CN104086472A - Method for preparing 13-cis isotretinoin - Google Patents
Method for preparing 13-cis isotretinoin Download PDFInfo
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Abstract
The invention discloses a method for preparing 13-cis isotretinoin. The method comprises the following steps: directly adding an acid to a solution containing a compound represented by formula I and a compound represented by formula IV and generated through a WITTIG reaction to adjust the pH value to 5-10, adding a palladium compound or a rhodium compound, and carrying out an isomerization reaction to obtain a product with the configuration represented by formula I. The 13-cis isotretinoin preparation is completed in a one step mode through a series of reactions comprising the WITTIG reaction and the isomerization reaction without hydrolysis, extraction or distillation after the WITTIG reaction, so the method has the advantages of step simplification, yield increase, total yield reaching 90%, low cost, and suitableness for industrial production.
Description
Technical field
The invention belongs to chemosynthesis technical field, be specifically related to the method for a kind of 13-of preparation along vitamin A acid.
Background technology
13-along vitamin A acid also referred to as isotretinon and isotretinoin, structural formula is suc as formula shown in I, it is the metabolic intermediate of vitamin A (Vogan-Neu), have compared with suppressing by force and fast the hyperplasia of glandula integumentaria cell and the function of atomization, belong to retinoid medicine, clinical serious acne of failing to respond to any medical treatment for other medicines, cystic acne, acne conglobata, especially be also applicable to serious difficult treated acne nodosum (acne nodosum, it is the inflammatory damage of diameter >=5mm, tubercle may suppurate or be hemorrhage), also can be used for pityriasis rubra pilaris, acne, pityriasis rubra, the diseases such as Dermatology Department.
From structure, 13-is the molecule of height conjugation along vitamin A acid (suc as formula I), form by a substituted tetrahydrobenzene part with the polyene hydrocarbon side chain of 9 carbon of a terminal carboxyl(group), in all pairs of keys in its side chain, only having two keys (the two keys of C-13) is cis, this pair of stereospecificity structure that key is this polyene hydrocarbon side chain.This unique structure has proposed challenge to the brainstrust of the field of chemical synthesis.
At present, it is more with [3-methyl-5-(2 that the published 13-of preparation adopts along the method for vitamin A acid, 6,6-trimethyl cyclohexene-1-yl)-2,4-pentadiene]-triphenylphosphine salt (formula II) is raw material, with 5-hydroxy-4-methyl-2-5[H]-furanone (formula III) carries out WITTIG and reacts, but because WITTIG reaction can produce its cis-isomeride of 11, (structural formula suc as formula IV, and show that by high performance liquid chromatography (HPLC) method its purity is 60-70%) causes 13-on the low side along the yield of vitamin A acid.At present, a large amount of R&D works concentrates on and how the cis-isomeride selectivity isomery shown in formula IV is turned to the 13-shown in formula I along vitamin A acid.The method of introducing in document US4556518 is with [3-methyl-5-(2,6,6-trimethyl cyclohexene-1-yl)-2,4-pentadiene]-triphenylphosphine villaumite is raw material, with 5-hydroxy-4-methyl-2-5[H] after-furanone reacted, through hydrolysis, extract, distillation obtains after nitration mixture (mixture of formula I and formula IV), be dissolved in after the mixed solvent of acetonitrile and tetrahydrofuran (THF), make the transition and obtain product through the composite catalyst of Palladous nitrate.After this method WITTIG has reacted, need hydrolysis, extract, distillation, complex operation, and 13-own is just unstable along vitamin A acid, in the time of distillation, some product can be converted into all-trans-retinoic acid (formula V), causes yield on the low side, suitability for industrialized production difficulty.
The method that document US20050192351 introduces is with [3-methyl-5-(2,6,6-trimethyl cyclohexene-1-yl)-2,4-pentadiene]-triphenylphosphine villaumite is raw material, with 5-hydroxy-4-methyl-2-5[H]-furanone reacted after after hydrolysis, extraction, distilling off solvent, be dissolved in ethyl acetate, make the transition and obtain product by the composite catalyst of Palladous nitrate.After this method WITTIG has reacted, still need hydrolysis, extract, distillation, complex operation, aftertreatment distillation temperature is reduced to 20 DEG C-25 DEG C, and the vitamin A acid changing into can reduce relatively, but because distillation temperature is low, distillation time can be very long, and require high vacuum tightness, is difficult to realize suitability for industrialized production.
