CN107011228A - A kind of preparation method of clemastine fumarate - Google Patents
A kind of preparation method of clemastine fumarate Download PDFInfo
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- CN107011228A CN107011228A CN201710374858.8A CN201710374858A CN107011228A CN 107011228 A CN107011228 A CN 107011228A CN 201710374858 A CN201710374858 A CN 201710374858A CN 107011228 A CN107011228 A CN 107011228A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B57/00—Separation of optically-active compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract
The present invention relates to a kind of preparation method of clemastine fumarate, methods described comprises the following steps：Step 1：Using N methyl 2 (2 ethoxy) pyrrolidines as initiation material, chlorination substitution is carried out to hydroxyl, N methyl 2 (2 chloroethyl) pyrrolidines is prepared；Step 2：Using (2 chloroethyl) pyrrolidines of N methyl 2 and 1 (4 chlorphenyl) 1 phenyl) ethanol is raw material, reaction obtains the clemastine of racemization in the presence of Sodamide, butanedioic acid is added, the clemastine succinate of racemization is prepared；Step 3：Clemastine succinate using racemization is split as raw material in acetone and water with L (+) tartaric acid, is eventually adding fumaric acid and is obtained clemastine fumarate crude product into salt；Step 4：Clemastine fumarate crude product, is recrystallized with aqueous acetone solution, obtains clemastine fumarate sterling.
Description
Technical field
The present invention relates to a kind of synthetic method of medical compounds, more particularly to a kind of antihistamine drug fumaric acid chlorine Maas
The new preparation method in spit of fland
Clemastine fumarate is a quick-acting, long-acting, efficient, safe and reliable antihistamine.Clemastine fumarate piece
Show in human pharmacokineticses, this product oral absorption is fast, is taken effect after 30 minutes, symptom, blood concentration after 1 hour are released rapidly
Contrasted up to peak with similar antihistamine such as Astemizole, Loratadine, this product is fastest.Its antihistamine effect can
Continue 12 hours, antihistamine effect is stronger than chlorpheniramine 10 times, drowsiness side effect (central action) is slight.Treat allergic rhinitis total
Effective percentage is 98%, treatment chronic urticaria nettle cure rate 61.3%.Clemastine is not only to basophil and lung tissue institute
The histamine of release has antagonism, and also has certain antagonism to cytotoxin in high concentration, and the medicine is to allergy
Property disease has many therapeutic actions.Clinically it is mainly used in allergic rhinitis, nettle rash, eczema and other anaphylaxis skins
It is scorching.Fumaric acid Maas spit of fland structural formula is as follows：
Chemical name：(R- (R*, R*)) -1- methyl -2- (2- (1- (4- chlorphenyls) -1- benzene ethyoxyl) ethyl)-pyrroles
Alkane (E)-(E)-butenedioic acid salt.
The preparation of existing clemastine fumarate is included in the following documents：
GB 942152(1963 to Sandoz).
Synthesis and abs config:A.H.P.Weber,Helv.Chim.Acta 59,2462(1976).
Chinese patent 201310330986 discloses a kind of method of chiral synthesis, and this method complex operation, step is more, into
This height, this method step is as follows：
Clemastine is the simplest using the method that will synthesize obtained clemastine mesotomy as chiral isomer
It is single, therefore its last splitting step of prior art is frequently with chemical method fractionation, process of the present inventor in research chemical resolution
In, find to there are problems that under existing solvent not crystallization, fractionation.
The present invention is studied method for splitting, finds to be combined method for splitting using L- (+)-tartaric acid and fumaric acid,
The clemastine fumarate product of chiral configuration needed for can successfully obtaining.
The present invention is on the basis of clemastine succinate highly finished product are obtained, to be alkalized, extracted, being spin-dried for obtaining height
Purity free state clemastine, then in acetone aqueous solvent, using the effect of L- (+)-tartaric acid and the Compound-acid of fumaric acid
The clemastine fumarate product of chiral configuration needed for lower crystallization is obtained.
The present invention can improve the chiral resolution efficiency of clemastine fumarate, improve yield and quality.
