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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- CN
- China
- Prior art keywords
- clemastine
- preparation
- acetone
- added
- pyrrolidines
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- PMGQWSIVQFOFOQ-BDUVBVHRSA-N (e)-but-2-enedioic acid;(2r)-2-[2-[1-(4-chlorophenyl)-1-phenylethoxy]ethyl]-1-methylpyrrolidine Chemical compound OC(=O)\C=C\C(O)=O.CN1CCC[C@@H]1CCOC(C)(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 PMGQWSIVQFOFOQ-BDUVBVHRSA-N 0.000 title claims abstract description 29
- 229960002689 clemastine fumarate Drugs 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 70
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 27
- 238000000034 method Methods 0.000 claims abstract description 22
- 229960002881 clemastine Drugs 0.000 claims abstract description 21
- YNNUSGIPVFPVBX-NHCUHLMSSA-N clemastine Chemical compound CN1CCC[C@@H]1CCO[C@@](C)(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 YNNUSGIPVFPVBX-NHCUHLMSSA-N 0.000 claims abstract description 19
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims abstract description 16
- 230000006340 racemization Effects 0.000 claims abstract description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000012043 crude product Substances 0.000 claims abstract description 14
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims abstract description 12
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 8
- 239000001530 fumaric acid Substances 0.000 claims abstract description 8
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims abstract description 8
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims abstract description 7
- 239000001358 L(+)-tartaric acid Substances 0.000 claims abstract description 7
- 235000011002 L(+)-tartaric acid Nutrition 0.000 claims abstract description 7
- FEWJPZIEWOKRBE-LWMBPPNESA-N L-(+)-Tartaric acid Natural products OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 claims abstract description 7
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000002994 raw material Substances 0.000 claims abstract description 6
- 229960005137 succinic acid Drugs 0.000 claims abstract description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 4
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 3
- 230000000977 initiatory effect Effects 0.000 claims abstract description 3
- 239000000463 material Substances 0.000 claims abstract description 3
- 150000003839 salts Chemical class 0.000 claims abstract description 3
- 238000006467 substitution reaction Methods 0.000 claims abstract description 3
- 238000003756 stirring Methods 0.000 claims description 21
- 150000003235 pyrrolidines Chemical class 0.000 claims description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 13
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 239000007787 solid Substances 0.000 claims description 12
- 238000002425 crystallisation Methods 0.000 claims description 11
- 230000008025 crystallization Effects 0.000 claims description 11
- 230000015572 biosynthetic process Effects 0.000 claims description 8
- 239000003208 petroleum Substances 0.000 claims description 8
- 238000003786 synthesis reaction Methods 0.000 claims description 8
- 238000005352 clarification Methods 0.000 claims description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 5
- 239000012074 organic phase Substances 0.000 claims description 5
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 239000000243 solution Substances 0.000 claims description 4
- 238000010792 warming Methods 0.000 claims description 4
- 230000006837 decompression Effects 0.000 claims description 3
- 239000011259 mixed solution Substances 0.000 claims description 3
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 2
- 229910052708 sodium Inorganic materials 0.000 claims 2
- 239000011734 sodium Substances 0.000 claims 2
- 229910021529 ammonia Inorganic materials 0.000 claims 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 1
- -1 chlorphenyl Chemical group 0.000 abstract description 3
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 abstract description 3
- RMGFLMXDCGQKPS-UHFFFAOYSA-N 1-(2-chloroethyl)pyrrolidine Chemical class ClCCN1CCCC1 RMGFLMXDCGQKPS-UHFFFAOYSA-N 0.000 abstract 1
- CLVNTYZKUHNUEF-UHFFFAOYSA-N 2-(2-chloroethyl)-1-methylpyrrolidine Chemical class CN1CCCC1CCCl CLVNTYZKUHNUEF-UHFFFAOYSA-N 0.000 abstract 1
- MRGOBKTYMCELNB-UHFFFAOYSA-N 2-ethoxy-1-methylpyrrolidine Chemical class CCOC1CCCN1C MRGOBKTYMCELNB-UHFFFAOYSA-N 0.000 abstract 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract 1
- 239000012065 filter cake Substances 0.000 description 8
- 238000012216 screening Methods 0.000 description 6
- 239000000739 antihistaminic agent Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000003643 water by type Substances 0.000 description 5
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 4
- 230000001387 anti-histamine Effects 0.000 description 4
- 239000002826 coolant Substances 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- 238000001291 vacuum drying Methods 0.000 description 4
- 238000000605 extraction Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- 206010039085 Rhinitis allergic Diseases 0.000 description 2
- 201000010105 allergic rhinitis Diseases 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000008485 antagonism Effects 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 238000005194 fractionation Methods 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- HXRVTZVVSGPFEC-NTJRUYKKSA-N (E)-but-2-enedioic acid (2R,3R)-2,3-dihydroxybutanedioic acid Chemical compound OC(=O)\C=C\C(O)=O.OC(=O)[C@H](O)[C@@H](O)C(O)=O HXRVTZVVSGPFEC-NTJRUYKKSA-N 0.000 description 1
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- 101710112752 Cytotoxin Proteins 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010041349 Somnolence Diseases 0.000 description 1
- 241000219422 Urtica Species 0.000 description 1
- 235000009108 Urtica dioica Nutrition 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- 206010052568 Urticaria chronic Diseases 0.000 description 1
- BZHJMEDXRYGGRV-UHFFFAOYSA-N Vinyl chloride Chemical class ClC=C BZHJMEDXRYGGRV-UHFFFAOYSA-N 0.000 description 1
- IWUWUBNCZVJDGG-TYYBGVCCSA-N [Cl].OC(=O)\C=C\C(O)=O Chemical compound [Cl].OC(=O)\C=C\C(O)=O IWUWUBNCZVJDGG-TYYBGVCCSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 229940124623 antihistamine drug Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- GXDALQBWZGODGZ-UHFFFAOYSA-N astemizole Chemical compound C1=CC(OC)=CC=C1CCN1CCC(NC=2N(C3=CC=CC=C3N=2)CC=2C=CC(F)=CC=2)CC1 GXDALQBWZGODGZ-UHFFFAOYSA-N 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 210000003651 basophil Anatomy 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- SOYKEARSMXGVTM-UHFFFAOYSA-N chlorphenamine Chemical compound C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 SOYKEARSMXGVTM-UHFFFAOYSA-N 0.000 description 1
- 229960003291 chlorphenamine Drugs 0.000 description 1
- 208000024376 chronic urticaria Diseases 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 239000002619 cytotoxin Substances 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 229960003088 loratadine Drugs 0.000 description 1
- JCCNYMKQOSZNPW-UHFFFAOYSA-N loratadine Chemical compound C1CN(C(=O)OCC)CCC1=C1C2=NC=CC=C2CCC2=CC(Cl)=CC=C21 JCCNYMKQOSZNPW-UHFFFAOYSA-N 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 238000005360 mashing Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
- 229910001948 sodium oxide Inorganic materials 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B57/00—Separation of optically-active compounds
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrrole Compounds (AREA)
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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| 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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| 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 |
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| 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 |
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| 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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