Above-mentioned method all relates to after WITTIG has reacted needs the steps such as hydrolysis, extraction, distillation to carry out isomerization reaction again, complex operation, and be difficult for realizing industrial scale production.
In prior art, by [3-methyl-5-(2,6,6-trimethyl cyclohexene-1-yl)-2,4-pentadiene]-triphenylphosphine salt and the formula shown in formula II
shown 5-hydroxy-4-methyl-2-5[H]-furanone raw material reaction, after having reacted, WITTIG needs just can carry out isomerization reaction through troublesome operation such as hydrolysis, extraction, distillations, in the present invention, by [3-methyl-the 5-(2 shown in formula II, 6,6-trimethyl cyclohexene-1-yl)-2,4-pentadiene]-triphenylphosphine salt and formula
shown 5-hydroxy-4-methyl-2-5[H]-furanone material dissolution is in solvent, under the effect of alkali, there is WITTIG reaction, after finishing, reaction do not need to carry out the post-processing operation as hydrolysis, extraction and solvent distillation etc., after directly adding acid for adjusting pH, carry out isomerization reaction, be easy to suitability for industrialized production, the 13-obtaining is high along vitamin A acid purity, and yield is high.
Described reaction raw materials [3-methyl-5-(2,6,6-trimethyl cyclohexene-1-yl)-2,4-pentadiene]-triphenylphosphine salt (suc as formula II), can make according to US3932485 above, and its X can be Cl, Br or HSO
4.Also can commercial sources buy.
Described 5-hydroxy-4-methyl-2-5[H]-furanone (structural formula is as formula III) raw material can buy by commercial sources.
Described raw material [3-methyl-5-(2,6,6-trimethyl cyclohexene-1-yl)-2,4-pentadiene]-triphenylphosphine salt (structural formula is suc as formula II) and 5-hydroxy-4-methyl-2-5[H] mol ratio of-furanone (structural formula is as formula III) is preferably 1:0.7-1.8, more preferably 1:0.8-1.6.
Solvent described in above-mentioned reaction is to [3-methyl-5-(2,6,6-trimethyl cyclohexene-1-yl)-2,4-pentadiene] shown in formula II-triphenylphosphine salt and formula
shown 5-hydroxy-4-methyl-2-5[H]-furanone raw material has resolvability, and as preferred method, described solvent is selected from one or more in methyl alcohol, ethanol, Virahol and butanols.
In above-mentioned reaction, alkali used is R
1oM or MOH, wherein R
1for alkyl, be preferably C
1-C
6alkyl, M is Na, K, Li, i.e. C
1-C
6an alkali metal salt of alkanol or metal hydroxides, as sodium methylate, potassium methylate, lithium methoxide, sodium ethylate, potassium ethylate, potassium isopropoxide, potassium tert.-butoxide, sodium hydroxide, potassium hydroxide, lithium hydroxides etc., are preferably potassium hydroxide.
As preferred scheme, described WITTIG reaction is to carry out under protection of inert gas.
As preferred scheme, [3-methyl-5-(2,6,6-trimethyl cyclohexene-1-yl)-2,4-pentadiene]-triphenylphosphine salt and the formula shown in formula II
shown 5-hydroxy-4-methyl-2-5[H] mol ratio of-furanone is 1:0.7-1.8, is preferably 1:0.8-1.6; The temperature of described WITTIG reaction is-50 DEG C-30 DEG C, and preferable reaction temperature is-5-5 DEG C.The reaction times of described WITTIG reaction is 1-24 hour, and the preferred reaction time is 3-4 hour.
