CN1178895C - Naprosyn precusor, its synthesis method and application - Google Patents
Naprosyn precusor, its synthesis method and application Download PDFInfo
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- CN1178895C CN1178895C CNB021349827A CN02134982A CN1178895C CN 1178895 C CN1178895 C CN 1178895C CN B021349827 A CNB021349827 A CN B021349827A CN 02134982 A CN02134982 A CN 02134982A CN 1178895 C CN1178895 C CN 1178895C
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- Prior art keywords
- naproxen
- precusor
- naprosyn
- naproxen base
- ester
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- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 title claims abstract description 75
- 229940090008 naprosyn Drugs 0.000 title claims description 24
- 238000001308 synthesis method Methods 0.000 title abstract 2
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 claims abstract description 61
- 229960002009 naproxen Drugs 0.000 claims abstract description 61
- -1 alcohol ester Chemical class 0.000 claims abstract description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229940040145 liniment Drugs 0.000 claims abstract description 6
- 239000000865 liniment Substances 0.000 claims abstract description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- 238000005303 weighing Methods 0.000 claims description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 7
- 239000008346 aqueous phase Substances 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 7
- 239000012074 organic phase Substances 0.000 claims description 7
- 238000010992 reflux Methods 0.000 claims description 7
- 229920006395 saturated elastomer Polymers 0.000 claims description 7
- 238000005406 washing Methods 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 6
- 229910021536 Zeolite Inorganic materials 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- HNPSIPDUKPIQMN-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane Chemical compound O=[Si]=O.O=[Al]O[Al]=O HNPSIPDUKPIQMN-UHFFFAOYSA-N 0.000 claims description 5
- 150000002148 esters Chemical class 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 239000010457 zeolite Substances 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 229910052742 iron Inorganic materials 0.000 claims description 3
- RUTXIHLAWFEWGM-UHFFFAOYSA-H iron(3+) sulfate Chemical compound [Fe+3].[Fe+3].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O RUTXIHLAWFEWGM-UHFFFAOYSA-H 0.000 claims description 3
- 229910000360 iron(III) sulfate Inorganic materials 0.000 claims description 3
- 238000010189 synthetic method Methods 0.000 claims description 3
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 claims description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 3
- 239000011592 zinc chloride Substances 0.000 claims description 3
- 235000005074 zinc chloride Nutrition 0.000 claims description 3
- ZXAUZSQITFJWPS-UHFFFAOYSA-J zirconium(4+);disulfate Chemical compound [Zr+4].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O ZXAUZSQITFJWPS-UHFFFAOYSA-J 0.000 claims description 3
- GNEPLYVYORHREW-UHFFFAOYSA-N 1,1,3,3,6-pentamethyl-7-nitro-2h-inden-5-amine Chemical compound CC1=C(N)C=C2C(C)(C)CC(C)(C)C2=C1[N+]([O-])=O GNEPLYVYORHREW-UHFFFAOYSA-N 0.000 claims description 2
- 241000723346 Cinnamomum camphora Species 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 2
- 239000003814 drug Substances 0.000 abstract description 22
- 239000003795 chemical substances by application Substances 0.000 abstract description 10
- 229940079593 drug Drugs 0.000 abstract description 10
- 238000000034 method Methods 0.000 abstract description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 abstract description 2
- 239000002243 precursor Substances 0.000 abstract 4
- 230000035699 permeability Effects 0.000 abstract 1
- 210000003491 skin Anatomy 0.000 description 16
- 239000003960 organic solvent Substances 0.000 description 13
- 239000000126 substance Substances 0.000 description 12
- 239000003921 oil Substances 0.000 description 10
- 230000000694 effects Effects 0.000 description 8
- 239000012043 crude product Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 208000030208 low-grade fever Diseases 0.000 description 6
- 238000007670 refining Methods 0.000 description 6
- 238000005057 refrigeration Methods 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- 238000004821 distillation Methods 0.000 description 5
- 230000035515 penetration Effects 0.000 description 5
- DTGKSKDOIYIVQL-WEDXCCLWSA-N (+)-borneol Chemical group C1C[C@@]2(C)[C@@H](O)C[C@@H]1C2(C)C DTGKSKDOIYIVQL-WEDXCCLWSA-N 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 210000000434 stratum corneum Anatomy 0.000 description 4
