CN104030896A - Method for simply removing specific impurities from ospemifene - Google Patents
Method for simply removing specific impurities from ospemifene Download PDFInfo
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- CN104030896A CN104030896A CN201310071637.5A CN201310071637A CN104030896A CN 104030896 A CN104030896 A CN 104030896A CN 201310071637 A CN201310071637 A CN 201310071637A CN 104030896 A CN104030896 A CN 104030896A
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- ospemifene
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- LUMKNAVTFCDUIE-VHXPQNKSSA-N ospemifene Chemical compound C1=CC(OCCO)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 LUMKNAVTFCDUIE-VHXPQNKSSA-N 0.000 title claims abstract description 36
- 229960003969 ospemifene Drugs 0.000 title claims abstract description 35
- 238000000034 method Methods 0.000 title claims abstract description 32
- 239000012535 impurity Substances 0.000 title claims abstract description 16
- 238000002425 crystallisation Methods 0.000 claims abstract description 23
- 230000008025 crystallization Effects 0.000 claims abstract description 23
- 239000012043 crude product Substances 0.000 claims abstract description 17
- 239000002904 solvent Substances 0.000 claims abstract description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 239000007787 solid Substances 0.000 claims description 20
- 238000003756 stirring Methods 0.000 claims description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- 238000001816 cooling Methods 0.000 claims description 9
- 238000006519 Mcmurry reaction Methods 0.000 claims description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 5
- 230000001476 alcoholic effect Effects 0.000 claims description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 3
- 238000004821 distillation Methods 0.000 claims description 2
- 238000001172 liquid--solid extraction Methods 0.000 claims description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims 3
- 238000002156 mixing Methods 0.000 claims 2
- 239000000047 product Substances 0.000 abstract description 8
- 230000000694 effects Effects 0.000 abstract description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 39
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 15
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 13
- 239000002253 acid Substances 0.000 description 13
- 238000001514 detection method Methods 0.000 description 13
- 238000004128 high performance liquid chromatography Methods 0.000 description 13
- 229910052698 phosphorus Inorganic materials 0.000 description 13
- 239000011574 phosphorus Substances 0.000 description 13
- 229910052760 oxygen Inorganic materials 0.000 description 12
- 239000001301 oxygen Substances 0.000 description 12
- 238000004458 analytical method Methods 0.000 description 8
- 230000006837 decompression Effects 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- 230000001076 estrogenic effect Effects 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 5
- 210000000988 bone and bone Anatomy 0.000 description 5
- 239000013557 residual solvent Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 4
- 125000004464 hydroxyphenyl group Chemical group 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- 239000011701 zinc Substances 0.000 description 4
- VCNYPJMEQHTAHS-UHFFFAOYSA-N 1-(3-chlorophenyl)propan-2-one Chemical compound CC(=O)CC1=CC=CC(Cl)=C1 VCNYPJMEQHTAHS-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 206010006187 Breast cancer Diseases 0.000 description 3
- 208000026310 Breast neoplasm Diseases 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000000262 estrogen Substances 0.000 description 3
- 229940011871 estrogen Drugs 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 210000005075 mammary gland Anatomy 0.000 description 3
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 239000000333 selective estrogen receptor modulator Substances 0.000 description 3
- 210000004291 uterus Anatomy 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- ARSRBNBHOADGJU-UHFFFAOYSA-N 7,12-dimethyltetraphene Chemical compound C1=CC2=CC=CC=C2C2=C1C(C)=C(C=CC=C1)C1=C2C ARSRBNBHOADGJU-UHFFFAOYSA-N 0.000 description 2
- ABCHBTHULWULDU-UHFFFAOYSA-N CCOC1=C(C=CC(=C1C2=CC=CC=C2)C(=O)C3=CC=CC=C3)O Chemical compound CCOC1=C(C=CC(=C1C2=CC=CC=C2)C(=O)C3=CC=CC=C3)O ABCHBTHULWULDU-UHFFFAOYSA-N 0.000 description 2