Above-mentioned method also can be produced on specific equipment, the reacted reaction solution of WITTIG does not need to carry out aftertreatment (hydrolysis, extract and solvent distillation), do not need to separate yet, can directly in same container, carry out isomerization reaction, therefore, method of the present invention, WITTIG reaction and isomerization reaction can be produced by one kettle way, described production equipment special comprises: reactor, rare gas element input unit, isomerization reaction monitoring device and filtration unit, described reactor is provided with material admission port, rare gas element input aperture, alkali liquor inlet, acid solution entrance and material liquid outlet, described rare gas element input unit is connected by pipeline with rare gas element input aperture, described material liquid outlet is connected with filtration unit, described isomerization reaction monitoring device is connected with reactor, described isomerization reaction monitoring device is high performance liquid chromatography,
Described method is specially: in reactor, add suitable solvent by material admission port, rare gas element input unit passes into rare gas element by rare gas element input aperture in reactor, under the protection of rare gas element, in reactor, add [3-methyl-the 5-(2 shown in formula II by material admission port again, 6, 6-trimethyl cyclohexene-1-yl)-2, 4-pentadiene] the 5-hydroxy-4-methyl-2-5[H shown in-triphenylphosphine salt and formula III]-furanone, be stirred to solution clarification, then in reactor, add alkali by alkali liquor inlet, under alkali effect, there is WITTIG reaction, after reaction finishes, be directly 5-10 to adding acid for adjusting pH in the reaction solution of reactor by acid solution entrance, add again isomerization catalyst to carry out isomerization reaction by material admission port, by isomerization reaction monitoring device monitoring isomerization reaction degree, in described filtration unit, add water, after isomerization reaction, gained reaction solution passes in filtration unit by material liquid outlet, acid neutralization pH to 2-3, filtration obtains the 13-shown in formula I along vitamin A acid crude product,
Wherein, the X in formula II is Cl, Br, HSO
4.
Described solvent is selected from one or more in methyl alcohol, ethanol, Virahol and butanols.
Alkali used is ROM or MOH, and wherein R is alkyl, is preferably C
1-C
6alkyl, M is Na, K, Li, i.e. C
1-C
6an alkali metal salt of alkanol or metal hydroxides, as sodium methylate, potassium methylate, lithium methoxide, sodium ethylate, potassium ethylate, potassium isopropoxide, potassium tert.-butoxide, sodium hydroxide, potassium hydroxide, lithium hydroxides etc., are preferably potassium hydroxide.
Rare gas element used is preferably nitrogen.
Described acid can be selected mineral acid and/or organic acid equally, its mineral acid be in sulfuric acid, hydrochloric acid, phosphoric acid and Hydrogen bromide etc. one or more all can, organic acid is C
1-C
6alkyl acid, as in formic acid, glacial acetic acid, propionic acid and butyric acid etc. one or more all can, preferably hydrochloric acid.
The compound of palladium used comprises PdCl
2, PdBr
2, PdI
2, PdF
2, PdS(CH
3cN)
2pdCl
2, Pd (OAc)
2, (PhCN)
2pdCl
2, Pd (NO
3)
4(NH
4)
2, Pd (NH
3)
2cl
2, PdS
2, K
2pdCl
6, Pd (NH
3)
2(NO
2)
2, Pd (NO
2)
4(NH
3)
2, (PhCN)
2pdBr
2, (NH
4)
2pdCl
4, (NH
4)
2pdCl
6, (Ph
3p)
4pd (0), (Et
3p)
4pd (0), (Ph
3p)
3pdCl
2,pd(NO
3)
2+ Ph
3p.
The chemicals of rhodium used are salt or the mixture identical with palladium.
Palladous nitrate or Palladous nitrate and triphenylphosphine (Pd(NO in above catalyzer
3)
2+ Ph
3p) under triethylamine exists, be dissolved in the good catalytic activity of the mixture generating in acetonitrile, described mixture is the mixture of the triphenylphosphine of 1mol Palladous nitrate, 4mol and the triethylamine of 2mol preferably.
[3-methyl-5-(2,6,6-trimethyl cyclohexene-1-yl)-2,4-pentadiene]-triphenylphosphine salt and formula shown in described formula II
shown 5-hydroxy-4-methyl-2-5[H] mol ratio of-furanone is 1:0.7-1.8, is preferably 1:0.8-1.6; The temperature of described WITTIG reaction is-50-30 DEG C that preferable reaction temperature is-5-5 DEG C.The reaction times of described WITTIG reaction is 1-24 hour, and the preferred reaction time is 3-4 hour.
The temperature condition of described isomerization reaction is 30-80 DEG C, is preferably 50-60 DEG C.
Method of the present invention is prepared 13-along vitamin A acid, can be optionally by described react by WITTIG the solution Chinese style IV that contains compound shown in formula I and formula IV that produces shown in isomer selectivity isomery turn to the 13-shown in formula I along vitamin A acid; Reacting by WITTIG the solution that contains compound shown in formula I and formula IV producing does not need to be hydrolyzed, to extract, distill, complete by cascade reaction (WITTIG reaction and isomerization reaction) step, simplify step, improve yield, its total recovery can reach 90%, cost is low, is suitable for suitability for industrialized production.