- 230000037317 transdermal delivery Effects 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N ethyl acetate Substances CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 230000008337 systemic blood flow Effects 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000001263 acyl chlorides Chemical class 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 239000003961 penetration enhancing agent Substances 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- CQBPOPVKDNHISM-UHFFFAOYSA-N propane-1,2,3-triol;propan-2-one Chemical compound CC(C)=O.OCC(O)CO CQBPOPVKDNHISM-UHFFFAOYSA-N 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 229920001661 Chitosan Polymers 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 206010020649 Hyperkeratosis Diseases 0.000 description 1
- 208000001126 Keratosis Diseases 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 206010039361 Sacroiliitis Diseases 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000013583 drug formulation Substances 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 239000005038 ethylene vinyl acetate Substances 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000008591 skin barrier function Effects 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
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Abstract
The present invention relates to a medicine, a synthesis method thereof and the application thereof. In the method, a Naproxen precursor is designed as natural alcohol ester. The method comprises: a carboxy group of the Naproxen is linked with natural alcohol to generate the natural alcohol ester of the Naproxen. The Naproxen precursor is combined with various medicines together to obtain liniment, or the Naproxen precursor is combined with the medicines to obtain a corresponding film applying agent. The present invention has the advantage that the percutaneous permeability of the Naproxen precursor is higher than that of the Naproxen.
Description
The present invention relates to a kind of medicine, synthetic method and application thereof.
Transdermal delivery system is a kind of newtype drug formulation by intact skin sustained release medicine, and this formulation receives the very big concern of the world of medicine in recent years and obtained application widely because of many advantages are arranged.But, because skin has restricted the percutaneous seepage velocity of medicine to the barrier action of foreign matter, the major obstacles that becomes the development transdermal delivery system and produce related products.Overcome the skin barrier effect make medicine within a certain period of time transdermal penetration to reach therapeutic dose be one of key of many medicine transdermal delivery systems exploitation.The percutaneous permeation of medicine is subjected to the influence of the physico-chemical property of medicine to a great extent, such as: the solubleness in molecular weight, fusing point, oil/water partition coefficient, thermodynamic activity and oil, the water etc.But for a lot of medicines, because the factor of its physico-chemical property, percutaneous permeation does not still reach the useful range of treatment, has limited the application of transdermal delivery system to a great extent.
Naproxen Base (Naproxen) is a NSAID (non-steroidal anti-inflammatory drug) commonly used at present, and anti-inflammatory analgesic action is preferably arranged, and diseases such as sacroiliitis is had the curative effect of wanting very much.But Naproxen Base polarity is bigger than normal, and it is fat-soluble relatively poor, and relatively poor by the ability of keratoderma, effect is undesirable during percutaneous dosing.
The objective of the invention is to be prepared into Naprosyn precusor by the structure of Naproxen Base is carried out certain chemically modified, make Naprosyn precusor can waltz through stratum corneum, this prodrug enzymes metabolism in skin in the process of skin permeation discharges the Naproxen Base parent, thereby finally reaches the percutaneous dosing effect that improves Naproxen Base.
Second purpose of the present invention provides the preparation method of Naprosyn precusor.
The 3rd purpose of the present invention provides the application of Naprosyn precusor.
Basic technical scheme of the present invention is, Naprosyn precusor is designed to the ester of natural alcohol, promptly connects natural alcohol on the carboxyl of Naproxen Base, generates the natural alcohol ester of Naproxen Base.Thereby can reduce interaction between polar group after the Naproxen Base esterification and improve that it is fat-soluble, make Naprosyn precusor waltz through stratum corneum.Because have many non-exclusive enzymes in the skin, these enzymes can carry out metabolism to the Naprosyn precusor that enters skin, under the degraded of skin endoenzyme, recover it and have the former medicine structure of Naproxen Base of physiologically active, enter the body circulation through the capillary vessel absorption.
