CN1830950A - Method synthesizing arotinoid acid and arotinoid ethylester, and its pharmaceutical application - Google Patents
Method synthesizing arotinoid acid and arotinoid ethylester, and its pharmaceutical application Download PDFInfo
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- CN1830950A CN1830950A CN 200510020500 CN200510020500A CN1830950A CN 1830950 A CN1830950 A CN 1830950A CN 200510020500 CN200510020500 CN 200510020500 CN 200510020500 A CN200510020500 A CN 200510020500A CN 1830950 A CN1830950 A CN 1830950A
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Abstract
A process for synthesizing aryltretinoin and aryltretinoin ethylester, used for preparing capsules to treat psoriasis, includes such steps as reaction between [1-(5,6,7,,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-ethyl]-phosphine triphenylbromide and p-ethoxycarbonyl benzaldehyde in isopropanol to obtain P-[(E)-2 -(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl]-ethyl benzoate, that is, aryltretinoin ethylester, and adding it to alcohol to synthesize P-[(E)-2 -(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl]-benzoate, that is, aryltretinoin.
Description
Technical field
The present invention relates to a kind of synthetic method of chemical substance and the application of medicine, be specifically related to the synthetic method of aryltretinoin and RO and the application in pharmacy.
Background technology
On July 4th, 1979, Britain issued the name be called " stilbene derivatives ", application number is the patent application of No.7849418.This patent application discloses a kind of preparation method of stilbene derivatives, and the applicant thinks according to said method can prepare derivatives hundreds of even thousands of kinds.Because the derivative that is comprised is too many, only done the guidance of principle to preparing a spot of derivative, therefore, for each concrete derivative, just inadequately in detail with concrete.In the example of this patent application, also be mentioned to aryltretinoin, be P-[(E)-2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl) propenyl]-phenylformic acid and RO, be P-[(E)-2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl) propenyl]-preparation of ethyl benzoate, but, do not have concrete technical process.According to the disclosed technical scheme of this patent application, the target compound that has can not synthesize fully, thereby must be improved this technology.
In this patent application, disclose stilbene derivatives and had drug effect and be worth: can be used as local and systematic treating is optimum and malignant tumour, and system and local these patient's condition of prevention have worsened preceding infringement to human body; Also available treatment acne, psoriasis and other tetter, rheumatic arthritis; Can also be used to control and inflammation or sex change or the relevant membrane disease of conversion.But, do not have to disclose fully and particularly its application on pharmacology.
Summary of the invention
One of purpose of the present invention provides the synthetic method of aryltretinoin and RO, can progressively synthesize aryltretinoin and RO quickly and safely with the generalization compound on the market, reduces production costs.
Another object of the present invention provides the application in pharmacy by this method synthetic aryltretinoin and RO, particularly the application in the medicine of preparation treatment and prevention skin day photoaging, treatment ichthyosis and psoriasis pustulosa.
