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CN103601645A - Preparation method of 1-(phenethylamino) propane-2-alcoholic compounds or salts thereof - Google Patents

Preparation method of 1-(phenethylamino) propane-2-alcoholic compounds or salts thereof Download PDF

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CN103601645A
CN103601645A CN201310551829.6A CN201310551829A CN103601645A CN 103601645 A CN103601645 A CN 103601645A CN 201310551829 A CN201310551829 A CN 201310551829A CN 103601645 A CN103601645 A CN 103601645A
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CN103601645B (en
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何爱民
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Hangzhou Ledun Technology Co ltd
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HANGZHOU LEDUN TECHNOLOGY Co Ltd
SHANGHAI SHIJI BIOLOGICAL TECHNOLOGY Co Ltd
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Abstract

本发明涉及一种式II所示的1-(苯乙基氨基)丙烷-2-醇类化合物或其盐的制备方法，所述制备方法包括以下步骤：使式I化合物与环氧丙烷反应生成式II化合物。本发明制备方法使用价廉易得的原料，通过一步反应就得到目标化合物，成本低、操作简便、收率良好、环境友好、适合工业化生产。本发明还涉及氯卡色林或其盐的制备方法，是以本发明得到的高纯度的1-((4-氯苯乙基)氨基)丙烷-2-醇或其盐为原料制备而成，有利于提高产物的质量和稳定性。The present invention relates to a preparation method of 1-(phenethylamino)propane-2-alcohol compound represented by formula II or a salt thereof, the preparation method comprising the following steps: reacting the compound of formula I with propylene oxide to form Compound of formula II. The preparation method of the invention uses cheap and easy-to-obtain raw materials, obtains the target compound through one-step reaction, has low cost, is simple and convenient to operate, has good yield, is environmentally friendly, and is suitable for industrialized production. The present invention also relates to a preparation method of lorcaserin or its salt, which is prepared from the high-purity 1-((4-chlorophenethyl)amino)propan-2-ol or its salt obtained in the present invention , which is conducive to improving the quality and stability of the product.

Description

The preparation method of 1-(styroyl is amino) propane-2-alcohol compound or its salt
Technical field
The present invention relates to pharmaceutical chemistry synthesis technical field.In particular to the preparation method of a kind of 1-(styroyl amino) propane-2-alcohol compound or its salt, also relate to 1-(styroyl is amino) propane-2-alcohol compound of gained or its salt for the preparation of the method for chlorine Ka Selin.
Background technology
Chlorine Ka Selin (Lorcaserin, trade(brand)name Belviq) is a kind of novel diet pill that U.S. FDA is ratified over 13 years first.In June, 2012 27， FDA (Food and Drug Adminstration) (FDA) official approval the new diet pill hydrochloric acid chlorine Ka Selin listing of Arena drugmaker.This medicine is got permission the fat or super severe one for the constitutional index of being grown up (BMI) >=27, and patient has a disease relevant to body weight (as hypertension, diabetes B or hyperlipidaemia) at least.Its mechanism of action is that the 5-hydroxytryptamine receptor of exciting hypothalamus carrys out appetite control, and the activation of this acceptor can help patient to eat still less, and strengthens satiety.Compare with phentermine as Phenfluoramine with at present commercially available other diet pill, the advantage of hydrochloric acid chlorine Ka Selin is that the target organ of its effect is only limited to cerebral tissue, and unlike other two medicines, the 5-hydroxytryptamine receptor of whole body is all had to effect, therefore can not cause causing because of near the 5-hydroxytryptamine receptor exciting heart the generation of lular heart disease.
Key intermediate 1-((4-chlorobenzene ethyl) amino) propane-2-alcohol of preparing chlorine Ka Selin is 1-(styroyl is amino) propane-2-alcohol compound, and its structural formula is as follows, and molecular weight is 213.70.
Figure BSA0000097327130000011
In patent documentation CN200780045133.9, disclose that to take 1-amino-2-propyl alcohol and 4-Chlorophenylacetic acid be raw material, first synthesizing amide compound, then obtain 1-((4-chlorobenzene ethyl) amino) propane-2-alcohol (seeing following formula) through reductive agent reduction.The method is two-step reaction, because reduction time is used borine or iodine, all belongs to the chemical that toxicity is larger, experimenter is had certain dangerous and to shortcomings such as environment may pollute.
Figure BSA0000097327130000021
Patent documentation WO2010148207 take chlorophenethylol by two-step reaction, obtain 1-((4-chlorobenzene ethyl) amino) propane-2-alcohol (seeing following formula) as raw material, and overall yield has 71.7%.But this technique starting raw material is higher to the commercial price of chlorophenethylol, and second step reacts long-time high temperature, and energy consumption is higher.
Figure BSA0000097327130000022
Patent documentation WO2009111004A1 take chlorophenethylol by two-step reaction, obtain 1-((4-chlorobenzene ethyl) amino) propane-2-alcohol (seeing following formula) as raw material, and overall yield has 67.2%.This technique starting raw material is higher to the commercial price of chlorophenethylol, and HBr toxicity is larger, and experimenter is had certain danger and environment may be polluted.
Figure BSA0000097327130000023
Above-mentioned formerly document is not all reported the purity of gained 1-((4-chlorobenzene ethyl) amino) propane-2-alcohol or its salt.