- 102100038595 Estrogen receptor Human genes 0.000 description 2
- 230000008484 agonism Effects 0.000 description 2
- 150000001336 alkenes Chemical group 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 210000000748 cardiovascular system Anatomy 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000000328 estrogen antagonist Substances 0.000 description 2
- 238000002657 hormone replacement therapy Methods 0.000 description 2
- 210000004994 reproductive system Anatomy 0.000 description 2
- 229940095743 selective estrogen receptor modulator Drugs 0.000 description 2
- 229960001603 tamoxifen Drugs 0.000 description 2
- ODDBBUZTMLEZBW-UHFFFAOYSA-N 1-chlorohex-3-ene Chemical compound CCC=CCCCl ODDBBUZTMLEZBW-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 206010003694 Atrophy Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 108010007005 Estrogen Receptor alpha Proteins 0.000 description 1
- 102100029951 Estrogen receptor beta Human genes 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 206010019851 Hepatotoxicity Diseases 0.000 description 1
- 101001010910 Homo sapiens Estrogen receptor beta Proteins 0.000 description 1
- 229910010082 LiAlH Inorganic materials 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- MKYQPGPNVYRMHI-UHFFFAOYSA-N Triphenylethylene Chemical group C=1C=CC=CC=1C=C(C=1C=CC=CC=1)C1=CC=CC=C1 MKYQPGPNVYRMHI-UHFFFAOYSA-N 0.000 description 1
- 229910007565 Zn—Cu Inorganic materials 0.000 description 1
- YLWAOUBSKRXACR-UHFFFAOYSA-N [2-(4-hydroxyphenyl)phenyl]-phenylmethanone Chemical compound C1=CC(O)=CC=C1C1=CC=CC=C1C(=O)C1=CC=CC=C1 YLWAOUBSKRXACR-UHFFFAOYSA-N 0.000 description 1
- -1 aldehyde ketone Chemical class 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 229940046836 anti-estrogen Drugs 0.000 description 1
- 230000001833 anti-estrogenic effect Effects 0.000 description 1
- 230000037444 atrophy Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- TVZPLCNGKSPOJA-UHFFFAOYSA-N copper zinc Chemical compound [Cu].[Zn] TVZPLCNGKSPOJA-UHFFFAOYSA-N 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 108010038795 estrogen receptors Proteins 0.000 description 1
- 230000007686 hepatotoxicity Effects 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 208000001685 postmenopausal osteoporosis Diseases 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- HWJMPVSUEAHLGH-UHFFFAOYSA-J titanium(4+);zinc;tetrachloride Chemical compound [Zn].Cl[Ti](Cl)(Cl)Cl HWJMPVSUEAHLGH-UHFFFAOYSA-J 0.000 description 1
- 229960005026 toremifene Drugs 0.000 description 1
- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 description 1
- 208000012991 uterine carcinoma Diseases 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/34—Separation; Purification; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/34—Separation; Purification; Stabilisation; Use of additives
- C07C41/36—Separation; Purification; Stabilisation; Use of additives by solid-liquid treatment; by chemisorption
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/34—Separation; Purification; Stabilisation; Use of additives
- C07C41/40—Separation; Purification; Stabilisation; Use of additives by change of physical state, e.g. by crystallisation
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Crystallography & Structural Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention relates to a method for simply removing specific impurities from ospemifene. A crude product is washed and starched by a proper solvent in advance, parts of impurities can be removed by utilizing the difference of the dissolvability of ospemifene and the dissolvability of the impurities, a good effect can be obtained by crystallizing at a proper temperature, and a qualified product according with the quality standard requirements can be obtained after one or two time crystallization.
Description
Technical field
The present invention relates to medical chemistry field, particularly, the present invention relates to simple and easy removal Z-2[4-(4-chloro-1,2-phenylbenzene-but-1-ene base) benzene oxygen] method of the special impurity of ethanol (below using its common name ospemifene), can obtain highly purified ospemifene, meet medicinal requirements.