The chemical structure of Naproxen Base as shown in Figure 1.
The present invention is designed to Naprosyn precusor the ester of natural alcohol.Natural alcohol can be ring-type or the straight chain natural alcohol with 6～10 carbochains.Its chemical structure of general formula as shown in Figure 2.Wherein radicals R is respectively menthyl, linalyl, bornyl, isobornyl, acetone glycerol base etc. contracts.The chemical structure of these groups is respectively as Fig. 3～shown in Figure 7.
The invention has the advantages that: the percutaneous permeation of the relative Naproxen Base of these prodrugs all has raising in various degree.Every character such as the percutaneous permeation of their percutaneous permeation and Naproxen Base is relatively listed as table 1.
The character of table 1 Naproxen Base and Naprosyn precusor
Naproxen Base or profit divide system of disposition transdermal penetration coefficient transdermal penetration enzyme generation
Naproxen ester number (logP) (mg.cm
-2.h
-1) thank to rate (%)
Naproxen Base 0.98 0.2169
Naproxen Base menthyl ester 2.219 0.3603 63.37
Naproxen Base virtue camphor tree ester 1.735 0.4852 68.46
Naproxen Base norbornene ester 1.565 0.2413 50.14
Naproxen Base isobornyl thiocyanoacetate 1.683 0.2952 51.24
The Naproxen Base acetone glycerol ester 0.178 0.3101 45.05 that contracts
The method of the synthetic Naprosyn precusor of the present invention has following several:
Method 1 is got Naproxen Base and is dissolved in the dry organic solvent, and (acylating agent comprises SOCl to add 1～2 times of (mol ratio) acylating agent of new distillatory
2, PCl
3, PCl
5Deng) be dissolved in the exsiccant organic solvent.Under isolated wet steam, ice bath refrigerative condition, acylating agent solution is dropwise added in the Naproxen Base solution, react 1～2h under the room temperature, low-grade fever (50～70 ℃), backflow 12～24h.Water-bath, underpressure distillation add the exsiccant organic solvent again with the solvent evaporate to dryness, repeat distillation, remove remaining acylating agent.
Get 1～3 times of (mol ratio) natural alcohol in the exsiccant container, add the exsiccant organic solvent, dissolving.Above-mentioned Naproxen Base acyl chlorides is dissolved in the exsiccant organic solvent, dropwise adds, reflux 8～15h cools off then.Use saturated NaHCO respectively
3, saturated NaCl washing, aqueous phase discarded is collected organic phase and is also used anhydrous sodium sulfate drying.With the organic solvent evaporate to dryness in the product, with ether-sherwood oil recrystallization, decompress filter, obtain the crude product of naproxen ester, further separation, refining is treated in refrigeration.
Method 2 takes by weighing Naproxen Base and adds in the benzene, and Naproxen Base is dissolved fully.Add 1～1.5 times (mol ratio) corresponding alcohol.The catalyzer of adding 1%, catalyzer comprises mineral acid, example hydrochloric acid, sulfuric acid and phosphoric acid and organic acid p-methyl benzenesulfonic acid add zeolite, load onto water trap then.Reflux 15～30 h no longer include moisture to the water trap and go out.After the cooling, use saturated NaHCO respectively
3, saturated NaCl washing, aqueous phase discarded is collected organic phase and is also used anhydrous sodium sulfate drying.With the organic solvent evaporate to dryness in the product, obtain the crude product of naproxen ester, further separation, refining is treated in refrigeration.
Method 3 takes by weighing Naproxen Base and is dissolved in organic solvent, adds 1～1.5 times (mol ratio) corresponding alcohol.The catalyzer of adding 1%, catalyzer comprises iron(ic) chloride, ferric sulfate, zinc chloride, tin chloride, zirconium sulfate, adds zeolite, loads onto water trap then.Reflux 15～30h no longer includes moisture to the water trap and goes out.After the cooling, use saturated NaHCO respectively
3, saturated NaCl washing, aqueous phase discarded is collected organic phase and is also used anhydrous sodium sulfate drying.With the organic solvent evaporate to dryness in the product, obtain the crude product of naproxen ester, further separation, refining is treated in refrigeration.