Therefore, about the known preparation method of 1-(styroyl amino) propane-2-alcohol compound or its salt, remain in certain deficiency, develop its new preparation method and have important practical significance.
Summary of the invention
For the deficiencies in the prior art, the new preparation method who the object of this invention is to provide a kind of 1-(styroyl amino) propane-2-alcohol compound or its salt, the method raw material is easy to get, reactions steps is few, easy and simple to handle, yield good, environmental friendliness, be applicable to suitability for industrialized production.
The preparation method who the invention provides (styroyl the is amino) propane-2-alcohol compound of 1-shown in a kind of formula II or its salt, comprises the following steps: make formula I compound and propylene oxide reaction generate described formula II compound;
Wherein, R 1be selected from the C of H, straight or branched 1～C 4alkyl, halogen, methoxyl group, nitro or-OH; R 2be selected from the C of H, straight or branched 1～C 4alkyl, methoxyl group, carbobenzoxy-(Cbz), tertbutyloxycarbonyl, methylsulfonyl, p-toluenesulfonyl, benzyl or be with substituent benzyl, described substituting group is selected from the C of straight or branched 1～C 4the C of alkyl ,-OH, straight or branched 1～C 4alkoxyl group, halogen, 4-nitro, 4-amino or 4-trifluoromethyl.
Described halogen is fluorine, chlorine, bromine or iodine.
Preferably, R 1for halogen, R 2for H.
More preferably, R 1for chlorine and for contraposition (being 4-chlorine), R 2for H.
Preferably, the mol ratio of described propylene oxide and described formula I compound is 1～10: 1; React solvent-free or use following solvent: methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol, the trimethyl carbinol, isopropylcarbinol, tetrahydrofuran (THF), 2-methyltetrahydrofuran, ethyl acetate, N-Methyl pyrrolidone, acetone, butanone, pentanone, 1, the mixture of 4-dioxane, water, DMF, dimethyl sulfoxide (DMSO) or its arbitrary proportion; Temperature of reaction is 5～189 ℃; Reaction times is 2～18 hours.
More preferably, the mol ratio of described propylene oxide and described formula I compound is 1.5～2: 1; React solvent-free or use following solvent: the mixture of methyl alcohol, ethanol, water, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane or its arbitrary proportion; Temperature of reaction is 30～90 ℃; Reaction times is 6～16 hours.
The preparation method of described formula II compound 1-provided by the invention (styroyl is amino) propane-2-alcohol compound or its salt, further comprise the steps: to add recrystallization solvent in described formula II compound, reflux, then cooling makes to separate out solid and carrys out formula II compound described in purifying.Preferably, described recrystallization solvent is selected from the mixture of methyl alcohol, ethanol, propyl alcohol, Virahol, tetrahydrofuran (THF), 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, methylene dichloride, acetone, sherwood oil, normal hexane, hexanaphthene, normal heptane, toluene, dimethylbenzene, methyl tertiary butyl ether or its arbitrary proportion; Recrystallization temperature is 0～110 ℃; The recrystallization time is 2～18 hours.More preferably, described recrystallization solvent is selected from the mixture of sherwood oil, normal hexane, normal heptane, ethyl acetate or its arbitrary proportion; Recrystallization temperature is 40～100 ℃; The recrystallization time is 1～2 hour; Temperature after cooling is-10～30 ℃, is preferably room temperature.Can obtain thus the sterling of the formula II compound of HPLC purity > 95%.
The preparation method of (styroyl the is amino) propane-2-alcohol compound of the 1-shown in described formula II provided by the invention or its salt, further comprises the steps: to make described formula II compound and acid to carry out the acid salt that salt-forming reaction obtains formula II compound; Wherein, described acid is selected from hydrochloric acid, Hydrogen bromide, acetic acid, formic acid, trifluoroacetic acid, difluoroacetic acid, sulfuric acid, phosphoric acid, nitric acid, methanesulfonic, oxalic acid, citric acid, oxysuccinic acid or tartrate.Preferably, described acid is selected from hydrochloric acid, sulfuric acid, oxalic acid, citric acid or methanesulfonic.
The mol ratio of described acid and formula II compound is 1～3: 1, be preferably 1～1.5: 1; Reaction solvent is selected from ethyl acetate, toluene, methylene dichloride, methyl tertiary butyl ether, normal hexane, sherwood oil, heptane, ether, methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol, the trimethyl carbinol, isopropylcarbinol, tetrahydrofuran (THF), 2-methyltetrahydrofuran, N-Methyl pyrrolidone, acetone, butanone, pentanone, 1, the mixture of 4-dioxane, water or its arbitrary proportion, is preferably the mixture of ethyl acetate, methyl alcohol, methylene dichloride, toluene, water or its arbitrary proportion; Temperature of reaction is 0～90 ℃, is preferably 0～50 ℃; Reaction times is 0.5～12 hour, is preferably 1～4 hour.
In preparation method's the most preferred embodiment of the present invention, i.e. R 1for 4-chlorine, R 2the preparation method who relates to 1-((4-chlorobenzene ethyl) amino) propane-2-alcohol or its hydrochloric acid during for H, be specially: will generate to chlorobenzene ethamine (compound 1) and propylene oxide reaction that (1-((4-chlorobenzene ethyl) amino) propane-2-alcohol (compound 2), compound 2 obtains (1-((4-chlorobenzene ethyl) amino) propane-2-alcohol hydrochloride (compound 3) with hydrochloric acid salify.
