CN111704588A - Preparation method of amorolfine hydrochloride - Google Patents
Preparation method of amorolfine hydrochloride Download PDFInfo
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- CN111704588A CN111704588A CN202010481027.2A CN202010481027A CN111704588A CN 111704588 A CN111704588 A CN 111704588A CN 202010481027 A CN202010481027 A CN 202010481027A CN 111704588 A CN111704588 A CN 111704588A
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- 229960005279 amorolfine hydrochloride Drugs 0.000 title claims abstract description 36
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- MQHLMHIZUIDKOO-AYHJJNSGSA-N amorolfine Chemical compound C1=CC(C(C)(C)CC)=CC=C1CC(C)CN1C[C@@H](C)O[C@@H](C)C1 MQHLMHIZUIDKOO-AYHJJNSGSA-N 0.000 title claims abstract 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 24
- YGTZHUMRZRLTKX-UHFFFAOYSA-N 2-methyl-3-[4-(2-methylbutan-2-yl)phenyl]propan-1-ol Chemical compound CCC(C)(C)C1=CC=C(CC(C)CO)C=C1 YGTZHUMRZRLTKX-UHFFFAOYSA-N 0.000 claims abstract description 16
- HNVIQLPOGUDBSU-OLQVQODUSA-N (2s,6r)-2,6-dimethylmorpholine Chemical compound C[C@H]1CNC[C@@H](C)O1 HNVIQLPOGUDBSU-OLQVQODUSA-N 0.000 claims abstract description 11
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims abstract description 11
- 239000007789 gas Substances 0.000 claims abstract description 11
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims abstract description 11
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims abstract description 11
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 35
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 15
- 238000003756 stirring Methods 0.000 claims description 14
- 239000007787 solid Substances 0.000 claims description 13
- 229960003204 amorolfine Drugs 0.000 claims description 11
- 230000008569 process Effects 0.000 claims description 11
- MQHLMHIZUIDKOO-OKZBNKHCSA-N (2R,6S)-2,6-dimethyl-4-[(2S)-2-methyl-3-[4-(2-methylbutan-2-yl)phenyl]propyl]morpholine Chemical compound C1=CC(C(C)(C)CC)=CC=C1C[C@H](C)CN1C[C@@H](C)O[C@@H](C)C1 MQHLMHIZUIDKOO-OKZBNKHCSA-N 0.000 claims description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 10
- 150000007530 organic bases Chemical class 0.000 claims description 10
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 239000007810 chemical reaction solvent Substances 0.000 claims description 6
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 5
- 229940011051 isopropyl acetate Drugs 0.000 claims description 5
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 3
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 238000010534 nucleophilic substitution reaction Methods 0.000 abstract 1
- XZKWIPVTHGWDCF-KUZYQSSXSA-N amorolfine hydrochloride Chemical compound Cl.C1=CC(C(C)(C)CC)=CC=C1CC(C)CN1C[C@@H](C)O[C@@H](C)C1 XZKWIPVTHGWDCF-KUZYQSSXSA-N 0.000 description 26
- 238000006243 chemical reaction Methods 0.000 description 19
- 239000012074 organic phase Substances 0.000 description 12
- 238000001035 drying Methods 0.000 description 9
- 239000000047 product Substances 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000007341 Heck reaction Methods 0.000 description 3
- 150000008052 alkyl sulfonates Chemical class 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- 239000013067 intermediate product Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- HWZHDJOIEFHSGN-UHFFFAOYSA-N 2-methyl-2-[3-(2-methylbutan-2-yl)phenyl]propanal Chemical compound C(C)(C)(CC)C=1C=C(C=CC1)C(C=O)(C)C HWZHDJOIEFHSGN-UHFFFAOYSA-N 0.000 description 2
- 102000005782 Squalene Monooxygenase Human genes 0.000 description 2
- 108020003891 Squalene monooxygenase Proteins 0.000 description 2
- -1 alkyl sulfonic acid Chemical compound 0.000 description 2