The synthetic method of RO of the present invention may further comprise the steps:
With [1-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-ethyl]-phosphine triphenylbromide, in the ethoxy carbonyl phenyl aldehyde adding Virahol, feed nitrogen, when being heated to 65 ℃, add ethanol and sodium Metal 99.5, the reaction back is except that desolvating;
In residuum, add methyl alcohol, isolate solid and be P-[(E)-2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl) propenyl]-ethyl benzoate, be called for short RO or Artinoid ethyltester (Arotinoidethylester);
Dissolving crude product is removed most of normal hexane in normal hexane, add ethanol, and precipitate is an elaboration, and fusing point is 98～99 ℃, and its structural formula is:
What synthetic RO was used prepares by following steps the ethoxy carbonyl phenyl aldehyde:
To add in the ethanol carboxyl benzaldehyde, add the vitriol oil again, after the backflow reactant be poured in the trash ice, regulate pH value to 6～7, use benzene extraction again;
Extracting solution is used Na after cleaning with saturated NaCl solution
2SO
4Drying is removed and to be desolvated, collect 135～155 ℃/-the 0.093MPa fraction, the survey diopter is η
D 201.5200, be the ethoxy carbonyl phenyl aldehyde, also be 4-ethoxycarbonyl phenyl aldehyde, its structural formula is:
The 1-that synthetic RO is used (5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-ethyl]-phosphine triphenylbromide, prepare by following steps:
A, with 2,5-dimethylhexane glycol-2,5 preparation 2,5-dimethylhexane two chloro-2,5
With 2,5-dimethylhexane glycol-2,5 adds in the concentrated hydrochloric acid, at room temperature leaves standstill 24 hours, isolates solid, washes disacidify earlier with water, and methyl alcohol is washed secondary again, and after the drying, surveying fusing point is 64～65 ℃, and this is 2,5-dimethylhexane two chloro-2,5, and its structural formula is:
B, with 2,2,5 preparations 5,6,7 of 5-dimethylhexane two chloro-, 8-tetrahydrochysene-5,5,8,8-tetramethyl--naphthalene
With 2,5-dimethylhexane two chloro-2,5 add in the benzene, add aluminum chloride again, and heating refluxes, and removes benzene, collect 90～105 ℃/-the 0.093MPa fraction, the survey diopter is η
D 201.5200, be 5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--naphthalene, its structural formula is:
C, with 5,6,7,8-tetrahydrochysene-5.5,8,8-tetramethyl--naphthalene preparation (5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-methyl ketone
Earlier Acetyl Chloride 98Min. is added in the oil of mirbane and cool off, gradation adds aluminum chloride, adds 5,6 again, 7,8-tetrahydrochysene-5,5,8,8-tetramethyl--naphthalene, then, the intensification stirring reaction is poured the reactant that obtains in the trash ice into, uses benzene extraction 2 times, after extracting solution cleans with the NaOH solution of 2N, again with saturated NaCl solution clean to the pH value of washing lotion be 5～6, at last, with removing benzene, oil of mirbane behind the anhydrous sodium sulfate drying, collect 140～155 ℃/-the 0.093MPa fraction, the survey diopter is η
D 201.5400, being (5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-methyl ketone, its structural formula is:
D is with (5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-methyl ketone preparation 5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthalene-ethanol
(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-methyl ketone is joined in the methyl alcohol, and the cooling back adds NaBH
4, promptly sodium borohydride adds hydrochloric acid after the reaction, uses Petroleum ether extraction again, and extracting solution is used Na earlier
2CO
3Solution cleans, and cleans with saturated sodium chloride solution again, desolventizes under normal pressure, and residuum is 5,6,7,8-tetrahydrochysene-5,5,8, and 8-tetramethyl--2-naphthalene-ethanol, fusing point are 62～64 ℃, its structural formula is:
E, with 5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthalene-ethanol preparation 2-(bromotrifluoromethane)-5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--naphthalene
Hexane at 15: 1: in the ether, add red phosphorus, pyridine and 5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthalene-ethanol, cooling adds bromine, adds the back and continues reaction;
Reaction mixture is poured in the trash ice, told organic layer, water layer; The water layer hexane extraction, extract merges to organic layer, and the pH value that cleans to washing lotion with saturated sodium chloride solution is 3～4, feed nitrogen again and drive away remaining sour gas, the organic layer dried over sodium sulfate is removed and is desolvated, residuum back to be crystallized cleans to crystallization with a small amount of dehydrated alcohol and loosens, and promptly obtains 2-(bromotrifluoromethane)-5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--naphthalene, fusing point are 63～66 ℃, and its structural formula is:
F, with 2-(bromotrifluoromethane)-5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--naphthalene preparation [1-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-ethyl]-phosphine triphenylbromide
With 2-(bromotrifluoromethane)-5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--naphthalene, triphenyl phosphine add in the dimethylbenzene, reacting by heating is isolated solid, cleans to crystallization with acetone and loosens, it is 172～174 ℃ or 212～214 ℃ that fusing point is surveyed in dry back, is that [1-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-ethyl]-phosphine triphenylbromide, its structural formula is:
Aforesaid 2-(bromotrifluoromethane)-5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--naphthalene, also available tribromo phosphorus is PBr
3Preparation:
Earlier in sherwood oil, add normal hexane, add 5,6,7 again, 8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthalene-ethanol, pyridine, the cooling back adds PBr
3, reaction again;
Reactant is poured in the trash ice, used Petroleum ether extraction, extracting solution cleans with sodium carbonate solution earlier, and the back is cleaned with saturated sodium chloride solution;
Remove and desolvate, residuum is 2-(bromotrifluoromethane)-5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--naphthalene, 62～65 ℃ of fusing points.
