CN118026955A - Preparation method of optically active timolol maleate - Google Patents
Preparation method of optically active timolol maleate Download PDFInfo
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- CN118026955A CN118026955A CN202410171331.5A CN202410171331A CN118026955A CN 118026955 A CN118026955 A CN 118026955A CN 202410171331 A CN202410171331 A CN 202410171331A CN 118026955 A CN118026955 A CN 118026955A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- WLRMANUAADYWEA-NWASOUNVSA-N (S)-timolol maleate Chemical compound OC(=O)\C=C/C(O)=O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 WLRMANUAADYWEA-NWASOUNVSA-N 0.000 title claims abstract description 15
- 229960005221 timolol maleate Drugs 0.000 title claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 26
- 229960004605 timolol Drugs 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 18
- TWBNMYSKRDRHAT-RCWTXCDDSA-N (S)-timolol hemihydrate Chemical compound O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 TWBNMYSKRDRHAT-RCWTXCDDSA-N 0.000 claims abstract description 17
- 239000002904 solvent Substances 0.000 claims abstract description 15
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims abstract description 11
- 230000008569 process Effects 0.000 claims abstract description 11
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims abstract description 11
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000011976 maleic acid Substances 0.000 claims abstract description 10
- 239000003054 catalyst Substances 0.000 claims abstract description 7
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 claims abstract description 7
- BRLQWZUYTZBJKN-GSVOUGTGSA-N (+)-Epichlorohydrin Chemical compound ClC[C@@H]1CO1 BRLQWZUYTZBJKN-GSVOUGTGSA-N 0.000 claims abstract description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 45
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- DWUZILHYAJBUBR-UHFFFAOYSA-N 4-morpholin-4-yl-1,2,5-thiadiazol-3-one Chemical compound OC1=NSN=C1N1CCOCC1 DWUZILHYAJBUBR-UHFFFAOYSA-N 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- -1 alkali metal bicarbonate Chemical class 0.000 claims description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- 239000002585 base Substances 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 150000003462 sulfoxides Chemical class 0.000 claims description 2
- 239000005456 alcohol based solvent Substances 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 68
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- 238000001035 drying Methods 0.000 description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 15
- 238000001816 cooling Methods 0.000 description 11
- 238000010438 heat treatment Methods 0.000 description 11
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 10
- 230000000694 effects Effects 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 239000008346 aqueous phase Substances 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000012043 crude product Substances 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 230000006872 improvement Effects 0.000 description 5
- 238000004321 preservation Methods 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 238000000967 suction filtration Methods 0.000 description 5
- 208000010412 Glaucoma Diseases 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- BLJRIMJGRPQVNF-SNVBAGLBSA-N (R)-timolol Chemical compound CC(C)(C)NC[C@@H](O)COC1=NSN=C1N1CCOCC1 BLJRIMJGRPQVNF-SNVBAGLBSA-N 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- MNQZXJOMYWMBOU-VKHMYHEASA-N D-glyceraldehyde Chemical compound OC[C@@H](O)C=O MNQZXJOMYWMBOU-VKHMYHEASA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- 206010061216 Infarction Diseases 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 208000007950 Ocular Hypotension Diseases 0.000 description 2
- 206010030348 Open-Angle Glaucoma Diseases 0.000 description 2
- WYNCHZVNFNFDNH-UHFFFAOYSA-N Oxazolidine Chemical compound C1COCN1 WYNCHZVNFNFDNH-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000335 effect on glaucoma Effects 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000004410 intraocular pressure Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 208000010125 myocardial infarction Diseases 0.000 description 2
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N 2-propanol Substances CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 206010030043 Ocular hypertension Diseases 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 208000001871 Tachycardia Diseases 0.000 description 1
- 230000001384 anti-glaucoma Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 235000019658 bitter taste Nutrition 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- JEHCHYAKAXDFKV-UHFFFAOYSA-J lead tetraacetate Chemical compound CC(=O)O[Pb](OC(C)=O)(OC(C)=O)OC(C)=O JEHCHYAKAXDFKV-UHFFFAOYSA-J 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000011112 process operation Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 229960003712 propranolol Drugs 0.000 description 1
- 210000001747 pupil Anatomy 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000001603 reducing effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001975 sympathomimetic effect Effects 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000006794 tachycardia Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YSHCAWNMHTVFQX-UHFFFAOYSA-J tetrasodium;4-amino-1,1-diphosphonatobutan-1-ol Chemical compound [Na+].[Na+].[Na+].[Na+].NCCCC(O)(P([O-])([O-])=O)P([O-])([O-])=O YSHCAWNMHTVFQX-UHFFFAOYSA-J 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a preparation method of optically active timolol maleate, which belongs to the technical field of organic chemical synthesis and comprises the following steps: s1, (S) -epichlorohydrin reacts with tert-butylamine in a solvent to obtain an optically active intermediate 1; s2.3-hydroxy-4-morpholine-1, 2, 5-thiadiazole is mixed with the intermediate 1, and a catalyst is added for reaction to obtain optically active timolol; s3, timolol reacts with maleic acid to prepare the optically active timolol maleate. The method has the advantages of low cost and simple operation process.