- 238000012658 bimolecular nucleophilic substitution Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 238000003912 environmental pollution Methods 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000006268 reductive amination reaction Methods 0.000 description 2
- HQSAFEQSBITLFW-UHFFFAOYSA-N 1-iodo-3-(2-methylbutan-2-yl)benzene Chemical compound IC1=CC(=CC=C1)C(C)(C)CC HQSAFEQSBITLFW-UHFFFAOYSA-N 0.000 description 1
- QYIMSPSDBYKPPY-BANQPHDMSA-N 2,3-epoxysqualene Chemical compound CC(C)=CCC\C(C)=C\CC\C(C)=C\CC\C=C(/C)CC\C=C(/C)CCC1OC1(C)C QYIMSPSDBYKPPY-BANQPHDMSA-N 0.000 description 1
- BYDRTKVGBRTTIT-UHFFFAOYSA-N 2-methylprop-2-en-1-ol Chemical compound CC(=C)CO BYDRTKVGBRTTIT-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010017533 Fungal infection Diseases 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- 229940123185 Squalene epoxidase inhibitor Drugs 0.000 description 1
- CKUAXEQHGKSLHN-UHFFFAOYSA-N [C].[N] Chemical compound [C].[N] CKUAXEQHGKSLHN-UHFFFAOYSA-N 0.000 description 1
- 238000007171 acid catalysis Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 231100001224 moderate toxicity Toxicity 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 239000012434 nucleophilic reagent Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000006462 rearrangement reaction Methods 0.000 description 1
- 206010040872 skin infection Diseases 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- CRNIHJHMEQZAAS-UHFFFAOYSA-N tert-amyl chloride Chemical compound CCC(C)(C)Cl CRNIHJHMEQZAAS-UHFFFAOYSA-N 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 238000004065 wastewater treatment Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to the technical field of pharmaceutical preparations, and discloses a preparation method of amorolfine hydrochloride, which takes 3- (4-tert-amylphenyl) -2-methyl propanol as a raw material, reacts with methanesulfonyl chloride under alkaline conditions, then carries out nucleophilic substitution reaction with cis-2, 6-dimethylmorpholine, and finally forms hydrochloride from hydrogen chloride gas to obtain the product.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, and in particular relates to a preparation method of amorolfine hydrochloride.
Background
Amorolfine hydrochloride (amorolfine hydrochloride), chemical name 4- (3-p-tert-pentylphenyl-2-methylpropyl) -cis-2, 6-dimethylmorpholine hydrochloride, CAS registry number 78613-38-4, chemical structural formula as follows:
amorolfine hydrochloride is an antifungal drug, developed by Roche, registered in Europe in 3 months 2002 by Gaodemei, France under the trade name Loceryl, has an action mechanism of Squalene epoxide enzyme inhibitors-Squalene epoxidase inhibitor and a Squalene monooxygenase (SQLE) target point, and is suitable for skin infection and fungal infection. With regard to the synthesis process of amorolfine hydrochloride, the prior art has been described:
the synthetic route of the original patent EP1749826 amorolfine hydrochloride is as follows:
synthetic route of primary patent EP 1749826: (1) carrying out condensation reaction on 2-methyl-3-phenylallylaldehyde and cis-2, 6-dimethyl morpholine to obtain cis-4- (3-phenyl-2-methylpropyl) -2, 6-dimethyl morpholine hydrochloride, (2) carrying out acid catalysis on the cis-4- (3-phenyl-2-methylpropyl) -2, 6-dimethyl morpholine hydrochloride and 2-chloro-2-methylbutane to carry out Heck reaction to obtain amorolfine, and finally carrying out hydrochloride formation of hydrogen chloride gas to obtain the amorolfine hydrochloride. The palladium-carbon catalytic hydrogenation in the step (1) has higher cost; in addition, various rearrangement reactions are possible in the step (2), by-products are more, the product purification is difficult, the yield is low, ultralow temperature equipment is required, and the energy consumption is high.