The synthetic method of aryltretinoin, its step is as follows:
With aforesaid method synthetic RO, i.e. P-[(E)-2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl) propenyl]-ethyl benzoate adds in the ethanol, adds the NaOH of 0.5N again, refluxed 2.5 hours;
Sulfuric acid with 0.5N is adjusted pH value to 1～2, isolates solid, the washing disacidify;
With the methylene chloride reflux dissolving, reclaim and remove most of methylene dichloride, in surplus solution, add normal hexane, separate out solid, be P-[(E)-2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl) propenyl]-phenylformic acid, be called for short aryltretinoin or fragrant tretinoin (Arotinoic acid), 248～249 ℃ of fusing points, its structural formula is:
Above synthetic method is compared with prior art, has the following advantages: the synthetic time that needs shortens, and cost reduces, production safety, and good product quality, the purity of synthetic RO reaches 98.82%, and the purity of aryltretinoin reaches 98.54%.
Warp has following pharmaceutical use to the further research of the pharmacological action of aryltretinoin and RO:
Anti-keratinization; Desmosome and tonofilament that aryltretinoin and RO can suppress epidermal keratinocytes form, and the keratinization that suppresses under the various pathological conditions is excessive.
Anti-inflammatory action; Aryltretinoin and RO can suppress leukocyte chemotaxis, the inflammation-inhibiting reaction.
Antivirus action; Aryltretinoin and RO have the inhibition virus function.
Strengthen cellular immune function; Aryltretinoin and RO can the enhancing body cellular immune functions.
Suppress smegma; Aryltretinoin and RO can suppress smegma.
Anti-aging effects; Aryltretinoin and RO have remarkable effect to antioxidant radical, can resist skin and organism aging process, and sun-induced skin injury is had tangible preventive and therapeutic effect; Can remove the epidermis fines makes skin smooth ruddy; Can increase the dermal matrix composition, recover skin elasticity, smooth away wrinkles; Energy restraint of tyrosinase activity reduces chromogenesis, makes skin pale.
Though at present skin photoage lacks reliable and practical phantom, the skin premature aging appear be Dermatology Department in clinical application " 8-methoxypsoralen long wave ultraviolet photochemical therapy " common major side effects (PUVA) time.Through decreasing district's corium with the non-skin in PUVA treatment psoriasis vulgaris patient back is object, adopt technology and methods such as HE dyeing, Verhoeff dyeing, Electronic Speculum, enzyme histochemistry, immunohistochemistry (LCC), in situ hybridization (ISHH), three-primer PCR, studied PUVA the influence of skin photoage formation and the antagonistic action of RO.The result is under the PUVA effect, and the non-skin in patient back decreases that district's corium is very fast the distinctive change of skin photoage to have occurred having.The change of histological characteristic is, the minimizing of dermal collagen composition, sex change, sex change spandex increase, distortion, arrangement disorder; Biological characteristics is that following the change appears in dermal fibroblast: 1. SA-β-Gal expresses increase; 2. the p16 protein expression increases; 3. MMP-1, MMP-3mRNA continuous expression, TIMP-1 only one are crossed property and are slightly expressed; 4. mtDNA 4977bp disappearance accumulation in a large number in dermal tissue.And oral RO to PUVA induce appearance have that the distinctive dermal tissue of skin photoage is learned and biological characteristics changes obvious antagonistic action is arranged.
