CN108997246B - Preparation method of amorolfine hydrochloride - Google Patents
Preparation method of amorolfine hydrochloride Download PDFInfo
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- CN108997246B CN108997246B CN201710416117.1A CN201710416117A CN108997246B CN 108997246 B CN108997246 B CN 108997246B CN 201710416117 A CN201710416117 A CN 201710416117A CN 108997246 B CN108997246 B CN 108997246B
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Abstract
The invention provides amorolfine hydrochlorideThe preparation method of (1). The method specifically comprises the following reaction steps: adding a compound shown in a formula IIa into an organic solvent, then adding an amidation reaction catalyst, stirring for reaction, then adding cis-2, 6-dimethylmorpholine, and reacting to obtain a compound III. And (3) refluxing and stirring the compound shown in the formula III in anhydrous methanol, adding magnesium chips in batches, and reacting to obtain a compound shown in the formula IV. And reacting the compound IV under the action of a reducing agent to obtain a compound V. The method has the advantages of novel process route, cheap and easily-obtained raw materials, low cost, simplified process operation, shortened production period, mild reaction conditions, high yield, good product quality and suitability for industrial production.
Description
Technical Field
The invention belongs to the technical field of medicine production, and particularly relates to a preparation method of amorolfine hydrochloride.
Background
Amorolfine hydrochloride (amorolfine hydrochloride), chemical name is cis-4- [3- [4- (1, 1-dimethyl-propyl) phenyl ] -2-methylpropyl ] -2, 6-dimethyl-morpholine hydrochloride, CAS registry number is 78613-38-4, chemical structural formula is as follows:
the prior art reports the following preparation methods of amorolfine hydrochloride:
US7795425 discloses condensation reaction of 2-methyl cinnamaldehyde as raw material with cis-2, 6-dimethyl morpholine to obtain cis-4- (3-phenyl-2-methylpropyl) -2, 6-dimethyl-morpholine hydrochloride, and acid catalysis of the hydrochloride with 2-methyl-2-chlorobutane to produce Heck reaction to obtain amorolfine. The method uses expensive palladium catalyst, which is not favorable for industrial scale production. The synthetic route is as follows:
international patent application WO2007113218a1 discloses a synthesis method of amorolfine hydrochloride, comprising a first step of Heck reaction, reacting 4-iodo-tert-pentylbenzene with 2-methylallyl alcohol in the presence of a palladium catalyst and a base to obtain 3-tert-pentylphenyl-2-methylpropionaldehyde; secondly, reductive amination reaction is carried out, 3-tert-amylphenyl-2-methylpropionaldehyde reacts with cis-2, 6-dimethylmorpholine to obtain amorolfine, and a reducing agent is selected from palladium catalytic hydrogenation or metal borohydride; the scheme also needs to use an expensive palladium catalyst, and has the advantages of lower total yield and higher process cost. The synthetic route is as follows:
the existing process route generally has the problems of longer steps, low yield and higher cost, and a new process which has low production cost and simple process and is suitable for industrial production is urgently needed to be found.
Disclosure of Invention
The invention aims to provide a preparation method of amorolfine hydrochloride.
The object of the invention can be achieved by the following measures:
the preparation method of amorolfine comprises the following synthetic routes:
the preparation method of amorolfine comprises the following steps:
A. adding a compound shown in a formula IIa into an organic solvent, then adding an amidation reaction catalyst, stirring for reaction, then adding cis-2, 6-dimethylmorpholine, and reacting to obtain a compound III.
B. And (3) refluxing and stirring the compound III in absolute methanol, adding magnesium chips in batches, and performing reflux reaction to obtain a compound IV.
C. And reacting the compound IV under the action of a reducing agent to obtain a compound V.
In one embodiment, the organic solvent in step a is selected from any one of N, N-dimethylformamide, tetrahydrofuran, dichloromethane, dioxane, N-dimethylacetamide and chloroform, and the catalyst for amidation is selected from any one or a combination of HBTU, HATU, HOBT, EDCI, HOBT, DCC and DIEA. Further, the reaction of step a is carried out at normal or room temperature.
In one embodiment, the feeding ratio of magnesium to the compound of formula III in step B is 3 to 30 molar equivalents (eq), preferably 5 to 8 molar equivalents, and more preferably the feeding ratio of magnesium to the compound of formula III in step B is 6 to 7 molar equivalents;
when the feeding molar ratio of magnesium to the compound of formula III is greater than 8 molar equivalents, the yield and product purity of the reaction in this step are not significantly reduced, but the production cost is increased, and the reaction process is easy to be flushed, which is not favorable for production safety.