Figure BSA0000097327130000041
Further, the invention provides the 1-shown in the formula II being prepared from by aforesaid method (styroyl is amino) propane-2-alcohol compound or its salt,
Figure BSA0000097327130000042
Wherein, R 1and R 2definition 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 take the 1-that aforesaid method prepares (styroyl is amino) propane-2-alcohol compound or its salt to be prepared from as raw material, preferably take 1-((4-chlorobenzene ethyl) amino) propane-2-alcohol or its salt to be prepared from as raw material.
Below the synthetic route of chlorine Ka Selin hydrochloride semihydrate:
Figure BSA0000097327130000051
Compound 2 or 3 prepares chlorine Ka Selin hydrochloride semihydrate by reactions such as chloro, F-C ring closure reaction, tartrate fractionation, salifies.
The invention provides the preparation method of 1-(styroyl is amino) propane-2-alcohol compound or its salt, the replacement that use business is easy to get or unsubstituted phenylethylamine and propylene oxide are raw material, by single step reaction, just can obtain 1-(styroyl is amino) propane-2-alcohol compound, by simple salt-forming reaction, get final product to obtain the salt of 1-(styroyl amino) propane-2-alcohol compound again, after salify, purity is higher, the complete raw material of unreacted can be applied mechanically after simple recovery, overall yield is good, simplified operation steps, reduced production cost, environmental friendliness, is applicable to suitability for industrialized production.In addition, the 1-that preparation method of the present invention obtains (styroyl is amino) propane-2-alcohol compound or its salt have high purity as the intermediate of preparing chlorine Ka Selin or its salt, are conducive to improve quality and the stability of product.
Embodiment
By following embodiment, will contribute to further to understand the present invention, but be not used in restriction content of the present invention.
The all ingredients using in embodiment is all that business is bought.
" room temperature " described in embodiment refers to 10 ℃～30 ℃.
Test analytical instrument in embodiment and condition:
AV-400 nuclear magnetic resonance analyser (German Bruker company);
LC-20AT type high performance liquid chromatograph (Japanese Shimadzu company);
LCMS instrument is Thermo Lcq Fleet2 (U.S. power & light company).
HPLC test condition: chromatographic column Prevail tMc18,5 μ m, 4.6mm * 250mm; Detection time 15min; Moving phase: 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, moving phase is normal hexane: Virahol: trifluoroacetic acid: triethylamine=950: 50: 2: 1.
embodiment 1
Figure BSA0000097327130000061
method A
1 pair of chlorobenzene ethamine of compound (250.00g, 1.6mol) and propylene oxide (93.00g, 1.6mol) are dissolved in dehydrated alcohol (1605mL), are heated to back flow reaction 8～10h.After reaction finishes, removal of solvent under reduced pressure, obtains pale yellow oily liquid body.To above-mentioned oily matter, add normal hexane (500mL), 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 normal hexane, collects filter cake.Dry.Obtain white solid compound 2 (1-((4-chlorobenzene ethyl) amino) propane-2-alcohol), output 158.2g, HPLC=98.8%. 1H?NMR(400MHz，CDCl 3，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 underpressure distillation, reclaims and obtains 1 couple of chlorobenzene ethamine 94.6g of unreacted colourless liquid compound, 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 ethyl acetate (437.6mL), and ice bath stirs, and slowly passes into HCl gas to being acid, makes pH=1～2.Add rear stirring 2h, suction filtration, filter cake washs by a small amount of ethyl acetate, collects solid, dry.Obtain white solid compound 3 (1-((4-chlorobenzene ethyl) amino) propane-2-alcohol hydrochloride), output 99.4g, productive rate is 91.3%, HPLC=99.5%. 1H?NMR(400MHz，DMSO?d 6，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
1 pair of chlorobenzene ethamine of compound (200.00g, 1.28mol) and propylene oxide (96.9g, 1.66mol) are dissolved in dehydrated alcohol (1284mL), are heated to 70 ℃ of reaction 8h.After reaction finishes, removal of solvent under reduced pressure, obtains pale yellow oily liquid body.To above-mentioned oily matter, 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 washs with a small amount of normal heptane, collects filter cake.Dry.Obtain white solid compound 2 (1-((4-chlorobenzene ethyl) amino) propane-2-alcohol), output 115.7g, HPLC=98.4%. 1H?NMR(400MHz，CDCl 3，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 underpressure distillation, reclaims and obtains 1 couple of chlorobenzene ethamine 70.3g of unreacted colourless liquid compound, HPLC=96.5%.Disregard unreactedly to chlorobenzene ethamine, productive rate is 65%.
Compound 21-((4-chlorobenzene ethyl) amino) propane-2-alcohol (60.00g, 0.28mol) is dissolved in ethyl acetate (282mL), and ice bath stirs, and slowly drips concentrated hydrochloric acid (37%) to being acid, makes pH=1～2.Add rear stirring 1h, organic solvent is removed in decompression, and residuum suction filtration is collected filter cake, dry.Obtain white solid compound 3 (1-((4-chlorobenzene ethyl) amino) propane-2-alcohol hydrochloride), output 59.7g, productive rate is 85%, HPLC=99.1%. 1H?NMR(400MHz，DMSO?d 6，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
Figure BSA0000097327130000071
method A
1 pair of chlorobenzene ethamine of compound (150.00g, 0.963mol) and propylene oxide (55.90g, 0.963mol) are dissolved in anhydrous methanol (1000mL), are heated to back flow reaction 10～12h.After reaction finishes, removal of solvent under reduced pressure, obtains pale yellow oily liquid body.To above-mentioned oily matter, add sherwood oil (300mL), be 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) amino) propane-2-alcohol), output 92.6g, HPLC=98.6%. 1H?NMR(400MHz，CDCl 3，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 underpressure distillation, reclaims and obtains 1 couple of chlorobenzene ethamine 55g of unreacted colourless liquid compound, HPLC=96.8%.Disregard unreactedly to chlorobenzene ethamine, productive rate is 71%.