The application in pharmacy of aryltretinoin and RO, make oral capsule respectively:
The RO capsule, every contains RO 0.03mg, starch 200mg; With " psoralene long wave ultraviolet photochemical therapy " combination therapy psoriatic, " 8-methoxypsoralen long wave ultraviolet photochemical therapy " treats routinely, and patient's every day, oral this RO capsule was 1 time, each 1.
The application of aryltretinoin in pharmacy, make oral capsule respectively: the aryltretinoin capsule, every contains aryltretinoin 0.01mg, starch 200mg; With " 8-methoxypsoralen long wave ultraviolet photochemical therapy " combination therapy psoriatic, " 8-methoxypsoralen long wave ultraviolet photochemical therapy " treats routinely, and patient's every day, oral this aryltretinoin capsule was 3 times, each 1.
Use RO and " 8-methoxypsoralen long wave ultraviolet photochemical therapy " conjoint therapy and treat 126 routine psoriatics, 83 examples are cured as a result, account for 66%; 34 examples are near, and it is remarkable to account for 27%, 9 routine effect, accounts for 7%.The beginning responding time is 3.1 ± 0.9 days, and the irradiation number of times is 2.5 ± 0.8 times.The treatment fate that reaches healing is 14.3 ± 6 days, and the irradiation number of times is 12.5 ± 5.2 times, and the UVA total amount is 35.1 ± 17.8J/cm
2Side effect is slight, is mainly xerocheilia, skin pruritus, epigastric discomfort, feels sick, dizziness, erythema, pigmentation etc., continues to treat but do not influence.Follow up a case by regular visits to 67 examples, recurrence rate 51.0%, uniform release 6.5 months.This is that curative ratio is the highest up to now, healing is fastest, side effect is less, recurrence rate is lower, medical expense is lower, one of simple new therapy of methods of treatment.
Embodiment
Embodiment one: synthetic RO, i.e. P-[(E)-2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl) propenyl]-phenylformic acid second fat.
The first step, preparation [1-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-ethyl]-phosphine triphenylbromide, its step is as follows:
A, preparation 2,5-dimethylhexane two chloro-2,5
With 365g 2,5-dimethylhexane glycol-2,5 adds in 2500 milliliters of concentrated hydrochloric acids, at room temperature leaves standstill 24 hours, isolate solid, wash disacidify earlier with water, wash secondary with methyl alcohol again, it is 64～65 ℃ that fusing point is surveyed in dry back, this is 2,5-dimethylhexane two chloro-2,5;
B, preparation 5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--naphthalene
With 73.2g 2,5-dimethylhexane two chloro-2,5 add in 500 milliliters of benzene, add the 10.5g aluminum chloride again, are heated to 60～80 ℃, reflux after 6 hours, remove benzene, collect 90～105 ℃/-the 0.093MPa fraction, the survey diopter is η
D 201.5200, be 5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--naphthalene;
C, preparation (5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-methyl ketone
Earlier the 86.4g Acetyl Chloride 98Min. is joined in 450 milliliters of oil of mirbane, be cooled to that gradation adds the 174g aluminum chloride under 0～5 ℃ the condition, in temperature is to add 5,6,7 of 188g below 10 ℃, 8-tetrahydrochysene-5,5,8,8-tetramethyl--naphthalene, then, be heated under 25 ℃ the condition stirring reaction 2 hours, the reactant that obtains is poured in the trash ice of 800g, with benzene extraction 2 times, after the NaOH cleaning of extracting solution with 2N, again with saturated NaCl clean to the Ph value of washing lotion be 5～6, last, with removing benzene behind the anhydrous sodium sulfate drying, oil of mirbane, collect 140～155 ℃/-the 0.093MPa fraction, the survey diopter is η