The content of the invention：
The present invention provides a kind of synthetic method of clemastine fumarate, the described method comprises the following steps：
Step 1：The synthesis of intermediate N methyl -2- (2- chloroethyls) pyrrolidines
Using N- methyl -2- (2- ethoxys) pyrrolidines as initiation material, chlorination substitution is carried out to hydroxyl, N- first is prepared
Base -2- (2- chloroethyls) pyrrolidines；
Specific steps can use following methods：
(1) N- methyl -2- (2- ethoxys) pyrrolidines, dichloromethane are mixed, is passed through nitrogen, is cooled to 0~10 DEG C；
(2) thionyl chloride and dichloromethane mixed solution are added；
(3)；40~50 DEG C are warming up to react 2 hours；
(4) solvent is evaporated off；
(5) petroleum ether is added into residue, is stirred；
(6) filter, be dried to obtain N- methyl -2- (2- chloroethyls) pyrrolidines；
Step 2：The synthesis of the clemastine succinate of intermediate racemization
Using N- methyl -2- (2- chloroethyls) pyrrolidines and 1- (4- chlorphenyls) -1- phenyl) ethanol is raw material, in Sodamide
In the presence of reaction obtain the clemastine of racemization, add butanedioic acid, prepare the clemastine succinate of racemization；
Specific steps can use following methods：
(1) by 1- (4- chlorphenyls) -1- phenyl) ethanol, N- methyl -2- (2- chloroethyls) pyrrolidines and toluene mixing, plus
Enter Sodamide；
(2) temperature reaction 4~5 hours；
(3) it is cooled to room temperature；
(4) filter；
(5) solvent is evaporated off in filtrate decompression；
(6) added into residue and 60~65 DEG C are heated under ethyl acetate, stirring；
(7) butanedioic acid is added, cool crystallization；
(8) filter；It is dried to obtain white solid；
Step 3：The preparation of clemastine fumarate crude product
Clemastine succinate using racemization is split, most as raw material in acetone and water with L- (+)-tartaric acid
Fumaric acid is added afterwards obtains clemastine fumarate into salt.
Specific steps can use following methods：
(1) the clemastine succinate of racemization is added to the water, pH value is adjusted to 10 or so with sodium hydrate aqueous solution,
Petroleum ether extraction, organic phase removes solvent under reduced pressure；
(2) mixed solvent of acetone and water is added into residue, 50~60 DEG C are heated under stirring；
(3) L- (+)-tartaric acid, fumaric acid cooling crystallization are added；
(9) filter, be dried to obtain white solid.
Wherein, the volume ratio of acetone and water is 15-25:1, preferably 19-21:1, most preferably 20:1.
Present invention additionally comprises the method for the clemastine fumarate for obtaining step 3 purifying, methods described step is as follows：Step
Rapid 4：Purifying
Clemastine fumarate crude product, is recrystallized with aqueous acetone solution, obtains clemastine fumarate sterling, HPLC
Detection, purity is 99.5%, and optical purity is 99.9%.
Specific steps can use following methods：
(1) clemastine fumarate crude product and aqueous acetone solution are mixed and heated to 50~60 DEG C, dissolving clarification；
(2) activated carbon is added, is kept for 50~60 DEG C stir 30 minutes；Filtering, filtrate cooling crystallization；
(3) filter, be dried to obtain white solid.
Wherein, the volume ratio of acetone and water is 15-25:1, preferably 19-21:1, most preferably 20:1.