In one scheme, the mass ratio of the methanol in the step B to the feeding volume relative to the compound of the formula III is 10-40 ml/g, and further preferably 12-14 ml/g;
when the amount of methanol is more than 14ml/g, the yield and product purity of the reaction in this step are not significantly reduced, but the production cost is increased.
In one embodiment, the reducing agent in step C is optionally selected from lithium aluminum hydride, borane, boron trifluoride, 9-borabicyclo (3,3,1) -nonane, BH3-THF, (sodium dihydrobis (2-methoxyethoxy) aluminate, sodium borohydride plus a Lewis acid reagent, and the like, and the Lewis acid reagent is optionally selected from ZnCl2，CoCl2，TiCl4，SnCl4Or I2。
Further, under the action of any one of concentrated sulfuric acid, aluminum trichloride or ferric trichloride, the compound V and tert-amyl alcohol or chloro-tert-pentane undergo a Friedel-crafts alkylation reaction to obtain amorolfine (compound VI).
In one scheme, the preparation of amorolfine comprises the following steps:
adding the compound IIa, benzotriazole-N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HBTU) and N, N-Diisopropylethylamine (DIEA) into N, N-dimethylacetamide, stirring at normal temperature for reaction, adding cis-2, 6-dimethylmorpholine, and reacting at room temperature to obtain the compound III.
Adding the compound shown in the formula III into anhydrous methanol, uniformly stirring, heating to 60-70 ℃, stirring and refluxing, adding magnesium chips in batches, and performing reflux reaction for 18-20 hours to obtain a compound shown in the formula IV.
Adding lithium aluminum hydride into anhydrous tetrahydrofuran, slowly heating to 35 ℃, stirring, adding the compound shown in the formula IV into the tetrahydrofuran, uniformly stirring at room temperature, slowly dropwise adding the compound into a lithium aluminum hydride solution at 35 ℃, continuously reacting for 10-12 h at 35 ℃, and carrying out aftertreatment to obtain the compound shown in the formula V.
The Chinese names of the compound abbreviations referred to in the specification are as follows:
the Chinese name of HBTU is benzotriazole-N, N, N ', N' -tetramethyluronium hexafluorophosphate;
HATU is named as 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate
HOBT Chinese name 1-hydroxybenzotriazole
The Chinese name of EDCI is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride
DCC Chinese name dicyclohexylcarbodiimide
DIEA Chinese name is N, N-diisopropylethylamine
The invention has the beneficial effects that: the method has the advantages of novel process route, cheap and easily-obtained raw materials, low cost, simplified process operation, shortened production period, mild reaction conditions, high yield, good product quality and suitability for industrial production.
Detailed Description
For the sake of understanding, the present invention will be described in detail below by way of specific examples. It is specifically intended that the examples be given solely for the purpose of illustration and that all modifications that would be apparent to one skilled in the art from this disclosure are within the scope of the invention.
Example 1
(E) Synthesis of (E) -1- ((2R,6S) -2, 6-dimethylmorpholine) -2-dimethyl-3-phenyl-2-en-1-one Compound of formula III
Compound IIa (15.00g, 0.092mol), HBTU (34.89g, 0.092mol), N, N-diisopropylethylamine (23.78g, 0.184mol) were added to N, N-dimethylacetamide (150mL) respectively and stirred well. After reacting for 0.5h at 25 ℃, adding cis-2, 6-dimethylmorpholine (12.73g, 0.110mol) and reacting for 2-3 h at 25 ℃. Cooling to room temperature, adding the reaction liquid into water, extracting the dichloromethane phase by using saturated saline solution, taking an organic layer, and concentrating to dryness to obtain a yellow oily compound shown as a formula III, wherein the yield is 95.36%, and the purity is 98.79% by HPLC (high performance liquid chromatography).
