CN103601645B - The preparation method of 1-(phenethyl amino) propane-2-alcohol compound or its salt - Google Patents
The preparation method of 1-(phenethyl amino) propane-2-alcohol compound or its salt Download PDFInfo
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Abstract
The preparation method who the present invention relates to (phenethyl amino) propane-2-alcohol compound of the 1-shown in a kind of formula II or its salt, described preparation method comprises the following steps: make formula I compound and propylene oxide reaction production II compound. Preparation method of the present invention uses raw material cheap and easy to get, just obtains target compound by single step reaction, and cost is low, easy and simple to handle, yield is good, environmental friendliness, be applicable to suitability for industrialized production. The invention still further relates to the preparation method of chlorine Ka Selin or its salt, be highly purified 1-((4-chlorobenzene ethyl) amino) propane-2-alcohol of obtaining taking the present invention or its salt as raw material is prepared from, be conducive to improve quality and the stability of product.
Description
Technical field
The present invention relates to pharmaceutical chemistry synthesis technical field. In particular to a kind of 1-(phenethyl amino) propane-2-The preparation method of alcohol compound or its salt, also relates to 1-(phenethyl amino) propane-2-alcohol compound or its salt of gainedFor the preparation of the method for chlorine Ka Selin.
Background technology
Chlorine Ka Selin (Lorcaserin, trade name Belviq) is novel the subtracting of one that U.S. FDA is ratified over 13 years firstFertile medicine. On June 27th, 2012, FDA (Food and Drug Adminstration) (FDA) official approval the new slimming drugs salt of Arena drugmakerAcid chlorine Ka Selin listing. This medicine is got permission the fat or super severe one for the constitutional index of being grown up (BMI) >=27, and patient has at leastA disease relevant to body weight (as hypertension, diabetes B or hyperlipidemia). Its mechanism of action is exciting hypothalamus5-hydroxytryptamine receptor carrys out appetite control, and the activation of this acceptor can help patient to eat still less, and strengthens satiety. With current cityOther slimming drugs of selling are compared with Phentermine as fenfluramine, and the advantage of hydrochloric acid chlorine Ka Selin is that the target organ of its effect only limitsIn brain tissue, and unlike other two medicines, the 5-hydroxytryptamine receptor of whole body is all had to effect, therefore can not cause because swashingNear aroused in interest 5-hydroxytryptamine receptor dirty and cause the generation of heart valve disease.
Key intermediate 1-((4-chlorobenzene ethyl) amino) propane-2-alcohol of preparing chlorine Ka Selin is 1-(phenethyl amino)Propane-2-alcohol compound, its structural formula is as follows, and molecular weight is 213.70.
In patent documentation CN200780045133.9, disclose taking 1-amino-2-propyl alcohol and 4-Chlorophenylacetic acid as raw material, firstSynthesizing amide compound, then obtain 1-((4-chlorobenzene ethyl) amino) propane-2-alcohol (seeing following formula) through reducing agent reduction. The methodFor two-step reaction, during due to reduction, use borine or iodine, all belong to the chemicals that toxicity is larger, experimenter is had certainDangerous and to shortcomings such as environment may pollute.
Patent documentation WO2010148207 is so that chlorophenethylol is obtained to 1-((4-chlorobenzene second by two-step reaction as raw materialBase) amino) propane-2-alcohol (seeing following formula), gross production rate has 71.7%. But the commercial price of this technique initiation material to chlorophenethylolHigher, and second step reacts long-time high temperature, and energy consumption is higher.
Patent documentation WO2009111004A1 is also so that chlorophenethylol is obtained to 1-((4-chlorine by two-step reaction as raw materialPhenethyl) amino) propane-2-alcohol (seeing following formula), gross production rate has 67.2%. The business valency of this technique initiation material to chlorophenethylolLattice are higher, and HBr toxicity is larger, and experimenter is had certain danger and environment may be polluted.
Above-mentioned formerly document is not all reported the purity of gained 1-((4-chlorobenzene ethyl) amino) propane-2-alcohol or its salt.
Therefore, remain about the known preparation method of 1-(phenethyl amino) propane-2-alcohol compound or its saltCertain deficiency, develops its new preparation method and has important practical significance.
Summary of the invention
For the deficiencies in the prior art, the object of this invention is to provide a kind of 1-(phenethyl amino) propane-2-alcoholsThe new preparation method of compound or its salt, the method raw material is easy to get, reactions steps is few, easy and simple to handle, yield is good, environment is friendlyGood, applicable suitability for industrialized production.
The invention provides the preparation side of (phenethyl amino) propane-2-alcohol compound of 1-shown in a kind of formula II or its saltMethod, comprises the following steps: make formula I compound and propylene oxide reaction generate described formula II compound;
Wherein, R1Be selected from the C of H, straight or branched1～C4Alkyl, halogen, methoxyl group, nitro or-OH; R2Be selected from H, straight chainOr the C of side chain1～C4Alkyl, methoxyl group, benzyloxycarbonyl group, tertbutyloxycarbonyl, mesyl, p-toluenesulfonyl, benzyl or band are gotThe benzyl of Dai Ji, described substituting group is selected from the C of straight or branched1～C4The C of alkyl ,-OH, straight or branched1～C4Alkoxyl,Halogen, 4-nitro, 4-amino or 4-trifluoromethyl.
Described halogen is fluorine, chlorine, bromine or iodine.
Preferably, R1For halogen, R2For H.
More preferably, R1For chlorine and for contraposition (being 4-chlorine), R2For H.
Preferably, the mol ratio of described expoxy propane and described formula I compound is 1～10: 1; React solvent-free or useFollowing solvent: methyl alcohol, ethanol, propyl alcohol, isopropyl alcohol, n-butanol, the tert-butyl alcohol, isobutanol, oxolane, 2-methyltetrahydrofuran,Ethyl acetate, 1-METHYLPYRROLIDONE, acetone, butanone, pentanone, Isosorbide-5-Nitrae-dioxane, water, DMF, diformazanThe mixture of base sulfoxide or its arbitrary proportion; Reaction temperature is 5～189 DEG C; Reaction time is 2～18 hours.
