pressure or open-angle glaucoma.
| [Production methods]
Thiourea (1.287kg, 16.93mo1), benzyl chloride (1.858L, 2.044 kg, 16.14mo1), 13.5 L of ethanol and 4.5 L of water, reflux for 2 h. Cool to 74 °C in 20 min. Followed by adding 3-acetyl-2,5-dichloro-thiophene (3.0 kg, 15.38 mol) and 10L4 mol/L aqueous sodium hydroxide. Reflux for 3 h until completion of reaction, cooled to room temperature overnight. Add 10 L of water, stir for 30min, then add 3L 5.25% sodium hypochlorite solution, stir again for 30min. The solid was collected by filtration and washed with 4×2.5 L of water and 3×2L isopropanol. Dry in air at room temperature to constant weight to give 4.224 kg compound (I), 97% yield; its m.p. 86~88 °C.
Compound (I) (1kg, 3.53mo1) was dissolved in 20 L ethyl acetate, stir at 2~10 °C, pour chlorine gas until no Compound (I) detection. Blow a large air flow for 1h, then pour ammonia gas and then, keep the temperature 5~15 °C, keep the reaction until the intermediate thionyl chloride being complete converted. Then further use air for blowing 1h, add 5L of water cooled to 15 °C. Add sodium tungstate trihydrate (583g, 1.77mo1), further add 8 L 30% hydrogen peroxide in 5min. The mixture is stirred for 2 h at 35 °C, and further stirred at room temperature for 16 h; add 5L of water and separate the organic layer, and then add 5L of water again. Sodium bisulfite is added until no detectable hydroperoxide; separate the organic layer; wash with saturated sodium bicarbonate to PH value of 8; then wash with saturated NaCl solution, dry, filter, and concentrate; add tert-butyl methyl ether to the residue; filter to collect the solid; wash with tert-butyl methyl ether, and dry it in air to constant weight to yield Compound 597g (II), yield(71%), m.p. 178~179 °C.
Compound (II) (1.087kg, 4.55mo1) was dissolved in 22L of ethyl acetate; cool in an ice bath; add 90% hydrogen bromide-bromopyridine through anchor (1.305kg, 3.67mo1); 544 mL sulfuric acid is added in 10min and the temperature was raised to 5 °C. After stirring for 1 h until the reaction is completed, stir again for 30min; add 5L of water and stir for 5min; then separate the organic layer and washed with 4 × 5L saturated brine to until the Ph value of 3. Dry, filter, and concentrate; add 2L of methylene chloride to the residue, freeze for 15min. The solid was collected by filtration, air dry at room temperature to a constant weight to give 1.041kg compound (III), yield:72%, mp 147~148 °C.
Under the protection of nitrogen, add compound III (4855g, 2.68mo1) and 12.5 L tert-butyl methyl ether to the reaction flask, stir and cool to-40 °C. Within 30 min, add 4.5L 1.2mol/L of alkyl tert-butyl methyl ether solution of (+)-β-chloro-diisocyanate loose camphene boron. Stir at-25 ~-20 °C for 3.5h until the completion of the reaction, raise the temperature to 0 °C, added 11L 1mol/L aqueous sodium hydroxide solution in 10 min so that the temperature is raised to 22 °C. Stir vigorously at room temperature for 2 h to separate the organic layer; the aqueous layer is extracted with 3L tert-butyl methyl ether with the remaining aqueous layer being acidified with concentrated hydrochloric acid to a Ph value 1; extract it with 2 × 4 L ethyl acetate; ethyl acetate extract was washed with 3L brine, dry, filter, and concentrate. Add 2L of toluene and the crystals are further collected by filtration; wash it with 2L of toluene, then further wash with 2L of methylene chloride; dry it in air at room temperature to constant weight to give 498 g Compound IV), yield. 77%, melting point 126~127 °C.
Compound (IV) (5350g, 1.46mo1), 1.75L dimethyl sulfoxide and potassium carbonate (605g, 4.38mo1) are mixed and separated into 8 parts with each part being added 1-bromo-3-methoxy propane (268g, 1.75mo1) at a interval of 1h. After the completion of the addition, it takes 1.5 h for the completion of the reaction. Under stirring, pour the reaction solution into a saturated 18 L saline with the original reactor washed with water and tert-butyl methyl ether wash. The reaction liquid and washings are combined and further extracted with 2×4L tert-butyl methyl ether. The extract is further washed by 2 L 1mol/L aqueous sodium hydroxide solution, 2L 1: 1 sodium hypochlorite/water, and 2L brine. Filter and evaporate most of the solvent, then concentrate under reduced pressure at 50 deg. to get 427g compound (V), 94% yield, as light yellow oil.
Under the protection of nitrogen, the compound (V) (1.065kg, 3.42mo1) is added into 27 L dry tetrahydrofuran and cooled to-70 °C; Within 2.5h, add drop wise 3.08 L of 2.5 mol/L hexane solution of n-butyllithium. Maintain the reaction mixture temperature below-66 °C. After 1 h of the reaction, sulfur dioxide is passed into until the Ph value of 4. The temperature is raised to room temperature; keep the mixture stand overnight. Concentrate and dissolve the residue in 5L of water. Add it into sodium acetate trihydrate (0 °C, 2.796kg, 20.5mo1) and hydroxylamine-O-sulfonic acid (1.549kg, 13.7mo1) and dissolve in 6L of water, and increase the temperature to 25 °C. After stirring at room temperature for 15h, 3 × 4L ethyl acetate is used for extracting it. The extract is first washed with saturated sodium bicarbonate solution until the washing becomes basic, then further wash with saturated brine. Dry, filter, and concentrate. Add 6 L methylene chloride to the residue and further add 5g seed for crystallization. The crystals are collected by filtration, washed with dichloromethane, and dried with air at room temperature to constant weight to get 748g compound VI) with a yield of 61%, m.p.111~113 °C.
Compound (VI) (28.5g, 0.08 mo1), 285ml of acetonitrile and 23.4ml trimethyl orthoacetate are mixed and refluxed for 16h. Cool for 1h and distill off the solvent with the residue being dissolved in 150ml of dry tetrahydrofuran. Under the protection of nitrogen, add 24.5ml triethylamine and 30.5g p-toluenesulfonyl chloride at 4°C and stir at 4~7 °C for 2 h. Add drop wise 70% solution of triethylamine (260ml, 2.80mo1) within 30min while maintaining the temperature below 15 °C. After addition, the mixture is further stirred at room temperature for 18.5h. Cool to 5 °C, and add drop wise 280 mL concentrated hydrochloric acid within 1 hour while maintaining the temperature below 30 °C. Extract with 2 × 250ml of ether and further extract with 200 mL 1mol/L hydrochloric acid. Hydrochloric acid extract is adjusted to pH 8 with solid sodium bicarbonate, and frozen for 2h. Filter and collect the crystals, wash with water. The filtrate also contains the product which is further extracted with ethyl acetate. The obtained crystals can also be dissolved in the extract supplemented with ethyl acetate. Dry, filter, and concentrate to get 24 g product with yield 78%; Re-crystallize with isopropanol, m.p. 125~127 °C.
|
|
|