Use Naprosyn precusor with various medicine prescriptions, make corresponding liniment, this agent is coated with puts on the skin on the skin surface of certain limit.Medicine sees through skin smoothly under the effect of promotor, enters subcutaneous capillary vessel and enters the systemic blood circulation then, reaches result of treatment.
Use Naprosyn precusor and various medicament composing prescription, make corresponding membranous patch, this agent is attached on the specific skin.
In the accompanying drawing, Fig. 1 is the chemical structural drawing of Naproxen Base; Fig. 2 is the chemical structure of general formula figure of Naprosyn precusor of the present invention; Fig. 3 is that R is the chemical structural drawing of menthyl; Fig. 4 is the chemical structural drawing for the R linalyl; Fig. 5 is that R is the chemical structural drawing of bornyl; Fig. 6 is that R is the chemical structural drawing of isobornyl; Fig. 7 is that R is the chemical structural drawing of acetone glycerol base of contracting.
Provide embodiment below.
Embodiment 1Take by weighing Naproxen Base 2.3g (0.01mol) in 100mL exsiccant round-bottomed flask, add 30mL through the dried benzene of sodium Metal 99.5, low-grade fever is dissolved Naproxen Base fully.Take by weighing new distillatory SOCl
21.8g (about 0.015moL) is dissolved in the 20mL exsiccant benzene.Under isolated wet steam, ice bath refrigerative condition with SOCl
2Benzole soln dropwise add the benzole soln (being about 1h) of Naproxen Base, react 2h under the room temperature, low-grade fever (50-60 ℃), backflow 12h.Water-bath, underpressure distillation add 20mL, 10mL and 10mL exsiccant benzene again with the solvent evaporate to dryness, repeat distillation, remove remaining SOCl
2
Take by weighing corresponding pure 0.015mol among Fig. 3～Fig. 7, pipette pyridine 0.6mL, add 20mL exsiccant benzene, dissolving in 100mL exsiccant round-bottomed flask.Above-mentioned Naproxen Base acyl chlorides is dissolved in 30mL exsiccant benzene, dropwise adds in the flask through dropping funnel, reflux 12h cools off then.Be transferred to separating funnel, use saturated NaHCO respectively
3, saturated NaCL washing three times, aqueous phase discarded is collected organic phase and is also used anhydrous sodium sulfate drying.With the organic solvent evaporate to dryness in the product, with ether-sherwood oil recrystallization, decompress filter, obtain the crude product of naproxen ester, further separation, refining is treated in refrigeration.
Embodiment 2Take by weighing Naproxen Base 2.3g (about 0.01mol) in the 100mL round-bottomed flask, add 50mL benzene, low-grade fever is dissolved Naproxen Base fully.Take by weighing that corresponding pure 0.012mol adds above-mentioned round-bottomed flask among Fig. 3～Fig. 7.The catalyzer of adding 1%, catalyzer comprises mineral acid, example hydrochloric acid, sulfuric acid and phosphoric acid and organic acid p-methyl benzenesulfonic acid add zeolite, load onto water trap, prolong then.Reflux 24h no longer includes moisture to the water trap and goes out.After the reactant cooling, be transferred to separating funnel, use saturated NaHCO respectively
3, saturated NaCl washing three times, aqueous phase discarded is collected organic phase and is also used anhydrous sodium sulfate drying.With the organic solvent evaporate to dryness in the product, obtain the crude product of naproxen ester, further separation, refining is treated in refrigeration.
Embodiment 3 takes by weighing Naproxen Base 2.3g (about 0.01moL) in the 100mL round-bottomed flask, adds 50mL benzene, and low-grade fever is dissolved Naproxen Base fully.Take by weighing that corresponding pure 0.012mol adds above-mentioned round-bottomed flask among Fig. 3～Fig. 7.The catalyzer of adding 1%, catalyzer comprises iron(ic) chloride, ferric sulfate, zinc chloride, tin chloride, zirconium sulfate, adds zeolite, loads onto water trap, prolong then.Reflux 24h no longer includes moisture to the water trap and goes out.After the reactant cooling, be transferred to separating funnel, use saturated NaHCO respectively
3, saturated NaCl washing three times, aqueous phase discarded is collected organic phase and is also used anhydrous sodium sulfate drying.With the organic solvent evaporate to dryness in the product, obtain the crude product of naproxen ester, further separation, refining is treated in refrigeration.