More preferably, the mol ratio of described expoxy propane and described formula I compound is 1.5～2: 1; React solvent-free or makeUse following solvent: the mixture of methyl alcohol, ethanol, water, oxolane, Isosorbide-5-Nitrae-dioxane or its arbitrary proportion; Reaction temperature is30～90 DEG C; Reaction time is 6～16 hours.
The preparation of described formula II compound 1-(phenethyl amino) propane-2-alcohol compound provided by the invention or its saltMethod, further comprises the steps: to add recrystallization solvent in described formula II compound, adds hot reflux, and then cooling makesSeparate out solid and carry out formula II compound described in purifying. Preferably, described recrystallization solvent be selected from methyl alcohol, ethanol, propyl alcohol, isopropyl alcohol,Oxolane, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, carrene, acetone, benzinum, n-hexane, hexamethyleneThe mixture of alkane, normal heptane, toluene, dimethylbenzene, methyl tertiary butyl ether(MTBE) or its arbitrary proportion; Recrystallization temperature is 0～110 DEG C;The recrystallization time is 2～18 hours. More preferably, described recrystallization solvent is selected from benzinum, n-hexane, normal heptane, acetic acid secondThe mixture of ester or its arbitrary proportion; Recrystallization temperature is 40～100 DEG C; The recrystallization time is 1～2 hour; Temperature after coolingDegree, for-10～30 DEG C, is preferably room temperature. Can obtain thus the sterling of the formula II compound of HPLC purity > 95%.
The preparation of (phenethyl amino) propane-2-alcohol compound of the 1-shown in described formula II provided by the invention or its saltMethod, further comprises the steps: to make described formula II compound and acid to carry out the acid that salt-forming reaction obtains formula II compound and addsSalify; Wherein, described acid is selected from hydrochloric acid, hydrobromic acid, acetic acid, formic acid, trifluoroacetic acid, difluoroacetic acid, sulfuric acid, phosphoric acid, nitric acid, firstAlkyl sulfonic acid, oxalic acid, citric acid, malic acid or tartaric acid. Preferably, described acid is selected from hydrochloric acid, sulfuric acid, oxalic acid, citric acid or firstAlkyl sulfonic acid.
The mol ratio of described acid and formula II compound is 1～3: 1, be preferably 1～1.5: 1; Reaction dissolvent is selected from acetic acid secondEster, toluene, carrene, methyl tertiary butyl ether(MTBE), n-hexane, benzinum, heptane, ether, methyl alcohol, ethanol, propyl alcohol, isopropyl alcohol,N-butanol, the tert-butyl alcohol, isobutanol, oxolane, 2-methyltetrahydrofuran, 1-METHYLPYRROLIDONE, acetone, butanone, pentanone, 1,The mixture of 4-dioxane, water or its arbitrary proportion, is preferably ethyl acetate, methyl alcohol, carrene, toluene, water or itsThe mixture of meaning ratio; Reaction temperature is 0～90 DEG C, is preferably 0～50 DEG C; Reaction time is 0.5～12 hour, is preferably 1～4 hours.
In preparation method's the most preferred embodiment of the present invention, i.e. R1For 4-chlorine, R2During for H, relate to 1-((4-chlorobenzene secondBase) amino) preparation method of propane-2-alcohol or its hydrochloric acid, be specially: will be anti-to chlorobenzene ethamine (compound 1) and expoxy propaneShould generate that (1-((4-chlorobenzene ethyl) amino) propane-2-alcohol (compound 2), compound 2 obtains (1-((4-chlorine with hydrochloric acid salifyPhenethyl) amino) propane-2-alcohol hydrochloride (compound 3).
Further, the invention provides the 1-shown in the formula II being prepared from by said method (phenethyl amino) thirdAlkane-2-alcohol compound or its salt,
Wherein, R1And R2Definition with aforesaid identical. Most preferably, described formula II compound is 1-((4-chlorobenzene ethyl)Amino) propane-2-alcohol or its salt.
Further, the invention provides the preparation method of a kind of chlorine Ka Selin or its salt, it is to be prepared into said methodTo 1-(phenethyl amino) propane-2-alcohol compound or its salt be that raw material is prepared from, preferably with 1-((4-chlorobenzene secondBase) amino) propane-2-alcohol or its salt is that raw material is prepared from.
Below the synthetic route of chlorine Ka Selin hydrochloride semihydrate:
Compound 2 or 3 prepares chlorine Ka Selin by reactions such as chloro, F-C ring closure reaction, tartaric acid fractionation, salifiesHydrochloride semihydrate.
The invention provides the preparation method of 1-(phenethyl amino) propane-2-alcohol compound or its salt, use businessThe replacement being easy to get or unsubstituted phenyl ethylamine and expoxy propane are raw material, just can obtain 1-(phenethyl amino) by single step reactionPropane-2-alcohol compound, then get final product to obtain 1-(phenethyl amino) propane-2-alcohol compound by simple salt-forming reactionSalt, after salify, purity is higher, and the complete raw material of unreacted can be applied mechanically after simple recovery, and gross production rate is good, has simplified operating procedure,Reduced production cost, environmental friendliness, is applicable to suitability for industrialized production. In addition, 1-(the phenethyl ammonia that preparation method of the present invention obtainsBase) propane-2-alcohol compound or its salt has high-purity as the intermediate of preparing chlorine Ka Selin or its salt, is conducive to improveThe quality of product and stability.
Detailed description of the invention
To contribute to further to understand the present invention by following embodiment, but be not used in restriction content of the present invention.
The various reagent that use in embodiment are all that business is bought.
" room temperature " described in embodiment refers to 10 DEG C～30 DEG C.