Background technology
Oestrogenic hormon is the important hormonal substance of a class in human body, except working in reproductive system, also affects the function of other system, as bone, cardiovascular systems etc.After postmenopausal women, body inner estrogen level declines, and causes thus involution syndrome, osteoporosis, senile dementia and cardiovascular disorder etc.At present, generally adopt clinically Hormone Replacement Therapy (HRT) to treat or prevent these symptoms that are prone to climacteric.But unfortunately, HRT can cause several untoward reactions, comprise that the initiation potential of hemorrhage, swelling, mammary gland tenderness and uterus carcinoma and mammary cancer increases.Therefore, be necessary that screening has estrogen-like stirring effect to bone and cardiovascular systems, has the ideal medicament of oestrogenic hormon antagonistic effect simultaneously to uterus and mammary gland.Selective estrogen receptor regulating (SERM) has the medicine of this specific character just.SERMs is the medicine of a class synthetic, has oestrogenic hormon agonism in bone, liver, and in mammary gland, uterus, has antagonism oestrogenic hormon or extremely weak oestrogenic hormon agonism.
Ospemifene (Ospemifene, FC-1271a, chemical name Z-2[4-(4-chloro-1,2-phenylbenzene-but-1-ene base) benzene oxygen] ethanol is a kind of novel triphenylethylene SERM, is the important meta-bolites of one of toremifene.
This compound is a kind of tissue specificity oestrogenic hormon/antiestrogen, and affinity and the tamoxifen of this medicine and estrogen receptor alpha (ER α) and β (ER β) are suitable.Ospemifene can prevent the caused bone of estrogen decrease to run off in animal model, and can suppress the growth of human breast cancer MCF7 cell and tumour, also can suppress the growth of the breast tumor that dimethylbenzanthracene (DMBA) causes.This medicine also can reduce serum cholesterol level.Ospemifene has faint oestrogenic hormon and estrogen antagonist effect to uterus, but bone is had to significant estrogen effect.In addition, this medicine does not cause the hepatotoxicity that tamoxifen produces.Therefore, ospemifene is further studied the atrophy (modern medicines and clinical, 2010,25(5) that is used for treating postmenopausal osteoporosis and reproductive system, 390).
Ospemifene molecule has alkene structures, WO2011/89385 adopts and is reacted in DMF with ethylene bromohyrin and obtained 4-hydroxy ethoxy phenyl benzophenone (3) by 4-dihydroxy benaophenonel (2), under the catalysis of titanium tetrachloride-zinc, there is McMurry with 3-chlorophenyl acetone by (3) again and react, directly generate ospemifene.
Or the method for employing WO2008/099059; 4-dihydroxy benaophenonel first reacts and obtains compound 5-chloro-1 through McMurry with 3-chlorophenyl acetone; 2 phenylbenzene-1-(4-hydroxyphenyl)-1-amylene (4), then obtain (5) and protective reaction generation ospemifene through WILLIAMS-DARLING Ton reaction.
The committed step of method is that two kinds of ketone generation linked reactions generate two keys, is called McMurry reaction.This reaction is that aldehyde ketone is at reducing metal (Li, Na, Mg, Zn, LiAlH
4, Zn-Cu) and lower valency titanium (TiCl
3, TiCl
4) lower two the carbonyl condensation deoxidations of effect obtain alkene.Although McMurry reaction step is fairly simple, reaction conditions is harsher, and self coupling and cis-trans isomerism are difficult to avoid.Therefore prepare in ospemifene process, McMurry reaction easily produces multiple side reaction products, and this can be on the mass formation impact of the finished product.Pharmacopoeia of each country has very strict restriction to the single impurity of bulk drug, and general requirement is less than below 0.1%.In the technique and quality approach process of ospemifene, separate and determine issuable impurity, then according to the structure of impurity, infer issuable reason and approach, in technological process, avoid as far as possible.And if impurity has produced, adopt good method to remove them according to the character of impurity, there is very large help to preparing highly purified ospemifene.
Summary of the invention
The object of the invention is to, a kind of preparation method of high purity ospemifene is provided.
Technical scheme provided by the invention is as follows:
According to the method for patent WO2011/89385 or WO2008/099059, prepare ospemifene, obtain lurid thickness oily matter, TLC thin layer finds except product point have multiple impure points to occur.