D 201.5400, be (5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-methyl ketone;
D, preparation 5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthalene-ethanol
500 ml methanol are joined in 230g (5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-methyl ketone, are the NaBH that adds 30.4g under 0～5 ℃ the condition in temperature
4, promptly sodium borohydride reacted after 1 hour, added 100 milliliters of the hydrochloric acid of 1N, used Petroleum ether extraction again, and extracting solution is earlier with 5% Na
2CO
3Solution cleans, and cleans with saturated nacl aqueous solution again, desolventizes under normal pressure, and residuum is 5,6,7,8-tetrahydrochysene-5,5,8, and 8-tetramethyl--2-naphthalene-ethanol, fusing point are 62～64 ℃;
E, preparation 2-(bromotrifluoromethane)-5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--naphthalene
In 120 milliliters of (15: 1) hexane-ether, add 5,6,7 of red phosphorus 1.7g, 2 of pyridines and 25.2g, 8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthalene-ethanol is cooled to 0 ℃, adds bromine 26.4g, adds the back and continues reaction 1 hour, and reaction finishes; Reaction mixture poured in 300 milliliters the trash ice, tell organic layer, water layer; The water layer hexane extraction, extract merges to organic layer, and the pH value that cleans to washing lotion with saturated sodium chloride solution is 3～4, feed nitrogen again and drive away remaining sour gas, organic layer removes and desolvates with saturated dried over sodium sulfate, residuum back to be crystallized cleans to crystallization with a small amount of dehydrated alcohol and loosens, and promptly obtains 2-(bromotrifluoromethane)-5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--naphthalene, fusing point are 63～66 ℃;
F, preparation [1-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-ethyl]-phosphine triphenylbromide
With the 2-(bromotrifluoromethane)-5,6 of 295g, 7,8-tetrahydrochysene-5,5,8,8-tetramethyl--naphthalene, 340g triphenyl phosphine add in 400 milliliters of dimethylbenzene, are heated to 100 ℃ of reactions 9 hours, isolate solid, it is loose to clean to crystallization with acetone, and it is 172～174 ℃ or 212～214 ℃ that fusing point is surveyed in dry back, is that [1-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-ethyl]-phosphine triphenylbromide;
Second step prepared the ethoxy carbonyl phenyl aldehyde,
150g is added in 1200 milliliters of ethanol carboxyl benzaldehyde, add 75 milliliters of vitriol oils again, reflux after 5 hours, reactant is poured in the 1000g trash ice into Na with 9%
2CO
3Solution is regulated pH value to 6～7, uses benzene extraction again, and extracting solution is used Na after cleaning with saturated NaCl solution
2SO
4Drying is removed and to be desolvated, collect 135～155 ℃/-the 0.093MPa fraction, the survey diopter is η
D 201.5200, be the ethoxy carbonyl phenyl aldehyde, also be 4-ethoxycarbonyl phenyl aldehyde,
The 3rd step, synthetic RO
With 212g[1-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-ethyl]-phosphine triphenylbromide 130～150g adds in 1200 milliliters of Virahols the ethoxy carbonyl phenyl aldehyde, feed nitrogen, when being heated to 65 ℃, add 160 milliliters of ethanol, the 7g sodium Metal 99.5 reacts after 11 hours, remove and desolvate, in residuum, add 400 milliliters of methyl alcohol, isolate solid and be P-[(E)-2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl) propenyl]-ethyl benzoate, be called for short RO or Artinoid ethyltester (Arotinoid ethylester); Crude product is dissolved in 2000 ml n-hexanes, reclaims 1500 ml n-hexanes, and rest solution adds 500 milliliters of ethanol, and precipitate is an elaboration, and fusing point is 98～99 ℃.