Advantages of the present invention is mainly reflected in step 3 and step 4, and present invention step is proved below by way of comparative experimental data
Rapid 3 and the advantage of step 4：
Step 3
The method for splitting of the present invention is obtained by screening, and screening process is as follows：
The ratio screening of acetone and water：
| Yield | Optical purity | |
| Acetone：Water=1:1 | 52% | 79% |
| Acetone：Water=5:1 | 54% | 87% |
| Acetone：Water=10:1 | 56% | 95% |
| Acetone：Water=20:1 | 60% | 99% |
| Acetone：Water=30:1 | It cannot get solid | / |
Step 4
Recrystallization solvent used in the present invention is obtained by screening, and screening process is as follows：
The ratio screening of acetone and water：
| Yield | Optical purity | |
| Acetone：Water=1:1 | 72% | 97.5% |
| Acetone：Water=5:1 | 73% | 96.0% |
| Acetone：Water=10:1 | 75% | 98.5% |
| Acetone：Water=20:1 | 80% | 99.9% |
| Acetone：Water=30:1 | Crystallization is difficult, yield 70% | 98.5% |
As a result show, method best results of the invention.
Embodiment
The present invention is further illustrated by the following examples, but not as limitation of the present invention.
Embodiment 1
Step one：The synthesis of intermediate N methyl -2- (2- chloroethyls) pyrrolidines
(1) 1kg N- methyl -2- (2- ethoxys) pyrrolidines, 4L dichloromethane are added into 10L three-necked flasks, is passed through nitrogen
Gas, preventing and treating humid air enters, and 0~10 DEG C is cooled under stirring；
(2) by 1.11kg thionyl chlorides and the lower instillation three-necked flask of 1L dichloromethane mixed solution stirring, speed is added dropwise in control
Degree makes temperature be no more than 50 DEG C, prevents bumping；
(3) completion of dropping, is warming up to 40~50 DEG C and reacts 2 hours；
(4) TLC detections reaction is completed, and 40~50 DEG C remove solvent under reduced pressure；
(5) 1L petroleum ethers are added into residue, continues 40~50 DEG C and removes solvent under reduced pressure；Repeat 4~5 times, until going out
Existing blocks of solid；5L petroleum ethers are added into residue, mashing 1 hour is stirred at room temperature；
(6) filter, filter cake is eluted with petroleum ether；40~50 DEG C of vacuum drying obtain brown solid N- methyl -2- (2- chloroethenes
Base) pyrrolidines 1.36kg, yield about 95%
Step 2：The synthesis of the clemastine succinate of intermediate racemization
(1) by 1.48kg1- (4- chlorphenyls) -1- phenyl) ethanol, 1.30kg N- methyl -2- (2- chloroethyls) pyrrolidines
10L three-necked flasks are added with 6.5L toluene, 1.10kg Sodamides are added portionwise under stirring；
(2) add and finish, be warming up to 80 DEG C and react 4~5 hours；
(3) TLC is monitored, and reaction is finished, and stirring decline is warmed to room temperature；
(4) filter, reaction bulb and filter cake are eluted with 1.3L toluene；Filter cake is quenched with 95% ethanol；
(5) solvent is evaporated off in filtrate decompression；
(6) 13L ethyl acetate is added into residue, 60~65 DEG C are heated under stirring；
(7) lower addition 1.00kg butanedioic acids, dissolving clarification are stirred；Insulated and stirred 30 minutes, then be cooled to analysis is stirred at room temperature
It is brilliant 2 hours；
(8) it is cooled to 0~10 DEG C of stirring and crystallizing 2 hours；
(9) filter, filter cake is eluted with ethyl acetate coolant；
(10) filter cake is added in 3.9L purified waters, be stirred at room temperature lower with 20% sodium hydrate aqueous solution regulation pH value to 10
Left and right, adds 3.9L petroleum ether extractions 2 times；Merge organic phase, remove solvent under reduced pressure；
(11) 10L ethyl acetate is added into residue, 60~65 DEG C are heated under stirring；
(12) lower addition 0.83kg butanedioic acids, dissolving clarification are stirred；Insulated and stirred 30 minutes, then be cooled to analysis is stirred at room temperature
It is brilliant 2 hours；
(13) it is cooled to 0~10 DEG C of stirring and crystallizing 2 hours；
(14) filter, filter cake is eluted with ethyl acetate coolant；40~50 DEG C of vacuum drying obtain white solid about
1.6kg, yield about 55%
Step 3：The preparation of clemastine fumarate crude product