International patent WO2007113218A1 improves the synthesis method of amorolfine hydrochloride, the first step of Heck reaction, under the condition of palladium catalysis and alkali, 4-iodo-tert-pentylbenzene reacts with 2-methylallyl alcohol to obtain 3-tert-pentylphenyl-2-methylpropionaldehyde; and a second step of reductive amination reaction, namely reacting the 3-tert-pentylphenyl-2-methylpropionaldehyde with cis-2, 6-dimethylmorpholine to obtain amorolfine, and finally reacting hydrogen chloride gas into hydrochloride to obtain the amorolfine hydrochloride. The synthetic route is as follows:
the improvement of WO2007113218A1 over the prior art is still insufficient: (1) the first step of Heck reaction, the reaction solvent DMF is of moderate toxicity, the wastewater treatment cost is high, and the high temperature decomposition is easy; (2) and the second step of reductive amination reaction has high palladium catalysis cost, and the metal borohydride generates a large amount of hydrogen, so that the safety risk is high.
Therefore, the method for preparing the amorolfine hydrochloride has the advantages of improving the process, reducing pollution, improving the yield and the product quality and being suitable for industrial production.
Disclosure of Invention
The purpose of the invention is as follows: aiming at the problems in the prior art, the invention provides the preparation method of the amorolfine hydrochloride, which has the advantages of reasonable process, small environmental pollution, low cost, high yield and high product quality and is suitable for industrial production.
The technical scheme is as follows: the invention provides a preparation method of amorolfine hydrochloride, which comprises the following steps: (a) adding 3- (4-tert-amylphenyl) -2-methylpropanol, organic base and solvent into a reactor, slowly dropwise adding methanesulfonyl chloride into the reactor at 0 ℃, stirring for 4-6h at 25 ℃ after dropwise adding is finished, and extracting and washing by using a reaction solvent to obtain a first intermediate; (b) sequentially adding the first intermediate, organic base, cis-2, 6-dimethyl morpholine and a solvent into a reactor, stirring for 6-8h at 25 ℃, and extracting by using a reaction solvent and washing by using a hydrochloric acid aqueous solution to obtain a second intermediate; (c) adding the second intermediate and isopropyl acetate into a reactor, introducing hydrogen chloride gas under stirring at 0 ℃, separating out a large amount of white solids, centrifuging to obtain white solids, crystallizing isopropanol, and decolorizing with activated carbon to obtain amorolfine hydrochloride shown in the formula I;
preferably, in step (a), the molar ratio of 3- (4-tert-pentylphenyl) -2-methylpropanol to methanesulfonyl chloride to organic base is 1.0 (1.2-2.0) to (1.5-3.0). Preferably 1.0:1.2:2.0, and the preferable ratio can effectively reduce the cost under the condition of ensuring the yield and the purity.
Preferably, in step (b), the molar ratio of the first intermediate cis-2, 6-dimethylmorpholine to the organic base is 1.0 (1.1-2.0) to 1.5-3.0. Preferably 1.0 (1.1-1.5) to (1.5-2.0), and the preferable proportion range can effectively reduce the cost under the condition of ensuring the yield and the purity.
Preferably, the organic base in step (a) and/or step (b) is triethylamine, pyridine or N, N-diisopropylethylamine; triethylamine is preferred.
Preferably, the equivalent weight of the organic base in step (a) is 1.5 to 2.0 equivalent weight of 3- (4-tert-amylphenyl) -2-methylpropanol.
Preferably, the solvent described in step (a) and/or step (b) is toluene, xylene, tetrahydrofuran, dichloromethane, etc.; toluene is preferred.
Preferably, the solvent amount of the solvent in the step (a) is 5 to 8 times that of 3- (4-tert-pentylphenyl) -2-methylpropanol.
Preferably, the equivalent of methanesulfonyl chloride in step (a) is 1.2 to 1.5 equivalents of 3- (4-tert-pentylphenyl) -2-methylpropanol.
