CN103087081A - Method for preparation of brinzolamide and intermediates thereof - Google Patents
Method for preparation of brinzolamide and intermediates thereof Download PDFInfo
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- CN103087081A CN103087081A CN2011103427081A CN201110342708A CN103087081A CN 103087081 A CN103087081 A CN 103087081A CN 2011103427081 A CN2011103427081 A CN 2011103427081A CN 201110342708 A CN201110342708 A CN 201110342708A CN 103087081 A CN103087081 A CN 103087081A
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- QHZYXIZUBNZSKX-JTQLQIEISA-N CCN([C@@H](CN1CCCOC)c(cc([s]2)Cl)c2S1(=O)=O)P Chemical compound CCN([C@@H](CN1CCCOC)c(cc([s]2)Cl)c2S1(=O)=O)P QHZYXIZUBNZSKX-JTQLQIEISA-N 0.000 description 1
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The invention discloses a method for preparation of a compound shown in formula (II). The method mainly includes two steps: an amination reaction and introduction of an amino protection group. The invention also discloses a method for preparation of brinzolamide through the compound in formula (II), and the method mainly consists of: sulfamation of the compound in formula (II) and amino protection group removal of the sulfamation product. According to the method, a protection group is first introduced at site C-3, then a sulfonamide group is introduced at site C-6, and finally the protection group at site C-3 is removed, so that the synthesis operations of brinzolamide become easier, the security risk and the cost are lower, and the total yield of brinzolamide is significantly enhanced. Therefore, the feasibility of large-scale industrial production and the competitive advantage of the product in the market are improved.
Description
Technical field
The present invention relates to the organic synthesis field, particularly relate to a kind of method for the preparation of brinzolamide and intermediate thereof.
Background technology
Brinzolamide (Brinzolamide) is the active constituents of medicine of Azopt eye drop, it is by Alcon Laboratories, Inc. exploitation, went on the market in the U.S. in 1998, be applicable to reduce the intraocular pressure of ocular hypertension, open angle glaucoma rising, and can be used as invalid to beta-blocker or the patient's who uses contraindication independent medicine is arranged, perhaps as the Synergistic treatment medicine of beta-blocker.Studies show that, brinzolamide is less to the stimulation of eye, and tolerance and security are good, is a kind of very valuable anti-glaucoma new drug.
The chemistry of brinzolamide is by name:
R-(+)-4-ethylamino-2-(3-methoxycarbonyl propyl)-3,4-dihydro-2H-thieno-[3,2-e]-1,2-thiazines-6-sulfanilamide (SN)-1,1-dioxide
Structural formula is:
About synthesizing of brinzolamide, be called in name in " Preparation of carbonic anhydrase inhibitors " United States Patent (USP) (patent No. US5344929), put down in writing following complete synthesis route (route one):
Route one
The main drawback of said synthesis route one is:
1. raw material 3-ethanoyl-2, the price comparison of 5-dichloro-thiophene (1-1) and the raw material 1-bromo-3-methoxy propane that will adopt when synthetic intermediate (1-6) is expensive, is unfavorable for the industrialization cost control;
2. productive rate (lower than 70%) on the low side during synthetic intermediate (1-7), and to use organolithium greater than 2.0 equivalents when alkylsulfonyl is introduced in the C-6 position, increased danger and the cost produced;
3. productive rate is lower.To C-6 position introducing sulfahydantoin, then to C-3 position introducing ethylamino-, the productive rate in these two steps is about 40%; And from raw material 3-ethanoyl-2,5-dichloro-thiophene (1-1) approximately only has 15% to the overall yield of brinzolamide (I).
Another name be called " IMPROVED PROCESS FOR THE PREPARATION OF (R)-(+)-4-(ETHYIAMINO)-3; 4-DIHYDRO-2-(3-METHOXYPROPYL)-2H-THIENO[3; 2-E]-L; 2-THIAZINE-6-SULFONAMIDE-L; L-DIOXIDE " patent documentation of (publication number WO2008062463), the another kind of synthetic method (route two) of brinzolamide is disclosed:
Route two
The main drawback of above-mentioned circuit two is:
1. raw material 3-acetyl thiophene (2-1) price comparison is expensive, is unfavorable for the industrialization cost control;
2. security risk is large.During synthetic intermediate (2-4), introduce alkylsulfonyl in the C-2 position and need to adopt the more expensive and dangerous larger organolithium reagent of price; During synthetic intermediate (2-9), introducing alkylsulfonyl in the C-6 position need to have alkyl lithium reagents more than 2.0 molar equivalents, and consumption is on the high side, has increased cost and danger.