Adopt column chromatography method, separation, purifying and Structural Identification, confirm possible impurity as follows:
(E/Z) 1, two (4-the hydroxy phenyl)-stilbene of 2-
(E/Z) 1, two (4-hydroxyethyl oxygen base the phenyl)-stilbene of 2-
(E/Z) 3,4-hexichol-1, the chloro-3-hexene of 6-bis-
E-2[4-(4-chloro-1,2-phenylbenzene-but-1-ene base) benzene oxygen] ethanol
1-phenyl-(4-hydroxyethyl oxygen base phenyl) methyl alcohol
Wherein, (E/Z) 1, two (the 4-hydroxy phenyls)-1 of 2-, 2-toluylene, (E/Z) 1, two (4-hydroxyethyl oxygen base phenyl)-stilbene of 2-and (E/Z) 3,4-hexichol-1,6-dichloro hexene is that the by product that McMurry linked reaction obtains occurs two kinds of ketone raw materials self; E-2[4-(4-chloro-1,2-phenylbenzene-but-1-ene base) benzene oxygen] the ethanol cis-trans-isomer that is ospemifene; 1-phenyl-(4-hydroxyethyl oxygen base phenyl) methyl alcohol is the by product of ketone reduction.
Adopt McMurry reaction to obtain product, by the method for general direct crystallization, no matter be to adopt a kind of solvent or the method for mixed solvent, owing to having comprised a large amount of impurity, crystallization is difficult to separate out, or the product after crystallization is still the repeated multiple times crystallization of thick needs, the quality of product and yield are all difficult to ensure.We find in test, when the solvent with suitable is washed and starched crude product in advance, utilize the deliquescent difference of product and impurity, remove a part of impurity, and adopt suitable temperature crystallization, can receive unexpected good effect, general only need once or secondary crystal, just can obtain meeting the qualified product that quality standard requires.
The step method that test adopts is as follows:
(1) adopt McMurry reaction to obtain ospemifene crude product;
(2) with the less organic solvent of polarity, crude product is carried out to liquid-solid extraction, discard organic solvent and obtain solid matter;
(3), after the solid matter of underpressure distillation step (2), use alcoholic solvent heating for dissolving;
(4) cooling, leaves standstill crystallization, filters and obtains high purity ospemifene.
Wherein, in step (3), (4), also can adopt alcoholic solvent room temperature to dissolve, leave standstill nature crystallization, filter and obtain high purity ospemifene.
Embodiment
Referring to specific embodiment, the present invention is described.It will be appreciated by those skilled in the art that these embodiment are only for illustrating object of the present invention, the scope that it does not limit the present invention in any way.
embodiment 1(E/Z) 1, two (4-the hydroxy phenyl)-stilbene of 2-
Obtain Z-4-(4-chloro-1,2-phenylbenzene)-but-1-ene phenol crude product with reference to WO2008/099059 method, adopt column chromatography method, ethyl acetate: sherwood oil=1:2 wash-out, obtain white solid, be (E/Z) 1, two (4-the hydroxy phenyl)-stilbene of 2-.
HPLC moving phase: 0.5% triethylamine solution (with phosphorus acid for adjusting pH value to 3.0)-acetonitrile=60:40; Flow velocity: 1.0mlmin
-1; Detection wavelength is 277nm.
1hNMR:4.58 (s, 2H ,-OH), 6.61-7.12 (m, 18, phenyl ring). ultimate analysis: C
26h
20o
2calculated value C85.69%, H5.53%; Measured value C85.42%, H5.25%.
embodiment 2(E/Z) 1, two (4-the hydroxy phenyl)-stilbene of 2-
Zn powder 2.3g and THF40ml join in three-necked bottle, are cooled to-10 DEG C, pass into N
2, stir the lower TiCl of dropping
42ml(0.01mol), finish reaction 30min, then move in the oil bath of 65 DEG C and continue reaction 2h, be cooled to 40 DEG C, add the THF10ml mixed solution of 4-hydroxy phenyl benzophenone (2.0g, 0.01mol), then temperature is elevated to 65 DEG C of stirring reaction 3.5h.