The principle and the beneficial effects are as follows: the invention takes toluene as solvent, under alkaline condition, 3- (4-tert-amylphenyl) -2-methyl propanol shown in formula (II) and methanesulfonyl chloride are subjected to alkyl sulfonic acid esterification reaction, so as to obtain a first intermediate with pure quality and high yield, wherein the reaction equation is as follows:
then, in an organic solvent, under the alkaline condition, carrying out bimolecular nucleophilic substitution reaction on the first intermediate shown in the formula (III) and cis-2, 6-dimethylmorpholine to obtain a second intermediate shown in the formula (IV), wherein the reaction equation is as follows:
finally, salifying the second intermediate to convert the second intermediate into 4- (3-p-tert-pentylphenyl-2-methylpropyl) -cis-2, 6-dimethylmorpholine hydrochloride (amorolfine hydrochloride), wherein the reaction equation is as follows:
compared with the prior art, the invention has the following advantages:
the alkyl sulfonic acid esterification reaction is a reaction of generating alkyl sulfonate from alcoholic hydroxyl and alkyl sulfonyl chloride under an alkaline condition, wherein 3- (4-tert-amylphenyl) -2-methyl propanol is used as a starting material, is cheap and easy to obtain, and does not need to be replaced by other raw materials. The reaction solvent is toluene, so the method has low toxicity, can be recycled, has less environmental pollution and can effectively reduce the cost.
The bimolecular nucleophilic substitution reaction is a simple method for converting alkyl sulfonate into amine, and nucleophilic reagent amine attacks leaving group alkyl sulfonate, leaving group leaves, and then carbon nitrogen coupling reaction for substituting amine is generated. The method avoids the use of noble metal catalysts and ultralow temperature equipment, has few by-products, mild reaction conditions, easy control, high safety, convenient post-treatment, easy purification and high yield.
The whole technology of the invention has reasonable design, the product amorolfine hydrochloride is easy to purify, the total yield is high, and the invention is suitable for industrial production.
Detailed Description
The present invention will be described in detail with reference to specific examples.
The raw materials and reagents used in the present invention are all commercially available products.
Embodiment 1:
1. preparation of a first intermediate of formula iii:
10Kg of 3- (4-tert-amylphenyl) -2-methylpropanol shown as formula II, 9Kg of triethylamine, 80Kg of toluene, slowly dropwise adding 6Kg of methanesulfonyl chloride at 0 ℃, after the dropwise adding, heating to 25 ℃, stirring for 6h, after the reaction is completed, adding water, separating and collecting an organic phase, extracting an aqueous phase once by using 20Kg of toluene, combining the organic phase, drying by using anhydrous sodium sulfate, filtering, and concentrating a dry solvent to obtain 12Kg of a first intermediate product shown as formula III, wherein the yield is 88.6%.
2. Preparation of a second intermediate of formula IV:
taking 6.5Kg of a first intermediate shown as a formula III, 4.4Kg of triethylamine, 3Kg of cis-2, 6-dimethylmorpholine and 52Kg of toluene, stirring for 8 hours at 25 ℃, after the reaction is completed, adjusting the reaction pH to 3-4 with hydrochloric acid, separating out an organic phase, extracting an aqueous phase once with 13Kg of toluene, combining the organic phases, drying with anhydrous sodium sulfate, filtering, and concentrating a dry solvent to obtain 6Kg of a second intermediate, namely amorolfine oily substance shown as a formula IV, wherein the yield is 87.0%.
3. Preparation of amorolfine hydrochloride of formula I:
taking 5Kg of a second intermediate amorolfine shown as a formula IV and 25Kg of isopropyl acetate, introducing hydrogen chloride gas under stirring at 0 ℃ until the pH value of the reaction is 3-4, stopping introducing the hydrogen chloride gas, separating out a large amount of white solids, centrifuging, and drying under reduced pressure at 45 ℃ to obtain 5Kg of white solids, wherein the yield is 89.7%; heating and dissolving 5Kg of white solid and 25Kg of isopropanol, adsorbing by active carbon, filtering while hot, cooling and crystallizing, centrifuging, and drying under reduced pressure at 45 ℃ to obtain 4Kg of amorolfine hydrochloride product shown in formula I with the yield of 80.0%.