Test analytical instrument in embodiment and condition:
AV-400 NMR (German Bruker company);
LC-20AT type high performance liquid chromatograph (Japanese Shimadzu company);
LCMS instrument is ThermoLcqFleet2 (power & light company of the U.S.).
HPLC test condition: chromatographic column PrevailTMC18,5 μ m, 4.6mm × 250mm; Detection time 15min; FlowPhase: acetonitrile: water (0.01% trifluoroacetic acid), gradient: time 0min acetonitrile 5%, time 15min acetonitrile 85%.
Chirality test condition: AgilentAD-H chiral column, flow velocity is 1ml/min, mobile phase is n-hexane: isopropyl alcohol: threeFluoroacetic acid: triethylamine=950: 50: 2: 1.
Embodiment 1
Method A
Compound 1 is dissolved in anhydrous to chlorobenzene ethamine (250.00g, 1.6mol) and expoxy propane (93.00g, 1.6mol)In ethanol (1605mL), be heated to back flow reaction 8～10h. After reaction finishes, removal of solvent under reduced pressure, obtains pale yellow oily liquid body.Add n-hexane (500mL) to above-mentioned grease, be warming up to backflow, insulation 1h. Be cooled to room temperature, have solid to separate out, suction filtration, filterCake washs with a small amount of n-hexane, collects filter cake. Dry. Obtain white solid compound 2 (1-((4-chlorobenzene ethyl) amino) thirdAlkane-2-alcohol), output 158.2g, HPLC=98.8%.1HNMR(400MHz，CDCl3，δ)：7.42(d，2H)，7.32(d，2H)，4.58(m，1H)，3.45(m，2H)，3.25(m，2H)，3.02(m，2H)，2.88(d，1H)，1.56(d，3H)。LCMS：213.8-215.8 (MH). HPLC retention time 7.8min. Filtrate is reclaimed, removal of solvent under reduced pressure, and decompression distillation, recovery obtains unreactedColourless liquid compound 1 is to chlorobenzene ethamine 94.6g, HPLC=97%. Disregard unreactedly to chlorobenzene ethamine, productive rate is 74%.
Compound 21-((4-chlorobenzene ethyl) amino) propane-2-alcohol (93.00g, 0.435mol) is dissolved in to ethyl acetate(437.6mL) in, ice bath stirs, and slowly passes into HCl gas to being acid, makes pH=1～2. Add rear stirring 2h, suction filtration, filter cakeWith a small amount of ethyl acetate washing, collect solid, dry. Obtain white solid compound 3 (1-((4-chlorobenzene ethyl) amino) thirdAlkane-2-alcohol hydrochloride), output 99.4g, productive rate is 91.3%, HPLC=99.5%.1HNMR(400MHz，DMSOd6，δ)：9.55(s，1H)，9.15(s，1H)，7.42(d，2H)，7.32(d，2H)，4.58(m，1H)，3.45(m，2H)，3.25(m，2H)，3.02 (m, 2H), 1.56 (d, 3H). LCMS:213.8-215.8 (MH). HPLC retention time 5.8min.
Method B
Compound 1 is dissolved in anhydrous to chlorobenzene ethamine (200.00g, 1.28mol) and expoxy propane (96.9g, 1.66mol)In ethanol (1284mL), be heated to 70 DEG C of reaction 8h. After reaction finishes, removal of solvent under reduced pressure, obtains pale yellow oily liquid body. UpwardsState grease and add normal heptane (400mL), be warming up to backflow, insulation 1h. Be cooled to room temperature, have solid to separate out, suction filtration, filter cake is usedA small amount of normal heptane washing, collects filter cake. Dry. Obtain white solid compound 2 (1-((4-chlorobenzene ethyl) amino) propane-2-Alcohol), output 115.7g, HPLC=98.4%.1HNMR(400MHz，CDCl3，δ)：7.42(d，2H)，7.32(d，2H)，4.58(m，1H)，3.45(m，2H)，3.25(m，2H)，3.02(m，2H)，2.88(d，1H)，1.56(d，3H)。LCMS：213.8-215.8 (MH). HPLC retention time 7.8min. Filtrate is reclaimed, removal of solvent under reduced pressure, and decompression distillation, recovery obtains unreactedColourless liquid compound 1 is to chlorobenzene ethamine 70.3g, HPLC=96.5%. Disregard unreactedly to chlorobenzene ethamine, productive rate is65％。
Compound 21-((4-chlorobenzene ethyl) amino) propane-2-alcohol (60.00g, 0.28mol) is dissolved in to ethyl acetate(282mL) in, ice bath stirs, and slowly drips concentrated hydrochloric acid (37%) to being acid, makes pH=1～2. Add rear stirring 1h, decompressionRemove organic solvent, residue suction filtration, collects filter cake, dry. Obtain white solid compound 3 (1-((4-chlorobenzene ethyl) ammoniaBase) propane-2-alcohol hydrochloride), output 59.7g, productive rate is 85%, HPLC=99.1%.1HNMR(400MHz，DMSOd6，δ)：9.55(s，1H)，9.15(s，1H)，7.42(d，2H)，7.32(d，2H)，4.58(m，1H)，3.45(m，2H)，3.25(m，2H), 3.02 (m, 2H), 1.56 (d, 3H). LCMS:213.8-215.8 (MH). HPLC retention time 5.8min.