3. productive rate is low.This route adopts two kinds of methods to obtain brinzolamide: (a) to C-6 position introducing alkylsulfonyl, then at C-3 position introducing ethylamino-, productive rate is lower than 40%; (b) first introduce C-3 position ethylamino-, then introduce sulfahydantoin to the C-6 position, productive rate approximately 20%.And approximately only have 6% from 3-acetyl thiophene (2-1) to the overall yield of brinzolamide (I).
Name is called the United States Patent (USP) (US5378703) of " Sulfonamides useful as carbonic anhydrase inhibitors ", has disclosed the third synthetic method (route three) of brinzolamide.The shortcoming of this route three is:
1. raw material (3-1) or price comparison (3-2) are expensive;
2. during synthetic intermediate (3-3), C-2 introduces the position alkylsulfonyl and needs with price more expensive and dangerous larger organolithium reagent;
3. during synthetic intermediate (3-9), introduce methoxyl group productive rate low (only having 78%), increased raw material and production cost;
4. productive rate is low.After introducing sulfahydantoin to the C-6 position, oxidation, reduction, amination are carried out in the C-3 position obtain brinzolamide, its productive rate is about 20%; And the overall yield from intermediate (3-2) to brinzolamide (I) is lower, approximately only has 5%.
In addition, the name European patent (EP1985618) that is called " Process for the preparation of brinzolamide and intermediates thereof " has disclosed the 4th kind of synthetic method (route four) of brinzolamide.Its shortcoming is:
1. raw material (4-1) price comparison is expensive;
2. when adopting two pairs of toluyl tartrate resolving racemics of L-(4-5) synthetic intermediates (4-6), productive rate only has 33%, too low gain in yield cost;
3. during synthetic intermediate (4-2), introduce methoxypropyl groups and need to adopt raw material 3-methoxyl group-1-propylamine, its price comparison is expensive, is unfavorable for the industrialization cost control;
4. structure (4-5) obtains brinzolamide through chiral separation, amido protection, sulfurous acidylate, amination, Deprotection, and productive rate is about 22%, and described route is the lab scale route of a few grams amounts; And the overall yield from raw material (4-1) to brinzolamide (I) is approximately 12%.
Route three
Route four
All in all, said synthesis route exists all that cost is high, production exercise is felt embarrassed and security is low, from the problem such as the former overall yield of expecting the final product brinzolamide is low, therefore, limited to a certain extent brinzolamide applying on market.
Summary of the invention
One of the technical problem to be solved in the present invention is to provide a kind of method for the preparation of formula (II) compound.
Wherein, P is amino protecting group.
For solving the problems of the technologies described above, the method for the preparation of formula (II) compound of the present invention comprises the steps:
1) make formula (1) compound and ethamine carry out amination reaction, production (2) compound, chemical equation is as follows:
2) make the reaction of formula (2) compound and amido protecting agent, at C-3 position introducing amino protecting group, the compound of production (II), chemical equation is as follows:
Described amino protecting group is preferably benzyl or tertbutyloxycarbonyl.
Two of the technical problem to be solved in the present invention is to provide the method for brinzolamide shown in the above-mentioned formula of a kind of use (II) compound preparation formula (I).
For solving the problems of the technologies described above, the method for preparing brinzolamide of the present invention comprises the steps:
1) make the compound of formula (II) and compound and the sulfanilamide (SN) reagent of R-M structure carry out the sulfanilamide (SN) reaction, the compound of production (3), chemical equation is as follows:
Wherein, R is fatty group, aryl or the heteroaryl group that replaces arbitrarily, and M is metal (for example, alkali metal lithium, sodium, potassium);
2) formula (3) compound carries out hydrogenation with Pd/C, and the deaminize protecting group obtains formula (I) brinzolamide, and chemical equation is as follows:
The mole dosage of the compound of described R-M structure is 0.5～2.0 times of formula (II) compound mole number, is preferably 0.8～1.6 times.
When selecting n-Butyl Lithium as the compound of R-M structure, its mole dosage is preferably 0.8～1.1 times of formula (II) compound mole number.Add the temperature of n-Butyl Lithium should be controlled at-65 ℃～-70 ℃.
The present invention is by first adding protecting group in the C-3 position; then at C-6 position introducing sulfahydantoin; slough again the mode of the protecting group of C-3 position; come the brinzolamide shown in composite structure formula (I); solved the existing synthetic method problem that productive rate is low to C-6 position introducing sulfahydantoin the time, R-M structural compounds consumption is large; not only make the synthetic operation of brinzolamide easier; security risk and cost are lower; and improved the overall yield of brinzolamide; thereby increased industrial operability, and made product have more the Cost Competition advantage in market.