Example 1.1
Intermediate iii reaction solvents were optimized for screening according to the procedure of example 1 and the results are shown in the table below.
| Serial number | Reaction solvent | HPLC(％) |
| 1 | Methylene dichloride | 96.13％ |
| 2 | Tetrahydrofuran (THF) | 98.38％ |
| 3 | N, N-dimethylformamide | 98.47％ |
| 4 | 1, 4-dioxane | 97.20％ |
Example 1.2
The condensing agent reacted with intermediate III was optimized by screening according to the method of example 1, and the experimental results are shown in the following table.
| Serial number | Condensing agent | HPLC(％) |
| 1 | HATU | 85.20％ |
| 2 | HOBT/EDCI | 68.64％ |
| 3 | HOBT/DCC | 69.17％ |
| 4 | HBTU | 98.67％ |
Example 2
(E) Synthesis of (E) -1- ((2R,6S) -2, 6-dimethylmorpholine) -2-dimethyl-3-phenyl-1-one Compound formula IV
Adding a compound shown in a formula III (10.00g, 0.038mol) into anhydrous methanol (200mL), uniformly stirring, heating to 60-70 ℃, stirring and refluxing, adding magnesium chips (6.93g, 0.285mol) in batches, and performing reflux reaction for 18-20 h. After cooling to 0 ℃ and stirring, the residual magnesium was quenched by slowly adding 6M hydrochloric acid (140mL) dropwise. The reaction solution was poured into water, extracted with dichloromethane, and concentrated to dryness to give the compound formula iv as a pale yellow oil with a yield of 96.72% and a purity of 99.11%.
Example 2.1
The amount of magnesium was optimized by screening according to the method of example 2, and the results are shown in the following table.
| Serial number | Magnesium (eq) | HPLC(％) |
| 1 | 3.0eq | 73.53％ |
| 2 | 4.0eq | 90.51％ |
| 3 | 5.0eq | 93.05％ |
| 4 | 6.0eq | 99.11％ |
| 5 | 7.0eq | 99.02％ |
Example 2.2
The amount of methanol was optimized by screening according to the method of example 2, and the results are shown in the following table.
| Serial number | Methanol (v) | Reaction conditions | HPLC(％) |
| 1 | 6v | The system can not be stirred | —— |
| 2 | 8v | The system can not be stirred | —— |
| 3 | 10v | Slightly viscous | 92.09％ |
| 4 | 12v | Is normal | 99.26％ |
| 5 | 14v | Is normal | 99.06％ |
| 6 | 16v | Is normal | 99.01％ |
Remarking: v represents the volume-to-mass ratio ml/g of solvent to compound of formula III substrate
Example 3
Synthesis of (2R,6S) -2, 6-dimethyl-4- (2-methyl-3-phenylpropyl) morpholine hydrochloride Compound
Lithium aluminum hydride (3.64g, 0.096mol) was added to tetrahydrofuran (60mL) and the temperature was slowly raised to 35 ℃ with stirring. Adding the compound IV (8.50g, 0.032mol) prepared in the previous step into tetrahydrofuran (40mL), uniformly stirring at room temperature, slowly dropwise adding into a lithium aluminum hydride solution at 35 ℃, and continuously reacting for 10-12 h at 35 ℃. Slowly pouring the reaction liquid into ice water, adjusting the pH value to 3-4 by 37% hydrochloric acid, adjusting the pH value to 8-9 by using sodium carbonate, separating out white floccules, extracting and separating liquid by using ethyl acetate, and concentrating to be dry to obtain yellow oily matters. Adding the yellow oily matter into isopropanol (20mL), adjusting the pH value to 3-4 by 37% hydrochloric acid, stirring for 0.5h, concentrating the reaction solution to dryness to obtain a light yellow solid, and recrystallizing and refining the isopropanol to obtain the off-white solid compound shown in the formula V, wherein the yield is 80.69%, and the purity is 99.71%.
1H-NMR(400MHz,CDCl3,δ):1.11(6H,dd),1.20(3H,d),2.14(1H,t),2.33(2H,m),2.57(1H, m),2.71(1H,m),2.84(2H,m),3.22(2H,q),4.37(2H,d),7.12(2H,m),7.20(1H,m),7.27(2H,m), 12.45(1H,bs)；13C-NMR(400MHz,CDCl3,δ):18.5,19.6,30.6,41.6,55.9,57.8,63.6,68.3,126.7, 128.6,129.1,138.5。
Example 4
Synthesis of (2R,6S) -2, 6-dimethyl-4- (2-methyl-3- (4- (tert-amyl) phenyl) propyl) morpholine Compound formula VI
The compound of formula V prepared in the above step (2.00g, 7.05mmol) was added to dichloromethane (12mL) and stirred well. Cooled to-10 ℃ and concentrated sulfuric acid (8.28g, 82.70mmol) was added slowly and stirring continued for 10 min. Tert-amyl alcohol (1.24g, 14.10mmol) was added to dichloromethane (6mL) and stirred well at room temperature. Slowly dropping the mixture into the reaction solution at the temperature of minus 10 ℃, and continuously reacting for 1-2 h. And adding the reaction solution into ice water, separating, taking an organic layer, and concentrating to dryness to obtain a yellow oily compound shown in the formula VI, wherein the yield is 91.64%, and the purity is 97.75%.