(1) the clemastine succinates of 1.50kg racemizations is added in 4.5L purified waters, is stirred at room temperature and lower uses 20% hydrogen
Aqueous solution of sodium oxide adjusts pH value to 10 or so, adds 4.5L petroleum ether extractions 2 times；Merge organic phase, use 4.5L purified waters
It washed once, point sub-cloud aqueous phase, upper organic phase removes solvent under reduced pressure；
(2) 7.5L acetone and 0.38L purified waters are added into residue, 50~60 DEG C are heated under stirring；
(3) 0.49kg L- (+)-tartaric acid is added under stirring, dissolving clarification；Insulated and stirred 30 minutes；
(4) 0.38kg fumaric acid is added under agitation again, dissolving clarification；Insulated and stirred 30 minutes；
(8) it is cooled to and crystallization is stirred at room temperature 1 hour, then is cooled to -10~0 DEG C of stirring and crystallizing 2 hours；
(9) filter, -10~0 DEG C of acetone coolant elution of filter cake use；40~50 DEG C of vacuum drying obtain white solid about
900g, yield about 60%
Step 4：Purifying
(1) 900g clemastine fumarates crude product and 5L acetone and 0.25L purified waters are added into 10L three-necked flasks, stirring
It is heated to 50~60 DEG C, dissolving clarification；
(2) 27g activated carbons are added, are kept for 50~60 DEG C stir 30 minutes；Filter while hot, filtrate stirring decline is warmed to room temperature
Crystallization 1 hour；- 10~0 DEG C of stirring and crystallizing is cooled to again 2 hours；
(3) filter, -10~0 DEG C of acetone coolant elution of filter cake use；40~50 DEG C of vacuum drying obtain white solid about
730g, yield about 81%, purity, 99.5%, optical purity 99.9%.
Claims (8)
1. a kind of preparation method of clemastine fumarate, it is characterised in that methods described, comprises the following steps：
Step 1：Using N- methyl -2- (2- ethoxys) pyrrolidines as initiation material, chlorination substitution is carried out to hydroxyl, N- is prepared
Methyl -2- (2- chloroethyls) pyrrolidines；
Step 2：Using N- methyl -2- (2- chloroethyls) pyrrolidines and 1- (4- chlorphenyls) -1- phenyl) ethanol is raw material, in amino
Reaction obtains the clemastine of racemization in the presence of sodium, adds butanedioic acid, prepares the clemastine succinate of racemization；
Step 3：Clemastine succinate using racemization is split as raw material in acetone and water with L- (+)-tartaric acid,
It is eventually adding fumaric acid and obtains clemastine fumarate crude product into salt；
Step 4：Clemastine fumarate crude product, is recrystallized with aqueous acetone solution, obtains clemastine fumarate sterling.
2. preparation method according to claim 1, it is characterised in that methods described, comprises the following steps：Step 1：It is middle
The synthesis of body N- methyl -2- (2- chloroethyls) pyrrolidines
(1) N- methyl -2- (2- ethoxys) pyrrolidines, dichloromethane are mixed, is passed through nitrogen, is cooled to 0~10 DEG C；
(2) thionyl chloride and dichloromethane mixed solution are added；
(3)；40~50 DEG C are warming up to react 2 hours；
(4) solvent is evaporated off；
(5) petroleum ether is added into residue, is stirred；
(6) filter, be dried to obtain N- methyl -2- (2- chloroethyls) pyrrolidines；
Step 2：The synthesis of the clemastine succinate of intermediate racemization
(1) by 1- (4- chlorphenyls) -1- phenyl) ethanol, N- methyl -2- (2- chloroethyls) pyrrolidines and toluene mixing, add ammonia
Base sodium；
(2) temperature reaction 4~5 hours；
(3) it is cooled to room temperature；
(4) filter；
(5) solvent is evaporated off in filtrate decompression；
(6) added into residue and 60~65 DEG C are heated under ethyl acetate, stirring；
(7) butanedioic acid is added, cool crystallization；
(8) filter；It is dried to obtain white solid；
Step 3：The preparation of clemastine fumarate crude product
(1) the clemastine succinate of racemization is added to the water, pH value is adjusted to 10 or so, oil with sodium hydrate aqueous solution
Ether is extracted, and organic phase removes solvent under reduced pressure；
(2) mixed solvent of acetone and water is added into residue, 50~60 DEG C are heated under stirring；
(3) L- (+)-tartaric acid, fumaric acid cooling crystallization are added；
(9) filter, be dried to obtain white solid.