Embodiment
Below in conjunction with specific embodiment, then method of the present invention is further described in detail.In following examples, be if no special instructions ordinary method.
Embodiment 1
1. amination reaction
Add the compound 1g shown in formula (1) and tetrahydrofuran (THF) 10ml in reaction vessel, be cooled to 0 ℃, add triethylamine 0.8mL, stir at this temperature and spend the night, TLC follows the tracks of reaction result.
Be cooled to-10 ℃, add 70% ethylamine solution 1mL, react completely under room temperature.
The ice bath cooling adds concentrated hydrochloric acid 11mL, and in controlling, temperature below 20 ℃, stirred 1 hour.
Methylene dichloride 20mL * 2 extractions, anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated.
Oily matter is dissolved with ethyl acetate 20mL, then add the 20mL normal hexane, stir, filter, obtain the faint yellow solid 0.8g shown in formula (2).
Mass spectrum (ESI) [M-HCl+1]=375.
2. introduce protecting group (benzyl)
Add the compound 0.5g shown in formula (2) in reaction vessel, with the dissolving of 10mL methylene dichloride, add triethylamine 0.34g, 5 ℃ are stirred half an hour.0.4g Benzyl Chloride dropwised in 10 minutes, under room temperature, reaction is spent the night.
Use successively 1N dilute hydrochloric acid 10mL * 2, saturated aqueous common salt 10mL washing, the organic phase anhydrous sodium sulfate drying filters, and concentrating under reduced pressure obtains the oily matter 0.6g shown in formula (II).
3. sulfanilamide (SN) reaction
Formula (II) the oily matter 0.5g that adds step 2 to obtain in the reaction vessel adds tetrahydrofuran (THF) 5mL under nitrogen protection.Be cooled to-70 ℃, begin to drip n-Butyl Lithium 0.07g, temperature control is below-65 ℃, pass into after 2 hours sulfur dioxide gas to the pH value in 4 left and right.Under room temperature, reaction is spent the night, and is spin-dried for, and adds entry 2.5mL in residual night, and is stand-by.
The mixed solution of preparation 0.13g acetic acid, 0.7g azanol oxygen sulfonic acid (HOSA) and 3mL water drops to residual night in mixture under 0 ℃.
React completely rear with FA (ethyl acetate) 15mL extraction, successively with saturated sodium bicarbonate 10mL, salt solution 10mL washing.The organic phase anhydrous sodium sulfate drying.Filter, filtrate is revolved and is steamed to doing, and gets oily matter 0.47 gram of structural formula (3).
4. Deprotection
Formula (3) the oily matter 0.2g that adds step 3 to obtain in the reaction vessel, add tosic acid 0.25g and 3mL methyl alcohol, add 5%Pd/C (50%, 30 milligram) to carry out normal pressure hydrogenation reaction, TLC (thin-layer chromatography) tracking test result under room temperature.
Remove by filter Pd/C (palladium carbon), concentrating under reduced pressure.Residual ight 10mLEA and 5mL saturated sodium bicarbonate solution separatory, water are with the 5mLEA extraction once.Merge organic phase, anhydrous sodium sulfate drying.Filter, concentrating under reduced pressure gets yellow oily liquid.Add the 15mL Virahol, heated and stirred is molten clear, and-20 ℃ of left and right crystallizatioies are taken advantage of cold filtration, and solid dries to get 0.23 gram product (brinzolamide).
5. interpretation of result
Measure fusing point and the proton nmr spectra of above-mentioned final product, obtain following result:
Fusing point: 125-127 ℃
Proton nmr spectra
1HNMR (400MHz, solvent are deuterated methanol (CD3OD)):
δ：7.69(s，1H)，4.17(m，1H)，3.83～4.00(m，2H)，3.51(m，3H)，3.36(s，3H)，3.33(m，1H)，3.25(m，1H)，2.68(m，2H)，1.91(m，2H)，1.17(t，J＝8Hz，3H)
The said determination result confirms that final product is brinzolamide.
The synthetic route of above-described embodiment please refer to shown in route five.By this route, the overall yield that obtains brinzolamide is 55.7%, and by above-mentioned sulfanilamide (SN) reaction and two steps of Deprotection, obtains the productive rate of brinzolamide higher than 60%.
Route five
Wherein, P represents amino protecting group.In embodiment 1, P is benzyl.
Above-described embodiment is only a preferred embodiment of the present invention, can not be for limiting scope of the invention process to the explanation of this embodiment.