Summary of the invention
In view of the foregoing, an object of the present invention is to provide the method for a kind of 13-of preparation along vitamin A acid, the method unit operation is few, is easy to suitability for industrialized production, and yield is high, and cost is low.
Another object of the present invention is to provide a kind of production equipment special that utilizes and carries out the method for one kettle way production 13-along vitamin A acid, in the method, the product that WITTIG reaction generates does not separate, does not shift, WITTIG reaction and isomerization reaction are carried out in same equipment, realize commercialization scale operation.
For achieving the above object, technical scheme of the present invention is:
A kind ofly prepare the method along vitamin A acid suc as formula the 13-shown in I, regulate pH value for 5-10 by react the solution that contains compound shown in formula I and formula IV producing by WITTIG, add the compound of palladium and/or the compound of rhodium to carry out isomerization reaction, obtain the product of configuration shown in formula I;
。
How the cis-isomeride isomery shown in formula IV being turned to the 13-shown in formula I is the emphasis that current chemosynthesis expert pays close attention to along vitamin A acid.Existing method comprises use iodine (J.Chem.Soc. (C), 1982,1968), transition-metal catalyst (U.S. Patent No. 4556518), photosensitizers B as red in algae, rose-red etc. (U.S. Patent No. 5424465) carry out photoisomerization, but these methods are not all suitable for the commercial production of 13-along vitamin A acid because of a variety of causes.The present inventor finds, the pH value that contains the solution of compound shown in formula I and formula IV that WITTIG reaction is produced is adjusted to suitable scope, add the compound of palladium or the compound of rhodium to carry out isomerization reaction, optionally the cis-isomeride selectivity isomery shown in formula IV is turned to the 13-shown in formula I along vitamin A acid.The scope that in the present invention, pH value is suitable is 5-10, is preferably 7-8.If pH value is too low, impact makes the transition, and pH value Tai Gaoyi produces impurity, is all unfavorable for producing.The adjusting of pH value is the routine operation that adopts chemical field, as by pH value from high toward low-key, generally to adopt acid, mineral acid and/or organic acid all can, as preferred scheme, the present invention adopts following acid for adjusting pH value, and mineral acid is as one or more in sulfuric acid, hydrochloric acid, phosphoric acid and Hydrogen bromide etc., and organic acid is as C
1-C
6alkyl acid (as formic acid, glacial acetic acid, propionic acid and butyric acid etc.) in one or more all can, be preferably hydrochloric acid.
As preferred scheme, the temperature condition of described isomerization reaction is 30-80 DEG C.As low in temperature, isomerized speed is slow, and temperature is high, isomerized speed is fast, but impurity easily increases, more preferably 50-60 DEG C, in the present invention, the isomerized time does not have specific limited, can react until isomerization reaction completes by the monitoring of high performance liquid chromatography (HPLC) method.
In the present invention, whether completely high performance liquid chromatography (HPLC) method of the isomerization reaction shown in monitoring formula IV is:
Chromatographic column: (4.6 х 150mm, 3 μ m) for Waters ODS
Moving phase: methyl alcohol: water: glacial acetic acid=800:225:5
Flow velocity: 1ml/min, column temperature: 30 DEG C, detect wavelength: 355
After monitoring isomerization reaction and completing, by reaction solution impouring water, acid neutralization, filter 13-along vitamin A acid crude product, obtain product through crystallization.Described acid can be selected mineral acid and/or organic acid equally, its mineral acid be in sulfuric acid, hydrochloric acid, phosphoric acid and Hydrogen bromide etc. one or more all can, organic acid is C
1-C
6alkyl acid, as in formic acid, glacial acetic acid, propionic acid and butyric acid etc. one or more all can, preferably hydrochloric acid.