By compound 21-((4-chlorobenzene ethyl) amino) propane-2-alcohol (38.01g, 0.18mol) be dissolved in methyl alcohol (200mL), be cooled to 0～5 ℃, drip oxalic acid (16.06g, methyl alcohol 0.18mol) (60mL) solution, within 25～30 minutes, add, in dropping process, separate out white solid, add rear stirring at room 1h.After removal of solvent under reduced pressure, add ethyl acetate (250mL), stirring at room, suction filtration after 1h, filter cake washs by a small amount of ethyl acetate, collects filter cake, dry, obtain white solid compound 4 (1-((4-chlorobenzene ethyl) amino) propane-2-alcohol oxalate), output 47.85g, productive rate 88.6%, HPLC=99.1%. 1HNMR(400MHz，DMSOd 6，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
1 pair of chlorobenzene ethamine of compound (5.00g, 0.032mol) and propylene oxide (1.86g, 0.032mol) are dissolved in anhydrous methanol (20mL), be warming up to backflow, complete reaction not after 3h, adds propylene oxide (0.93g, 0.016mol) and continues reaction 6h.After reaction finishes, removal of solvent under reduced pressure, obtains pale yellow oily liquid body.To above-mentioned oily matter, add sherwood oil (10mL), be 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) amino) propane-2-alcohol), output 2.8g, HPLC=98.4%. 1HNMR(400MHz，CDCl 3，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 underpressure distillation, reclaims and obtains 1 couple of chlorobenzene ethamine 1.75g of unreacted colourless liquid compound, HPLC=96.5%.Disregard unreactedly to chlorobenzene ethamine, productive rate is 62.7%.
By compound 21-((4-chlorobenzene ethyl) amino) propane-2-alcohol (2.5g, 0.012mol) be dissolved in methyl alcohol (10mL), be cooled to 0～5 ℃, drip oxalic acid (1.05g, water 0.012mol) (5mL) solution, in dropping process, separate out white solid, add rear stirring at room 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 oxalate), output 2.95g, productive rate 83%, HPLC=99%. 1H?NMR(400MHz，DMSO?d 6，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 4.5min.
embodiment 3
Figure BSA0000097327130000091
method A
1 pair of chlorobenzene ethamine of compound (5.0g, 0.032mol), propylene oxide (2.05g, 0.035mol), water (60mL) are mixed and be warming up to 80 ℃ and react 10h, then add methylene dichloride (50mL) extraction, merge organic phase, revolve steaming, obtain faint yellow oily matter.To above-mentioned oily matter, add normal hexane (10mL), 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 normal hexane, collects filter cake.Dry.Obtain white solid compound 2 (1-((4-chlorobenzene ethyl) amino) propane-2-alcohol), output 3.07g, HPLC=98.7%. 1HNMR(400MHz，CDCl 3，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 underpressure distillation, reclaims and obtains unreacted 1 pair of chlorobenzene ethamine of colourless liquid compound (1.8g, HPLC=96.7%).Disregard unreactedly to chlorobenzene ethamine, productive rate is 70%.
Be cooled to below 20 ℃, by compound 21-((4-chlorobenzene ethyl) amino) propane-2-alcohol (1.0g, 0.0047mol) be dissolved in methyl alcohol (7mL), drip methylsulphonic acid (0.45g, 0.0047mol), after solvent vacuum rotary steam, add ethyl acetate (5mL), drip sherwood oil, white solid is separated out, suction filtration after 2 hours, obtains white solid compound 5 (1-((4-chlorobenzene ethyl) amino) propane-2-alcohol mesylate), output 1.27g, productive rate is 87.5%, HPLC=99.1%. 1H?NMR(400MHz，DMSO?d 6，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 1 pair of chlorobenzene ethamine of compound (10.0g, 0.064mol), propylene oxide (4.47,0.077mol), water (120mL) mixes and be warming up to 80 ℃ of reaction 6h, then add methylene dichloride (100mL) extraction, merge organic phase, revolve steaming, obtain faint yellow oily matter.To above-mentioned oily matter, add normal hexane (20mL), 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 normal hexane, collects filter cake.Dry.Obtain white solid compound 2 (1-((4-chlorobenzene ethyl) amino) propane-2-alcohol), output 5.2g, HPLC=98.5%. 1H?NMR(400MHz，CDCl 3，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 underpressure distillation, reclaims and obtains 1 couple of chlorobenzene ethamine 3.5g of unreacted colourless liquid compound, HPLC=97.1%.Disregard unreactedly to chlorobenzene ethamine, productive rate is 58.2%.