In addition, be PBr if can obtain tribromo phosphorus
3, also can prepare 2-(bromotrifluoromethane)-5,6,7 according to the following steps, 8-tetrahydrochysene-5,5,8, the 8-tetramethyl-:
The normal hexane that adds 200 milliliters in 600 milliliters of sherwood oils adds 5,6,7 of 232g again, 8-tetrahydrochysene-5,5,8, and 8-tetramethyl--2-naphthalene-ethanol, 1 milliliter of pyridine is cooled to 0～5 ℃, adds the PBr of 147g
3, reacted again 1 hour;
Reactant is poured in the 500g trash ice, uses Petroleum ether extraction, and extracting solution elder generation is cleaned with 5% sodium carbonate solution, and the back is cleaned with saturated sodium chloride solution;
Remove and desolvate, residuum is 2-(bromotrifluoromethane)-5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--naphthalene, 62～65 ℃ of fusing points.
Embodiment two. synthetic aryltretinoin, and its step is as follows:
With embodiment one synthetic RO, i.e. P-[(E)-2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl) propenyl]-ethyl benzoate 50g adds in 1100 milliliters of ethanol, adds the NaOH of 500 milliliters of 0.5N again, refluxed 2.5 hours;
With 0.5N sulfuric acid adjust pH to 1～2, isolate solid, the washing disacidify;
With the methylene chloride reflux dissolving, reclaim and remove most of methylene dichloride, in surplus solution, add normal hexane, separate out solid, be P-[(E)-2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl) propenyl]-phenylformic acid, be called for short aryltretinoin or fragrant tretinoin (Arotinoic acid), 248～249 ℃ of fusing points.
Embodiment three. the RO capsule, and every contains RO 0.03mg, starch 200mg; With " 8-methoxypsoralen long wave ultraviolet photochemical therapy " combination therapy psoriatic, " 8-methoxypsoralen long wave ultraviolet photochemical therapy " treats routinely, and patient's every day, oral this RO capsule was 1 time, each 1.
Embodiment four. the aryltretinoin capsule, and every contains aryltretinoin 0.01mg, starch 200mg; With " 8-methoxypsoralen long wave ultraviolet photochemical therapy " combination therapy psoriatic, " 8-methoxypsoralen long wave ultraviolet photochemical therapy " treats routinely, and patient's every day, oral this aryltretinoin capsule was 3 times, each 1.
Embodiment five. the RO capsule, and every contains RO 0.03mg, starch 200mg; Be used for the treatment of pustular psoriasis, oral one of patient first every day in odd-numbered day week, oral two of every day in even-numbered days, second week was played oral one of every day, postevaluation curative effect all around; In the 30 routine volunteers that finish treatment, 11 examples of fully recovering in the recent period, cure rate 36.67%; Produce effects 18 examples, obvious effective rate 60%; Invalid 1 example, inefficiency 3.33%.
Embodiment six, the RO capsule, and every contains RO 0.03mg, starch 200mg; Be used for the treatment of ichthyosis, oral one of patient every day, change oral every other day one into, eight all postevaluation curative effects after serveing on for two weeks; In the 31 routine volunteers that finish treatment, 18 examples of fully recovering in the recent period, cure rate 58.06%: produce effects 13 examples, obvious effective rate 41.93%; Total effective rate 100%.
Aryltretinoin and RO also can be made into exterior-applied formulation, as ointment, tincture, emulsifiable paste, spray, gelifying agent etc.