Described catalyzer is the compound of palladium or the compound of rhodium, and the compound of palladium comprises PdCl
2, PdBr
2, PdI
2, PdF
2, PdS(CH
3cN)
2pdCl
2, Pd (OAc)
2, (PhCN)
2pdCl
2, Pd (NO
3)
4(NH
4)
2, Pd (NH
3)
2cl
2, PdS
2, K
2pdCl
6, Pd (NH
3)
2(NO
2)
2, Pd (NO
2)
4(NH
3)
2, (PhCN)
2pdBr
2, (NH
4)
2pdCl
4, (NH
4)
2pdCl
6, (Ph
3p)
4pd (0), (Et
3p)
4pd (0), (Ph
3p)
3pdCl
2,pd(NO
3)
2+ Ph
3p, the salt that rhodium is identical with palladium or mixture also can be utilized.Palladous nitrate or Palladous nitrate and triphenylphosphine (Pd(NO in above catalyzer
3)
2+ Ph
3p) under triethylamine exists, be dissolved in the good catalytic activity of the mixture generating in acetonitrile, described mixture is the mixture of the triphenylphosphine of 1mol Palladous nitrate, 4mol and the triethylamine of 2mol preferably, and triphenylphosphine and triethylamine also can be added, but can increase Financial cost.
The compound of palladium and/or the compound of rhodium are at the 13-shown in preparation formula I along the application in vitamin A acid, and described application is to add the compound of palladium and/or the compound of rhodium to carry out isomerization reaction for after 5-10 formula I and formula IV mixture adjusting pH value again.
The consumption of catalyzer is a small amount of, and in the present invention, the mol ratio of the reaction raw materials shown in the catalyst levels that isomerization reaction is required and formula II is 0.0001-0.02:1.
As preferred scheme, described to react by WITTIG the solution that contains compound shown in formula I and formula IV producing be by the preparation of following method: by [3-methyl-the 5-(2 shown in formula II, 6,6-trimethyl cyclohexene-1-yl)-2,4-pentadiene] the 5-hydroxy-4-methyl-2-5[H shown in-triphenylphosphine salt and formula III]-furanone material dissolution is in solvent, under the effect of alkali, there is WITTIG reaction, after reaction finishes, obtain the solution that contains compound shown in formula I and formula IV;
Wherein, the X in formula II is Cl, Br, HSO
4.
brief description of the drawings
Fig. 1 is that the present invention prepares the structural representation of 13-along the specific equipment of vitamin A acid.
embodiment
In order to make the object, technical solutions and advantages of the present invention clearer, below the preferred embodiments of the present invention are described in detail.
Yield in following embodiment all by concrete each step feed intake substrate as calculate denominator.
HPLC instrument and testing conditions related in following examples are as follows:
Chromatographic column: (4.6 х 150mm, 3 μ m) for Waters ODS
Moving phase: methyl alcohol: water: glacial acetic acid=800:225:5
Flow velocity: 1ml/min
Column temperature: 30 DEG C
Detect wavelength: 355
first part: 13-is along the preparation of vitamin A acid
embodiment 1
[3-methyl-5-(2 of 372g, 6, 6-trimethyl cyclohexene-1-yl)-2, 4-pentadiene]-triphenylphosphine villaumite is dissolved in ethanol 1000ml, under logical nitrogen, add 5-hydroxy-4-methyl-2-5[H of 84.6g]-furanone, be stirred to solution clarification, cool to-5 DEG C, drip 2NKOH ethanolic soln 1200ml, maintain the temperature at 0 ± 5 DEG C, react 2 hours, then be 7-8 with salt acid for adjusting pH value, add the 250mg Palladous nitrate that is dissolved in 150ml acetonitrile, be warmed up to 50 DEG C, by high performance liquid chromatography (HPLC) detection reaction result, after isomerization reaction completes, in impouring water, acid neutralization is to pH2-3, suction filtration obtains crude product, obtain product 201.5g through ethyl acetate crystallization, purity 99.69%, yield 90.3%.
embodiment 2
[3-methyl-5-(2 of 372g, 6, 6-trimethyl cyclohexene-1-yl)-2, 4-pentadiene]-triphenylphosphine villaumite is dissolved in ethanol 1000ml, under logical nitrogen, add 5-hydroxy-4-methyl-2-5[H of 84.6g]-furanone, be stirred to solution clarification, cool to-20 DEG C, drip 2NKOH ethanolic soln 1200ml, maintain the temperature at-20 ± 5 DEG C, react 2 hours, then be 7-8 with salt acid for adjusting pH value, add the 250mg Palladous nitrate that is dissolved in 150ml acetonitrile, be warmed up to 35 DEG C, by high performance liquid chromatography (HPLC) detection reaction result, after isomerization reaction completes, in impouring water, acid neutralization is to pH2-3, suction filtration obtains crude product, obtain product 200.2g through ethyl acetate crystallization, purity 99.7%, yield 89.9%.