Embodiment 2
Method A
Compound 1 is dissolved in chlorobenzene ethamine (150.00g, 0.963mol) and expoxy propane (55.90g, 0.963mol)In absolute methanol (1000mL), be heated to back flow reaction 10～12h. After reaction finishes, removal of solvent under reduced pressure, obtains faint yellow oilyLiquid. Add benzinum (300mL) to above-mentioned grease, be warming up to backflow, insulation 1h. Be cooled to room temperature, have solid to separate out, take outFilter, a small amount of petroleum ether of filter cake, collects filter cake. Dry. Obtain white solid compound 2 (1-((4-chlorobenzene ethyl) ammoniaBase) propane-2-alcohol), output 92.6g, HPLC=98.6%.1HNMR(400MHz，CDCl3，δ)：7.42(d，2H)，7.32(d，2H)，4.58(m，1H)，3.45(m，2H)，3.25(m，2H)，3.02(m，2H)，2.88(d，1H)，1.56(d，3H)。LCMS：213.8-215.8 (MH). HPLC retention time 7.8min. Filtrate is reclaimed, removal of solvent under reduced pressure, and decompression distillation, reclaims and obtains notThe colourless liquid compound 1 of reaction is to chlorobenzene ethamine 55g, HPLC=96.8%. Disregard unreactedly to chlorobenzene ethamine, productive rate is71％。
Compound 21-((4-chlorobenzene ethyl) amino) propane-2-alcohol (38.01g, 0.18mol) is dissolved in to methyl alcohol(200mL), be cooled to 0～5 DEG C, drip methyl alcohol (60mL) solution of oxalic acid (16.06g, 0.18mol), within 25～30 minutes, add,In dropping process, separate out white solid, add rear stirring at room temperature 1h. After removal of solvent under reduced pressure, add ethyl acetate (250mL), chamberTemperature stirs, suction filtration after 1h, and filter cake washs with a small amount of ethyl acetate, collects filter cake, dry, obtains white solid compound 4 (1-((4-chlorobenzene ethyl) amino) propane-2-alcohol oxalates), output 47.85g, productive rate 88.6%, HPLC=99.1%.1HNMR(400MHz，DMSOd6，δ)：10.65(s，1H)，9.55(s，1H)，9.15(s，1H)，7.42(d，2H)，7.32(d，2H)，4.58(m，1H)，3.45(m，2H)，3.25(m，2H)，3.02(m，2H)，1.56(d，3H)。LCMS：213.8-215.8(MH)。HPLC retention time 4.8min.
Method B
Compound 1 is dissolved in anhydrous to chlorobenzene ethamine (5.00g, 0.032mol) and expoxy propane (1.86g, 0.032mol)In methyl alcohol (20mL), be warming up to backflow, complete reaction not after 3h, adds expoxy propane (0.93g, 0.016mol) and continues reaction6h. After reaction finishes, removal of solvent under reduced pressure, obtains pale yellow oily liquid body. Add benzinum (10mL) to above-mentioned grease, heat upTo refluxing, insulation 1h. Be cooled to room temperature, have solid to separate out, suction filtration, a small amount of petroleum ether of filter cake, collects filter cake. Dry.Obtain white solid compound 2 (1-((4-chlorobenzene ethyl) amino) propane-2-alcohol), output 2.8g, HPLC=98.4%.1HNMR(400MHz，CDCl3，δ)：7.42(d，2H)，7.32(d，2H)，4.58(m，1H)，3.45(m，2H)，3.25(m，2H)，3.02 (m, 2H), 2.88 (d, 1H), 1.56 (d, 3H). LCMS:213.8-215.8 (MH). HPLC retention time 7.8min. FilterLiquid reclaims, removal of solvent under reduced pressure, and decompression distillation, reclaims and obtains unreacted colourless liquid compound 1 to chlorobenzene ethamine 1.75g,HPLC=96.5%. Disregard unreactedly to chlorobenzene ethamine, productive rate is 62.7%.
Compound 21-((4-chlorobenzene ethyl) amino) propane-2-alcohol (2.5g, 0.012mol) is dissolved in to methyl alcohol (10mL),Be cooled to 0～5 DEG C, drip water (5mL) solution of oxalic acid (1.05g, 0.012mol), in dropping process, separate out white solid, addComplete rear stirring at room temperature 1h. Organic solvent is removed in decompression, and suction filtration is collected filter cake, dry, obtains white solid compound 4 (1-((4-Chlorobenzene ethyl) amino) propane-2-alcohol oxalates), output 2.95g, productive rate 83%, HPLC=99%.1HNMR(400MHz，DMSOd6，δ)：10.65(s，1H)，9.55(s，1H)，9.15(s，1H)，7.42(d，2H)，7.32(d，2H)，4.58(m，1H), 3.45 (m, 2H), 3.25 (m, 2H), 3.02 (m, 2H), 1.56 (d, 3H). LCMS:213.8-215.8 (MH). HPLC retainsTime 4.5min.
Embodiment 3
Method A
By compound 1 to chlorobenzene ethamine (5.0g, 0.032mol), expoxy propane (2.05g, 0.035mol), water (60mL)Mix and be warming up to 80 DEG C of reaction 10h, then adding carrene (50mL) extraction, merging organic phase, revolving steaming, obtaining faint yellowGrease. Add n-hexane (10mL) to above-mentioned grease, be warming up to backflow, insulation 1h. Be cooled to room temperature, have solid to separate out,Suction filtration, filter cake washs with a small amount of n-hexane, collects filter cake. Dry. Obtain white solid compound 2 (1-((4-chlorobenzene ethyl) ammoniaBase) propane-2-alcohol), output 3.07g, HPLC=98.7%.1HNMR(400MHz，CDCl3，δ)：7.42(d，2H)，7.32(d，2H)，4.58(m，1H)，3.45(m，2H)，3.25(m，2H)，3.02(m，2H)，2.88(d，1H)，1.56(d，3H)。LCMS：213.8-215.8 (MH). HPLC retention time 7.8min. Filtrate is reclaimed, removal of solvent under reduced pressure, and decompression distillation, reclaims and obtains notThe colourless liquid compound 1 of reaction is to chlorobenzene ethamine (1.8g, HPLC=96.7%). Disregard unreacted to chlorobenzene ethamine, produceRate is 70%.