Claims (8)
1, the synthetic method of RO may further comprise the steps:
With [1-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-ethyl]-phosphine triphenylbromide, in the ethoxy carbonyl phenyl aldehyde adding Virahol, feed nitrogen, when being heated to 65 ℃, add ethanol and sodium Metal 99.5, the reaction back is except that desolvating;
In residuum, add methyl alcohol, isolate solid and be P-[(E)-2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl) propenyl]-ethyl benzoate, be called for short RO or Artinoid ethyltester (Arotinoidethylester);
Dissolving crude product is removed most of normal hexane in normal hexane, add ethanol, and precipitate is an elaboration, and fusing point is 98～99 ℃, and its structural formula is:
2, the synthetic method of RO according to claim 1, synthesize usefulness the ethoxy carbonyl phenyl aldehyde is prepared by following steps:
To add in the ethanol carboxyl benzaldehyde, add the vitriol oil again, after the backflow reactant be poured in the trash ice, regulate pH value to 6～7, use benzene extraction again;
Extracting solution is used Na after cleaning with saturated NaCl solution
2SO
4Drying is removed and to be desolvated, collect 135～155 ℃/-the 0.093MPa fraction, the survey diopter is η
D 201.5200, be the ethoxy carbonyl phenyl aldehyde, also be 4-ethoxycarbonyl phenyl aldehyde, its structural formula is:
3, the synthetic method of RO according to claim 1,1-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-the naphthyl)-ethyl of synthetic usefulness]-the triphen bromination sees, prepares by following steps:
A, with 2,5-dimethylhexane glycol-2,5 preparation 2,5-dimethyl ethane two chloro-2,5
With 2,5-dimethylhexane glycol-2,5 adds in the concentrated hydrochloric acid, at room temperature leaves standstill 24 hours, isolates solid, washes disacidify earlier with water, and methyl alcohol is washed secondary again, and after the drying, surveying fusing point is 64-65 ℃, and this is 2,5-dimethylhexane two chloro-2,5, and its structural formula is:
B, with 2,2,5 preparations 5,6,7 of 5-dimethylhexane two chloro-, 8-tetrahydrochysene-5,5,8,8-tetramethyl--naphthalene
With 2,5-dimethylhexane two chloro-2,5 add in the benzene, add aluminum chloride again, and heating refluxes, and removes benzene, collect 90～105 ℃/-the 0.093MPa fraction, the survey diopter is η
D 2015200, be 5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--naphthalene, its structural formula is:
C, with 5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--naphthalene preparation (5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-methyl ketone
Earlier Acetyl Chloride 98Min. is added in the oil of mirbane and cool off, gradation adds aluminum chloride, adds 5,6 again, 7,8-tetrahydrochysene-5,5,8,8-tetramethyl--naphthalene, then, the intensification stirring reaction is poured the reactant that obtains in the trash ice into, uses benzene extraction 2 times, after extracting solution cleans with the NaOH solution of 2N, again with saturated NaCl solution clean to the pH value of washing lotion be 5～6, at last, with removing benzene, oil of mirbane behind the anhydrous sodium sulfate drying, collect 140～155 ℃/-the 0.093MPa fraction, the survey diopter is η
D 201.5400, being (5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-methyl ketone, its structural formula is:
D is with (5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-methyl ketone preparation 5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthalene-ethanol
(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-methyl ketone is joined in the methyl alcohol, and the cooling back adds NaBH
4, promptly sodium borohydride adds hydrochloric acid after the reaction, uses Petroleum ether extraction again, and extracting solution is used Na earlier
2CO
3Solution cleans, and cleans with saturated sodium chloride solution again, desolventizes under normal pressure, and residuum is 5,6,7,8-tetrahydrochysene-5,5,8, and 8-tetramethyl--2-naphthalene-ethanol, fusing point are 62～64 ℃, its structural formula is:
E, with 5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthalene-ethanol preparation 2-(bromotrifluoromethane)-5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--naphthalene
Hexane at 15: 1: in the ether, add red phosphorus, pyridine and 5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthalene-ethanol, cooling adds bromine, adds the back and continues reaction;
Reaction mixture is poured in the trash ice, told organic layer, water layer; The water layer hexane extraction, extract merges to organic layer, and the pH value that cleans to washing lotion with saturated sodium chloride solution is 3～4, feed nitrogen again and drive away remaining sour gas, the organic layer dried over sodium sulfate is removed and is desolvated, residuum back to be crystallized cleans to crystallization with a small amount of dehydrated alcohol and loosens, and promptly obtains 2-(bromotrifluoromethane)-5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--naphthalene, fusing point are 63～66 ℃, and its structural formula is:
F, with 2-(bromotrifluoromethane)-5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--naphthalene preparation [1-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-ethyl]-phosphine triphenylbromide
With 2-(bromotrifluoromethane)-5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--naphthalene, triphenyl phosphine add in the dimethylbenzene, reacting by heating is isolated solid, cleans to crystallization with acetone and loosens, it is 172～174 ℃ or 212～214 ℃ that fusing point is surveyed in dry back, is that [1-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-ethyl]-phosphine triphenylbromide, its structural formula is:
4, the synthetic method of RO according to claim 3, described 2-(bromotrifluoromethane)-5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--naphthalene, also available tribromo phosphorus is PBr
3Preparation:
Earlier in sherwood oil, add normal hexane, add 5,6,7 again, 8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthalene-ethanol, pyridine, the cooling back adds PBr
3, reaction again;
Reactant is poured in the trash ice, used Petroleum ether extraction, extracting solution cleans with sodium carbonate solution earlier, and the back is cleaned with saturated sodium chloride solution;
Remove and desolvate, residuum is 2-(bromotrifluoromethane)-5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--naphthalene, 62～65 ℃ of fusing points.