React complete solution and add in 10% wet chemical 30ml and stir, separate out a large amount of solids.Leave standstill, filter filtrate decompression evaporate to dryness.Add ethyl acetate 20ml to dissolve, washing, organic layer anhydrous sodium sulfate drying, solvent evaporated obtains yellow oil.Obtain white solid 1.4g with methanol-water (6:1) recrystallization, productive rate is 76.9%.HPLC moving phase: 0.5% triethylamine solution (with phosphorus acid for adjusting pH value to 3.0)-acetonitrile=60:40; Flow velocity: 1.0mlmin
-1; Detection wavelength is 277nm.
1hNMR:4.58 (s, 2H ,-OH), 6.61-7.12 (m, 18, phenyl ring). ultimate analysis: C
26h
20o
2calculated value C85.69%, H5.53%; Measured value C85.39%, H5.76%.
embodiment 3(E/Z) 1, two (4-hydroxyethyl oxygen base the phenyl)-stilbene of 2-
Obtain ospemifene crude product with reference to WO2008/099059 method, adopt column chromatography method, ethyl acetate: sherwood oil=1:2 wash-out, obtains white solid.HPLC moving phase: 0.5% triethylamine solution (with phosphorus acid for adjusting pH value to 3.0)-acetonitrile=60:40; Flow velocity: 1.0mlmin
-1; Detection wavelength is 277nm.
1hNMR:2.02 (t, 2H ,-OH), 3.89 (d, 4H ,-CH
2cH
2oH), 3.99 (d, 4H ,-CH
2cH
2oH), 6.61-7.24 (m, 18, phenyl ring).Ultimate analysis: C
30h
28o
4calculated value C79.62%, H6.24%; Measured value C79.55%, H6.44%.
embodiment 4(E/Z) 1, two (4-hydroxyethyl oxygen base the phenyl)-stilbene of 2-
Zn powder 2.3g and THF40ml join in three-necked bottle, are cooled to-10 DEG C, pass into N
2, stir the lower TiCl of dropping
42ml(0.01mol), finish reaction 30min, then move into and in the oil bath of 65 DEG C, continue reaction 2h, be cooled to 40 DEG C, add 2-(4-benzoyl phenoxy group) the THF10ml mixed solution of-1-ethanol (2.4g, 0.01mol), then temperature is elevated to 65 DEG C of stirring reaction 3.5h.
React complete solution and add in 10% wet chemical 30ml and stir, separate out a large amount of solids.Leave standstill, filter filtrate decompression evaporate to dryness.Add ethyl acetate 20ml to dissolve, washing, organic layer anhydrous sodium sulfate drying, solvent evaporated obtains yellow oil.Obtain white solid 1.9g with methanol-water (6:1) recrystallization, productive rate is 79.8%.HPLC moving phase: 0.5% triethylamine solution (with phosphorus acid for adjusting pH value to 3.0)-acetonitrile=60:40; Flow velocity: 1.0mlmin
-1; Detection wavelength is 277nm.
1hNMR:2.02 (t, 2H ,-OH), 3.89 (d, 4H ,-CH
2cH
2oH), 3.99 (d, 4H ,-CH
2cH
2oH), 6.61-7.24 (m, 18, phenyl ring).Ultimate analysis: C
30h
28o
4calculated value C79.62%, H6.24%; Measured value C79.58%, H6.51%.
embodiment 5(E/Z) 3,4-hexichol-1,6-dichloro hexene
Obtain ospemifene crude product with reference to WO2008/099059 method, adopt column chromatography method, ethyl acetate: sherwood oil=1:3 wash-out, obtains white solid.HPLC moving phase: 0.5% triethylamine solution (with phosphorus acid for adjusting pH value to 3.0)-acetonitrile=60:40; Flow velocity: 1.0mlmin
-1; Detection wavelength is 240nm.