Be cooled to below 20 DEG C, by compound 21-((4-chlorobenzene ethyl) amino) propane-2-alcohol (1.0g,0.0047mol) be dissolved in methyl alcohol (7mL), drip pyrovinic acid (0.45g, 0.0047mol), after solvent vacuum rotary steam, add acetic acidEthyl ester (5mL), drips benzinum, and white solid is separated out, and suction filtration after 2 hours obtains white solid compound 5 (1-((4-chlorobenzeneEthyl) amino) propane-2-alcohol mesylate), output 1.27g, productive rate is 87.5%, HPLC=99.1%.1HNMR(400MHz，DMSOd6，δ)：9.55(s，1H)，9.15(s，1H)，7.42(d，2H)，7.32(d，2H)，4.58(m，1H)，3.45(m，2H)，3.25(m，2H)，3.23(s，3H)，3.02(m，2H)，1.56(d，3H)。LCMS：213.8-215.8(MH)。HPLC retention time 4.7min.
Method B
By compound 1 to chlorobenzene ethamine (10.0g, 0.064mol), expoxy propane (4.47,0.077mol), water (120mL)Mix and be warming up to 80 DEG C of reaction 6h, then adding carrene (100mL) extraction, merging organic phase, revolving steaming, obtaining faint yellowGrease. Add n-hexane (20mL) to above-mentioned grease, be warming up to backflow, insulation 1h. Be cooled to room temperature, have solid to separate out,Suction filtration, filter cake washs with a small amount of n-hexane, collects filter cake. Dry. Obtain white solid compound 2 (1-((4-chlorobenzene ethyl) ammoniaBase) propane-2-alcohol), output 5.2g, HPLC=98.5%.1HNMR(400MHz，CDCl3，δ)：7.42(d，2H)，7.32(d，2H)，4.58(m，1H)，3.45(m，2H)，3.25(m，2H)，3.02(m，2H)，2.88(d，1H)，1.56(d，3H)。LCMS：213.8-215.8 (MH). HPLC retention time 7.8min. Filtrate is reclaimed, removal of solvent under reduced pressure, and decompression distillation, reclaims and obtains notThe colourless liquid compound 1 of reaction is to chlorobenzene ethamine 3.5g, HPLC=97.1%. Disregard unreacted to chlorobenzene ethamine, productive rateBe 58.2%.
Be cooled to below 20 DEG C, by compound 21-((4-chlorobenzene ethyl) amino) propane-2-alcohol (2.0g, 0.0094mol)Be dissolved in methyl alcohol (15mL), drip water (4.5mL) solution of pyrovinic acid (0.9g, 0.0094mol), add rear stirring 1h. DecompressionRemove organic solvent, suction filtration, obtains white solid compound 5 (1-((4-chlorobenzene ethyl) amino) propane-2-alcohol mesylate),Output 2.4g, productive rate is 83.2%, HPLC=99%.1HNMR(400MHz，DMSOd6，δ)：9.55(s，1H)，9.15(s，1H)，7.42(d，2H)，7.32(d，2H)，4.58(m，1H)，3.45(m，2H)，3.25(m，2H)，3.23(s，3H)，3.02(m，2H), 1.56 (d, 3H). LCMS:213.8-215.8 (MH). HPLC retention time 4.7min.
Embodiment 4
By compound 1 to chlorobenzene ethamine (10.0g, 0.064mol), expoxy propane (3.73g, 0.064mol), THF(80mL) mix and be warming up to 65 DEG C reaction 11h. After reaction finishes, removal of solvent under reduced pressure, obtains pale yellow oily liquid body. To above-mentionedGrease adds ethyl acetate (3mL), and benzinum (15ml) is warming up to backflow, insulation 1h. Be cooled to room temperature, have solid to separate out,Suction filtration, a small amount of petroleum ether of filter cake, collects filter cake. Dry. Obtain white solid compound 2 (1-((4-chlorobenzene ethyl) ammoniaBase) propane-2-alcohol), output 4.5g, HPLC=98.2%.1HNMR(400MHz，CDCl3，δ)：7.42(d，2H)，7.32(d，2H)，4.58(m，1H)，3.45(m，2H)，3.25(m，2H)，3.02(m，2H)，2.88(d，1H)，1.56(d，3H)。LCMS：213.8-215.8 (MH). HPLC retention time 7.8min. Filtrate is reclaimed, removal of solvent under reduced pressure, and decompression distillation, reclaims and obtains notThe colourless liquid compound 1 of reaction is to chlorobenzene ethamine 3.7g, HPLC=97%. Disregard unreactedly to chlorobenzene ethamine, productive rate is52％。
Be cooled to 20 DEG C below by compound 21-((4-chlorobenzene ethyl) amino) propane-2-alcohol (2.0g, 0.0094mol)Be dissolved in methyl alcohol (15mL), drip sulfuric acid (0.9g, 0.0094mol), after solvent vacuum rotary steam, add ethyl acetate (10mL), dripBenzinum, white solid is separated out, suction filtration after 2 hours, obtain white solid compound 6 (1-((4-chlorobenzene ethyl) amino) propane-2-alcohol sulfate), output 2.24g, productive rate is 80%, HPLC=98.9%.1HNMR(400MHz，DMSOd6，δ)：9.55(s，1H)，9.15(s，1H)，7.42(d，2H)，7.32(d，2H)，4.58(m，1H)，3.45(m，2H)，3.25(m，2H)，3.02(m，2H), 1.56 (d, 3H). LCMS:213.8-215.8 (MH). HPLC retention time 4.9min.