Be cooled to below 20 ℃, compound 21-((4-chlorobenzene ethyl) amino) propane-2-alcohol (2.0g, 0.0094mol) is dissolved in to methyl alcohol (15mL), drips methylsulphonic acid (0.9g, water 0.0094mol) (4.5mL) solution, adds rear stirring 1h.Organic solvent is removed in decompression, and suction filtration, obtains white solid compound 5 (1-((4-chlorobenzene ethyl) amino) propane-2-alcohol mesylate), output 2.4g, and productive rate is 83.2%, HPLC=99%. 1H?NMR(400MHz，DMSO?d 6，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
1 pair of chlorobenzene ethamine of compound (10.0g, 0.064mol), propylene oxide (3.73g, 0.064mol), THF (80mL) are mixed and be warming up to 65 ℃ and react 11h.After reaction finishes, removal of solvent under reduced pressure, obtains pale yellow oily liquid body.To above-mentioned oily matter, add ethyl acetate (3mL), sherwood oil (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) amino) propane-2-alcohol), output 4.5g, HPLC=98.2%. 1H?NMR(400MHz，CDCl 3，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 underpressure distillation, reclaims and obtains 1 couple of chlorobenzene ethamine 3.7g of unreacted colourless liquid compound, HPLC=97%.Disregard unreactedly to chlorobenzene ethamine, productive rate is 52%.
Be cooled to 20 ℃ 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), drip sherwood oil, 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%. 1H?NMR(400MHz，DMSO?d 6，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
Figure BSA0000097327130000111
1 pair of chlorobenzene ethamine of compound (10.0g, 0.064mol), propylene oxide (3.73g, 0.064mol), Isosorbide-5-Nitrae-dioxane (75mL) are mixed and be warming up to 85 ℃ and react 10h.After reaction finishes, removal of solvent under reduced pressure, obtains pale yellow oily liquid body.To above-mentioned oily matter, add sherwood oil (20ml) to be 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) amino) propane-2-alcohol), output 4.8g, HPLC=98.4%. 1H?NMR(400MHz，CDCl 3，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 underpressure distillation, reclaims and obtains 1 couple of chlorobenzene ethamine 3.8g of unreacted colourless liquid compound, HPLC=97.3%.Disregard unreactedly to chlorobenzene ethamine, productive rate is 56.3%.
Be cooled to below 20 ℃, 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, suction filtration after 2 hours, obtains white solid compound 7 (1-((4-chlorobenzene ethyl) amino) propane-2-alcohol Citrate trianion), output 4.62g, productive rate is 81.2%, HPLC=99.1%. 1H?NMR(400MHz，DMSO?d 6，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
By 1 pair of chlorobenzene ethamine of compound (10.0g, 0.064mol), propylene oxide (3.73g, 0.064mol), mix and be warming up to 33 ℃ and react 16h.After reaction finishes, in above-mentioned reaction solution, add sherwood oil (20ml) to be 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) amino) propane-2-alcohol), output 4.1g, HPLC=98.6%. 1H?NMR(400MHz，CDCl 3，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 underpressure distillation, reclaims and obtains 1 couple of chlorobenzene ethamine 4.5g of unreacted colourless liquid compound, HPLC=97.2%.Disregard unreactedly to chlorobenzene ethamine, productive rate is 54.3%.
Figure BSA0000097327130000122
Compound 2 (4.5g, 1.0eq), N,N-dimethylacetamide (0.55g, 0.3eq) are added in toluene (21.5ml), change nitrogen, be warming up to 50-55 ℃.Drip thionyl chloride (1.98ml, 1.5eq), within 5-10 minute, add, during maintain the temperature at 50-60 ℃.After adding, be warming up to 60-65 ℃, in process, carry out TLC monitoring, complete reaction after 3h.Be cooled to 15 ℃ of left and right by 1 hour, toluene (15ml) adds, and stirs 30 minutes.Suction filtration, toluene for filter cake (10ml * 2) is washed, and collects filter cake, in filter cake, add in Virahol (11.8ml) and water (1.2ml), be warming up to backflow, stir cooling after 1 hour, by about 2 hours, be down to 15 ℃, be incubated after 30 minutes, by within 30 minutes, being cooled to 0-5 ℃, insulation 1h, suction filtration, a small amount of isopropyl alcohol wash for filter cake, collects filter cake, dry.Obtain white solid compound 4 (5.0g), productive rate is 88.3%. 1H?NMR(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 Aluminum chloride anhydrous (3.74g, 1.5eq) add in orthodichlorobenzene (14.4g), change nitrogen, are warming up to 135-140 ℃, carry out TLC monitoring in process, reaction 8-10h.After complete reaction, be cooled to 30-35 ℃ 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 ℃.Stir suction filtration after 15 minutes, filter cake is washed with 50-60 ℃ of water (15ml).Filtrate is cooled to 20-25 ℃ and stirs 30 minutes, and separatory is collected water.Orthodichlorobenzene phase again water (15ml) extracts 2-3 time.Merge water, hexanaphthene (20ml) adds, and separatory abandons hexanaphthene phase.Water regulates pH >=13 with 30% sodium hydroxide solution, and hexanaphthene (20ml) extracts three times.Merge organic phase, water (15ml) is washed, saturated aqueous common salt (15ml) is washed, dry, and removal of solvent under reduced pressure, obtains oily liquids compound 5 (3.50g), and productive rate is 96.1%, directly as next step reaction.