Example 5
Synthesis of amorolfine hydrochloride compound formula I
Adding a compound shown in a formula VI (1.14g, 3.59mmol) into isopropanol (20ml), uniformly stirring at room temperature, adjusting the pH value to be 3-4 by 37% hydrochloric acid, continuously stirring for 0.5h, and concentrating a reaction solution to dryness to obtain a white-like solid compound shown in a formula I, wherein the yield is 93.36%, and the purity is 99.24%.
1H-NMR(400MHz,CDCl3,δ):0.66(3H,t),1.15(6H,dd),1.28(9H,q),1.59(2H,q),2.03(1H, m),2.29(2H,m),2.63(2H,m),2.85(2H,m),3.24(2H,t),4.43(2H,m),7.08(2H,d),7.28(2H,d), 12.62(1H,bs)；13C-NMR(400MHz,CDCl3,δ):1.02,9.18,18.5,20.1,28.4,30.7,36.8,37.6,41.3, 55.7,57.9,63.6,68.3,126.2,128.7,135.2,148.0。
Claims (8)
1. The preparation method of amorolfine comprises the following synthetic routes:
A. adding a compound shown in a formula IIa into an organic solvent, then adding an amidation reaction catalyst, adding cis-2, 6-dimethylmorpholine after reaction, and reacting to obtain a compound III;
B. refluxing and stirring the compound III in absolute methanol, adding magnesium chips in batches, and performing reflux reaction to obtain a compound IV;
C. and reacting the compound IV under the action of a reducing agent to obtain a compound V.
2. The process according to claim 1, wherein the organic solvent in step A is one or more selected from the group consisting of N, N-dimethylformamide, tetrahydrofuran, dichloromethane, dioxane, N, N-dimethylacetamide and chloroform, and the catalyst for the amidation reaction is one or more selected from the group consisting of HBTU, HATU, EDCI, HOBT, DCC and DIEA.
3. The method according to claim 1, wherein the amount of magnesium added in step B is 3 to 30 molar equivalents (eq) relative to the compound of formula III.
4. The method according to claim 3, wherein the amount of magnesium added in step B is 5 to 8 molar equivalents (eq) relative to the compound of formula III.
5. The method according to claim 4, wherein the amount of magnesium added in step B is 6 to 7 molar equivalents (eq) relative to the compound of formula III.
6. The method according to claim 1, wherein the mass ratio of methanol to the compound of formula III fed in step B is 10 to 40 g/ml.
7. The method according to claim 6, wherein the mass ratio of methanol to the compound of formula III fed in step B is 12-14 g/ml.
8. The method according to claim 1, wherein the method further comprises subjecting compound V to Friedel-crafts alkylation with t-amyl alcohol or chloro-t-pentane in the presence of a catalyst selected from concentrated sulfuric acid, aluminum trichloride or ferric trichloride to obtain amorolfine (compound VI)
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1749825A1 (en) * | 2005-07-28 | 2007-02-07 | Galderma S.A. | Process of producing amorolfine |
| CN102887872A (en) * | 2011-12-30 | 2013-01-23 | 浙江海翔药业股份有限公司 | Method for preparing amorolfine hydrochloride |
| CN103288768A (en) * | 2013-06-18 | 2013-09-11 | 中国人民解放军第四军医大学 | Asymmetric synthetic method of optical pure amorolfine hydrochloride |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1749825A1 (en) * | 2005-07-28 | 2007-02-07 | Galderma S.A. | Process of producing amorolfine |
| CN102887872A (en) * | 2011-12-30 | 2013-01-23 | 浙江海翔药业股份有限公司 | Method for preparing amorolfine hydrochloride |
| CN103288768A (en) * | 2013-06-18 | 2013-09-11 | 中国人民解放军第四军医大学 | Asymmetric synthetic method of optical pure amorolfine hydrochloride |
Non-Patent Citations (1)
| Title |
|---|
| 抗真菌药阿莫罗芬的合成;冯志祥，等;《中国药物化学杂志》;20000331;第10卷(第1期);第64-65页 * |
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