Embodiment 2:
1. preparation of a first intermediate of formula iii:
10Kg of 3- (4-tert-amylphenyl) -2-methylpropanol shown as formula II, 12Kg of N, N-diisopropylethylamine and 80Kg of toluene are slowly dripped with 7.8Kg of methanesulfonyl chloride at the temperature of 0 ℃, after the dripping is finished, the temperature is raised to 25 ℃, the mixture is stirred for 6 hours, after the reaction is completed, water is added, an organic phase is separated and collected, an aqueous phase is extracted once by 20Kg of toluene, the organic phase is combined, dried by anhydrous sodium sulfate, filtered, and a dry solvent is concentrated to obtain 11Kg of a first intermediate product shown as formula III, and the yield is 84.2%.
2. Preparation of a second intermediate of formula IV:
taking 6.5Kg of first intermediate shown in formula III, 5.6Kg of triethylamine, 2.8Kg of cis-2, 6-dimethylmorpholine and 52Kg of dichloromethane, stirring for 8h at 25 ℃, after the reaction is completed, adjusting the reaction pH to 3-4 with hydrochloric acid, separating out an organic phase, extracting an aqueous phase once with 13Kg of dichloromethane, combining the organic phases, drying with anhydrous sodium sulfate, filtering, and concentrating a dry solvent to obtain 5.8Kg of second intermediate amorolfine oily matter shown in formula IV, wherein the yield is 84.0%.
3. Preparation of amorolfine hydrochloride of formula I:
taking 5Kg of a second intermediate amorolfine shown as a formula IV and 25Kg of isopropyl acetate, introducing hydrogen chloride gas under stirring at 0 ℃ until the pH value of the reaction is 3-4, stopping introducing the hydrogen chloride gas, separating out a large amount of white solids, centrifuging, and drying under reduced pressure at 45 ℃ to obtain 4.8Kg of white solids, wherein the yield is 87.2%; 4.8Kg of white solid and 24Kg of isopropanol are heated and dissolved, then are adsorbed by active carbon, are filtered while hot, are cooled and crystallized, and are centrifuged and dried under reduced pressure at 45 ℃ to obtain 3.8Kg of amorolfine hydrochloride product shown in the formula I, and the yield is 79.2%.
Embodiment 3:
1. preparation of a first intermediate of formula iii:
10Kg of 3- (4-tert-amylphenyl) -2-methylpropanol shown as formula II, 14Kg of triethylamine, 80Kg of dichloromethane, slowly dropwise adding 10Kg of methanesulfonyl chloride at 0 ℃, after the dropwise adding, heating to 25 ℃, stirring for 6h, after the reaction is completed, adding water, separating and collecting an organic phase, extracting an aqueous phase once by using 20Kg of toluene, combining the organic phase, drying by using anhydrous sodium sulfate, filtering, and concentrating a dry solvent to obtain 10.8Kg of a first intermediate product shown as formula III, wherein the yield is 80.0%.
2. Preparation of a second intermediate of formula IV:
taking 6.5Kg of a first intermediate shown as a formula III, 8.4Kg of N, N-diisopropylethylamine, 3.8Kg of cis-2, 6-dimethylmorpholine and 52Kg of tetrahydrofuran, stirring for 8h at 25 ℃, after the reaction is completed, adjusting the reaction pH to 3-4 with hydrochloric acid, separating out an organic phase, extracting an aqueous phase once with 13Kg of dichloromethane, combining the organic phase, drying with anhydrous sodium sulfate, filtering, and concentrating a dry solvent to obtain 5.5Kg of a second intermediate amorolfine oily substance shown as a formula IV, wherein the yield is 80.2%.
3. Preparation of amorolfine hydrochloride of formula I:
taking 5Kg of a second intermediate amorolfine shown as a formula IV and 25Kg of isopropyl acetate, introducing hydrogen chloride gas under stirring at 0 ℃ until the pH value of the reaction is 3-4, stopping introducing the hydrogen chloride gas, separating out a large amount of white solids, centrifuging, and drying under reduced pressure at 45 ℃ to obtain 4.6Kg of white solids, wherein the yield is 83.6%; 4.6Kg of white solid and 23Kg of isopropanol are heated and dissolved, then are adsorbed by active carbon, are filtered while hot, are cooled and crystallized, and are centrifuged and dried under reduced pressure at 45 ℃ to obtain 3.6Kg of amorolfine hydrochloride product shown in the formula I, and the yield is 78.3%.