Embodiment 5
By compound 1 to chlorobenzene ethamine (10.0g, 0.064mol), expoxy propane (3.73g, 0.064mol), Isosorbide-5-Nitrae-dioxySix ring (75mL) mix and be warming up to 85 DEG C reaction 10h. After reaction finishes, removal of solvent under reduced pressure, obtains pale yellow oily liquid body. ToAbove-mentioned grease adds benzinum (20ml) to be warming up to backflow, insulation 1h. Be cooled to room temperature, have solid to separate out, suction filtration, filter cake is usedA small amount of petroleum ether, collects filter cake. Dry. Obtain white solid compound 2 (1-((4-chlorobenzene ethyl) amino) propane-2-Alcohol), output 4.8g, HPLC=98.4%.1HNMR(400MHz，CDCl3，δ)：7.42(d，2H)，7.32(d，2H)，4.58(m，1H)，3.45(m，2H)，3.25(m，2H)，3.02(m，2H)，2.88(d，1H)，1.56(d，3H)。LCMS：213.8-215.8(MH). HPLC retention time 7.8min. Filtrate is reclaimed, removal of solvent under reduced pressure, and decompression distillation, reclaims and obtains unreacted colourless liquidBody compound 1 is to chlorobenzene ethamine 3.8g, HPLC=97.3%. Disregard unreactedly to chlorobenzene ethamine, productive rate is 56.3%.
Be cooled to below 20 DEG C, by compound 21-((4-chlorobenzene ethyl) amino) propane-2-alcohol (3.0g, 0.014mol)Be dissolved in methyl alcohol (15mL), citric acid (2.7g, 0.014mol), adularescent solid is separated out, and suction filtration after 2 hours, obtains white solidCompound 7 (1-((4-chlorobenzene ethyl) amino) propane-2-alcohol citrate), output 4.62g, productive rate is 81.2%, HPLC=99.1％。1HNMR(400MHz，DMSOd6，δ)：9.55(s，1H)，9.15(s，1H)，7.42(d，2H)，7.32(d，2H)，4.58(m，1H)，3.45(m，2H)，3.25(m，2H)，3.02(m，2H)，2.62(m，2H)，2.53(m，2H)，1.56(d，3H)。LCMS:213.8-215.8 (MH). HPLC retention time 5.7min.
Embodiment 6
Compound 1, to chlorobenzene ethamine (10.0g, 0.064mol), expoxy propane (3.73g, 0.064mol), is mixed and risenTemperature is to 33 DEG C of reaction 16h. After reaction finishes, in above-mentioned reactant liquor, add benzinum (20ml) to be warming up to backflow, insulation 1h. FallTemperature, to room temperature, has solid to separate out, suction filtration, and a small amount of petroleum ether of filter cake, collects filter cake. Dry. Obtain white solid chemical combinationThing 2 (1-((4-chlorobenzene ethyl) amino) propane-2-alcohol), output 4.1g, HPLC=98.6%.1HNMR(400MHz，CDCl3，δ)：7.42(d，2H)，7.32(d，2H)，4.58(m，1H)，3.45(m，2H)，3.25(m，2H)，3.02(m，2H)，2.88(d，1H), 1.56 (d, 3H). LCMS:213.8-215.8 (MH). HPLC retention time 7.8min. Filtrate is reclaimed, removal of solvent under reduced pressure,Decompression distillation, reclaims and obtains unreacted colourless liquid compound 1 to chlorobenzene ethamine 4.5g, HPLC=97.2%. Disregard not anti-Answer to chlorobenzene ethamine, productive rate is 54.3%.
Compound 2 (4.5g, 1.0eq), DMA (0.55g, 0.3eq) are added to toluene (21.5ml)In, change nitrogen, be warming up to 50-55 DEG C. Drip thionyl chloride (1.98ml, 1.5eq), within 5-10 minute, add, keep during this time temperatureAt 50-60 DEG C. After adding, be warming up to 60-65 DEG C, in process, carry out TLC monitoring, complete reaction after 3h. Be cooled to by 1 hour15 DEG C of left and right, toluene (15ml) adds, and stirs 30 minutes. Suction filtration, toluene for filter cake (10ml × 2) is washed, and collects filter cake, to filter cakeIn add in isopropyl alcohol (11.8ml) and water (1.2ml), be warming up to backflow, stir after 1 hour cooling, by about 2 hours, fallTo 15 DEG C, be incubated after 30 minutes, by within 30 minutes, being cooled to 0-5 DEG C, insulation 1h, suction filtration, a small amount of isopropyl alcohol wash filter cake for, collectionFilter cake, dry. Obtain white solid compound 4 (5.0g), productive rate is 88.3%.1HNMR(400MHz，DMSO，δ)：9.55(s，1H)，9.15(s，1H)，7.42(d，2H)，7.32(d，2H)，4.58(m，1H)，3.45(m，2H)，3.25(m，2H)，3.02(m，2H)，1.56(d，3H)。LCMS：232-234(MH)。
Compound 4 (5.0g, 1.0eq) and anhydrous Aluminum chloride (3.74g, 1.5eq) add in o-dichlorohenzene (14.4g), changeNitrogen, is warming up to 135-140 DEG C, carries out TLC monitoring in process, reaction 8-10h. After complete reaction, be cooled to 30-35 DEG C of left and right,Be added drop-wise in the suspension of water (8g) and silica gel (0.8g) formation, keep temperature to be less than 60 DEG C. Stir suction filtration after 15 minutes, filter cakeWash with 50-60 DEG C of water (15ml). Filtrate is cooled to 20-25 DEG C and stirs 30 minutes, and separatory is collected water. O-dichlorohenzene is used mutually againWater (15ml) extraction 2-3 time. Merge water, cyclohexane (20ml) adds, and separatory abandons cyclohexane phase. Water 30% hydrogen-oxygenChange sodium solution and regulate pH >=13, cyclohexane (20ml) extraction three times. Merge organic phase, water (15ml) is washed, saturated aqueous common salt(15ml) wash, be dried, removal of solvent under reduced pressure, obtains oily liquids compound 5 (3.50g), and productive rate is 96.1%, is directly used as downSingle step reaction.
To in compound 5 (3.50g, 1.0eq), add the tert-butyl alcohol (12.6g), room temperature (25 DEG C) is lower to be stirred. By L-TARTARIC ACIDAfter (0.55g, 0.22eq) water-soluble (0.8g), be added drop-wise in the t-butanol solution of compound 5, have immediately precipitation to generate, 10 pointsClock adds. After dropwising, at 20-25 DEG C, stir 16-18 hour. Suction filtration, filter cake is washed with a small amount of acetone, collects filter cake, obtainsWhite solid (1.9g, Ee=73.1%). Directly be used as next step.