Embodiment 4With the sand core funnel is packed column, and silica gel is stationary phase.Under the condition of suction filtration, gradually silica gel is inserted sand core funnel, the blended rubber plug constantly beats hopper walls, the generation that evenly closely prevents air filled cavity that silica gel is filled.Measure sherwood oil (30-60 ℃) 5mL, add the crude product of naproxen ester, low-grade fever makes it dissolving and gets dried silica gel 10mg, adds above-mentioned solution, stir, sherwood oil is removed in water-bath, porphyrize, move into dry 2h in the moisture eliminator, the same method is seated in the upper strata of packed column, and compresses as far as possible.At filter paper of packed column surface coverage.When preventing wash-out, the packed column surface is impacted, and influence separates.
Press sherwood oil (90-120 ℃)-ethyl acetate=10: 1, sherwood oil (90-120 ℃)-ethyl acetate=5: 1, sherwood oil (90-120 ℃)-ethyl acetate=change the gradient of eluent at 1: 1, elutriant is accepted in the device of decompress filter in turn by receiving bottle, collects 15-20mL at every turn.Method with tlc analysis detects each elutriant of collecting, and merges required elutriant, and distillation removes and desolvates, and obtains the purified naproxen ester
Embodiment 5Made compound is pressed table 5 prescription as transdermal penetration promotor with various medicines, make corresponding liniment, this agent is coated with puts on the skin on the skin surface of certain limit.Medicine sees through skin smoothly under the effect of promotor, enters subcutaneous capillary vessel and enters the systemic blood circulation then, reaches result of treatment.
Table 5 liniment prescription
| Composition | Prescription 1 (finish) | Prescription 2 (O/W emulsion) | Prescription 3 (W/O emulsion) |
| Naprosyn precusor | 0.1～10g | 0.1～10g | 0.1～10g |
| Penetration enhancer | 1～5g | 1～5g | 1～5g |
| Organic solvent | 0～95g | 0～5g | 0～25g |
| Solubilizing agent | 1～15g | ||
| Emulsifying agent | 5g | 5g | 5g |
| Mineral oil | 10g | 35g | |
| Higher fatty acid | 5g | 2g | |
| High fatty alcohol | 10g | 8g | |
| High-grade aliphatic ester | 5g | 10g | |
| Propylene glycol | 1～10g | 1～10g | 1～10g |
| Potassium hydroxide | 1g | ||
| Deionized water | 0～95g | Add to total amount 100g | Add to total amount 100g |
| Sanitas | 0.1～0.5g | 0.1～0.5g | 0.1～0.5g |
Mouse skin stratum corneum is affixed between supply chamber and the receiving chamber towards supply chamber, adds the phosphate buffer soln of pH7.2 in the receiving chamber, place 37 ± 0.5 ℃ circulator bath, use induction stirring in the receiving chamber.2ml finish in table 5 prescription or 2 gram emulsions are added in the supply chambers (Naprosyn precusor changes Naproxen Base in the controlled trial prescription), in 12 hours, carry out content measuring from receiving chamber's sampling in different timed interval, calculate the drug release feature of liniment.
Embodiment 6Made compound is pressed table 6 prescription as transdermal penetration promotor with various medicines, make corresponding membranous patch, this agent is attached on the specific skin.Medicine sees through skin smoothly under the effect of promotor, enters subcutaneous capillary vessel and enters the systemic blood circulation then, reaches result of treatment.