Figure BSA0000097327130000132
To in compound 5 (3.50g, 1.0eq), add the trimethyl carbinol (12.6g), room temperature (25 ℃) is lower to be stirred.By after L-TARTARIC ACID (0.55g, 0.22eq) water-soluble (0.8g), be added drop-wise in the t-butanol solution of compound 5, there is immediately precipitation to generate, within 10 minutes, add.After dropwising, at 20-25 ℃, stir 16-18 hour.Suction filtration, filter cake is washed with a small amount of acetone, collects filter cake, obtains white solid (1.9g, Ee=73.1%).Directly be used as next step.
Above-mentioned gained white solid (1.9g) is added in the trimethyl carbinol (13.2g) and water (0.3g), be warming up to 76 ℃ of backflows, drip water (1.2g) to clarification, after insulation 1h, lower the temperature, within 2.5-3.5 hour, be down to 25 ℃ of room temperatures, at 20-25 ℃, stir 16-18 hour, suction filtration, filter cake is washed with a small amount of acetone, collects filter cake, obtain white solid (1.41g, Ee=89.5%).Directly be used as next step.
Above-mentioned gained white solid is dissolved in the trimethyl carbinol (13g), be warming up to 76 ℃ of backflows, drip water (1.67g) to clarification, after insulation 1h, lower the temperature, 2.5-3.5 hour be down to 25 ℃ of room temperatures, at 20-25 ℃, stir 16-18 hour, suction filtration, filter cake is washed with a small amount of acetone, collect filter cake, obtain white solid compound 6 (1.2g, Ee=99.5%), productive rate 24.1%.
Compound 6 (1.2g, 1.0eq) is added in salt of wormwood (0.99g, 3.2eq), water (10g) and ethyl acetate (10g), stir after 0.5h, separatory, collects organic phase.Ethyl acetate for water (10ml) extracting twice.Merge organic phase, organic phase water (10ml) is washed, saturated aqueous common salt (10ml) is washed, dry, removal of solvent under reduced pressure, obtains thick liquid (0.83g), is dissolved in ethyl acetate (8g) and water (0.05g), be cooled to 0～5 ℃, drip ethyl acetate (HCl gas) to reaction solution and be acid pH=1-2.Adularescent Precipitation in dropping process, after adding, 0～5 ℃ is stirred 1.5h, suction filtration, filter cake is washed by a small amount of ethyl acetate, collects filter cake, and dry (at 35 ℃), obtain compound 7 (0.8g), productive rate 78%. 1H?NMR(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
Figure BSA0000097327130000142
Compound 3 (110.30g, 1.0eq), N,N-dimethylacetamide (11.52g, 0.3eq) add in toluene (450ml), change nitrogen, are warming up to 50-55 ℃.Drip thionyl chloride (41.5ml, 1.5eq), within 15-20 minute, add, during maintain the temperature at 50-60 ℃.After adding, be warming up to 60-65 ℃, in process, carry out TLC monitoring, complete reaction after 3h.Be cooled to 15 ℃ of left and right by 1 hour, toluene (300ml) adds, and stirs 30 minutes.Suction filtration, toluene for filter cake (200ml * 2) is washed, and collects filter cake (white-yellowish solid), in filter cake, add in Virahol (246ml) and water (24.6ml), be warming up to backflow, stir cooling after 1 hour, by about 2 hours, be down to 15 ℃, be incubated after 30 minutes, by within 30 minutes, being cooled to 0-5 ℃, insulation 1h, suction filtration, a small amount of isopropyl alcohol wash for filter cake, collects filter cake, dry.Obtain white solid compound 4 (101.45g), productive rate is 85.66%. 1H?NMR(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)。
Figure BSA0000097327130000151
Compound 4 (101.45g, 1.0eq) and Aluminum chloride anhydrous (75.83g, 1.5eq) are added in orthodichlorobenzene (292g), change nitrogen, be warming up to 135-140 ℃.In process, carry out TLC monitoring, reaction 8-10h.After complete reaction, be cooled to 30-35 ℃ of left and right, be added drop-wise in the suspension of water (163g) and silica gel (16.3g) formation, keep temperature to be less than 60 ℃.Stir suction filtration after 15 minutes, filter cake is washed with 50-60 ℃ of water (82ml).Filtrate is cooled to 20-25 ℃ and stirs 30 minutes, and separatory is collected water.Orthodichlorobenzene phase again water (100ml) extracts 2-3 time.Merge water, hexanaphthene (80ml) adds, and separatory abandons hexanaphthene phase.Water regulates pH >=13 with 30% sodium hydroxide solution, and hexanaphthene (240ml) extracts three times.Merge organic phase, water (100ml) is washed, saturated aqueous common salt (100ml) is washed, and 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.
Figure BSA0000097327130000152
Upwards walk in the compound 5 of gained and add the trimethyl carbinol (266.33g), stir at 27 ℃.By after L-TARTARIC ACID (11.56g, 0.22eq) water-soluble (16.71g), be added drop-wise in the t-butanol solution of compound 4, there is immediately precipitation to generate, within 15 minutes, add.After dropwising, at 20-25 ℃, stir 16-18 hour.Suction filtration, filter cake is washed with a small amount of acetone, collects filter cake, obtains white solid (38.16g, Ee=72.7%).Directly be used as next step.