Above-mentioned gained white solid (1.9g) is added in the tert-butyl alcohol (13.2g) and water (0.3g), is warming up to 76 DEG C of backflows,Drip water (1.2g) to clarification, insulation is lowered the temperature after 1h, within 2.5-3.5 hour, is down to 25 DEG C of room temperatures, stirs 16-18 at 20-25 DEG C littleTime, suction filtration, filter cake is washed with a small amount of acetone, collects filter cake, obtains white solid (1.41g, Ee=89.5%). Directly be used as nextStep.
Above-mentioned gained white solid is dissolved in the tert-butyl alcohol (13g), is warming up to 76 DEG C of backflows, drip water (1.67g) to clearClearly, insulation is lowered the temperature after 1h, within 2.5-3.5 hour, is down to 25 DEG C of room temperatures, stirs 16-18 hour at 20-25 DEG C, suction filtration, and filter cake is with fewAmount acetone is washed, and collects filter cake, obtains white solid compound 6 (1.2g, Ee=99.5%), productive rate 24.1%.
Compound 6 (1.2g, 1.0eq) is added to potash (0.99g, 3.2eq), water (10g) and ethyl acetate (10g)In, stirring after 0.5h, separatory, collects organic phase. Ethyl acetate for water (10ml) extracting twice. Merge organic phase, organic phaseWater (10ml) is washed, and saturated aqueous common salt (10ml) is washed, and dry, removal of solvent under reduced pressure, obtains thick liquid (0.83g), is dissolved in secondIn acetoacetic ester (8g) and water (0.05g), be cooled to 0～5 DEG C, drip ethyl acetate (HCl gas) to reactant liquor and be acid pH=1-2. Adularescent Precipitation in dropping process, after adding, 0～5 DEG C is stirred 1.5h, suction filtration, filter cake is washed with a small amount of ethyl acetate, receivesCollection filter cake, dry (at 35 DEG C), obtain compound 7 (0.8g), productive rate 78%.1HNMR(400MHz，DMSO)δ9.68(s，2H)，7.24(s，3H)，3.58-3.44(m，1H)，3.32-3.16(m，3H)，3.03(dd，1H)，2.88(dd，2H)，1.36(d，3H)。LCMS：196-197(MH)。
Embodiment 7
Compound 3 (110.30g, 1.0eq), DMA (11.52g, 0.3eq) add toluene (450ml)In, change nitrogen, be warming up to 50-55 DEG C. Drip thionyl chloride (41.5ml, 1.5eq), within 15-20 minute, add, keep during this time temperatureAt 50-60 DEG C. After adding, be warming up to 60-65 DEG C, in process, carry out TLC monitoring, complete reaction after 3h. Be cooled to by 1 hour15 DEG C of left and right, toluene (300ml) adds, and stirs 30 minutes. Suction filtration, toluene for filter cake (200ml × 2) is washed, and collects filter cake (yellowish-whiteLook solid), in filter cake, add in isopropyl alcohol (246ml) and water (24.6ml), be warming up to backflow, stir cooling after 1 hour, logicalCross about 2 hours and be down to 15 DEG C, be incubated after 30 minutes, by within 30 minutes, being cooled to 0-5 DEG C, insulation 1h, suction filtration, filter cake is with a small amount ofIsopropyl alcohol wash, collects filter cake, dry. Obtain white solid compound 4 (101.45g), productive rate is 85.66%.1HNMR(400MHz，DMSO，δ)：9.55(s，1H)，9.15(s，1H)，7.42(d，2H)，7.32(d，2H)，4.58(m，1H)，3.45(m，2H)，3.25(m，2H)，3.02(m，2H)，1.56(d，3H)。LCMS：232-234(MH)。
Compound 4 (101.45g, 1.0eq) and anhydrous Aluminum chloride (75.83g, 1.5eq) are added to o-dichlorohenzene (292g)In, change nitrogen, be warming up to 135-140 DEG C. In process, carry out TLC monitoring, reaction 8-10h. After complete reaction, be cooled to 30-35 DEG CLeft and right, is added drop-wise in the suspension of water (163g) and silica gel (16.3g) formation, keeps temperature to be less than 60 DEG C. Stir after 15 minutesSuction filtration, filter cake is washed with 50-60 DEG C of water (82ml). Filtrate is cooled to 20-25 DEG C and stirs 30 minutes, and separatory is collected water. Adjacent dichloroBenzene phase again water (100ml) extracts 2-3 time. Merge water, cyclohexane (80ml) adds, and separatory abandons cyclohexane phase. Water is used30% sodium hydroxide solution regulates pH >=13, cyclohexane (240ml) extraction three times. Merge organic phase, water (100ml) is washed, is satisfiedWith saline solution (100ml) washes, dry, removal of solvent under reduced pressure, obtains oily liquids compound 5 (73.90g), and productive rate is 100%(having dissolvent residual). Directly as next step reaction.
Upwards walk in the compound 5 of gained and add the tert-butyl alcohol (266.33g), stir at 27 DEG C. By L-TARTARIC ACIDAfter (11.56g, 0.22eq) water-soluble (16.71g), be added drop-wise in the t-butanol solution of compound 4, have immediately precipitation to generate, 15Minute add. After dropwising, at 20-25 DEG C, stir 16-18 hour. Suction filtration, filter cake is washed with a small amount of acetone, collects filter cake,Obtain white solid (38.16g, Ee=72.7%). Directly be used as next step.
Above-mentioned gained white solid (38.16g) is added in the tert-butyl alcohol (265.40g) and water (5.63g), be warming up to 76 DEG CReflux, drip water (24.90g) to clarification, insulation is lowered the temperature after 1h, within 2.5-3.5 hour, is down to 25 DEG C of room temperatures, stirs at 20-25 DEG C16-18 hour, suction filtration, filter cake is washed with a small amount of acetone, collects filter cake, obtains white solid (27.83g, Ee=89.2%). DirectlyBe used as next step.