1hNMR:2.31 (q, 2H, CH
2), 2.59 (m, 2H ,-CH
2), 4.25 (m, 2H, CH
2), 4.34 (m, 2H, CH
2), 6.90～7.24 (m, 10, phenyl ring).Ultimate analysis: C
18h
18cl
2calculated value C70.83%, H5.94%, Cl23.23%; Measured value C71.02%, H5.77%, Cl23.28%.
embodiment 6(E/Z) 3,4-hexichol-1,6-dichloro hexene
Zn powder 2.3g and THF40ml join in three-necked bottle, are cooled to-10 DEG C, pass into N
2, stir the lower TiCl of dropping
31.8ml(0.01mol), iodine 0.1g, finishes reaction 30min, then moves in the oil bath of 65 DEG C and continues reaction 2h, is cooled to 0～5 DEG C, adds the THF10ml mixed solution of 3-chlorophenyl acetone (1.7g, 0.01mol), stirring reaction 5h.
React complete solution and add in 10% wet chemical 30ml and stir, separate out a large amount of solids.Leave standstill, filter filtrate decompression evaporate to dryness.Add ethyl acetate 20ml to dissolve, washing, organic layer anhydrous sodium sulfate drying, solvent evaporated obtains oily matter.Obtain white solid 1.0g with methanol-water (6:1) recrystallization, productive rate is 65.5%.HPLC moving phase: 0.5% triethylamine solution (with phosphorus acid for adjusting pH value to 3.0)-acetonitrile=60:40; Flow velocity: 1.0mlmin
-1; Detection wavelength is 240nm.
1hNMR:2.31 (q, 2H, CH
2), 2.59 (m, 2H ,-CH
2), 4.25 (m, 2H, CH
2), 4.34 (m, 2H, CH
2), 6.90～7.24 (m, 10, phenyl ring).Ultimate analysis: C
18h
18cl
2calculated value C70.83%, H5.94%, Cl23.23%; Measured value C70.90%, H5.67%, Cl23.26%.
embodiment 7e-2[4-(4-chloro-1,2-phenylbenzene-but-1-ene base) benzene oxygen] ethanol
Obtain ospemifene crude product with reference to WO2008/099059 method, adopt column chromatography method, ethyl acetate: sherwood oil: acetic acid=1:3:0.2 wash-out, obtains white solid.HPLC moving phase: 0.5% triethylamine solution (with phosphorus acid for adjusting pH value to 3.0)-acetonitrile=60:40; Flow velocity: 1.0mlmin
-1; Detection wavelength is 277nm.
1HNMR(400MHz,CDCl
3)δ(ppm)2.93(2H,t)，3.45(2H,t),4.10～4.16（4H,m）,6.50（2H,d）,6.83（2H,d），7.10～7.45(10H,m)。Ultimate analysis: C
24h
23clO
2calculated value C76.08%, H6.12%, Cl9.36%; Measured value C76.21%, H6.40%, Cl9.22%.
embodiment 81-phenyl-(4-hydroxyethyl oxygen base phenyl) methyl alcohol
Obtain ospemifene crude product with reference to WO2008/099059 method, adopt column chromatography method, ethyl acetate: sherwood oil=1:3 wash-out, obtains white solid.HPLC moving phase: 0.5% triethylamine solution (with phosphorus acid for adjusting pH value to 3.0)-acetonitrile=60:40; Flow velocity: 1.0mlmin
-1; Detection wavelength is 277nm.
1hNMR:1.90 (t, 1H, OH), 3.85 (q, 2H, CH
2), 3.93 (m, 2H ,-CH
2), 4.65 (s, 1H), 6.65 (d, 2H, phenyl ring), 6.90～7.24 (m, 7H, phenyl ring).Ultimate analysis: C
15h
16o
3calculated value C73.75%, H6.60%; Measured value C73.55%, H6.24%.
embodiment 9ospemifene purifying
Ospemifene crude product 20g is added to normal hexane 10ml, and 40 DEG C are stirred 30min, slightly cold, leave standstill 1h hypsokinesis and go out liquid, and then add normal hexane 10ml, repeat aforesaid operations.Decompression steams residual solvent, and residue adds methyl alcohol and alcohol mixeding liquid 160ml heating for dissolving, is cooled to 40 DEG C, keeps this temperature to leave standstill and adds crystal seed crystallization.After crystallization, continue cooling and stirring crystallization, then freezing-25 DEG C placement.Filter, obtain white solid 15.2g, yield 76%, HPLC moving phase: 0.5% triethylamine solution (with phosphorus acid for adjusting pH value to 3.0)-acetonitrile=60:40; Flow velocity: 1.0mlmin
-1; Detection wavelength is 277nm, content 99.92%.