Except the brinzolamide shown in preparation formula (I), method of the present invention can also further be applied to the chemosynthesis of salt, solvate or the hydrate of brinzolamide.
Claims (9)
1. method for the preparation of formula (II) compound,
Wherein, P is amino protecting group,
It is characterized in that, described method comprises the steps:
1) make formula (1) compound and ethamine carry out amination reaction, production (2) compound, chemical equation is as follows:
2) make the reaction of formula (2) compound and amido protecting agent, production (II) compound, chemical equation is as follows:
2. method according to claim 1, is characterized in that, described amino protecting group is benzyl.
3. method according to claim 2, is characterized in that step 2) in, described amido protecting agent is Benzyl Chloride.
4. method according to claim 1, is characterized in that, described amino protecting group is tertbutyloxycarbonyl.
5. based on any one method in claim 1 to 4, the method for brinzolamide shown in preparation formula (I),
It is characterized in that, the described method for preparing brinzolamide comprises the steps:
1) make the compound of formula (II) and compound and the sulfanilamide (SN) reagent react of R-M structure, the compound of production (3), chemical equation is as follows:
Wherein, R is fatty group, aryl or the heteroaryl that replaces arbitrarily, and M is metal;
2) formula (3) compound carries out hydrogenation with Pd/C, and the deaminize protecting group obtains the brinzolamide shown in formula (I), and chemical equation is as follows:
6. method according to claim 5, is characterized in that step 1) in, the mole dosage of the compound of described R-M structure is 0.5～2.0 times of formula (II) compound mole number.
7. method according to claim 6, is characterized in that, the mole dosage of the compound of described R-M structure is 0.8～1.6 times of formula (II) compound mole number.
8. method according to claim 7, is characterized in that, the compound of described R-M structure is n-Butyl Lithium, and the mole dosage of described n-Butyl Lithium is 0.8～1.1 times of formula (II) compound mole number.
9. method according to claim 8, is characterized in that, adds the temperature of described n-Butyl Lithium to be controlled at-65 ℃～-70 ℃.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103755727A (en) * | 2013-12-20 | 2014-04-30 | 南京华威医药科技开发有限公司 | Preparation method of brinzolamide intermediate |
| CN107722043A (en) * | 2016-08-10 | 2018-02-23 | 上海博石睿生命科技有限公司 | A kind of preparation method of chiral amino compound and its intermediate |
| CN113354665A (en) * | 2021-03-05 | 2021-09-07 | 株洲壹诺生物技术有限公司 | Method for synthesizing key intermediate of brinzolamide |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008132114A1 (en) * | 2007-04-27 | 2008-11-06 | Duke Chem, S. A. | Process for the preparation of brinzolamide and intermediates thereof |
| CN102056914A (en) * | 2008-06-16 | 2011-05-11 | Phf股份公司 | Process for the preparation of 3,4-dihydro-2H-thien[3,2-E]-1,2-thiazin-4-ol 1, 1-dioxide derivatives and intermediates |
| EP2348026A1 (en) * | 2009-12-22 | 2011-07-27 | Duke Chem, S. A. | Process for the preparation of brinzolamide and intermediates thereof |
-
2011
- 2011-11-03 CN CN2011103427081A patent/CN103087081A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008132114A1 (en) * | 2007-04-27 | 2008-11-06 | Duke Chem, S. A. | Process for the preparation of brinzolamide and intermediates thereof |
| CN102056914A (en) * | 2008-06-16 | 2011-05-11 | Phf股份公司 | Process for the preparation of 3,4-dihydro-2H-thien[3,2-E]-1,2-thiazin-4-ol 1, 1-dioxide derivatives and intermediates |
| EP2348026A1 (en) * | 2009-12-22 | 2011-07-27 | Duke Chem, S. A. | Process for the preparation of brinzolamide and intermediates thereof |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103755727A (en) * | 2013-12-20 | 2014-04-30 | 南京华威医药科技开发有限公司 | Preparation method of brinzolamide intermediate |
| CN107722043A (en) * | 2016-08-10 | 2018-02-23 | 上海博石睿生命科技有限公司 | A kind of preparation method of chiral amino compound and its intermediate |
| CN113354665A (en) * | 2021-03-05 | 2021-09-07 | 株洲壹诺生物技术有限公司 | Method for synthesizing key intermediate of brinzolamide |
| CN113354665B (en) * | 2021-03-05 | 2022-04-22 | 株洲壹诺生物技术有限公司 | Method for synthesizing key intermediate of brinzolamide |
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Application publication date: 20130508 |