Description
Technical Field
The invention relates to the technical field of organic chemical synthesis, in particular to a preparation method of optically active timolol maleate.
Background
Timolol maleate, chinese name: s- (-) -1- (tert-butylamino) -3- [ (4-morpholino-1, 2, 5-thiadiazol-3-yl) oxy ] -2-propanol maleate, chemical name: s- (-) -1- (t-butyl) -3- [ (4-morpholino-1, 2, 5-thiadiazole-3-) oxy ] -2-propanol, the structural formula is represented by formula I. White crystalline powder; no odor; bitter taste. Melting point 199-203 deg.C (decomposition upon melting). It is soluble in water or methanol, slightly soluble in ethanol, slightly soluble in chloroform, and hardly soluble in diethyl ether. The aqueous solution is stable at pH=12, is a novel powerful beta receptor blocker, has blocking effect on beta 1 and beta 2 receptors, has action strength which is 8 times that of propranolol, has no membrane stabilization effect, has no endogenous sympathomimetic activity, has no direct cardiac inhibition effect, and has obvious intraocular pressure reducing effect. Is clinically used for treating hypertension, angina, tachycardia and glaucoma. Has good curative effect on mild and moderate hypertension, has no obvious adverse reaction, and can be used together with diuretics. The occurrence rate and death rate of re-infarction can be reduced after the myocardial infarction patient takes the medicine for a long time. Has good effect on glaucoma, especially primary, open angle glaucoma, and is superior to traditional ocular hypotension drugs. The Chinese medicinal composition has the characteristics of quick response, less adverse reaction, good tolerance, and no influence on pupil size, photoreaction and vision. The product can reduce the occurrence rate and death rate of re-infarction after long-term administration of patients with myocardial infarction. Has good effect on glaucoma, especially primary and open angle glaucoma, and is superior to traditional ocular hypotension medicine, and has the characteristics of quick effect, small side effect and good tolerance. The eye pressure begins to drop after 20 minutes of eye drop, the maximum effect is achieved after 1-2 hours, and the effect can last for 24 hours. In some patients, it can be used in combination with some anti-glaucoma drugs. In addition, it has certain curative effect on secondary glaucoma, ocular hypertension and other glaucoma which is ineffective for medicine and operation.
At present, the chiral synthesis method of (S) -timolol maleate [ (S) - (-) -Timolol) ] mainly comprises 2 modes:
Route one: the S- (-) -propanediol amine derivative (1) is obtained by the catalytic hydrogenation reaction of D-glyceraldehyde serving as a raw material and tert-butylamine in the presence of Pd/C, and the yield is 54%. The obtained S- (-) -propanediol amine derivative reacts with 3-chloro-4- (N-morpholin) -1,2, 5-thiadiazole to obtain S- (-) -1-tert-butylamino-3- [ (4-morpholino-1, 2, 5-thiadiazol-3-yl) oxy ] -2-propanol (2), and then salifies with maleic acid to obtain (S) - (-) -Timolol, but the yield of the step is very low.