embodiment 10ospemifene purifying
Ospemifene crude product 20g is added to hexanaphthene 100ml, and stirring at room temperature 30min, is cooled to 0 DEG C, leaves standstill 1h hypsokinesis and goes out liquid, and then add hexanaphthene 60ml, repeats aforesaid operations.Decompression steams residual solvent, and residue adds ethanol 200ml heating for dissolving, is cooled to 40 DEG C, slowly drips water 20ml, keeps this temperature to leave standstill and adds crystal seed crystallization.After crystallization, continue cooling and stirring crystallization, 25 DEG C of placements of room temperature.Filter, obtain white solid 14.8g, yield 74%, HPLC moving phase: 0.5% triethylamine solution (with phosphorus acid for adjusting pH value to 3.0)-acetonitrile=60:40; Flow velocity: 1.0mlmin
-1; Detection wavelength is 277nm, content 99.89%.
embodiment 11ospemifene purifying
Ospemifene crude product 20g is added to heptane 50ml, stirring at room temperature 30min, cooling room temperature, leaves standstill 1h hypsokinesis and goes out liquid, and then add heptane 20ml, repeats aforesaid operations.Decompression steams residual solvent, and residue adds Virahol 160ml heating for dissolving, is cooled to 30 DEG C, slowly drips water 16ml, keeps this temperature to leave standstill and adds crystal seed crystallization.After crystallization, continue to be cooled to 0 DEG C of stirring and crystallizing, room temperature is placed.Filter, obtain white solid 15.8g, yield 79%, HPLC moving phase: 0.5% triethylamine solution (with phosphorus acid for adjusting pH value to 3.0)-acetonitrile=60:40; Flow velocity: 1.0mlmin
-1; Detection wavelength is 277nm, content 99.85%.
embodiment 12ospemifene purifying
Ospemifene crude product 20g is added to hexanaphthene 40ml, stirring at room temperature 30min, cooling room temperature, leaves standstill 1h hypsokinesis and goes out liquid, and then add hexanaphthene 20ml, repeats aforesaid operations.Decompression steams residual solvent, and residue adds methyl alcohol 200ml heating for dissolving, is cooled to 30 DEG C, slowly drips water 20ml, keeps this temperature to leave standstill and adds crystal seed crystallization.After partial crystallization goes out, continue to be cooled to 0 DEG C of stirring and crystallizing.Filter, obtain white solid 16.2g, yield 81%, HPLC moving phase: 0.5% triethylamine solution (with phosphorus acid for adjusting pH value to 3.0)-acetonitrile=60:40; Flow velocity: 1.0mlmin
-1; Detection wavelength is 277nm, content 99.90%.
embodiment 13ospemifene purifying
Ospemifene crude product 20g is added to normal hexane 200ml, stirring at room temperature 30min, cooling room temperature, leaves standstill 1h hypsokinesis and goes out liquid, and then add normal hexane 20ml, repeats aforesaid operations.Decompression steams residual solvent, and residue adds methyl alcohol, ethanol and Virahol mixed solution 300ml stirring at room temperature 1h, keeps this temperature to leave standstill and adds crystal seed crystallization.Filter, obtain white solid 12.4g, yield 62%, HPLC moving phase: 0.5% triethylamine solution (with phosphorus acid for adjusting pH value to 3.0)-acetonitrile=60:40; Flow velocity: 1.0mlmin
-1; Detection wavelength is 277nm, content 99.93%.
Claims (6)
1. a method for the special impurity of simple and easy removal ospemifene, is characterized in that passing through following steps:
(1) adopt McMurry reaction to obtain ospemifene crude product;
(2) use alkanes organic solvent, crude product is carried out to liquid-solid extraction, discard organic solvent and obtain solid matter;
(3), after the solid matter of underpressure distillation step (2), use alcoholic solvent heating for dissolving;
(4) cooling leaves standstill crystallization, filters and obtains high purity ospemifene.
2. method according to claim 1, is characterized in that, described in step (2), alkane solvents is selected from normal hexane, hexanaphthene, heptane.