embodiment 3
[3-methyl-5-(2 of 372g, 6, 6-trimethyl cyclohexene-1-yl)-2, 4-pentadiene]-triphenylphosphine villaumite is dissolved in ethanol 1000ml, under logical nitrogen, add 5-hydroxy-4-methyl-2-5[H of 84.6g]-furanone, be stirred to solution clarification, cool to-40 DEG C, drip 2NKOH ethanolic soln 1200ml, maintain the temperature at-40 ± 5 DEG C, react 2 hours, then be 7-8 with salt acid for adjusting pH value, add the 250mg Palladous nitrate that is dissolved in 150ml acetonitrile, be warmed up to 60 DEG C, by high performance liquid chromatography (HPLC) detection reaction result, after isomerization reaction completes, in impouring water, acid neutralization is to pH2-3, suction filtration obtains crude product, obtain product 204.7g through ethyl acetate crystallization, purity 99.7%, yield 92.1%.
embodiment 4
[3-methyl-5-(2 of 372g, 6, 6-trimethyl cyclohexene-1-yl)-2, 4-pentadiene]-triphenylphosphine villaumite is dissolved in ethanol 1000ml, under logical nitrogen, add 5-hydroxy-4-methyl-2-5[H of 84.6g]-furanone, be stirred to solution clarification, cool to 15 DEG C, drip 2NKOH ethanolic soln 1200ml, maintain the temperature at 15 ± 5 DEG C, react 2 hours, then be 7-8 with salt acid for adjusting pH value, add the 250mg Palladous nitrate that is dissolved in 150ml acetonitrile, be warmed up to 70 DEG C, by high performance liquid chromatography (HPLC) detection reaction result, after isomerization reaction completes, in impouring water, acid neutralization is to pH2-3, suction filtration obtains crude product, obtain product 198.4g through ethyl acetate crystallization, purity 99.5%, yield 88.7%.
embodiment 5
[3-methyl-5-(2 of 372g, 6, 6-trimethyl cyclohexene-1-yl)-2, 4-pentadiene]-triphenylphosphine villaumite is dissolved in ethanol 1000ml, under logical nitrogen, add 5-hydroxy-4-methyl-2-5[H of 84.6g]-furanone, be stirred to solution clarification, cool to 25 DEG C, drip 2NKOH ethanolic soln 1200ml, maintain the temperature at 25 ± 5 DEG C, react 2 hours, then be 7-8 with salt acid for adjusting pH value, add the 250mg Palladous nitrate that is dissolved in 150ml acetonitrile, be warmed up to 50 DEG C, by high performance liquid chromatography (HPLC) detection reaction result, after isomerization reaction completes, in impouring water, acid neutralization is to pH2-3, suction filtration obtains crude product, obtain product 199.4g through ethyl acetate crystallization, purity 99.8%, yield 89.2%.
second section: 13-is along the preparation optimal conditions test example of vitamin A acid
in test example 1 and the test of pH value
Carry out according to the condition of embodiment 1, just change the pH value that hydrochloric acid regulates, isomerization result is as following table:
the test of the kind of test example 2 catalyzer
Carry out according to the condition of embodiment 1, just change the kind of catalyzer, isomerization result is as following table:
the test of the temperature of test example 3 isomerization reactions
Carry out according to the condition of embodiment 1, just change the temperature of isomerization reaction, acquired results is as following table:
Note: "----" represent not detect.
Total chemical equation is as follows:
The structural representation of the production equipment special adopting as shown in Figure 1, comprise: reactor 1, rare gas element input unit 2, isomerization reaction monitoring device 3 and filtration unit 4, described reactor 1 is provided with material admission port 11, rare gas element input aperture 12, alkali liquor inlet 13, acid solution entrance 14 and material liquid outlet 15, described rare gas element input unit 2 is connected by pipeline with rare gas element input aperture 12, described material liquid outlet 15 is connected with filtration unit 4, described isomerization reaction monitoring device 3 is connected with reactor 1, described isomerization reaction monitoring device 3 is high performance liquid chromatography,
The method of described production is specially: in reactor 1, add suitable solvent by material admission port 11, rare gas element input unit 2 passes into rare gas element by rare gas element input aperture 12 in reactor, under the protection of rare gas element, in reactor 1, add [3-methyl-the 5-(2 shown in formula II by material admission port 11 again, 6, 6-trimethyl cyclohexene-1-yl)-2, 4-pentadiene] the 5-hydroxy-4-methyl-2-5[H shown in-triphenylphosphine salt and formula III]-furanone, be stirred to solution clarification, then in reactor 1, add alkali by alkali liquor inlet 13, under alkali effect, there is WITTIG reaction, after reaction finishes, be directly 5-10 to adding acid for adjusting pH in the reaction solution of reactor 1 by acid solution entrance 14, add again isomerization catalyst to carry out isomerization reaction by material admission port 11, monitor isomerization reaction degree by isomerization reaction monitoring device 3, in described filtration unit 4, add water, after isomerization reaction, gained reaction solution passes in filtration unit 4 by material liquid outlet 15, acid neutralization pH to 2-3, filtration obtains the 13-shown in formula I along vitamin A acid crude product, crude product is the dissolving crystallized product that obtains further.