Route two: to avoid the disadvantage of difficult sources of D-glyceraldehyde, D-mannitol-1, 2,5, 6-diacetone fork (6) may be used instead. D-mannitol-1, 2,5, 6-diacetone acetonylidene (6) generates 2 molecules of (R) -glyceraldehyde acetonylidene (7) under the action of lead tetraacetate, the (7) is reduced, aminated and hydrolyzed to obtain (1) with the yield of 70 percent, the (1) is condensed with benzaldehyde to form oxazolidine, the oxazolidine is reacted with 3-chloro-4- (N-morpholine) -1,2, 5-thiadiazole to generate (2) under the action of potassium tert-butoxide, and the (2) is salified with maleic acid to obtain (S) - (-) -Timolol.
Although chiral synthetic methods of (S) - (-) -Timolol were reported, relatively few studies of timolol (R) - (+) -Timolol) maleate were performed, and furthermore, related studies suggest that the R-enantiomer of timolol maleate (i.e., R- (+) -3-morpholin-4- (3-tert-butylamino-2-hydroxypropoxy) -1,2, 5-thiadiazole) may be a better choice for treating glaucoma, and that the R-enantiomer of timolol maleate may significantly lower intraocular pressure in animal experiments with fewer side effects than the S-enantiomer of timolol maleate.
Accordingly, there is a need to provide a process for preparing (R) - (+) -Timolol, in particular in a more convenient and efficient manner than conventional processes.
Disclosure of Invention
The invention aims to provide a preparation method of optically active timolol maleate, which has the advantages of low cost and simple preparation mode.
The technical scheme of the invention is realized as follows:
the invention provides a preparation method of optically active timolol maleate, which comprises the following steps:
S1, (S) -epichlorohydrin reacts with tert-butylamine in a solvent to obtain an optically active intermediate 1;
s2.3-hydroxy-4-morpholine-1, 2, 5-thiadiazole is mixed with the intermediate 1, and a catalyst is added for reaction to obtain optically active timolol;
S3, timolol reacts with maleic acid to prepare the optically active timolol maleate.
As a further improvement of the present invention, the solvent in the step S1 is one of an alcohol solvent, an amide solvent, a sulfoxide solvent and a heterocyclic solvent.
As a further improvement of the present invention, the catalyst in step S2 is one of an alkali metal hydroxide, an alkali metal carbonate, an alkali metal bicarbonate, triethylamine, potassium hydroxide, sodium hydroxide, potassium carbonate and a heterocyclic base.
As a further development of the invention, the molar ratio of 3-hydroxy-4-morpholino-1, 2, 5-thiadiazole to catalyst in step S2 is from 1:0.1 to 0.6.
As a further development of the invention, the molar ratio of intermediate 1 to 3-hydroxy-4-morpholin-1, 2, 5-thiadiazole in step S2 is 1-3:1.
As a further improvement of the invention, the reaction time in step S2 is 5-10 hours.
As a further development of the invention, the reaction temperature in step S2 is 60-90 ℃.
As a further development of the invention, the reaction temperature in step S3 is 25-85 ℃.
As a further improvement of the invention, the reaction time in step S3 is 10-30min.
The invention has the following beneficial effects: the method has the advantages of convenient operation, no special equipment requirement, low price of the used raw materials, minimized column chromatography in process operation, capability of large-scale preparation at kilogram level, high purity and clear industrialization prospect.
Detailed Description
The following description of the technical solutions in the embodiments of the present invention will be clear and complete, and it is obvious that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Preparation example 1:
This preparation example 1 provides a process for the preparation of intermediate 1, as shown in equation 1, by adding 160ml THF, 7.6g (82 mmol) (S) -epichlorohydrin and 24g (0.33 mol) t-butylamine to a 500ml glass reaction flask, heating to 45℃for 16h, and evaporating the solvent after completion of the reaction. To the residue was added 200mL of water and 40mL of methylene chloride, the pH of the concentrated hydrochloric acid was adjusted to 2, the layers were separated, and the aqueous layer was extracted 1 time with 40mL of methylene chloride. The aqueous phase was adjusted to pH 14 with sodium hydroxide, extracted 3 times with 60mL of methylene chloride, the combined organic phases were washed 2 times with 60mL of water and 1 time with 60mL of 10% strength by mass aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. 100ml of 2M NaOH solution was added thereto and the mixture was reacted at 30℃for 1 hour. Extracting with dichloromethane, drying under reduced pressure, and purifying by column chromatography to obtain intermediate 1.m/z:130.2[ M+H ] +.