Step 4：Purifying
(1) clemastine fumarate crude product and aqueous acetone solution are mixed and heated to 50~60 DEG C, dissolving clarification；
(2) activated carbon is added, is kept for 50~60 DEG C stir 30 minutes；Filtering, filtrate cooling crystallization；
(3) filter, be dried to obtain white solid.
3. preparation method according to claim 1, it is characterised in that
Step 3：The preparation of clemastine fumarate crude product, wherein, the volume ratio of acetone and water is 15-25:1.
4. preparation method according to claim 1, it is characterised in that
Step 3：The preparation of clemastine fumarate crude product, wherein, the volume ratio of acetone and water is 19-21:1.
5. preparation method according to claim 1, it is characterised in that
Step 3：The preparation of clemastine fumarate crude product, wherein, the volume ratio of acetone and water is 20:1.
6. preparation method according to claim 1, it is characterised in that
Step 4：Purifying, wherein, the volume ratio of acetone and water is 15-25:1.
7. preparation method according to claim 1, it is characterised in that
Step 4：Purifying, wherein, the volume ratio of acetone and water is 19-21:1.
8. preparation method according to claim 1, it is characterised in that
Step 4：Purifying, wherein, the volume ratio of acetone and water is 20:1.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111302996A (en) * | 2020-03-19 | 2020-06-19 | 山东科源制药股份有限公司 | Preparation method of high-chiral-purity chloromalastine fumarate |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB942152A (en) * | 1960-01-19 | 1963-11-20 | Sandoz Ltd | Improvements in or relating to benzhydryl ethers |
| JPS52136165A (en) * | 1976-05-10 | 1977-11-14 | Teijin Ltd | Purification of pyrrolidine derivatives |
| JPS535157A (en) * | 1976-06-30 | 1978-01-18 | Wako Pure Chem Ind Ltd | Preparation of optical active 2-#n-#(halo-#-alkyl-#-phenylbenzyl)oxyalkyl#-1-alkylpyprolidines and their salts |
| JPS5312857A (en) * | 1976-07-22 | 1978-02-04 | Kongou Kagaku Kk | Method of optical resolution of cremastin |
| CN103387528A (en) * | 2013-08-01 | 2013-11-13 | 刘怀振 | Resolution method of N-methyl-2(2-hydroxyethyl)pyrrolidine and application thereof |
-
2017
- 2017-05-24 CN CN201710374858.8A patent/CN107011228B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB942152A (en) * | 1960-01-19 | 1963-11-20 | Sandoz Ltd | Improvements in or relating to benzhydryl ethers |
| JPS52136165A (en) * | 1976-05-10 | 1977-11-14 | Teijin Ltd | Purification of pyrrolidine derivatives |
| JPS535157A (en) * | 1976-06-30 | 1978-01-18 | Wako Pure Chem Ind Ltd | Preparation of optical active 2-#n-#(halo-#-alkyl-#-phenylbenzyl)oxyalkyl#-1-alkylpyprolidines and their salts |
| JPS5312857A (en) * | 1976-07-22 | 1978-02-04 | Kongou Kagaku Kk | Method of optical resolution of cremastin |
| CN103387528A (en) * | 2013-08-01 | 2013-11-13 | 刘怀振 | Resolution method of N-methyl-2(2-hydroxyethyl)pyrrolidine and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| ANTON EBNOTHER ET AL.: "Synthese und absolute Konfiguration von Clemastin und seiner Isomeren", 《HELVETICA CHIMICA ACTA》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111302996A (en) * | 2020-03-19 | 2020-06-19 | 山东科源制药股份有限公司 | Preparation method of high-chiral-purity chloromalastine fumarate |
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