5, the synthetic method of aryltretinoin, its step is as follows:
With aforesaid method synthetic RO, i.e. P-[(E)-2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl) propenyl]-ethyl benzoate adds in the ethanol, adds the NaOH of 0.5N again, refluxed 2.5 hours;
Sulfuric acid with 0.5N is adjusted pH value to 2, isolates solid, the washing disacidify;
With the methylene chloride reflux dissolving, reclaim and remove most of methylene dichloride, in surplus solution, add normal hexane, separate out solid, be P-[(E)-2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl) propenyl]-phenylformic acid, be called for short aryltretinoin or fragrant tretinoin (Arotinoic acid), 248～249 ℃ of fusing points, its structural formula is:
6, aryltretinoin and the RO application in pharmacy, make oral capsule respectively:
The RO capsule, every contains RO 0.03mg, starch 200mg; With " 8-methoxypsoralen long wave ultraviolet photochemical therapy " combination therapy psoriatic, " 8-methoxypsoralen long wave ultraviolet photochemical therapy " treats routinely, and patient's every day, oral this RO capsule was 1 time, each 1.
The application of aryltretinoin in pharmacy, make oral capsule respectively: the aryltretinoin capsule, every contains aryltretinoin 0.01mg, starch 200mg; With " 8-methoxypsoralen long wave ultraviolet photochemical therapy " combination therapy psoriatic, " 8-methoxypsoralen long wave ultraviolet photochemical therapy " treats routinely, and patient's every day, oral this aryltretinoin capsule was 3 times, each 1.
7, aryltretinoin according to claim 6 and the RO application in pharmacy, be used for the treatment of psoriasis pustulosa, oral one of patient first every day in odd-numbered day week, oral two of every day in even-numbered days, second week was played oral one of every day, postevaluation curative effect all around.
8, aryltretinoin according to claim 6 and the RO application in pharmacy is used for the treatment of ichthyosis, oral one of patient every day, changes oral every other day one into, eight all postevaluation curative effects after serveing on for two weeks.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102336660A (en) * | 2010-07-19 | 2012-02-01 | 重庆华邦胜凯制药有限公司 | Synthesis method of substituted stilbene derivative |
| CN101747194B (en) * | 2008-12-08 | 2013-05-01 | 重庆华邦制药有限公司 | Synthesis method of etretinate ether |
-
2005
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101747194B (en) * | 2008-12-08 | 2013-05-01 | 重庆华邦制药有限公司 | Synthesis method of etretinate ether |
| CN102336660A (en) * | 2010-07-19 | 2012-02-01 | 重庆华邦胜凯制药有限公司 | Synthesis method of substituted stilbene derivative |
| CN102336660B (en) * | 2010-07-19 | 2016-06-29 | 重庆华邦胜凯制药有限公司 | A kind of substituted diphenylamine ethene derivatives synthetic method |
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