Above-mentioned gained white solid (38.16g) is added in the trimethyl carbinol (265.40g) and water (5.63g), be warming up to 76 ℃ of backflows, drip water (24.90g) to clarification, after insulation 1h, lower the temperature, within 2.5-3.5 hour, be down to 25 ℃ of room temperatures, at 20-25 ℃, stir 16-18 hour, suction filtration, filter cake is washed with a small amount of acetone, collects filter cake, obtain white solid (27.83g, Ee=89.2%).Directly be used as next step.
Above-mentioned gained white solid is dissolved in the trimethyl carbinol (264g), be warming up to 76 ℃ of backflows, drip water (33.26g) to clarification, after insulation 1h, lower the temperature, 2.5-3.5 hour be down to 25 ℃ of room temperatures, at 20-25 ℃, stir 16-18 hour, suction filtration, filter cake is washed with a small amount of acetone, collect filter cake, obtain white solid compound 6 (25.95g, Ee=99.6%), productive rate 25%.
Figure BSA0000097327130000161
Compound 6 (22.36g, 1.0eq) is added in salt of wormwood (18.44g, 3.2eq), water (62.8g) and ethyl acetate (62.8g), stir after 0.5h, separatory, collects organic phase.Ethyl acetate for water (60ml) extracting twice.Merge organic phase, organic phase water (40ml) is washed, saturated aqueous common salt (40ml) is washed, dry, removal of solvent under reduced pressure, obtains thick liquid (15.50g), is dissolved in ethyl acetate (85.04g) and water (0.97g), be cooled to 0～5 ℃, drip ethyl acetate (HCl gas) to reaction solution and be acid pH=1-2.Adularescent Precipitation in dropping process, after adding, 0～5 ℃ is stirred 1.5h, suction filtration, filter cake is washed by a small amount of ethyl acetate, collects filter cake, and dry (at 35 ℃), obtain compound 7 (14.9g), productive rate 80.2%. 1H?NMR(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 specification sheets, can make some modifications or variation to the present invention.These modifications and variations also should be within the scope of the claims in the present invention.

Claims (10)

1.一种式II所示的1-(苯乙基氨基)丙烷-2-醇类化合物或其盐的制备方法，其特征在于，所述制备方法包括以下步骤：1. a preparation method of 1-(phenylethylamino) propane-2-alcohol compound or its salt shown in formula II, it is characterized in that, described preparation method comprises the following steps:
Figure FSA0000097327120000011
Figure FSA0000097327120000011
 使所述式I化合物与环氧丙烷反应生成所述式II化合物，其中R1选自H、直链或支链的C1～C4烷基、卤素、甲氧基、硝基或-OH，R2选自H、直链或支链的C1～C4烷基、甲氧基、苄氧羰基、叔丁氧羰基、甲磺酰基、对甲苯磺酰基、苄基或者带取代基的苄基，所述取代基选自直链或支链的C1～C4烷基、-OH、直链或支链的C1～C4烷氧基、卤素、4-硝基、4-氨基或4-三氟甲基。The compound of formula I is reacted with propylene oxide to generate the compound of formula II, wherein R 1 is selected from H, linear or branched C 1 ~C 4 alkyl, halogen, methoxy, nitro or -OH , R 2 is selected from H, straight chain or branched C 1 ~C 4 alkyl, methoxy, benzyloxycarbonyl, tert-butoxycarbonyl, methanesulfonyl, p-toluenesulfonyl, benzyl or substituted Benzyl, the substituent is selected from straight chain or branched C 1 ~C 4 alkyl, -OH, straight chain or branched C 1 ~C 4 alkoxy, halogen, 4-nitro, 4- amino or 4-trifluoromethyl. 2.根据权利要求1所述的制备方法，其特征在于，其中R1为卤素，R2为H；优选地，R1为氯且为对位，R2为H。2. The preparation method according to claim 1, wherein R 1 is halogen, R 2 is H; preferably, R 1 is chlorine and para-position, R 2 is H. 3.根据权利要求1或2所述的制备方法，其特征在于，其中所述环氧丙烷与所述式I化合物的摩尔比为1～10∶1；反应无溶剂或使用以下溶剂：甲醇、乙醇、丙醇、异丙醇、正丁醇、叔丁醇、异丁醇、四氢呋喃、2-甲基四氢呋喃、乙酸乙酯、N-甲基吡咯烷酮、丙酮、丁酮、戊酮、1，4-二氧六环、水、N，N-二甲基甲酰胺、二甲基亚砜或其任意比例的混合物；反应温度为5～189℃；反应时间为2～18小时。3. The preparation method according to claim 1 or 2, wherein the molar ratio of the propylene oxide to the compound of formula I is 1 to 10: 1; the reaction is solvent-free or uses the following solvents: methanol, Ethanol, propanol, isopropanol, n-butanol, tert-butanol, isobutanol, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, N-methylpyrrolidone, acetone, methyl ethyl ketone, pentanone, 1,4 - dioxane, water, N, N-dimethylformamide, dimethyl sulfoxide or a mixture thereof in any proportion; the reaction temperature is 5-189° C.; the reaction time is 2-18 hours. 4.