Embodiment 18 illustrates with a specific embodiment, specific as follows:
embodiment 18
250L Virahol is added in reactor 1 by material admission port 11, rare gas element input unit 2 passes into nitrogen by rare gas element input aperture 12 in reactor, then by [3-methyl-5-(2 of 93kg, 6, 6-trimethyl cyclohexene-1-yl)-2, 4-pentadiene] 5-hydroxy-4-methyl-2-5[H of-triphenylphosphine villaumite and 21.3kg]-furanone joins in reactor 1 by material admission port 11 successively, be stirred to solution clarification, by extremely-10 DEG C of the greenhouse coolings of reactor, maintain the temperature at-5 ± 5 DEG C, in reactor 1, drip 2NKOH ethanolic soln 300L by alkali liquor inlet 13, under alkali effect, there is WITTIG reaction, react after 2 hours, directly in the reaction solution of reactor 1, add salt acid for adjusting pH to 7.5-7.7 by acid solution entrance 14, in reactor 1, add the 67g Palladous nitrate that is dissolved in 18L acetonitrile by material admission port 11 again, the solution that 100g triphenylphosphine and 25g triethylamine are made into, reactor 1 is heated to 50 DEG C-55 DEG C, carry out isomerization reaction, monitor isomerization reaction degree by isomerization reaction monitoring device 3, first in described filtration unit 4, add water, after treating isomerization reaction, in reactor 1, gained reaction solution passes in filtration unit 4 by material liquid outlet 15, add in hydrochloric acid and pH to 2-3, suction filtration obtains crude product, obtain product 50kg through ethyl acetate crystallization, purity 99.75%, yield 89.7%.
In the present embodiment, described isomerization reaction monitoring device 3) be high-efficient liquid phase chromatogram HPLC), its content by detection reaction liquid Chinese style IV is monitored extent of reaction, testing conditions: adopt chromatographic column Waters ODS (4.6 х 150mm, 3 μ m), taking methyl alcohol: water: glacial acetic acid=800:225:5 is as moving phase, and flow velocity is 1ml/min, column temperature is 30 DEG C, and detection wavelength is 355nm.
Finally explanation is, above embodiment is only unrestricted in order to technical scheme of the present invention to be described, although the present invention is had been described in detail with reference to preferred embodiment, those of ordinary skill in the art is to be understood that, can modify or be equal to replacement technical scheme, and not departing from aim and the scope of technical solution of the present invention, it all should be encompassed in the middle of claim scope of the present invention.
Claims (10)
1. prepare the method along vitamin A acid suc as formula the 13-shown in I for one kind, it is characterized in that: regulate pH value for 5-10 by react the solution that contains compound shown in formula I and formula IV producing by WITTIG, then add the compound of palladium and/or the compound of rhodium to carry out isomerization reaction, obtain the product of configuration shown in formula I;
。
2. method according to claim 1, it is characterized in that: it is 5-10 that the solution that contains compound shown in formula I and formula IV directly adds acid for adjusting pH value, described acid is that sulfuric acid, hydrochloric acid, phosphoric acid, Hydrogen bromide and general formula are one or more in R-COOH alkyl acid, and wherein R is H or C
1-C
5alkyl.
3. method according to claim 1 and 2, is characterized in that: the temperature condition of described isomerization reaction is 30-80 DEG C.