3. method according to claim 1, is characterized in that, alkane solvents described in step (2) and formula I crude product additional proportion are 1～8:1(V/M, volume mass ratio).
4. method according to claim 1, is characterized in that, in step (3) alcoholic solvent be selected from methyl alcohol, ethanol, Virahol any, the mixing of two kinds or the mixing of three kinds.
5. method according to claim 1, is characterized in that, leaves standstill crystallization and can be divided into two steps in step (4), and the first step is directly lower the temperature or add water for cooling, and temperature is 25～40 DEG C, and second step is for stirring cooling crystallization, and temperature is-25～25 DEG C.
6. method according to claim 1, is characterized in that, also can adopt alcoholic solvent room temperature to dissolve in step (3), (4), leaves standstill nature crystallization, filters and obtains high purity ospemifene.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016108172A1 (en) | 2014-12-29 | 2016-07-07 | Olon S.P.A. | Process for the preparation of ospemifene and fispemifene |
| WO2017159669A1 (en) * | 2016-03-15 | 2017-09-21 | 塩野義製薬株式会社 | Method for producing phenoxyethanol derivative |
| EP3181545A4 (en) * | 2014-09-16 | 2018-08-01 | Shionogi & Co., Ltd. | Method for producing triphenylbutene derivative |
| CN108514539A (en) * | 2018-07-11 | 2018-09-11 | 广州市雅薏诗化妆品有限公司 | One kind being based on mild effect anticorrosive composite used for cosmetic and the cosmetics preparation method |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1291178A (en) * | 1998-02-19 | 2001-04-11 | 欧里恩公司 | E-2-[4-(4-chloro-1,2-diphenyl-but-1-enyl) phenoxy] ethanol and pharmaceutical compositions thereof |
| CN102770402A (en) * | 2010-01-19 | 2012-11-07 | 坎布雷卡尔斯库加公司 | New processes for producing benzophenone derivatives |
-
2013
- 2013-03-07 CN CN201310071637.5A patent/CN104030896A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1291178A (en) * | 1998-02-19 | 2001-04-11 | 欧里恩公司 | E-2-[4-(4-chloro-1,2-diphenyl-but-1-enyl) phenoxy] ethanol and pharmaceutical compositions thereof |
| CN102770402A (en) * | 2010-01-19 | 2012-11-07 | 坎布雷卡尔斯库加公司 | New processes for producing benzophenone derivatives |
Non-Patent Citations (1)
| Title |
|---|
| 刘红英: "《有机化学实验》", 31 January 2008 * |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3181545A4 (en) * | 2014-09-16 | 2018-08-01 | Shionogi & Co., Ltd. | Method for producing triphenylbutene derivative |
| WO2016108172A1 (en) | 2014-12-29 | 2016-07-07 | Olon S.P.A. | Process for the preparation of ospemifene and fispemifene |
| WO2017159669A1 (en) * | 2016-03-15 | 2017-09-21 | 塩野義製薬株式会社 | Method for producing phenoxyethanol derivative |
| CN108137457A (en) * | 2016-03-15 | 2018-06-08 | 盐野义制药株式会社 | The manufacturing method of Phenoxyethanol derivative |
| US10472312B2 (en) | 2016-03-15 | 2019-11-12 | Shionogi & Co., Ltd. | Method for producing phenoxyethanol derivative |
| EA039048B1 (en) * | 2016-03-15 | 2021-11-26 | Сионоги Энд Ко., Лтд. | Method for producing phenoxyethanol derivatives |
| CN108137457B (en) * | 2016-03-15 | 2022-09-06 | 盐野义制药株式会社 | Method for producing phenoxyethanol derivative |
| CN108514539A (en) * | 2018-07-11 | 2018-09-11 | 广州市雅薏诗化妆品有限公司 | One kind being based on mild effect anticorrosive composite used for cosmetic and the cosmetics preparation method |
| CN108514539B (en) * | 2018-07-11 | 2021-07-27 | 广州市腾宇化妆品有限公司 | Antiseptic composition for cosmetics based on mild effect and preparation method of cosmetics |
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