根据权利要求3所述的制备方法，其特征在于，其中所述环氧丙烷与所述式I化合物的摩尔比为1.5～2∶1；反应无溶剂或使用以下溶剂：甲醇、乙醇、水、四氢呋喃、1，4-二氧六环或其任意比例的混合物；反应温度为30～90℃；反应时间为6～16小时。4. The preparation method according to claim 3, wherein the molar ratio of the propylene oxide to the compound of formula I is 1.5 to 2: 1; the reaction is solvent-free or uses the following solvents: methanol, ethanol, Water, tetrahydrofuran, 1,4-dioxane or a mixture thereof in any proportion; the reaction temperature is 30-90° C.; the reaction time is 6-16 hours. 5.根据权利要求1～4中任一项所述的制备方法，其特征在于，所述方法进一步包括如下步骤：向得到的式II化合物中加入重结晶溶剂，加热回流，然后降温使析出固体来纯化所述式II化合物。5. The preparation method according to any one of claims 1 to 4, characterized in that, the method further comprises the steps of: adding a recrystallization solvent to the obtained compound of formula II, heating to reflux, and then cooling to precipitate a solid To purify the compound of formula II. 6.根据权利要求5所述的制备方法，其特征在于，其中所述重结晶溶剂选自甲醇、乙醇、丙醇、异丙醇、四氢呋喃、2-甲基四氢呋喃、乙酸乙酯、乙酸异丙酯、二氯甲烷、丙酮、石油醚、正己烷、环己烷、正庚烷、甲苯、二甲苯、甲基叔丁基醚或其任意比例的混合物；重结晶温度为0～110℃；重结晶时间为2～18小时。6. The preparation method according to claim 5, wherein the recrystallization solvent is selected from methanol, ethanol, propanol, isopropanol, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate Esters, dichloromethane, acetone, petroleum ether, n-hexane, cyclohexane, n-heptane, toluene, xylene, methyl tert-butyl ether or their mixtures in any proportion; the recrystallization temperature is 0-110°C; The crystallization time is 2 to 18 hours. 7.根据权利要求6所述的制备方法，其特征在于，其中所述重结晶溶剂选自石油醚、正己烷、正庚烷、乙酸乙酯或其任意比例的混合物；重结晶温度为40～100℃；重结晶时间为1～2小时。7. preparation method according to claim 6 is characterized in that, wherein said recrystallization solvent is selected from sherwood oil, normal hexane, normal heptane, ethyl acetate or the mixture of any proportion thereof; Recrystallization temperature is 40～ 100°C; recrystallization time is 1-2 hours. 8.根据权利要求1～7中任一项所述的制备方法，其特征在于，所述方法进一步包括如下步骤：使式II化合物与酸进行成盐反应得到式II化合物的盐；其中所述酸选自盐酸、氢溴酸、乙酸、甲酸、三氟乙酸、二氟乙酸、硫酸、磷酸、硝酸、甲烷磺酸、草酸、柠檬酸、苹果酸或酒石酸；优选地，所述酸选自盐酸、硫酸、草酸、柠檬酸或甲烷磺酸。8. The preparation method according to any one of claims 1 to 7, characterized in that, the method further comprises the steps of: making the compound of formula II react with an acid to obtain a salt of the compound of formula II; wherein The acid is selected from hydrochloric acid, hydrobromic acid, acetic acid, formic acid, trifluoroacetic acid, difluoroacetic acid, sulfuric acid, phosphoric acid, nitric acid, methanesulfonic acid, oxalic acid, citric acid, malic acid or tartaric acid; preferably, the acid is selected from hydrochloric acid , sulfuric acid, oxalic acid, citric acid or methanesulfonic acid. 9.根据权利要求8所述的制备方法，其特征在于，其中所述酸与式II化合物的摩尔比是1～3∶1，优选为1～1.5∶1；反应溶剂选自乙酸乙酯、甲苯、二氯甲烷、甲基叔丁基醚、正己烷、石油醚、庚烷、乙醚、甲醇、乙醇、丙醇、异丙醇、正丁醇、叔丁醇、异丁醇、四氢呋喃、2-甲基四氢呋喃、N-甲基吡咯烷酮、丙酮、丁酮、戊酮、1，4-二氧六环、水或其任意比例的混合物，优选为乙酸乙酯、甲醇、二氯甲烷、甲苯、水或其任意比例的混合物；反应温度为0～90℃，优选为0～50℃；反应时间为0.5～12小时，优选为1～4小时。9. The preparation method according to claim 8, wherein the molar ratio of the acid to the compound of formula II is 1 to 3: 1, preferably 1 to 1.5: 1; the reaction solvent is selected from ethyl acetate, Toluene, dichloromethane, methyl tert-butyl ether, n-hexane, petroleum ether, heptane, diethyl ether, methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, isobutanol, tetrahydrofuran, 2 -Methyltetrahydrofuran, N-methylpyrrolidone, acetone, butanone, pentanone, 1,4-dioxane, water or a mixture thereof in any proportion, preferably ethyl acetate, methanol, methylene chloride, toluene, Water or a mixture thereof in any proportion; the reaction temperature is 0-90°C, preferably 0-50°C; the reaction time is 0.5-12 hours, preferably 1-4 hours. 10.一种氯卡色林或其盐的制备方法，其特征在于，所述方法是以权利要求1～9中任一项制备方法得到的1-(苯乙基氨基)丙烷-2-醇类化合物或其盐为原料而制备氯卡色林或其盐。10. A preparation method for lorcaserin or a salt thereof, characterized in that, the method is 1-(phenylethylamino)propan-2-alcohol obtained by any one of the preparation methods in claims 1 to 9 Lorcaserin or a salt thereof is prepared from a compound or a salt thereof as a raw material.
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