4. method according to claim 1 and 2, it is characterized in that: described in contain compound shown in formula I and formula IV solution be by the preparation of following method: by [3-methyl-the 5-(2 shown in formula II, 6,6-trimethyl cyclohexene-1-yl)-2,4-pentadiene] the 5-hydroxy-4-methyl-2-5[H shown in-triphenylphosphine salt and formula III]-furanone material dissolution is in solvent, under the effect of alkali, there is WITTIG reaction, after reaction finishes, obtain the solution that contains compound shown in formula I and formula IV;
Wherein, the X in formula II is Cl, Br, HSO
4.
5. method according to claim 4, is characterized in that: described solvent is selected from one or more in methyl alcohol, ethanol, Virahol and butanols.
6. method according to claim 4, is characterized in that: described alkali is R
1oM or MOH, wherein R
1for C
1-C
6alkyl, M is Na, K, Li.
7. method according to claim 4, is characterized in that: described WITTIG reaction is to carry out under protection of inert gas.
8. method according to claim 4, is characterized in that, [3-methyl-5-(2,6,6-trimethyl cyclohexene-1-yl)-2,4-pentadiene]-triphenylphosphine salt and the formula shown in formula II
shown 5-hydroxy-4-methyl-2-5[H] mol ratio of-furanone is 1:0.7-1.8, the temperature of described WITTIG reaction is-50 DEG C-30 DEG C.
The compound of palladium and/or the compound of rhodium at the 13-shown in preparation formula I along the application in vitamin A acid, it is characterized in that, described application is to add the compound of palladium and/or the compound of rhodium to carry out isomerization reaction after the solution that contains compound shown in formula I and formula IV that WITTIG reaction is produced regulates pH value for 5-10 again.
10. in production equipment special, carry out the method for one kettle way production based on method claimed in claim 7, it is characterized in that, described production equipment special comprises: reactor (1), rare gas element input unit (2), isomerization reaction monitoring device (3) and filtration unit (4), described reactor (1) is provided with material admission port (11), rare gas element input aperture (12), alkali liquor inlet (13), acid solution entrance (14) and material liquid outlet (15), described rare gas element input unit (2) is connected by pipeline with rare gas element input aperture (12), described material liquid outlet (15) is connected with filtration unit (4), described isomerization reaction monitoring device (3) is connected with reactor (1), described isomerization reaction monitoring device (3) is high performance liquid chromatography, described method is specially: in reactor (1), add solvent by material admission port (11), rare gas element input unit (2) passes into rare gas element by rare gas element input aperture (12) in reactor, under the protection of rare gas element, in reactor (1), add [3-methyl-the 5-(2 shown in formula II by material admission port (11) again, 6, 6-trimethyl cyclohexene-1-yl)-2, 4-pentadiene] the 5-hydroxy-4-methyl-2-5[H shown in-triphenylphosphine salt and formula III]-furanone, be stirred to solution clarification, then in reactor (1), add alkali by alkali liquor inlet (13), under alkali effect, there is WITTIG reaction, after reaction finishes, be directly 5-10 to adding acid for adjusting pH in the reaction solution of reactor (1) by acid solution entrance (14), add again the compound of palladium or the compound of rhodium to carry out isomerization reaction by material admission port (11), by isomerization reaction monitoring device (3) monitoring isomerization reaction degree, in described filtration unit (4), add water, after isomerization reaction, gained reaction solution passes in filtration unit (4) by material liquid outlet (15), acid neutralization pH to 2-3, filtration obtains the 13-shown in formula I along vitamin A acid crude product,
Wherein, the X in formula II is Cl, Br, HSO
4.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106483202A (en) * | 2015-08-25 | 2017-03-08 | 重庆华邦制药有限公司 | A kind of separation and the method measuring alitretinoin and isomer |
| CN111423348A (en) * | 2020-04-26 | 2020-07-17 | 上海新华联制药有限公司 | Isotretinoin, and preparation method and application thereof |
| CN111454141A (en) * | 2020-04-26 | 2020-07-28 | 上海新华联制药有限公司 | Isotretinoin condensation compound and preparation method and application thereof |
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| CN111423348A (en) * | 2020-04-26 | 2020-07-17 | 上海新华联制药有限公司 | Isotretinoin, and preparation method and application thereof |
| CN111454141A (en) * | 2020-04-26 | 2020-07-28 | 上海新华联制药有限公司 | Isotretinoin condensation compound and preparation method and application thereof |
| CN111423348B (en) * | 2020-04-26 | 2021-10-22 | 上海新华联制药有限公司 | Isotretinoin, and preparation method and application thereof |
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