Preparation example 2:
This preparation example 2 provides a preparation method of intermediate 1, as shown in reaction equation 1, in a 500ml glass reaction flask were added 160ml absolute ethanol, 7.6g (82 mmol) (S) -epichlorohydrin and 24g (0.33 mol) tert-butylamine, heated to 45℃for 16h, and after the reaction, the solvent was distilled off. To the residue was added 200mL of water and 40mL of methylene chloride, the pH of the concentrated hydrochloric acid was adjusted to 2, the layers were separated, and the aqueous layer was extracted 1 time with 40mL of methylene chloride. The aqueous phase was adjusted to pH 13 with sodium hydroxide, extracted 3 times with 60mL of methylene chloride, the combined organic phases were washed 2 times with 60mL of water and 1 time with 60mL of 10% strength by mass aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. 100ml of 2M NaOH solution was added thereto and the mixture was reacted at 30℃for 1 hour. Extracting with dichloromethane, drying under reduced pressure, and purifying by column chromatography to obtain intermediate 1.m/z:130.2[ M+H ] +.
Preparation example 3:
This preparation example 3 provides a method for preparing intermediate 1 by adding 160ml DCM, 7.6g (82 mmol) (S) -epichlorohydrin and 24g (0.33 mol) tert-butylamine to a 500ml glass reaction flask as shown in equation 1, heating to 45℃for 16h, and evaporating the solvent after the reaction. To the residue was added 200mL of water and 40mL of methylene chloride, the pH of the concentrated hydrochloric acid was adjusted to 2, the layers were separated, and the aqueous layer was extracted 1 time with 40mL of methylene chloride. The aqueous phase was adjusted to pH 14 with sodium hydroxide, extracted 3 times with 60mL of methylene chloride, the combined organic phases were washed 2 times with 60mL of water and 1 time with 60mL of 10% strength by mass aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. 100ml of 2M NaOH solution was added thereto and the mixture was reacted at 30℃for 1 hour. Extracting with dichloromethane, drying under reduced pressure, and purifying by column chromatography to obtain intermediate 1.m/z:130.2[ M+H ] +.
Preparation example 4:
This preparation example 4 provides a process for preparing intermediate 2, which comprises adding 400mL of water to a 1L glass reaction flask, adding 39g (0.975 mol) of sodium hydroxide at 30℃and 50g (0.243 mol) of 3-morpholine-4-chloro-1, 2, 5-thiadiazole and 50mL of dimethyl sulfoxide, heating to 100℃for reaction for 4 hours, cooling to room temperature, adjusting pH to 2 with dilute hydrochloric acid, suction-filtering, drying at 80℃to constant weight to obtain 42g of white solid intermediate 2, yield 93％.m/z：188.67[M+H]+;1H-NMR(400MHz,CDCl3)：δ3.43(s,4H),δ3.69(s,4H),δ12.85(s,1H).
Example 1:
This example 1 provides a process for the preparation of timolol (R) -maleate, as shown in equation 3, by adding 30g (0.23 mol) of intermediate 1, 43g (0.23 mol) of intermediate 2 and 11.6g (0.12 mol) of triethylamine to a 500ml reaction flask and heating potassium iodide (57 mmol) to 75℃for 6h. After the reaction, cooling to 0 ℃, adding 1mol/L hydrochloric acid to adjust the pH to 6, extracting with dichloromethane, adjusting the pH of the aqueous phase to 9 with 2mol/L sodium hydroxide, extracting with dichloromethane, drying the organic phase with anhydrous sodium sulfate, filtering, spin-drying under reduced pressure, adding 160ml of absolute ethanol, heating to 75 ℃, adding 0.23mol of maleic acid, and stirring for 30min under heat preservation. Cooling to 10 ℃, carrying out suction filtration, and drying the filter cake at 60 ℃ to constant weight to obtain 30g of crude product. Further ethanol recrystallization gave 26g of timolol (R) -maleate as a white solid .m/z：318.06[M+2H]+;1H-NMR(400MHz,DMSO-d6)：δ1.30(s,9H),δ2.51～2.52(d,J＝4Hz,2H),δ2.87～2.93(m,J＝24Hz,1H),δ3.13～3.16(d,J＝12Hz,1H),δ3.46(s,4H),δ3.71(s,4H),δ4.20(s,1H),δ4.34～4.40(m,J＝24Hz,2H),δ6.04(s,2H),δ8.40(s,2H).