Table 6 membranous patch prescription
| Composition | Prescription 1 (water-soluble) | Prescription 2 (oil soluble) |
| Naprosyn precusor | 0.1～10g | 0.1～10g |
| Penetration enhancer | 1～5g | 1～5g |
| Solubilizing agent | 1～10g | 1～5g |
| Increase north agent | 1～8g | 1～5g |
| Ethylene-vinyl acetate copolymer | 40g | |
| Polyvinyl alcohol | 50g | |
| Hydroxypropylcellulose | 5～10g | |
| Cm-chitosan | 5～10g | |
| Propylene glycol | 1～10g | 1～10g |
| Sanitas | 0.1～0.5g | 0.1～0.5g |
The pad pasting (Naprosyn precusor changes Naproxen Base in the controlled trial prescription) that table 6 prescription is made is cut into the diaphragm of 2cm * 2cm specification, with non-setting adhesive itself and mouse skin stratum corneum is clinged.Diaphragm is clipped between supply chamber and the receiving chamber towards supply chamber, adds the phosphate buffer soln of pH7.2 in the receiving chamber, places 37 ± 0.5 ℃ circulator bath, uses induction stirring in the receiving chamber., in 24 hours, carry out content measuring from receiving chamber's sampling in different timed interval, calculate the drug release feature of obedient film.
Claims (4)
1, a kind of Naprosyn precusor is characterized in that: this Naprosyn precusor is Naproxen Base virtue camphor tree ester, Naproxen Base norbornene ester, Naproxen Base isobornyl thiocyanoacetate, the Naproxen Base acetone glycerol ester that contracts.
2, a kind of synthetic method of Naprosyn precusor is characterized in that comprising the steps: to take by weighing Naproxen Base adds in the benzene, dissolves Naproxen Base fully; Add 1～1.5 times of corresponding alcohol in molar ratio, add 1% catalyzer, catalyzer comprises hydrochloric acid, sulfuric acid, phosphoric acid, p-methyl benzenesulfonic acid, iron(ic) chloride, ferric sulfate, zinc chloride, tin chloride or zirconium sulfate, adds zeolite, loads onto water trap then; Reflux 15～30h no longer includes moisture to the water trap and goes out; After the cooling, use saturated NaHCO respectively
3, saturated NaCl washing, aqueous phase discarded is collected organic phase and is used anhydrous sodium sulfate drying; Solvent evaporate to dryness with in the product obtains naproxen ester.
3, a kind of liniment that is used for skin surface is characterized in that comprising the pharmaceutical composition that acceptable carrier on described Naprosyn precusor of claim 1 and the pharmacology or vehicle are formed.
4, a kind of membranous patch that is used for skin surface is characterized in that comprising the pharmaceutical composition that acceptable carrier on described Naprosyn precusor of claim 1 and the pharmacology or vehicle are formed.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB021349827A CN1178895C (en) | 2002-10-18 | 2002-10-18 | Naprosyn precusor, its synthesis method and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB021349827A CN1178895C (en) | 2002-10-18 | 2002-10-18 | Naprosyn precusor, its synthesis method and application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1410413A CN1410413A (en) | 2003-04-16 |
| CN1178895C true CN1178895C (en) | 2004-12-08 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB021349827A Expired - Fee Related CN1178895C (en) | 2002-10-18 | 2002-10-18 | Naprosyn precusor, its synthesis method and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1178895C (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102659597A (en) * | 2012-05-18 | 2012-09-12 | 吉林大学 | Naproxen eugenol ester medicinal compound and preparation method of naproxen eugenol ester medicinal compound |
| CN103242162A (en) * | 2013-05-22 | 2013-08-14 | 华东理工大学 | Borneol ester derivative of carboxylic acid nonsteraidal anti-inflammatory medicaments as well as preparation method and application of borneol ester derivative |
| CN110204436A (en) * | 2019-06-04 | 2019-09-06 | 斯诺科(杭州)生物科技有限公司 | A kind of method for splitting of naproxen enantiomter |
| CN113603570B (en) * | 2021-09-28 | 2022-02-11 | 潍坊科技学院 | Leonurine borneol derivative, preparation method and application thereof |
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2002
- 2002-10-18 CN CNB021349827A patent/CN1178895C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN1410413A (en) | 2003-04-16 |
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