Above-mentioned gained white solid is dissolved in the tert-butyl alcohol (264g), is warming up to 76 DEG C of backflows, drip water (33.26g) extremelyClarification, insulation is lowered the temperature after 1h, within 2.5-3.5 hour, is down to 25 DEG C of room temperatures, stirs 16-18 hour at 20-25 DEG C, suction filtration, filter cake is usedA small amount of acetone is washed, and collects filter cake, obtains white solid compound 6 (25.95g, Ee=99.6%), productive rate 25%.
Compound 6 (22.36g, 1.0eq) is added to potash (18.44g, 3.2eq), water (62.8g) and ethyl acetate(62.8g) in, stir after 0.5h, separatory, collects organic phase. Ethyl acetate for water (60ml) extracting twice. Merge organic phase,Organic phase water (40ml) is washed, and saturated aqueous common salt (40ml) is washed, and dry, removal of solvent under reduced pressure, obtains thick liquid (15.50g),Be dissolved in ethyl acetate (85.04g) and water (0.97g), be cooled to 0～5 DEG C, drip ethyl acetate (HCl gas) to reactant liquor and beAcid pH=1-2. Adularescent Precipitation in dropping process, after adding, 0～5 DEG C is stirred 1.5h, suction filtration, a small amount of acetic acid of filter cakeEthyl ester is washed, and collects filter cake, and dry (at 35 DEG C), obtain compound 7 (14.9g), productive rate 80.2%.1HNMR(400MHz，DMSO)δ9.68(s，2H)，7.24(s，3H)，3.58-3.44(m，1H)，3.32-3.16(m，3H)，3.03(dd，1H)，2.88(dd，2H)，1.36(d，3H)。LCMS：196-197(MH)。
It will be understood by those skilled in the art that under the instruction of this description, can make some amendments to the present inventionOr change. These modifications and variations also should be within the scope of the claims in the present invention.
Claims (5)
1. a preparation method for (phenethyl amino) propane-2-alcohol compound of the 1-shown in formula II or its salt, its feature existsIn, described preparation method comprises the following steps:
(1)
Make described formula I compound and propylene oxide reaction generate described formula II compound; Wherein R1For chlorine and for contraposition, R2For H;The mol ratio of wherein said expoxy propane and described formula I compound is 1.5～2: 1; Reaction is used following solvent: methyl alcohol, ethanolOr water; Reaction temperature is 30～90 DEG C; Reaction time is 6～16 hours;
(2) in the formula II compound obtaining, add recrystallization solvent, add hot reflux, then cooling makes to separate out solid, obtainsDescribed formula II compound after purifying; Wherein said recrystallization solvent is selected from benzinum or n-hexane; Recrystallization temperature is 40～100 DEG C; The recrystallization time is 1～2 hour.
2. preparation method according to claim 1, is characterized in that, described method further comprises the steps: to make formulaThe salt of formula II compound is carried out salt-forming reaction and obtains in II compound and acid; Wherein said acid is selected from hydrochloric acid, hydrobromic acid, acetic acid, firstAcid, trifluoroacetic acid, difluoroacetic acid, sulfuric acid, phosphoric acid, nitric acid, Loprazolam, oxalic acid, citric acid, malic acid or tartaric acid.
3. preparation method according to claim 2, is characterized in that, described acid is selected from hydrochloric acid, sulfuric acid, oxalic acid, citric acidOr Loprazolam.
4. preparation method according to claim 2, is characterized in that, the mol ratio of wherein said acid and formula II compound is1～3: 1; Reaction dissolvent is selected from ethyl acetate, toluene, carrene, methyl tertiary butyl ether(MTBE), n-hexane, benzinum, heptane, secondEther, methyl alcohol, ethanol, propyl alcohol, isopropyl alcohol, n-butanol, the tert-butyl alcohol, isobutanol, oxolane, 2-methyltetrahydrofuran, N-methylThe mixture of pyrrolidones, acetone, butanone, pentanone, Isosorbide-5-Nitrae-dioxane, water or its arbitrary proportion; Reaction temperature is 0～90DEG C; Reaction time is 0.5～12 hour.
5. preparation method according to claim 4, is characterized in that, the mol ratio of wherein said acid and formula II compound is1～1.5: 1; Reaction dissolvent is selected from the mixture of ethyl acetate, methyl alcohol, carrene, toluene, water or its arbitrary proportion; ReactionTemperature is 0～50 DEG C; Reaction time is 1～4 hour.
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Effective date of registration: 20201214 Address after: Room 213, building 3, No. 618, west section of Shifu Avenue, Jiaojiang District, Taizhou City, Zhejiang Province Patentee after: Seasons Biotechnology (Taizhou) Co.,Ltd. Patentee after: HANGZHOU LEDUN TECHNOLOGY Co.,Ltd. Address before: Room 329, No.1, Lane 2351, Wangyuan Road, Fengxian District, Shanghai, 201499 Patentee before: Shanghai Shiji Biological Technology Co.,Ltd. Patentee before: HANGZHOU LEDUN TECHNOLOGY Co.,Ltd. |
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Addressee: Patent director of Shanghai Shiji Biotechnology Co.,Ltd. Document name: Notification of eligibility |
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Effective date of registration: 20210810 Address after: 310020 room 16-1004, Hexiang science and technology center, Qiantang new area, Hangzhou, Zhejiang Patentee after: HANGZHOU LEDUN TECHNOLOGY Co.,Ltd. Address before: Room 213, building 3, No. 618, west section of Shifu Avenue, Jiaojiang District, Taizhou City, Zhejiang Province Patentee before: Seasons Biotechnology (Taizhou) Co.,Ltd. Patentee before: HANGZHOU LEDUN TECHNOLOGY Co.,Ltd. |