Example 2:
this example 2 provides a process for the preparation of timolol (R) -maleate in a 500ml reaction flask, as shown in equation 3, by adding 30g (0.23 mol) of intermediate 1, 43g (0.23 mol) of intermediate 2 and 0.12mol of N, N-diisopropylethylamine, and potassium iodide (57 mmol) to 75℃and reacting for 6h. After the reaction, cooling to 0 ℃, adding 1mol/L hydrochloric acid to adjust the pH to 5, extracting with dichloromethane, adjusting the pH of the aqueous phase to 8 with 2mol/L sodium hydroxide, extracting with dichloromethane, drying the organic phase with anhydrous sodium sulfate, filtering, spin-drying under reduced pressure, adding 160ml of absolute ethanol, heating to 75 ℃, adding 0.23mol of maleic acid, and stirring for 30min under heat preservation. Cooling to 10 ℃, carrying out suction filtration, and drying the filter cake at 60 ℃ to constant weight to obtain 21g of crude product. Further ethanol recrystallization gave 15g of timolol (R) -maleate as a white solid .m/z：318.06[M+2H]+;1H-NMR(400MHz,DMSO-d6)：δ1.30(s,9H),δ2.51～2.52(d,J＝4Hz,2H),δ2.87～2.93(m,J＝24Hz,1H),δ3.13～3.16(d,J＝12Hz,1H),δ3.46(s,4H),δ3.71(s,4H),δ4.20(s,1H),δ4.34～4.40(m,J＝24Hz,2H),δ6.04(s,2H),δ8.40(s,2H).
Example 3:
This example 3 provides a process for the preparation of timolol (R) -maleate in a 500ml reaction flask, as shown in equation 3, by adding 30g (0.23 mol) of intermediate 1, 43g (0.23 mol) of intermediate 2 and 0.12mol of piperidine, and heating potassium iodide (57 mmol) to 75℃to react for 6h. After the reaction, cooling to 0 ℃, adding 1mol/L hydrochloric acid to adjust the pH to 6, extracting with dichloromethane, adjusting the pH of the aqueous phase to 9 with 2mol/L sodium hydroxide, extracting with dichloromethane, drying the organic phase with anhydrous sodium sulfate, filtering, spin-drying under reduced pressure, adding 160ml of absolute ethanol, heating to 75 ℃, adding 0.23mol of maleic acid, and stirring for 30min under heat preservation. Cooling to 10 ℃, carrying out suction filtration, and drying the filter cake at 60 ℃ to constant weight to obtain 23g of crude product. Further ethanol recrystallization gave 17g of timolol (R) -maleate as a white solid .m/z：318.06[M+2H]+;1H-NMR(400MHz,DMSO-d6)：δ1.30(s,9H),δ2.51～2.52(d,J＝4Hz,2H),δ2.87～2.93(m,J＝24Hz,1H),δ3.13～3.16(d,J＝12Hz,1H),δ3.46(s,4H),δ3.71(s,4H),δ4.20(s,1H),δ4.34～4.40(m,J＝24Hz,2H),δ6.04(s,2H),δ8.40(s,2H).