The above embodiments are merely illustrative of the technical concepts and features of the present invention, and the purpose of the embodiments is to enable those skilled in the art to understand the contents of the present invention and implement the present invention, and not to limit the protection scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.
Claims (9)
1. The preparation method of amorolfine hydrochloride is characterized by comprising the following steps:
(a) adding 3- (4-tert-amylphenyl) -2-methylpropanol, organic base and solvent into a reactor, slowly dropwise adding methanesulfonyl chloride into the reactor at 0 ℃, stirring for 4-6h at 25 ℃ after dropwise adding is finished, and extracting and washing by using a reaction solvent to obtain a first intermediate;
(b) sequentially adding the first intermediate, organic base, cis-2, 6-dimethyl morpholine and a solvent into a reactor, stirring for 6-8h at 25 ℃, and extracting by using a reaction solvent and washing by using a hydrochloric acid aqueous solution to obtain a second intermediate amorolfine;
(c) and salifying the second intermediate amorolfine into the amorolfine hydrochloride.
2. A process for the preparation of amorolfine hydrochloride according to claim 1 characterised in that: in the step (a), the molar ratio of the 3- (4-tert-amylphenyl) -2-methylpropanol to the methanesulfonyl chloride to the base is 1.0 (1.2-2.0) to 1.5-3.0.
3. A process for the preparation of amorolfine hydrochloride according to claim 1 characterised in that: in the step (b), the molar ratio of the first intermediate cis-2, 6-dimethylmorpholine to the base is 1.0 (1.1-2.0) to 1.5-3.0.
4. A process for the preparation of amorolfine hydrochloride according to claim 1 characterised in that: in step (c), the second intermediate is salified to amorolfine hydrochloride by:
adding the second intermediate and isopropyl acetate into a reactor, introducing hydrogen chloride gas under stirring at 0 ℃, separating out a large amount of white solids, centrifuging to obtain white solids, crystallizing by using isopropanol, and decoloring by using activated carbon to obtain the amorolfine hydrochloride shown in the formula I.
5. A process for the preparation of amorolfine hydrochloride according to any one of claims 1 to 4 characterised in that: the organic base in the step (a) and/or the step (b) is triethylamine, pyridine or N, N-diisopropylethylamine.
6. A process for the preparation of amorolfine hydrochloride according to claim 5 characterised in that: the equivalent of the organic base in the step (a) is 1.5-2.0 equivalent of 3- (4-tert-amylphenyl) -2-methyl propanol.
7. A process for the preparation of amorolfine hydrochloride according to any one of claims 1 to 4 characterised in that: the solvent in step (a) and/or step (b) is toluene, xylene, tetrahydrofuran, or dichloromethane.
8. A process for the preparation of amorolfine hydrochloride according to any one of claims 1 to 4 characterised in that: the solvent amount of the solvent in the step (a) is 5 to 8 times of that of the 3- (4-tert-amylphenyl) -2-methylpropanol.
9. A process for the preparation of amorolfine hydrochloride according to any one of claims 1 to 4 characterised in that: the equivalent of the methanesulfonyl chloride in the step (a) is 1.2-1.5 equivalent of 3- (4-tert-amylphenyl) -2-methylpropanol.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117209443A (en) * | 2023-07-31 | 2023-12-12 | 合肥远志医药科技开发有限公司 | Preparation method of 4-cyclododecyl-2, 6-dimethyl morpholine |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117209443A (en) * | 2023-07-31 | 2023-12-12 | 合肥远志医药科技开发有限公司 | Preparation method of 4-cyclododecyl-2, 6-dimethyl morpholine |
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Application publication date: 20200925 |