Example 4:
This example 4 provides a process for the preparation of timolol (R) -maleate in a 500ml reaction flask, as shown in equation 3, by adding 30g (0.23 mol) of intermediate 1, 43g (0.23 mol) of intermediate 2 and 0.12mol of NaOH, and potassium iodide (57 mmol) to 75℃and reacting for 6h. After the reaction, cooling to 0 ℃, adding 1mol/L hydrochloric acid to adjust the pH to 5, extracting with dichloromethane, adjusting the pH of the aqueous phase to 9 with 2mol/L sodium hydroxide, extracting with dichloromethane, drying the organic phase with anhydrous sodium sulfate, filtering, spin-drying under reduced pressure, adding 160ml of absolute ethanol, heating to 75 ℃, adding 0.23mol of maleic acid, and stirring for 30min under heat preservation. Cooling to 10 ℃, carrying out suction filtration, and drying the filter cake at 60 ℃ to constant weight to obtain 17g of crude product. Further ethanol recrystallization gave 9g of timolol (R) -maleate as a white solid .m/z：318.06[M+2H]+;1H-NMR(400MHz,DMSO-d6)：δ1.30(s,9H),δ2.51～2.52(d,J＝4Hz,2H),δ2.87～2.93(m,J＝24Hz,1H),δ3.13～3.16(d,J＝12Hz,1H),δ3.46(s,4H),δ3.71(s,4H),δ4.20(s,1H),δ4.34～4.40(m,J＝24Hz,2H),δ6.04(s,2H),δ8.40(s,2H).
Example 5:
This example 5 provides a process for the preparation of timolol (R) -maleate in a 500ml reaction flask, as shown in equation 3, by adding 30g (0.23 mol) of intermediate 1, 43g (0.23 mol) of intermediate 2 and 0.12mol of sodium bicarbonate, and heating potassium iodide (57 mmol) to 75℃to react for 6h. After the reaction, cooling to 0 ℃, adding 1mol/L hydrochloric acid to adjust the pH to 5, extracting with dichloromethane, adjusting the pH of the aqueous phase to 9 with 2mol/L sodium hydroxide, extracting with dichloromethane, drying the organic phase with anhydrous sodium sulfate, filtering, spin-drying under reduced pressure, adding 160ml of absolute ethanol, heating to 75 ℃, adding 0.23mol of maleic acid, and stirring for 30min under heat preservation. Cooling to 10 ℃, carrying out suction filtration, and drying the filter cake at 60 ℃ to constant weight to obtain 14g of crude product. Further ethanol recrystallization gave 6g of timolol (R) -maleate as a white solid .m/z：318.06[M+2H]+;1H-NMR(400MHz,DMSO-d6)：δ1.30(s,9H),δ2.51～2.52(d,J＝4Hz,2H),δ2.87～2.93(m,J＝24Hz,1H),δ3.13～3.16(d,J＝12Hz,1H),δ3.46(s,4H),δ3.71(s,4H),δ4.20(s,1H),δ4.34～4.40(m,J＝24Hz,2H),δ6.04(s,2H),δ8.40(s,2H).
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, alternatives, and improvements that fall within the spirit and scope of the invention.
Claims (9)
1. The preparation method of the optically active timolol maleate is characterized by comprising the following steps:
S1, (S) -epichlorohydrin reacts with tert-butylamine in a solvent to obtain an optically active intermediate 1;
s2.3-hydroxy-4-morpholine-1, 2, 5-thiadiazole is mixed with the intermediate 1, and a catalyst is added for reaction to obtain optically active timolol;
S3, timolol reacts with maleic acid to prepare the optically active timolol maleate.
2. The method according to claim 1, wherein the solvent in step S1 is one of an alcohol-based solvent, an amide-based solvent, a sulfoxide-based solvent and a heterocyclic-based solvent.
3. The preparation method according to claim 1, wherein the catalyst in step S2 is one of an alkali metal hydroxide, an alkali metal carbonate, an alkali metal bicarbonate, triethylamine, potassium hydroxide, sodium hydroxide, potassium carbonate, and a heterocyclic base.
4. The process according to claim 1, wherein the molar ratio of 3-hydroxy-4-morpholino-1, 2, 5-thiadiazole to catalyst in step S2 is 1:0.1-0.6.
5. The process according to claim 1, wherein the molar ratio of intermediate 1 to 3-hydroxy-4-morpholin-1, 2, 5-thiadiazole in step S2 is 1-3:1.
6. The method according to claim 1, wherein the reaction time in step S2 is 5 to 10 hours.
7. The process according to claim 1, wherein the reaction temperature in step S2 is 60-90 ℃.
8. The method according to claim 1, wherein the reaction temperature in step S3 is 25 to 85 ℃.
9. The method according to claim 1, wherein the reaction time in step S3 is 10 to 30min.
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